Ustekinumab, a new anti-interleukin-12/23 antibody, is an effective treatment for ulcerative colitis; however, data regarding predictive factors of its efficacy are limited. This study aimed to identify biomarkers that can predict the long-term outcome of ustekinumab treatment. We retrospectively reviewed the records of patients with active ulcerative colitis treated with ustekinumab at our hospital from June 2020 to January 2023. We divided patients into non-remission and remission groups, and examined whether baseline biomarkers, including C-reactive protein-to-lymphocyte ratio, and early treatment response could predict clinical remission at week 48 of ustekinumab treatment. Of the 33 patients included in the study, 21 (63.6%) were in clinical remission at week 48 of ustekinumab treatment. The baseline C-reactive protein-to-lymphocyte ratio value was identified as an independent prognostic factor for clinical remission at week 48 (odds ratio: 10, 95% confidence interval: 1.6–62.4, p=0.014), with the cutoff value of 3.353 showing excellent prognostic performance (sensitivity: 71.4%, specificity: 83.3%). Furthermore, the clinical response at week 4 (p=0.009) and that at week 8 (p=0.005) were significantly associated with clinical remission at week 48. The baseline C-reactive protein-to-lymphocyte ratio value and early treatment response are useful biomarkers to predict the long-term efficacy of ustekinumab treatment.

Type 2 diabetes mellitus may be complicated with chronic complications including diabetic neuropathy (DN). Timely diagnosis is crucial in treatment and maybe reversal of this complication. C reactive protein to albumin ratio (CAR) is considered as a marker of inflammation in various diseases that characterized with acute or chronic inflammation. Since diabetic neuropathy and type 2 diabetes mellitus are also associated with chronic, low grade inflammation, we aimed to study CAR levels of type 2 diabetic subjects with diabetic neuropathy and to compare to those in patients without diabetic neuropathy. Type 2 diabetic patients presented to our institutional outpatient clinics were divided into two according to the presence of DN. Subjects with DN were listed as DN group and others were as non-DN group. Characteristics and laboratory data, including CAR, in DN and non-DN groups were compared. Median CAR of the DN and non-DN groups were 2,19 (0,2-49)% and 0,56 (0,02-5,8)%, respectively (p<0.001). CAR was significantly and positively correlated with age (r=0.15, p<0.001), weight (r=0.19, p=0.01), BMI (r=0.11, p=0.03), waist circumference (r=0.10, p=0.046), fasting plasma glucose (r=0.14, p=0.004), serum creatinine (r=0.25, p<0.001), triglyceride (r=0.17, p<0.001), and LDL-cholesterol (r=0.13, p=0.001) levels. Moreover, CAR was inversely correlated with eGFR levels (r=-0.16, p<0.001). The sensitivity and specificity of CAR (when higher than 1,02%) in predicting diabetic neuropathy were 78% and 73%, respectively (AUC: 0.84, p<0.001, 95% CI: 0,82-0,87). Moreover, high CAR level was an independent risk factor of diabetic neuropathy (p<0.001, OR: 1.34, 95% CI: 0.48-1.62). In conclusion, elevated CAR levels could be considered as a marker of diabetic neuropathy.

C-reactive protein to lymphocyte ratio (CLR) has been shown to be associated with diseases characterized by chronic, low-grade inflammation. Since type 2 diabetes (T2DM) is also associated with inflammation, we aimed to study the association between CLR and T2DM. Patients with T2DM who presented to internal medicine outpatient clinics of our institution were divided into 2 groups according to their glycosylated hemoglobin (HbA1c) levels as well-controlled (HbA1c<7%) and poorly controlled (HbA1c≥7%) T2DM groups. Subjects assigned as healthy in routine check-up were included as control group. CLR values of the well and poorly controlled diabetics and control cases were compared. CLR of T2DM group (3.51 (0.03-21.78)) was significantly higher than that of the controls (0.65 (0.02-2.92)) (p<0.001). CLR was found to have a sensitivity of 63.2% and a specificity of 97.3% in predicting T2DM. The CLR value of patients with poor diabetic control was 4.76 (0.06-21.78), while the CLR value of patients with well controlled disease was 2.53 (0.03-12.07) (p<0.001). The sensitivity and specificity of the CLR in demonstrating poor diabetic control was 41.2% and the 86.1%, respectively. In conclusion, elevated CLR in T2DM patients and even more increased levels in poorly controlled diabetics suggest that CLR could be a useful additional diagnostic tool in treatment follow-up of the T2DM population.

Sickle cell disease (SCD) is an inherited disorder of major health challenge in Nigeria. Micronutrients deficiencies often associated with the disorder may cause inflammation and abnormal metabolisms in the body. The copper-to-zinc ratio is a more important assessment than the concentrations of either of the metals in clinical practice. This study seeks to evaluate serum levels of c-reactive protein (CRP), copper, zinc and copper-to-zinc ratio and to correlate copper-to-zinc ratio with CRP in adult subjects with SCD. Serum copper, zinc, CRP and plasma fibrinogen were assayed in 100 confirmed SCD patients in steady clinical state and 100 age and sex matched subjects with normal haemoglobin. Serum copper and zinc were assayed by colorimetric method using reagents supplied by Centronic, Germany while CRP and fibrinogen were assayed using reagents supplied by Sigma (St. Louis, MO, USA) and Anogen (Ontario, Canada), respectively. The copper to zinc ratio was calculated from serum levels of copper and zinc. The measured parameters were compared between the groups using Students t-test and Pearson correlation coefficient was used to relate CRP with the other parameters. Serum copper, CRP, fibrinogen and copper-to-zinc ratio were significantly higher (p < 0.001) while zinc level was lower in SCD patients than controls. Serum CRP concentration correlated with copper (r = 0.10; p < 0.02), zinc (r = −0.199; p < 0.05) and Copper-to-zinc ratio (r = 0.312; p < 0.002) but the correlation between CRP and fibrinogen was not significant. Inflammatory condition may modulate copper and zinc homeostasis and copper-to-zinc ratio may be used as marker of nutritional deficiency and inflammation in SCD patients.

Nonalcoholic fatty liver disease (NAFLD) is a liver metabolism-associated steatohepatitis caused by non-alcoholic factors. NAFLD is currently the most prevalent liver disease in the world, affecting one-fourth of the world's population, and its prevalence increases with age. There are no approved drugs specifically for the treatment of NAFLD, and one important reason hindering drug development is the lack of effective biomarkers. C-reactive protein (CRP), a marker of inflammation, has been linked to NAFLD and aging in recent studies. Coincidentally, hepatocytes are responsible for the major CRP production, and the levels of CRP increase with age. Therefore, CRP is not only a potential marker, but also acts as a key factor driving liver aging and NAFLD. Herein, we reviewed the biological function and production mechanism of CRP and the relationship between CRP and NAFLD. We also comprehensively described the potential molecular mechanisms of CRP-mediated signaling in aging-associated NAFLD. Finally, we proposed possible therapeutic approaches based on the mechanism of CRP signaling in the pathogenesis of NAFLD. We hope this study can provide new insights into the development of aging associated NAFLD biomarkers and suggest that modulation of CRP signaling is a potential therapeutic target.

Background: Inflammation is an important mechanism in atherosclerosis and plaque formation. C-reactive protein (CRP) is a common inflammatory biomarker associated with the risk of coro-nary heart disease. We investigated the relationship of CRP with findings from myocardial per-fusion imaging (MPI). Methods: In this retrospective study, 102 consecutive patients (mean age 71 years, 68% males) that underwent MPI (for diagnostic reasons or quantification of myocardial ischemia) and CRP determination (upper limit: 6mg/L) within 1 month from MPI, were included. Patients had no infection or recent acute coronary syndrome. Results: the median CRP level was 4mg/L (2,10) among the study population. Patients with raised CRP had higher summed stress score (SSS) (P = 0.006) and summed rest score (SRS) (P = 0.001) and higher risk for SSS > 3 (OR 9.25, 95% CI 2.03-42.13, P = 0.001) compared to those with low CRP. The association of SSS and SRS with CRP levels was more evident in patients over 70 years (P = 0.027 and P = 0.005 respectively). No significant difference in summed difference score was shown. The two groups had no difference in other risk factors (p > 0.05 for all comparisons). Conclusion: A high level of CRP was associated with the presence and extent of stress-induced myocardial ischemia in MPI.

The role of biomarkers in the diagnosis of inflammatory bowel disease is not fully characterized. C-reactive protein has a short half-life and elevates quickly after the onset of an inflammatory process, the performance is better in Crohn’s disease than in ulcerative colitis. Erythrocyte sedimentation rate is easy to determine, widely available, and cheap but the long half-life the influence of age, anemia, smoking, and drugs limit its usefulness. Fecal markers have good specificity, but suboptimal accuracy. Microbial antibodies and novel immunological markers show promise but need further evidence before entering clinical practice. Proteomic methods could represent the dawn of a new era of stool protein/peptide biomarker panels able to select patients at risk of inflammatory bowel disease.

Background: The fulminant course of COVID-19, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents with a high mortality rate and still lacks a causative treatment. C-reactive protein (CRP) has been shown to increase dramatically during the disease progression and correlates with deleterious outcomes. Selective CRP apheresis can reduce circulating CRP levels fast and effective. Methods: Seven hospitalized patients with documented severe COVID-19 progression, elevated CRP plasma levels (> 100 mg/L) and signs of respiratory failure were treated with CRP apheresis. 2-12 CRP apheresis sessions were performed generally in 24 h time intervals and depending on CRP plasma levels. Results: CRP apheresis reduced CRP plasma levels by up to 84% within a few hours, without exhibiting side effects in any patient. Despite signs of severe lung infiltration in all patients, only one patient died. The other patients showed improvements within the chest x-ray after CRP apheresis and were able to recover regardless of intubation and/or ECMO (4 patients). All remaining six patients were discharged from the hospital in good clinical condition. All patients had comorbidities. Conclusions: This case series presents a mortality rate of only 14%, which is dramatically lower than expected from the presented CRP levels as well as comorbidities and ventilation require-ments. Our clinical observations regarding the here presented seven patients support the hypoth-esis that CRP is a candidate to be therapeutically targeted in the early stage of severe COVID-19.

Endometrial Cancer (EC) is the sixth most commonly occurring cancer in women with 380 000 cases in 2018. Sadly, EC morbidity and mortality are continuously increasing, therefore the medical society have a substantial need for an accurate and inexpensive diagnostic test for EC early detection and a prognostic tool for treatment planning and evaluation. Considering experience with different types of cancers C-reactive protein (CRP) appears to be a promising diagnostic and prognostic factor. Aiming to investigate its potential and in view of EC authors, this paper reviewed the following databases for metanalysis, randomized controlled trials and review articles published up to June 2020: Pubmed, Scopus, Google scholar and ClinicalKey. Studies indicate CRP >3.33 mg/l correlate with EC incidence with HR = 2.29 (p<0.05). Moreover, High-sensitivity CRP assay allows to detect CRP in very low concentrations and distinguish patients with endometriosis, soft tissue sarcomas and possibly EC. Preoperational and postoperational CRP, as well as its dynamic change are independent prognostic factors for EC and are more reliable if analyzed together. However, CRP-to-albumin ratio as well as Glasgow Prognostic Scale have greater prognostic value that CRP alone. Additionally, CRP is possibly a mediator of carcinogenesis and cancer progression through activation of inter alia FcgRs/MAPK/ERK, FcgRs/IL-6/AKT/STAT3 and FcgRs/NF-κB/NLRP3 pathways.

Background: Acute pancreatitis is a common emergency. Morbidity control requires early detection of disease severity. METHODS: A total of 131 AP patients were analyzed retrospectively. Patients were divided into two groups mild AP (MAP: Ranson score <3) and severe AP (SAP: Ranson score ≥3), according to Ranson’s criteria. Demographic data, hospitalization duration, PNI, CRP, and RDW levels were compared. Any p-value below 0.05 (p<0.05) was accepted as statistically significant. RESULTS: Study included 67 (51.15%) males and 64 (48.85%) females. The age average was 59.74 (19-90) years. 95 (72.52%) patients had MAP, and 36 (27.48%) patients had SAP. Mean hospitalization time, PNI, and CRP differed significantly between the two groups (p=0.010, p<0.05, p<0.05, respectively). The RDW (p=0.380) level difference was insignificant. For SAP prediction; the sensitivity, specificity and cut-off value according to Ranson code cut-off point for PNI were determined as 80.0% (95% CI:54.8-85.8), %72.2 (95% CI:70.5-87.5) and ≤45.6 (gr/L) + (mm3), respectively, and 94.7% (95% CI:57.8-87.9), %75.0 (95% CI:88.1-98.3) and >105,1 mg/L, respectively for CRP. CONCLUSION: PNI and CRP values (but not RDW values) were compatible with the disease severity determined by the Ranson criteria.

Adenoviruses are associated with respiratory tract, gastrointestinal or, less frequently, other involvement. Epidemics of adenovirus infections occur globally, in communities and in closed or crowded settings. In our institution, an outbreak of Adenovirus infection in infants and children was recently observed. Two main patterns of clinical presentation were observed: 68 patients had mainly respiratory symptoms (pharyngitis n=67, cough n=44; tonsillar exudate n=17; other respiratory signs n=4) while 26 patients showed prevalent gastrointestinal involvement (diarrhea n=26, vomiting n=8). Patients with respiratory symptoms had a significantly higher count of WBC, PMN and platelets, while CRP level approached statistical significance (p=0.07) for higher values in the patients with diarrhea. In order to explore the impact of selected presenting features, possible association between level of CRP and presence of pharyngeal exudate, cough, vomiting, diarrhea, duration of fever, number of neutrophils, and administration of antibiotics was analyzed. Patients falling in the tertile with more elevated CRP values had significantly more often tonsillar exudate and diarrhea, while those in the lower tertile had a 4.4 days duration of fever, vs. ≥5.0 days in the remaining patients. Antibiotic therapy was administered more frequently to patients with higher values of CRP (p=0.006). Duration of hospitalization was not associated with the CRP level. The median time from the receipt of positive adenovirus PCR test result to patient discharge was 1 day in 73% of cases. The number of copies of adenovirus detected by PCR ranged between 47 million and 15/L. Falling in the highest terzile of copy number was significantly associated with pharyngitis. The 24 patients with evidence of viral coinfection had no difference in the demographics or presenting features, with the only exception of a significantly higher leukocyte count. Rapid turn-around of results of molecular testing of adenovirus genome on pharyngeal swab allowed us to rapidly diagnose adenovirus infection, allowing stopping antibiotic therapy and immediate discharge, with reduced discomfort for the families and more appropriate use of hospital beds. A high copy number of adenovirus from pharyngeal swab should not be taken as an indicator of worse prognosis, thus allowing preferential use of qualitative rather than quantitaive assay.

Background: Although lower extremity revascularization is commonly performed in hemodialysis patients, poor prognosis remains a major problem. Protein-energy wasting is reportedly associated with chronic inflammation and advanced atherosclerosis in hemodialysis patients. We investigated the association between the geriatric nutritional risk index (GNRI) as a surrogate marker of protein-energy wasting, C-reactive protein (CRP), and their joint roles in the prediction of amputation and/or mortality. Methods: We enrolled 800 patients successfully underwent lower extremity revascularization. Patients were divided into low, middle and high tertile (T1, T2 and T3) according to GNRI and CRP levels, respectively. Results: Amputation-free survival rates for 8 years were 47.0%, 56.9%, and 69.5% in T1, T2, and T3 of the GNRI, and 65.8%, 58.7%, and 33.2% for T1, T2, and T3 of CRP, respectively (p<0.0001 for both). Declined GNRI [adjusted hazard ratio (aHR) 1.78, 95% confidence interval (CI) 1.24-2.59, p=0.0016 for T1 vs. T3] and elevated CRP (aHR 1.86, 95%CI 1.30-2.70, p=0.0007 for T3 vs. T1) were independent predictors of amputation and/or mortality. In the combined setting of both variables, the risk was 3.77-fold higher (95% CI 1.97-7.69, p<0.0001) in the T1 of GNRI with T3 of CRP than in the T3 of GNRI with T1 of CRP. Conclusions: Patients with pre-procedural decreased GNRI and elevated CRP levels frequently experienced amputation and/or mortality, and a combination of both variables could more accurately stratify the risk.

Leucine-rich α-2 glycoprotein1 (LRG1) is a member of the leucine-rich repeat (LRR) family that was implicated in multiple diseases including cancer, aging and heart failure as well as diabetes and obesity. LRG1 plays a key role in diet-induced hepatosteatosis and insulin resistance by mediating the crosstalk between adipocytes and hepatocytes. LRG1 also promotes hepatosteatosis by upregulating de novo lipogenesis in the liver and suppressing fatty acid β oxidation. In this study, we investigated the association of LRG1 with obesity markers including leptin and other adipokines in adolescents (11-14 years; n=425). BMI-for-age classification based on WHO growth charts was used to define obesity. Plasma LRG1 was measured by ELISA while other markers were measured by multiplexing assay. Median (IQR) of LRG1 levels was higher in obese [30 (25, 38) µg/mL] and overweight [30 (24, 39) µg/mL] adolescents, compared to normal-weight participants [27 (22, 35) µg/mL]. The highest tertile of LRG1 had an OR [95%CI] of 2.55 [1.44, 4.53] for obesity. LRG1 was positively correlated to plasma levels of HsCRP (R=0.2), Leptin (R=0.2) and Chemerin (R=0.24) with p<0.001. Additionally, it was positively associated with plasma level of IL6 (R=0.17) and IL10 (R=0.14) but not TNF-α. In conclusion, LRG1 levels are increased in obese kids and associate with increased levels of adipogenic markers. These results suggest the usefulness of LRG1 as an early biomarker for obesity and its related pathologies in adolescents.

In the multicenter, non-randomized, exploratory C-reactive protein (CRP) Apheresis in Myocardial Infarction (CAMI-1) study, CRP apheresis after ST-Elevation Myocardial Infarction (STEMI) significantly decreased blood CRP concentrations in humans. Cardiac damage was assessed by Cardiac Magnetic Resonance (CMR1) 3-9 d after onset of STEMI symptoms and quantified by myocardial infarct size (IS; %), left ventricular ejection fraction (LVEF; %), circumferential strain (CS) and longitudinal strain (LS) Compared with the control group (n=34), cardiac damage was significantly lower in the apheresis group (n=32). These findings suggested improved wound healing due to CRP apheresis already within few days after the STEMI event. In the current supplementary data analysis of CAMI-1, we have tested by a follow-up CMR (CMR2) after an average of 88 (65-177) d whether the effect of CRP apheresis is clinically maintained. After this time period wound healing in STEMI is considered complete. Whereas patients with low CRP production and a CRP gradient cut off of &lt;0.6 mg/L/h in the hours after STEMI (9 of 32 patients in the CRP apheresis group) did not significantly benefit from CRP apheresis in CMR2, patients with high CRP production and a CRP gradient cut off of &gt;0.6 mg/L/h (23 of 32 patients in the CRP apheresis group) showed significant treatment benefit. In the latter patients, CMR2 revealed a lower IS (-5.4%; p=0.05), a better LVEF (+6.4%; p=0.03), and an improved CS (-6.1%; p=0.005). No significant improvement, however, was observed for LS (-2.9%; p=0.1). These data suggest a sustained positive effect of CRP apheresis on the heart physiology in STEMI patients with high CRP production well beyond the period of its application. The data demonstrate the sustainability of the CRP removal from plasma which is associated with less scar tissue.

Background and Objectives: Obesity-related elevated body mass index (BMI) across life is associated with chronic low-grade inflammation and increased levels of C-reactive protein (CRP) in blood. CRP is a marker and promoter of inflammation. The objectives of this study were to examine the effect of obesity on the relationship between peripheral and gingival CRP levels and examine the effects of gingival CRP levels on gingival fluid inflammatory cytokines in periodontitis resistant obese individuals. Materials and Methods: Thirty-nine, periodontally healthy subjects were enrolled. Based on BMI scores, 20 subjects were categorized as lean and 19 as obese. A comprehensive periodontal examination was performed. Gingival crevicular fluid (GCF) and blood samples were collected. Both GCF and blood samples were assessed for interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), interleukin-17A (IL-17A) and CRP. Results: GCF CRP levels were significantly higher in obese than lean individuals. No statistically significant differences were noted between the two groups in both GCF and blood on any of the inflammatory cytokine levels. IL-17A was not detected in GCF of most subjects in both groups. GCF CRP levels were positively associated with blood CRP levels, the association tended to be stronger in obese individuals. GCF CRP showed no associations with GCF IL-10 in both groups. Although GCF CRP levels positively associated with multiple GCF inflammatory cytokines (e.g., IL-1β, IL-6, IL-8 and TNF-α) in all subjects, the associations tended to be weaker in obese individuals (e.g., IL-1β, IL-6, TNF-α). Furthermore, the levels of GCF inflammatory cytokines IL-6 and TNF-α were depressed in obese individuals. Conclusions: Obesity unfavorably influences the relationship between blood and GCF CRP levels and promotes increased CRP levels in GCF. Collectively, the findings suggest a dysregulated inflammatory cytokine response in the gingival tissues of obese individuals.

Background and Objective: Although whole body-electromyostimulation (WB-EMS) has been shown to favorably improve body composition in several research studies, it has not been confirmed how it affects adipose tissue-derived biomarkers and circumferences of the abdomen and thighs. Materials and Methods: Twenty participants of obese elderly women were randomly classified into an EMS group (EMSG; n = 10) or a non-EMS group (CON; n = 10). The WB-EMS suits used in this study enabled the simultaneous activation of 8 muscle groups with selectable intensities for each phase. Stimulation frequency was selected at 85 Hz, impulse-width at 350 μ seconds, and impulse-rise as a rectangular application. Impulse duration was 6 seconds with a 4-second break between impulses. The EMS sessions were combined with aerobic dancing 3 times a week for 12 weeks. Both groups received the same program; however, the CON did not receive electrical stimuli. Biomarkers and body composition including circumferences of the abdomen and thighs were measured on Week 0 and Week 12. Results: Compared with the CON, 1) a significant effect of the EMS-intervention concerning decreased body weight (p = 0.032) and increased basal metabolic rate (p = 0.029) were evident. The thigh subcutaneous fat and total fat of EMSG were not significantly changed, but those of CON were significantly increased after 12 weeks. 2) The biomarkers of CON either increased or showed no change, although the interleukin (IL)-6 was significantly (p = 0.028) decreased in EMSG. Specifically, C-reactive protein (CRP; p = 0.005) and alpha-fetoprotein (p = 0.050) of CON were significantly increased after 12 weeks. In addition, the IL-6 (p = 0.034), CRP (p = 0.001), carcinoembryonic antigen (p = 0.017), and low density lipoprotein (p = 0.005) of EMSG were lower than those of CON in the end of experiment. 3) Conclusions: The results indicate that EMS intervention improved body composition and reduced negative biomarkers, thus highlighting its effectiveness.

Hepatitis C virus (HCV) core protein is a multifunctional protein that is involved in proliferation, inflammation and apoptosis mechanism of hepatocytes. HCV core protein genetic variability has been implicated in various outcomes of HCV pathology and treatment. In the present study, we aimed to analyze the role of HCV core protein in tumor necrosis factor α (TNFα)-induced death under the viewpoint of HCV genetic variability. Immortalized hepatocytes (IHH), and not the Huh7.5 hepatoma cell line, stably expressing HCV subtype 4a and HCV subtype 4f core proteins showed that only HCV 4a core protein could increase sensitivity to TNFα-induced death. Development of two transgenic mice expressing the two different core proteins under the liver-specific promoter of transthyretin (TTR) allowed for the in vivo assessment of the role of core in TNFα-induced death. Using the TNFα-dependent model of lipopolysaccharide/D-galactosamine (LPS/Dgal) we were able to recapitulate the in vitro results in IHH cells in vivo. Transgenic mice expressing HCV 4a core protein were more susceptible to the LPS/Dgal model while mice expressing HCV 4f core protein had the same susceptibility as their littermate controls. Transcriptome analysis in liver biopsies from these transgenic mice gave insights into HCV core molecular pathogenesis, while linking HCV core protein genetic variability to differential pathology in vivo.

C-reactive protein (CRP) and leukocytes are blood biomarkers involved in "Inflamm-Aging", which is a risk factor for the onset and progression of age-related diseases. Studies show that higher serum concentrations of these biomarkers are associated with functional disability, increased risk of low muscle strength, decreased muscle mass and mortality in the elderly. The objective was to estimate the predictive power and discriminating criteria of C-reactive protein and leukocyte concentrations for the risk of adverse health factors in the elderly within 30 days after hospital discharge (HD). Prospective cohort study using exploratory methods and blood biomarkers with 135 older adults admitted to medical and surgical clinics at a government hospital. The elderly were monitored at home after 30 days of HD for adverse health factors (rehospitalization, falls, amount of medication consumed, disability in basic and instrumental activities of daily living and mortality). CRP> 2.4; ≥ 0.7 and> 24.7 mg / dL and leukocytes ≥ 6.410; ≥ 8.690 and> 8.310 mm³ were discriminant for rehospitalization, falls and mortality within 30 days after HD, respectively. The cut-off points described may be used as a reference in the screening of hospitalized elderly vulnerable to adverse health events after hospital discharge.

Background: Effective identification and management in the early stages of sepsis are critical for achieving positive outcomes. In this context, neutrophil activation status (NEUT-RI) emerges as a promising and easily interpretable parameter. This study aimed to assess the predictive value of NEUT-RI in diagnosing sepsis and to evaluate its prognostic significance in distinguishing 28-day mortality outcomes. Materials: The study is a secondary retrospective observational analysis. Clinical data upon ICU admission were collected. A control group of critically ill patients without sepsis criteria was included. Patients were divided into subgroups based on renal function for biomarker evaluation, with 28-day outcomes reported for septic and non-septic patients. Results: 200 patients were included in the study. A significant difference between the "septic" and "non-septic" groups was detected in the NEUT-RI plasma concentration (53.80 [49.65–59.05] vs. 48.00 [46.00–49.90], p< 0.001, respectively). NEUT-RI and PCT distinguished between not complicated sepsis and septic shock (PCT 1.71 [0.42 - 12.09] vs 32.59 [8.83 - 100.00], < 0.001 and NEUT-RI 51.50 [47.80 - 56.30] vs 56.20 [52.30 - 61.92], p=0.005). NEUT-RI, PCT and CRP values were significantly different in patients with “renal failure”. NEUT-RI and PCT at admission in ICU in septic group were higher in patients who died (58.80 [53.85-73.10] vs 53.05 [48.90-57.22], p=0.005 and 39.56 [17.39-83.72] vs 3.22 [0.59-32.32], p=0.002, respectively). Both NEUT-RI and PCT showed high negative predictive value and low positive predictive value. Conclusions: The inflammatory biomarkers assessed in this study offer valuable support in the early diagnosis of sepsis. NEUT-RI elevation appears particularly promising for early sepsis detection and severity discrimination upon admission

Febrile infections are a common cause of presentation to the emergency department (ED) in chil-dren. While viral infections are usually self-limiting, sometimes bacterial illnesses may lead to sepsis and severe complications. Inflammatory biomarkers such as C reactive protein (CRP) and procalcitonin are usually the first blood exams performed in the ED to differentiate bacterial and viral infections; the better understanding of immunochemical pathways has nowadays led to the discovery of new and more specific biomarkers that could play a role in the emergency setting. The aim of this narrative review is to provide the most recent evidence on biomarkers and predictor models combining them for serious bacterial infections (SBI) diagnosis in febrile children. Litera-ture analysis showed that inflammatory response is a complex mechanism in which many bio-chemical and immunological factors contribute to host response in SBI. CRP and procalcitonin still represent the most used biomarkers in the pediatric ED for the diagnosis of SBI. Their sensibility and sensitivity increase when combined and for this reason it is reasonable to take them both into consideration in the evaluation of a febrile children. The potential of machine learning tools, who represent a real novelty in medical practice, in conjunction with routine clinical and biological in-formation, may improve accuracy of diagnosis and target therapeutic options in SBI. However, studies on this matter are not yet validated in younger populations, making their relevance in pe-diatric precision medicine still uncertain. More data from further researches are needed to improve clinical practice and decision making using these new technologies.

Background: Polycystic ovary syndrome is a common reproductive and endocrinological disease characterized by ovulatory dysfunction, polycystic ovaries, and hyperandrogenism. Adipokines are believed to contribute to developing polycystic ovary syndrome and its accompanying metabolic complications such as dyslipidemia, insulin resistance, and cardiovascular diseases. Oncostatin M, a novel adipokine, plays a role in oogenesis, lipogenesis, and inflammation and may contribute to polycystic ovary syndrome pathogenesis and its related metabolic problems. Methods: In this case-control study, the patients were grouped in a 1:1 ratio into either the polycystic ovary syndrome (n = 32) or the control group (n = 32). Blood samples were obtained between the third and fifth days of the menstrual cycle. Serum levels of fasting glucose, insulin, C-reactive protein, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, white blood cell count, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, total testosterone, prolactin, estradiol, homeostasis model assessment of insulin resistance and oncostatin M were analyzed. Results: Oncostatin M levels were significantly lower, but C-reactive protein levels were substantially higher in the polycystic ovary syndrome group than in the control group (p = 0.002, p = 0.001, respectively). Oncostatin M was inversely correlated with total cholesterol, non-high-density lipoprotein cholesterol, fasting glucose, and the luteinizing hormone/follicle-stimulating hormone ratio (ρ = -0.329, p =0 .017; ρ = -0.386, p = 0.005; ρ = -0.440, p = 0.001; ρ = -0.316, p = 0.023, respectively). Conversely, there was no correlation between oncostatin M and total testosterone level (ρ = 0.220; p = 0.118). In the context of inflammation and metabolic parameters, oncostatin M was inversely correlated with C-reactive protein, homeostatic model assessment for insulin resistance score, and low-density lipoprotein cholesterol (ρ = -0.353, p = 0.019; ρ = -0.275, p = 0.048; ρ = -0.470, p &lt; 0.001, respectively). The diagnostic performance of oncostatin M, C-reactive protein, homeostasis model assessment of insulin resistance, and non-high-density lipoprotein cholesterol for polycystic ovary syndrome is as follows: Oncostatin M, sensitivity: 50%, specificity: 75%, Accuracy: 63%, p = 0.009; C-reactive protein, sensitivity: 84%, specificity: 61%, Accuracy: 74%, p = 0.004; homeostasis model assessment of insulin resistance, sensitivity: 72%, specificity: 81%, Accuracy: 77%, p &lt; 0.001; and non-high-density lipoprotein cholesterol; sensitivity: 72%, specificity: 75%, accuracy: 73%, p &lt; 0.001. Conclusions: Plasma oncostatin M levels were considerably lower in patients with polycystic ovary syndrome than in the control group, and this was inversely correlated with the hormonal and metabolic parameters of polycystic ovary syndrome. Thus, oncostatin M may be a novel therapeutic target for polycystic ovary syndrome and its metabolic complications.

Unhealthy diet can lead to the development of metabolic disorders, and studies have shown strong associations between those conditions, c-reactive protein (CRP) and adiponectin. We report on associations between targeted metabolic markers and active nutrients from diet and Sujiaonori algal supplement (SBM), a natural adiponectin modulation inducer (NAMI) containing 60% of bioactive ulvan-rich fiber, in Japanese women. The study comprised dietary survey and intervention conducted in Kochi, Japan (2016-2017), involving 31 women who completed a dietary survey and provided biospecimen for CRP and adiponectin measurement using ELISA. Sixteen women received 3g SBM daily for one month and 15 others (controls) received 3g of corn starch. In SBM group, mean age was 23.06 (2.21) years [vs. 23.06 (1.55)], BMI was 21.11 (0.59) kg/m2 [vs. 21.43 (0.60) in controls], and daily intake of n3-PUFA [3.83 (0.24) vs. 2.21 (0.33) mg/day; p=0.042] and total fiber [364.12 (2.45) vs. 48.13 (1.57) mg/day in controls; p=0.000] were markedly higher. Furthermore, CRP was inversely associated with total fiber, total n3-PUFA, SBM-n3PUFA, vitamin D and vitamin B6, whereas adiponectin was strongly and positively associated with SBM-fiber and total n3-PUFA. Thus ulvan-rich SBM supplement, which contains ulvan-rich fiber and n3-PUFA, might be beneficial in reducing metabolic risk.

Unhealthy diet can lead to the development of metabolic disorders, and studies have shown strong associations between those conditions and biomarkers, such as c-reactive protein (CRP) and adiponectin. Recently, marine algal biomaterials have been investigated extensively due to their health benefits. We report on associations between metabolic markers and bioactive nutrients from diet and Sujiaonori algal biomaterial (SBM), a natural adiponectin modulation inducer (NAMI) containing 60% of ulvan-rich fiber, in a sample of Japanese women. The study comprised dietary survey and intervention conducted in Kochi, Japan (2016-2017), involving 31 women who completed a dietary survey and provided biospecimen for CRP and adiponectin measurement using ELISA. Sixteen women received 3g SBM daily for one month and 15 others (controls) received 3g of corn starch. In SBM group, mean age was 23.06 (2.21) years [vs. 23.06 (1.55)], BMI was 21.11 (0.59) kg/m² [vs. 21.43 (0.60) in controls], and daily intake of n3-PUFA [3.83 (0.24) vs. 2.21 (0.33) mg/day; p=0.042] and total fiber [364.12 (2.45) vs. 48.13 (1.57) mg/day in controls; p=0.000] were markedly higher. Furthermore, CRP was inversely associated with total fiber, total n3-PUFA, SBM-n3PUFA, vitamin D and vitamin B6, whereas adiponectin was strongly and positively associated with SBM-fiber and total n3-PUFA. Thus ulvan-rich SBM supplement, which contains ulvan-rich fiber and n3-PUFA, might be beneficial in reducing metabolic risk.

The delivery of Cytochrome c (Cyt c) to the cytosol stimulates apoptosis in cells were its release from mitochondria and apoptosis induction is inhibited. We developed a drug delivery system consisting of Cyt c nanoparticles decorated with folate-poly(ethylene glycol)-poly(lactic-co-glycolic acid)-thiol (FA-PEG-PLGA-SH) to deliver Cyt c into cancer cells and test their targeting in the Lewis Lung Carcinoma (LLC) mouse model. Cyt c-PLGA-PEG-FA nanoparticles (NPs) of 253 ± 55 and 354 ± 11 nm were obtained by Cyt c nanoprecipitation, followed by surface decoration with the co-polymer SH-PLGA-PEG-FA, and compared to a nanoparticle-free formulation. Overexpression of FA in LLC cells and internalization of Cyt c-PLGA-PEG-FA nanoparticles (NPs) was confirmed by confocal microscopy. Caspase activation assays show NPs retain 88-96% Cyt c activity. The NP formulations were more efficient in decreasing LLC cell viability than the NP-free formulation, with IC50: 49.2 to 70.1 μg/ml versus 129.5 μg/ml, respectively. Our NP system is thrice as selective towards cancerous than normal cells. In-vivo studies using tagged nanoparticles show accumulation in mouse LLC tumor 5 min post-injection. In conclusion, our NP delivery system for Cyt c shows superiority over the NP-free formulation and reaches a folic acid-overexpressing tumor in an immune-competent animal model.

The article presents comparative results from 5 categories of animals (4 samples originating from pigs, 2 from cows, 1 from chicken, 1 from ostriches, 1 from horses, samples quantified with A, B, C, D, E, F, G, H, I). These samples were collected from large, medium and small (family) farms. The results were validated by the biogas production generated by the respective samples, using the Automatic Methane Potential Test System (AMPTS II) bio-processor. The largest amounts of biogas (2,464.5 Nml, 2,262.0 Nml) were recorded for the samples from pig farms (Sample B and Sample D), whereas the lowest values were obtained in the case of Sample A (414.1 Nml) and Sample C (558.3 Nml). The heavy metals analyzed in the article are Zn, Cu, Fe, Mn, Ca, K, As. The results corroborate that the C/N ratio can also vary to values lower than 20-30, without affecting the biogas production process, and the heavy metal content must be known especially for the full management of the wastes. All final data presented in the article are based on repeated, triplicate experiments, with less as 2% deviation between data.

Background: Schizophrenia is a mental disorder associated with inflammatory and oxidative stress markers such as lactate; in addition, the rate of physical inactivity in this population is very high, which leads to physical and metabolic alterations. Aims: This study measured the effect of assisted physical exercise over lactate levels in schizophrenia. Methods: Stable outpatients with schizophrenia and a group of Healthy controls received two different programs of Physical exercise (Aerobic and Functional) in a clinical trial. Results: Patients had higher lactate compared to healthy controls before and after intervention, and had higher rate of lactate increase after activity. The finding of increased lactate in schizophrenia detected before and after physical exercise deserve further attention in biomarker studies and in the development of physical rehabilitation in schizophrenia, suggesting different profile of oxidative metabolism after physical exercise. Basal increased lactate may reflect mitochondrial dysfunction or metabolic dysregulation, and the higher rate of increase may reflect a different metabolic and oxidative process. Conclusion: The finding is in line with recent studies as surrogate of mitochondrial dysfunction in schizophrenia and points to the need of additional studies on mitochondrial activity in schizophrenia, and to additional care in the design of physical interventions in schizophrenia.

The Mediterranean diet (MedDiet) is recognised to reduce risk of coronary heart disease (CHD), in part, via its anti-inflammatory properties. Diet efficacy via this mechanism is however unclear in patients with diagnosed CHD. This study aimed to determine the effect of MedDiet versus low-fat diet intervention on inflammatory biomarkers and adiposity in a pilot cohort of Australian patients post coronary event. Participants (62±9 years, 83% male) were randomised to the MedDiet (n=34) or low-fat diet (n=31). At 0-, 3- and 6-months, dietary counselling, anthropometry, body composition (Dual-energy X-ray Absorptiometry) and venepuncture was conducted. Participants adhered well to the MedDiet intervention, however, there were no significant changes in body composition or inflammatory biomarkers hs-C-reactive protein or hs-interleukin-6 in the MedDiet compared to the low-fat diet group after 6-months. Adiponectin, an anti-inflammatory adipokine, tended to increase in response to the MedDiet (+1.1±4.2ng/mL, p=0.11) and decrease in response to the low-fat diet (-0.9±3.3ng/mL, p=0.20). In the pooled cohort, participants with greatest improvement in MedDiet adherence score had significantly lower waist circumference and subcutaneous fat levels at 6-months. A clinically significant effect of the MedDiet on inflammation and adiposity in CHD patients may require a larger sample, adjunct exercise intervention and/or caloric restriction.

In an attempt to correct misunderstandings this article brings together the observations on Calcium, Myosin Binding Protein-C and Hypertrophic Cardiomyopathy in the basic function of cardiac muscle. A finding of many years ago is reiterated in a novel enzyme kinetic format with defined rate limiting step which makes CaATP the apparent substrate of the actomyosin cross-bridge. The relationship of these kinetics to recent observations on disruption of myosin binding protein-C is described along with how this bears on the understanding of the related cardiomyopathies.

Glutathione peroxidases (GPxs) form a broad family of antioxidant proteins essential for maintaining redox homeostasis in eukaryotic cells. In this study, we used an integrative approach that combines bioinformatics, molecular biology, and biochemistry to investigate the role of GPxs in reactive oxygen species detoxification in the unicellular eukaryotic model organism Tetrahymena thermophila. Both phylogenetic and mechanistic empirical model analyses provided indications about the evolutionary relationships among the GPXs of Tetrahymena and the orthologous enzymes of phylogenetically related species. In-silico gene characterization and text mining were used to predict the functional relationships between GPxs and other physiologically-relevant processes. The GPx genes contain conserved transcriptional regulatory elements in the promoter region, which suggest that transcription is under tight control of specialized signaling pathways. The bioinformatic findings were next experimentally validated by studying the time course of copper (Cu)-dependent regulation of gene transcription and enzymatic activity. Results emphasize the role of GPxs in the detoxification pathways that, by complex regulation of Cu-dependent GPx gene expression, enables Tetrahymena to survive in high Cu concentrations and the associated redox environment.

(1) Background: Neonatal early-onset sepsis (EOS) is associated with important mortality and morbidity. The aims of this study were to evaluate the association between serum biomarkers with early onset neonatal sepsis in a cohort of patients with prolonged rupture of membranes (PROM), and to calculate their diagnostic accuracy. (2) Methods: A retrospective cohort study was conducted on 1355 newborns with PROM admitted between January 2017 and March 2020, who were divided in two groups: group A, with PROM ≥ 18 hours and group B, with PROM < 18 hours. Both groups were further split into subgroups: proven sepsis, probable sepsis and no sepsis. Descriptive statistics, ANOVA analysis, and a Random Effects Generalized Least Squares (GLS) regression were used to evaluate the data. (3) Results: The statistically significant predictors of neonatal sepsis were the high white blood cells count from the first (p = 0.005) and third day (p = 0.028), and high CRP values from the first day (p = 0.004). Procalcitonin (area under the curve - AUC = 0.78) and CRP (AUC = 0.76) measured on the first day had the best predictive performance for early onset neonatal sepsis. (4) Conclusions: Further studies are needed to explore other bi-omarkers of sepsis in both pregnant women and newborns to better predict EOS.

Vitamin C is an essential enzyme cofactor and antioxidant with pleiotropic roles in human physiology. Circulating vitamin C concentrations are lower in people with diabetes mellitus suggesting a higher dietary requirement for the vitamin. We interrogated the NHANES 2017/2018 and EPIC-Norfolk datasets to compare vitamin C requirements between those with and without diabetes mellitus using dose-concentration relationships fitted with sigmoidal (four parameter logistic) curves. The NHANES cohort (n=2828 non-supplementing adults) comprised 488 (17%) participants with diabetes (self-reported or HbA1c ≥6.5%). The participants with diabetes had a lower vitamin C status (median [IQR]) than those without (38 [17, 52] µmol/L vs 44 [25, 61] µmol/L, p&lt;0.0001), despite comparable dietary intakes between the two groups (51 [26, 93] mg/d vs 53 [24, 104] mg/d, p=0.5). Dose-concentration relationships indicated that the group without diabetes reached adequate vitamin C concentrations (50 µmol/L) with an intake of 81 (72, 93) mg/d, whilst the those with diabetes required an intake of 166 (126, NA) mg/d. In the EPIC-Norfolk cohort, comprising 20692 non-supplementing adults, 475 (2.3%) had self-reported diabetes at baseline. The EPIC cohort had lower a BMI than the NHANES cohort (26 [24, 28] kg/m2 vs 29 [25, 34] kg/m2, respectively). Correspondingly, the EPIC participants without diabetes required a lower vitamin C intake of 64 (63, 65) mg/d while those with diabetes required 129 (104, NA) mg/d to reach adequate circulating vitamin C status. C-reactive protein concentrations were strongly correlated with body weight and BMI and provided a surrogate biomarker for vitamin C requirements. In conclusion, people with diabetes have 1.4- to 1.6-fold higher requirements for vitamin C than those without diabetes. This corresponds to additional daily vitamin C intake requirements of ~30-40 mg for people with diabetes.

The Ramazzottius varieornatus tardigrade is an extremotolerant terrestrial invertebrate belonging to the phylum of Tardigrada. At a length of 0.1-1.0 mm, tardigrades are small animals with an exceptional tolerance to extreme conditions such as high pressure, chemicals and irradia-tion. These properties have been attributed to the recently-discovered Dsup protein. Dsup is a nucleosome-binding protein that prevents DNA damage against X-ray and oxidative stress without impairing cell life, also in Dsup-transfected animal and plant cells. However, the precise “protective” role of this protein is still under study. We performed experiments on human cells and shows that, as compared to control cells, Dsup+ cells are more resistant to UV-C exposure and H2O2. Real-time PCR identified different expression patterns of endogenous genes involved in apoptosis, cell survival and DNA damage repair in Dsup+ cells in response to H2O2 and UV-C. While H2O2 treatment in Dsup+ cells only marginally involved the activation of pathways responsible for DNA repair reinforcing the idea of a direct protective effect of the protein on DNA, in UV-C exposed cells, Dsup efficiently upregulates DNA damage repair genes. In conclusion, our data may help to delineate the different mechanisms by which the Dsup protein operates in response to different insults.

Background and Objectives: High job strain is worsening the outcome in coronary artery disease, CAD. Severe dissatisfaction on workplace, imbalance between high demands , and low rewards, are affecting the quality of life, and diminishing the duration of life, especially in CAD patients. Our study included two samples : CAD patients (experimental group), and without CAD patients, but with traditional risk factors (control group). The main objective of the study was the role played by high sensitivity C reactive protein, hs CRP, and microalbuminuria, as mediators of job strain and CAD relationship. Secondary objectives were the following: identification of the most vulnerable patients( with significant job strain) and intervention towards this category, for cardiovascular events prevention (primary or secondary). Materials and Methods: The utilized methods were the following : clinical exam; electrocardiogram; echocardiogram; non contrast enhanced computed chest tomography; laboratory findings ( lipid profile, glycemia, hs CRP, microalbuminuria); type D scale, DS 14; depression questionnaire, PHQ-9; and satisfaction with work scale, SWWS. Results: The highest values for hs CRP and microalbuminuria were noticed in patients with the lowest Likert score, for both samples CAD, and without CAD patients. The highest job strain was noticed in females. More than half of CAD patients ,with low Likert scores, revealed myocardial infarction. Conclusions: Microalbuminuria and hs CRP were statistical significant in the study as intercessors, in job strain and CAD relationship. The most vulnerable patients for vascular events were females, in both groups : CAD and “CAD waiting desk”. In CAD sample, the vascular vulnerability was also increased by high job strain.

Candida (C.) infections represent a serious health risk for people affected by inflammatory bowel disease. An important fungal virulence factor is the capacity to form biofilms on the colonized surface of the host. This research study aimed to determine the effect of C. tropicalis and C. albicans co-infection on dextran sodium sulfate (DSS)-induced colitis in mice. Colitis severity was evaluated using histology and colonoscopy. Mice were mono-inoculated with C. albicans, C. tropicalis or co-challenged with both species. Mice were administered 3% DSS to induce acute colitis. Biofilm activity was assessed using (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl] 2H-tetrazoliumhydroxide (XTT) assay. Abundance of C. albicans in the colon tissues was assessed by immunohistochemistry. Co-challenged mice showed decreased colitis severity compared to mono-inoculated mice. The XTT assay demonstrated a marked decrease of C. albicans biofilm production in a C. albicans culture incubated with C. tropicalis supernatant. Immunohistochemical staining showed that C. albicans was more abundant in the mucosa of C. albicans mono-inoculated mice compared to the co-inoculated group. These data indicate an antagonistic microbial interaction between the two Candida species, where C. tropicalis may produce molecules capable of limiting the ability of C. albicans to adhere to the host intestinal surface leading to a reduction in biofilm formation.

Huntington’s disease (HD) is a late-onset; progressive, dominantly inherited neurological disorder marked by an abnormal expansion of polyglutamine (poly Q) repeats in Huntingtin (HTT) protein. The pathological effects of mutant Huntingtin (mHTT) are not restricted to the nervous system but systemic abnormalities including immune dysregulation have been evidenced in clinical and experimental settings of HD. Indeed, mutant huntingtin (mHTT) is ubiquitously expressed and could induce cellular toxicity by directly acting on immune cells. However, it is still unclear if selective expression ofmHTT exon1 in neurons could induce immune responses and hemocyte function. In the present study, we intended to monitor perturbations in the hemocytes population and their physiological functions in Drosophila, caused by pan-neuronal expression of mHTT protein. We found that pan-neuronal expression of mHtt significantly alters crystal cells and plasmatocyte count in larvae and adults with disease progression. Interestingly, plasmatocytes isolated from diseased conditions exhibit a gradual decline in phagocytic activity ex vivo at progressive stages of the disease as compared to age-matched control groups. We also observed an increased production of reactive oxygen species (ROS) in plasmatocytes at advanced stages of the disease. In addition, diseased flies displayed elevated reactive oxygen species (ROS) in circulating plasmatocytes at the larval stage and in sessile plasmatocytes of hematopoietic pockets at of disease. All the parameters were monitored progressively, targeting the circulation at larvae stage and hematopoietic pockets in adults at different disease stages, and many alterations were documented in the early stage itself. These findings strongly implicate that neuronal expression of mHtt alone is sufficient to induce non-cell-autonomous immune dysregulation in vivo. Based on these findings, we propose that further insight into the mechanisms through which neuronal expression of mHtt might be inflicting the innate immune responses would facilitate therapeutic inventions aimed at amelioration of HD pathology and improving the quality of life of the patients.

The present study was aimed to evaluate the levels of oxidative stress markers in breast diseases by measuring the 8-hydoxy-2-deoxyguanosine (8-OHdG), vitamin A, vitamin C, vitamin E and total antioxidant status (TAS) alterations in relation to cell proliferation activity and disease progression. Significant increases in the level of oxidative damage marker 8-OHdG and cell proliferation activity were observed in breast carcinoma patients in comparison to benign and normal controls, which were accompanied by significant decrease in non enzymatic antioxidants and TAS concentrations. 8-OHdG and cell proliferation level were negatively correlated with non enzymatic antioxidants viz., Vitamin A, Vitamin C, vitamin E level and total antioxidant activity. Altered levels of biomarkers of oxidative stress and cell proliferation activity amongst the malignant, benign and controls suggest a correlation of increased oxidative stress and cell proliferation activity in the progression of disease in breast carcinoma patients. Among the oxidative stress markers and cell proliferation index, decreased level of vitamin A, vitamin C, vitamin E, TAS and increased level of 8-OHdG, cell proliferation index emerged as best predicted biomarkers for subjects with malignancy and benign breast disease.

Efforts towards an effective HIV-1 vaccine have remained mainly unsuccessful. There is increasing evidence for a potential role of HLA-C-restricted CD8+ T cell responses in HIV-1 control, including our recent report of HLA-C*03:02 among African children. However, there are no documented optimal HIV-1 CD8+ T cell epitopes restricted by HLA-C*03:02; additionally, the structural influence of HLA-C*03:02 on epitope binding is undetermined. Immunoinformatics approaches provide a fast and inexpensive method to discover HLA-restricted epitopes. Here, we employed immunopeptidomics to identify HLA-C*03:02-restricted CD8+ T cell epitopes. We identified a clade-specific Gag-derived GY9 (GTEELRSLY) HIV-1 p17 matrix epitope exclusively restricted to HLA-C*03:02. Residues E62, T142, and E151 in the HLA-C*03:02 binding groove and positions p3, p6, and p9 on the GY9 epitope are crucial in shaping and stabilizing the epitope binding. Our findings support the growing evidence of the contribution of HLA-C molecules to HIV-1 control and provide a prospect for vaccine strategies.

Proposed fundamental laws of biology and a model of health and disease underscore the importance of the lymphatic system. The lymphatics are responsible for two of the laws of biology and the fulcrum of health and disease balancing proliferation with regeneration through the immune system. It is responsible for protection from the environment and repair of senile and damaged tissue. Life is constantly bombarded by forces that increase entropy. Lymphatics provide negative entropy to maintain health. Lymphatics help maintain cellular homeostasis removing products of metabolism. Using these principles, the role of lymphatics is investigated in salt sensitivity hypertension, cardiorenal system, the new pillar of heart failure and kidney disease - Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors, and brain diseases. The realization of organ lymphatics in maintenance of health and disease opens the avenue to new therapeutics. This is the unrealized potential of lymphatic study.

Emerging pollutants as pharmaceuticals have been focusing international attention for few decades. Ciprofloxacin (CIP) is a common drug widely found in effluents from hospitals, industrial and different wastewater treatment plants, as well as rivers. In this work, the lab-scale 3D-BER system was established, and more than 90% of the antibiotic CIP removal from the Low C/N wastewater. Best results were obtained with current intensity, and different C/N ratio significantly improve the removal of CIP and nitrates, when the ideal conditions were; C/N = 1.5-3.5, pH =7.0-7.5, and I = 60 mA. The highest removal efficiency of CIP = 94.20 %, NO3--N= 95.53 % and total nitrogen (TN) = 84.27 %, respectively. In this novel system, the autotrophic-heterotrophic denitrifying bacteria played vital role for the removal of CIP and enhanced denitrification process. Thus, autotrophic denitrifying bacteria uses CO2 and H2 as carbon sources to reduce nitrates to N2. This system has the assortment and prosperous community revealed at the current intensity of 60 mA, and the analysis of bacterial community structure in effluent samples fluctuates under different condition of C/N ratios. According to the results of LC-MS/MS analysis, the intermediate products were proposed after efficient biodegradation of CIP. Microbial community on biodegrading was mostly found at phylum, and class level was dominantly responsible for the NO3--N and biodegradation of CIP. This work can provide some new insights towards the biodegradation of CIP and the efficient removal of nitrates from low C/N wastewater treatment by the novel 3D-BER system.

Exposure to ionizing radiation, accidental or intentional, may lead to delayed effects of acute radiation exposure (DEARE) that manifest as injury to organ systems including kidney, heart, and brain. This study examines the role of activated protein C (APC), a known mitigator of radiation-induced early toxicity, in long-term plasma metabolite and lipid panels that may be associated with DEARE. Male and female cohorts of C57BL/6N wild-type and APCHi transgenic mice were exposed to 9.5 Gy γ-rays with their hind-legs shielded to allow long-term survival that is necessary to monitor DEARE, and plasma was collected at 6 months for LC-MS based metabolomics and lipidomics. We observed significant dyslipidemia, indicative of inflammatory phenotype, upon radiation exposure. Additionally, observance of several other metabolic dysregulations was suggestive of gut damage, perturbations in TCA and urea cycles, and arginine metabolism. We also observed gender and genotype modulated metabolic perturbations post radiation exposure. The APCHi mice showed near normal abundance for several lipids. Moreover, restoration of plasma levels of some metabolites including amino acids, citric acid, and hypoxanthine in APCHi mice are indicative of APC-mediated protection from radiation injuries. With the help of these findings the role of APC in plasma molecular events after acute -radiation exposure in a gender-specific manner can be established for the first time.

In Southeast Asia, the incidence of Leukemia, a malignant blood cancer originating from hema-topoietic progenitor cells, is on the rise, marked by a concerning 54% mortality rate. This study focuses on enhancing early-stage prediction to improve patient recovery prospects significantly. Leveraging Machine Learning and Data Science, we employ protein sequential data from frequently mutated genes such as BCL2, HSP90, PARP, and RB to predict Chronic Myeloid Leukemia (CML). Our approach relies on robust feature extraction techniques, namely Di-peptide Composition (DPC), Amino Acid Composition (AAC), and Pseudo amino acid composition (Pse-AAC), with prior attention to addressing outliers and validating feature selection through the Pearson Corre-lation Coefficient. Data augmentation ensures a well-rounded dataset for analysis. Employing a range of Machine Learning models, including Support Vector Machine (SVM), XGBoost, Random Forest (RF), K Nearest Neighbor (KNN), Decision Tree (DT), and Logistic Regression (LR), we achieve accuracy rates spanning from 66% to 94%. These classifiers undergo comprehensive as-sessment using performance metrics such as accuracy, sensitivity, specificity, F1-score, and the confusion matrix. Our proposed solution, encompassing a user-friendly web application dashboard, presents an invaluable tool for early CML diagnosis with profound implications for practitioners, offering a deploy-able asset within healthcare institutions and hospitals.

Estrogens play a protective role during early life stages. However, endogenous 17β-estradiol (E2) can accelerate atherosclerosis progression in low-grade inflammatory conditions like established atherosclerosis. Our single-center cohort study assessed sex-specific associations of gonadal hormones with oxidative stress, inflammation, and myocardial injury markers in 111 patients (37% women) diagnosed with acute myocardial infarction (MI) between July 2011 and December 2013. Blood samples were collected within 48 hours of symptom onset, and we measured sex steroids (E2, total testosterone [T]), oxidized low-density lipoproteins, high-sensitive C-reactive protein (CRP), white blood cell counts (WBC), and cardiac enzymes (creatine kinase [CK], the CK Muscle-Brain fraction [CK-MB], and high-sensitive troponin T [hsTnT]). The SYNTAX score gauged coronary disease severity from coronary angiography results. In men with acute MI, peak cardiac enzyme levels were predicted by post-percutaneous coronary intervention (PCI) E2 plasma levels (OR 1.011, p=0.047 - CK; OR 1.018, p=0.013 - CK- MB; OR 1.019, p=0.005 - TnT), peak WBC count (OR 1.487, p=0.015 - CK ; OR 1,709, p=0,005 - CK- MB; OR 1.391, p=0.012 - TnT), and peak CRP plasma levels (OR 1.040, p=0.033 - CK; OR 1.024, p=0.029 - CK-MB; OR 1.063, p=0.006 - TnT). T levels and E2/T ratio were associated with post-PCI CRP in these men (OR 0.980, p = 0.024 - T, OR 1.010, p = 0.076 - CRP). For women, peak WBC was a marker of highest testosterone (OR 1.348, p = 0.062), and only WBC was a significant indicator of myocardial injury extent (OR 1.426, p=0.039 - CK; OR 1.384, p=0.036 - CK-MB; OR 1.299, p=0.048 - TnT). During acute MI, elevated endogenous estradiol levels correlate with myocardial necrosis severity in men, while in women, increased leukocyte levels indicate acute myocardial damage. Elevated plasma T is associated with increased WBC in women. In men, post-PCI plasma CRP specifically indicates endogenous T levels and E2/T ratio during the acute phase.

This review article focuses on the current state-of-the-art in the area of cellular and molecular biotechnology for over-production of clinically relevant therapeutic and anabolic growth factors. We discuss how the currently available tools and emerging technologies can be used for the regenerative treatment of osteoarthritis (OA). Transfected protein packaging cell lines such as GP-293 cells may be used as “cellular factories” for large-scale production of therapeutic proteins and pro-anabolic growth factors, particularly in the context of cartilage regeneration. However, when irradiated with gamma or x-rays, these cells lose their capacity for replication, which actually makes them safe for use as a live cell component of intra-articular injections. This innovation is already here, in the form of TissueGene-C, a new biological drug which consists of normal allogeneic primary chondrocytes combined with transduced GP2-293 cells that overexpress the growth factor transforming growth factor β1 (TGF-β1). TissueGene-C has revolutionized the concept of cell therapy, allowing drug companies to develop live cells as biological drug delivery systems for direct intra-articular injection of growth factors whose half-lives are in the order of minutes. Therefore, in this paper, we discuss the potential for new innovations in regenerative medicine for degenerative diseases of synovial joints using mammalian protein production platforms, specifically protein packaging cell lines, for over-producing growth factors for cartilage tissue regeneration and give recent examples. Mammalian protein production platforms that incorporate protein packaging eukaryotic cell lines are superior to prokaryotic bacterial expression systems and are likely to have a significant impact on the development of new humanized biological growth factor therapies for treating focal cartilage defects and more generally for the treatment of degenerative joint diseases such as OA, especially when injected directly into the joint.

Avian metapneumovirus subgroup C (aMPV/C) causes respiratory diseases and egg dropping in chickens and turkeys, resulting in severe economic losses to the poultry industry worldwide. Integrin β1 (ITGB1), a transmembrane cell adhesion molecule, is present in various cells and mediates numerous viral infections. Herein, we demonstrate that ITGB1 is essential for aMPV/C infection in cultured DF-1 cells, as evidenced by the inhibition of viral binding by EDTA blockade, Arg-Ser-Asp (RSD) peptide, monoclonal antibody against ITGB1, and ITGB1 short interfering (si) RNA knockdown in cultured DF-1 cells. Simulation of the binding process between the aMPV/C fusion (F) protein and avian-derived ITGB1 using molecular dynamics showed that ITGB1 may be a host-factor for benefiting aMPV/C attachment or internalization. Transient expression of avian ITGB1 rendered porcine and feline non-permissive cells (DQ cells and CRFK cells, respectively) susceptible to aMPV/C infection. Replication kinetic of aMPV/C in siRNA-knockdown cells revealed that ITGB1 plays an important role in aMPV/C infection at the early stage (attachment and internalization). aMPV/C was also able to infect efficiently human non-small cell lung cancer (A549) cells. This may be due to a consequence of the similar structures of both metapneumovirus F protein-specific motifs (RSD for aMPV/C and RGD for human metapneumovirus) recognized by ITGB1. Overexpression of avian-derived ITGB1 and human-derived ITGB1 in A549 cells enhanced aMPV/C infectivity. Taken together, this study demonstrated that ITGB1 acts as an essential receptor for aMPV/C attachment and internalization into host cells in which facilitates aMPV/C infection.

Rotavirus species H (RVH) has been detected in pigs, humans and bats. Moreover, porcine RVHs have been recently identified in several swine-producing countries. Despite their zoonotic impact, genome information of RVHs is still limited. This study aimed to establish a tentative complete genome-based genotyping system for RVHs, by appending genomic sequences from 12 porcine RVHs identified in Japan between 2013 and 2015 to those from human and other porcine RVHs reported in previous studies. Phylogenetic analysis of 11 RNA segments indicated that porcine RVHs could be classified into multiple genotypes. Consequently, the genotype classification for RVHs revealed the existence of genotypes 10G, 6P, 6I, 3R, 4C, 7M, 6A, 2N, 4T, 6E, 3H for the genes VP7, VP4, VP6, VP1, VP2, VP3, NSP1, NSP2, NSP3, NSP4 and NSP5, respectively. Surprisingly, two distinctive types in NSP1 and NSP3 genes were identified from among the twelve porcine RVHs. Our data suggest a potentially novel gene rearrangement event between porcine RVH and rotavirus species C in the NSP3 gene. These findings would provide a new insight in understanding for evolution of RV.

Familial colorectal cancer (CRC) is only partially explained by known germline predisposing genes. We performed whole genome sequencing in 15 Polish families of many affected individuals, without mutations in known CRC predisposing genes. We focused on loss-of-function variants and functionally characterized them. We identified a frameshift variant in the CYBA gene (c.246delC) in one family and a splice site variant in the TRPM4 gene (c.25-1 G>T) in another family. While both variants were absent or extremely rare in gene variant databases, we identified four additional Polish familial CRC cases and two healthy elderly individuals with the CYBA variant (odds ratio 2.46, 95% confidence interval 0.48-12.69). Both variants led to a premature stop codon and to a truncated protein. Functional characterization of the variants showed that knockdown of CYBA or TRPM4 depressed generation of reactive oxygen species (ROS) in LS174T and HT-29 cell lines. Knockdown of TRPM4 resulted in decreased MUC2 protein production. CYBA encodes a component in the NADPH oxidase system which generates ROS and controls, e.g., bacterial colonization in the gut. Germline CYBA variants are associated with early onset inflammatory bowel disease, supported with experimental evidence on loss of intestinal mucus barrier function due to ROS deficiency. TRPM4 encodes a calcium-activated ion channel, which in a human colonic cancer cell line controls calcium-mediated secretion of MUC2, a major component of intestinal mucus barrier. We suggest that the gene defects in CYBA and TRPM4 mechanistically involve intestinal barrier integrity through ROS and mucus biology, which converges in chronic bowel inflammation.

Adenosine to inosine (A-to-I) RNA editing is a highly conserved regulatory process carried out by adenosine-deaminases (ADARs) on dsRNAs. Although a considerable fraction of the transcriptome is edited, the function of most editing sites is unknown. Previous studies indicate changes in A-to-I RNA editing frequencies following exposure to several stress types. However, the overall effect of stress on the expression of ADAR targets is not fully understood. Here, we performed high-throughput RNA sequencing of wild-type and ADAR mutant C. elegans worms after heat-shock to analyze the effect of heat-shock stress on the expression pattern of genes. We found that ADAR regulation following heat-shock does not directly involve heat-shock related genes. Our analysis also revealed that lncRNAs and pseudogenes, which have a tendency for secondary RNA structures, are enriched among upregulated genes following heat-shock in ADAR mutant worms. The same group of genes is downregulated in ADAR mutant worms under permissive conditions, which is likely, considering that A-to-I editing protects endogenous dsRNA from RNA-interference (RNAi). Therefore, temperature increases may destabilize dsRNA structures and protect them from RNAi degradation, despite the lack of ADAR function. These findings shed new light on the dynamics of gene expression under heat-shock in relation to ADAR function.

I have recently reiterated that the cross-bridge is a calcium ATPase that is inhibited by magnesium and this arises because in normal hearts Myosin binding Protein-C prevents the use of MgATP as rate limiting substrate ensuring that Ca²⁺ replaces Mg²⁺ in the excitation pathway. Here I revisit the studies on [Ca²⁺] dependency of ATPase and tension under diastolic stretch with a different conclusion on Hill coefficients. This reveals the underlying mechanisms of the Frank-Starling Law and Hypertrophic myopathy are not the same, the former being kinase controlled.

Insulin-like growth factor binding proteins (IGFBPs) are critical modulators of the metabolism. In adults, IGFBPs are associated with obesity and insulin resistance but the association of IGFBPs with metabolic homeostasis in children and adolescents is not fully characterized. In this study we investigated the association of plasma IGFBPs (IGFBP-1, 3 and 7) with weight status, central adiposity and cardiovascular disease markers Hs-CRP and Ox-LDL. A total of 420 adolescents (age 11-14 years) were randomly recruited from public middle schools in Kuwait. IGFBPs were measured using bead-based multiplexing while Hs-CRP and Ox-LDL were measured using ELISA. IGFBP-1 levels were significantly lower in obese and overweight participants compared to normal weight children. Only IGFBP-1 was negatively associated with waist circumference to height (WC/Ht) ratio. IGFBP-1 was negatively correlated with Hs-CRP while IGFBP-3 and IGFBP-7 were negatively correlated with Ox-LDL. These data demonstrate a robust negative association of IGFBP-1, but not IGFBP-3 or -7, with overweight and obesity, and the inflammation marker Hs-CRP. Central adiposity (WC/Ht ratio) was a stronger predictor of IGFBP-1 than BMI-for-age z-score. IGFBP-1 could thus be used as a sensitive predictive diagnostic tool for obesity and its subsequent effects in screening and monitoring of obesity-related metabolic complications in adolescents.

Background: Risk tratification based on pre-test probability may improve the diagnostic accuracy of temporal artery high-resolution compression sonography (hrTCS) in the diagnostic workup of cranial giant cell arteriitis (cGCA). Methods: A logistic regression model with candidate items was derived from a cohort of patients with suspected cGCA (n = 87). The diagnostic accuracy of the model was tested in the derivation cohort and in an independent validation cohort (n = 114) by receiver operator characteristics (ROC)-analysis. The clinical items were composed to a clinical prediction rule, integrated into a stepwise diagnostic algorithm together with CRP-values and hrTCS-values. Results: The model consisted of 4 clinical variables (age &gt; 70, headache, jaw claudication, anterior ischemic optic neuropathy). The diagnostic accuracy of the model for discrimination of patients with and without a final clinical diagnosis of cGCA was excellent in both cohorts (AUC 0.96 and AUC 0.92, respectively). The diagnostic algorithm improved the positive predictive value of hrCTS substantially. Within the algorithm, 32.8% of patients (derivation cohort) and 49.1% (validation cohort) would not have been tested by hrtCS. None of these patients had a final diagnosis of cGCA. Conclusion: A diagnostic algorithm based on a clinical prediction rule improves the diagnostic accuracy of hrTCS.

A whole-exome capture and next-generation sequencing applied to an 11 y/o patient with a clinical history of congenital hypotonia, generalized motor and cognitive neurodevelopmental delay, severe cognitive deficit, without any identifiable Syndromic pattern, and to her parents, disclosed a de novo heterozygous pathogenic mutation, c.697_699del p.Phe233del (rs786204835)(ACMG classification PS2, PM1, PM2, PP5), harbored in the PURA gene (MIM*600473) (5q31.3), associated to Autosomal Dominant Mental Retardation 31 (MIM # 616158). We used the significant improvement in the accuracy of protein structure prediction recently implemented in AlphaFold that incorporates novel neural network architectures and training procedures based on the evolutionary, physical, and geometric constraints of protein structures. The wild-type (WT) sequence and the mutated one, missing the Phe233, were reconstructed. The predicted local Distance Difference Test (lDDT) for the PURA WT and the PURA-Phe233del showed that the occurrence of the Phe233del affects between 220-320 amino acids. The distortion in the PURA structural confor-mation in the ~5Å surrounding area after the p.Phe233del produces a conspicuous disruption of the repeat III, where the DNA and RNA helix unwinding capability occurs. PURA Protein-DNA Docking corroborated these results in silico Analysis that showed a loss of the contact of the PURA-Phe233del III repeat domain model with the DNA. Together, i) the energetic and stereochemical, ii) the hydropathic indices and polarity surfaces, and iii) the hybrid Quantum Mechanics-Molecular Mechanics (QM-MM) analyses of the PURA molecular models demarcate at the atomic resolution the specific surrounding region affected by these mutations and paves the way for future cell-based functional analysis. To the best of our knowledge, this is the first report of a de novo mutation underpinning a PURA syndrome in a Latin American patient and highlights the importance of predicting the molecular effects in protein structure using artificial intelligence algorithms and molecular and atomic resolution stereochemical analyses.

Background: We previously reported that human keratinocytes express protease-activated receptor (PAR)-2 and play an important role in activated protein C (APC)-induced cutaneous wound healing. This study investigated the involvement of PAR-2 in the production of gelatinolytic matrix metalloproteinases (MMP)-2 and -9 by APC during cutaneous wound healing. Methods: Full-thickness excisional wounds were made on the dorsum of male C57BL/6 mice. Wounds were treated with APC on days 1, 2, and 3 post-wounding. Cultured neonatal foreskin keratinocytes were treated with APC with or without intact PAR-2 signalling to examine the effects on MMP-2 and MMP-9 production. Murine dermal fibroblasts from PAR2 knock-out (KO) mice were also assessed. MMP-2 and -9 were measured by gelatin zymography, fluorometric assay, and immunohistochemistry. Results: APC accelerated wound healing in WT mice, but had negligible effect in PAR-2 KO mice. APC stimulated murine cutaneous wound healing was associated with differential 0temporal production of MMP-2 and MMP-9, with the latter peaking on Day 1 and the former on Day 6. In-hibition of PAR-2 in human keratinocytes reduced APC-induced MMP-2 activity 25~50, but had little effect on MMP-9. Similarly, APC-induced MMP-2 activation was reduced by 40% in cultured dermal fibroblasts derived from PAR-2 KO mice. Conclusion: This study shows for the first time that PAR-2 is essential for APC-induced MMP-2 production. Considering the important role of MMP-2 in wound healing, this work helps explain the underlying mechanisms of action of APC to promote wound healing through PAR2.

Using a safe subset of C++ is a promising direction for increasing the safety of the programming language while maintaining its performance and productivity. In this paper, we examine how close existing C/C++ code is to conforming to a safe subset of C++. We examine the rules presented in existing safe C++ standards and safe C++ subsets. We analyze the code characteristics of 5.8 million code samples from the Exebench benchmark suite and 5 modern C++ applications using a static analysis tool. We find that raw pointers, unsafe casts, and unsafe library functions are used in both C++ code at large and modern C++ applications. In general, C++ code at large does not differ much from modern C++ code, and continued work will be required to transition from existing C/C++ code to a safe subset of C++.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a decline in cognitive function with neuronal damage. Although the precise pathobiology of AD is still elusive, accumulating evidences suggest that mitochondrial dysfunction is one of the underlying causes of AD. Mutations of mitochondrial or nuclear DNA that encode mitochondrial constituents may cause mitochondrial dysfunctions. In particular, dysfunction of electron transport chain complexes along with interactions of mitochondrial pathological proteins are associated with mitochondrial dysfunctions in AD. Mitochondrial dysfunction causes an imbalance in reactive oxygen species, leading to oxidative stress (OS) and vice-versa. Neuroinflammation is another potential contributory factor to induce mitochondrial dysfunction. Phytochemicals or other natural compounds have the potential to scavenge oxygen free radicals and enhance cellular antioxidant defense system, and thereby protect against OS-mediated cellular damage. Phytochemicals can also modulate other cellular processes, including autophagy and mitochondrial biogenesis. Pharmacological intervention through neuroprotective phytochemicals can, therefore, be a potential strategy to combat mitochondrial dysfunctions as well as AD. This review focuses on the role of phytochemicals to mitigate mitochondrial dysfunction in the therapy of AD pathogenesis.

The mass concentration of particulate matter (PM) has been systematically used in epidemiological studies as exposure indicator, to relate airborne concentrations with a wide variety of human health effects, which can be hardly explained by using this single parameter. In fact, PM is a “particle cocktail” that includes a complex mixture of compounds with a wide range of sizes, chemical compositions and emission sources. Current research hypothesizes that many of the adverse health effects are derived from oxidative stress in biological systems caused by the deposition of PM into the lungs. This emerging hypothesis is called the oxidative stress paradigm. In this commentary article we analize how this new paradigm could help to answer the as-of-yet unanswered questions related to the mechanism of action of PM pollution on human health. Acellular oxidative potential (OP) assays have been emerged as a promising approach to quantify the PM potential to induce oxidative stress and to relate it with the chemical composition and size distribution of PM. Recent researches have shown that the OP is related to the presence of metals, organic carbon, polyaromatic hydrocarbons and quinones. However, the association between PM and particle-induced toxicity is still largely unknown. Therefore, additional research is needed to identify the specific PM characteristic(s), such as its specific size, emission source or chemical content, which contribute the most to its redox activity. Thus, the OP measurements provide information that allows us to evaluate and integrate the toxic potential of PM in a unique parameter, whose relationships with emission sources, size distribution and/or chemical composition should be faced in the near future.

In this paper, we present a new concept of the generalized core orthogonality (called the C-S orthogonality) for two generalized core invertible matrices $A$ and $B$. $A$ is said to be C-S orthogonal to $B$ if $A^{\tiny\textcircled{S}}B=0$ and $BA^{\tiny\textcircled{S}}=0$, where $A^{\tiny\textcircled{S}}$ is the generalized core inverse of $A$. The characterizations of C-S orthogonal matries and the C-S additivity are also provided. And the connection between the C-S orthogonality and C-S partial order has been given using their canonical form. Moreover, the concept of the strongly C-S orthogonality is defined and characterized.

Anthelmintic drugs are the major line of defense against parasitic nematode infections, but the arsenal is limited and resistance threatens sustained efficacy of the available drugs. Discoveries of the modes of action of these drugs and mechanisms of resistance have predominantly come from studies of a related non-parasitic nematode species, Caenorhabditis elegans, and the parasitic nematode Haemonchus contortus. Here, we discuss how our understanding of anthelmintic resistance and modes of action came from the interplay of results from each of these species. We argue that this “cycle of discovery”, where results from one species inform the design of experiments in the other, can use the complementary strengths of both to understand anthelmintic modes of action and mechanisms of resistance.

The study aimed to determine, through a systematic review, the relationship between Reactive Attachment Disorder (RAD) and the presence of psychopathology in children and adolescents and to determine the existence of differences about the presence of internalising and externalising psychological problems between the RAD group and groups with other disorders or with typical development. Following the PRISMA methodology, a search was carried out in the Web of Science, PubMed and Scopus databases. The search yielded 770 results, of which only 25 met the inclusion criteria. The results, indicate a relationship between the presence of RAD and/or Disinhibited social engagement disorder (DSED) with the presence of internalising and externalising problems. These difficulties are more present in children with RAD compared to children without personal difficulties, or children with DSED, children with autism, children with intellectual disabilities or children with hyperactivity. It can be concluded that the presence of RAD has negative consequences on the mental health of children and adolescents, with these being greater in the inhibited group than in the disinhibited group, and with respect to children with autism or hyperactivity.

The brain's unique characteristics make it exceptionally susceptible to oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) production, reactive nitrogen species (RNS) production, and antioxidant defense mechanisms. This review explores the factors contributing to the brain vascular tone vulnerability in the presence of oxidative damage, which can be of clinical interest in critically ill patients or presenting acute brain injuries. The brain's high metabolic rate and inefficient electron transport chain in mitochondria lead to significant ROS generation. Moreover, non-replicating neuronal cells and low repair capacity increase susceptibility to oxidative insult. ROS can influence cerebral vascular tone and permeability, with a potential impact on cerebral autoregulation. Different ROS species, including superoxide and hydrogen peroxide, exhibit vasodilatory or vasoconstrictive effects on cerebral blood vessels. Reactive nitrogen species (RNS), particularly NO and peroxynitrite, also exert vasoactive effects. This review further investigates the neuroprotective effects of antioxidants, including superoxide dismutase (SOD), vitamin C, vitamin E, and the glutathione redox system. Various studies suggest that these antioxidants could be used as adjunct therapies to protect the cerebral vascular tone during high oxidative stress conditions. Nevertheless, more extensive research is required to comprehensively grasp the relationship between oxidative stress and cerebrovascular tone, as well as to explore the potential benefits of antioxidants as adjunctive therapies in critical illnesses and acute brain injuries.

Nonhost disease resistance is the most common type of plant defense mechanism against potential pathogens. In this study, the metabolic enzyme formate dehydrogenase (FDH1) was identified to be involved in nonhost disease resistance in Nicotiana benthamiana and Arabidopsis thaliana. In Arabidopsis, AtFDH1 was highly upregulated in response to both host and nonhost bacterial pathogens. Arabidopsis Atfdh1 mutants were compromised in nonhost resistance, basal resistance, and gene-for-gene resistance. The expression patterns of salicylic acid (SA) and jasmonic acid (JA) marker genes after pathogen infections in Atfdh1 mutant indicated that SA is most likely involved in the FDH1-mediated plant defense response to both host and nonhost bacterial pathogens. Previous studies reported that FDH1 localizes to only mitochondria, or both mitochondria and chloroplasts. Our results showed that the AtFDH1 localized to mitochondria and the amount of FDH1 localized to mitochondria increased upon infection with host or nonhost pathogens. Interestingly, the subcellular localization of FDH1 was observed in both mitochondria and chloroplasts after infection with a nonhost pathogen in Arabidopsis. We speculate that FDH1 plays a role in cellular signaling networks between mitochondria and chloroplasts to produce coordinated defense responses such as SA-induced reactive oxygen species (ROS) generation and hypersensitive response (HR)-induced cell death against nonhost bacterial pathogens.

Soil pH, either low (acidity) or high (alkalinity) is one of the major constraints that affect many biochemical and biological processes within the cell. The present study was carried out to understand the oxidative damage and antioxidant defense in wheat (Triticum aestivum L. cv. BARI Gom-25) grown under different pH regimes. Eight-day-old seedlings were exposed to growing media with different pH levels (4.0, 5.5, 7.0 and 8.5). Seedlings grown in pH 4.0 and in pH 8.5 showed reductions in biomass, water, and chlorophyll contents; whereas plants grown at pH 7.0 (neutral) exhibited better performance. Extremely acidic (pH 4.0) and/or strongly alkaline (pH 8.5)-stress also increased oxidative damages in wheat by excess reactive oxygen species (ROS) generation and methylglyoxal (MG) production, which increased lipid peroxidation and disrupted the redox state. In contrary, the lowest oxidative damage was observed at neutral condition followed by strong acidic condition (pH 5.5), which was attributed mainly due to better performance of the antioxidant defense and glyoxalase systems. Interestingly, seedlings grown at pH 5.5 showed a significant increase in morphophysiological attributes compared with extreme acidic (pH 4.0)- and strong alkaline (pH 8.5)-stress treatments, which indicates the tolerance of wheat to the acidic condition.

In osteoarthritis (OA), oxidative stress plays a crucial role in maintaining and sustaining cartilage degradation. Current OA management requires a combination of pharmaceutical and non-pharmacological strategies, including intraarticular injections of hyaluronic acid (HA). However, several lines of evidence reported that HA oxidation by reactive oxygen species (ROS) is linked with HA cleavage and fragmentation, resulting in reduced HA viscosity. Resolvin D1 (RvD1) is a lipid mediator that is biosynthesized from omega-3 polyunsaturated fatty acids and is a good candidate with the potential to regulate of panoply of biological processes, including tissue repair, inflammation, oxidative stress, and cell death in OA. Herein, newly designed, and synthesized imidazolium RvD1 analogues were introduced to compare their potential antioxidant properties with commercially available RvD1. Their antioxidant capacities were investigated by several in vitro chemical assays including Oxygen Radical Absorbance Capacity, 2,2-Diphenyl-1-picrylhydrazyl Radical Scavenging, Ferric Ion Reducing Antioxidant Power, Hydroxyl Radical Scavenging, and HA Fragmentation Assay. All results proved that imidazolium RvD1 analogues showed excellent antioxidant performance compared to RvD1 due to their structural modifications. Interestingly, they scavenged the formed reactive oxygen species (ROS) and protected HA from degradation, as verified by agarose gel electrophoresis and gel permission chromatography. A computational study using Gaussian 09 with DFT calculations and B3LYP/6-31 G (d, p) basis set was also employed to study the relationship between the antioxidant properties and chemical structures as well as calculation of the molecular structures, frontier orbital energy, molecular electrostatic potential, and bond length. The results showed that the antioxidant activity of our analogues was higher than that of RvD1. In conclusion, the findings suggest that imidazolium RvD1 analogues can be good candidates as antioxidant molecules for the treatment of oxidative stress-related diseases like OA. Therefore, they can prolong the longevity of HA in the knee and thus may improve the mobility of the articulation.

The regulation of multiple bacterial phenotypes was found to depend on different cyclic di-nucleotides (CDNs) that constitute intracellular signalling second messenger systems. Most notably, c-di-GMP, along with proteins related to its synthesis, sensing and degradation, was identified as playing a central role in the switching from biofilm to planktonic modes of growth. Recently, this world has been under expansion, with the discoveries of other signalling CNDs in bacteria (c-di-AMP and cGAMP) and also in eukaryotes, novel protein and RNA receptors of CDNs, and the numerous functions related to these molecules. In this work, we comprehensively review and analyse the structural biology data about the systems that bacteria use to synthesise and recognise CDNs, detailing their interactions at molecular level with their products/ligands. Additional interesting observations were made, including that different receptor types can bind CDNs in similar conformations and that, based on genomic data, different CDN second messenger systems may coexist in many organisms. The large amount of sequence and structural data available allows a broad view of the importance of CDNs in bacteria, but how cells coordinate these molecules to ensure adaptation to changing environmental conditions is still open for much further exploration.

The manufacture of SiC-based composites is quite widespread, and currently different methods are employed for to produce them. The most efficient method, taking into account the cost/performance ratio, is reactive melt infiltration. It consists in infiltrating liquid silicon into a porous preform that must contain carbon, so that SiC is produced during infiltration. This chemical reaction is, in fact, the driving force of the process. In the present work, the synthesis of two SiC-based composite materials with very different applications and microstructures has been studied and optimized. In both cases, materials have been obtained with suitable properties for the selected applications. One of the materials studied is SiCp/Si for protection systems such as armor jackets, and the other one is Cf/SiC for use in braking systems. For the optimization, the dwell time and the atmosphere (Ar or primary vacuum) were used as variables. It has been found that in both preforms the optimum conditions are 1 hour dwell time and a vacuum atmosphere at 1450 °C. The effect of these parameters on microstructure and infiltration kinetics are discussed.

Objectives: 1) to demonstrate the anti-inflammatory and anabolic effect of Ozone by determining in serum samples the biochemical levels of IL-6 and IGF-1 in knee osteoarthritis (OA) patients in a real world in Rehabilitation Setting; 2) to evaluate clinical effectiveness by Visual Analog Scale (VAS) and WOMAC scale, and biochemical effect by C-reactive protein (CRP), uric acid and erythrocyte sedimentation rate (ESR). Material and methods: 65 patients with knee OA Kellgren Lawrence (KL) grade 2 or more were analyzed in a retrospective observational study. The study run from January 2018 to September 2021. Inclusion criteria: a) patients 18 years or older; b) with knee OA KL 2º or more; c) biochemical analysis before-and-after treatment; d) pain more than 3 on VAS. Exclusion Criteria: a) previous knee surgery; b) favism; c) pregnancy; d) any other disease that originates lack of collaboration for infiltration. Primary Outcome variables: a) IL-6; b) IGF-1 in diabetes mellitus (DM)/obese and non-DM/non-obese patients; both before-and-after Ozone treatment. Secondary Outcome variables: a) CRP, b) ESR, c) uric acid, d) VAS pain, e) WOMAC pain, function and stiffness. Ozone protocol consisted of 4 sessions (once a week) of an intra-articular infiltration of 20 mL (20µg/mL concentration) of a gas mixture of Oxygen-Ozone 95-5% (produced by Ozone generator Ozonosan-α Plus ®). For biochemical evaluation, SNIBE MAGLUMI ™ IL-6 (CLIA) and SNIBE MAGLUMI ™ IGF-1 (CLIA) kits were used. CRP and uric acid were analyzed by Abbott Alinity c kit; and ESR was evaluated by DIESSE VES MATIC CUBE 30. Results: There is a linear correlation between age and OA severity. IL-6 decreased both in DM and non-DM patients and in all OA KL grades (from 2.7 to 1.59 pg/mL). IGF-1 decreased in total group (OA + DM + obesity) from 112.09 to 107.19 ng/mL. When only knee OA patients were analyzed, Ozone improved IGF-1 levels (from 100.17 to 102.03 ng/mL). Ozone decreased CRP, ESR, uric acid, and improved VAS pain, WOMAC pain, function and stiffness (p<0.05). Conclusions: Ozone is a valid option for the management of knee osteoarthritis in real world Rehabilitation Setting, because of its anti-inflammatory, metabolic and anabolic properties. Ozone downregulates pro-inflammatory IL-6 cytokine. Ozone has a metabolic/hypoglycemic effect on obese/diabetic knee osteoarthritis patients by reducing IGF-1. Ozone has an anabolic effect on non-diabetic/non-obese patients by improving IGF-1. Ozone reduces other biomarkers of inflammation (CRP, ESR and uric acid) and improves, pain, function and quality of life.

Background: Strong indicators of inflammation, such as C-reactive protein (CRP), hypersensitive CRP (hs-CRP), and a series of hematological indices, including platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), hematocrit (HCT) and red blood cell distribution width (RDW), are regarded related with the incidence of contrast induced nephropathy (CIN) closely. Whereas, it remains unclear whether they can function as predictors of CIN onset. The objective of this meta-analysis was to determine the relationship between above indicators and CIN incidence among patients receiving coronary intervention. Methods: Clinical studies were retrieved from the electronic databases of PubMed, EMBASE, Google Scholar, Clinical Trials, and science direct from their inception to June 3rd, 2020. Meta-analysis was performed on pool eligible studies. Two reviewers screened all titles and abstracts and independently assessed all articles. Results: A total of 26 studies involving 29,454 patients were included in the meta-analysis. Pooled analysis results revealed that patients with higher CRP (odds ratio [OR]=1.06, 95% confidence interval [CI]: 1.01–1.12, P=0.02), hs-CRP (OR=1.03, 95% CI: 1.01–1.06, P=0.004), NLR (OR=1.11, 95% CI: 1.01–1.20, P=0.02), RDW (OR=1.35, 95% CI: 1.19–1.53, P<0.00001), and lower HCT (OR=0.94, 95% CI: 0.92–0.97, P=0.0003) all exhibited significantly higher CIN rates, but there was no significant association between PLR and CIN risk (OR=1.12, 95% CI: 0.99–1.26, P=0.07). Conclusion: The meta-analysis reported here demonstrates that pre-angiography CRP/hs-CRP and some hematological indices are associated with CIN.

This article introduces new method using ANN to control SVC in order to correct the source power factor of low voltage network. Two ANN approaches are investigated to design accurate and fast power factor correction (PFC) controller. First approach uses simple ANN (SANNA). Second approach uses cascaded ANN (CANNA). ANN regression, performance and the calculated error for both approaches are investigated to select between the two approaches. CANNA is selected as a better solution and it used to build the ANN PFFC controller using database, generated by MATLAB-Simulink, for standard three low voltage levels (240V, 220V and 110V). Nine test cases are carried out to validate the performance of proposed ANN PFC controller with a network has variable loads and low power factor (0.6 approximately). In order to extend the use of the controller to other voltage levels not included in the training process of the cascaded ANN, only the SVC is resized. Another nine cases are carried out with the same loads using the same ANN controller, as it is, to test its performance with the extended voltage level range (415V, 230V and 120V). The results show accurate and fast response in all test cases.

Higher body weight is known to negatively impact plasma vitamin C status. However, despite this well-documented inverse association, recommendations on daily vitamin C intakes by health authorities worldwide do not include particular reference values for people of higher body weight. This suggests that people of higher body weight and people with obesity may be insufficient in vitamin C in spite of ingesting the amounts recommended by their health authorities. The current preliminary investigation sought to estimate how much additional vitamin C people with higher body weights need to consume in order to attain a comparable vitamin C status to that of a lower weight person consuming an average Western vitamin C intake. Data from two published vitamin C dose-concentration studies were used to generate the relationship: a detailed pharmacokinetic study with seven healthy non-smoking men and a multiple depletion-repletion study with 68 healthy non-smoking men of varying body weights. Our estimates suggest that an additional intake of 10 mg vitamin C/day is required for every 10 kg increase in body weight to attain a comparable plasma concentration to a 60 kg individual with a vitamin C intake of ~110 mg/day, which is the daily intake recommended by the European Food Safety Authority (EFSA). Thus, individuals weighing e.g. 80 and 90 kg will need to consume ~130 and 140 mg vitamin C/day, respectively. People with obesity will likely need even higher vitamin C intakes. As poor vitamin C status is associated with increased risk of several chronic diseases including cardiovascular disease, these findings may have important public health implications. As such, dose-finding studies are required to determine optimal vitamin C intakes for overweight and obese people.

A clear relationship between the tau assemblies and toxicity has still to be established. To correlate the tau conformation with its proteotoxic effect in vivo we developed an innovative cell-worm-based approach. HEK293 cells expressing tau P301L under a tetracycline-inducible system (HEK T-Rex) were employed to produce different tau assemblies whose proteotoxic potential was evaluated using C. elegans. Lysates from cells induced for five days, significantly reduced the worm’s locomotor activity. This toxic effect was not related to the total amount of tau produced by cells or to its phosphorylation state but was related to the formation of multimeric tau assemblies, particularly tetrameric ones. We investigated the applicability of this approach for testing compounds acting against oligomeric tau toxicity, using doxycycline (Doxy) as prototype drug. Doxy affected the tau solubility and promoted the disassembly of already formed toxic aggregates in lysates of cells induced for five days. These effects translated into a dose-dependent protective action in C. elegans. These findings confirm the validity of the combined HEK T-Rex cells and C. elegans-based approach as a platform for pharmacological screening.

Background: Macrophage inflammatory protein-1 alpha (MIP-1α) and C-reactive protein (CRP) are pro-inflammatory biomarkers that quantify clinical and subclinical inflammation in cardiac ischemia in cardiac inflammation and disease. Adiponectin is an anti-inflammatory marker associated with good health. The susceptibility of periodontitis patients to cardiovascular events needs to be evaluated. Objective: This study aims to assess the levels of biomarkers in periodontitis patients with and without acute myocardial infarction (AMI) compared to controls. Material and methods: Pro-inflammatory and anti-inflammatory analytes were examined by collecting unstimulated saliva from three groups (n = 20/each): healthy individuals, individuals with stage III periodontitis, and post-myocardial infarction patients with stage III periodontitis. The samples were collected within 48 hours of AMI. Results: Adiponectin levels were significantly lower in patients with periodontitis with and without AMI compared to controls, while CRP and MIP-1α were significantly higher in patients with periodontitis with and without AMI compared to controls. The highest titers for MIP-1α and CRP were detected among patients with periodontitis with and AMI. Conclusion: Our study provides evidence of the association between periodontitis and salivary analytes that occur in tandem with cardiovascular disease. The lower levels of Adiponectin and higher levels of CRP and MIP-1α in patients with periodontitis indicate that this condition is a potential risk factor for cardiovascular disease. The findings emphasize the importance of early detection and intervention for periodontitis patients to prevent cardiovascular events.

Reactive oxygen species and reactive nitrogen species in semen are both essential for fertilization process; however, they become harmful at excessive levels, causing oxidative stress and nitrosative stress, respectively. Recently, oxidation–reduction potential (ORP) has been used as a marker for measuring oxidative stress, and this study investigated the possibility of comprehensively evaluating nitrosative stress. The correlation between standardized ORP (sORP) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) and NOx per unit sperm was tested. Based on the previously reported cutoff value, samples were classified into oxidative stress-positive and negative groups. Thereafter, a receiver operating characteristic curve was drawn on 8-OHdG and NOx, and each optimal cutoff value was determined. Both standardized 8-OHdG and NOx significantly correlated with sORP. Although both correlated significantly with sORP in the oxidative stress group, no correlation was found in the nonoxidative stress group. The optimal standardized 8-OHdG level to determine oxidative stress status was 0.52 ng/106 spermatozoa, and the standardized NOx was 0.17 µM/106 spermatozoa/mL. The ORP is a simpler and quicker assay that can comprehensively assess oxidative and nitrosative stresses. Optimal cutoff values for both stresses were established in this study.

The treatment of the bulky Rind-based dibromosilanes, (Rind)2SiBr2 (2) [Rind = 1,1,7,7-tetra-R1-3,3,5,5-tetra-R2-s-hydrindacen-4-yl: EMind (a: R1 = Et, R2 = Me) and Eind (b: R1 = R2 = Et)], with two equivalents of tBuLi in Et2O at low temperatures resulted in the formation of blue solutions derived from the diarylsilylenes, (Rind)2Si: (3). Upon warming the solutions above −20 °C, the blue color gradually faded, accompanying the decomposition of 3 and yielding the cyclic hydrosilanes (4) via intramolecular C−H bond insertion at the Si(II) center. The molecular structures of the bulky Eind-based 3b and 4b were confirmed by X-ray crystallography. Thus, at −20 °C, blue crystals were formed (Crystal-A), which were identified as mixed crystals of 3b and 4b. Additionally, colorless crystals of 4b as a singular component were isolated (Crystal-B), whose structure was also determined by an X-ray diffraction analysis. Although the isolation of 3 was difficult due to their thermally-labile nature, their structural characteristics and electronic properties were discussed based on the experimental findings complemented by computational results. We also examined the hydrolysis of 3b to afford the silanol, (Eind)2SiH(OH) (5b).

Ready-to-eat fresh fruit have an increasing presence in international markets due to its convenience and health benefits. However, these produces are highly perishable and efficient technologies to increase their shelf life are needed. In the present research, different citrus fruit species and cultivars from organic farming were assayed to obtain enzymatically citrus segments. The best results in terms of segment quality were observed for ‘Hernandina’ clementine which was chosen to make a new ready-to-eat produce based on peeled citrus segments packaged in glass jars with slight syrup made on citrus juice and organic sugar cane. The most appreciated syrup was those containing 50-50 (v/v) of ‘Fino’ lemon juice and ‘Hernandina’ clementine based on the sensory scores given by the panellists. In addition, different pasteurization treatments were assayed to preserve the new produce safety and nutritional and sensory quality properties during storage at cold temperature. Results showed that pasteurization treatment at 50 °C for 45 min could be enough to avoid microbial contamination with mesophilic and psychrophilic aerobic bacteria or yeast and mould and to maintain sensory properties until five weeks of storage at 4 °C. In addition, only a 10 % reduction of vitamin C was observed from fresh segments or syrup until the end of storage period, showing that the new ready-to-eat produce would conserve high bioactive compound content and health benefits after pasteurization and prolonged cold storage.

Genetic, developmental, biochemical, and environmental variables interact intricately to produce sex differences. The significance of sex differences in cancer susceptibility is being clarified by numerous studies. Epidemiological research and cancer registries have revealed over the past few years that there are definite sex variations in cancer incidence, progression, and survival. However, oxidative stress and mitochondrial dysfunction also have a significant impact on the response to treatment of neoplastic diseases. Young women may be more protected from cancer than men because most of the proteins implicated in the regulation of redox state and mitochondrial function are under the control of sexual hormones. In this review, we describe how sexual hormones control the activity of antioxidant enzymes and mitochondria, as well as how they affect several neoplastic diseases. The molecular pathways that underlie the gender-related discrepancies in cancer that have been identified may be better understood, which may lead to more effective precision medicine and vital information on treatment options for both males and females with neoplastic illnesses.

We suggest a new solution to the strong CP problem. The solution is based on the proper use of the boundary conditions for the QCD generating functional integral. It obeys the principle of renormalizability of Quantum Field Theory and does not involve new particles like axions.

SiC is a material with excellent mechanical and thermal properties, but with a high production cost. Obtaining SiC by reactive infiltration is an attractive method and at a much lower cost than the traditional sintering process. However, the reactive infiltration process presents a serious problem, which is the high residual silicon content, which decreases its range of application. The replacement of silicon with silicides is a widely used alternative. The present investigation shows the good mechanical properties of the SiC/IrSi₃ composite material obtained by reactive infiltration of SiC/C preforms with Ir-Si alloys. The thermomechanical analysis shows a high compatibility of silicide with SiC. The presence of the silicide shows a substantial improvement against the oxidation of the SiC/Si composites.

This paper updates earlier thoughts by the author on a putative propulsion system. The concept was based around static electromagnetic momentum, as expounded in the “Feynman Disk” and experimentally verified by Graham and Lahoz. That said, naïve static electromagnetic momentum schemes to achieve linear translation are defeated by “hidden momentum” mechanisms, so too are simple arrangements just cycling the fields; we shall survey the flaws in their arguments. It may however be possible to achieve linear translation by means of arrangements of torques with a novel mechanism to break the symmetry of forces (or torques) on the second half of the cycle as the field is switched off. At the time of earlier presentation no mechanism could be found to explain the momentum balance for the process but it was believed that momentum was being given to the zero-point of the field. We show that it is possible to dump angular momentum and thence linear momentum to the ground state by standard quantum analysis of the EM field. None of this violates the conservation of momenergy.

Among the plant nutrients potassium (K) is one of the vital elements required for plant growth and physiology. Potassium is not only a constituent of plant structure but also plays regulatory function in several biochemical processes related to protein synthesis, carbohydrate metabolism, enzyme activation. There are several physiological processes like stomatal regulation and photosynthesis are dependent on K. In the recent decades K was found to provide abiotic stress tolerance. Under salt stress, K helps in maintaining ion homeostasis and regulation of osmotic balance. Under drought stress condition K regulates the stomatal opening and makes the plants adaptive to water deficit. Many reports provided the notion that K enhances the antioxidant defense in plants and therefore, protects the plants from oxidative stress under various environmental adversities. Also, it provides some cellular signaling alone or in association with other signaling molecules and phytohormones. Although a considerable progress in understanding K-induced abiotic stress tolerance in plants has been achieved the exact molecular mechanisms of such protections are still under research. In this review, we summarized the recent literature on the biological functions of K, its uptake, and translocation and its role in plant abiotic stress tolerance.

The current communication presents the application of a consolidated model combination strategy to analyze the medium-term carbon fluxes in two Mediterranean pine wood ecosystems. The modelling strategy is based on the use of a NDVI-driven parametric model, Modified C-Fix, and of a bio-geochemical model, BIOME-BGC, the outputs of which are combined taking into account the actual development phase of each ecosystem. The two pine ecosystems examined correspond to an old-growth forest and to a secondary succession after clearcuts, which differently respond to the same climatic condition during a ten-year period (2013-2022). Increasing dryness, in fact, exerts a fundamental role in controlling the gross primary and net ecosystem production of the mature stand, while the effect of forest regeneration is prevalent for the uprising of the same variables in the other stand. In particular, the simulated net carbon exchange fluctuates around 200 g C m-2 year-1 in the first stand and rises to over 600 g C m-2 year-1 in the second stand; correspondingly, the accumulation of new biomass is nearly undetectable in the former case while becomes notable in the latter. The study therefore supports the potential of the applied strategy for predicting the forest carbon balances consequent on diversified natural and human-induced factors.

IHepatitis C virus (HCV) has a high genetic diversity, with seven genotypes with 86 subtypes. This genetic variability confers persistence in the infection and escape of the immune system with evolution to cirrhosis and cancer. Environmental factors can contribute to different disease progression, being essential to assess the viral genotype in the infection and discuss the environmental particularities of Eastern Amazon, and the frequencies of Liver fibrosis between different HCV genotypes in patients living in a region of the Brazilian Eastern Brazilian Amazon. Consists in an observational cross-sectional study. Sociodemographic and clinical data of 76 individuals diagnosed with Hepatitis C between 2019 and 2020 in public health services were selected. Data collected was tabulated in Microsoft Excel 2010TM spreadsheets and analysed in GraphPad Prism 5.0TM. Liver fibrosis was associated with genetic subtypes. Subtype 1b was predominant (42.1%), followed by 1a (13%) and 3a (1.3%). 69.7% of participants had chronic hepatitis, with mild fibrosis (F1/F2) being the most prevalent (38.1%). Severe fibrosis was detected in 75% of individuals infected with the subtype 1b, that is associated with more severe disease. We suggest further studies, to assess other communities in the region, as well as the monitoring of these patients with Liver Elastography to determine the disease evolution and its better management.

This work demonstrates that a plasmid can function as an efficient biocatalyst in mediating the nitroaldol (Henry) reaction at high temperatures in ultrapure water. Compared with ssDNA, the plasmid displayed a remarkable catalytic efficiency (97% yield within 20 min). Aromatic aldehydes which bear strong or moderate electron-withdrawing groups reacted satisfactorily with nitromethane, which afforded the corresponding β-nitroalcohols in good yields within 2 h (up to 98%). By contrast, aliphatic and aromatic aldehydes with electron-donating groups did not react. Moreover, the yield significantly dropped when the size of the carbanion increased, and the yield was only 10% when nitropropane was used as the donor.

COVID-19 has become a severe global public health concern. The critical illness has a mortality rate of 61.5%, and thus, reducing the severity and mortality is top priority. Currently, inflammatory storms are considered as the cause of critical illness and death due to COVID-19. However, After systematical review of the literature, we proposed that cross-reactive antibodies-associated antibody-dependent enhancement (ADE) may actually be the cause of cytokine storms. If the activation of memory B cells can be selectively inhibited in high-risk patients at an early stage of COVID-19 to reduce the production of cross-reactive antibodies of the virus, we speculate that the ADE can be avoided and severe symptoms can be prevented. The mammalian target of rapamycin (mTOR) inhibitors satisfy such conditions. We recommend that pharmaceutical companies conduct clinical trials urgently.

One of the earliest hallmarks of plant immune response is production of reactive oxygen spe-cies (ROS) in different subcellular compartments, which regulate plant immunity. A suitable equilibrium, which is crucial to prevent ROS over-accumulation leading to oxidative stress, is maintained by salicylic acid (SA), a chief regulator of ROS. However, ROS are not only acting downstream of SA signaling, but were also proposed to be a central component of a self-amplifying loop that regulates SA signaling as well as the interaction balance between dif-ferent phytohormones. The exact role of this crosstalk, the position where SA interferes with ROS signaling and ROS interferes with SA signaling and the outcome of this regulation depend on the origin of ROS but also on the pathosystem. The precise spatiotemporal regulation of or-ganelle specific ROS and SA levels determine the effectiveness of pathogen arrest and is there-fore crucial for a successful immune response. However, the regulatory interplay behind still remain poorly understood, as up till now, the role of organelle specific ROS and SA in HR-conferred resistance has mostly been studied by altering the level of a single component. In order to address these aspects, a sophisticated combination of research methods for monitoring the spatiotemporal dynamics of key players and transcriptional activity in plants is needed, and will most probably consist of biosensors and precision transcriptomics.

Aims TRAIL is a promising anticancer agent that has the potential to sensitize a wide variety of cancer or transformed cells by inducing apoptosis. However, resistance to TRAIL is a growing concern. Current manuscript aimed to employing combination treatment to investigate resveratrol induced TRAIL sensitization in NSCLC. Method A549 and HCC-15 cells were used in experimental design. Cell viability was determined by morphological image, crystal violet staining and MTT assay. Apoptosis was evaluated by LDH assay, Annexin V and DAPI staining. Autophagy and apoptosis indicator protein were examined by western blotting. TEM and puncta assay were carried out to evaluate the autophagy. MTP and ROS activity were evaluated by JC-1 and H₂DCFDA staining. Findings Resveratrol is a polyphenolic compound capable of activation of tumor suppressor p53 and its pro-apoptotic modulator PUMA. Herein, we showed the p53-independent apoptosis by decrease the expression of phosphorylated Akt-mediated suppression of NF-κB that is also substantiated with the downregulation of anti-apoptotic factors Bcl-2 and Bcl-xl in NSCLC, resulting in an attenuation of TRAIL resistance in combined treatment. Furthermore, apoptosis was induced in TRAIL-resistant lung cancer cells with a co-treatment of resveratrol and TRAIL assessed by the loss of MMP, ROS generations which resulting the translocation of cytochrome c from the mitochondria into the cytosol due to mitochondrial dysfunction. Moreover, autophagy flux was not affected by resveratrol-induced TRAIL-mediated apoptosis in NSCLC. Significance Overall, targeting the NF-κB (p65) pathway via resveratrol attenuates TRAIL resistance and induces TRAIL-mediated apoptosis which could be the effective TRAIL-based cancer therapy regimen.

The catalytically inactive caspase-8-homologous protein, c-FLIP, is a potent antiapoptotic protein highly expressed in various types of cancers. c-FLIP competes with caspase-8 for binding to the adaptor protein FADD (Fas-Associated Death Domain) following Death Receptors (DRs) activation by the ligands of the TNF-R family. As a consequence, the extrinsic apoptotic signaling pathway involving DRs is inhibited. Inhibition of c-FLIP activity in tumor cells might enhance DR-mediated apoptosis and overcome immune and anticancer drug resistance. Based on an in silico approach, the aim of this work was to identify, new small inhibitory molecules able to bind selectively to c-FLIP and block its anti-apoptotic activity. Using a homology 3D model of c-FLIP, an in silico screening of 1880 compounds from the NCI database (National Cancer Institute) was performed. Nine molecules were selected for in vitro assays, based on their binding affinity to c-FLIP and their high selectivity compared to caspase-8. These compounds selectively bind to the Death Effector Domain 2 (DED2) of c-FLIP. We have tested in vitro the inhibitory effect of these 9 molecules using the human lung cancer cell line H1703 overexpressing c-FLIP. Our results showed that 6 of these newly identified compounds efficiently prevent FADD/c-FLIP interactions in a molecular pull-down assay, as well as in a DISC Immunoprecipitation assay. Overexpression of c-FLIP in H1703 prevents TRAIL-mediated apoptosis, however, combination of TRAIL with these selected molecules signifi-cantly restored TRAIL-induced cell death by rescuing caspase cleavage and activation. Altogether, our findings indicate that new inhibitory chemical compounds efficiently prevent c-FLIP recruit-ment into the DISC complex, thus restoring caspase-8 dependent apoptotic cascade. These results pave the way to design new c-FLIP inhibitory compounds that may serve as anticancer agents in tumors overexpressing c-FLIP.

The transportation system has evolved into a complex cyber-physical system with the introduction of wireless communication and the emergence of connected travelers and connected automated vehicles. Such applications create an urgent need to develop high-fidelity transportation modeling tools that capture the mutual interaction of the communication and transportation systems. This paper addresses this need by developing a high-fidelity, large-scale dynamic and integrated traffic and direct cellullar vehicle-to-vehicle and vehicle-to-infrastructure (collectively known as V2X) modeling tool. The unique contributions of this work are (1) we developed a scalable analytical communication model that captures packet movement at the millisecond level; (2) we coupled the communication and traffic simulation models in real-time to develop a fully integrated dynamic connected vehicle modeling tool; and (3) we developed scalable approaches that adjust the frequency of model coupling depending on the number of concurrent vehicles in the network. The proposed scalable modeling framework is demonstrated by running on the Los Angeles downtown network considering the morning peak hour traffic demand (145,000 vehicles), running faster than real-time on a regular personal computer (1.5 hours to run 1.86 hours of simulation time). Spatiotemporal estimates of packet delivery ratios for downtown Los Angeles are presented. This novel modeling framework provides a breakthrough in the development of urgently needed tools for large-scale testing of Direct C-V2X enabled applications.

Nickel based superalloys finds extensive usage in manufacturing of intricate part shapes in gas turbine, aircraft, submarine, and chemical industries owing their excellent mechanical property and heat resistant abilities. However, machining of such difficult-to-machine alloys up to the desired accuracy and preciseness is a complex task owing to a rapid tool wear and failure. In view of this, present work proposes an experimental investigation and optimization of process parameters of the cryogenic assisted turning process during machining of Nimonic C-263 super alloy with a multilayer CVD insert. Taguchi’s L-27 orthogonal array is used plan the experiments. Effect of input parameters viz. cutting speed (N), cutting feed (f), depth of cut (d) are studied on responses viz. surface roughness (SR), nose wear (NW) and cutting forces (F) under hybrid cryogenic (direct+indirect) machining environment. A scanning electron microscope (SEM) analysis is carried out to explore the post-machining outcomes on the performance measures. The multiple responses are converted in to single response and ranked according to Taguchi based gray relational grade (TGRG). Feed rate (f) is found to be the most influential parameter from the analysis of variance of GRG. The means of GRG for each level of process parameters are used to improve the optimal process parameters further. Finally, the confirmative experiment is performed with these optimal set of process parameters which showed an improvement of 9.34% in the value of GRG. The proposed work can be beneficial to choose ideal process conditions to enhance the performance of turning operation.

Due to the widespread application of (hetero)arylazoles, the development of straightforward functional group-tolerant synthetic methods that enable selective heteroaromatic elaboration under mild conditions aroused considerable attention. Over the last years we were interested in studies aimed to broaden the substrate scope of the direct functionalization of azoles and, in particular, to develop efficient synthetic protocols for the carbon-carbon bond forming reaction by selective palladium-catalyzed Csp2-H bond activation of imidazole derivatives. During these studies, we discovered that the outcome of the Pd-catalyzed arylation of imidazoles with aryl bromides is deeply influenced by the nature of the reaction solvent. Specifically, it is well known that the Pd-catalyzed direct arylation of imidazoles with aromatic halides selectively leads to C-5 monoarylation products when polar aprotic solvents such as DMF (or DMA) are used as a reaction medium, but these solvents are coded as dangerous according to EHS (Environmental, Health, Safety) parameters. Instead, the use of aromatic solvents as the reaction medium for direct arylations, although some of them show good EHS values, is poorly reported, probably due to their low solvent power against reagents and their potential involvement in undesired side reactions. So, with the intention of filling this gap, in this paper, we have developed a selective C-5 arylation procedure in anisole as the solvent, discovering also the unprecedented role of benzoic acid as a promoter of the coupling.

The objective of this investigation was to enhance the sensory appeal of Cerasus humilis (C. humilis) juice and ascertain potential interactions among bioactive compounds within a functional juice matrix. Sensory attributes, color, antioxidant potential, polyphenol and vitamin C (VC) concentrations, and sugar levels were assessed. Diverse dosage combinations were examined to determine their impact on the quality of both C. humilis and Green grape juices. Among the formulations, CG5 exhibited elevated antioxidant activit y and polyphenol content (455.02 mg TE/100 ml and 173.1 mg/100 ml, respectively), coupled with favorable consumer preference. Notable variations in compound content were observed across the seven analyzed juices. In the blended juices (CG1–CG5), interactions between distinct juices influenced VC and sugar levels, with other bioactives contributing to beneficial modifications, displaying a progressive rise. This study innovatively crafted delectable and convenient C. humilis juice, upholding its intrinsic high antioxidant activity, thereby presenting a novel avenue for marketable functional juice offerings.

A major limitation of near-infrared spectroscopy (NIRS) is its high sensitivity to the scalp and low sensitivity to the brain of adult humans. In the present work we use multi-distance hyperspectral NIRS (hNIRS) to investigate the optimal source-detector distances, range of wavelengths, and analysis techniques to separate cerebral responses to 30-s breath holds (BHs) from the responses in the superficial tissue layer in healthy adult humans. We observed significant responses to BHs in the scalp hemodynamics. Cerebral responses to BHs were detected in the cytochrome C oxidase redox (rCCO) at 4 cm without using data from the short-distance channel. Using the data from the 1 cm channel in the two-layer regression algorithm showed that hemodynamic and rCCO responses also occurred at 3cm. We found that the waveband 700-900 nm was optimal for the detection of cerebral responses to BHs in adults.

The α(1,2)fucosyltransferase (Se enzyme) encoded by FUT2 is involved in the secretor status of ABH(O) blood group antigens. The sedel2 allele is one of the non-functional FUT2 (se) alleles in which 9.3 kb containing the entire coding region of FUT2 is deleted by Alu-mediated nonhomologous recombination. In addition to this allele, three SNPs of FUT2, c.375A>G, c.385A>T, and c.571C>T, appear to be prevalent in certain Oceanian populations such as Polynesians. Recently, we developed an endpoint genotyping assay to determine the sedel2 zygosity, using a FAM-labeled probe for detection of the sedel2 allele and a VIC-labeled probe for detection of FUT2. In this study, instead of the VIC probe, a HEX-labeled probe covering both c.375A>G and c.385A>T and a Cy5-labeled probe covering c.571C>T were added to the sedel2 allele assay mixture to allow simultaneous detection of these four variations by endpoint genotyping for the sedel2 zygosity and fluorescence melting curve analysis for c.375A>G, c.385A>T, and c.571C>T genotyping. The results obtained from 24 Samoan subjects with this method were identical to those obtained with previous methods. Therefore, it appears that present method can accurately determine these four variations simultaneously.

Immune disorders, characterized by dysregulation at cellular and inflammatory levels, result from a complex interplay of genetics and environmental factors that lead to an abnormal immune response against autoantigens, triggering tissue damage. Recent research highlights reactive antibodies as key players in autoimmune diseases and graft rejection, but the complexity of their determination limits their use in clinic. Hence, we studied the specific binding profile of serological antibodies against a panel of cellular membranes in order to determine whether this antigenic panel could be used to diagnose specific immune disorders in humans. For this purpose, cell membrane microarrays of spleen, liver, and kidney tissues of monkey, rat, and human were developed, and human sera were analyzed, including healthy controls, patients with autoimmune disorders, and kidney transplant patients. A significant increase in antibody reactivity against specific monkey kidney and spleen membranes was observed in the serum of patients with lupus nephritis, while kidney transplant patients showed a significant enhancement against human tissues and Human embryonic kidney 293 cells. These results show the potential importance for clinical and basic research purposes of studying the presence of specific IgG against membrane antigens in the serum of patients as potential biomarkers of immune disorders.

Schizophrenia is a spectrum of neuropsychiatric deformities, characterized by hallucination, delusion, mood disorders, speech pathology, and neurocognitive deficits. Among various clinical manifestations, hallucination has been recognized as a core psychotic symptom that occurs more frequently in schizophrenia. A significant number of subjects with neurocognitive disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and other neurological diseases like stroke and epileptic seizure also experience hallucinations. While aberrant neurotransmission has been linked to the neuropathogenic events of schizophrenia, the specific cellular mechanism contributing to hallucinations remains ambiguous. Neurodegeneration in the hippocampus of the brain has been identified as a predominant pathogenic determinant of dementia. While the scientific proof for the neurodegeneration in schizophrenia is limited, the occurrence of dementia in schizophrenia has become increasingly evident. To note, both neurodegenerative, neurodevelopmental, and neuropsychiatric disorders display impaired neurogenesis in the brain. Impaired neurogenesis in the hippocampus has been linked to dementia and mood disorders. Notably, the early phase of many neurodegenerative disorders has been characterized by reactive neuroblostosis and aberrant cell cycle activation in mature neurons leading to the fluctuation in neurogenic processes leading to abnormal synaptogenesis and neurotransmission in the brain. Thus, this article emphasizes a hypothesis that aberrant neurogenic processes could be an underlying mechanism of hallucination in schizophrenia and other neurological diseases.

Activity of the Nox1 centered NADPH oxidase complex depends on the activator NoxA1 and the organizer NoxO1. NoxO1 itself is not involved in electron transfer for superoxide formation. Instead, by creating proximity of all components in the right place NoxO1 enables a constitutive formation of reactive oxygen species by that complex. All subunits should form the complex in a 1:1:1 ratio. When analyzing different cell lines in this study, we found an unequal expression of the component on mRNA level with an excess of NoxO1. Even with plasmid-based overexpression of individual components of Nox1 centered NADPH oxidase complex results in different expression of their mRNA, with NoxO1 mRNA being best expressed. Despite an unchanged high level of NoxO1 mRNA over a wide range of transfected plasmid, protein expression is increased with accelerating plasmid concentrations. We thought to analyze the ability of NoxO1 to induce ROS formation, when present in different ratio to Nox1 and NoxA1. To this end, we used Hek293 cells with constitutive expression of Nox1 and NoxA1 transfected with increasing concentrations of NoxO1. Our results suggest that ROS formation by the Nox1 centered NADPH oxidase strongly depends on the level of NoxO1 and a surplus of NoxO1 further increases the activity of the complex.

The involvement of the angiotensin II type 1 receptor in the Frank-Starling Law of the Heart, where the various activations are very limited, allows simple analysis of the kinase systems involved and thence extrapolation of the mechanism to that of angiotensin control of activation of cardiac and skeletal muscle contraction. The involvement of phosphorylation of the myosin light chain in the control of contraction is accepted but not fully understood. The involvement of troponin-I phosphorylation is also indicated but of unknown mechanism. There is no known signal for activation of myosin light chain kinase or Protein Kinase C-βII other than Ca²⁺/calmodulin but the former is constitutively active and thus has to be under control of a regulated inhibitor, the latter kinase may also be the same. Ca²⁺/calmodulin is not activated in Frank-Starling, i.e. there are no diastolic or systolic [Ca²⁺] changes. I suggest here that that the regulated inhibition is by myosin light chain phosphatase and/or β-arrestin. Angiotensin activation is by translocation of the β-arrestin from the sarcoplasm to the PM thus reducing its kinase inhibition action in the sarcoplasm, this reduced inhibition has been wrongly attributed to a mythical downstream agonist property of β-arrestin.

Sputtered reactive multilayers applied as a heat source in electronic joining processes are an emerging technology. Their use promises low-stress assembly of components while improving the thermal contact and reducing the thermal resistance. Nanostructured surface modifications can significantly enhance adhesion and reliability of joints between different materials. This work examines reactive multilayer of nickel and aluminum, directly sputtered on nanostructured black silicon surfaces and compares their phase transformation with reference samples deposited on pristine silicon surface. The investigation of the quenched self-propagating reaction reveals a clear influence of the nanostructured surface on the prolongation of the phase transition. Rapid thermal annealing tests result in the formation of Al_1.1Ni_0.9 phase. The nanostructured interface seems to hinder the full transformation of the parent material. The surface modification improves the adhesion of the formed alloy on silicon surfaces and can possibly increase the reliability of joints based on reactive aluminum/nickel multilayer. The use of black silicon, a nanostructured surface modification, is thus a promising approach to realize reliable multi-material joints in complex systems.

High-penetration of Distributed Energy Resources (DER) in low voltage distribution grids, mainly photovoltaics (PV), might lead to overvoltage in the point of common coupling. Volt-VAr is one of the common control functions for DER power converters used to enhance the stability and the reliability of the voltage in the distribution system and, thus, fulfilling the network operator requirements. In this study, a centralized algorithm will provide local Volt-VAr control parameters to each PV inverter, based on the electrical grid characteristics where each equipment is installed. Since accurate information of grid characteristics is typically not available, the parametrization of the electrical grid is done using power meter data in DER location and a voltage sensitivity matrix. The algorithm has different optimization modes to both minimize voltage deviation and line current. In order to validate the effectiveness of the algorithm and its deployment in real infrastructure, it has been tested in an experimental setup with PV emulators in a set of 5-day tests. Volt-VAr control algorithm successfully adapted its parameters based on grid topology and PV inverter characteristics, achieving a voltage reduction up to 25% of the allowed voltage deviation.

Previously, we reported that MTH1 inhibitors TH588 and TH1579 selectively induce oxidative damage and kill Ras expressing or transforming cancer cells, as compared to non-transforming immortalized or primary cells. While this explains the impressive anti-cancer properties of the compounds, the molecular mechanism remains elusive. Oncogenes induce replication stress, re-sulting in under replicated DNA and replication continuing into mitosis, where TH588 and TH1579 treatment cause toxicity and incorporation of oxidative damage. Hence, we hypothesized that oncogene-induced replication stress explains the cancer selectivity. To test this, we overex-pressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but interestingly not by nucleoside supplementation. This suggest that cancer selectivity is unrelated oncogene-induced replication stress. We conclude that the molecular toxi-cological mechanisms how TH588 and TH1579 kill c-Myc overexpressing cells have several com-ponents and involves MTH1-independent proteosomal degradation of c-Myc itself, c-Myc driven transcription and CDK activation, and is likely unrelated to oncogene-induced replication stress.

Vitamin C status is known to be associated with several demographic and lifestyle factors. These include gender, age, ethnicity, pregnancy/lactation, body weight, smoking status and dietary habits. In the present study, our aim was to interrogate the National Health and Nutrition Examination Survey (NHANES) 2017-2018 datasets to assess the impact of these factors on vitamin C dose-concentration relationships to establish if there are higher requirements for vitamin C in certain subpopulations and the possible extent of these additional requirements. The relevant data were extracted from the NHANES 2017-2018 datasets, the final cohort of which comprised 2828 non-supplementing adult males and females (aged 18 – 80+ years) with both vitamin C serum concentrations and dietary intake data available. The data was subsequently stratified by gender, age tertiles (≤36, 37-58, ≥59 years), ethnicity (non-Hispanic white, non-Hispanic black, and total Hispanic), socioeconomic tertiles (poverty income ratios: &gt;3.0, 1.36 – 3.0, ≤1.35), weight tertiles (≤72, 72-91, ≥91 kg), BMI tertiles (≤26, 26-32, ≥32 kg/m2) and smoking status. Sigmoidal (four parameter logistic) curves with asymmetrical 95% confidence intervals were fitted to the dose-concentration data. We found that males required vitamin C intakes ~1.2-fold higher than females to reach ‘adequate’ serum concentrations of 50 µmol/L. Males had both higher body weight and a higher prevalence of smoking than females. Smokers required vitamin C intakes ~2.0-fold higher than non-smokers to reach adequate vitamin C concentrations. Relative to adults in the lighter weight tertile, adults in the heaver weight tertile required ~2.0-fold higher dietary intakes of vitamin C to reach adequate serum concentrations. We did not observe any impact of ethnicity or socioeconomic status on the vitamin C dose-concentration relationship, and although no significant difference between younger and older adults was observed at vitamin C intakes &gt; 75 mg/day, at intakes &lt; 75 mg/day, older adults had an attenuated serum response to vitamin C intake. In conclusion, certain demographic and lifestyle factors, specifically gender, smoking and body weight, have a significant impact on vitamin C requirements. Overall, the data indicate that the general population must consume ~110 mg/day of vitamin C to attain adequate serum concentrations, smokers require ~165 mg/day relative to non-smokers, and heavier people (100+ kg) require ~155 mg/day to reach the same vitamin C concentrations. These findings have important implications for global vitamin C dietary recommendations.

Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the intensive care unit (ICU); mean age 68 ± 17 years, 54% male. Clinical, microbiological and haematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, a marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 ± 14 µmol/L vs 56 ± 24 µmol/L, P <0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 ± 3 µmol/L vs 24 ± 14 µmol/L, P = 0.02). The total pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls (P < 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples form 28% of the cohort (mean 2.7 ± 1.7 days; range 1-7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values (P = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Due to the important roles that vitamin C plays in the immune system, low vitamin C status is possibly both a cause and a consequence of the disease. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease oxidative stress and aid in their recovery.