Notes

Peptidomics Analysis of Virulent Peptides Involved in Streptococcus suis Pathogenesis.
CD11c+ macrophages/dendritic cells (MDCs) are increased and display the classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into the M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed a high-fat diet (HFD). Compared with littermate controls, cKO mice fed an HFD (16 weeks) had reductions in MDC (mainly CD11c+ macrophage) M1-like polarization and interferon-γ-expressing T-helper type 1 (Th1) cells but increases in interleukin 5-expressing Th2 cells and eosinophils in perigonadal and inguinal AT, and enhanced inguinal AT browning, with increased energy expenditure. cKO mice compared with controls also had significant reductions in triglyceride content in the liver and skeletal muscle and exhibited improved insulin sensitivity and glucose tolerance. Taken together, our results demonstrate that Stat1 in MDCs plays an important role in obesity-induced MDC M1-like polarization and AT inflammation and contributes to insulin resistance and metabolic dysfunctions in obese mice.
Neutralising antibodies are key effectors of infection-induced and vaccine-induced immunity. Quantification of antibodies' breadth and potency is critical for understanding the mechanisms of protection and for prioritisation of vaccines. Here, we used a unique collection of human specimens and HCV strains to develop HCV reference viruses for quantification of neutralising antibodies, and to investigate viral functional diversity.

We profiled neutralisation potency of polyclonal immunoglobulins from 104 patients infected with HCV genotype (GT) 1-6 across 13 HCV strains representing five viral GTs. Using metric multidimensional scaling, we plotted HCV neutralisation onto neutralisation maps. We employed K-means clustering to guide virus clustering and selecting representative strains.

Viruses differed greatly in neutralisation sensitivity, with J6 (GT2a) being most resistant and SA13 (GT5a) being most sensitive. They mapped to six distinct neutralisation clusters, in part composed of viruses from differenle high resolution profiling of HCV neutralisation and they may reflect viral functional and antigenic properties important to consider in HCV vaccine design.There is renewed interest in the central role of the sphenopalatine ganglion (SPG) in cerebrovascular autonomic physiology and the pathophysiology of different primary and secondary headache disorders. (R,S)-3,5-DHPG in vivo There are diverse neural structures (parasympathetic, sympathetic and trigeminal sensory) that convene into the SPG which is located within the pterygopalatine fossa (PPF). This makes the PPF an attractive target to neuromodulatory interventions of these different neural structures. Some experts advocate for the nasal application of local anesthetics as an effective route for SPG block with the belief that the local anesthetic can freely access the PPF. It is time to challenge this historical concept from the early 1900s. In this daring discourse, I will review anatomical studies, CT and MRI reports to debunk this old myth. Will provide anatomical evidence to explain that all these assumptions are untrue and the local anesthetic has to magically 'travel' a distance of 4-12 mm of adipose and connective tissue to reach the SPG in sufficient concentration and volume to effectively induce SPG blockade. Future research should focus on assessing a clinical biomarker to confirm SPG blockade. It could be regional cerebral blood flow or lacrimal gland secretion.Hyperuricemia is more prevalent among people with obesity and metabolic syndrome, and is associated with adverse clinical outcomes. We hypothesized that increased renal reabsorption of uric acid (UA) in obesity and metabolic syndrome may be an adaptive response of the kidney when faced with fatty acid-induced oxidative stress. To test this hypothesis, we examined lipid accumulation, markers of oxidative stress, and renal UA handling in Zucker diabetic fatty (ZDF) rats, and in matched lean control animals. Rats were randomized to either normal rodent chow or a diet supplemented with antioxidants (α-tocopheryl acetate, sodium selenite, zinc sulfate, and ascorbic acid), and were followed up for either 4 or 20 weeks after randomization. Dietary antioxidant supplementation had no significant effects in lean control rats but led to partial improvement in markers of elevated oxidative stress in the kidney of ZDF rats. Renal UA handling was not affected by antioxidant supplementation. We observed robust correlations between renal lipid content and oxidative stress markers in the pooled experimental groups, particularly in older animals after 20 weeks on the study diets. Dietary antioxidant supplementation did not prevent the gradual decline in renal function observed in older ZDF rats. These findings suggest that hyperuricemia in the ZDF rat model of obesity and the metabolic syndrome is not caused by renal oxidative stress, that there may be a pathophysiological link between lipid accumulation and oxidative stress in the kidney, and that antioxidant supplementation does not prevent age-related decline in renal function in ZDF rats.Prognosis for patients with metastatic bladder carcinoma (mBC) remains limited and in need of novel therapies. We retrospectively analyzed medical records of 43 patients with platinum-refractory metastatic bladder cancer (mBC) who participated in one or more phase I trials of various investigational therapies. Patients' tumors or circulating tumor DNA were analyzed by next-generation sequencing. The median progression-free survival was 4.2 months, the median overall survival was 9.6 months, and the overall response rate was 17.5%. TP53, ERBB2, PI3KCA, FGFR3, and ARID1A alterations were detected in 66%, 29%, 27%, 24%, and 22% of all patients, respectively. Alterations in FGFR3 were almost mutually exclusive of TP53. More than half (64%) of patients with an FGFR alt received an FGFR inhibitor, 67% of which achieved disease control. Among patients with urothelial carcinoma histology, those harboring a TP53 alteration had a shorter median progression-free survival (PFS) compared with those whose tumors carry wild-type TP53. The reverse relationship was observed in patients harboring an FGFR alteration. IMPLICATIONS Patients with platinum-refractory mBC derive clinical benefit from participating in early-phase clinical trials and their survival outcomes correlate with the genetic profile of the tumor. link2 VISUAL OVERVIEW http//mcr.aacrjournals.org/content/molcanres/19/3/395/F1.large.jpg.
To provide global, regional, and national estimates of target population sizes for coronavirus disease 2019 (covid-19) vaccination to inform country specific immunisation strategies on a global scale.

Descriptive study.

194 member states of the World Health Organization.

Target populations for covid-19 vaccination based on country specific characteristics and vaccine objectives (maintaining essential core societal services; reducing severe covid-19; reducing symptomatic infections and stopping virus transmission).

Size of target populations for covid-19 vaccination. Estimates use country specific data on population sizes stratified by occupation, age, risk factors for covid-19 severity, vaccine acceptance, and global vaccine production. These data were derived from a multipronged search of official websites, media sources, and academic journal articles.

Target population sizes for covid-19 vaccination vary markedly by vaccination goal and geographical region. Differences in demographic structure, equitable and efficient plan for vaccine prioritisation and allocation. Each country should evaluate different strategies and allocation schemes based on local epidemiology, underlying population health, projections of available vaccine doses, and preference for vaccination strategies that favour direct or indirect benefits.
The distribution of target groups at country and regional levels highlights the importance of designing an equitable and efficient plan for vaccine prioritisation and allocation. Each country should evaluate different strategies and allocation schemes based on local epidemiology, underlying population health, projections of available vaccine doses, and preference for vaccination strategies that favour direct or indirect benefits.CD1d-restricted invariant NKT (iNKT) cells are innate-like T cells that respond to glycolipids, a class of Ags that are invisible to conventional T cells. iNKT cells develop in the thymus where they receive strong "agonist" TCR signals. During their ontogeny, iNKT cells differentiate into discrete iNKT1, iNKT2, and iNKT17 effector subsets akin to helper CD4 T cells. In this study, we found that transgenic (Tg) expression of the canonical Vα14-Jα18 TCRα-chain at the double-positive thymocyte stage led to premature iNKT cell development and a cell-intrinsic bias toward iNKT2 cells, due to increased TCR signaling upon selection. Consistent with the strong iNKT2 bias, innate memory CD8+ T cells were found in greater numbers in Vα14 Tg mice, whereas the prevalence of mucosa-associated invariant T cells was reduced. iNKT cells from Vα14 Tg mice were hyporesponsive to stimulation by their cognate Ag α-galactosylceramide. Finally, Vα14 Tg mice displayed increased B16F10 melanoma tumor growth compared with wild-type mice. This study reveals some of the limitations of Vα14 Tg mice and warrants the cautious interpretation of past and future findings using this mouse model.Adverse neurocognitive sequelae following clinical radiation therapy (RT) for CNS malignancies are often long-lasting and lack any clinical recourse. Despite recent progress, the cellular mechanisms mediating RT-induced cognitive deficits (RICD) are poorly understood. The complement system is an immediate sensor of a disturbed inflammatory environment and a potent mediator of gliosis with a range of non-immune functions in the CNS, including synaptic pruning which is detrimental if dysregulated. We hypothesize that complement-mediated changes in glial cell function significantly contribute to RICD. Underlying alterations in CNS complement cascade proteins (C1q, C3), TLR4 and, co-labeling with glia (IBA1, GFAP) were examined using gene expression, immunofluorescence and in silico modeling approaches in the adult mouse brain following 9 Gy cranial RT. 3D volumetric quantification showed elevated molecular signatures of gliosis at short- and long-term post-RT times. Following RT, significant elevations in complement C1q, C3 and TLR4 were accompanied by increased co-labeling of astrocytes and microglia. To address the mechanism of RT-induced complement cascade activation, neuroinflammation, and cognitive dysfunction, conditional, microglia-selective C1q (Flox) knockdown mice were used to determine whether a glia-specific, upstream complement cascade contributed to RICD. link3 C1q-Flox mice exposed to cranial RT showed no cognitive deficits compared to irradiated WT mice. Irradiated C1q-Flox mice were protected from RT-induced microglial activation and synaptic loss and elevation of anaphylatoxin C5a receptor, astrocytic C3, and microglial TLR4 expression in the brain. Our findings demonstrate for the first time a microglia-specific mechanism of RICD involving an upstream complement cascade component, C1q.
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