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Summary: Adipose tissue stores excess energy and produces a broad range of factors that regulate multiple physiological processes including systemic energy homeostasis. Visceral adipose tissue (VAT) plays a particularly important role in glucose metabolism as its endocrine function underpins food uptake and energy expenditure. Caloric excess triggers VAT inflammation which can impair insulin sensitivity and cause metabolic deregulation. Regulatory T cells (Tregs) that reside in the VAT suppress inflammation and protect from metabolic disease. The cellular components of VAT and its secretory products play a vital role in fostering the differentiation and maintenance of VAT Tregs. Critically, the physiology and inflammatory tone of VAT exhibit sex‐specific disparities, resulting in substantial VAT Treg heterogeneity. Indeed, cytokines and sex hormones promote the differentiation of distinct populations of mature VAT Tregs, each characterized by unique phenotypes, homeostatic requirements, and functions. This review focuses on key findings that have significantly advanced our understanding of VAT Treg biology and the current state of the field, while also discussing open questions that require further exploration. [ABSTRACT FROM AUTHOR]

Background: The IWATE criteria, a four‐level classification system for laparoscopic hepatectomy, measures technical complexity but lacks studies on its impact on outcomes and costs, especially in robotic surgeries. This study evaluated the effects of technical complexity on perioperative outcomes and costs in robotic hepatectomy. Methods: Since 2013, we prospectively followed 500 patients who underwent robotic hepatectomy. Patients were classified into four levels of IWATE scores; (low [0–3], intermediate [4–6], advanced [7–9], and expert [10–12]) determined by tumor characteristics, liver function and resection extent. Perioperative variables were analyzed with significance accepted at a p‐value ≤.05. Results: Among 500 patients, 337 (67%) underwent advanced to expert‐level operations. Median operative duration was 213 min (range: 16–817 min; mean ± SD: 240 ± 116.1 min; p <.001) and estimated blood loss (EBL) was 95 mL (range: 0–3500 mL; mean ± SD:142 ± 171.1 mL; p <.001). Both operative duration and EBL showed positive correlations with increasing IWATE scores. Median length of stay (LOS) of 3 days (range: 0–34; mean ± SD:4 ± 3.0 days; p <.001) significantly correlated with IWATE score. Total cost of $25 388 (range: $84–354 407; mean ± SD: 29752 ± 20106.8; p <.001) also significantly correlated with operative complexity, however hospital reimbursement did not. No correlation was found between IWATE score and postoperative complications or mortality. Conclusions: Clinical variables such as operative duration, EBL, and LOS correlate with IWATE difficulty scores in robotic hepatectomy. Financial metrics such as costs but not reimbursement received by the hospital correlate with IWATE scores. [ABSTRACT FROM AUTHOR]

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Private Partners Scientific Board (PPSB) encompasses members from industry, biotechnology, diagnostic, and non‐profit organizations that have until recently been managed by the Foundation for the National Institutes of Health (FNIH) and provided financial and scientific support to ADNI programs. In this article, we review some of the major activities undertaken by the PPSB, focusing on those supporting the most recently completed National Institute on Aging grant, ADNI3, and the impact it has had on streamlining biomarker discovery and validation in Alzheimer's disease. We also provide a perspective on the gaps that may be filled with future PPSB activities as part of ADNI4 and beyond. Highlights: The Private Partners Scientific board (PPSB) continues to play a key role in enabling several Alzheimer's Disease Neuroimaging Initiative (ADNI) activities.PPSB working groups have led landscape assessments to provide valuable feedback on new technologies, platforms, and methods that may be taken up by ADNI in current or future iterations. [ABSTRACT FROM AUTHOR]

Recently, the environmental contamination caused by toxic dyes has posed a severe threat to human health. Semiconductor‐based photocatalysis is gaining a lot of attention due to its potential applications in environmental remediation. Herein, photocatalytic reactive FeCoWO4/g‐C3N4 nanocomposites were prepared through a facile route hydrothermal process. The bare FeCoWO4, g‐C3N4 and FeCoWO4/g‐C3N4 nanocomposites possess specific features, including reactive surface sites, improved efficiency of charge transfer, and accelerated separation of photogenerated electron‐hole pairs. As a result, the photocatalytic activity towards methylene blue dye (MB) degradation activity of FeCoWO4/g‐C3N4 nanocomposites is significantly improved. Thus, photocatalysts exhibited the highest degradation activities and could remove 91.5 % of MB dye within 120 minutes of visible light irradiation. The enhanced photocatalytic activity with excellent recyclability shows potential for the practical application of FeCoWO4/g‐C3N4 nanocomposites for wastewater treatment. [ABSTRACT FROM AUTHOR]

This article discusses the effectiveness and safety of vitamin D supplementation in reducing the risk of asthma exacerbation and improving asthma control. The authors conducted a meta-analysis of 20 studies involving both children and adults with asthma. The results showed that vitamin D supplementation did not reduce the proportion of participants experiencing asthma exacerbations or improve asthma control. However, the analysis did not include many patients with extreme vitamin D deficiency or severe asthma, so further research is needed in these populations. The safety profile of vitamin D supplementation was found to be good. Overall, the article suggests that vitamin D supplementation may not be beneficial for improving asthma outcomes. [Extracted from the article]

There is a lack of research on the combined effects of genetic variations (specifically CD36 SNPs—rs1761667 and rs1527483), dietary food habits (vegetarian or not), and the salivary environment on obesity and taste sensitivity, especially in the Indian population. The current study aims to better understand the relationship between impaired taste perception, fat consumption, higher BMI and obesity development by examining the combined association between CD36 SNPs, oleic acid (OA) detection threshold, and food habits among Indian participants. Furthermore, the relationship between oral fatty acid (FAs) sensitivity and taste physiology factors linked to inflammation and salivary proteins was considered. Participants with the minor allele (AA/AG) of CD36 (in both rs1527483 and rs1761667) consumed more fat, particularly saturated FAs (p = 0.0351). Salivary lipopolysaccharide, which causes inflammation, was significantly greater in non‐vegetarians with a higher BMI (p < 0.05), and it exhibited a negative correlation (r = −0.232 and p < 0.05) with Ki67 gene expression, a marker for taste progenitor cells. A positive correlation (r = 0.474, p = 0.04) between TLR4 mRNA levels and the OA detection threshold was also observed. Participants with BMI > 25 kg/m2 had substantially higher TNF‐α and IL‐6 receptor mRNA expression levels, but there were no significant differences between the vegetarian and non‐vegetarian groups. However, salivary CA‐VI, which has a buffering capability on the oral environment, was lower in non‐vegetarian adults with BMI >25. Thus, it was shown that non‐vegetarians with overweight and obesity in India were in at‐risk groups for the CD36 SNP (AA/AG at rs1761667 and rs1527483) and had higher levels of inflammatory markers, which exacerbated alterations in food behaviour and physiological changes, indicating their relevance in the development of obesity. [ABSTRACT FROM AUTHOR]

Aim: Obesity is a major public health issue, which is associated with several chronic diseases. In rodents, voluntary wheel running (VWR) is a type of exercise that influences ingestive behavior. This study aims to investigate the possible function of VWR activity in the perception of fat taste and if it mitigates the immediate effects of fatty acid (FA) ingestion. Methods: Male C57BL/6 mice were arbitrarily assigned to either a sedentary (SED) lifestyle or free access to a running wheel after 5 weeks of dietary regimen. Later these mice groups were used in the investigations on fat preference, metabolic tolerance, and electrophysiology. Diet‐induced alterations in CD36 and GPR120 expression that are related to fat perception and the capacitative calcium signaling caused by FA in taste bud cells (TBCs) were also examined. Results: In obese groups, VWR temporarily reduced body weight, demonstrated improvement in preference scores for FA, and recovered from a deterioration in glucose homeostasis. In CD36‐positive TBCs, electrophysiological investigations showed alterations in [Ca2+]i caused by FA. Further, in the TBCs of circumvallate papillae, there are differences in the expression of the genes CD36 and GPR120 between the active and SED controls. Obese mice also show lower incentive salience for long‐chain fatty acids (LCFA) and adapted to the reward system of VWR which may lead to improved incentive salience accredited to wheel running. Conclusion: In conclusion, this study provides the first evidence that VWR causes orosensory adaptations to fat and appears to alter taste preference for LCFAs. [ABSTRACT FROM AUTHOR]

The article presents the discussion on sex-bias in CD8+ T-cell stemness and exhaustion in cancer. Topics include sex differences in the immune system being well documented in a wide range of organisms such as sea urchins, fruit flies, mice and humans; and T-cell exhaustion marked by the downregulation of cytokine production and continuous expression of co-inhibitory receptors.

Introduction: The acceleration of biological aging is a risk factor for Alzheimer's disease (AD). Here, we performed weighted gene co‐expression network analysis (WGCNA) to identify modules and dysregulated genesinvolved in biological aging in AD. Methods: We performed WGCNA to identify modules associated with biological clocks and hub genes of the module with the highest module significance. In addition, we performed differential expression analysis and association analysis with AD biomarkers. Results: WGCNA identified five modules associated with biological clocks, with the module designated as "purple" showing the strongest association. Functional enrichment analysis revealed that the purple module was related to cell migration and death. Ten genes were identified as hub genes in purple modules, of which CX3CR1 was downregulated in AD and low levels of CX3CR1 expression were associated with AD biomarkers. Conclusion: Network analysis identified genes associated with biological clocks, which suggests the genetic architecture underlying biological aging in AD. Highlights: Examine links between Alzheimer's disease (AD) peripheral transcriptome and biological aging changes.Weighted gene co‐expression network analysis (WGCNA) found five modules related to biological aging.Among the hub genes of the module, CX3CR1 was downregulated in AD.The CX3CR1 expression level was associated with cognitive performance and brain atrophy. [ABSTRACT FROM AUTHOR]

Background: Eyebrows are an important esthetic feature of the face. In cosmetic surgery, knowledge about the patient's preference of eyebrow apex position is important to achieve agreeable esthetic results. Aim: To study the preference of eyebrow apex positions on the different facial shapes in the Malaysian population. Methods: A frontal view photograph of a female model was morphed into oval, square, round, and long facial shapes. Four types of brow apex were created on each facial shape, A. above the midpupil (A‐MP), B. above the lateral limbus (A‐LL), C. halfway between the lateral limbus and lateral canthus (A‐HF) and D. above the lateral canthus (A‐LC). Out of the four brow apexes, the respondent selected one esthetically appealing brow apex for each facial shape. A total of 441 Malaysians completed the survey questionnaire. Differences in preference between the ethnic groups were analyzed by the chi‐square test. Results: The majority of Malaysian Chinese (MC) and Malaysian Indians (MI) subjects found A‐LL as attractive on the oval (MC‐73%, MI‐52%), square (MC‐42%, MI‐42%), round (MC‐45%, MI‐40%) and long (MC‐39%, MI‐44%) shape, but the Malaysian Malays preferred more the A‐HF on long (42%) and round (42%) face. While the Malaysian Indians least preferred the A‐MP on the oval (4%), square (5%), round (6%), and long (5%). A significant difference in preference of apex position was observed between MC versus MI and MC versus MM in both oval and square faces. On the round face, the difference was noted between all the ethnic groups. However, on the long face, a significant difference was noted only between MI and MM. Conclusions: Significant interethnic differences exist in the preference of eyebrow apex position on the facial shapes. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is one of the most common forms of dementia globally and is defined by accumulation of extracellular amyloid plaques and intracellular tau‐containing neurofibrillary tangles in neuronal cells. These pathological changes occur more than a decade prior to symptom onset. Given that disease modifying therapies are geared towards asymptomatic/early AD patients, identification of asymptomatic individuals at risk of progression is key. Genome‐Wide Association Studies(GWAS) for AD have implicated many single nucleotide polymorphisms (SNPs) associated with disease risk. Whereas a minority of early onset AD cases are driven by mutations in genes, sporadic AD cases have complex genetic architecture and are highly heritable. Polygenic Risk Scores (PRS), which aggregate genome‐wide risk loci, have been shown to predict AD onset with AUCs of 75‐84%. Methods: The PRS approach used in this study is built from a sum of weighted contributions of over 100,000s SNPs associated with disease. We utilized PRS (genoSCORE™) to predict cognitive function decline in a cohort of 280 AD patients in a Ph2 clinical trial for Tilavonemab, a monoclonal antibody targeting the N‐terminus of human tau. Additionally, genoTOR™ was calculated to identify pathways most impacted by the genetic variants enriched in the cohort. Results: Given that tilavonemab did not alter Clinical Dementia Rating‐Sum of Boxes(CDR‐SB), we tested differences in cognitive decline between high PRS and low PRS individuals defined using a threshold of 0.6 in the entire cohort and found no difference. Upon stratification by APOE status, higher PRS(> = 0.6) predicted an increase in CDR‐SB of an average of 1.0 at week 72 (p<0.1) and week 96 (p<0.05) compared to participants with lower PRS(<0.6) within the APOE3 population. Additional analyses of the genoTOR™ signaling pathways are ongoing. Conclusions: The results of these analyses demonstrate that genoSCORE™ may be helpful to enrich for APOE3 individuals most susceptible to cognitive decline over time. Since the majority of genetic risk studies have focused on an APOE4 population, this method provides a novel tool to enrich for individuals at high risk for cognitive decline over time in a less studied population in which there is difficulty with prediction of disease progression. [ABSTRACT FROM AUTHOR]

More than 15 million people have been affected by coronavirus disease 2019 (COVID‐19) and it has caused 640 016 deaths as of July 26, 2020. Currently, no effective treatment option is available for COVID‐19 patients. Though many drugs have been proposed, none of them has shown particular efficacy in clinical trials. In this article, the relationship between the Adrenergic system and the renin‐angiotensin‐aldosterone system (RAAS) is focused in COVID‐19 and a vicious circle consisting of the Adrenergic system‐RAAS‐Angiotensin converting enzyme 2 (ACE2)‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) (which is referred to as the "ARAS loop") is proposed. Hyperactivation of the ARAS loop may be the underlying pathophysiological mechanism in COVID‐19, and beta‐adrenergic blockers are proposed as a potential treatment option. Beta‐adrenergic blockers may decrease the SARS‐CoV‐2 cellular entry by decreasing ACE2 receptors expression and cluster of differentiation 147 (CD147) in various cells in the body. Beta‐adrenergic blockers may decrease the morbidity and mortality in COVID‐19 patients by preventing or reducing acute respiratory distress syndrome (ARDS) and other complications. Retrospective and prospective clinical trials should be conducted to check the validity of the hypothesis. Also see the video abstract here https://youtu.be/uLoy7do5ROo. [ABSTRACT FROM AUTHOR]

HTN after renal transplantation is associated with cardiovascular morbidity. ABPM allows diagnosis of masked HTN and isolated nocturnal HTN. Longitudinal ABPM data in children post‐transplant are limited. ABPM was performed in children post‐transplant and repeated in 6‐12 months. BP indices were used to determine the prevalence of masked HTN, masked uncontrolled HTN (masked HTN in patients on antihypertensive medications), and isolated nocturnal HTN. Linear regression determined the association between LVMI and ABPM indices. Thirty children underwent a baseline ABPM. Ambulatory HTN was present in 25 (83%). Masked HTN was present in 18 (60%) and isolated nocturnal HTN in 13 (43%). Nocturnal ambulatory BP was higher than corresponding daytime BPs (P <.001 for systolic and diastolic) and 25 (83%) had a blunted nocturnal dip. Prednisone dose predicted nocturnal DBP index and DBP load (r2 =.40, P =.024 and r2 =.178, P =.02). ABPM was repeated in 18 patients within 11 (±3) months. BP indices decreased with time, but nocturnal BPs remained higher than daytime (P <.001 for SBP and DBP). Blunted nocturnal dip did not improve. LVH was present in 12 (57%). LVMI was directly related to the nocturnal SBP index (r2 =.377, P =.003) and nocturnal DBP index (r2 =.493, P <.001). We found no association between LVMI and daytime BP indices. The prevalence of masked HTN, isolated nocturnal HTN, and blunted nocturnal dip was high in children with kidney transplants. Nocturnal BP predicted LVMI. Ambulatory BP improved on longitudinal follow‐up, but the pattern of isolated nocturnal HTN persisted. [ABSTRACT FROM AUTHOR]

This article reviews recent arguments in contemporary political philosophy on victims' duties to resist their oppression. It begins by presenting two approaches to these duties. First, that victims' duties are self‐regarding duties that victims owe to their self‐respect or to their well‐being, and second, that victims' duties are other‐regarding duties that arise from victims' duties of justice or of assistance. The second part elaborates on what resistance consists in. The article then considers and responds to two prominent objections to arguments for victims' duties: that they are too demanding, and that they are unfair and exploitative. It concludes by gesturing towards future areas of engagement, in particular, theorising the agents and mechanisms of oppression, and more explicitly engaging with methodological debates about non‐ideal theory. [ABSTRACT FROM AUTHOR]

Background: Identifying biomarkers associated with neurodegenerative diseases and their progression may enable patient enrichment and improve clinical trial designs. Method: Genomic studies have revealed correlations between genetics, transcriptomics, and epigenetics with disease pathology and diagnosis in the brain and peripheral blood. For example, previous studies have showed that rate of cognitive decline estimated by slopes of cognitive scores associated with change in DNA methylation. Result: Several of these genomic marks point to proteomic changes, especially given the chromosomal location of these differentially expressed or methylated marks. Moreover, since proteins represent a key class of biomolecules that will help illustrate real‐time human biology, we tested a targeted proteomic analysis using the Olink platform. Conclusion: Data from the analysis of targeted proteomic analysis in the context of clinical data as well other omics datasets for the same participants will be discussed at this session. [ABSTRACT FROM AUTHOR]

GLO:FRK/01jul21:imcb12461-toc-0001.jpg PHOTO (COLOR): . gl Regulatory T (Treg) cells play a critical role in suppressing self-reactive T cells to preserve immune homeostasis.1 In the context of cancers, however, Treg cells dampen the function of anti-tumor immune cells to promote cancer progression.1 Altered cellular metabolism is one of the hallmarks of cancer cells. Zappazodi I et al i . used Glut1 and LDHA deficient Treg cells to demonstrate impaired glycolysis and short-term restoration of Treg cell function; however, the long-term maintenance was impaired. [Extracted from the article]

Three copper(I) complexes, [CuCl(L)(PPh3)2] [L = FL (1), BL (2) or TL (3)] were prepared from [(PPh3)2Cu(µ‐Cl)2Cu(PPh3)] and N‐carbamothioylfuran‐2‐carboxamide (FL), N‐carbamothioylbenzamide (BL) or N‐carbamothioylthiophene‐2‐carboxamide (TL) ligands in benzene and four‐coordinated tetrahedral copper complexes were well characterized by various spectroscopic techniques (UV/Vis, FT‐IR, 1H NMR, 13C NMR and 31P NMR). The molecular structure of the ligands (FL and BL) and complexes was established from single‐crystal X‐ray diffraction studies. Copper complexes have been shown to catalyse the one‐pot synthesis of imines and quinoxalines. Heterogenized catalyst (4) was prepared by reacting more active complex 3 with polystyrene supported triphenylphosphane, and characterized by elemental analyses, and DRS‐UV, FT‐IR, ICP‐OES, and solid‐state NMR techniques. Catalytic activity of the complexes (3 and 4) was tested in the formation of imines from alcohols and amines, and quinoxalines from hydroxy ketones and diamines. Heterogeneity and reusability of catalyst 4 were evaluated, and the catalyst can be reused for four runs without any loss in activity. [ABSTRACT FROM AUTHOR]

Background: Postoperative heart block is common among patients undergoing surgery for infective endocarditis (IE). Limited data exists allowing cardiologists to predict who will require permanent pacemaker (PPM) implantation postoperatively. We aimed to determine the rate of postoperative PPM insertion, predictors for postoperative PPM, and describe PPM utilization and rates of device‐related infection during follow‐up. Materials and Methods: A retrospective analysis was performed of 191 consecutive patients from a single institution who underwent cardiac surgery for IE between 2001 and 2017. Preoperative and operative predictors for postoperative PPM were evaluated using univariate and multivariate logistic regression. Results: The rate of postoperative PPM implantation was 11% (17/154). The PPM group had more preoperative prolonged PR interval alone (33% vs 12%; P = .03), coexistent prolonged PR and QRS durations (13% vs 2%; P = .01), infection beyond the valve leaflets (82% vs 41%; P = .001), aortic root debridement (65% vs 23%; P = <.001), patch repair (47% vs 20%; P = .01), postoperative prolonged PR interval (50% vs 24%; P = .01), and prolonged QRS duration (47% vs 15%; P = .001). On multivariate analysis, infection beyond the valve leaflets emerged as an independent predictor for postoperative PPM (odds ratio, 1.94, 95% confidence interval, 1.14‐3.28; P = .014). A reduction in PPM utilization was observed in five patients while eight patients continued to show significant ventricular pacing with no underlying rhythm at 12 months. There were no device‐related infections. Conclusion: Postoperative PPM was required in 11% of patients undergoing surgery for IE over a 16‐year period. Infection beyond the valve leaflet was an independent predictor for postoperative PPM insertion. [ABSTRACT FROM AUTHOR]

Abstract: Victims of injustice are prominent protagonists in efforts to resist injustice. I argue that they have a duty to do so. Extant accounts of victims’ duties primarily cast these duties as self‐regarding duties (say, of Kantian self‐respect) or duties based on collective identities and commitments. I provide an account of victims’ duties to resist injustice that is grounded in the duty to assist. I argue that victims are epistemically privileged with respect to injustice and are therefore uniquely positioned to assist fellow victims. Primarily, they discharge this duty through testimony: victims alert other actors to the need for assistance and initiate and coordinate resistance efforts. I briefly provide an account of oppression that ranges from persecution to structural injustice. Through the examples of torture and ‘manterrupting’, I illustrate the duty and its limits. I outline shortcomings in victims’ epistemic privilege and explore means by which these can be overcome. I respond to objections from demandingness and fairness, arguing that victims have an essential, albeit circumscribed, role to play in defeating injustice. [ABSTRACT FROM AUTHOR]

Summary: Combined antifungal and antioxidant therapy may help to reduce oxidative stress in fungal keratitis. Experimental Fusarium solani keratitis was induced by application of F. solani conidia to scarified cornea (right eye) of 16 rabbits (another four rabbits were negative controls [Group I]). Five days later, F. solani‐infected animals began receiving hourly topical saline alone (Group II), voriconazole (10 mg/mL) alone (Group III), epigallocatechin gallate (EGCG, 10 mg/mL) alone (Group IV) or voriconazole and EGCG (Group V). Twenty days post‐inoculation, corneal lesions were graded. After animal sacrifice, excised corneas underwent histopathological and microbiological investigations. Corneal tissue levels/activities of interleukin 1 beta (IL‐1β) and tumour necrosis factor alpha (TNF‐α) gene mRNA transcripts, matrix metalloproteinase (MMP) 2 and 9 proteins, malondialdehyde (MDA) and reduced glutathione (GSH), and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), were also measured. Clinical and histopathological scores (severity of corneal lesions; [P < .05]) and mean levels (P < .05) of IL‐1β and TNF‐α mRNA transcripts, MMP 2, MMP 9 and MDA were Group II > Groups IV and III > Groups V and I. Mean SOD, CAT, GPx and GSH levels (P < .05) were Group II < Groups IV and III < Groups V and I. Topical voriconazole with EGCG apparently reduces inflammation in experimental F. solani keratitis, as manifested by improved clinical, histological, microbiological and molecular parameters. [ABSTRACT FROM AUTHOR]

Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 ( PRC2) together with Suz12 and Eed. However, Ezh2 can also modify non-histone substrates, although it is unclear whether this mechanism has a role during development. Here, we present evidence for a chromatin-independent role of Ezh2 during T-cell development and immune homeostasis. T-cell-specific depletion of Ezh2 induces a pronounced expansion of natural killer T ( NKT) cells, although Ezh2-deficient T cells maintain normal levels of H3K27me3. In contrast, removal of Suz12 or Eed destabilizes canonical PRC2 function and ablates NKT cell development completely. We further show that Ezh2 directly methylates the NKT cell lineage defining transcription factor PLZF, leading to its ubiquitination and subsequent degradation. Sustained PLZF expression in Ezh2-deficient mice is associated with the expansion of a subset of NKT cells that cause immune perturbation. Taken together, we have identified a chromatin-independent function of Ezh2 that impacts on the development of the immune system. [ABSTRACT FROM AUTHOR]

TylP is one of five regulatory proteins involved in the regulation of antibiotic (tylosin) production, morphological and physiological differentiation in Streptomyces fradiae. Its function is similar to those of various γ-butyrolactone receptor proteins. In this report, N-terminally His-tagged recombinant TylP protein (rTylP) was overproduced in Escherichia coli and purified to homogeneity. The rTylP protein was crystallized from a reservoir solution comprising 34%( v/ v) ethylene glycol and 5%( v/ v) glycerol. The protein crystals diffracted X-rays to 3.05 Å resolution and belonged to the trigonal space group P3121, with unit-cell parameters a = b = 126.62, c = 95.63 Å. [ABSTRACT FROM AUTHOR]

Background: Intracellular abnormal aggregation of hyperphosphorylated tau protein is a neuropathological hallmark associated with Alzheimer's Disease (AD). The insoluble tau aggregates called neurofibrillary tangles lead to microtubule dysfunction and neurodegeneration with AD progression. The TG4510 transgenic mice overexpressing the P301L mutant human tau protein exhibit region‐specific tau inclusions, brain atrophy, and behavioral deficits, thereby serving as a widely used animal model of tauopathy in AD. This study aims to characterize the tissue‐specific transcriptomic and epigenomic signatures of progressive tau pathology in TG4510 mice as well as investigate the correlation of brain and blood expression and epigenomic changes. Method: Using UMI‐based bulk RNA‐Sequencing and Reduced‐representation Bisulfite Sequencing (RRBS), we profiled the gene expression and DNA‐methylation changes respectively, in the cortex, hippocampus, cerebellum and pre‐sacrifice and terminal whole blood between three age groups (2‐3 months, 6‐7 months, 8‐9 months old; N=20/tissue/group) of male and female TG4510 mice. Result: The cortex and hippocampus show the largest transcriptional differences between mice, recapitulating phenotype differences with loss of neurotransmission and increased inflammation in these tissues. Systems‐level co‐expression analysis reveals common gene modules in immune system, behaviour and cognition and ECM/synaptic pathways between cortex/hippocampus and blood. Furthermore, the genes correlated between brain regions and blood in these mice were prioritized as potential biomarkers of tau pathology, which can be further validated in preclinical animal models and ultimately human studies. Conclusion: This study serves as one of the first evidence of multiomic molecular underpinnings in a tauopathy mouse model providing potential novel targets and biomarkers of progressive tau pathology in AD. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. [ABSTRACT FROM AUTHOR]

Background Pharmacologic stress testing is utilized in preference to exercise stress echocardiography ( ESE) for cardiac risk evaluation in potential renal transplant recipients due to the perceived lower feasibility of ESE for achieving adequate workload and target heart rate ( THR) in this population. Methods Consecutive patients referred for cardiac risk evaluation prior to potential kidney transplantation were evaluated. All patients attempted ESE before pharmacologic testing was considered. Treadmill ESE utilized BRUCE protocol to maximum capacity. THR was defined as >85% of the maximum predicted heart rate (220-age). Functional capacity was assessed by metabolic equivalents ( METs) and the rate pressure product ( RPP). Results Of 535 patients (349 male, age 56±11), 372(70%) reached THR. Mean METs were 10±3 with 531(99%) achieving ≥4 METs and 87% ≥7 METs. Mean RPP was 25 821±5820 bpm×mm Hg (83% achieving >20 000 bpm×mm Hg). On multivariate analysis, independent predictors of failure to reach THR were rate-control medication and diabetes; failure to reach 7 METs: females, diabetics, age≥65, and previous cardiac disease; failure to reach RPP>20 000: rate-control medication. There were 97% of ESE completed to physiologic endpoints. Conclusion In unselected potential renal transplant candidates, cardiac assessment by ESE is well tolerated, with 9-in-10 exercising to satisfactory functional capacity. ESE should be considered a feasible alternative to pharmacologic testing in this population. [ABSTRACT FROM AUTHOR]

The article discusses the possibility of political representation in government in exile and its impact on the dilemmas of transnational politics. Topics discussed include the parliamentary elections in Tibetan diaspora, the intervention of exiles in homeland affairs and the role of exiles in establishing independent states and international recognition.

Aim To use continuous glucose monitoring to examine the effects of insulin initiation with glargine, with or without glulisine, on glycaemic variability and glycaemia in a cohort of people with Type 2 diabetes receiving maximum oral hypoglycaemic agents in primary healthcare. Methods We conducted a post hoc analysis of continuous glucose monitoring data from 89 participants at baseline and at 24 weeks after insulin commencement. Indicators of glycaemic variability (standard deviation, J-index and mean amplitude of glycaemic excursion) and glycaemia (HbA1c, mean glucose, area under the glucose-time curve) were assessed. Multi-level regression analysis was used to identify the predictors of change. Results Complete glycaemic variability data were available for 78 participants. Of these participants, 41% were women, their mean ( sd) age was 59.2 (10.4) years, the median (interquartile range) diabetes duration was 10.4 (6.5, 13.3) years and the median (interquartile range) baseline HbA1c was 82.5 (71.6, 96.7) mmol/mol [9.7 (8.7, 11.0)%]. At baseline, BMI correlated negatively with standard deviation ( r = −0.30) and mean amplitude of glycaemic excursion ( r = −0.26), but not with J-index; HbA1c correlated with J-index ( r = 0.61) but not with mean amplitude of glycaemic excursion and standard deviation. After insulin initiation the mean ( sd) glucose level decreased [from 12.0 (3.0) to 8.5 (1.6) mmol/l; P < 0.001], as did the median (interquartile range) J-index [from 66.9 (47.7, 95.1) to 36.9 (27.6, 49.8) mmol/l; P < 0.001]. Baseline HbA1c correlated with a greater J-index reduction ( r = −0.45; P < 0.001). The mean amplitude of glycaemic excursion and standard deviation values were unchanged. The baseline temporal profile, showing elevated postprandial morning glucose levels, was unchanged after insulin initiation, despite an overall reduction in glycaemia. Conclusion Insulin initiation reduced hyperglycaemia but did not alter glycaemic variability in adults with Type 2 diabetes receiving maximum oral hypoglycaemic agents. The most significant postprandial excursions were seen in the morning, which identifies prebreakfast as the most effective target for short-acting insulin therapy. [ABSTRACT FROM AUTHOR]

Amidated kyotorphin (L-Tyr-L-Arg-NH2; KTP-NH2) causes analgesia when systemically administered. The lipophilic ibuprofen-conjugated derivative of KTP-NH2 has improved analgesic efficacy. However, fast degradation by peptidases impacts negatively in the pharmacodynamics of these drugs. In this work, selected derivatives of KTP and KTP-NH2 were synthesized to combine lipophilicity and resistance to enzymatic degradation. Eight novel structural modifications were tested for the potential to transverse lipid membranes and to evaluate their efficacy in vivo. The rationale behind the design of the pool of the eight selected molecules consisted in the addition of individual group at the N-terminus, namely the tert-butyloxycarbonyl (Boc), γ-aminobutyric acid (GABA), acetyl, butanoyl, and propanoyl or in the substitution of the tyrosine residue by an indole moiety and in the replacement of the peptidic bond by a urea-like bond in some cases. All the drugs used in the study are intrinsically fluorescent, which enables the use of spectrofluorimetry to sample the drugs in the permeation assays. The results show that the BOC and indolyl derivatives of KTP-NH2 have maximal ability to permeate membranes with concomitant maximal analgesic power. Overall, the results demonstrate that membrane permeation is correlated with analgesic efficacy. However, this is not the only factor accounting for analgesia. KTP-NH2 for instance has low passive permeation but is known to have central action. In this case, hypothetical transcytosis over the blood-brain barrier seems to depend on dipeptide transporters. [ABSTRACT FROM AUTHOR]

Streptomyces are a major group of soil bacteria that produce wide range of bioactive compounds including antibiotics. Daunorubicin is a chemotherapeutic agent for treatment of certain types of cancer, which is produced as a secondary metabolite by S. peucetius. Owing to the significance of this drug in treating cancer, understanding the molecular mechanism of its biosynthesis will assist in the genetic manipulation of this strain for better drug yields. Additionally, the knowledge can also be applied to design hybrid antibiotics that can be made in vivo by transferring genes from one Streptomyces species to another. Biosynthesis of daunorubicin in S. peucetius is accomplished by the function of 30 enzyme-coding genes in a sequential and coordinated fashion. In addition to these enzymes, three transcriptional regulators DnrO, DnrN and DnrI regulate this multi-step process by forming a coherent feed forward loop regulatory circuit, consequently controlling the entire enzyme coding genes. Since daunorubicin is a DNA intercalating drug, maintaining an optimal intracellular drug concentration is pivotal to prevent self-toxicity. Commencement of daunorubicin biosynthesis also activates the feedback mechanisms mediated by the metabolite. At exceeding intracellular concentrations, daunorubicin intercalates into DNA sequences and impedes the binding of these transcription factors. This feedback repression is relieved by a group of self-resistance genes, which concurrently efflux the excess intracellular daunorubicin. This review will discuss the mechanistic role of each transcription factor and their interplay in initiating and maintaining the biosynthesis of daunorubicin in S. peucetius. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are a specialized subset of CD4 T cells that have an indispensable role in maintaining immune homeostasis and tolerance. Although studies in mice and humans have clearly highlighted that the absence of these cells results in severe autoimmunity and inflammation, increased Treg numbers and/or function is not always beneficial. This is best exemplified in certain cancers where increased Tregs promote cancer progression by interfering with immune surveillance. Conversely, in other types of cancers that have an inflammatory component, Tregs can inhibit cancer progression by dampening inflammation. In this review article, we provide a historical perspective of the discovery of Tregs, followed by a summary of the existing literature on the role of Tregs in malignancy. [ABSTRACT FROM AUTHOR]

Tr1 cells are non-Foxp3-expressing regulatory CD4+ T cells that execute suppressor functions by secreting the anti-inflammatory cytokine IL-10. Differentiation of this T-cell subset is facilitated by the heterodimeric cytokine IL-27, which can activate transcription factors such as c-Maf and Ahr to positively regulate the differentiation of Tr1 cells and their IL-10 production. In this issue of the European Journal of Immunology, an alternate transcriptional network regulated by IL-27 to induce IL-10 production in Tr1 cells is reported by Iwasaki et al. [Eur. J. Immunol. 2013. 43: 1063-1073]. This study shows that IL-27 initiates tandem activation of the transcription factors STAT3 and Egr-2 to induce il10 in Tr1 cells in a Blimp1-dependent fashion. These findings indicate a c-Maf/Ahr independent mechanism that activates IL-10 production by Tr1 cells and suggest that Il10 induction may depend on both the cytokine environment and the molecular context. Thus, Tr1 cells may be another example of the remarkable plasticity of CD4+ T cells and indeed may not constitute a separate lineage of CD4+ T cells but rather represent a developmental endpoint of several T helper cell differentiation pathways. [ABSTRACT FROM AUTHOR]

Biodiesel is one of the alternative fuels that can help in reducing oil dependence. β-Zeolite was modified with phosphoric acid and the modified β-zeolite was used as catalyst for the esterification of free fatty acids (FFA) present in pinnai oil and its effect on esterification reaction was studied. Influence of catalyst amount, methanol to oil ratio and temperature on specific reaction rate was modelled using Langmuir-Hinshelwood (LH) kinetics, pseudo first order kinetics and Arrhenius equation, respectively. The kinetic constant values obtained in LH kinetics show that the adsorption capacity of FFA on catalyst surface was approximately 23 times higher than that of methanol. From pseudo first order kinetic modelling it is found that methanol to oil molar ratio of 9 gives the optimum k value. Thermodynamic studies were also performed to prove the endothermic nature of Pβ catalysed esterification reaction. © 2011 Canadian Society for Chemical Engineering [ABSTRACT FROM AUTHOR]

Summary: Although the diverse functions served by the nuclear factor-κB (NF-κB) pathway in virtually all cell types are typically employed to deal with stress responses, NF-κB transcription factors also play key roles in the development of hemopoietic cells. This review focuses on how NF-κB transcription factors control various aspects of thymic T-cell and myeloid cell differentiation that include its roles in hemopoietic precursors, conventional αβ T cells, CD4+ regulatory T cells, natural killer T cells, γδ T cells, macrophages, and dendritic cells. [ABSTRACT FROM AUTHOR]

In a recent study, we reported a previously undescribed behavior in which a bark beetle exuded oral secretions containing bacteria that have antifungal properties, and hence defend their galleries against pervasive antagonistic Hyphomycete fungi. Actinobacteria, a group known for their antibiotic properties, were the most effective against fungi that invade the spruce beetle galleries. In the present study, we describe the isolation and identification of microorganisms from oral secretions of three bark beetles (Coleoptera: Curculionidae: Scolytinae): the spruce beetle, Dendroctonus rufipennis Kirby, the mountain pine beetle, Dendroctonus ponderosae Hopkins, and the pine engraver, Ips pini Say. Bacteria isolated from these three species span the major bacterial classes α-, β-, and γ-Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria, except for D. ponderosae, which yielded no α-proteobacteria or Bacteroidetes isolates. Spruce beetles and pine engraver beetles had similar numbers of α-proteobacteria isolates, but pine engravers yielded twice as many Bacteroidetes isolates as spruce beetles. In contrast, mountain pine beetles yielded more isolates in the β- and γ-proteobacteria than spruce beetles and pine engravers. The highest percentage of Actinobacteria was obtained from spruce beetles, followed by pine engravers and mountain pine beetles. All of the fungal isolates obtained from the three beetle species were Ascomycetes. The greatest fungal diversity was obtained in spruce beetles, which had nine species, followed by pine engravers with five, and mountain pine beetles with one. [ABSTRACT FROM AUTHOR]

Background: Identifying biomarkers associated with Alzheimer's disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome‐wide association studies (EWAS) have revealed correlations between DNA methylation level at cytosine‐phosphate‐guanine (CpG) sites and AD pathology in the brain or diagnosis in peripheral blood. Method: We performed cross‐sectional analysis of DNA methylation in peripheral blood as a predictor of AD progression in participants in the Alzheimer's Disease Neuroimaging Initiative cohort. Result: The rate of cognitive decline in participants from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACCdigit and mPACCtrailsB) and Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. Two differentially methylated positions were identified (P < 5.79 × 10−8 [Bonferroni correction threshold]): cg00386386 was associated with the slope of mPACCdigit in CN participants, and cg09422696 annotated to RP11‐661A12.5 was associated with the slope of CDR‐SB in MCI participants. No CpG sites significantly associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 70, 76, and 102 differentially methylated regions (DMRs) with Sidak‐corrected P < 0.05 were identified as associated with the slopes of mPACCtrailsB, mPACCdigit in CN participants, and CDR‐SB in MCI participants, respectively; these included DMRs annotated to HOXA4, HOXB6, and HOXB9. Overall, 75 and 123 DMRs were associated with conversion status in participants with CN and with MCI, respectively. The most significant DMR was annotated to an AD‐associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak‐corrected P = 7.74 × 10−24), which was associated with both the slope of CDR‐SB and the MCI conversion status. The identified DMRs were enriched in CpG islands, promoter, and exons, including 5' untranslated region and protein coding, whereas intergenic region, short and long interspersed nuclear element repeats, and introns were depleted. Conclusion: Candidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in CN and MCI participants, respectively, in the longitudinal ADNI cohort. [ABSTRACT FROM AUTHOR]

The indispensability of biotin for crucial processes like lipid biosynthesis coupled to the absence of the biotin biosynthesis pathway in humans make the enzymes of this pathway, attractive targets for development of novel drugs against numerous pathogens including M. tuberculosis . We report the spectral and kinetic characterization of the Mycobacterium tuberculosis 7,8-Diaminopelargonic acid (DAPA) synthase, the second enzyme of the biotin biosynthesis pathway. In contrast to the E. coli enzyme, no quinonoid intermediate was detected during the steady state reaction between the enzyme and S -adenosyl-L-methionine (SAM). The second order rate constant for this half of the reaction was determined to be 1.75 ± 0.11 M -1 s -1 . The K m values for 7-keto-8-aminopelargonic acid (KAPA) and SAM are 2.83 μM and 308.28 μM, respectively whereas the V max and k cat values for the enzyme are 0.02074 μmoles/min/ml and 0.003 s -1 , respectively. Our initial studies pave the way for further detailed mechanistic and kinetic characterization of the enzyme. iubmb Life , 58: 225–223, 2006 [ABSTRACT FROM AUTHOR]

The generally accepted role of iron-regulatory protein 1 (IRP1) in orchestrating the fate of iron-regulated mRNAs depends on the interconversion of its cytosolic aconitase and RNA-binding forms through assembly/disassembly of its Fe–S cluster, without altering protein abundance. Here, we show that IRP1 protein abundance can be iron-regulated. Modulation of IRP1 abundance by iron did not require assembly of the Fe–S cluster, since a mutant with all cluster-ligating cysteines mutated to serine underwent iron-induced protein degradation. Phosphorylation of IRP1 at S138 favored the RNA-binding form and promoted iron-dependent degradation. However, phosphorylation at S138 was not required for degradation. Further, degradation of an S138 phosphomimetic mutant was not blocked by mutation of cluster-ligating cysteines. These findings were confirmed in mouse models with genetic defects in cytosolic Fe–S cluster assembly/disassembly. IRP1 RNA-binding activity was primarily regulated by IRP1 degradation in these animals. Our results reveal a mechanism for regulating IRP1 action relevant to the control of iron homeostasis during cell proliferation, inflammation, and in response to diseases altering cytosolic Fe–S cluster assembly or disassembly. [ABSTRACT FROM AUTHOR]

Abstract: A simple, efficient and stereospecific approach for the homologation of urethane-protected α-amino acids to β-amino acids by the Arndt–Eistert method employing Fmoc-/Boc-α-amino acid and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate mixture for the acylation of diazomethane synthesizing the key intermediates Fmoc-/Boc-α-aminodiazomethanes as crystalline solids is described. [ABSTRACT FROM AUTHOR]

The article discusses the study regarding the transcriptional repressor Bach2 which regulates regulatory T cells development programs of conventional CD4 T cells. It mentions that Bach2 is a factor that strikes multiple levels in controlling the immune hoeostasis. It focuses on the deleterious effects of tolerance breakdown and inflammatory T-cell expansion in Bach2 mice.