The ground consists of many layers of soil with different properties. The propagation speed and path of seismic waves are affected by different soil layers. It is necessary to understand that layered soil exhibits different dynamic behaviors and responses under the action of seismic waves. This study utilized weathered soil and silica sand as materials to create multi-layered soil conditions with varying degrees of compaction. By conducting 1 g shaking table test on multi-layered soil, the interaction and influence between different soil layers under different earthquake conditions were observed. The approach of numerical analysis aims to validate the experimental results and provide an in-depth understanding of the dynamic behaviors of multi-layered soil grounds during seismic events. The results of this study show that the amplification effect of seismic waves is related to the number of soil layers and the degree of compaction of the soil layers. This indicates that the multi-layered soil ground and the behavior of the soil layers play an important role in the propagation and impact of seismic waves, and this amplification effect is of great significance in actual seismic disaster risk assessment and design.

Neurofibromatosis type 2 (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2-deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2-deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.

Ipomoea batatas L. (IBL) has gained significant popularity as a complementary therapy or herbal medicine in the treatment of anti-diabetes. The objective of this review is to examine the mechanism of action of flavonoid compounds found in IBL that can activate GLP-1 as an anti-diabetic agent. The review article refers to PRISMA guidelines. The literature search was conducted using electronic databases such as Crossref, Pubmed, Scopus, and Science Direct. The search query was based on specific keywords, including Ipomoea batatas OR sweet potato AND anti-diabetic OR hypoglycemic. A total of 1055 articles were found, but only 32 articles were selected for further review based on inclusion and exclusion criteria. IBL contains various compounds, including phenolic acid, flavonols, flavanols, flavones, and anthocyanins, which exhibit activity against anti-diabetes. Flavonols, flavonols, and flavones belong to a group of flavonoids that possess the ability to form complexes with AlCl3 and Ca2+. Retention of Ca2+ within intracellular L cells, resulting in the release of GLP-1. Flavonols, flavones, and flavone groups have been found to strongly interact with DPP-IV, which inhibits the degradation of GLP-1. This mechanism effectively prolongs the half-life of GLP-1 in the systemic system, thereby contributing to the anti-diabetic activity of IBL

The three dimensional conformable time fractional Kadomtsev-Petviashvili and the conformable time fractional modified Kawahara equations are solved by implementing the Kudryashov's procedure. The corresponding wave transformation reduces both equations to some ODEs. Balancing the nonlinear and the highest order derivative terms gives the structure of the solutions in the finite series form. The useful symbolic tools are used to solve the resultant algebraic systems. The solutions are expressed in explicit forms.

Glucose is the primary energy fuel used by the brain and is transported across the blood-brain barrier (BBB) by the glucose transporter type 1 and 2.[1] A GLUT1 genetic defect is responsible for glucose transporter type 1 deficiency syndrome (GLUT1DS). Patients with GLUT1DS may present with pharmaco-resistant epilepsy, developmental delay, microcephaly, and/or abnormal movements, with tremendous phenotypic variability. Diagnosis is made by the presence of specific clinical features, hypoglycorrhachia and an SLC2A1 gene mutation. Treatment with a ketogenic diet therapy (KDT) is the standard of care as it results in production of ketone bodies which can readily cross the BBB and provide an alternate energy source to the brain in the absence of glucose. KDTs have been shown to reduce seizures and abnormal movements in children diagnosed with GLUT1DS. However, little is known about the impact of KDT on cognitive function, seizures and movement disorders in adults newly diagnosed with GLUT1DS and started on a KDT in adulthood, or the appropriate ketogenic diet therapy to administer. This case report demonstrates the potential benefits of using a modified Atkins diet (MAD), a less restrictive ketogenic diet therapy on cognition, seizure control and motor function in an adult with newly-diagnosed GLUT1SD.

Akt1 is a proto-oncogene that is over active in most cancers. Akt1 activation requires phosphorylation at Thr308; phosphorylation at Ser473 further enhances catalytic activity. Akt1 activity is also regulated via interactions between the kinase domain and the N-terminal auto-inhibitory pleckstrin homology (PH) domain. As it was previously difficult to produce Akt1 in site-specifically phosphorylated forms, the contribution of each activating phosphorylation site to auto-inhibition was unknown. Using a combination of genetic code expansion and in vivo enzymatic phosphorylation, we produced Akt1 variants containing programmed phosphorylation to probe the interplay between Akt1 phosphorylation status and the auto-inhibitory function of the PH domain. Deletion of the PH domain increased the enzyme activity for all three phosphorylated Akt1 variants. For the doubly phosphorylated enzyme, deletion of the PH domain relieved auto-inhibition by 295-fold. We next found that phosphorylation at Ser473 provided resistance to chemical inhibition by Akti-1/2 inhibitor VIII. The Akti-1/2 inhibitor was most effective against pAkt1T308 and showed 4-fold decreased potency with Akt1 variants phosphorylated at Ser473. The data highlight the need to design more potent Akt1 inhibitors that are effective against the doubly phosphorylated and most pathogenic form of Akt1.

Recently, Shehata et al. [37] introduced the r+1Rs(B;C; z) matrix function and established some properties. The aim of this study established to devote and derive certain basic properties including analytic properties, recurrence matrix relations, dierential properties, new integral representations, k- Beta transform, Laplace transform, fractional k-Fourier transform, fractional integral properties, the k-Riemann{Liouville and k-Weyl fractional integral and derivative operators an extended version of r+1Rs;k matrix function. We establish its relationships with other well known special matrix functions which have some particular cases in the context of three parametric Mittag-Leer matrix function, k- Konhauser and k-Laguerre matrix polynomials. Finally, some special cases of the established formulas are also discussed.

Novel severe acute respiratory syndrome coronavirus 2 infection (SARS-Cov-2) is an acute respiratory and infectious disease. This perspective aims to provide the basic understanding of the inflammation caused by SARS-Cov-2 and relation to trigeminal ganglion (TG). Virus enters through the mucous membranes of orofacial region and reach the TG where it resides and take control of its peptides including Substance P (SP).SP is the main neuropeptide, neuromodulator and neuro-hormone of TG, associated with nociception and inflammation under noxious stimulus. SP release is triggered and consequently, it affects the immune cells, blood vessels to release the mediators for inflammation. Cytokine storming is initiated and cause respiratory distress, bronchoconstriction and death in complicated cases. Neurokinin-1 Receptor (NK-1R) antagonist and glucocorticoids may be used to alleviate the symptoms and treat this infection. SP is the main culprit seem to be involved in the triggering of inflammatory pathways in SARS-Cov-2 infection. It has direct association with cardiorespiratory rhythm, sleep-wake cycle, nociception, ventilator responses and regulates many important physiological and pathological roles. Its over-secretion should be blocked by NK-1R antagonist. However, experimental work leading to clinical trials are mandatory for further confirmation.

The uneven immunogenicity of the attenuated tetravalent dengue vaccine has created the diffi-culty to achieve a balanced protection against all four serotypes of dengue virus (DENV). To overcome this problem, non-replicative-based vaccines have come into focus as their immuno-genicity is adjustable. This approach is excellent for multivalent vaccines but commonly faces the issue of low immunogenicity. In this present study, we developed a non-replicating dengue vaccine composing of UV-inactivated dengue-2 virus (UV-DENV2) and DENV-2 NS1-279 protein encapsidated within nanoparticles. This vaccine candidate was administered in the presence of BCG cell wall cytoskeleton (BCG-CWS) as an adjuvant. We revealed, here, that encapsidated immunogens with BCG-CWS exerted potent activities on both B and T cells and elicited Th-1/Th-2 responses in mice. This was evidenced by strong neutralizing antibody activity with an unde-tectable antibody enhancing activity in a group of mice receiving encapsidated immunogens with BCG-CWS. Importantly, BCG-CWS significantly augmented antibody-mediated comple-ment-fixing activity, strongly stimulated the antigen-specific polyfunctional T cell responses as well as activated mixed Th-1/Th-2 responses specific to DENV2- and NS1-279 antigens. In conclu-sion, BCG-CWS potently adjuvanted the inactivated DENV-2 and subunit DENV immunogens. The mechanism of adjuvanticity remains unclear. This study revealed the potential use of BCG-CWS in vaccine development.

Mangifera indica (mango), a member of the Anacardiaceae family, is renowned for its diverse pharmacological properties, encompassing antidiabetic, antioxidant, antiviral, cardiotonic, hypotensive, and anti-inflammatory effects. The present study delves the insulin-releasing and glucose-lowering potential of the ethanolic extract of Mangifera indica (EEMI) leaves in streptozotocin (STZ)-induced type 2 diabetic rats, concurrently investigating its phytoconstituents. EEMI's effects on insulin secretion were measured using BRIN BD11 β-cells and isolated mouse islets. It’s enzymatic inhibitory properties on carbohydrate digestion, glucose absorption, and free radicals were investigated using starch digestion, glucose diffusion and DPPH assay methods. In-vivo parameters including lipid profile and liver glycogen content were assessed on streptozotocin-induced type 2 diabetic rats. EEMI exhibited a dose-dependent increase in insulin secretion from clonal pancreatic BRIN BD11 β-cells and isolated mouse islets. EEMI inhibited starch digestion, glucose diffusion over time and DPPH activity in vitro. In acute in vivo studies, EEMI improved food intake, oral glucose tolerance. Moreover, following 28 days of treatment with EEMI, a remarkable amelioration in body weight, fasting blood glucose, plasma insulin, liver glycogen content, total cholesterol, triglyceride, LDL, VLDL and HDL levels were observed. Further phytochemical analysis with EEMI identified the presence of alkaloids, tannins, saponins, steroids, glycosides, flavonoids, and reducing sugar. The synergistic effects of EEMI, potentially attributable to naturally occurring phytoconstituents, hold promise for the development of enriched antidiabetic therapies, offering a promising avenue for the management of type 2 diabetes.

A novel effective vibrational mode was discovered in the conventional transducer with an array of orthogonal (square) regular piezoelectric rods in 1-3 piezocomposite, containing the damping backing and front matching layers. The operational resonance in the structure was determined as the Surface Acoustic Wave (SAW) on the backing boundary excited by the adjacent piezo-rods, with its frequency typically near 3 times lower the fundamental half-lambda conventional piezocomposite resonance. Pulse-echo sensitivity and transmitting sound-pressure-level (SPL) in air showed that the signal strength is roughly comparable to the industrial similar air transducers at the frequency range 100…700 kHz, where at these frequencies the lateral and longitudinal piezoelement dimensions in the conventional transducer design are typically close to each other causing interference with unwanted coupling modes. As was determined theoretically and proved in experiments, the backing SAW resonance effect in the transducer performance is inherent just to the regular periodic 1-3 piezocomposite structure, and does occur neither with randomly located/oriented piezo-rods, nor in the homogeneous piezo-plate at least with the same lateral cross-section as the connected to it backing. The purpose of the article is to investigate a newly discovered operational vibrational mode of a SAW type in 1-3 regular piezocomposite, other than piezoelectric resonance. The investigated phenomena can improve the transceiver sensitivity, bandwidth, providing lower drive voltage, and smaller and lighter weight ultrasonic transducers. Based on the piezocomposites with thickness’ 1…1.5 mm (rod resonance near 2…3 MHz), pillar width 0.2…0.8 mm, kerf width 0.1…0.4 mm, the transceivers with an operating frequency from 140 kHz to 650 kHz were designed and fabricated with a conventional backing of a mixture of high-density tungsten powder and epoxy, and a matching layer of a mixture of low-density glass bubbles and epoxy. Experimental evaluation of their acoustical performance showed expected characteristics suitable for practical applications.

Background. Waning of neutralizing and cell-mediated immune response after the primary vac-cine cycle (PVC) and the first booster dose (BD) is of concern, especially for PLWH with a CD4 count ≤200 cells/ mm3.Methods.Neutralizing antibodies (nAbs) titers by microneutralization assay against WD614G /Omicron BA.1 and IFNγ production by ELISA assay were measured in samples of PLWH at 4 time points [2 and 4 months post-PVC (T1 and T2), 2 weeks and 5 months after the BD (T3 and T4)]. Participants were stratified by CD4 count after PVC (LCD4, <200/mm3; ICD4, 201-500/mm3 and HCD4, >500/mm3). Mixed models were used to compare mean responses over T1-T4 across CD4 groups. Results. 314 PLWH on ART (LCD4=56; ICD4=120; HCD4=138) were enrolled. At T2, levels of nAbs were significantly lower in LCD4 vs ICD4/HCD4 (p=0.04). BD was crucial for increasing nAbs titres above 1:40 at T3 and up to T4 for WD614G. A positive T cell response after PVC was observed in all groups, regardless of CD4 (p=0.31). Conclusions. Waning of nAbs after PVC was more important in LCD4 group. BD managed to re-establish higher levels of nAbs against WD614G which were retained for 5 months. The level of T-cellular response was significantly higher in HCD4 and ICD4 compared to the LCD4 group although it remained above detectable levels over the entire study period regardless of CD4 count. Keywords: HIV-1 infection; SARS-CoV-2 infection;

Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers). These peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability. Our results demonstrate that several peptoids exhibit potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection. Visualization by cryo-EM shows viral envelope disruption similar to what has been observed with AMP activity against other viruses. This suggests a common or biomimetic mechanism, possibly due to the differences between the phospholipid head group makeup of viral envelopes and host cell membranes. Furthermore, we observed no cytotoxicity against primary cultures of oral epithelial cells, thus underscoring the potential of this class of molecules as safe and effective broad-spectrum antiviral agents.

HIV-1 transcribes only one kind of transcript – the full length genomic RNA. To make the mRNA transcripts for the accessory proteins Tat and Rev, the genomic RNA must completely splice. The mRNA transcripts for Vif, Vpr, and Env must splice but not completely. Genomic RNA (which also functions as mRNA for the Gag and Gag/Pro/Pol precursor polyproteins) must not splice at all. HIV-1 can tolerate a surprising range in the relative abundance of individual transcript types, and a surprising amount of aberrant and even odd splicing; however, it must not over-splice, which results in the loss of full length genomic RNA and has a dramatic fitness cost. Cells typically do not tolerate unspliced/incompletely spliced transcripts, so HIV-1 has to circumvent this cell policing mechanism to allow some splicing while suppressing most. Splicing is controlled by RNA secondary structure, cis-acting regulatory sequences which bind splicing factors, and the viral protein Rev. There is still much work to be done to clarify the combinatorial effects of these splicing regulators. These control mechanisms represent attractive targets to induce over-splicing as an antiviral strategy. Finally, splicing has been implicated in latency, but to date there is little supporting evidence for such a mechanism. In this review we apply what is known of cellular splicing to understand splicing in HIV-1, and also present data from our newer and more sensitive deep sequencing assays quantifying the different HIV-1 transcript types.

Background: The global prevalence of anxiety and depressive symptoms in adolescents has increased considerably during the COVID-19 pandemic. Mental health problems may compromise glycemic control in young people with type 1 diabetes; however, evidence of improved glycemic control in adolescents with T1D appeared early during the pandemic. This qualitative study aimed to provide a more in-depth understanding of how the COVID-19 pandemic affected adolescents with type 1 diabetes routines, experiences, T1D management, behaviors, and mental health. Methods: 24 adolescents, aged 15-18 years, with DM1, joined the discussion of focus groups in the context of the summer camp for diabetes. Word frequency and thematic analysis were conducted on adolescents’ narratives. Results: The word Frequency Analysis identified 'friends', 'family', and 'home' as the most frequent terms. Seven themes were identified: (1) COVID-19 and T1D; (2) emotional reactions to the COVID-19 pandemic; (3) changes in daily life; (4) feelings of loss; (5) coping with the COVID-19 pandemic; (6) the COVID-19 pandemic as an opportunity; (7) return to (new) normality. Conclusions The COVID-19 pandemic may have represented a more stressful condition for adolescents with DM1, facing additional challenges compared to their healthy peers. The results offer directions to the diabetes care team for a customized intervention while the consequences of the pandemic on adolescents’ health continue.

When it is in the template RNA, the naturally occurring m¹A epitranscriptomic RNA modification was recently reported to be able to stop the RNA polymerization reaction catalyzed by the RNA dependent RNA polymerase (RdRp) of SARS-CoV-2. In this report, we report that m¹A via its triphosphate form (m¹ATP) can be incorporated into RNA by the same RdRp. These two findings point a new direction for antiviral drug development based on m¹A for combatting COVID-19. More broadly, it is possible that the large pool of epigenetic RNA as well as DNA modifications could serve as a treasury for drug discovery aimed at combating various infectious and other diseases.

Results showed that mulberry leaves could significantly reduce backfat thickness (P&lt;0.05) and increase intramuscular fat (IMF) content (P&lt;0.05). Lipidomics analysis showed that mulberry leaves improved lipid profile composition and increased the proportion of triglycerides (TG). Interestingly, IMF content was positively correlated with acyl C18:2 and negatively correlated with C18:1 of differential TGs. In addition, cecal microbiological analysis showed that mulberry leaves could increase the abundance of bacteria such as UCG−005, Muribaculaceae_norank, Prevotellaceae_NK3B31_group, Limosilactobacillus, and so on. At the same time improve the L-tyrosine-baton rouge ester, Oleic acid methyl ester, 21-deoxycortisol, N-acetyldihydrosphingosine, Mulberrin relative abundance. In this study, we found that mulberry leaves could extremely significantly increasing the mRNA relative expression of lipoprotein lipase (LPL), fatty acid-binding protein 4 (FABP4) and peroxisome proliferators-activated receptor γ (PPARγ) in muscle (P＜0.01), significantly increasing mRNA relative expression of diacylglycerol acyltransferase 1 (DGAT1) (P＜0.05) and significantly decreasing the mRNA relative expression of acetyl CoA carboxylase (ACC) (P＜0.05), and aignificantly upregulated hormone-sensitive triglyceride lipase (HSL), peroxisome proliferators-activated receptor α (PPARα) mRNA relative expression (P＜0.05) in backfat. In addition mulberry leaves could increased serum leptin and adiponectin (P＜0.01). Ultimately lead to up-regulation of IMF and down-regulation of backfat.

Proprotein convertases activate various envelope glycoproteins and participate in cellular entry of many viruses. We recently showed that the convertase furin is critical for the infectivity of SARS-CoV-2. This study investigated the implication of the two cholesterol-regulating convertases SKI-1 and PCSK9 in SARS-CoV-2 entry. We used cell-to-cell fusion assays in HeLa cells and pseudoparticle entry into Calu-3 cells. SKI-1 increases cell-to-cell fusion by enhancing the activation of SREBP-2, whereas PCSK9 reduces cell-to-cell fusion by promoting the cellular degradation of ACE2. Metalloprotease activation is sensitive to enhanced cholesterol levels resulting from SKI-1-activated SREBP-2 that leads to enhanced S2’ formation. However, high metalloprotease activity results in S2’ shedding into a new C-terminal fragment (S2”), leading to reduced cell-to-cell fusion. Indeed, S-mutants that increase S2’’ formation, abolish S2’ and cell-to-cell fusion, as well as pseudoparticles entry, indicating that the formation of S2’’ prevents SARS-CoV-2 cell-to-cell fusion and entry. We next demonstrated that PCSK9 enhanced the cellular degradation of ACE2, thereby reducing cell-to-cell fusion. However, different from the LDLR, a canonical target of PCSK9, the C-terminal CHRD domain of PCSK9 is dispensable for the PCSK9-induced degradation of ACE2. Molecular modeling suggested binding of ACE2 to the Pro/Catalytic domains of mature PCSK9. Thus, both cholesterol-regulating convertases SKI-1 and PCSK9 can modulate SARS-CoV-2 entry via two independent mechanisms.

The premise regarding COVID-19 disease is that it is a spectrum which begins with infection with viral SARS-CoV-2 exposure via airborne or oral virus particles. The individual response to it depends on many factors including co-morbid conditions. An important aspect of SARS-CoV-2 virus infection is the cytokine storm that develops after the infection. The immuno-chemical chaos created in this cytokine storm is to the benefit of the virus. In this meta analysis the authors explore ways to let the cytokine storm die down by looking into the role of histamine. Histamine is a metabolic product of the essential aminoacid histidine. Histamine has 4 known receptors: H1, H2, H3 and H4. The immunoglobulines IgE and IgM are indicative for a COVID-19 infection. This immune response is related to inflammation. Inflammation, in turn, runs mainly via histamine after e.g. virus inoculation. The goal of the meta-study is to gather evidence to primarily block the H4 receptor (H4R) in gastrointestinal cells to diminish the cytokine overproduction in the $\approx$ 30\% of the patients suffering from gastrointestinal problems caused by SARS-CoV-2. Our concept is as follows. If we can strike a careful balance between hampering the gastrointestinal spreading of the virus and histamine antagonists to tackle the cytokine storm, then the natural immunity can later on come on line again and attack the virus without being led astray by cytokine chaos. We will concentrate on H4R but also look at H1R and H2R related effects. The proposed substances in our systemic approach can be balanced for an effective early treatment. The nature of our work is by its method and results theoretical. In that respect we also may note the structural chemistry indol skeleton resemblance among a number of different drugs.

In a recent study, the PD-1 inhibitor has been widely used in clinical trials and shown to improve various cancers. However, PD-1/PD-L1 inhibitors showed a low response rate and showed to be effective for a small number of cancer patients. Thus, it is important to identify key genes, which can enhance the PD-1/PD-L1 response for promoting immunotherapy. Here, we used ssGSEA and unsupervised clustering analysis to identify three clusters to show different immune cell infiltration status, prognosis, and biological action. The cluster C showed a better survival rate, high immune cells infiltration, and immunotherapy effect enriched in a variety of immune active pathways, including T and B cell signal receptors. Besides, it showed more immune subtypes C2 and C3. Further, we used WGCNA analysis to confirm the cluster C correlated genes. The red module highly correlated with cluster C for 111 genes which were enriched in a variety of immune-related pathways. To pick candidate genes in SD/PD and CR/PR patients, we used the Least Absolute Shrinkage and SVM-RFE algorithms. In conclusion, our LASSO analysis and SVM-RFE based research identified targets with better prognosis, activated immune-related pathways, and better immunotherapy. The KLRC3 was identified as the key gene which can efficiently respond to immunotherapy with greater efficacy and better prognosis.

Immunotherapy has been considered for years as a viable and attractive treatment option for patients with cancer. Among immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionized the treatment of several subtypes of tumours. These approaches aimed at restoring an effective anti-tumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells, and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because in these diseases the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and will build a projection of how the field may evolve in the near future. In particular, we will analyze the current strategies being evaluated both preclinically and clinically with the aim to foster the use of immune-checkpoint inhibitors in non-Hodgkin lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.

Bovine Respiratory Disease Complex, a complex respiratory ailment in cattle, results from a combination of viral and bacterial factors, compounded by environmental stressors such as overcrowding, transportation, and adverse weather conditions. Its impact extends beyond mere health concerns, posing significant economic threats to the cattle industry. This study presents an extensive investigation into viral pathogens associated with BRDC in Serbian cattle, utilizing serum samples and nasal swabs. A cross-sectional study was conducted in 2024 across 65 randomly selected dairy farms in Serbia, excluding vaccinated farms. Farms were categorized by livestock count: small (≤50 animals), medium-sized (51-200 animals), and large (&gt;200 animals). Serum samples from adult cattle older than 24 months were tested for antibodies against BVDV, BHV-1, BRSV, and BPIV3. Nasal swab samples from animals with respiratory signs were tested using PCR for viral genome detection. Results showed seropositivity for all four viruses across all farms, with BPIV3 exhibiting universal seropositivity. Medium-sized and large farms demonstrated higher seropositivity for BRSV and BHV-1 compared to small farms (p&lt;.05). True seroprevalence estimates at the animal level were 84.29% for BRSV, 54.08% for BVDV, 90.61% for BHV-1, and 84.59% for BPIV3. PCR analysis of nasal swabs revealed positive detections for BRSV (20%), BHV-1 (1.7%), BVDV (8%), and BPIV3 (10.9%). Influenza D virus was not found in any of samples. This study provides critical insights into the prevalence and circulation of viral pathogens associated with BRDC in Serbian cattle, emphasizing the importance of surveillance and control measures to mitigate the impact of respiratory diseases in cattle populations.

Satellite Crop Detection technologies are focused on detection of different types of crops on the field in the early stage before harvesting. Crop detection is usually done on a time series of satellite data by classification of the desired fields. Currently, data obtained from Remote Sensing (RS) are used to solve tasks related to the identification of the type of agricultural crops, also modern technologies using AI methods are desired in the postprocessing part. In this challenge Sentinel-1 and Sentinel-2 time series data were used due to their periodic availability. Our focus was to develop methodology for classification of time series of Sentinel 2 and Sentinel 1 data and compare how accuracy of classification can be increased, but also how to guarantee availability of data. We analyse phenology of single crops and on the basis of this analysis we started to provide crop classification. Original crop classifications were made from Enhanced Vegetation Index (EVI) layers made from Sentinel-2 time-series data and then we added also . To increase accuracy we also integrate into the process parcel borders and provide classification of fields..

A timely inventory of agricultural areas and crop types is an essential requirement for ensuring global food security. Satellite remote sensing has proven to be an increasingly more reliable tool to identify crop types. With the Copernicus program and its Sentinel satellites, a growing source of satellite remote sensing data is publicly available at no charge. Here we use joint Sentinel-1 radar and Sentinel-2 optical imagery to create a crop map for Belgium. To ensure homogenous radar and optical input across the country, Sentinel-1 12-day backscatter composites were created after incidence angle normalization, and Sentinel-2 NDVI images were smoothed to yield dekadal cloud-free composites. An optimized random forest classifier predicted the 8 crop types with a maximum accuracy of 82% and a kappa coefficient of 0.77. We found that a combination of radar and optical imagery always outperformed a classification based on single-sensor inputs, and that classification performance increased throughout the season until July, when differences between crop types are largest. Furthermore we showed that the concept of classification confidence derived from the random forest classifier provided insight in the reliability of the predicted class for each pixel, clearly showing that parcel borders have a lower classification confidence. We concluded that the synergistic use of radar and optical data for crop classification led to richer information increasing classification accuracies compared to optical-only classification. Further work should focus on object-level classification and crop monitoring to exploit the rich potential of combined radar and optical observations.

Pteridine reductase 1 is a trypanosomatid multifunctional enzyme that provides a mechanism for escape of Dihydrofolate reductase (DHFR) inhibition. This is because PTR1 can reduce pterins and folates. Trypanosomes require folates and pterins for survival and are unable to synthesize them de novo. Currently there are no anti-folate based Human African Trypanosomiasis (HAT) chemotherapeutics in use. Thus, successful dual inhibition of TbDHFR and TbPTR1 has implications in the exploitation of anti-folates. We carried out molecular docking of a ligand library of 5742 compounds against TbPTR1 and identified 18 compounds showing promising binding modes. The protein-ligand complexes were subjected to Molecular dynamics to characterize their molecular interactions and energetics followed by in vitro testing. In this study, we identified five potential TbPTR1 inhibitors that showed low micromolar Trypanosome growth inhibition in in vitro experiments with no significant human cell cytotoxicity. Compounds RUBi004, RUBi007, RUBi014, and RUBi018 displayed moderate to strong antagonism when used in combination with the known TbDHFR inhibitor, WR99210. This gave an indication that the compounds might inhibit both TbPTR1 and TbDHFR. RUBi016 showed an additive effect in the isobologram assay. Our results provide a basis for scaffold optimization for further studies in the development of HAT antifolates.

Type 2 Diabetes Mellitus (T2DM) is associated with a high risk of atherosclerotic cardiovascular (CV) disease. Contributing pathophysiologic factors include endothelial dysfunction caused by excessive production of reactive oxygen species (ROS), increased activity of nuclear factor kB (NFkB), altered macrophage polarization, and reduced synthesis of endothelial progenitor cells (EPC). Consequently, there can be a potentially rapid progression of the atherosclerotic disease with a higher propensity to unstable plaque, leading to increased cardiovascular mortality. Management is aimed at prevention, early diagnosis, and treatment of hyperglycemia and vascular complications. Innovative therapeutic approaches for T2DM seek to customize the antidiabetic treatment to each patient in order to optimize glucose-lowering effects, minimize hypoglycemia and adverse effects, and prevent cardiovascular events. The newer drugs (Glucagon Like Peptide-1 Receptor Agonists, GLP-1 RAs; Sodium GLucose coTransporter-2 inhibitors, SGLT2is; DiPeptidyl Peptidase-4 inhibitors, DPP4is) impact body weight, lipid parameters, and blood pressure, as well as endothelial function, inflammatory markers, markers of oxidative stress, and subclinical atherosclerosis. The present review summarizes the results of trials that evaluated the cardiovascular safety of these drugs and found them to be safe from the CV standpoint.

Objective: To analyze the relation between alterations in the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis during the first 6 months of life and weight in children born in the Lower Middle São Francisco region. Methods: This is an analytical cohort, with a quantitative approach and a translational perspective. Thirty children with low and normal birth weight were initially identified in a hospital and reapproached at 3 and 6 months of age. Birth weight and alterations in GH/IGF-1 curves at birth, third month, and sixth month of life. Results: Weight gain during the 6 months of follow-up in newborns with low birth weight was greater compared to newborns with normal birth weight. All children who were born with low birth weight had an altered GH/IGF-1 curve at birth (p = 0.002). Most newborns with low birth weight maintained the alteration in the GH/IGF-1 curve at the third month of life (p = 0.027). Regarding the GH/IGF-1 curve at the sixth month, alteration persisted in greater proportion among children with low birth weight. Conclusion: Alterations in insulin resistance markers, demonstrated by increased GH without a proportional increase in IGF-1, were observed to be significant in children with low birth weight, with greater adiposity in this group, which may increase the risk of metabolic diseases in later life.

Antisense oligonucleotide (ASO)-mediated exon skipping has emerged as a powerful tool for examining the function of genes and exons in basic research, as well as gene therapy. Computational methods, such as eSkip-Finder, have been developed to predict the efficacy of ASOs via exon skipping using machine learning. However, these methods can be computationally demanding and the prediction accuracy of the tool is not yet optimal. In this study, we propose an approach to reduce computational burden and improve prediction performance by utilizing feature selection within machine learning algorithms and employing ensemble learning techniques. The method was evaluated using a dataset of genes with experimentally validated exon skipping events. The dataset was divided into training and testing sets to assess the accuracy of the algorithm. Our results demonstrate that using a 3-way voting approach with random forest, gradient boosting, and XGBoost can significantly reduce computation time to under ten seconds while improving prediction performance, as measured by R2 for both 2’-O-methyl nucleotides (2OMe) and phosphorodiamidate morpholino oligomers (PMOs). Additionally, the feature importance ranking derived from our approach is in good agreement with previously published results. These findings suggest that this approach has the potential to enhance the efficiency and accuracy of predicting ASO efficacy via exon skipping, facilitating the development of novel therapeutic strategies.

Introduction: The objective of the study is to assess the failure of therapies with HFNO (High-Flow Nasal Oxygen), CPAP, Bilevel or combined therapy in patients with hypoxemic acute respiratory failure due to SARS-CoV-2 during their hospitalization. Methods: Retrospective and observational study of SARS-CoV-2 positive patients who required non-invasive respiratory support (NIRS), at the Reina Sofía General University Hospital of Murcia between March 2020 and May 2021. Results: Of 7355 patients, 197 (11,8%) were included. 95 of them failed this therapy (48,3%). We objectivated that during hospitalization in the ward the combined therapy with HFNO and CPAP had a lower failure rate overall and the highest treatment purely with Bilevel (p = 0,005). In the comparison of failure in therapy without two levels of airway pressure, HFNO, CPAP and combined therapy of HFNO with CPAP, (35,6% of patients) presented a 24,2% failure compared to those who did have two levels of pressure with Bilevel and combined therapy of HFNO with Bilevel (64,4% of patients) with 75,8% associated failure (OR: 0, 374; CI 95%: 0,203-0,688. p=0,001).Conclusions: The use of NIRS in conventional hospitalization is safe and effective in patients with respiratory failure secondary to SARS-CoV-2 infection. The therapeutic strategy with Bilevel increases the probability of failure, with the combined therapy strategy with CPAP and HFNO being the most promising option.

Surface soil moisture (SSM) is a significant factor affecting crop growth. This paper presents a method for retrieving SSM over wheat-covered areas using synergy dual-polarization C-band Sentinel-1 synthetic aperture radar and Sentinel-2 optical data. Firstly, a modified water cloud model (WCM) was proposed to remove the influence of vegetation from the backscattering coefficient of the radar data. The vegetation fraction was then introduced in this WCM, and the vegetation water content (VWC) was calculated using multiple linear regression model. Subsequently, the support vector regression technique was used to retrieve the SSM. This approach was validated using in-situ measurements of the wheat field in Hebi, in the north of Henan Province. The key findings of this study are as follows: (1) Based on vegetation indices obtained from Sentinel-2; the proposed VWC estimation model can effectively eliminate the influence of vegetation; (2) compared with vertical transmit and horizontal receive polarization, vertical transmit and vertical receive polarization is better for detecting changes in SSM at different growth stages of wheat; and, (3) the validation results indicated that the proposed approach, based on Sentinel-1 and Sentinel-2 data, successfully retrieved SSM in the study area.

Abstract: Several publications have raised the issue that the development of diabetes is preceded by alteration of the microbiome (dysbiosis) and hence, the role of environmental factors, triggering dysbiosis, should be considered. Antibiotics are powerful agents inducing dysbiosis and the authors wanted to explore the possible relationship between the consumption of different major classes of antibiotics and the prevalence of diabetes (type-1, /T1D/, type-2 /T2D/) in thirty European countries. According to our hypothesis, if such association exists, the dominant use of certain major antibiotic classes might be reflected in the prevalence of T1D and T2D in different countries. Comparisons were performed between the prevalence of diabetes (T1D and T2D) estimated for 2019 and featured in the Diabetes Atlas with the average yearly consumption of major antibiotic classes of the previous 10 years (2010-19) extracted from the ECDC yearly reports on antibiotic consumption in Europe. Pearson correlation and variance analysis were used to estimate the possible relationship. Strong, positive (enhancer) associations were found between the prevalence of T1D and the consumption of tetracycline (J01A /p: 0.001/) and the narrow spectrum penicillin (J01CE /p: 0,006/, CF /p: 0.018/). Strong negative (inhibitor) association was observed with broad-spectrum, beta-lactamase resistant penicillin (J01CR /p: 0.003/), macrolide (J01F /p: 0.008/) and quinolone (J01M /p: 0.001/). T2D showed significant positive associations with cephalosporin (J01D /p: 0.048/) and quinolone (J01M /p: 0.025/), and a non-significant negative association was detected with broad-spectrum, beta-lactamase-sensitive penicillin (J01CA /p: 0.67/). Countries with the highest prevalence of diabetes (first 10 positions) showed concordance with the higher consumption of “enhancer” and the lower consumption of “inhibitor” antibiotics (first 10 positions) as indicated by variance analysis. Countries with high prevalence of T1D showed high consumption of tetracycline (p: 0.015), and narrow spectrum, beta-lactamase sensitive penicillin (p: 0.008), and low consumption of “inhibitor” antibiotics (broad-spectrum, beta-lactamase resistant, combination penicillin (p: 0.005), cephalosporin (p: 0.036), and quinolone (p: 0.003). Countries with a high prevalence of T2D consumed more cephalosporin (p: 0.084), quinolone (p: 0.54), and less broad-spectrum, beta-lactamase sensitive penicillin (p: 0.012) than other countries. Conclusion/Interpretation: The development of diabetes-related dysbiosis might be attached to higher consumption of specific classes of antibiotics, showing positive (enhancer) associations with the prevalence of diabetes, and the low consumption of other classes of antibiotics shoving negative (inhibitory) associations. Those groups of antibiotics are different in T1D and T2D

Fluorinated compounds and co-enzymes are being widely researched and employed throughout research community because of their versatile physical, chemical and biological properties. In this work, we synthesized NiS-NiO/S-g-C3N4, a highly effective photocatalyst for C(sp3)-F bond activation and the regeneration of coenzyme (1,4-NADH) employing a new and ecologically acceptable route. The obtained photocatalyst exhibited important photocatalytic properties, such as good solar light harvesting ability, suitability of the optical band-gap, and facilitating efficient charge migrations. As a result, the newly designed NiS-NiO/S-g-C3N4 photocatalyst shows the excellent yield for regenerations of 1,4-NADH (51%). Further, a method of combining C(sp3)-F bond activation with photocatalysis has been demonstrated that represents a very powerful and sustainable approach, that can be a major breakthrough for the field of pharmaceutical.

Tdp1 and Tdp2 are DNA repair enzymes that repair DNA damages caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reasons of resistance to such widely used drugs as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (-)-usnic acid. Both (+)- and (-)-enantiomers of compounds act equally effectively against Tdp1, and only (-)-enantiomers inhibited Tdp2. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide but potentiate it against Tdp2 knockout cells. We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with effective inhibition of Tdp1, which could take over the functions of Tdp2.

Mexico shows a high birth prevalence of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD). PAX8 defects underlie only 1% of these cases and NKX2-1 does not seem to be involved. Here, we analyzed other TD-related genes in 128 non-related Mexican patients (females 77.3%; 6 months to 16.6 years) with non-syndromic CH-TD diagnosis established by clinical evaluation, thyroid hormone serum profiling, and scintigraphy (74%) or ultrasonography (26%). We performed Sanger sequencing of FOXE1, NKX2-5, and TSHR and evaluated copy number variations (CNVs) in TSHR, FOXE1, PAX8, and NKX2-1 by multiplex ligation-dependent probe amplification. Odds ratios for TD risk were explored for FOXE1 polyalanine stretches [polyAla-rs71369530] in cases and controls (N=116). Five rare missense changes cataloged as benign (NKX2-5:p.(Ala119Ser)-rs137852684), of unknown significance (FOXE1:p.(Ala335Gly)-rs543372757; TSHR:p.(Asp118Asn)-rs1414102266), and likely pathogenic (FOXE1:p.(Gly124Arg)-rs774035532; TSHR:p.(Trp422Arg)-rs746029360) accounted for 1.5% (N=2/128) of clinically relevant genotypes (supported in part by protein modeling) in CH-TD. No CNVs were identified, nor did polyAla &gt;14 alanines in FOXE1 significantly protect against TD. The present and previously published data collectively show that small clinically relevant germline variants in PAX8, FOXE1, and TSHR are found in only a very small proportion (2.5%) of isolated CH-TD Mexican patients.

We study the μ-μ45-T phase diagram of the 2+1-dimensional Gross-Neveu model, where μ denotes the ordinary chemical potential, μ45 the chiral chemical potential and T the temperature. We use the mean-field approximation and two different lattice regularizations with naive chiral fermions. An inhomogeneous phase at finite lattice spacing is found for one of the two regularizations. Our results suggest that there is no inhomogeneous phase in the continuum limit. We show that a chiral chemical potential is equivalent to an isospin chemical potential. Thus, all results presented in this work can also be interpreted in the context of isospin imbalance.

Early-season crop-type data are required for a variety of agricultural monitoring and decision-making applications. The early season in this study referred to the prophase and middle of a growth season. Early-season detection of crop types remains challenging because of limited discriminative features, especially for landscapes that are characterized by complex cropping patterns. In fact, different remote-sensing satellites can increase the frequency of data acquisition, which can provide more information in the early season. Moreover, optical and radar sensors have different degrees of sensitivity to crop parameters. Therefore, the integration and application of two types of multitemporal data are of great significance to improve the accuracy and timeliness of crop type detection.In deep learning (DL), convolutional neural network (CNN) and recurrent neural network (RNN) models have great potential for temporal feature extraction. Compared with RNNs, CNNs usually have fewer parameters and are more conducive to determining early-season detection dates of different crop types, which requires a lot of training because of the need to model on different dates. Nevertheless, revisit dates and temporal intervals of different satellites are usually different, resulting in different data acquisition time series; these data cannot be directly used as input for the same convolutional layer. To address this challenge, a Dual-1DCNN was bulit based on the CNN model in this study. Moreover, an incremental training method was used to attain the network on each data acquisition date and obtained the best detection date for each crop type in the early season. A case study for Hengshui City in China was conducted using time series of Sentinel-1A (S1A) and Sentinel-2 (S2). To verify this method, classical methods support vector machine (SVM) and random forest (RF) were implemented. The results demonstrated the following: (1) the Dual-1DCNN extracted discriminative features from S1A and S2 time series at the early season by producing the highest overall accuracy (OA: 87.23%); (2) for summer maize, cotton, and common yam rhizome, the Dual-1DCNN achieved F1 values of 92.39%, 87.71%, and 84.38%, respectively, at the early season (moreover, the early seasons were almost 40, 70, and 80 days before the end of the growth seasons, respectively). These findings suggested that the Dual-1DCNN is promising for the accurate and timely detection of crop types.

At present, the world is at the peak of production of traditional fossil fuels. Much of the resources that humanity has been consuming (oil, coal and natural gas) are coming to an end. The human being faces a future that must necessarily go through a paradigm shift, which includes a progressive movement towards increasingly less polluting and energetically viable resources. In this sense, nanotechnology has a transcendental role in this change. For decades, new materials capable of being used in energy processes have been synthesized that undoubtedly will be the cornerstone of the future development of the planet. In this review, we report on the current progress in the synthesis and use of one-dimensional (1D) nanostructured materials (specifically nanowires, nanofibers, nanotubes and nanorods), with compositions based on oxides, nitrides, or metals, for applications related to energy. Due to its extraordinary surface-volume relationship, tunable thermal and transport properties, and its high surface area, these 1D nanostructures have become fundamental elements for the development of energy processes. The most relevant 1D nanomaterials, their different synthesis procedures, and useful methods for assembling 1D nanostructures in functional devices will be presented. Applications in relevant topics such as optoelectronic and photochemical devices, hydrogen production or energy storage, among others, will be discussed. The present review concludes with a forecast on the directions towards which future research could be directed on this class of nanostructured materials.

This study presents a vibration control using actively tunable vibration absorbers (ATVA) to suppress vibration of a thin plate. The ATVA’s is made of a sandwich hollow structure embedded with the electrorheological fluid (ERF). ERF is considered to be one of the most important smart fluids and it is suitable to be embedded in a smart structure due to its controllable viscosity property. ERF’s apparent viscosity can be controlled in response to the electric field and the change is reversible in 10 microseconds. Therefore, the physical properties of the ERF-embedded smart structure, such as the stiffness and damping coefficients, can be changed in response to the applied electric field. A mathematical model is difficult to be obtained to describe the exact characteristics of the ERF embedded ATVA because of the nonlinearity of ERF’s viscosity. Therefore, a fuzzy modeling and experimental validations of ERF-based ATVA from stationary random vibrations of thin plates are presented in this study. Because Type-2 fuzzy sets generalize Type-1 fuzzy sets so that more modelling uncertainties can be handled, a semi-active vibration controller is proposed based on Type-2 fuzzy sets. To investigate the different performances by using different types of fuzzy controllers, the experimental measurements employing type-1 fuzzy and interval type-2 fuzzy controllers are implemented by the Compact RIO embedded system. The fuzzy modeling framework and solution methods presented in this work can be used for design, performance analysis, and optimization of ATVA from stationary random vibration of thin plates.

Diagnosis of kidney diseases has recently become more comprehensive and accurate by using new renal markers. Despite the fact that creatinine and cystatin c have been sufficient in determining kidney function, they did not indicate the exact site of the damage and they were often insufficient in predicting the course of the disease. Aim of the study was to evaluate the potential correlations and differences in levels of six factors related to kidney function and injury: kidney injury molecule-1 (KIM-1), ncalbindin (CALB), glutathione S-transferase Pi (GST-Pi), calbindin and monocyte chemoattractant protein-1 (MCP-1), between renal patients with diabetic nephropathy (DM), congenital defects (CD) of the kidney and glomerulonephritis (GN). Study involved 75 patients: 49 with diabetic nephropathy, 12 with congenital defects and 14 with glomerulonephritis. Levels of renalase was measured using immunoenzymatic tests. Levels of other markers: calbindin, glutathione-S-transferase (GST-pi), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1) and monocyte chemoattractant protein-1 (MCP-1), were analyzed using Kidney Toxicity-1 Panel and BioPlex system, designed for analyses in urine and optimized by us for serum.From all analyzed markers, only levels of KIM-1 differed significantly between any subgroups, and that was for CD and DM. Renalase correlated significantly negatively with creatinine and positively with all other markers, apart from MCP-1. Obtained results indicate, that serum renalase, KIM-1, calbindin and GST-pi are related to kidney function, with KIM-1 being the most exact, while MCP-1 levels are unrelated to creatinine and glucose levels, does not differ between patients with diabetic nephropathy and other subgroups, and therefore seem to be independent of diabetes. Also, serum-optimized Kidney Toxicity Panel 1 kit for determination of selected markers gave results similar to previous ones and therefore the method can be valuable in determination of analyzed factors.

Multiple myeloma (MM) accounts for about 10 to 15% of all diagnosed hematologic malignancies and about 1-2% of all cancer cases. Approximately 80-90% of MM patients develop bone disease and the changes rarely regress. It is only possible to stop or slow their progression. A major role in bone destruction in MM is attributed to the Wnt signaling pathway, and its action can be modified by various types of interventions including training and diet. Therefore, the aim of this project was to evaluate the effects of a Nordic Walking (NW) training cycle and intermittent fasting (IF) on the levels of selected bone turnover markers associated with the Wnt pathway in patients with MM. Results from 35 patients divided into training (NW and IF NW) and non-training (IF and control) groups were included in the analysis. A 6-week training cycle involving 60-minute workouts 3 times a week was conducted. Body mass and composition and the levels of: vitamin D, calcium and phosphorus, beta2-microglobulin and albumin were examined before and after completion of training cycle. Markers of bone turnover were also determined: sclerostin (SOST), Dickkopf-related protein 1 (DKK-1), osteoprotegrin (OPG), osteopontin (OPN) and Tartrate-resistant acid phos-phatase 5b (TRACP 5b). There was no negative effect of IF or combined training and fasting on the nutritional status of the patients (the level of albumines was unchanged). Both training groups showed an increase in serum concentrations of the active metabolite of vitamin D (IF NW and NW: p=0.001 and p=0.022, re-spectively). The change in the concentration of this vitamin negatively correlated with the con-centration of TRACP 5b (r=-0.413, p=0.014). Evaluating the concentrations of markers related to bone turnover, a reduction in the concentrations of SOST (time: p=0.026, time vs. group: p=0.033) and TRACP 5b (time: p

Pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R) has a higher affinity for pituitary adenylate cyclase- activating polypeptide (PACAP) than for vasoactive intestinal peptide (VIP). PACAP exerts its neuroprotective effects through PAC1-R. PAC1-R has become a target for drug development, and we targeted PAC1-R to screen small positive allosteric modulator 1 (SPAM1). SPAM1 has a neuroprotective effects, and in the D-galactose (D-gal) mouse model, SPAM1 improved the structure of the hippocampal dentate gyrus and restored the number of neurons. Compared with D-gal model mice, SPAM1 treatment upregulated the expression of Sirtuin 6 (SIRT6) and Lamin B1, and downregulated the expression of YinYang 1 (YY1) and p16. Consistent with this, the same results were obtained in senescent RGC-5 cells. Meanwhile, SPAM1 was also found to up-regulate SIRT6 and down-regulate YY1 expression in normal RGC-5 cells. Then, we further explored the mechanism of SPAM1 neuroprotection by whole transcriptome sequencing and proteomic analysis, and found that SPAM is involved in the longevity regulating pathway, and confirmed the up-regulation of neurofilament light polypeptide and neurofilament medium polypeptide by western blot, thus laying a pharmacological foundation for SPAM1 as a therapeutic agent for neurodegenerative diseases. polypeptide and neurofilament medium polypeptide. Thus, it lays a pharmacological foundation for SPAM1 as a therapeutic drug for neurodegenerative diseases.

The article describes the rational for inhibition of the angiotensin-converting enzyme 2 (ACE2) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent the establishment of positive feedback loops triggered by COVID-19 in some predisposed subjects. Making use of a large quantity of published reports in which human/rodent ACE2 pathway inhibitors were administered in vivo, it is hypothesized a possible therapeutic pharmacological intervention through an inhibition strategy of the zinc metalloprotease ACE2 and its downstream pathway for SARS-CoV-2 patients. Of even more interest, metal (zinc) chelators and renin inhibitors (both FDA approved drugs) may also work alone or in combination in inhibiting the positive feedback loops, initially triggered by COVID-19 and subsequently sustained by hypoxia independently on viral trigger, when both arms of renin-angiotensin system (ACE2 and ACE) are upregulated, leading to critical, advanced and untreatable stages of the disease.

Space-borne Synthetic Aperture Radar (SAR) Interferometry (InSAR) is now a key geophysical tool for surface deformation studies. The European Commission’s Sentinel-1 Constellation began acquiring data systematically in late 2014. The data, which are free and open access, have global coverage at moderate resolution with a 6 or 12-day revisit, enabling researchers to investigate large-scale surface deformation systematically through time. However, full exploitation of the potential of Sentinel-1 requires specific processing approaches as well as the efficient use of modern computing and data storage facilities. Here we present LiCSAR, an operational system built for large-scale interferometric processing of Sentinel-1 data. LiCSAR is designed to automatically produce geocoded wrapped and unwrapped interferograms and coherence estimates, for large regions, at 0.001° resolution (WGS-84 system). The products are continuously updated in a frequency depending on prioritised regions (monthly, weekly or live update strategy). The products are open and freely accessible and downloadable through an online portal. We describe the algorithms, processing, and storage solutions implemented in LiCSAR, and show several case studies that use LiCSAR products to measure tectonic and volcanic deformation. We aim to accelerate the uptake of InSAR data by researchers as well as non-expert users by mass producing interferograms and derived products.

Delineating the cropping area of cocoa agroforests is a major challenge for quantifying the contribution of the land use expansion to tropical deforestation. Discriminating cocoa agroforests from tropical transition forests using multi-spectral optical images is difficult due to a similarity in the spectral characteristics of their canopy; moreover, optical sensors are largely impeded by the frequent cloud cover in the tropics. This study explores multi-season Sentinel-1 C-band SAR image to discriminate cocoa agroforests from transition forests for a heterogeneous landscape in central Cameroon. We use an ensemble classifier, random forest, to average SAR image texture features of GLCM (Grey Level Co-occurrence Matrix) across seasons; next, we compare classification performance with results from RapidEye optical data. Moreover, we assess the performance of GLCM texture feature extraction at four different grey level quantization: 32bits, 8bits, 6bits, and 4bits. The classification overall accuracy (OA) of texture-based maps outperformed that from an optical image; the highest OA of 88.8% was recorded at 6bits grey level. This quantization level, in comparison to the initial 32bits in SAR images, reduced the class prediction error by 2.9%. Although this prediction gain may be large for the landscape area, the resultant thematic map reveals the decrease and fragmentation of forest cover by cocoa agroforests. According to our classification validation, the Shannon entropy (H) or uncertainty provides a reliable validation for class predictions and reveals detail inference for discriminating inherently heterogeneous vegetation categories. The texture-based classification achieved a reliable accuracy considering the heterogeneity of the landscape and vegetation classes.

Background: SARS-CoV-2 Omicron JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation. The immune evasion capability of JN.1 is a subject of scientific investigation. The US CDC used RT-qPCR SGTF as the proxy indicator of JN.1 infections for evaluation of the effectiveness of updated monovalent XBB.1.5 COVID-19 vaccines against JN.1 and recommended that all persons aged ≥6 months should receive an updated COVID-19 vaccine dose. Objective: Recommend Sanger sequencing for diagnosis of JN.1 infections to generate the data based on which guidelines are made to direct vaccination policies. Methods: The RNA in nasopharyngeal swab specimens from patients with clinical respiratory infection was subjected to nested RT-PCR, targeting a 398-base segment of the N-gene and a 445-base segment of the RBD of SARS-CoV-2 for amplification. The DNA sequences were analyzed for amino acid mutations. Results: The N-gene sequence showed Q229K, usually associated with Omicron BA.2.86 (+JN.1). The RBD sequence showed 24 amino acid mutations, including the hallmark L455S mutation for JN.1 and the V483del for BA.2.86 lineage. Conclusions: The CDC should consider Sanger sequencing of the RBD to diagnose JN.1 infections for statistical analysis in making vaccination policies.

The inaugural AIDS Program in Brazil was established in São Paulo in 1983, with the Instituto Adolfo Lutz appointed for laboratory assistance. Subsequently, research on HIV infections and HIV/HTLV (HIV/HTLV-1 and HIV/HTLV-2) co-infections were conducted. This narrative review focuses on studies from the Immunology Department (1983–2017) that significantly influenced AIDS diagnosis or provided epidemiological data such as prevalence rates, sex, age, and risk factors. Ten studies, encompassing over 8,000 individuals, are discussed. During 1983–1985, nearly all AIDS cases were attributed to homosexual/bisexual men aged 31 years old. Subsequently, heterosexual men and women emerged as risk groups owing to intravenous drug use (IDU) and/or unprotected sexual intercourse with AIDS patients or multiple partners per year. From 1985 onwards, vertical transmission led to child infections. HIV/HTLV co-infection rates decreased over time, initially associated with male IDU, and in the 2010s, with females, IDU, and individuals aged &gt;40 years. Trends in HIV and HIV/HTLV co-infections among younger men and women (&lt;30 years of age) were observed from 2015–2017. The changing characteristics and risk groups for HIV and HIV/HTLV co-infections over the years underscore the necessity for ongoing public policies to prevent retrovirus transmission, particularly among adolescents and young adults.

Infection with Zika virus (ZIKV), a member of the Flavivirus genus of the Flaviviridae family, typically results in mild self-limited illness, but severe neurological disease occurs in a limited subset of patients. In contrast, serious outcomes commonly occur in pregnancy that affect the developing fetus, including microcephaly and other major birth defects. The genetic similarity of ZIKV to other widespread flaviviruses, such as dengue virus (DENV), presents a challenge to the development of specific ZIKV diagnostic assays. Nonstructural protein 1 (NS1) is established for use in immunodiagnostic assays for flaviviruses. To address the cross-reactivity of ZIKV NS1 with proteins from other flaviviruses we used site-directed mutagenesis to modified putative epitopes. Goat polyclonal antibodies to variant ZIKV NS1 were affinity-purified to remove antibodies binding to the closely related NS1 protein of DENV. An antigen-capture ELISA configured with the affinity-purified polyclonal antibody showed a linear dynamic range between approximately 500 to 30 ng/mL, with a limit of detection of between 1.95 and 7.8 ng/mL. NS1 proteins from DENV, yellow fever virus, St. Louis encephalitis virus and West Nile virus showed significantly reduced reactivity in the ZIKV antigen-capture ELISA. Refinement of approaches similar to those employed here could lead to development of ZIKV-specific immunoassays suitable for use in areas where infections with related flaviviruses are common.

Astronauts at are risk of losing 1.0 – 1.5% of their bone mass for every month they spend in space despite their adherence to high impact exercise training programs designed to preserve the musculoskeletal system. This article reviews the basics of bone formation and resorption and details how exposure to microgravity or simulated microgravity affects the structure and function of osteoblasts, osteocytes, osteoclasts, and their mesenchymal and hematologic stem cell precursors. It details the critical roles that insulin-like growth facor-1 and its receptor IGFR1 play in maintaining bone homeostasis and how exposure of bone cells to microgravity affects the function of these growth factors. Lastly, it discusses the potential of tumor necrosis factor-related apoptosis-inducing ligand, syncytin-A, and sclerostin inhibitors and recombinant IGF-1 as a bone-saving treatment for astronauts in space and during their colonization of the Moon.

Expression of Krüppel–like factor 15 (KLF15), a stress induced transcription factor, is induced during bovine herpesvirus 1 (BoHV-1) reactivation from latency, and KLF15 stimulates BoHV-1 replication. Transient transfection studies revealed KLF15 and glucocorticoid receptor (GR) cooperatively transactivate the BoHV-1 immediate early transcription unit 1 (IEtu1), herpes sim-plex virus type 1 (HSV-1) infected cell protein 0 (ICP0), and ICP4 promoter. The IEtu1 promoter drives expression of bICP0 and bICP4, two key BoHV-1 transcriptional regulatory proteins. Based on these studies, we hypothesized infection is a stressful stimulus that increases KLF15 ex-pression and enhances productive infection. New studies demonstrated that silencing KLF15 impaired HSV-1 productive infection and KLF15 steady state protein levels were increased at late stages of productive infection. KLF15 was primarily localized to the nucleus following in-fection of cultured cells with HSV-1, but not BoHV-1. When cells were transfected with a KLF15 promoter construct and then infected with HSV-1, promoter activity was significantly increased. The ICP0 gene and to a lesser extent bICP0 transactivated the KLF15 promoter in the absence of other viral proteins. In contrast, BoHV-1 or HSV-1 encoded VP16 had no effect on KLF15 pro-moter activity. Collectively, these studies revealed HSV-1 and BoHV-1 productive infection in-creased KLF15 steady state protein levels, which correlated with increased virus production.

In the present study, we studied the effect of apolipoprotein A-1 (APOA1) on the spatial and molecular characteristics of bone marrow adipocytes, using well-characterized ApoA1 knockout mice. APOA1 is a central regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, and thus HDL; our recent work showed that deficiency of APOA1 increases bone marrow adiposity in mice. We found that ApoA1 deficient mice have greatly elevated adipocytes within their bone marrow compared to wild type counterparts. Morphologically, the increased adipocytes were similar to white adipocytes, and displayed proximal tibial-end localization. Marrow adipocytes from wild type mice were significantly fewer and did not display bone-end distribution pattern. The mRNA levels of the brown/beige adipocyte-specific markers Ucp1, Dio2, Pat2, Pgc1a, and the expression of leptin were greatly reduced in the ApoA1 knock-out in comparison to the wild-type mice. In the knock-out mice adiponectin was remarkably elevated. In keeping with the close ties of hematopoietic stem cells and marrow adipocytes, we found that the elevated adiposity in the ApoA1 knock out mice is associated with a significant reduction of the hematopoietic stem cells and common myeloid, but not common lymphoid, progenitors. Moreover, the “beiging”-related marker osteopontin and the angiogenic factor VEGF were also reduced in the ApoA1 knock-out mice, further supporting the notion that APOA1, and most probably HDL-C, regulate bone marrow microenvironment, favouring beige/brown adipocyte characteristics.

The study aimed to explore the correlation among Angiopoietin-1, (Ang-1) and Angiopoietin-2, (Ang-2) concentrations and the Angiopoietin-2/Angiopoietin-1 ratio, (Ang-2/Ang-1) with clinical outcomes, potentially serving as disease severity and survival biomarkers. A study at AHEPA University Hospital involved 90 COVID-19 adult patients, with 30 hospitalized in intensive care and 30 in ward units and 30 asymptomatic non-hospitalized individuals as controls. Estimated endothelial dysfunction markers related to angiogenesis were measured, and statistical analysis was performed using IBM SPSS Statistics software, version 29. There was a statistically significant difference only between outpatient and hospitalized patients (non-ICU -ICU groups) for the Ang-1 and Ang-2 indexes. The Ang-2/Ang-1 ratio has differed significantly among all individual patient groups. A ROC analysis was conducted to find an optimal threshold for distinguishing (outpatients – non-ICU) and (non-ICU –ICU) groups. It was based on Youden's Index and was 0.1122 and 0.3825, respectively. The Ang-1, Ang-2 levels, and Ang-2/Ang-1 ratio were analysed as indicators for severity in COVID-19 patients. The Ang-2/Ang-1 ratio demonstrated more excellent prognostic and diagnostic utility than individual biomarker levels. Monitoring the Ang-2/Ang-1 ratio can identify COVID-19 patients at risk and assist clinicians in tailoring treatment strategies for improved outcomes.

Incretin effect helps in regulating glucose homeostasis and maintaining glycaemic control within the human body. This effect is achieved by the two naturally occurring incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Such hormones released by specialized entero-endocrine cells of the gastrointestinal tract cause insulin augmentation after food consumption. However, incretin effects are impaired in type 2 diabetic, primarily attributed to the deterioration of GLP-1 function along with decreased GLP-1 receptor expression. Targeting this hormone has, therefore, become an important therapeutic approach to treat this diabetic condition. Native GLP-1’s brief half-life and rapid proteolytic degradation have generated significant enthusiasm in uncovering the long-acting GLP-1 receptor (GLP-1R) agonists to manage type 2 diabetes. These synthetic peptides mimic the natural GLP-1 to activate GLP-1R and effectively exert various physiological benefits in terms of weight management, blood pressure, lipid profile, obesity and major adverse cardiovascular event. This review paper provides insights into the structure, function and expression of GLP-1 and its receptor. It also summarizes existing literature regarding different types of GLP-1 receptor agonists, their effects on blood pressure and how they exert their actions. While animal models have contributed significantly to this area of study, the scarcity of human studies is noted, indicating a need for more investigation in this domain. Expanding research in humans will help in comprehending the impact of GLP-1 receptor agonists on blood pressure regulation and their underlying mechanisms.

The development of potent antiviral agents is of utmost importance to combat the global burden of viral infections. Traditional antiviral drug development involves targeting specific viral proteins, which may lead to the emergence of resistant strains. To explore alternative strategies, we investigated the antiviral potential of antimicrobial peptidomimetic compounds. In this study, we evaluated the antiviral potential of short anthranilamide-based peptidomimetic compounds 1-17 against two viruses: Murine Hepatitis Virus 1 (MHV-1-single stranded RNA virus) which is a surrogate of human coronaviruses and Herpes Simplex Virus 1 (HSV-1-double stranded DNA virus). The half-maximal inhibitory concentration (IC50) values of these compounds were determined in vitro to assess their potency as antiviral agents. Compounds 11 and 14 displayed the most potent inhibitory effect with IC50 values of 2.38μM, and 6.3μM against MHV-1 while compounds 9 and 14 showed IC50 values of 14.8μM and 13μM, against HSV-1. Multiple antiviral assessments and microscopic images obtained through transmission electron microscopy (TEM) collectively demonstrated that these compounds exert a direct influence on the viral envelope. Based on this outcome, it can be concluded that peptidomimetic compounds could offer a new approach for the development of potent antiviral agents.

Regulation (EU) No 305/2011 lays down harmonized conditions for marketing construction products in the European Union. One of its consequences has been the introduction of the product standard EN 50575 and standard EN 130501-6, concerning power, control, and communication cables permanently installed in buildings to prevent the risk of a fire and its consequences. EN 13501-6 provides the reaction to fire classifications for cables, the test methods to be performed, the requirements to meet a specific reaction to fire, and additional classifications for smoke production, flaming droplets, and acidity. EN 60754-2 is the technical standard used to assess acidity, and it defines three classes: a1, a2, and a3 (the less performant), based on pH and conductivity measurements. Due to the release of hydrogen chloride during the combustion, acidity is the weak point of PVC cables, which are not yet capable of achieving the a1 or a2 classes required in specific locations according to a fire risk assessment. EN 13501-6 does not include EN 60754-1. Both EN 60754-1 and EN 60754-2 are common standards for determining halogen gas content, acidity, and conductivity, respectively. They involve the same type of tube furnace but with different heating regimes, final temperatures, and detection methods. EN 60754-2 must be performed at temperatures between 935 – 965 °C. The paper demonstrates that, when EN 60754-2 is carried out with the thermal profile of EN 60754-1 or at 500 °C in isothermal conditions, the evolution of hydrogen chloride changes significantly if potent acid scavengers are utilized in the PVC compounds. The reason lies behind the kinetic of hydrogen chloride release during the combustion of PVC compounds: the higher the temperature or faster the heat release, the quicker hydrogen chloride evolution and the lower the probability for the acid scavenger to trap it. That further highlights the "fragility" of EN 60754-2 as a tool for assessing the risks associated with the release of hydrogen chloride in case of fire

Lung cancer is a common malignant tumor of the lung and the leading cause of cancer mortality worldwide. Non-small-cell lung cancer (NSCLC) accounts for 80%–85% of lung cancer, 40% of NSCLCs will have spread beyond the lungs by the time it is diagnosed. Long non-coding RNA (LncRNA) prostate androgen-regulated transcript 1 (PART-1) was reported that promote the development of several cancers. In the current study, we conducted experiments to investigate the role of PART-1 in the proliferation, invasion, and migration of NSCLC. The expression level of the PART-1 gene increased significantly in the NSCLC cell lines, including A549, H1229, H1650, H1975, and PC9. Knocking down of PART-1 inhibited the proliferation, invasion, and migration of A549 cells, moreover, decreased the tumor proliferation in nude mice. We confirmed that PART-1 targeted miR-204-3p directly, and miR-204-3p targeted the insulin-like growth factor binding protein 2 (IGFBP-2) directly. Furthermore, we discovered that PART-1 involved the NSCLC progression by regulating the miR-204-3p-targeted IGFBP-2 pathway. LncRNA PART-1 might be a target for treating NSCLC, and a warning sign of diagnosis of early lung cancer.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a human DNA repair protein. It is a member of the phospholipase D family based on the structure similarity. TDP1 is a key enzyme involved in repairing stalled topoisomerase 1 (TOP1)-DNA complexes. Previously we obtained with the CRISPR/Cas9 method HEK293A cells with the homozygous knockout of the Tdp1 gene and used knockout cells as a cellular model for studying the mechanisms of anticancer therapy. In this work we studied for the first time by transcriptomic analysis the effect of Tdp1 gene knockout on genes expression changes in human HEK293A cell line. We received original data that may indicate a role of TDP1 in other process besides repair of DNA-TOP1 complex. The differentially expressed genes (DEGs) analysis revealed that TDP1 could be involved in different processes such as cell adhesion and communication, spermatogenesis, mitochondrial function, neurodegeneration, cytokine response, and MAPK pathway signaling.

Quaking aspen (Populus tremuloides Michx.) is an important deciduous species in western U.S. forests. Existing maps of aspen distribution are based on Landsat imagery and often miss small stands (&lt;0.09 ha or 30 m²), which rapidly regrow when managed or following disturbance. In this study, we present methods for deriving a new regional map of aspen forests using one year of Sentinel-1 (S1) and Sentinel-2 (S2) imagery in Google Earth Engine. We assessed the annual phenology of aspen in the Southern Rockies and leveraged the frequent temporal resolution of S1 and S2 to create ecologically relevant seasonal composites. Additionally, we derived spectral indices and radar textural features targeting the canopy structure, moisture, and chlorophyll content. Using spatial block cross-validation and Random Forests, we assessed the accuracy of different scenarios and selected the best performing set of features for classification. Comparisons were then made with existing landcover products across the study region. The resulting map improves on existing landcover products in both accuracy (average F1-score = 93.1%) and detection of smaller forest patches. These methods enable accurate mapping at spatial and temporal scales relevant to forest management for one of the most widely distributed tree species in North America.

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are significantly changing treatment strategies for human malignant diseases including oral cancer. Cancer cells usually escape from immune system and acquire proliferative capacity and invasive/metastatic potential. We have focused on the two immune checkpoints, PD-1/PD-L1 and CD47/SIRPα in the tumor microenvironment of oral squamous cell carcinoma (OSCC), and performed a retrospective analysis of the expression of seven immune-related factors (PD-L1, PD-1, CD4, CD8, CD47, CD56 and CD11c), and examined their correlation with clinicopathological status. As a result, there were no significant findings relating seven immune-related factors and several clinicopathological statuses. However, the immune-checkpoint related factors (PD-1, PD-L1, CD47) were highly expressed in non-keratinized epithelium-originated tumors when compared to those in keratinized epithelium-originated tumors. It is of interest that immunoediting via immune checkpoint-related factors was facilitated in non-keratinized sites. Several researchers reported that keratinization of oral mucosal epithelia affected the immune response, but our present finding is the first study to show a difference of the tumor immunity in the originating-epithelium of OSCC, keratinized or non-keratinized. Tumor immunity, an immune escape status of OSCC might be different in the originating-epithelium, keratinized or non-keratinized.

Herpes simplex virus 1 (HSV-1) expresses a large number of miRNAs, and their function is still not completely understood. In addition, HSV-1 has been found to deregulate host miRNAs, which adds to the complexity of regulation of efficient virus replication. In this study, we comprehen-sively addressed the deregulation of host miRNAs by massive-parallel sequencing. We found that only miRNAs expressed from a single cluster, miR-183/96/182 are reproducibly deregulated dur-ing productive infection. These miRNAs are predicted to regulate a great number of potential tar-gets involved in different cellular processes and have only 33 shared targets. Among these, mem-bers of the FoxO family of proteins were identified as potential targets for all three miRNAs. However, our study shows that the upregulated miRNAs do not affect the expression of FoxO proteins, moreover these proteins were upregulated in HSV-1 infection. Furthermore, we show that the individual FoxO proteins are not required for efficient HSV-1 replication. Taken together, our results indicate a complex and redundant response of infected cells to the virus infection that is efficiently inhibited by the virus.

HIV-1 Tat protein interacts with TAR RNA and recruits CDK9/cyclin T1 and other host factors to induce HIV-1 transcription. Thus Tat-TAR RNA interaction, which is unique for HIV-1, represents an attractive target for anti-HIV-1 therapeutics. To target Tat-TAR RNA interaction, we used a crystal structure of TAR RNA with acetylpromazine bound to the bulge of TAR RNA, to dock compounds from Enamine database containing 1.6 million individual compounds. Docking identified 173 compounds that were analyzed for the inhibition of HIV-1 infection. Top ten inhibitory compounds with IC50 ≤ 6 µM were selected and the three least toxic compounds, T6780107 (IC50=2.97 μM), T0516-4834 (IC50=0.2 μM) and T5628834 (IC50=3.46 μM), were further tested for HIV-1 transcription inhibition. Only T0516-4834 compound showed selective inhibition of Tat-induced HIV-1 transcription, whereas T6780107 compound inhibited equally basal and Tat-induced transcription and T5628834 compound only inhibited basal HIV-1 transcription. The T0516-4834 compound also showed strongest inhibition of HIV-1 gag RNA expression and p24 production in CEM T cells infected with HIV-1 IIIB. Of the three compounds, only the T0516-4834 compound disrupted Tat-TAR RNA interaction indicating that it might target TAR RNA. Also, of the three tested compounds, T5628834 but not T6780107 or T0516-4834 disrupted Tat-CDK9/cyclin T1 interaction. Taken together, our study identified novel compound T0516-4834 that disrupted Tat-TAR RNA interaction and inhibited Tat-induced transcription and HIV-1 infection suggesting that this compound might serve as a new lead for anti-HIV-1 therapeutics.

Brazil, Russia, China, India, and the Republic of South Africa (BRICS) represent developing economies facing different energy and economic development challenges. The current study aims to forecast energy consumption in BRICS at aggregate and disaggregate levels using the annual time series data set from 1992 to 2019 and to compare results obtained from a set of models. The time-series data are from the British Petroleum (BP-2019) Statistical Review of World Energy. The forecasting methodology bases on a novel Fractional-order Grey Model (FGM) with different order parameters. This study contributes to the literature by comparing the forecasting accuracy and the forecasting ability of the FGM(1,1) with traditional ones, like standard GM(1,1) and ARIMA(1,1,1) models. Also, it illustrates the view of BRICS's nexus of energy consumption at aggregate and disaggregates levels using the latest available data set, which will provide a reliable and broader perspective. The Diebold-Mariano test results confirmed the equal predictive ability of FGM(1,1) for a specific range of order parameters and the ARIMA(1,1,1) model and the usefulness of both approaches for energy consumption efficient forecasting.

Tissue resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8 TRM, there has been recently an increased interest in defining the phenotype and the role of CD4 TRM in diseases. Circulating CD4 T cells seed tissue CD4 TRM, but there also appears to be an equilibrium between CD4 TRM and blood CD4 T cells. CD4 TRM are more mobile than CD8 TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8 TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4 and CD8 TRM persisting between lesions may control asymptomatic shedding through interferon gamma secretion, although this has been more clearly shown for CD8 T cells. The exact role of the CD4/CD8 TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4 TRM have now been shown to be a major target for productive and latent infection in cervix. In HSV and HIV co-infections, CD4 TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4 TRM and their induction by vaccines may help control sexual transmission by both viruses.

Solid tumor cells have an altered metabolism that can protect them from cytotoxic lymphocytes. The antidiabetic drug metformin modifies tumor cell metabolism and several clinical trials are testing its effectiveness for the treatment of solid cancers. The use of metformin in hematologic cancers has received much less attention, although allogeneic cytotoxic lymphocytes are very effective against these tumors. We show here that metformin induces expression of Natural Killer G2-D (NKG2D) ligands (NKG2DL) and intercellular adhesion molecule-1 (ICAM-1), a ligand of the lymphocyte function-associated antigen 1 (LFA-1). This leads to enhance sensitivity to cytotoxic lymphocytes. Overexpression of antiapoptotic Bcl-2 family members decrease both metformin effects. The sensitization to activated cytotoxic lymphocytes is mainly mediated by the increase on ICAM-1 levels, which favors cytotoxic lymphocytes binding to tumor cells. Finally, metformin decreases the growth of human hematological tumor cells in xenograft models, mainly in presence of monoclonal antibodies that recognize tumor antigens. Our results suggest that metformin could improve cytotoxic lymphocyte-mediated therapy.

The results of the most recent investigation of triterpenoid-based antiviral agents effective namely in the HIV-1 and HSV-1 treatment were reviewed and summarized. Several key historical achievements are included to stress consequences and continuity in this research. Most of the agents studied belong into a series of compound derived from betulin or betulinic acid, and their synthetic derivative called bevirimat. A termination of clinical trials of bevirimat in the Phase IIb initiated a search for more successful compounds partly derived from bevirimat or designed independently of bevirimat structure. Surprisingly, a majority of bevirimat mimics are derivatives of betulinic acid, while other plant triterpenoids, such as ursolic acid, oleanolic acid, glycyrrhetinic acid or other miscellaneous triterpenoids, are relatively rarely involved in a search for novel antiviral agent. Therefore, this review article is divided into three parts based on the leading triterpenoid core structure.

Background: Multidrug-resistant bacteria present resistance mechanisms against β-lactam antibiotics, such as Extended-Spectrum Beta-lactamases (ESBL) and Metallo-β-lactamases enzymes (MBLs) operon encoded in Gram-negative species. Likewise, Gram-positive bacteria have evolved other mechanisms through mec genes, which encode modified penicillin-binding proteins (PBP2). This study aimed to determine the presence and spread of β-lactam antibiotic resistance genes and the microbiome circulating in Quito’s Public Transport (QTP). Methods: A total of 29 station turnstiles were swabbed to extract the surface environmental DNA. PCRs were performed to detect the presence of 13 antibiotic resistance genes and to identify 16S rDNA barcoding, followed by clone analysis, Sanger sequencing and BLAST search. Results: ESBL genes blaTEM-1 and blaCTX-M-1 and MBL genes blaOXA-181 and mecA were detected along QPT stations. Two subvariants were found for blaTEM-1, blaCTX-M-1, and blaOXA-181. Almost half of the circulating bacteria found at QPT stations were common human microbiota species including those classified by the WHO as pathogens of critical and high-priority surveillance. Conclusions: β-lactam antibiotic resistance genes are widely spread throughout QPT. This is the first report of blaOXA-181 in environmental samples in Ecuador. Moreover, we detected a new putative variant of this gene. Some commensal coagulase-negative bacteria may have a role as mecA resistance reservoirs

Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared with that of normal lung, and high VCAM-1 expression correlated with poor survival of lung cancer patients. VCAM-1 knockdown reduced invasion in A549 human lung cancer cells, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1 (VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1-mediated A549 cell invasion. Next, we developed a human monoclonal antibody specific to human and mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody library using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar affinity for VCAM-1-D6 and that it potently suppressed invasion in A549 and NCI-H1299 lung cancer cell lines. Taken together, these results suggest that VCAM-1-D6 is a novel therapeutic target in VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6 huMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion.

Build a special identical equation, use its calculation characters to prove and search for solution of any odd converging to 1 equation through (*3+1)/2^k operation, change the operation to (*3+2^m-1)/2^k, and get a solution for this equation, give a specific example to verify. Thus prove the Collatz Conjecture is true. Furthermore, analysis the sequences produced by iteration calculation during the procedure of searching for solution, build a weight function model, prove it decrease progressively to 0, build a complement weight function model, prove it increase to its convergence state. Build a (*3+2^m-1)/2^k odd tree, prove if odd in (*3+2^m-1)/2^k long huge odd sequence can not converge, the sequence must outstep the boundary of the tree after infinite steps of (*3+2^m-1)/2^k operation.

Background: Hepatic erythrophagocytosis is augmented in NASH and amplifies inflammation and fibrosis. Although various pro-phagocytic signals have been identified on erythrocytes of NASH patients, the role of bound thrombospondin-1 (TSP-1), which acts as an “eat-me” signal, arginase-1, which regulates the levels of nitric oxide in erythrocytes, and phosphatidylethano-lamine (PE) which can amplify erythrophagocytosis and hepatic inflammation have not been explored. Hence, we sought to investigate the levels of arginase-1 and TSP-1 in erythrocyte lysate and PE in erythrocyte membranes of NASH patients. Methods: Twenty-four patients and 14 healthy controls participated in our study. The levels of TSP-1 and arginase were quantified by ELISA in erythrocyte lysates, and the levels of PE in erythrocyte membranes by thin layer chro-matography. Results: Erythrocytes of NAFLD patients exhibit lower levels of arginase-1 and TSP-1 (p<0.01). Erythrocyte-bound TSP-1 levels correlated with the levels of erythrocyte surface CD47. Phosphatidylethanolamine was increased in erythrocytes of NASH patients and was accompanied by increased release, indicating exposure. Conclusion: Our results imply reduced TSP-1 binding by erythrocytes which could allow free TSP-1 molecules to act on macrophages, enhancing erythrophagocytosis. Increased PE which could amplify inflammation after efferocytosis, while downregulation of arginase-1 could lead to defective efferocytosis.

Immune checkpoint blockade (ICB)-based therapy is revolutionizing cancer treatment by fostering successful immune surveillance and effector cell responses against various types of cancers. However, patients with HER2+ cancers are yet to benefit from this therapeutic strategy. Precisely, several questions regarding the right combination of drugs, drug modality, and effective dose recommendations pertaining to the use of ICB-based therapy for HER2+ patients remain unanswered. In this study, we use a mathematical modeling-based approach to quantify the growth inhibition of HER2+ breast cancer (BC) cell colonies (ZR75) when treated with anti-HER2; trastuzumab (TZ) and anti-PD-1/PD-L1 (BMS-202) agents. Our data show that a combination therapy of TZ and BMS-202 can significantly reduce the viability of ZR75 cells and trigger several morphological changes. The combination decreased the cell’s invasiveness along with altering several key pathways, such as Akt/mTor and ErbB2 compared to monotherapy. In addition, BMS-202 causes dose-dependent growth inhibition of HER2+ BC cell colonies alone, while this effect is significantly improved when used in combination with TZ. Based on the in-vitro monoculture experiments conducted, we argue that BMS-202 can cause tumor growth suppression not only by mediating immune response but also by interfering with the growth signaling pathways of HER2+ BC. Nevertheless, further studies are imperative to substantiate this argument and to uncover the potential crosstalk between PD-1/PD-L1 inhibitors and HER2 growth signaling pathways in breast cancer.

Understanding the phenomena underlying the non-selective susceptibility to ischemia of py-ramidal neurons in the CA3 area of the hippocampus is important from the point of view of elu-cidating the mechanisms of memory loss and the development of post-ischemic dementia. We used an ischemic model of Alzheimer's disease to study changes in amyloid protein precursor gene expression, its cleavage enzymes and tau protein in the CA3 area of the hippocampus af-ter a 10-minute brain ischemia with 12, 18, and 24-month survival. Quantitative reverse tran-scriptase PCR assay showed that the expression of all the genes that contribute to amyloid pro-duction was dysregulated within 2 years in the CA3 area of the hippocampus after ischemia. The expression of the amyloid protein precursor gene was above the control values at all times of the study. The expression of the α-secretase gene also exceeded the control values throughout the study. In contrast, the expression of the β-secretase gene reaching its maximum increase 12 months after ischemia, was below control values after 18 months and again above control values after 24 months of survival. Presenilin 1 and 2 gene expression was significantly elevated throughout the follow-up period, with peak expression of both genes occurring 12 months after ischemia. This suggests that the genes studied are involved in the non-amyloidogenic processing of amyloid protein precursor. Also, tau protein gene expression was significantly elevated throughout the observation period, and peak gene expression was present 12 months after is-chemia. Data indicate that an episode of brain ischemia with long-term survival causes damage and death of pyramidal neurons in the CA3 area of the hippocampus in a manner dependent on modified tau protein. Thus defining a new and important mechanism of pyramidal neuronal death in the CA3 area after ischemia. In addition tau protein gene modification after brain is-chemia is useful in identifying ischemic mechanisms occurring in Alzheimer's disease.

The combustion of PVC cables in fires results in the release of hydrogen chloride gas. In the European Union, Regulation (EU) No 305/2011, in force since 2017, requires the classification of cables permanently installed in buildings for reaction to fire, smoke, flaming droplets, and acidity. The additional classification for acidity is evaluated through EN 60754-2, involving pH and conductivity measurements. This study focuses on the essential research and development of low-smoke acidity PVC compounds for cables, mainly aiming to meet the stringent additional classifications for acidity, a1 or a2, which cannot be achieved with traditional PVC cables. Understanding the chemistry of thermal decomposition and combustion, especially in the presence of hydrogen chloride scavengers, is crucial for meeting the best acidity classification. The article reviews the current tube furnace tests used in the European Union for cable halogen and acidity assessments. It discusses the limitations of the existing method (EN 60754-2) and highlights the potential of emerging tests such as IEC EN 60754-3, which employs ion chromatography for improved sensitivity and specificity. In the experimental part of the article, various standard and low-smoke acidity cable compounds are tested using tube furnace experiments with different heating regimes. The concentrations of cations and anions in solution are measured through ion chromatography and inductively coupled plasma–optical emission spectrometry. This detailed analysis aims to identify the species influencing pH and conductivity, which is crucial for designing effective acid scavengers that do not impact conductivity. The conclusive results emphasize that HCl from PVC thermal decomposition is the primary driver of pH and conductivity, and the contribution from the decomposition of additives and byproducts from combustion is found to be negligible in most of the tested PVC compounds for cables. The findings underscore the importance of understanding the thermal decomposition of PVC compounds to design acid scavengers capable of trapping hydrogen chloride without adversely impacting conductivity.

Ulcerative colitis (UC) is a relatively frequent, chronic disease that impacts significantly the patient’s quality of life. Although many therapeutic options are available, additional approaches are needed because many patients either do not respond to current therapies or show significant side effects. Cardiotrophin-1 (CT-1) is a cytokine with potent cytoprotective, anti-inflammatory, and antiapoptotic properties. The purpose of this study was to assess if the administration of CT-1 could reduce colon damage in mice with experimental UC. UC was induced with 5% dextran sulfate sodium (DSS) in the drinking water. Some mice received i.v. dose of CT-1 (200 µg/kg) 2 hours before and 2 and 4 days after DSS administration. Animals were followed during 7 days after DSS. The severity of UC was measured by standard scores. Colon damage was assessed by histology and immunohistochemistry. Inflammatory mediators were measured by Western blot and PCR. CT-1 administration to DSS-treated mice ameliorated both the clinical course (disease activity index), histological damage, inflammation (colon expression of TNF-α, IL-17, IL-10, INF-γ, and iNOS), and apoptosis. Our results suggest that CT-1 administration before UC induction improves the clinical course, tissue damage and inflammation degree in DSS-induced UC in mice.

Background High Mobility Group Box-1 (HMGB-1) is implicated in the pathogenesis of thrombosis and cancer. In the present study, we aimed to evaluate its potential role as a diagnostic biomarker of portal vein thrombosis (PVT) among patients with hepatocellular carcinoma (HCC). Methods The study population included N=100 prospectively recruited patients with a novel diagnosis of HCC. We compared circulating HMGB-1 levels between 34 healthy controls, HCC patients with PVT (N=22), and HCC patients without PVT (N=78). Results HCC patients without PVT showed significantly higher median HMGB-1 serum levels (8.2 [5.5-13.1] ng/ml) than those observed in the case of HCC with PVT (5.5 [4.4-8.5] ng/ml; p=0.012) and in healthy controls (4.1 [3.1-8.2] ng/ml; p&lt;0.001). Among HCC patients, at univariate analysis, the presence of PVT was associated with higher median age (p=0.036), larger major cancer node diameter (p&lt;0.001), and lower HMGB-1 serum level (p=0.012). At multivariate analysis, the presence of PVT maintained a positive association with major node diameter p=0.001) and an inverse association with serum HMGB-1 levels (p=0.003). Conclusions These findings indicate that serum HMGB-1 bears an inverse association with PVT complicating HCC at the time of diagnosis and suggest that serum HMGB-1 depletion may mark PVT development in cirrhotic patients with HCC.

A 2-year prospective study carried out on ventilator-associated pneumonia (VAP) patients in the intensive care unit at King Khalid hospital, Hail, Kingdom of Saudi Arabia (KSA), revealed a high prevalence of extremely drug-resistant (XDR) Acinetobacter baumannii. About a 9% increase in the incidence rate of A. baumannii has occurred in the VAP patients between 2019 and 2020 (21.4% to 30.7%). In 2019 the isolates were positive for IMP-1 and VIM-2 (31.1% and 25.7%, respectively) as detected by PCR. In comparison, a higher proportion of isolates produced NDM-1 in 2020. Here, we observed a high resistant proportion of ICU isolates towards the most common antibiotics in use. Colistin sensitivity dropped to 91.4% in the year 2020 as compared to 2019 (100%). Thus, the finding of this study has a highly significant clinical implementation in the clinical management strategies for VAP patients. Furthermore, strict implementation of antibiotic stewardship policies, regular surveillance programs for antimicrobial resistance monitoring, and screening for genes encoding drug resistance phenotypes have become imperative.

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.

Stress Granules formation is a pro-survival mechanism helping cells to cope with environmental challenges. Stress Granules have been studied for two decades in fundamental research, and are now being examined in the context of human pathogenesis. Here, we review studies highlighting stress granules’ involvement in cancer development through translational pattern modification.

The effectiveness of immunotherapy for cervical adenocarcinoma (CA) has not been demonstrated yet. It may be possible for us to use programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and CD8 as biomarkers of response to immune therapy in CA patients. In the present study, we aimed to investigate whether the expression levels of PD-1, PD-L1, and CD8 can predict the prognosis of CA patients and their response to ICI therapy. The levels of the PD-1, PD-L1, and CD8 proteins were analyzed by immunohistochemical analysis from formalin-fixed, paraffin-embedded tumor samples. The correlation between the expression levels and patient prognosis was analyzed by the Kaplan–Meier method and univariate and multivariate Cox proportional hazard regression model. We observed a significant inverse-correlation between the PD-1 and CD8 expression (p=0.001, chi square test). We also found a significant inverse-correlation between the PD-L1 and CD8 expression (p=0.027). The overall survival was significantly worse in patients with positive PD-1 expression (p=0.027). Similarly, the progression-free survival was also worse (p=0.087). Our results demonstrate that a high level of PD-1 expression is associated with a poor prognosis in CA patients. Further research is necessary to identify the molecular mechanisms that mediate this association.

(R)-1-(4-Amino-3,5-dichlorophenyl)-2-bromoethan-1-ol has been synthesised in 93% enantiomeric excess (ee) by asymmetric reduction of the corresponding ketone catalysed by a ketoreductase and NADPH as the co-factor in DMSO. (S)-N-(2,6-Dichloro-4-(1-hydroxyethyl)phenyl)acetamide has been synthesised in >98% ee by the same system. Both synthons are potential precursors for clenbuterol enantiomers. Clenbuterol is a β₂-agonist used in veterinary treatment of asthma in several countries. The drug is listed on the World Anti-doping Agency’s Prohibited list due to its effect on increased protein synthesis in the body. However, racemic clenbuterol has recently been shown to reduce the risk of Parkinson’s disease. In order to reveal which one (or both) of the enantiomers that cause this effect, the pure enantiomers need to be studied separately. Our biocatalytic approach in order to obtain enantiopure clenbuterol should be applicable to industrial scale.

The incidence of Type 1 Diabetes (T1D) in the Arab world, particularly, oil and gas rich Gulf Cooperative Council (GCC) countries has more than doubled in the last twenty years. Therefore, there is a dire need for careful systematic familial cohort studies, especially in high-risk populations. Several immunogenetic factors affect the pathogenesis of the disease. Genes in the human leukocyte antigen (HLA) account for the major genetic susceptibility to the disease. The triggering agents initiate disease onset by destruction of pancreatic β-cells. The autoantibodies against glutamic acid decarboxylase (GADA), insulinoma antigen-2 (IA-2A), insulin (IAA), and zinc transporter-8 (ZnT-8A) comprise the most reliable biomarkers for T1D in both children and adults. Although three of the GCC countries, namely Kuwait, Saudi Arabia and Qatar are among the top 10 countries with high incidence rate of T1D, no proper diagnostic and prediction tools were applied in the region. Understanding the disease sequelae in a homogenous gene pool with high consanguinity in the GCC could help solve the challenges in understanding pathogenesis, as well as hasten the prevention of T1D. Arab states must incorporate T1D predictive and intervention policies on a war-footing basis to minimize the burden of this serious disease.

The BRAFV600E mutation, found in approximately 50% of melanoma cases, is associated with aggressive tumor behavior and poor prognosis. This study aimed to assess its impact on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of The Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, emphasizing a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors.

Background: Over the past years, there has been a rise in the incidence of type 1 diabetes, partic-ularly among younger individuals. This concerning trend has prompted investigations into po-tential contributing factors, with intestinal dysbiosis emerging as a likely culprit for the escalating annual rates of the disease; (2) Methods: We conducted a retrospective ecologic correlational study involving 37 children from the southern region of Romania between 2019-2021. All participants were within the first six months following the onset of the disease; (3) Results: In the microbiota of the patients we observed a dysbiosis marked by an overabundance of bacteria (Clostridium coccoides, Faecalibacterium, Bacterioides, Enterobacteriaceae) and fungi, compared to the healthy control group. The Spearman correlation revealed a positive association between the presence of Bacteroides (p=0.0442), Butyricicoccus (p=0.0164), and Clostridium leptum (p=0.0023) with recent diabetes onset. Furthermore, a significant correlation was observed between younger age at onset and the pres-ence of Butyricicoccus (p=0.019). The use of antibiotics in the month preceding admission was linked to the presence of fungi in the microbiota (Candida, p=0.0442); (4) Conclusions: The dysbiosis of Romanian type 1 diabetes children correlates with inflammation, more severe onset of the disease and other au-toimmune diseases.

Among cross-sectional imaging modalities, computed tomography (CT) is more available and faster; however, magnetic resonance (MR) performs better in terms of sensitivity and specificity, due to its higher contrast resolution. The appearance of peritoneal deposits on CT and MR depends mainly on the primary tumour histology: in case of unknown primary tumour (3-5% of cases), their behaviour at imaging may provide insights on the tumour origin. The time-point of tumour evolution, previous or ongoing treatments and the peritoneal spaces where they occur, also play an important role in determining the appearance of peritoneal deposits. Thus, knowledge of peritoneal anatomy and fluid circulation is mandatory in detection and characterization of peritoneal deposits. Several benign and malignant conditions may show similar imaging features that overlap those of PC, making the differential diagnosis challenging. Clinical history, laboratory findings and previous imaging examinations must be considered to achieve the correct diagnosis.

We describe an efficient approach to radiometrically flatten geocoded stacks of calibrated synthetic aperture radar (SAR) data for terrain-related effects. We use simulation to demonstrate that, for the Sentinel-1 mission, one static radiometric terrain flattening factor derived from actual SAR imaging metadata per imaging geometry is sufficient for flattening interferometrically compliant stacks of SAR data. We quantify the loss of precision due to application of static flattening factors, and show that these are well below stated requirements of change detection algorithms. Finally, we discuss the implications of applying radiometric terrain flattening to geocoded SAR data instead of the traditional approach of flattening data provided in the original SAR image geometry. The proposed approach allows for efficient and consistent generation of five different Committee of Earth Observation Satellites (CEOS) Analysis Ready Dataset (ARD) families - Geocoded Single Look Complex (GSLC), Interferometric Radar (InSAR), Normalized Radar Backscatter (NRB), Polarimetric Radar (POL) and Ocean Radar Backscatter (ORB) from SAR missions in a common framework.

We describe an efficient and cost effective data access mechanism for Sentinel-1 TOPS 1 mode bursts. Our data access mechanism enables burst-based data access and processing, thereby 2 eliminating ESA’s Sentinel-1 SLC data packaging conventions as a bottleneck to large scale processing. 3 Pipeline throughput is now determined by available compute resources and efficiency of the analysis 4 algorithms. For targeted infrastructure monitoring studies, we are able to generate coregistered, 5 geocoded stacks of SLCs for any AOI in the world in a few minutes. In addition, we describe our 6 global scale radar backscatter and interferometric products and associated pipeline design decisions 7 that ensure geolocation consistency across the suite of derived products from Sentinel-1 data. Finally, 8 we discuss the benefits and limitations of working with geocoded SAR SLC data.

Infection by human immunodeficiency virus type I (HIV-1) requires virus particle binding to host cell-surface receptor CD4 via the viral envelope glycoprotein gp120. HIV-1 therapy and prevention efforts involve development of mimetic or recombinant gp120 vaccines or deployment of antiviral agents that target specific epitopes of gp120. The unliganded conformational state of gp120 is closed, whereas the CD4-bound state is open. However, in between, there exist dynamic conformational states, indicating intrinsically flexible region(s) of structural dynamics, imposing a structural challenge for developing drug or antibody targets. Known conformational states of gp120 were determined by X-ray crystallographic and cryo-electron microscopy, and neither method captures the population of gp120 species arising from conformational plasticity, motions, and transitions. gp120 plasticity brings up several important questions. How will differences in conformation affect receptor binding, antibody recognition, and neutralization? Which regions are crucial for gp120 structural plasticity? How could structural dynamics influence HIV-1 evasiveness against host immunity and drugs or vaccines, and facilitate the viral entry into its host? This review explores the structural constraints presented by conformational states of the glycoprotein to antibodies or drugs and how these conformational states provide structural avenues for the virus to escape neutralizing agents and evade host immunity.

Before the adaptive immune response is established, retroviruses can be targeted by several cellular host factors at different stages of the viral replication cycle. This intrinsic immunity relies on a large diversity of antiviral processes. In the case of HTLV-1 infection, these active innate host defence mechanisms are debated. Among these mechanisms, we focused on a RNA decay pathway called nonsense-mediated mRNA decay (NMD), which can target multiple viral RNAs, including HTLV-1 unspliced RNA, as it has been recently demonstrated. NMD is a cotranslational process that depends on the RNA helicase UPF1 and regulates the expression of multiple types of host mRNAs. RNA sensitivity to NMD depends on mRNA organization and the ribonucleoprotein (mRNP) composition. HTLV-1 has evolved several means to evade the NMD threat, leading to NMD inhibition. In the early steps of infection, NMD inhibition favours the production of HTLV-1 infectious particles, which may contribute to the survival of the most fit clones despite genome instability; however, its direct long-term impact remains to be investigated.

Purinergic receptors are inflammatory mediators activated by extracellular nucleotides released by dying or injured cells. Several studies have described an important role for these receptors in HIV-1 entry, particularly regarding their activity on HIV-1 viral membrane fusion. Several reports identify purinergic receptor antagonists that inhibit HIV-1 membrane fusion; these drugs are suspected to act through antagonizing Env-chemokine receptor interactions. They also appear to abrogate activity of downstream mediators that potentiate activation of the NLRP3 inflammasome pathway. Here we review the literature on purinergic receptors, the drugs that inhibit their function, and the evidence implicating these receptors in HIV-1 entry.

BACKGROUND: During the natural history, the incidence HTLV-1 related diseases were 0.5% until 10% after decades of infection. Despite relative low lethality, previous study observed that HTLV-1 infection is associated with significantly increased mortality. For example, the incidence of ATLL and HAM/TSP, co-infections with HIV and HCV, parasitic co-infection with Strongyloides stercoralis may increase morbidity and mortality. OBJECTIVE: Determine the mortality rate and its major variables as possible risk factors, analyzing the HTLV Clinic at Emilio Ribas Institute, a continuous open cohort of HTLV patients since 1997. METHODS: This cohort open cohort possesses new patients added at a rate of approximately 50 patients/year. There were 1100 HTLV-infected subjects identified by September 30th 2018. All clinical data including clinical and laboratory data, which have been updated on a regular basis over the last 22 years, were entered into a specific REDCap database. The Ethical Board of the IIER approved the protocol. RESULTS: Along 22 years of clinical care in the HTLV-out clinic, 727 HTLV-1-infected subjects and 248 HAM/TSP cases. Four-hundred sixty-eight patients of whom remaining under active follow up. The mean follow-up time of the cohort was 12 years. Twenty-seven patients died (median age of 51,5 years old). From this total, 13 was asymptomatic carriers and 14 HAM/TSP subjects, 12 of asymptomatic and seven HAM/TSP possess co-infected with HIV or/and HCV. Other seven presented HAM/TSP without co-infection, and all was female, and sepsis was the majority cases the majority of cases of sepsis were related to infection of the urinary tract (p=0.058) and to ulcers of decubitus (p=0.021), and it was associated with risk factors for mortality. CONCLUSIONS: Overall, the mortality rate for HAM-TSP patients was six percent. The mean life expectancy in Brazil is about 78 years in 2018, twenty-two years higher than HAM/TSP patients without any other coinfection. This study highlights the possibility of higher death risk among HTLV-1-infected patients and HAM/TSP subjects in Brazil, and identified some risk factors for this outcome. Also, these patients may possess higher risk for morbidity, usually urinary tract infections and decubitus scars, which could increase risk for death.

Plasma osteopontin (OPN) levels are elevated in mycobacterium tuberculosis patients and may involve granuloma formation. New inhibitors using brefelamide, an aromatic amide isolated from Dictyostelium cellular slim molds which may inhibit OPN transcription at concentration of 1M, were synthesized as compounds C, D and E. Their inhibitory activity against OPN synthesis in phorbol 12-myristate 13-acetate (PMA)-stimulated THP-1 cells was confirmed using enzyme-linked immunosorbent assay (ELISA), a multicolor immune-fluorescent microscope and western blot analysis. For the ELISA performed using the full-length OPN, each compound showed significant inhibition. Detailed analysis were done using C and D. They also showed inhibitory activity when used on another ELISA system to detect the immune-related form of OPN and their IC50 were 0.6 and 1.2 M for compounds C and D, respectively. Fluorescent particle count of stained cell numbers by O-17 showed the inhibition. Antibodies for O-17 and 34E3, which recognize OPN N-terminus and thrombin-cleaved site, respectively, detected distinct bands on the western blots following PMA stimulation. The decrease in full-length OPN detected by O-17 in the compound-treated cells was identified via western blot analysis. These newly-developed compounds may therefore be used in clinical trials for cancer and infectious diseases.

Data that have been processed to allow analysis with a minimum of additional user effort are often referred to as Analysis Ready Data (ARD). The ability to perform large scale Landsat analysis relies on the ability to access observations that are geometrically and radiometrically consistent, and have had non-target features (clouds) and poor quality observations flagged so that they can be excluded. The United States Geological Survey (USGS) has processed all of the Landsat 4 and 5 Thematic Mapper (TM), Landsat 7 Enhanced Thematic Mapper Plus (ETM+), Landsat 8 Operational Land Imager (OLI) and Thermal Infrared Sensor (TIRS) archive over the conterminous United States (CONUS), Alaska, and Hawaii, into Landsat ARD. The ARD are available to significantly reduce the burden of pre-processing on users of Landsat data. Provision of pre-prepared ARD is intended to make it easier for users to produce Landsat-based maps of land cover and land-cover change and other derived geophysical and biophysical products. The ARD are provided as tiled, georegistered, top of atmosphere and atmospherically corrected products defined in a common equal area projection, accompanied by spatially explicit quality assessment information, and

This paper deals with the merger of the two lightweight stream ciphers—A5/1 and Trivium. The idea is to make the key stream generation more secure and to remove the attacks of the individual algorithms. The bits generated by the Trivium cipher (output) will act as the input of the A5/1 cipher. The registers used in the A5/1 cipher will be filled by the output bits of the Trivium cipher. The three registers will then be connected to generate an output which will be our required key stream.

Human Immunodeficiency Virus (HIV) infection and its latent recurrent infection make vaccine development a significant challenge for traditional vaccines; however, the mRNA delivery of multiepitope antigens capable of creating antibodies against the surface proteins of HIV-1 and HIV-2 along with their respective Nef proteins, responsible for the latent infection can bring a most effective, as well as affordable solution to the unresolved epidemics of HIV. In this paper, we present the complete design of a multiepitope vaccine to prevent acute infections and inactivate Nef proteins that block the MHC-1 and MHC-2 pathways to hide the virus for later reinfection.

Herpes simplex virus type 1 (HSV-1) is among the most widely spread viruses on the planet. However, the rate of binding to the receptor is not among the greatest ones. Gibbs energy of binding, which represents the driving force for antigen-receptor binding, of HSV-1 is less negative than can be expected. Furthermore, the Gibbs energy of biosynthesis of HSV-1 is among the most negative in nature. This implies high rate of multiplication of HSV-1. Obviously, HSV-1 uses specific strategy in virus-host interaction. While most other viruses increase infectivity through a high rate of antigen-receptor binding and cell entry/ highly negative Gibbs energy of binding, HSV-1 uses another strategy. It is related to a relatively slow reaction of antigen-receptor binding, which is followed by a higher rate of multiplication, which is a consequence of a highly negative Gibbs energy of biosynthesis. We can conclude empirically that both strategies are successful.

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improvement effects on insulin resistance-associated metabolic abnormalities including obesity and type 2 diebetes. However, the molecular mechanisms of theaflavins improving insulin sensitivity are still not clear. In this study, we investigated the protective effects and mechanisms of theaflavins on palmitic acid-induced insulin resistance in HepG2 cells. Theaflavins could significantly increase glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the glucose transporter 4 protein expression, increasing the phosphorylation of IRS-1 at Ser307, and reduced the phosphor-Akt (Ser473) level. Moreover, theaflavins were found to enhance mitochondrial DNA copy number through down-regulate the PGC-1β mRNA level and up-regulate PRC mRNA expression in insulin-resistant HepG2 cells. These results indicated that theaflavins could improve free fatty acid-induced hepatic insulin resistance by promoting mitochondrial biogenesis, and were promising functional food and medicines for insulin resistance-related disorders.

A finite-type immersion or smooth map is a nice tool to classify submanifolds of Euclidean space, which comes from eigenvalue problem of immersion. The notion of generalized 1-type is a natural generalization of those of 1-type in the usual sense and pointwise 1-type. We classify ruled surfaces with generalized 1-type Gauss map as part of a plane, a circular cylinder, a cylinder over a base curve of an infinite type, a helicoid, a right cone and a conical surface of $G$-type.

Let {$\Gamma(k)$} denote {$(k-1)!$}, and let {$\Gamma_{n}(k)$} denote {$(k-1)!$}, where {$n \in \{3,\ldots,16\}$} and {$k \in \{2\} \cup [2^{\textstyle 2^{n-3}}+1,\infty) \cap \mathbb N$}. For an integer {$n \in \{3,\ldots,16\}$}, let $\Sigma_n$ denote the following statement: if a system of equations {${\mathcal S} \subseteq \{\Gamma_{n}(x_i)=x_k:~i,k \in \{1,\ldots,n\}\} \cup \{x_i \cdot x_j=x_k:~i,j,k \in \{1,\ldots,n\}\}$} with $\Gamma$ instead of $\Gamma_{n}$ has only finitely many solutions in positive integers {$x_1,\ldots,x_n$}, then every tuple {$(x_1,\ldots,x_n) \in (\mathbb N \setminus \{0\})^n$} that solves the original system ${\mathcal S}$ satisfies {$x_1,\ldots,x_n \leqslant 2^{\textstyle 2^{n-2}}$}. Our hypothesis claims that the statements {$\Sigma_{3},\ldots,\Sigma_{16}$} are true. The statement {$\Sigma_6$} proves the following implication: if the equation {$x(x+1)=y!$} has only finitely many solutions in positive integers $x$ and $y$, then each such solution {$(x,y)$} belongs to the set {$\{(1,2),(2,3)\}$}. The statement {$\Sigma_6$} proves the following implication: if the equation {$x!+1=y^2$} has only finitely many solutions in positive integers $x$ and $y$, then each such solution {$(x,y)$} belongs to the set {$\{(4,5),(5,11),(7,71)\}$}. The statement {$\Sigma_9$} implies the infinitude of primes of the form {$n^2+1$}. The statement {$\Sigma_9$} implies that any prime of the form {$n!+1$} with {$n \geqslant 2^{\textstyle 2^{9-3}}$} proves the infinitude of primes of the form {$n!+1$}. The statement {$\Sigma_{14}$} implies the infinitude of twin primes. The statement {$\Sigma_{16}$} implies the infinitude of Sophie Germain primes.

The following system of equations {x_1 \cdot x_1=x_2, x_2 \cdot x_2=x_3, 2^{2^{x_1}}=x_3, x_4 \cdot x_5=x_2, x_6 \cdot x_7=x_2} has exactly one solution in ({\mathbb N}\{0,1})^7, namely (2,4,16,2,2,2,2). Hypothesis 1 states that if a system of equations S \subseteq {x_i \cdot x_j=x_k: i,j,k \in {1,...,7}} \cup {2^{2^{x_j}}=x_k: j,k \in {1,...,7}} has at most five equations and at most finitely many solutions in ({\mathbb N}\{0,1})^7, then each such solution (x_1,...,x_7) satisfies x_1,...,x_7 \leq 16. Hypothesis 1 implies that there are infinitely many composite numbers of the form 2^{2^{n}}+1. Hypotheses 2 and 3 are of similar kind. Hypothesis 2 implies that if the equation x!+1=y^2 has at most finitely many solutions in positive integers x and y, then each such solution (x,y) belongs to the set {(4,5),(5,11),(7,71)}. Hypothesis 3 implies that if the equation x(x+1)=y! has at most finitely many solutions in positive integers x and y, then each such solution (x,y) belongs to the set {(1,2),(2,3)}. We describe semi-algorithms sem_j (j=1,2,3) that never terminate. For every j \in {1,2,3}, if Hypothesis j is true, then sem_j endlessly prints consecutive positive integers starting from 1. For every j \in {1,2,3}, if Hypothesis j is false, then sem_j prints a finite number (including zero) of consecutive positive integers starting from 1.

We can analyze the properties of the Collatz Conjecture by using Terras’ Theorem, and computational graphical calculations. To do this, we introduce the concept of “tree" which shows the relationship between the input and output positive integers of the Collatz process. This approach offers a novel way for determining the non-existence of loops and diverge trees through computer simulations.

Angiogenesis is a critical physiological response to ischemia but becomes pathological when dysregulated and driven excessively by inflammation. We recently identified a novel angiogenic role for tripartite-motif-containing protein 2 (TRIM2) whereby lentiviral shRNA-mediated TRIM2 knockdown impaired endothelial angiogenic functions in vitro. This study sought to determine whether these effects could be translated in vivo and to determine the molecular mechanisms involved. CRISPR/Cas9-generated Trim2–/– mice that underwent a periarterial collar model of inflammation-induced angiogenesis exhibited significantly less adventitial macrophage infiltration relative to wildtype (WT) littermates, concomitant with decreased mRNA expression of macrophage marker Cd68 and reduced adventitial proliferating neovessels. Mechanistically, TRIM2 knockdown in endothelial cells in vitro attenuated inflammation-driven induction of critical angiogenic mediators, including nuclear HIF-1α, and curbed the phosphorylation of downstream effector eNOS. Conversely, in a hindlimb ischemia model of hypoxia-mediated angiogenesis, there were no differences in blood flow reperfusion to the ischemic hindlimbs of Trim2–/– and WT mice despite a decrease in proliferating neovessels and arterioles. TRIM2 knockdown in vitro attenuated hypoxia-driven induction of nuclear HIF-1α but had no further downstream effects on other angiogenic proteins. Our study has implications for understanding the role of TRIM2 in the regulation of angiogenesis in both pathophysiological contexts.

Actively combating post-harvest food spoilage and waste can dramatically increase the efficiency of food utilization worldwide. In climacteric fruits, chemical treatments such as 1-MCP are an effective way of reducing post-harvest spoilage and waste by inhibiting the fruit’s ability to perceive ethylene. 1-MCP treatment is increasingly being used to explore the complex nature of ripening physiology at a fundamental level, however, differences in application and quantitation methods create difficulties in comparing conclusions across studies. Here we report an effective and reproducible method for 1-MCP application and quantitation for small-medium sized research applications. By use of surrogate alkene standards 1-butene and cis-2-butene, the highly volatile and elusive 1-MCP molecule can be identified and quantified by gas chromatography and subsequent standard curves may be developed. It is hoped that the methodology outlined here can help standardize consistent 1-MCP application for post-harvest research without excessive investment in specialized equipment.