The potato tuber moth PTM, Phthorimaea operculella, is one of the most economically important potato pests worldwide. In the present study, the potential of Steinernema feltiae and Steinernema carpocapsae for controlling PTM in potato tubers was evaluated compared to alpha-cypermethrin. Steinernema carpocapsae in both concentrations (12.6×10⁶IJs and 6.2×10⁶IJs) showed a lower number of emerged insects than alpha-cypermethrin (10 mg ai l^-1). Alpha-cypermethrin (20 mg ai l^-1) showed the highest efficacy against PTM (81.17%), S.carpocapsae (12.6×10⁶IJs), and alpha-cypermethrin (10 mg ai l^-1) showed similar efficacy (72.53%) while S. feltiae (6.2×10⁶IJs) showed the lowest efficacy (39.04%). The results showed that S.carpocapsae in both concentrations and S. feltiae (12.6×10⁶IJs) were efficient the same as alpha-cypermethrin (10 mg ai l^-1) having no environmental and health adverse impacts issued in the chemical insecticides usage. Both concentrations of alpha-cypermethrin and S. carpocapsae showed the least tuber damage with no significant differences, while it was as high as the control (59.26%) in both concentrations of S. feltiae. This promising finding introduces EPNs as a part of the potato tuber protection program in storage. Accordingly, EPNs can be considered as an appropriate alternative to synthetic chemicals for PTM control without any residue and health problems.

Autism Spectrum disorder (ASD) and intellectual disability (ID) are the most frequent develop-mental disorders with a prevalence between 3% and 5% of the population. In addition, both ASD and ID can be found in the same patient. Mutations in several genes involved in the epigenetic regulation of gene expression have been linked to different ID associated with ASD features including alterations of the ly-sine-acetyltransferase 6A (KAT6A) gene in KAT6A syndrome. KAT6A enzyme participates in a wide range of critical cellular functions such as chromatin remodeling, gene expression, protein synthesis, cell metabolism, and replication. In this manuscript, we examined the pathophysiolog-ical alterations in fibroblasts derived from three patients harboring KAT6A mutations. We ad-dressed survival in stress medium, histone acetylation, protein expression patterns and tran-scriptome analysis as well as cell bioenergetics. In addition, we evaluated the therapeutic effec-tiveness of epigenetic modulators and mitochondrial boosting agents such as pantothenate and L-carnitine in correcting the mutant phenotype. Pantothenate and L-carnitine treatment increased histone acetylation and corrected protein and transcriptomic expression patterns in mutant KAT6A cells. Furthermore, cell bioenergetics of mutant cells was significantly improved. Our results suggest that pantothenate and L-carnitine can significantly correct the mutant phe-notype in cellular models of KAT6A syndrome.

Rheumatoid arthritis (RA) is an autoimmune disease in which joints are gradually de-stroyed, and early diagnosis and treatment before joint deformation or destruction is im-portant. The detection of novel RA biomarkers in saliva may facilitate the early detection of RA before the onset of disease. In this study, we conducted a comprehensive proteomic analysis of salivary proteins from RA model mice. Proteins were identified by Western blotting and enzyme-linked immunosorbent assay in serum, saliva, and ankle joints from DBA/1JJmsSlc mice, a model of rheumatoid arthritis. Ankle joints and submandibular glands were hematoxylin and eosin stained and immunostained, and the results were compared with those of control mice. Citrullinated α1 antitrypsin (A1AT, 46 kDa) was commonly detected in saliva, serum, and ankle joints of severe RA model mice, and was confirmed by proteome analysis. Western blotting detected a band corresponding to 46 kDa in serum, saliva and ankle joints, and immunostaining of ankle joints with A1AT an-tibody showed a strong positive signal in the synovium. In DBA/1JJmsSlc mice, not only cyclic citrullinated peptide antibodies but also A1AT may be involved in protein citrulli-nation and contribute to the development and severity of RA.

Some α-Pyrone derivatives isolated from Alternaria phragmospora fungus showed promising anti leukemic activities, while others were inactive. CRM1/XPO1 (chromosome region maintenance 1 protein, also called exportin1 or PO1 in humans) has been chosen as a target for antileukemic molecular docking study for those compounds to understand their modes of interaction and structure activity relationships. The results showed that two (2 and 4), out of six, natural α-Pyrone derivatives exhibited well-established interactions with the amino acids of the receptor, which was in agreement with the experimental anti-leukemic results of these compounds. Moreover, twenty hypothetical chemically modified α-Pyrone derivatives (7-27) have been designed. Compounds 7, 8, 22 and 24 showed more efficient docking properties than the previously considered natural compounds.

Stabilized melanocortin analog peptide ACTH(6-9)PGP (FRWGPGP) possess a wide range of neuroprotective activities. However, its mechanism of action remains poorly understood. In this paper, we studied the pro-proliferative and cytoprotective activity of the adrenocorticotropic hormone fragment 6-9 (FRWG) linked with the peptide Prolyl-Glycyl-Proline on the SH-SY5Y cells in the model of oxidative stress-related toxicity. The peptide dose-dependently protected cells from H2O2, tert-butyl hydroperoxide, and KCN. The mechanism of its action was the modu-lation of proliferation-related (NF-kB and Nrf-2) and antioxidant-related (HO-1, Nqo1, Gclc) genes and apoptosis decrease.

During the last trimester of gestation and for the first 18 months after birth, both docosahexaenoic acid,22:6n-3 (DHA) and arachidonic acid,20:4n-6 (ARA) are preferentially deposited within the cerebral cortex at a rapid rate. Although, the structural and functional roles of DHA in brain development are well investigated, similar roles of ARA are not well documented. The mode of action of these two fatty acids and their derivatives at different structural-functional roles and their levels in the gene expression and signaling pathways of the brain have been continuously emanating. In addition to DHA, importance of ARA has been much discussed in recent years for fetal and postnatal brain development and the maternal supply of ARA and DHA. These fatty acids are also involved in various brain developmental processes; however, their mechanistic cross talks are not clearly known yet. This review describes the importance of ARA, in addition to DHA to support the optimal brain development and growth and functional roles in the brain.

Type 2 diabetes mellitus (T2D) is a metabolic disorder characterized by inappropriate insulin function. Despite wide progress in genome studies, defects in gene expression for diabetes prognosis still incompletely identified. Prolonged hyperglycemia activates NF-κB, which is a main player in vascular dysfunctions of diabetes. Activated NF-κB, triggers expression of various genes that promote inflammation and cell adhesion process. Alteration of pro-inflammatory and profibrotic gene expression contribute to the irreversible functional and structural changes in the kidney resulting in diabetic nephropathy (DN). To identify the effect of some important NF-κB related genes on mediation of DN progression, we divided our candidate genes on the basis of their function exerted in bloodstream into three categories (Proinflammatory; NF-κB, IL-1B, IL-6, TNF-α and VEGF); (Profibrotic; FN, ICAM-1, VCAM-1) and (Proliferative; MAPK-1 and EGF). We analyzed their expression profile in leukocytes of patients and explored their correlation to diabetic kidney injury features. Our data revealed the overexpression of both proinflammatory and profibrotic genes in DN group when compared to T2D group and were associated positively with each other in DN group indicating their possible role in DN progression. In DN patients, increased expression of proinflammatory genes correlated positively with glycemic control and inflammatory markers indicating their role in DN progression. Our data revealed that the persistent activation NF-κB and its related genes observed in hyperglycemia might contribute to DN progression and might be a good diagnostic and therapeutic target for DN progression. Large-scale studies are needed to evaluate the potential of these molecules to serve as disease biomarkers.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a rare and potentially life-threatening systemic drug reaction with skin involvement. We present the unusual case of DRESS in a 16-year-old male that was treated with TMP-SMX for acne and was initially misdiagnosed with Steven Johnson Syndrome. Our case serves as an example to healthcare providers treating adverse drug reactions to having a high clinical suspicion for DRESS as delay in diagnosis and treatment can result in disseminated disease and higher patient mortality risk.

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.

The cytokinins play important roles in plant growth and development by regulating gene expression at genome wide level. DNA methylation is responsive to the external environment, but whether DNA methylation changes in response to cytokinin treatment to regulate gene expression is still unclear. Here, we used bisulfite sequencing and RNA sequencing to examine genome-wide DNA methylation and gene expression patterns in poplar (Populus tomentosa) after treatment with the synthetic cytokinin 6-benzylaminopurine (6-BA). We identified 566 significantly differentially methylated regions (DMRs) in response to 6-BA treatment. Transcriptome analysis showed that 501 protein-coding genes, 262 long non-coding RNAs, and 15,793 24-nt small interfering RNAs were differentially expressed under 6-BA treatment. Among these, 79% were differentially expressed between alleles in P. tomentosa. Combined DNA methylation and gene expression analysis demonstrated that DNA methylation plays an important role in regulating allele-specific gene expression. To further investigate the relationship between these 6-BA-responsive genes and phenotypic variation, we performed SNP analysis of 507 6-BA-responsive DMRs via re-sequencing using a natural population of P. tomentosa and identified 206 SNPs that were significantly associated with growth and wood properties. Association analysis indicated that 53% of loci with allele-specific expression had primarily dominant effects on poplar traits. Our comprehensive analyses of P. tomentosa DNA methylation and the regulation of allele-specific gene expression suggest that DNA methylation is an important regulator of imbalanced expression between allelic loci.

The number of people with neurodegenerative disease continues to increase every year. A new perspective is needed in overcoming this disease. In this review, researchers collected information about epigenetics and energy factors of neurodegenerative disease driven by mitochondria. Mitochondrial epigenetic dysregulation can cause damage to the neuron system. The increase in the amount and interaction of alpha-synuclein with SAMM50 in the mitochondria is one of the factors causing neurodegenerative disease. As an energy provider in the body, the existence of harmonization in the regulation of mitochondria specifically the mitochondrial outer membrane is important. Hydrogen peroxide (H₂O₂) has neuroprotective abilities to overcome the impairment function of mitochondria in neurodegenerative patients. Based on the computational simulation of this case, it can be used as the basic concept for the development of the role of H₂O₂ in neurodegenerative disease.

Background: The prognostic value of erythrocyte levels of the n-6 fatty acids (FAs) for total mortality and cardiovascular disease (CVD) outcomes remains an open question. Methods: We examined CV outcomes and death in 2500 individuals in the Framingham Heart Study Offspring cohort without prevalent CVD (mean age 66 years, 57% women) as a function of baseline levels of different length n-6 FAs (18 carbon, 20 carbon and 22 carbon) in the erythrocyte membranes. Clinical outcomes were monitored for up to 9.5 years (median follow up, 7.26 years). Cox proportional hazards models were adjusted for a variety of demographic characteristics, clinical status and RBC n-6 and long chain n-3 FA content. Results: There were 245 CV events, 119 CHD events, 105 ischemic strokes, 58 CVD deaths, and 350 deaths from all causes. Few associations between either mortality or CVD outcomes were observed for the n-6 FAs, with those that were observed becoming non-significant after adjusting for n-3 FA levels. Conclusions: Higher circulating levels of the marine n-3 FA levels are associated with reduced risk for incident CVD and ischemic stroke and for death from CHD and all-causes, however in the same sample, little evidence exists for association with n-6 FAs. Further work is needed to identify a full profile of FAs associated with cardiovascular risk and mortality.

Additionally, the League’s four observing states, with an additional population of 1.7 billion, if join the group, will form the world’s largest consortium to enhance the accessibility of biotechnology drugs. This effort will also remove the criticism of regulatory agencies that are well-equipped to regulate these products. This should also be a significant economic incentive to consortium states to develop these products, particularly biosimilars, to capture the most critical market anticipated. This plan will also reduce the cost burden on regulatory agencies. The program is divided into two classifications; for products sold in any of the Stringent Regulatory Authority (SRA) states, the registration is automatic but with several requirements that assure ongoing pharmacovigilance; this also applies to copies of reference products or biosimilars. For non-SRA sourcing, a stepwise plan requiring a rapporteur review, as practiced by the EMA and a third-party cGMP audit, is necessary to ensure data and product integrity. However, to reduce the cost burden, approval of these products is based on current scientific findings as presented in this paper.

Research for novel vaccine adjuvants remains a critical need to improve the immune responses to a recombinant vaccine antigen. Emulsion adjuvants such as AS03 and MF59, particularly in the area of Influenza vaccines, have shown antigen dose sparing and allowed reduced immunizations. It was previously demonstrated that these emulsion adjuvants can be formulated using a simpler, low shear process of self-emulsification. The role of alpha tocopherol as an immunomodulator in emulsion adjuvants is evident from the success of AS03 in the on-going covid-19 pandemic. Although, it was a challenge to formulate alpha tocopherol with a low shear process to get closer to the AS03 composition, the self-emulsified version referred as self-emulsifying adjuvant systems (SE-AS) showed comparable immune responses to AS03 when co-administered with a Quadrivalent influenza virus (QIV) vaccine. In this paper, we first optimized the SE-AS with alpha tocopherol referred to as SE-AS44 to allow sterile filtration. We compared the in vitro cytokine profile with self-emulsifying adjuvant 160 (SEA160), a squalene-only self-emulsified adjuvant with composition similar to MF59. We compared SE-AS44 and SEA160 co-administered with a recombinant cytomegalovirus (CMV) pentamer antigen, which is a less immunogenic antigen, in vivo to compare the antibody and T-cell responses, in different adjuvanted groups, in C57BL/6 mice.

Parkinson’s disease and Alzheimer’s disease are the most commonly diagnosed neurodegenerative disorders. Though these disorders differ in terms of their underlying pathophysiology as well as in their clinical features and course, there is a certain degree of overlap between them. This overlap may be partly related to α-synuclein-mediated neuropathological changes. Recent evidence has found that depression is associated with an increased subsequent risk of both these neurological disorders, and that α-synuclein may also play a pathogenic role in depression. The current study examines epidemiological, population genetic and environmental exposure data in relation to the estimated prevalence of depressive disorders, Parkinson’s disease and Alzheimer’s disease using a cross-sectional, country-level analysis. The results of this study are consistent with a significant relationship between depressive disorders and neurodegenerative disorders, a possible shared genetic vulnerability related to functional polymorphisms of the α-synuclein gene SNCA, and potential gene-environment interactions involving fine particulate matter pollution. The significance of these results is discussed in the light of existing translational, clinical and epidemiological research on the links between these disorders.

The successive waves of the Covid-19 pandemic are driven by SARS-CoV-2 variants that reached critical detection levels in different parts of the world. But how evolved the Wuhan virus since its detection in December 2019 into the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Omicron (B.1.1.529) variants of concern? This is a story of mice and men, of up to 1,000,000 infected cells in one person, where each cell produces between 10⁵ and 10⁶ viral RNAs, of immune-compromised patients, the digestive tract and viral recombination.

We consider the inverse function $z=g(w)$ of a (normalized) starlike function $w=f(z)$ of order $\alpha$ on the unit disk of the complex plane with $0<\alpha<1.$ Krzy{\. z}, Libera and Z\l otkiewicz obtained sharp estimates of the second and the third coefficients of $g(w)$ in their 1979 paper. Prokhorov and Szynal gave sharp estimates of the fourth coefficient of $g(w)$ as a consequence of the solution to an extremal problem in 1981. We give a straightforward proof of the estimate of the fourth coefficient of $g(w)$ together with explicit forms of the extremal functions.

Background: Despite hearing aids adequately compensate for hearing loss, a substantial proportion of the population leave their hearing difficulties untreated. Even though this is a well-known clinical issue, the optimal approach to address this issue during the hearing rehabilitation process is still unclear. Purpose: The present study aims to characterise behavioural and neurophysiological auditory and cognitive processing skills in experienced hearing aid users versus those with normal hearing, aimed at providing clinicians with the evidence required to adequately manage the expectations of their clients, thus indirectly reinforcing hearing-aid adoption within the adult population with hearing loss. Research design: Behavioural tests included auditory, cognitive, and speech-in-noise tasks; and neurophysiological testing included cortical auditory evoked potentials evoked by a /da/ stimulus presented at 65 dB SPL. The tests were selected based on previous literature supporting specific speech-understanding skills. Study sample: Ten participants (7 female, 21—68 years) with bilateral, mild-moderate to moderately-severe sensorineural hearing loss (HL), and 10 with clinically normal hearing (NH, 8 female, 19—62 years) participated in the study. Data collection and analysis: Behavioural data was analysed using multivariate analysis of variance (MANOVA) and neurophysiological analysis used measurements such as independent t-test, time-frequency analysis and inter-trial phase coherence. Results: The NH and HL groups presented similar scores in all the behavioural tasks. Time-frequency analysis revealed a statistically significantly reduction in alpha (8–12 Hz) synchronisation at the centro-frontal electrodes in the HL group – a brain activity pattern that has been associated with listening effort, inhibition and selective attention. Conclusions and significance: Results support the conclusion that hearing aids are effective in compensating for the audibility of their users, enabling them to perform at similar levels than their normal-hearing peers. However, the reduced alpha synchronisation observed in the HL population indicates that adequate audibility does not extend to improved neural responses. Future studies need to investigate the induced activity in speech understanding paradigms to explore the auditory processing differences at cortical level. The results are only from a small sample size but the findings have the potential to support clinicians in managing adequately the expectations of their clients in regards the benefits of hearing aid technologies.

Genetic variations at the Apolipoprotein E (ApoE) and microtubule-associated protein tau (MAPT) loci have been implicated in multiple neurogenerative diseases, but their exact molecular mechanisms are unclear. In this study we performed transcript level linear modelling using the blood whole transcriptome data and genotypes of the 570 subjects in the Parkinson’s progression markers initiative (PPMI) cohort. ApoE, MAPT haplotypes and two SNPs at the SNCA locus (rs356181, rs3910105) were used to detect expression quantitative trait loci eQTLs associated with the transcriptome and differential usage of transcript isoforms. As a result, we identified 151 genes associated with the genotypic variations, 29 cis and 122 trans eQTL positions. Profound effect with genome-wide significance of ApoE e4 haplotype on the expression of TOMM40 transcripts was identified. This finding potentially explain in part the frequently established genetic association with the APOE e4 haplotypes in neurodegenerative diseases. Moreover, MAPT haplotypes had significant differential impact on 23 transcripts from the 17q21.31 and 17q24.1 loci. MAPT haplotypes had also the largest (256) and smallest (-178) effect sizes measured as beta values on two different transcripts from the same gene (LRRC37A2). Intronic SNP in the SNCA gene, rs3910105, differentially induces expression of three SNCA isoforms. In conclusion, this study established clear association between well-known haplotypic variance and transcript specific regulation in the blood. APOE e4 and MAPT H1/H2 haplotypic variants are associated with the expression of several genes related to the neurodegeneration.

Cytokines are a family of proteins which play a major role in the regulation of immune system, and enter the development of several diseases from rheumatoid arthritis to cancer and, more recently, COVID-19. Therefore, many efforts are currently being spent in therapy and diagnosis, producing inhibitory drugs, as well as biosensors for a rapid, poor invasive, and effective detection. In this regards, even more efficient cytokine receptors are under investigation. In this paper we analyze a set of receptors of cytokine IL-6, investigating their topological features by means of a theoretical approach. Our results suggest a topological indicator that may help in the identification of those receptors having the highest complementarity with the protein, a feature expected to ensure a stable binding. Furthermore, we propose and discuss the use of these receptors in an ideal experiment.

Recent times have witnessed an increasing number of countries and private firms pledging carbon neutrality by mid-century. Whilst representing a significant improvement in intentions to tackle climate change, such pledges lack substance and structure. For instance, individual pledges lack coordination and aggregation among peers, while strategies and measures to achieve ambitious targets are largely absent. Moreover, current disagreements obstructing progress in international climate change negotiations further undermine the reliability of carbon neutrality objectives. Effective international policies are needed to foster aggregate mitigation ambitions and the creation of adequate supporting mechanisms. This theoretical paper describes a governance innovation aimed at overcoming such shortfalls and disagreements through a unifying yet customizable pathway towards carbon neutrality. It does so by first outlining a political governance framework based on a climate club interpretation of Article 6 of the Paris Agreement. Secondly, it proposes carbon emission mitigation effort sharing on a per capita basis to ensure efficiency, equity and political feasibility. Thirdly, this paper describes how the supply of certified mitigations of carbon emissions required to satisfy effort sharing-based demand can be assetized as carbon credits by operationalizing Article 6 as a joint certification mechanism. The resulting governance architecture for managing demand and supply of mitigations shifts efforts to tackle climate change from a ‘problem-driven’ cost approach to ‘opportunity-driven’ value creation pathways towards carbon neutrality.

Epidemiologic studies suggest an inverse correlation between coffee consumption and the occurrence of neurodegenerative diseases, but the role of caffeine and roasting degree are still matter of debate. The objective of this work was to evaluate the effects of caffeinated (light, medium, and dark roast) and decaffeinated instant coffee samples in acetylcholinesterase inhibition and antioxidant assays, as well as in animal models of Parkinson’s disease. Caffeinated coffees inhibited the acetylcholinesterase in much smaller concentrations than decaffeinated coffee. All coffee samples showed antioxidant capacity without relation with the caffeine content. Dopaminergic-like activity in the haloperidol-induced catalepsy test was observed with caffeinated coffee, but not in the decaffeinated sample. The medium roast coffee reduced the number of rotations of rats after methamphetamine administration on the 6-hydroxydopamine unilateral lesion of the medial forebrain bundle. However, the coffee treatment did not avoid the loss of dopaminergic neurons on substantia nigra pars compact and only the smallest dose of coffee was able to avoid the decrease of dopamine levels in the lesioned side of the striatum. Altogether, these results suggest that coffee exerts moderate pro-cholinergic and pro-dopaminergic effects and caffeine seems to be the main responsible for these effects.

The aim of this study was to assess the key laboratory features displayed by coronavirus disease 2019 (COVID-19) inpatients which associated with mild, moderate, severe and fatal course of the disease and, through longitudinal follow-up, to understand the dynamics of COVID-19 pathophysiology. All SARS-CoV-2 positive patients admitted to the University Hospital in Motol between March and June 2020 were included in this study. Severe course of COVID-19 was associated with elevation of proinflammatory markers, efflux of immature granulocytes into peripheral blood, activation of CD8 T cells, which infiltrate lungs, and transient liver disease. In particular, the elevation of serum gamma-glutamyl transferase (GGT) and histological signs of cholestasis were highly specific for patients with severe disease. In contrast, patients with fatal course of COVID-19 failed to upregulate markers of inflammation, showed dyscoordination of immune response and progressed towards acute kidney failure. COVID-19 is a disease with multi-organ affinity characterized by activation of innate and cellular adaptive immunity. Biliary lesion with elevation of GGT and organ-infiltration of IL-6 producing cells are defining characteristic for patients with fulminant disease.

Central adiposity is one of the significant determinants of obesity-related hypertension risk, which may arise due to the abdominal fat depot's pathogenic inflammatory nature. Pro-inflammatory cytokines and adipokines up-regulation through nuclear factor-kappa B (NF-κB) activation in adipose tissue has been considered an essential function in the pathogenesis of obesity-related hypertension. This study aimed to ascertain the NF-κB inhibitor (SN50) effect on TNF-α and angiotensinogen (AGT) secretion and expression in mediating the anti-inflammatory effect through its impact on NF-κB activity in humans adipose tissue. Primary human adipocytes were isolated from 20 subjects among 10 overweight and 10 obese with and without hypertension and treated with 10ng/ml LPS in the presence and absence of NF-κB inhibitor, SN50 (50μg/ml). TNF-α secretion and NF-κB p65 activity were detected in supernatants extracted from cultured cells treated and untreated with LPS (10ng/ml) and SN50 (50μg/ml) using enzyme-linked immunosorbent assay (ELISA). The western blot technique detected the protein of NF-κB p65 and AGT. Gene expression of TNF-α and AGT was detected in cells and performed using quantitative real-time polymerase chain reaction (RT-PCR). Treatment of AbdSc adipocytes with LPS (10ng/ml) caused a significant increase in NF-κB p65 among overweight and obese subjects with and without hypertension (P= 0.001) at 24 hours incubation. In contrast, SN50-NF-κB inhibitor causes a reduction of NF-κB p65 in overweight (P= <0.001) and obese subjects with and without hypertension (P= 0.001) at 24 hours incubation. Treatment of AbdSc adipocytes with 10ng/ml LPS caused a significant increase in TNF-α secretion in overweight and obese subjects at all-time points (P= <0.001), whereas SN50 leads to a decrease in TNF-α secretion at 3 and 12 hours incubation. Treatment of AbdSc adipocytes with LPS (10ng/ml) caused increased TNF-α and AGT gene expression twofold compared with untreated cells, whereas, in the presence of SN50, it reduces mRNA AGT levels in both groups. Taken together, these adipokines with NF-κB activation may represent essential biomarkers to evaluate hypertension risk and to provide insight into the pathogenesis of obesity-related hypertension.

The mutton quality of Chinese Tan lambs (Ovis aries) has declined as feeding patterns have shifted from pasturing to pen rationing. Mutton quality is affected by fatty acids, and rumen microorganisms play a role in the synthesis of short-chain fatty acids, long-chain fatty acids, and conjugated linoleic acids. We used 16S rDNA sequencing to analyze the effects of two feeding patterns on the rumen bacteria of Tan lambs. In a randomized block design with 24 newborn Tan lambs, 12 lambs were fed by ewes in pasture and 12 were fed by pen-fed ewes. At 2 months, the biceps femoris and the longissimus dorsi were analyzed by gas chromatography for intramuscular fat content and fatty acid composition, and DNA in the rumen contents was extracted and used to analyze the structure of the bacterial community. Different feeding patterns had no significant effect on the intramuscular fat content of the biceps femoris and longissimus dorsi of the lambs, but there was a significant effect on fatty acid composition. Rumen bacteria were significantly more diverse in the pasture group than in the pen-ration group (P < 0.01). Twenty-one phyla were identified in the pasture group, and 14 phyla were identified in the pen-ration group. The dominant phyla in the pasture group were Bacteroidetes and Fibrobacteres; the dominant phyla in the pen-ration group were Proteobacteria and Bacteroidetes. The relative abundance of Proteobacteria was significantly higher in the pen-ration group than in the pasture group (P < 0.01). Diversity at the genus level was also higher in the pasture group, with 176 genera in the pasture group and 113 genera in the pen-ration group. The dominant genera in the pasture group were Prevotella_1, Rikenellaceae_RC9_gut_group, and Bacteroidales_BS11_gut_group_Na; the dominant genera in the pen-ration group were Prevotella_1, Prevotella_7, Succinivibrionaceae_UCG-001, and Succinivibrionaceae_NA.

Our understanding and theoretical interpretation of observations in astrophysics and cosmology depends on our knowledge of the fundamental constants and their possible dependence on time and space. Atomic spectroscopy and radio astronomy give important information on the validity and stability of the fundamental constants. The possible dependence of the fine structure constant alpha on time and spatial direction is an active topic of research.Period doubling is a universal property of nonlinear dynamical systems, and the doubling is exact in principle. The value of the elementary charge squared can be calculated by the period doubling process from the Planck charge and thereby the value of alpha.If ‘old’ and ‘new’ electrons are identical, then the Planck charge, i.e. a set of natural constants, has remained constant over time. In this article we show that the value of alpha calculated from the Planck charge is 0.007 % smaller than the current accepted value of alpha.

3,4-dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (S), a major component of Lewy bodies. DOPAL potently oligomerizes S, and S oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intra-neuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with S, and vice versa, are poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intra-neuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

The aim of this study was to analyze other possible new markers of severity that can be assessed in patients with type 2 diabetes and SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) infection. Our study included 90 subjects: 45 patients with type 2 diabetes mellitus and infected with the SARS-CoV-2 virus, and 45 healthy persons as control. The serum level of ceruloplasmin at hospital admission was statistically significant directly correlated with the severity of COVID-19 (Coronavirus disease) (p=0.037) and with the serum level of IL-6 (Interleukine 6) (p=0.000). Ceruloplasmin was statistically significant inversely correlated with serum iron level (p=0.000). However, we observed that ACE (Angiotensin converting enzyme) decreased in severe forms of the infection with SARS-CoV-2 virus in patients with type 2 diabetes (p=0.001). Moreover, the decrease in ACE level was correlated with an increase in IL-6 level in these patients (p=0.001). IL-6 increase was statistically significant inversely correlated with serum iron, transferrin and ACE levels. There was a noticed a decreasing tendency of the transferrin depending on the severity of the COVID-19 infection (p=0.000). In addition to the known severity factors in the context of infection with the new coronavirus, decreased concentrations of ceruloplasmin, ACE and transferrin may represent new markers of COVID-19 severity in patients with type 2 diabetes. These parameters analyzed at the hospital admission could show the evolution towards the severe forms of infection with the SARS-CoV-2 virus.

From the wide range of engineering materials traditional Stellite 6 alloy exhibits excellent cavitation erosion (CE) resistance. In this work, the effect of nitrogen ion implantation of HIPed Stellite 6 on the improvement of CE resistance and both cobalt-rich matrix phase transformation due to nitrogen implantation and CE were stated. The CE resistance of stellites ion-implanted by 120 keV N+ ions two fluences: 5x1016 cm-2 and 1x1017 cm-2 were comparatively analysed with the unimplanted stellite and AISI 304 stainless steel. CE tests were conducted according to ASTM G32 with stationary specimen method. Erosion rate curves and mean depth of erosion confirm that the nitrogen implanted HIPed Stellite 6 two times exceeds the resistance to CE than unimplanted stellite, and has almost 10 times higher CE reference than stainless steel. The X-ray diffraction (XRD) confirms that HIPed Stellite 6 nitrogen ion implantation favours transformation of the ɛ(hcp) to γ(fcc) structure. Unimplanted stellite ɛ-rich matirx is less prone to plastic deformation than γ and consequently, increase of γ phase effectively holds carbides in cobalt matrix and prevents Cr7C3 debonding. This phenomenon elongates three times the CE incubation stage, slows erosion rate and mitigates the material loss. Metastable γ structure formed by ion implantation consumes the cavitation load for work-hardening and γ → ɛ martensitic transformation. In further CE stages, phases transform as for unimplanted alloy namely, the cavitation-inducted recovery process, removal of strain, dislocations resulting in increase of fcc phase. The CE mechanism was investigated using a surface profilometer, atomic force microscopy, SEM-EDS and XRD. HIPed Stellite 6 wear behaviour relies on the plastic deformation of cobalt matrix, starting at Cr7C3/matrix interfaces. Once the Cr7C3 losing their restrain, are debonding and removed. Carbides detachment creates cavitation pits which initiate cracks propagation through cobalt matrix, the loss of matrix phase and CE proceeds with a detachment of massive chunk of materials.

Background: Body dysmorphic disorder (BDD) is a psychiatric disorder characterized by excessive preoccupation with imagined defects in appearance. Optical illusions induce illusory effects that distort the presented stimulus thus leading to ambiguous percepts. Using electroencephalography (EEG), we investigated whether BDD is related to differentiated perception during illusory percepts. Methods: 18 BDD patients and 18 controls were presented with 39 optical illusions together with a statement testing whether or not they perceived the illusion. After a delay period, they were prompted to answer whether the statement is right/wrong and their degree of confidence for their answer. We investigated differences of BDD on task performance and self-reported confidence and analysed the brain oscillations during decision-making using nonparametric cluster statistics. Results: Behaviorally, the BDD group exhibited reduced confidence when responding incorrectly, potentially attributed to higher levels of doubt. Electrophysiologically, the BDD group showed significantly reduced alpha power at mid-central scalp areas, suggesting impaired allocation of attention. Interestingly, the lower the alpha power of the identified cluster, the higher the BDD severity, as assessed by BDD psychometrics. Conclusions: Results evidenced that alpha power during illusory processing might serve as a quantitative EEG biomarker of BDD, potentially associated with reduced inhibition of task-irrelevant areas.

Background: Acute intermittent porphyria (AIP) is caused by haploinsufficiency of porphobilin-ogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting and altera-tions in glucose metabolism, insulin resistance and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin-mimic, the α-lipoic acid (α-LA) as a potential therapeutic strategy. Methods: HepG2 cells were transfected with a siRNA targeting PBGD (siPBGD). Cells were cul-tured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glu-cose. Results: At baseline, siPBGD cells showed lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced gly-colysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mito-chondrial separation. Consistently, siPBGD cells in fasted state showed the lowest protein levels of Complex IV which belong to the oxidative phosphorylation (OXPHOS) machinery. α-LA up-regulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dys-functions in siPBGD hepatocytes. Keywords: AIP, PBGD, glucose metabolism, mitobiogenesis, α-lipoic acid

Excessive neutrophil influx and activation in lungs during infections, such as manifest during the ongoing SARS CoV-2 pandemic, have brought neutrophil extracellular traps (NETs) and the con-comitant release of granule contents that damage surrounding tissues into sharp focus. Neutro-phil proteases, which are known to participate in NET release, also enable the binding of the viral spike protein to cellular receptors and assist in the spread of infection. Blood and tissue fluids normally also contain liver-derived protease inhibitors that balance the activity of proteases. In-terestingly, neutrophils themselves also express the protease inhibitor alpha-1-antitrypsin (AAT), the product of the SERPINA-1 gene, and store it in neutrophil cytoplasmic granules. The absence of AAT or mutations in the SERPINA-1 gene promote lung remodeling and fibrosis in diseases such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and increase the risk of allergic responses. Recent observations point to the fact that re-duced activity of AAT presents a major susceptibility factor for severe COVID-19. Here, we focus attention on the mechanism of neutrophil elastase (NE) in NET release and its inhibition by AAT as an additional factor that may determine the severity of COVID-19

Human adipose stem cell-derived extracellular vesicles (hASC-EVs) are key mediators of paracrine signaling with promising therapeutic applications. Although hASC-EVs are derived from human cells and are less immunogenic, their immunogenicity cannot be completely excluded. Here, we evaluate the immune responses of ICR and C57BL/6 mice to high doses of hASC-EVs for 10 days after injection. Lymphocyte subpopulations are analyzed using flow cytometry at 0.5, 1, 3 and 24 h post injection. In the spleen and blood of C57BL/6 mice, neutrophils sharply increased at 0.5 h and decreased at 3 h following hASC-EV treatment. We observe increased proportions of monocytes, macrophages, and natural killer cells at 3 h but returned to similar level of vehicle control at 24 h post injection in the spleen and blood of ICR mice. Although the in vivo experiments reveal different immune responses to hASC-EV treatment in C57BL/6 and ICR strains, no major changes occur in human peripheral blood mononuclear cell composition after applying hASC-EVs in vitro. In conclusion, unlike those in mice, immune responses to hASC-EVs in humans are not detectable, indicating a minimal risk of fatal side-effects from hASC-EV-based therapies.

Photothrombotic stroke (PTS) stimulates the level of N- and C-terminal fragments of Amyloid precursor protein (APP) growth in the cytoplasm of ischemic penumbra cells not earlier but at 24 hours. Here we have shown that APP fragments are visualized in thin unmyelinated fibers of neurons, in containing mitochondria large fibers and in synapses but absent in the nuclei. At 24 hours after PTS, some elements of the destroyed tissue accumulated a significant amount of APP protein. The level of ADAM10 α-secretase decreased on the first day after PTS in the rat brain cortex and ADAM-10 co-localized with the lipid raft marker caveolin-1. PTS caused no changes in the level of β-secretase BACE1 either on the first day after PTS or in the early recovery period. The expression of proteins of the γ-secretase complex: presenilin-1 and nicastrin increased in astrocytes, but not in penumbra neurons after PTS. The β-secretase inhibitor LY2886721 did not affect the infarct size of the mouse cerebral cortex and the level of apoptosis of cells in the perifocal region after PTS. Whereas the inhibitor of γ-secretase DAPT reduced the expression of glial fibrillary acidic protein (GFAP) in astrocytes, prevented the growth of apoptosis of mouse cerebral cortex cells reducing the infarct volume on the 7th and 14th days after PTS. DAPT may be considered as a drug for stroke therapy.

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.

The dermatological manifestations of Long Covid (LC) have languished in the shadows of chronic fatigue and brain fog. Yet they are all linked by gut dysbiosis and the cytokine triad of TNF-α, IL-1β, and IL-6. The gut microbiome common not only to LC, psoriasis, AA, and vitiligo but also to neurodegenerative disease has been recently described. This gut microbiome induces an altered tryptophan metabolism linked to autoimmune disease. SARS CoV2 invades enterochromaffin cells rich in ACE2 receptors and curtails absorption of the essential amino acid tryptophan and subsequent synthesis of serotonin and melatonin. This review suggests that an etiologic prebiotic (d-mannose)/probiotic (lactobacilli, bifidobacteria)/postbiotic (butyrate) approach to autoimmune skin disease that improves intestinal barrier integrity and that suppresses the triad of TNF-α, IL-6, and IL-1β may enhance or even eliminate the traditional immunotherapy of targeted monoclonal antibodies, Janus kinase inhibitors, and steroids. Health benefits of this approach extend well beyond suppression of autoimmune skin disease.

Background: Phylogroup B2 Escherichia coli have been associated with Ulcerative Colitis (UC). In this study, we aimed to compare colonization with the UC-associated E. coli p19A in different mice strains, to investigate the role of alpha hemolysin in a UC mouse model. Methods: In this study, Sigirr -/- and C57BL/6 mice were chosen, and UC was induced by adding Dextran Sulfate Sodium (DSS) to the drinking water. The mice were pre-treated with ciprofloxacin. p19A expressing luminescence and GFP, alpha-hemolysin knock out p19A-∆hlyI II, and non-pathogenic lab E. coli DH10B were cultured in LB broth, and orally gavaged into the mice. Colonization with p19A WT was visualized using an in-vivo imaging system. Results: p19A WT colonized the colon, ileum, Peyer’s patches, liver, and spleen of infected C57BL/6 and Sigirr -/- mice. A total of 99% of the p19A WT infected C57BL/6 mice and 29% of the p19A WT infected Sigirr -/- mice survived to the 4th post infection day. Conclusion: UC-associated E. coli p19A WT colonized the intestines of DSS-treated mice and caused extra-intestinal infection. Hemolysin is an important factor in this pathogenesis, since isogenic hemolysin mutants did not cause the same inflammation.

We are all similar, but a bit different. These differences are partially due to variations in our genomes and are related to the heterogeneity of symptoms and responses to treatments that patients exhibit. Most animal studies are performed in one single strain with one manipulation. However, due to the lack of variability, therapies are not always reproducible when treatments are translated to humans. Panels of already sequenced organisms are valuable tools for mimicking human phenotypic heterogeneities and gene mapping. This review summarizes the current knowledge of mouse, fly and yeast panels with insightful applications for translational research.

Recent studies have been able to detect α-synuclein (αSyn) seeding in formaldehyde-fixed paraffin-embedded (FFPE) tissues from patients with synucleinopathies using seed amplification assays (SAAs), but with relatively low sensitivity due to limited protein extraction efficiency. With the aim of introducing an alternative option to frozen tissues, we developed a streamlined protein extraction protocol for evaluating disease-specific seeding in FFPE human brain. We evaluated the protein extraction efficiency of different tissue preparations, deparaffinizations, and protein extraction buffers using formaldehyde-fixed and FFPE tissue of a single Lewy body disease (LBD) subject. Alternatively, we incorporated heat-induced antigen-retrieval and dissociation using a commercially available kit. Our novel protein extraction protocol has been optimized to work with 10 sections of 4.5-µm-thickness or 2-mm-diameter micro-punch of FFPE tissue that can be used to seed SAAs. We demonstrated that extracted proteins from FFPE still preserve seeding potential and further show disease-specific seeding in LBD and multiple system atrophy. To the best of our knowledge, our study is the first to recapitulate disease-specific αSyn seeding behavior in FFPE human brain, with structural validation. Our findings open new perspectives in re-evaluating archived human brain tissue, extending the disease-specific seeding assays to larger cohorts to facilitate molecular subtyping of synucleinopathies.

This study aimed to use remote sensing and GIS to detect changes in surface water and wetlands in the Kumasi Metropolis over a period of 20 years (2002-2022). Landsat images were processed using the QGIS software, and the Maximum Likelihood Algorithm was used to perform supervised classification of land use land cover, while raster calculator aided in detecting wetlands by calculation for NDWI, MNDWI, and AWEI. The results showed that the majority of the landscape in the Kumasi metropolis was made up of built-up areas (79.4%), followed by agricultural lands (13.3%) and wetlands (7.3%). Over the 20-year period, built-up areas had gained 20.7% of the total landscape, while agricultural lands and wetlands had lost 16.7% and 4.0%, respectively. All water index methods recorded an increase in non-water cover and a loss of water cover over the period, with surface water decreasing by 5% and non-water land cover increasing by 5%. The study concludes that there have been significant changes in wetlands and surface water land use and land cover within the Kumasi Metropolis over the past 20 years, and recommends the enforcement of legislation on surface water protection in the area to protect wetlands

We investigate new graph characteristics namely total (vertex, edge) face irregularity strength of gen- eralized plane grid graphs Gmn under k-labeling Phi of type (Alpha, Beta, Gamma). The minimum integer k for which a vertex-edge labelled graph has distinct face weights is called the total face irregularity strength of the graph and is denoted by tfs(Gmn). In this article, the graphs G = (V;E; F) under consideration are simple, finite, undirected and planar. We will estimate the exact tight lower bounds for the total face irregularity strength of some families of generalized plane grid graphs.

Background: Diabetic patients are more likely to experience morbidity and mortality as a result of microvascular complications such as retinopathy, neuropathy, nephropathy, and stroke. There are many synthetic anti-diabetic agents available which are expensive and have undesirable pathological effects. Thus, it is essential to look for cost-effective, natural, and safe antidiabetic agents. The aim of this study was to screen phytoconstituent and evaluate the in-vitro and in-silico α-amylase inhibitory activity of ethanolic extract of Adhatoda vasica leaves. Method: The extraction of Adhatoda vasica leaves was performed with ethanol through Soxhlet extraction process. Different concentrations (0.1 mg/ml to 1 mg/ml) of ethanolic extract, Acarbose, and Sitagliptin, were prepared and all concentrations were evaluated for α-amylase inhibitory activity through the spectrophotometric method. Molecular docking (AutodockVina 1.2.0) and toxicity profiling (SToPToX web server) studies were performed. Results: The plant extract showed highest inhibition of α-amylase (56.763±0.0035) at a concentration of 1 mg/ml. This inhibitory activity was supported by the in-silico study. Vasicoline (C5) and quercetin (C9), active constitute of plant Adhatoda vasica, showed the best binding energy of 8.3 and 8.0 Kcal/mol respectively with α-amylase enzyme (PDBID: 4W93). Toxicity study revealed the safety profile of plant extract. Conclusion: It was concluded that Adhatoda vasica leaves possess some bioactive compounds which are responsible for controlling blood glucose levels and its identification, purification, and isolation may lead to the development of newer therapeutic agent with lesser side effects.

Leishmanial skin lesions are characterized by inflammatory hypoxia alongside the activation of hypoxia inducible factors, HIF-1a and HIF-2a, and subsequent expression of the HIF-a target VEGF-A during Leishmania major infection. However, the factors responsible for HIF-a activation are not known. We hypothesize hypoxia and pro-inflammatory stimuli contribute to HIF-a activation during infection. RNASeq on leishmanial lesions found transcripts associated with HIF-1a signaling are induced. To determine whether hypoxia contributes to HIF-a activation, we followed the fate of myeloid cells infiltrating from the blood and into hypoxic lesions. Recruited myeloid cells experience hypoxia when they enter inflamed lesions, and the length of time in lesions increases their hypoxic signature. To determine whether pro-inflammatory stimuli in the inflamed tissue can also influence HIF-a activation, we subjected macrophages to various pro-inflammatory stimuli and measured VEGF-A. While parasites alone did not induce VEGF-A, and pro-inflammatory stimuli only modestly induce VEGF-A, HIF- stabilization increases VEGF-A during infection. HIF-a stabilization does not impact parasite entry, growth or killing. Alternatively, the absence of ARNT/HIF- signaling enhances parasite internalization. Altogether, these findings suggest HIF-a is active during infection, and while macrophage HIF-a activation promotes lymphatic remodeling through VEGF-A production, HIF-a activation does not impact parasite internalization or control.

ORF7b-2 is an accessory protein of the SARS-CoV-2 virus of only 43 amino acids. It has been implicated in various functional hypotheses, some of which predict its involvement as a trans-membrane protein. In this study, ORF7b-2 has often been compared to ORF7b-1 of the SARS virus to highlight differences and similarities with a protein that should have a similar biological role. Structural analysis of ORF7b-2 and its electrostatic characteristics show a polypeptide with both ends negatively charged and a diffuse negative charge over the entire structure. Therefore, its behavior in solution is like that of a weak negative polyelectrolyte, more precisely a polyanion with a net charge of – 4 at neutral pH. Its structure was modeled with two different modeling systems, one of which was ab initio. The two best models are similar, as confirmed by the Ramachandran plot, and show a central alpha-helical structure with two disordered and mobile ends. A normal mode analysis characterized the low-frequency dynamic aspects of the protein. The analysis of the structural shows a rigid central segment with mobile and fluctuating extremities, involved in a conformational equilibrium of the helix ↔ coil type. The calculation of the dipole moment shows its vector is not aligned with the main axis of the structure with an outward tilt of 24°. Molecular dynamics simulations were also conducted and the one in water is in good agreement with the previous results. While, the simulation performed by inserting a pre-oriented dimer (OMP) into a solvated lipid showed the low tendency of the protein to solvate in the apolar environment of the membrane. ORF7b-2 also shows a widespread distribution of negative surfaces that dynamically adjust to changes in structural organization. The BioGrid platform's [Biological General Repository for Interaction Datasets] through the BioGrid COVID-19 Coronavirus Curation Project shows a very large number of experimentally proven physical interactions unique to ORF7b-2, some of them with cytoplasmic proteins. These features of ORF7b-2, evaluated together, suggest a remarkable propensity of ORF7b-2 to interact with multiple molecular partners on both an electrostatic and hydrophobic basis. All this makes it unreasonable that the only biological function of this protein should be that exerted as an intramembrane protein.

A particular challenge in the conceptual design of direct-from orbit delivery systems is the seemingly well-known kinematics retain fallacies whose efficacies are reduced over great distances. Rotation about the local wing of an aerospace vehicle is almost never the pitch angle, yet modern application of kinematics often assumes such (with accompanying angular error). The same assertion is usually true about the nature of roll and yaw angles. Expressing motion in coordinates of rotating reference frames necessitates transformation between reference frames, and one such transformation is embodied in the Direction Cosine Matrices (DCM) formed by a sequence of three successive frame rotations. One of two ubiquitous sequences of three rotations used to construct the DCM involves first a rotation around the inertial z-axis, then intermediate y-axis, then finally about the body’s x-axis; a sequence commonly called the “aerospace sequence” or the a “3-2-1 rotation sequence”. The second ubiquitous sequence is the so-called “orbital sequence” or “3-1-3 rotation sequence” with rotations about the inertial z axis first, then about the intermediate x-axis, then finally about the body z-axis. This manuscript evaluates which sequence is the most advantageous for an object starting in space and then travels through the atmosphere to a target on the Earth’s surface. Six degrees of freedom of vehicle motion were simulated starting in orbit with a given thrust and commanded maneuver. The simulation performs all twelve possible rotation sequences (transforming inertial coordinates to body coordinates) with comparison by computational burden and error representing rotations about body axes (roll, pitch, and yaw respectively). Simulation precision is validated using the quaternion normalization condition indicating near machine precision (0.9\times{10}^{-15}) and reveals the so-called 132 rotation is the most accurate with an average error of 0.14° and a computational time of 0.013 seconds: resulting in a 97.95% increase in accuracy over the so-called 321 rotation and a 99.84% increase over the so-called 313 rotation.

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.

Although many policosanols from different sources, such as sugar cane, rice bran, and insects, have been marketed worldwide, there has been no comparative study of the in vivo efficacy using a hyperlipidemic animal model. This study compared the efficacy of treating dyslipidemia with four different policosanols, including one sugar cane wax alcohol from Cuba (Raydel®) and three policosanols from China (Xi’an Natural sugar cane, Xi’an Realin sugar cane, and Shaanxi rice bran) in hyperlipidemic zebrafish. After 12 weeks of consumption of each policosanol (final 0.1% in diet, wt/wt) and high cholesterol diet (HCD, final 4%, wt/wt) in a tetrabit, the Raydel policosanol group and Xi’an Natural policosanol group showed the highest survivability of approximately 81%, whereas the Xi’an Realin policosanol group and Shaanxi policosanol group showed 57% and 67% survivability, respectively. Among five HCD groups, the Raydel policosanol group showed the lowest serum total cholesterol (TC, p<0.001 versus HCD control) and triglyceride (TG, p<0.001 versus HCD control) with the highest percentage of high-density lipoproteins (HDL)-C in TC. The Raydel policosanol group also showed the lowest serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels with the least infiltration of inflammatory cells and interleukin-6 production in hepatocytes. In the ovary, the Raydel policosanol group also showed the highest contents of mature vitellogenic oocytes with the lowest production of reactive oxygen species and cellular apoptosis in ovarian cells. In the testis, the Raydel policosanol group also showed the healthiest morphology for spermatogenesis with the least interstitial area and reactive oxygen species (ROS) production in testicular cells. In conclusion, 12 weeks of Raydel policosanol consumption resulted in remarkable improvement of the blood lipid profile, amelioration of inflammation in the liver, and enhancement of the cell morphology in the ovary and testis with the highest survivability under the HCD.

With the increase in life expectancy and consequent aging of the world’s population, the prevalence of many neurodegenerative diseases is increasing, without concomitant improvement in diagnostics and therapeutics. These diseases share neuropathological hallmarks, including mitochondrial dysfunction. In fact, as mitochondrial alterations appear prior to neuronal cell death at an early phase of the disease onset, the study and modulation of mitochondrial alterations rise as promising strategies to predict and prevent neurotoxicity and neuronal cell death before the onset of cell viability alterations. In this work, differentiated SH-SY5Y cells were treated with the mitochondrial-targeted neurotoxicants 6-hydroxydopamine and rotenone. These compounds were used at different concentrations and for different time points to understand the similarities and differences in their mechanisms of action. To accomplishing this, data on mitochondrial parameters was acquired and analyzed using unsupervised (hierarchical clustering) and supervised (decision tree) machine learning methods. Both biochemical and computational analyses resulted in an evident distinction between the neurotoxic effects of 6-hydroxydopamine and rotenone, specifically for the highest concentrations of both compounds.

The crystals, C11H4BrF5N2S, (I), 1-((4-bromothiophen-2-yl)methylene)-2-(perfluorophenyl)hydrazine and C12H6BrF5N2S, (II), 1-((4-bromo-5-methylthiophen-2-yl)methylene)-2-(perfluorophenyl)hydrazine are molecules with two rings and hydrazone part like a centre of the molecule. The compounds have been synthesized and characterized by elemental, spectroscopic (¹H-NMR) analysis. The crystal structures of the solid phase were determined by single crystal X-ray diffraction method. They crystallize in the monoclinic space group with Z = 4 and Z = 2 molecules per unit-cell. The compound (I) crystallizes as a racemate in the centrosymmetric space group and the compound (II) crystallizes as a non-racemate in the non-centrosymmetric space group. The “absolute configuration and conformation for bond values” were derived from the anomalous dispersion (ad) for (II). The crystal structures are revealed diverse non-covalent interactions such as intra- and interhydrogen bonding, π-ring···π-ring, C-H···π-ring and they were investigated. The expected stereochemistry of hydrazones atoms C7, N2 and N1 were confirmed for (I) and (II). The hole molecule of the (I), and (II) possesses “a boat conformation” like a 6-membered ring. The results of the single crystal studies are reproduced with the help of Hirshfeld surface study and Gaussian software.

Background: Osteoarthritis is the most common degenerative joint disease resulting in pain and altered joint function. Objective: We investigated the possible association between serum interleukin-6 and symptoms of knee osteoarthritis with regard to pain, stiffness, physical function, assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). We also examined the connections between serum interleukin-6 and radiographic severity in primary knee osteoarthritis patients. Methods: In this case-control study, fifty primary knee osteoarthritis patients and fifty age and sex matched controls were randomly recruited. Serum interleukin-6 levels were immunoassayed in patients’ and controls’ serum. Patients’ knee pain, stiffness and physical function were assessed by the respective subscales of the WOMAC Index. Standing anteroposterior radiographs of the knee joint were performed and graded with the Kellegren-Lawrence grade. Results: The mean serum IL-6 level was significantly higher in osteoarthritis patients (110.22 ± 46.98pg/ml) than controls (46.04 ± 12.34 pg/ml) (p=0.001). The WOMAC Index in patients ranged from 0 – 95 and the Kellegren-Lawrence score mean was 2.7 ± 0.76. There was a significant correlation between serum IL-6 levels and pain (r=0.595 p=0.001), physical function score (r=0.666, p=0.001)), and the radiographic score (r=0.799, p=0.001). Regression analysis showed that IL-6 level had a greater impact on both the WOMAC Index (p=0.005) and the Kellegren-Lawrence score (p=0.01). Conclusion: Serum IL-6 level is increased in primary knee osteoarthritis patients. Also, serum interlukin-6 is significantly related to osteoarthritis symptoms and radiographic severity.

Footprints are powerful indicators for evaluating the impact of the bioeconomy of a country on environmental goods, domestically and abroad. In this study, we apply a hybrid approach combining a Multi-Regional Input-Output model and land use modelling to compute the agricultural land footprint (aLF). Furthermore, we added information on land-use change to the analysis and allocated land conversion to specific commodities. The German case study shows that the aLF abroad is larger by a factor of 2.5 to 3 than the aLF in Germany. In 2005 and 2010, conversion of natural and semi-natural land-cover types abroad allocated to Germany due to import increases was 2.5 times higher than the global average. Import increases to Germany slowed down in 2015 and 2020, reducing land conversion attributed to the German bioeconomy to the global average. The case study shows that the applied land footprint provides clear and meaningful information for policymakers and other stakeholders. The presented methodological approach can be applied to other countries and regions covered in the underlying database EXIOBASE. It can be adapted, also for an assessment of other ecosystem functions, such as water or soil fertility.

The interleukin 6 (IL-6) receptor blocking antibody tocilizumab was repurposed in the coronavirus pandemic with the intention of blocking the excess inflammatory activation associated with severe disease. We retrospectively evaluated the response to tocilizumab based on measured levels of IL-6 as well as other inflammatory markers. In the sample of 41 patients with measured levels, 16 received tocilizumab. In patients who received tocilizumab, there was a statistically significant relationship between both higher IL-6 levels and measured acute phase reactants with mortality, but not in those who did not. Additionally, an improved mortality after tocilizumab was suggested with those with higher IL-6 measurements, but not in those with lower levels, but this finding failed to achieve statistical significance (p=0.14). Though this study is limited by a small sample size and retrospective design, an association is suggested between higher IL-6 levels and improved mortality after tocilizumab.

High dietary phosphate intake and poor adherence to phosphate-binding-therapy elevate the risk of hyperphosphatemia in maintenance hemodialysis (HD; MHD) patients. Therefore, chronic kidney disease-related mineral and bone disorder (CKD-MBD) indicators increase; consequently, risks of CKD-MBDs and inflammation are elevated. This double-blind, randomized control trial intervention study was designed to investigate the possibility of reducing blood CKD-MBD indicators and modulating inflammatory indicators by consuming low-phosphate (LP) meals accompanied by a minimum dose of a calcium-based phosphate binder (CaCO3). MHD patients were recruited and randomly assigned to an LP meal group (LP group) or a control group. After initial data collection, blood collection, and dietary counseling, subjects were asked to consume a washout diet for 1 week. During the washout diet period, subjects consumed their usual diet but took 1 tablet of calcium carbonate (1CaCO3) as a phosphate binder with each meal. After the washout diet period, subjects in the LP group and control group respectively consumed LP meals and regular meals twice a day for 1 week. Meat in the LP meals was boiled before the regular cooking process, but meat in control meals was not. All meals were supplied by a central kitchen so that the contents of phosphate and other nutrients could be identified. In total, 40 MHD patients completed the study program. After 1 week of the dietary intervention, the blood Ca x P product and dietary phosphate had significantly decreased in the LP group compared to the control group (p&lt;0.05). The LP group had significantly lower variations in dietary phosphate intake, blood calcium, Ca x P product, and tumor necrosis factor (TNF)-α than the control group by comparing differences between after the dietary intervention and the baseline (△after intervention - baseline, p&lt;0.05). The increase in dietary phosphate intake (△3rd - 2nd dietary phosphate intake) augmented the increase in the TNF-α level by 6.24-fold (odds ratio [95% confidence interval]: 6.24 [1.12~34.92], p&lt;0.05). These results highlighted the conclusion that LP meals accompanied by a minimum dose of CaCO3 downregulated pro-inflammation by reducing CKD-MBD indicators which was triggered by decreasing dietary phosphate intake.

Aggregated alpha-synuclein (-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of -synuclein exist, including phosphorylated and nitrated forms. It is unclear which -synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three -synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 -synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 -synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 -synuclein in MSA. Quantification of the LB scores revealed that pS129 -synuclein was the dominant and earliest -synuclein PTM followed by nY39 -synuclein, while lower amounts of pSer87 -synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.

Background: Newer personalized medicine including targeted therapies such as PARP inhibitors and CDK 4/6 inhibitors have shown to improve survival of breast and gynaecological cancer patients. However, efficacy outcomes may be hampered by treatment discontinuation due to targeted therapy-related adverse drug reactions or resistance. Studies suggest that add-on mistletoe (Viscum album L., VA) improves quality of life and ameliorates cytotoxic side effects of standard oncological therapy in cancer patients. The primary objective of this real-world data study was to determine the safety profile of targeted therapy in combination with add-on Helixor® VA therapy in breast and gynecological cancer patients. Methods: The present study is a real-world data study utilizing demographic and treatment data from the accredited national Network Oncology (NO) registry. The study has received ethics approval. The safety profile of targeted with or without Helixor® VA therapy as well as safety - associated variables were evaluated by univariate and adjusted multivariable regression analyses. Results: All stage breast or gynecological cancer patients (n = 242) were on average 54.5±14.2 years old. One hundred and sixty patients (66.1%) were in the control (CTRL, targeted therapy) and 82 patients (33.9%) in the combinational (COMB, targeted plus Helixor® VA therapy) group. The addition of Helixor® VA did not hamper the safety profile (χ2 = 0.107, p-value = 0.99) of targeted therapy. Furthermore, no adverse events and a trend towards an improved targeted therapy adherence were observed in the COMB group. Conclusions: The present study is the first of its kind showing the applicability of Helixor® VA in combination with targeted therapies. The results indicate that add-on Helixor® VA does not negatively alter the safety profile of targeted therapies in breast and gynaecological cancer patients.

As a result of scientific technological advancements in medical diagnostics, treatment modalities of non-communicable and communicable diseases, and palliative care approaches, the life expectancy of women is soaring than men across the globe, due to the longer telomere length and other protective factors. The main symptoms of menopause broadly be divided into psychological somatovegetative and urogenital. Neglected menopausal symptoms can lead to debilitating comorbidities which may end up in mortalities. Fortunately, modern treatment and therapeutic formalities based on pharmaceutical preparations, as well as lifestyle- modifications have provided long-lasting relief for the pre-menopausal woman. This can be done as per her preference if she is knowledgeable, resourceful, and cheerful. Menarchae is the “ alpha” and menopause is the “omega” phase in the reproductive lifecycle of any woman. Reproductive health is essentially an integral part of women’s health. In this 4^th industial revolution era information technology and digital science go hand in hand to improve the quality of life of populations across the globe irrespective of their educational and professional status. Health literacy among disadvantageous sub populations increased. Positive attitudes, perception and evidence-informed knowledge on adolesecent girls about not only ‘period pains’ but menopausal symptoms as an inevitable phase in a woman’s reproductive health may make a better sense at the dawn of evidence based medicine even in a low middle income country like Sri Lanka. Hence, this timely communication strengthens by, Do not fear when menopause is near: The Importance of a Preparatory Time and Space to face the consequences of Menopaus. How to forget the fact that alpha and the omega are inevitable phases in woman’s reproductive health trajectory. Moreover, the importance of a preparatory time and space well in advance preferably in peri-menopausal time to prevent and control the inevitable health consequences. Moreover, to invest in menopause for a brighter future in the modern personalized medicine era based on global scientific evidence.

Several studies suggest that children infected with SARS-CoV-2 have fewer clinical manifestations than adults; when they develop symptoms, they rarely progress to severe disease. Different immunological theories have been proposed to explain this phenomenon. In September 2020, 16% of the active COVID-19 cases in Venezuela were children under 19 years. We conducted a cross-sectional study of pediatric patients' immune response and clinical conditions with SARS-CoV-2 infection. The patients were admitted to the COVID-19 area of the emergency department of Dr José Manuel de los Ríos Children's Hospital (2021-2022). The lymphocyte subpopulations were analysed by flow cytometry, and IFNγ, IL-6 and IL-10 serum concentrations were quantified using commercial ELISA assays. The analysis was conducted on 72 patients aged one month and 18 years. The majority, 52.8%, had mild disease, and 30.6 % were diagnosed with MIS-C. The main symptoms reported were fever, cough and diarrhoea. A correlation was found between IL-10 and IL-6 concentrations and age group; lymphocyte subpopulations and nutritional status and steroid use; IL-6 concentrations and clinical severity. The results suggest a different immune response depending on age and nutritional status that should be considered for treating pediatric COVID-19 patients.

I present an experimental paradigm to explore the interpersonal dynamics generating a collective mind. I hypothesized that collective organization is based on dual interpersonal modes: (1) symmetrical and (2) anti‑symmetrical. I specified the geometric topology of these modes by detecting the spatiotemporal patterns that embed cooperative agents in a three‑dimensional matrix. I found that the symmetrical mode is executed automatically and without guidance. Conversely, the anti‑symmetrical mode required explicit direction and recruited attention for execution. I demonstrate that self‑other mirror‑symmetry stabilized group dynamics, enabled fast and efficient symmetrical imitation that optimized information transmission, whereas anti‑symmetrical imitation was comparatively slow, inefficient, and unstable. I determined that the anti‑symmetrical mode spontaneously transitioned to the symmetrical mode under perturbations. Crucially, this renormalization mechanism never transitioned from symmetrical to anti‑symmetrical. These self-organizing dynamics speak to interpersonal symmetry‑breaking. In the present work, spontaneous group choice mandated that agents synchronize cooperative cycles in symmetrical space under internal or external perturbations. I provide examples to illustrate that this self-regulating pullback attractor manifests in invertebrates and vertebrates alike. I conclude by suggesting that inter‑agent symmetry provides the social stability manifold through which attention-driven interactions enable intrapersonal and interpersonal change.

In this paper I will address Dr. Sonne’s questions about will, agency, choice, consciousness, relevant brain regions, impacts of disorders and their therapeutics, and I will do this by referring to my theory, Dual-brain Psychology, which posits that within most of us there exist two mental agencies with different experiences, wills, choices, and behaviors. Each of these agencies is associated as a trait with one brain hemisphere (either left or right) and its composite regions. One of these agencies is more adversely affected by past traumas and is more immature and more symptomatic while the other is more mature and healthier. The theory has extensive experimental support through 17 peer-reviewed publications with clinical and non-clinical research. I will discuss how this theory relates to the questions that Dr. Sonne presented and will discuss also my published theory on the physical nature of subjective experience and its relation to the brain and how that theory interacts with DBP, and how the 2 theories relate to subjective experience, will, behavior, psychopathology and its treatment.

We explored the outcomes of germline BRCA1/2 pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in overall survival (OS) and progression free survival (PFS) in gBRCA1/2m patients compared to both germinal BRCA1/2 wild type (gBRCA1/2wt) and to the untested population. Regarding the efficacy of PI3K inhibitors, there are no subgroup or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and BRCA1/2 at a molecular level could help us to understand the activity of these drugs when used to treat BC in BRCA1/2 PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal BRCA1/2 PVs/LPVs is lacking. Including germinal BRCA1/2 status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2-) and both HR+ and HR- metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline BRCA1/2 PVs/LPVs carriers and this data was not reported. Germline BRCA1/2 status will be available for a higher number of individuals with BC in the near future and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.

Mumps is the second-most reported infectious disease in South Korea; however, due to the low pathogen confirmation rate in laboratory diagnoses, we proposed a method for reevaluating the high incidence rate via the laboratory verification of other viral diseases. In 2021, 63 cases of pharyngeal or cheek mucosal swabs of suspected mumps cases in Gwangju, South Korea, were assessed for causative pathogens using massive simultaneous pathogen testing (TaqManTM Array Cards). More than one respiratory virus was detected in 60 cases (95.2%), 44 (73.3%) of which were co-detected. Human rhinovirus was detected in 47 cases, followed by human herpesvirus (HHV)6 in 30; HHV4 (17), human bocavirus (17), HHV5 (10), and human parainfluenza virus 3 (6) were also detected. Our findings suggest the need for further investigations on the pathogenesis of diseases mimicking mumps, which are considered to aid with appropriate public health responses, treatment, and the prevention of infectious disease outbreaks.

A unique two-column ²³⁰U/²²⁶Th generator has been developed. The focus was hold on obtaining ²²⁶Th of high purity in a solution amenable to further labeling. The first column of the proposed generator filled with TEVA Resin held ²³⁰U, from which ²²⁶Th was eluted with 7 M HCl solution. UTEVA Resin pretreated with nitric acid solution was used as a sorbent for the second column for thorium retention. ²²⁶Th was extracted with 0.01-0.05 M citric buffer solution. One cycle of generator milking took 5-7 minutes and produced > 90% of ²²⁶Th in 1.5 ml of eluate, pH 4.5-5.0. The proposed two-column ²³⁰U/²²⁶Th generator was tested over two months including a second loading of ²³⁰U additionally accumulated from ²³⁰Pa. The ²³⁰U impurity in ²²⁶Th eluate was less than 0.01% allowing to use it directly in synthesis of radiopharmaceutical compounds.

Diagnosis of bovine tuberculosis (bTB) may be confounded by immunological cross-reactivity to Mycobacterium bovis antigens when animals are sensitised by certain nontuberculous mycobacteria (NTMs). Therefore, this study aimed to investigate NTM species diversity in African buffalo (Syncerus caffer) respiratory secretions and tissue samples, using a combination of novel molecular tools. Oronasal swabs were collected opportunistically from 120 immobilised buffaloes in historically bTB-free herds. In addition, bronchoalveolar lavage fluid (BALF; n=10) and tissue samples (n=19) were obtained during post-mortem examination. Mycobacterial species were identified directly from oronasal swab samples using the Xpert MTB/RIF Ultra qPCR (14/120 positive) and GenoType CMdirect (104/120 positive). In addition, all samples underwent mycobacterial culture, and PCRs targeting hsp65 and rpoB were performed. Overall, 55 NTM species were identified in 36 mycobacterial culture-positive swab samples with presence of esat-6 or cfp-10 detected in 20 of 36 isolates. The predominant species were M. avium complex and M. komanii. Nontuberculous mycobacteria were also isolated from 6 of 10 culture-positive BALF and 4 of 19 culture-positive tissue samples. Our findings demonstrate that there is a high diversity of NTMs present in buffaloes, and further investigation should determine their role in confounding bTB diagnosis in this species.

HLA-G is an immune checkpoint molecule with immunosuppressive and anti-inflammatory activities, and its expression and level of its soluble form (sHLA-G) may play an important role in tumor prognosis. The HLA-G 14 bp ins/del polymorphism and the plasma level of soluble HLA-G (sHLA-G) were investigated by a polymerase chain reaction and ELISA, respectively, in 59 glioma patients. A significantly higher proportion of glioma patients had the 14 nt insert in both homozygous and heterozygous states compared to the control group. Glioma patients had also higher plasma levels of sHLA-G. Patients with methylated MGMT promoter had lower levels of sHLA-G than those with unmethylated MGMT promoter. Level of sHLA-G negatively correlated with the overall survival of patients. Glioblastoma patients who survived more than one year after diagnosis had lower levels of sHLA-G than those surviving less than one year. Patients with sHLA-G levels below the cut off value 40 U/mL survived significantly longer than patients with sHLA-G above 40 U/mL. The levels of sHLA-G also negatively correlated with the level of IL-6 (P=0.0004) and positively with IL-10/IL-6 (P=0.046). Conclusion: The presence of 14 nt insert in both homozygous and heterozygous states of the HLA-G 14 bp ins/del polymorphism is more frequent in glioma patients and the elevated plasma levels of sHLA-G are negatively associated with their survival.

Our knowledge of biology and mast cell (MC) function, as well as disorders associated with the pathologic activation of MCs has been evolving over the last few decades. Anaphylaxis, mast cell activation syndrome (MCAS) and mastocytosis are interrelated yet distinct conditions within the spectrum of mast cell activation disorders. Nevertheless, all three conditions can co-exist in one and same patient, as pathologic MC activation is the key finding in all three. When mediator release is excessive and involves multiple systems, anaphylaxis and MCAS may occur. Furthermore, mastocytosis is a clonal disorder of MCs and often presents with anaphylaxis and MCAS. Nevertheless, in some cases even proliferative and accumulative features of MCs in mastocytosis can account for symptoms and disease progression. In each case, diagnosis can be only made when diagnostic consensus criteria are fulfilled. The current article aims to provide a concise clinical update and pinpoint main difficulties in diagnosing these puzzling disorders of MCs in medical practice.

Porcine parvovirus (PPV) 1 is a major causative pathogen of reproductive failure, and porcine circovirus (PCV) 2 is an etiological pathogen causing PCV-associated and PCV diseases worldwide. PPV2–6 and PCV3 were recently identified as newly emerging viruses with unknown pathogeneses. However, little is known of PPV1–6 and PCV3 effects or their co-infections with PCV2. In this study, we examined 926 samples (272 aborted pig fetuses and 654 pig lung tissues) from domestic pig farms for the presence of PPV1–6 or PCV3 and for PCV2 co-infection with these seven viruses. The prevalence of PPV and PCV was significantly greater in lung tissue samples than aborted pig fetus samples. PPV3–6 were detected for the first time in Korean domestic pigs. Co-infection rates with PCV2 and other viruses were significantly higher in abattoir samples than that in aborted pig fetus samples. Concurrent infections are more common than single infection in pig population and nu-merous infectious pathogens such as PPV and PCV2 can impact the respiratory diseases. Fur-thermore, Korean PPV1 strain (PPV1-82) was identical to the virulent PPV-27a strain in this respect. Our results describe, for the first time the prevalence of PPV1–6 and PCV3 infections and their co-infection rates with PCV2 in Korean domestic pigs.

Antimicrobial application of carbon nanomaterials such as carbon nanotubes (CNTs), capped CNT, C60 fullerene, and C70 fullerene are increasing owing to their low cytotoxicity properties compared to other nanomaterials such as metallic nanoparticles. Enhanced mechanical property and antibacterial activity can be caused by incorporation of CNTs in 3-dimentional (3D) printed nanocomposites (NCs). Interruption of bacterial membrane resulting from cylindrical shape and high aspect ratio properties has been found as the prominent antibacterial mechanism of CNTs. However, unraveling interaction of CNT, capped CNT, C60 fullerene, and C70 fullerene with virulence factors of the main bacterial pathogenesis has not yet been known. Therefore, in the present study, interactions of CNT, capped CNT, C60, and C70 with the eight virulence factors including protein kinase A and ESX-secreted protein B of Mycobacterium tuberculosis, pseudomonas elastase and exotoxin A of Pseudomonas aeruginosa, alpha-hemolysin and penicillin binding protein 2a of Staphylococcus aureus and shiga toxin 2a and heat-labile enterotoxin of Escherichia coli have been evaluated by molecular docking method of AutoDock Vina. This study disclosed the binding strength followed the sequence CNT &gt; capped CNT &gt; C70 &gt; C60 towards alpha-hemolysin of S. aureus compared to other virulence factors with values of -19.6, -18.8, -13.6, and -12.8 kcal/mol, respectively. The lowest and highest binding affinity were found for CNT against 1TII and 1MWT by binding energy values of 97.4 and -20.1 kcal/mol. The stability of CNT-1MWT complex at the different times has resulted according to the normal mode analysis of elNémo and iMOD servers. Future studies should be focused on improving cellular uptake of CNTs, capped CNTs, C70, and C60 by surface functionalization for active targeting of bacteria.

We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1a protein and nuclear factor erythroid 2 like 2 (NFE2L2) gene, showed some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1a in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defense, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defense also contributed to that discrimination. A bioinformatic analysis showed that PGC-1a might coordinate the interplay between genes encoding proteins involved in antioxidant defense, senescence and autophagy in the aging retina. These data support importance of PGC-1a in AMD pathogenesis and confirm the utility of mice with PGC-1a knockout as an animal model to study AMD pathogenesis.

Cognitive deficit is a frequent non-motor symptom in Parkinson 's disease (PD) with an unclear pathogenesis. Recent research indicates possible involvement of insulin resistance and glutamate excitotoxicity in PD development. We investigated cognitive performance and the brain glutamate and insulin signaling in a rat model of PD induced by bilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA). Cognitive functions were assessed with Passive avoidance (PA) and Morris Water Maze (MWM) tests. The expression of tyrosine hydroxylase (TH) and proteins involved in insulin (IR, pI3K, ERK) and glutamate receptor (AMPAR, NMDAR) signaling was assessed in the hippocampus (HPC), hypothalamus (HPT) and striatum (S) by immunofluorescence, Western blot and ELISA. Three months after 6-OHDA treatment, cognitive deficit was accompanied by decreased AMPAR activity and TH levels (HPC, S), while levels of the proteins involved in insulin signaling remained largely unchanged. Spearman’s rank correlation revealed a strong positive correlation for pAMPAR-PA (S), pNMDAR-pI3K (HPC) and pNMDAR-IR (all regions). Additionally, a positive correlation was found for TH-ERK and TH-pI3K, and a negative one for TH-MWM/errors and pI3K-MWM/time (S). These results suggest a possible association between brain glutamate (but not insulin) signaling dysfunction and cognitive deficit in a rat PD model, detected three months after 6-OHDA treatment.

Currently, studies are being conducted on the possible role of the cytoprotective effect of biologically active substances in conditions of cerebral hypoxia or cardiomyopathies. At the same time, oxidative stress is considered as one of the important mechanisms of cellular cytotoxicity and a target for the action of cytoprotectors. The aim of this study is to search for derivatives of 3-(arylmethyl)-6-methyl-4-phenylpyridin-2(1H)-ones. The probability of cytoprotective action was assessed by two tests by measuring cell viability (with neutral red dye and MTT test). It was found that some derivatives of 3-(arylmethyl)-6-methyl-4-phenylpyridin-2(1H)-ones under the conditions of our experiment have a pronounced cytoprotective activity, providing better cell survival in vitro, including the MTT test and conditions of blood hyperviscosity. To correlate the obtained results in vitro, molecular docking of the synthesized derivatives was also carried out. The standard drug omeprazole (co-crystallized with the enzyme) was used as a standard. It was shown that all synthesized derivatives of 3-(arylmethyl)-6-methyl-4-phenylpyridin-2(1H)-ones had higher affinity for the selected protein than the standard gastro-cytoprotector omeprazole. The studied derivatives of 3-(arylmethyl)-6-methyl-4-phenylpyridin-2(1H)-ones also fully satisfy Lipinski's rule of thumb of five (RO5), which increases their chances for possible use as orally active drugs with a good ability to absorption and moderate lipophilicity. Thus, the results obtained make it possible to evaluate derivatives of 3-(arylmethyl)-6-methyl-4-phenylpyridin-2(1H)-ones as having a relatively high cytoprotective potential.

Acne vulgaris is a prevalent skin condition that affects people of all ages and can have significant physical and psychological impacts. Hydroxy acids, such as alpha-hydroxy acids (AHA) and beta-hydroxy acids (BHA), have demonstrated potential as effective ingredients for topical acne treatments due to their exfoliating and skin-rejuvenating properties. This study assessed the effectiveness of encapsulating AHA and BHA in pullulan-collagen nanofibers as a novel approach to acne treatment. The study involved preparing Pullulan and polyvinyl alcohol (PVA) solutions combined with sodium chloride (NaCl) to create a stable mixture. Collagen and Pullulan were then dissolved in deionized water and mixed to form a collagen-pullulan solution. Various weight ratios of Collagen to Pullulan were tested to optimize nanofiber formation. This research achieved electrospinning of nanofibers, confirmed by scanning electron microscopy (SEM) analysis, which revealed well-formed and continuous nanofiber structures in acidic solutions. Fourier transform infrared spectroscopy (FTIR) analysis provided insights into the chemical composition of the nanofibers, indicating the presence of ester, carboxylic acid, hydroxyl, and phenolic groups. Contact angle measurements demonstrated that the pullulan-collagen nanocomposite exhibited hydrophilic properties, albeit less hydrophilic than pure Collagen. Biocompatibility assays using mesenchymal stem cells (MSCs) and human skin fibroblasts (HSFs) revealed that the pullulan-collagen nanocomposite promoted higher cell viability compared to pure Collagen, suggesting its potential as a supportive matrix for cell growth and tissue regeneration. AHA-BHA-infused nanofiber skin masks hold promise as effective topical treatments for acne vulgaris. The successful encapsulation of hydroxy acids within pullulan-collagen nanofibers, in conjunction with their favourable chemical composition, hydrophilicity, and biocompatibility, positions them as promising candidates for delivering active ingredients and enhancing skin health. Further nanofiber formulation optimisation is necessary to exploit their therapeutic potential in skincare applications.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) often causes severe viral pneumonia, especially among older individuals and those with underlying health conditions. The C57BL/6 mouse is widely used to develop mouse models of obesity, diabetes, hypertension, and immune disorders, conditions that are associated with increased risk of severe COVID-19. Although many studies using these mouse models have examined the pathogenicity of SARS-CoV-2, COVID-19 pathogenesis remains poorly understood. In vivo imaging analysis using two-photon excitation microscopy is useful for elucidating the pathology of COVID-19, providing pathological insights that are not available from conventional histological analysis. However, there is no reporter SARS-CoV-2 that demonstrates pathogenicity in C57BL/6 mice and emits sufficient light intensity for two-photon in vivo imaging. Here, we generated SARS-CoV-2 expressing the fluorescent protein Venus to facilitate in vivo pathological studies using C57BL/6 mouse models. We generated a mouse-adapted strain of SARS-CoV-2, by performing sequential lung-to-lung passages in BALB/c mice, followed by in C57BL/6 mice. We observed that the C57BL/6-adapted SARS-CoV-2 (named MASCV2-p25) replicated efficiently in the lungs of C57BL/6 mice, causing fatal pneumonia. Histopathologic analysis revealed severe inflammation and infiltration of immune cells in the lungs of MASCV2-p25-infected C57BL/6J mice, not unlike that observed in COVID-19 patients with severe pneumonia. Subsequently, we generated a mouse-adapted reporter SARS-CoV-2 (named MASCV-Venus-p9) by inserting the fluorescent gene Venus into MASCV2-p25, and sequential lung-to-lung passages in C57BL/6 mice. C57BL/6 mice infected with MASCV2-Venus-p9 exhibited severe pneumonia similar to that induced by MASCV2-p25. In addition, two-photon excitation microscopy of the lungs of the infected C57BL/6J mice showed that the infected cells emitted sufficient levels of fluorescence for easy observation. These findings suggest that MASCV2-Venus-p9 will be useful for two photon in vivo imaging studies of the pathogenesis of severe COVID-19 and for the development of therapeutic agents for severe pneumonia.

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is the most common respiratory morbidity in preterm infants. "Old" or "Classic" BPD, as per the original description, is less common now. "New BPD," which presents with distinct clinical and pathological features, is more frequently observed in the current era of advanced neonatal care, where extremely premature infants are surviving due to medical advancements. The pathogenesis of BPD is complex and multifactorial and involves both genetic and environmental factors. This review provides an overview of the pathology of BPD and discusses the influence of several prenatal and postnatal factors on its pathogenesis, such as maternal factors, genetic susceptibility, ventilator-associated lung injury, oxygen toxicity, sepsis, patent ductus arteriosus (PDA), and nutritional deficiencies. This in-depth review draws on existing literature to explore these factors and their potential contribution to the development of BPD.

Mouse models are frequently used to study Huntington’s disease (HD). Onset and severity of neuronal and behavioral pathologies vary greatly between HD mouse models, which results from different huntingtin expression levels and different CAG repeat length. HD pathology appears to depend also on strain background of mouse models. Thus, behavioral deficits of HD mice are more severe in the FVB than in the C57BL/6 background. Alterations in medium spiny neuron (MSN) morphology and function has been well documented in young YAC128 mice in the FVB background. We here tested the relevance of strain background for mutant huntingtin (mHTT) toxicity on the cellular level by investigating HD pathologies in YAC128 mice in the C57BL/6 background (YAC128/BL6). Morphology, spine density, synapse function and membrane properties were not or only subtly altered in MSNs of 12-month-old YAC128/BL6 mice. Despite the mild cellular phenotype, YAC128/BL6 mice showed deficits in motor performance. More pronounced alterations in MSN function were found in the HdhQ150 mouse model in the C57BL/6 background (HdhQ150/BL6). Consistent with the differences in HD pathology, the number of inclusion bodies was considerably lower in YAC128/BL6 mice than HdhQ150/BL6 mice. This study highlights the relevance of strain background for mHTT toxicity in HD mouse models.

Differential RNA editing by adenosine deaminases that act on RNA (ADARs) has been implicat-ed in several neurological disorders, including Parkinson’s disease (PD). Here, we report results of an RNAi screen of genes differentially regulated in adr-2 mutants, normally encoding the only catalytically active ADAR in Caenorhabditis elegans, ADR-2. Subsequent analysis of candidate genes that alter the misfolding of human α-synuclein (α-syn) and dopaminergic neurodegenera-tion, two PD pathologies, reveal that reduced expression of xdh-1, the ortholog of human xanthine dehydrogenase (XDH), is protective against α-synuclein-induced dopaminergic neurodegenera-tion. Further RNAi experiments show that WHT-2, the worm ortholog of the human ABCG2 transporter and a predicted interactor of XDH-1, is the rate-limiting factor in the ADR-2, XDH-1, WHT-2 system for dopaminergic neuroprotection. Proteomic analysis indicates that the editing of one nucleotide in wht-2 RNA leads to the substitution of threonine with alanine at residue 124 in the WHT-2 protein, changing its structure. Thus, we propose a model where wht-2, is edited by ADR-2 which promotes optimal export of uric acid, a known substrate of WHT-2 and a product of XDH-1 activity. In the absence of editing, uric acid export is limited provoking a reduction in xdh-1 transcription to limit uric acid production and maintain cellular homeostasis. In turn, ele-vation of uric acid is protective against dopaminergic neuronal cell death. These data indicate that modifying specific targets of RNA editing may represent a promising therapeutic strategy for PD.

This review provides an overview of the biotransformation of limonene and α-pinene, which are commonly found in wood residues and citrus fruit by-products, to produce high-value-added products. Essential oils derived from various plant parts contain monoterpene hydrocarbons, such as limonene and pinenes which are often considered waste due to their low sensory activity, poor water solubility, and tendency to autoxidize and polymerise. However, these terpene hydrocarbons serve as ideal starting materials for microbial transformations. Moreover, agro-industrial byproducts can be employed as nutrient and substrate sources, reducing fermentation costs, and enhancing industrial viability. Terpenes, being secondary metabolites of plants, are abundant in byproducts generated during fruit and plant processing. Microbial cells offer advantages over enzymes due to their higher stability, rapid growth rates, and genetic engineering potential. Fermentation parameters can be easily manipulated to enhance strain performance in large-scale processes. The economic advantages of biotransformation are highlighted by comparing the prices of substrates and products. For instance, R-limonene, priced at US$34/L, can be transformed into carveol, valued at around US$530/L. This review emphasises the potential of biotransformation to produce high-value products from limonene and α-pinene molecules, particularly present in wood residues and citrus fruit by-products. The utilisation of microbial transformations, along with agro-industrial byproducts, presents a promising approach to extract value from waste materials and enhance the sustainability of the antimicrobial, the fragrance and flavour industry.

The aggregate aftermath of persistent inflammation in patients with inflammatory bowel disease (IBD) places them at increased risk for the advancement to colitis-associated colorectal cancer (CACRC). CACRC is preceded by IBD, the highly heterogenous, pharmacologically incurable, pertinacious, reverting/worsening, and immune-mediated inflammatory pathologies of the colon and rectum. The molecular and immunological basis of CACRC is highly correlated with the length/duration and stringency/severity of colon inflammation predisposed by the exogenous/free hemoglobin alpha chain (HbαC) the byproduct of infiltrating immune cells, extravasated erythrocytes, and macrophage erythrophagocytosis. The exogenous free HbαC prompts oxygen-free radical-arbitrated DNA damage (DNAD) through increased cellular reactive oxygen species (ROS) exacerbated by decreased tissue antioxidant defenses. Mitigation of Fenton reaction via pharmaceutical therapy would attenuate the ROS, promote apoptosis, DNAD repair, and subsequent prevent the incidence of CACRC. Three pharmaceutical options that attenuate hemoglobin toxicity include haptoglobin, deferoxamine, and flavonoids (vitamins C/E). Haptoglobin’s clearance rare from plasma is inversely correlated with its size; the smaller the size, the faster the clearance. Thus, the administration of Hp1-1 may prove to be beneficial. Furthermore, deferoxamine’s hydrophilic structure limits its ability to cross cell membranes. Thus, it may be beneficial if administered intracellularly to avoid the higher plasma concentrations and longer incubation periods associated with extracellular administration. Finally, the effectiveness of flavonoids and natural herb antioxidants is associated with high reactivity of hydroxyl substituents. Multiple analyses are currently underway to assess the clinical context of CACRC and outline the molecular basis of HbαC-induced ROS pathogenesis by exposing colonocytes and/or colonoids to HbαC. These cells are then treated with haptoglobin, deferoxamine (DFO), and flavonoids in order to separate free HbαC and measure their impact on hydroxyl radical formation therapies. The molecular pathogenesis of sporadic colorectal cancer (SCRC) i.e., “inflammation-dysplasia-carcinoma” progression sequence is well described, but the immunopathogenesis of CACRC herein reviewed is broadly still in prodromal stage/phase to be validated and understood. Therefore this timely review outlines the molecular and immunological basis of disease pathogenesis and the pharmaceutical intervention as a protective measure for CACRC.

Animal-assisted pedagogy (AAP) is well known in classroom practice, but scientific evidence is still lacking. At the same time, the biggest challenge in education systems worldwide is the social in-tegration of students. In a pre-post design, 30 heterogeneous students (16f/14m) from four different school classes (grades 5-7) were interviewed (problem-centred interview) about their social inclu-sion and their social climate in class before and after being taught selected subjects with a school dog (of different breeds) for one school term. At the second measurement point, they were also asked about their perception of AAP. The data was analysed both qualitatively (Kuckartz) and in terms of the number of quotes on the main topics using MAXQDA analysis software. The presence of a dog in the classroom leads to an improved social climate and more social integration. In ad-dition, the perception of the other students and the teacher changes to a more positive and friendly image. Through AAP, a new social role is added to the classroom, where caring and bonding are prioritised. Social interaction and norms are influenced and sterotypical and individual roles can be changed. Therefore, AAP can be a key to promoting social inclusion in the school environment.

De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities in de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have changed the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road towards a personalized treatment for de novo mHSPC is still long considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as predictive biomarker requires further validation, as well as it remains to ascertain how the genomic alterations detected in mHSPC, that are considered predictive in the castration-resistant disease, can be exploited in the mHSPC setting.

In order for the body to function properly, it needs not only food, but also nutrients and non-nutritive bioactive compounds that have an immunomodulating effect. This applies not only to healthy people, but especially to people with accompanying chronic diseases, including type 2 diabetes. Unfortunately, the current food industry and the use of highly processed food promote nutritional deficiencies. Many studies confirm their occurrence in patients with type 2 diabetes. The article presents the influence of selected nutrients on the functioning of the immune system, which ensures homeostasis of the body, with particular emphasis on type 2 diabetes. The role of macroelements, microelements, vitamins and selected substances, such as omega-3 acids, coenzyme Q10 and alpha-lipoic acid. The minimum scope of tests that should be performed in patients to directly or indirectly determine the degree of malnutrition in this group of patients is presented.

Mycobacterium tuberculosis (Mtb) the causative agent of human tuberculosis (TB) is one of the most successfully adapted-human pathogens. Human-to-human transmission occurs at high rates through aerosols containing bacteria, but the pathogen evolved prior to the establishment of crowded populations. Mtb has developed a particular strategy to ensure persistence in the host until an opportunity for transmission arise. It has refined its lifestyle to obviate the need for virulence factors such as capsules, flagella, pilli, or toxins to circumvent mucosal barriers. Instead, the pathogen uses host macrophages, where it establishes intracellular niches, for its migration into the lung parenchyma and other tissues and for the induction of long-lived latency in granulomas. Finally, at the end of the infection cycle Mtb induces necrotic cell death of macrophages to escape to extracellular milieu and instructs a strong inflammatory response required for progression from latency to disease and transmission. Common to all these events is ESAT-6, one of the major virulence factors secreted by the pathogen. This review highlights the recent advances in understanding the role of ESAT-6 in hijacking macrophage function to establish a successful infection and transmission and its use as a target for the development of diagnostic tools, and vaccines.

Malignant peripheral nerve sheath tumors (MPNSTs) are deadly sarcomas that desperately need effective therapies. Half of all MPNSTs arise in patients with Neurofibromatosis Type I (NF1), a common inherited disease. NF1 patients can develop benign lesions called Plexiform Neurofibromas (PNFs), often in adolescence, and over time some PNFs, but not all, will transform into MPNSTs. A deeper understanding of the molecular and genetic alterations driving PNF-MPNST transformation will guide development of more targeted and effective treatments for these patients. This review focuses on an oncogenic transcription factor, FOXM1, that is a powerful oncogene in other cancers but little studied in MPNSTs. Elevated expression of FOXM1 was seen in patient MPNSTs and correlated with poor survival, but otherwise its role in the disease is unknown. We discuss what is known about FOXM1 in MPNSTs relative to other cancers and how FOXM1 may be regulated by and/or regulate the most commonly altered players in MPNSTs, particularly in the MEK and CDK4/6 kinase pathways. We conclude by considering FOXM1, MEK, and CDK4/6 as new, clinically relevant targets for MPNST therapy.

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor positive metastatic breast cancer.

Inflammatory processes play major roles in carcinogenesis and progression of hepatocellular carcinoma (HCC) derived from non-alcoholic steatohepatitis (NASH). But there are no therapies for NASH related HCC, especially focusing on these critical steps. Previous studies reported that farnesyltransferase inhibitors (FTIs) have anti-inflammatory and anti-tumor effects. However, the influence of FTIs on NASH-related HCC has not been elucidated. In HCC cell lines, HepG2, Hep3B, and Huh-7, we confirmed expression of hypoxia-inducible factor (HIF)-1α, an accelerator of tumor aggressiveness and the inflammatory response. We established NASH-related HCC models under inflammation and free fatty acid burden and confirmed that HIF-1α expression was increased under both conditions. Tipifarnib, which is an FTI, strongly suppressed increased HIF-1α, inhibited cell proliferation, and induced apoptosis. Simultaneously, intracellular interleukin-6 as an inflammation marker was increased under both conditions and significantly suppressed by tipifarnib. Additionally, tipifarnib suppressed expression of phosphorylated nuclear factor-κB and transforming growth factor-β. Finally, in a NASH-related HCC mouse model burdened with diethylnitrosamine and a high fat diet, tipifarnib significantly reduced tumor nodule formation in association with decreased serum interleukin-6. In conclusion, tipifarnib has anti-tumor and anti-inflammatory effects in a NASH-related HCC model and may be a promising new agent to treat this disease.

Autoimmune limbic encephalitis (LE) is a rare, but devastating complication of allogeneic hem-atopoietic stem cell transplantation (HSCT). There is currently limited evidence describing the risk factors, laboratory features, and underlying mechanisms of this neurologic adverse event. We retrospectively reviewed available clinical, imaging, and laboratory data from adult patients with hematological malignancies who underwent haploidentical HSCT with cyclophosphamide (PTCy) at Chungnam National University Hospital from June 2016 to May 2020. Patients who developed LE were compared to those who did not based on clinical assessment, serum inflam-matory biomarkers, and reconstitution of various T cell populations. Of 35 patients, four devel-oped LE. There were no differences in patient demographics, donor demographics, or treatment conditions between patients that did and did not develop LE. Overall, patients with LE had worse clinical outcomes and overall survival than those without. In addition, they tended to have higher markers of systemic inflammation in the early post-transplant period, including fever, C-reactive protein (CRP), and cytokines. Remarkably, baseline interleukin-6 levels before HSCT were found to be higher in patients who developed LE than those who did not. In addition, analysis of T cell subsets showed impaired expansion of CD25+FOXP3+ regulatory T (Treg) cells in LE compared to non-LE patients despite appropriate reconstitution of the total CD4+ T cell population. Patients that developed LE within the first 30 days of HSCT were likely to have high serum IL-6 among other inflammatory cytokines coupled with suppression of regulatory T cell differentiation. Further work is needed on the mechanisms underlying impaired Treg expansion following HSCT and potential therapies.

Glutamate dehydrogenase (GDH) interconverts glutamate to a-ketoglutarate and ammonia, interconnecting amino acid and carbohydrate metabolism. In humans, two functional GDH genes, GLUD1 and GLUD2, encode for hGDH1 and hGDH2, respectively. GLUD2 evolved from retro-transponsition of the GLUD1 gene in the common ancestor of modern apes. These two isoenzymes are involved in the pathophysiology of neoplastic, neurodegenerative, and metabolic disorders. The 3D structures of hGDH1 and hGDH2 have been experimentally determined; however, no information is available about the path of GDH2 structure changes during primate evolution. Here, we compare the structures predicted by the AlphaFold Colab method for the GDH2 enzyme of modern apes and their extinct primate ancestors. Also, we analyze the individual effect of amino acid substitutions emerging during primate evolution. Our most important finding is that the predicted structure of GDH2 in the common ancestor of apes was the steppingstone for the structural evolution of primate GDH2s. Two changes with a strong functional impact occurring at the first evolutionary step, Arg443Ser and Gly456Ala, had a destabilizing and stabilizing effect, respectively, making this step the most important one. Subsequently, GDH2 underwent additional modifications that fine-tuned its enzymatic properties to adapt to the functional needs of modern-day primate tissues.

In this study we introduce the new classes $\mathcal{M}_{\alpha}(\sin)$ and $\mathcal{M}_{\alpha}(\cos)$ of $\alpha$-convex functions associated with sine and cosine functions. Also, we obtain the initial coefficient bounds for the first five coefficients of the functions that belong to these classes. Further, we determine the upper bound of Zalcman functional for the class $\mathcal{M}_{\alpha}(\cos)$ for the case $n=3$, showing that the Zalcman conjecture holds for this value. Moreover, the problem of the Fekete-Szeg\H{o} functional estimate for these classes is studied.

Coronavirus Disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a “cytokine storm,” and neuroinflammation. COVID-19’s upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by the formation of Lewy Bodies made of α-Synuclein protein encoded by synuclein alpha (SNCA). This study presents the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN’s Ingenuity Pathway Analysis, the study identifies the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream Effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation.

On April 17, 2019, a coach with tourists from Germany crashed in Madeira requiring repatriation by the German Air Force. The Advance Trauma Life Support (ATLS) concept was the central component of patient care. Data in Madeira were collected through a structured interview. The analysis of the Aeromedical Evacuation was based on intensive care transport records. In Germany all available were reviewed for data collection. Quality of life (HRQoL) was evaluated by the 12-item Short-Form Health Survey (SF-12). Twenty-eight prehospital patients were transported to the Level III Trauma Center in Funchal (Madeira). Five operative procedures were performed. Fifteen patients were eligible for Aeromedical Evacuation (AE). In the second hospital phase in Germany in total 82 radiological images and nine operations were performed. Hospital stay lasted 11 days (median, IQR 10–18). Median Follow-up (14 of 15 patients) was 16 months (IQR 16–21). 80% (8 out of 10) showed an increased risk for post-traumatic stress disorder (PTSD). Six key findings were identified in this study: divergent injury classification, impact of AE mission on health status, lack of communication, need of PTSD prophylaxis, patient identification, media coverage. Those findings may improve AE missions in the future e.g. required after armed conflicts.

The sustainability of Indigenous Socioecological Systems (ISES) faces significant threats from global anthropogenic environmental changes, endangering Indigenous People (IP), who safeguard a substantial portion of the world's natural capital. Indigenous Traditional Food Systems (ITFS) are crucial within ISES, providing not only diverse and nutritious food but also holding cultural, spiritual, and economic significance. Despite embodying sustainable lifestyles, Indigenous voices remain underrepresented in climate and sustainability discussions. Addressing this gap, the research adopts the Political Ecological Theoretical Framework (PETF) to analyze the regulatory impact on the adaptability, resilience, and sustainability of ITFS. Two Indigenous communities, the Karen in Thailand and various groups in the Republic of Sakha (Yakutia) in Russia, serve as case studies. The study aims to establish a theoretical framework integrating Indigenous concerns into policies and regulations, emphasizing self-determination, cultural preservation, and land rights. Findings emphasize the necessity for comprehensive legal frameworks prioritizing Indigenous involvement in climate resilience and sustainability efforts, moving beyond symbolic gestures towards meaningful collaboration and decision-making power. Recognizing Indigenous vulnerability and engaging them as active partners is essential for navigating climate challenges within ISES and ITFS.

Cancer patients may experience significant distress. The “Emotion Thermometers” (ETs) are a short visual analogue scale used to screen patients for psychosocial risk. This study aimed to assess emotional distress in a large sample of cancer patients attending psychological services at an NGO, and to explore factors that may contribute to it. The ETs were answered by 899 cancer patients. They were, on average, 59.9 years old, the majority were female, had breast cancer, were under treatment or were disease-free survivors, and reported high levels of emotional distress, above the cut-off (≥5). A Generalized Linear Model was used to measure the association between the level of Distress and 33 items of the problem list. Four items - sadness, depression, sleep and breathing - were found to be significantly related to a higher level of Distress. Additionally, women and those who were in the palliative phase also had significantly higher levels of Distress. Conclusions: The results confirm the need for early emotional screening in cancer patients, as well as the relevance of attending to the characteristics of each patient. Additionally, they highlight the utility of the ETs for the clinical practice, allowing to optimize the referral to specialized psy-chosocial services.

Cardiovascular diseases (CVDs) represent the leading cause of global mortality with 1,7 million deaths a year. One of the alternative systems to drug therapy to minimize the risk of CVDs is represented by alpha-linolenic acid (ALA), an essential fatty acid of the Omega-3 series, known for its cholesterol-lowering effect. The main purpose of this review is to analyze the effects of ALA and investigate the relevant n-6/n-3 ratio in order to maintain functionally beneficial effects. Concerning the lipid-lowering preventive effects, ALA may favorably affect the values of LDL-C and triglycerides in either adult and pediatric populations and it has a positive and protective effect against hypertension, suggesting that ALA is an useful diet-related antihypertensive compound. According to the 2009 EFSA statement, dietary ALA may contribute to reducing the risk of CVDs, thanks to anti-hypertensive, anti-atherosclerotic and cardio-protective effects.

Background and aim. The study aimed to assess the efficacy of the treatment of Kan Jang®, a fixed combination of Andrographis paniculata (Burm. F.) Wall. ex. Nees and Eleutherococcus senticosus (Rupr. & Maxim.) Maxim in patients with mild symptoms of COVID-19. Methods. One hundred forty patients received six capsules of Kan Jang® (n = 68, daily dose of andrographolides – 90 mg) or placebo (n=72) and supportive treatment (paracetamol) for 14 consecutive days in a randomized, quadruple-blinded, placebo-controlled, two-parallel-group design. The efficacy outcomes were the rate of cases turning to severe, the detection rate of SARS-CoV-2 virus over the time of treatment, the duration and the severity of symptoms (sore throat, runny nose, cough, headache, fatigue, loss of smell, taste, pain in muscles) in the acute phase of the disease. Other efficacy measures included improving cognitive and physical performance, quality of life, and the levels of inflammatory blood markers - IL-6, c-reactive protein, and D-dimer. Results. Kan Jang® significantly (p < 0.05) reduced the rate of cases turning to severe (5.36%) compared to placebo (17.86%) and decreased the detection rate of SARS-CoV-2 virus over the time of treatment. The statistical difference in the rates of patients with clinical deterioration in the Kan Jang treatment and placebo control groups was significant (p = 0.0176) both in 112 patients included per protocol (IPP) analysis and in 140 patients included per intention to treat (ITT) analysis (p = 0.0236); the absolute risk reduction of cases by Kan Jang treatment was 12.5%, and the number Needed to Treat by Kan Jang was 8. The patient's recovery time (Number of sick days at the home/clinic) was shorter in the Kan Jang group compared with the placebo group. The rate of resolution of inflammatory symptoms in the Kan Jang® group was significantly higher compared with the placebo group, and relief of the severity of cough, sore throat/pain, runny nose, and muscle soreness. Kan Jang® significantly decreased the Wisconsin Upper Respiratory Symptoms scores compared to placebo in the sample size of 140 patients. However, the relief of fatigue and headache and the decrease of IL-6 in the blood was observed only in a subset of the 86 patients infected during the second three waves of the pandemic. Kan Jang® significantly increased physical activity and workout; however, it did not affect cognitive functions (attention and memory), Quality of life Score, inflammatory markers D-dimer, and c-reactive protein compared with the placebo group. Conclusions. Overall, the results of this study suggest that Kan Jang® is effective in treating mild and moderate COVID-19 irrespective of SARS-Cov-2 variants infection.

Gold nanoparticles have been increasingly used in several electronic, material fabrication, and biomedical applications. Several methods have been reported to prepare gold nanoparticles of various shapes and sizes with different photophysical properties. Although useful to prepare gold nanoparticles, most of the methods are not stable enough and under degradation if stored at room temperatures (up to 30 C) for a few days. In this paper, we report a novel environmentally friendly method to synthesize self-assembled gold nanoparticles by using leaf extract of Cannabis indica as a reducing agent. The nanoparticles were found to be stable for more than a month when stored at room temperature (30 C). They were able to form stable conjugates with bovine α-lactalbumin protein that may possess anti-cancerous properties.

The TRPV3 calcium ion channel is vital for maintaining skin health and has been associated with various skin-related disorders. Since TRPV3 is involved in the development of skin inflammation, inhibiting TRPV3 could be a potential treatment strategy. Alpha-mangostin isolated from Garcinia mangostana L. extract exhibits diverse positive effects on skin health; however, the underlying mechanisms remain obscure. This study investigated the TRPV3-inhibitory properties of alpha-mangostin on TRPV3 hyperactive mutants associated with Olmsted syndrome and its impact on TRPV3-induced cytokine secretion and cell death. Our findings demonstrate that alpha-mangostin effectively inhibits TRPV3, with an IC50 of 0.077 ± 0.013 μM, showing inhibitory effects on both wild-type and mutant TRPV3. TRPV3 inhibition with alpha-mangostin decreased calcium influx and cytokine release, protecting cells from TRPV3-induced death. These results indicate that alpha-mangostin reduced inflammation in TRPV3-activated skin keratinocytes, suggesting that alpha-mangostin could be potentially used for improving inflammatory skin conditions such as dermatitis.

As the core components of water jet propulsion system, water jet pump, directly affect the ship's propulsion performance. 3D reverse design method can effectively suppress the impeller secondary flow to get better performing hydraulic models. Aiming at fast and efficient optimization of the impellers, we parameterize the impellers and runner, and coupled with optimization algorithms and numerical calculations. It is an efficient and feasible way to coupling optimization based on multi-parameter, multi-objective and optimization algorithms, and parameterizing the impellers and guide vane geometry based on the 3D model designed by 3D reverse design method. In this paper, the waterjet propulsion pump is taken as the research object. According to the design method of the waterjet propulsion pump hydraulic model, the traditional axial flow blade design method, the modern ternary design theory of the blades, and the parametric three-dimensional reverse design method are selected to constructing an optimal design optimization strategy for the impeller of water-jet propulsion pump based on multi-parameter and multi-object genetic algorithm. Under the design conditions, the optimized pump efficiency reaches 89.28%, which is 1.24% higher than the original hydraulic model. The optimized pump head is 13.51 m, which is 0.39m more than the original hydraulic model. Under the design condition, the test measured head is 13.26m, the numerical calculation result is 1.88% higher than the test result, the test measured efficiency is 87.1%, the numerical calculation result is 2.5% higher than the test result. From the test results, the optimized impeller has higher hydraulic performance. Experiments have shown that it is feasible to optimize the design strategy.

Hypertension (HT) is a very common risk factor and a frequent cause of morbidity and mortality worldwide mainly due to much increase in overweight (OW) and obesity that manifests in various forms of cardiovascular disease (CVD). There are a number of factors that may cause overweight hypertension (OHT). However, we planned to conduct the present work to study the HT and OHT men for finding the variation, interrelationship and association of important cytokines mainly serum leptin (Lep) and tumor necrosis factor-alpha (TNF-α), serum testosterone (ST), total cholesterol (TC) and inflammatory status by measuring interleukin-6 (IL-6). Three groups of subjects, the normal controls (NC; n:98; age range: 51-60 years), HT (n: 97; age range: 51-60 years) subjects, and OHT (n: 97; age range: 51-60 years) subjects were studied. Comparisons for Lep, ST, TNF-α, IL-6 and TC levels for the subject groups showed significant variations. The ST indicated significant difference only for NC vs. OHT. The IL-6 gave significant difference for NC vs. OHT and HT vs. OHT. The one-way ANOVA showed significant difference among groups for BMI, TC, IL-6, TNF-α, ST and Lep levels. Significant positive linear correlation for all groups among Lep, TNF-α, IL-6 and TC were found. The ST against TC for HT and OHT groups presented non-significant negative linear correlations. The ST showed significant negative linear correlation with other variables. Conclusively, the present study uncovers the interactive impact of serum leptin, TNF-α, testosterone, total cholesterol and IL-6 in hypertensive and overweight-related hypertensive men.

We previously reported a novel secondary progressive multiple sclerosis (SPMS) model, progressive experimental autoimmune encephalomyelitis (pEAE), in oligodendroglia-specific Cx47-inducible conditional knockout (Cx47 icKO) mice. Based on our prior study showing the efficacy of iguratimod (IGU), an anti-rheumatic drug, for acute EAE treatment, we aimed to elucidate the effect of IGU on the SPMS animal model. We induced pEAE by immunizing Cx47 icKO mice with myelin oligodendrocyte glycoprotein peptide 35–55. IGU was orally administered from 17 to 50 days postimmunization. We also prepared primary mixed glial cell culture and measured cytokine levels in the culture supernatant after stimulation with designated cytokines (IL-1α, C1q, TNF-α) and lipopolysaccharide. A migration assay was performed to evaluate the effect of IGU on the migration ability of T cells toward mixed glial cell cultures. IGU treatment ameliorated the clinical signs of pEAE, decreased the demyelinated area, and attenuated glial inflammation on immunohistochemical analysis. Additionally, IGU decreased the intrathecal IL-6 level and infiltrating Th17 cells. The migration assay revealed reduced Th17 cell migration and IL-6 levels in the culture supernatant after IGU treatment. Collectively, IGU successfully mitigated the clinical signs of pEAE by suppressing Th17 migration through inhibition of IL-6 production by proinflammatory-activated glial cells.

Natural image matting is an essential technique for image processing that enables various applications, such as image synthesis, video editing, and target tracking. However, the existing image matting methods may fail to produce satisfactory results when computing resources are limited. Sampling-based methods can reduce the dimensionality of the decision space and therefore reduce computational resources by employing different sampling strategies. While these approaches reduce computational consumption, they may miss an optimal pixel pair when the number of available high-quality pixel pairs is limited. To address this shortcoming, we propose a novel multi-criterion sampling strategy that avoids missing high-quality pixel pairs by incorporating multi-range pixel pair sampling and high-quality samples selection method. This strategy is employed to develop a multi-criterion matting algorithm via Gaussian process, which searches for the optimal pixel pair by using the Gaussian process fitting model instead of solving the original pixel pair objective function. Experimental results demonstrate that our proposed algorithm outperforms other methods even with 1% computing resources, and achieves alpha matte results comparable to those yielded by the state-of-the-art optimization algorithms.

Parkinson’s-disease (PD) is an incurable age-related neurodegenerative disease and its global prevalence of disability and death has increased exponentially. Although motor symptoms are the characteristic manifestations of PD, the clinical spectrum also contains a wide variety of non-motor symptoms, which are the main cause of disability and determinants of the decrease in a patient's quality of life. Noteworthy in this regard is the stress on the cardiac system that is often observed in the course of PD, however its effects have not yet been adequately researched. Here, an untargeted metabolomics approach was used to assess changes in cardiac metabolism in the 6-hydroxydopamine model of PD. Beta-sitosterol, campesterol, cholesterol, monoacylglycerol, α-tocopherol, stearic acid, beta-glycerophosphoric acid, o-phosphoethanolamine, myo-inositol-1-phosphate, alanine, valine and allothreonine, are the metabolites that significantly discriminate Parkinsonian rats from sham counterparts. Upon analysis of the metabolic pathways with the aim of uncovering the main biological pathways involved in concentration patterns of cardiac metabolites, biosynthesis of both phosphatidylethanolamine and phosphatidylcholine, glucose-alanine cycle, the glutathione metabolism and plasmalogen synthesis most adequately differentiated sham and Parkinsonian rats. Our results reveal that both lipid and energy metabolism are particularly involved in changes in cardiac metabolism in PD. These results provide insight into cardiac metabolic signatures in PD and indicate potential targets for further investigation.