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Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure–activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL–carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models. The efficacy of carbapenem antibiotics can be compromised by metallo-β-lactamases, but a high-throughput screen followed by optimization has now enabled the discovery of indole-2-carboxylates (InCs) as potent broad-spectrum metallo-β-lactamase inhibitors. The results highlight the potential of InC–carbapenem combinations for clinical use as well as mechanism-guided approaches to combatting globally disseminated antibiotic resistant mechanisms.

What is the sense in a juror telling a newspaper reporter that she is sure Shannon Murrin is a killer, that she is as upset as Mindy Tran's family and that the people of Newfoundland should be warned -- after she voted to let Mr.

The pool of beta cell-specific CD8 + T cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell ‘multipotency index’ and found that beta cell-specific CD8 + T cells retained a stem-like epigenetic multipotency score. Single-cell assay for transposase-accessible chromatin using sequencing confirmed the coexistence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8 + T cells. Assessment of beta cell-specific CD8 + T cell anatomical distribution and the establishment of stem-associated epigenetic programs revealed that self-reactive CD8 + T cells isolated from murine lymphoid tissue retained developmentally plastic phenotypic and epigenetic profiles relative to the same cells isolated from the pancreas. Collectively, these data provide new insight into the longevity of beta cell-specific CD8 + T cell responses and document the use of this methylation-based multipotency index for investigating human and mouse CD8 + T cell differentiation. Autoreactive T cells are subject to continuous antigenic stimulation yet sustain their autoreactive functionality. Youngblood and colleagues examine type 1 diabetes systems to show that a pool of autoreactive CD8 + T cells exhibits a stem cell–like signature that facilitates their durable activity.

The aim of this review is to collate data relevant to understanding the evolution of viviparity in general, and complex placentae in particular. The wide range of reproductive modes exhibited by lizards provides a solid model system for investigating the evolution of viviparity. Within the lizards are oviparous species, viviparous species that have a very simple placenta and little nutrient uptake from the mother during pregnancy (lecithotrophic viviparity), through a range of species that have intermediate placental complexities and placental nutrient provision, to species that lay microlecithal eggs and most nutrients are provided across the placenta during development (obligate placentotrophy). In its commonest form, lecithotrophic viviparity, some uptake of water, inorganic ions and oxygen occurs from the mother to the embryo during pregnancy. In contrast, the evolution of complex placentae is rare, but has evolved at least five times. Where there is still predominantly a reliance on egg yolk, the omphaloplacenta seems to be paramount in the provision of nutrition to the embryo via histotrophy, whereas the chorioallantoic placenta is more likely involved in gas exchange. Reliance on provision of substantial organic nutrient is correlated with the regional specialisation of the chorioallantoic placenta to form a placentome for nutrient uptake, particularly lipids, and the further development of the gas exchange capabilities of the other parts of the chorioallantois.

A proportion of individuals who have increased genetic risk of T1D progress at variable rates to immune activation and the development of islet autoimmunity. Risk of T1D Individuals with a first degree relative with T1D have an ~15-fold increased relative lifetime risk of T1D compared to the general population and the prevalence of T1D by age 20 years is ~5% compared to ~0.3%, respectively.1–3 However ~85% of individuals with a new diagnosis do not have a family history of T1D.4,5 The various stages inform the risk of progression; children with a single islet autoantibody have a ~ 15% risk of reaching Stage 3 T1D within 10 years.6 In contrast, children at Stage 1 have a 44% 5-year risk and 80≥90% 15-year risk of developing Stage 3 T1D, and children at Stage 2 have a 75% 5-year risk and a 100% lifetime risk of developing Stage 3 T1D.6–9 Genetic risk More than 70 genetic T1D variants have been identified through genome-wide association studies.10 HLA DR and HLA DQ loci confer approximately half of the genetic risk for T1D.11–13 The highest-risk HLA haplotypes are DRB1*03:01-DQA1*05:01-DQB1*02:01 (also expressed as DR3-DQ2) and DRB1*04-DQA1*03:01-DQB1*03:02 (also expressed as DR4-DQ8). In the general population, children with the HLA DR3-DQ2/DR4-DQ8 genotype have ~5% risk for islet autoimmunity and T1D.14–16 First-degree relatives carrying HLA DR3-DQ2/DR4-DQ8 have a further increase in risk that reaches ~20%.15,17 Additional risk provided by non-HLA risk genes is roughly equivalent to that provided by HLA DR-DQ alone.16 The highest non-HLA genetic contribution arises from the INS and PTPN22 genes.18 These, and other risk regions, are included in polygenic risk scores that combine HLA and non-HLA genes to substantially improve risk estimates for islet autoimmunity and T1D, particularly in the general population.16,19,20 Notably, the risk of developing islet autoimmunity declines exponentially with age as does the influence of genetic factors, although there is a paucity of data in adults.21–23 Furthermore, once a child develops multiple islet autoantibodies, HLA and polygenic risk scores have only limited further predictive value for stratifying the rate of progression to diabetes.3,24–26 Environmental exposures The increasing incidence of T1D globally coupled with a reduction in the proportion of individuals with the highest risk HLA haplotypes developing T1D, highlights the significant contribution environmental exposures play in the pathogenesis of T1D.27 Different environmental exposures likely interact with multiple risk genes to drive the development of islet autoimmunity and the progression to Stage 3 T1D. Screening programs significantly reduce DKA rates, usually to less than 5%, and reduce hospitalization when coupled with long-term monitoring.3,30–33 The rates of DKA at diagnosis range from 15% to 70% in Europe and North America and as high as 80% in under-resourced countries.34–39 DKA prevention at diagnosis has potential lifelong benefits, including avoidance of acute morbidity (cerebral oedema, shock), neurocognitive impairment, and mortality.40,41 There are also non-causal associations between DKA at onset and future risk of DKA,38,42 severe hypoglycemia42 and long-term hyperglycemia43–45 which increases the risk of serious future diabetes-related complications.46 Furthermore, parental anxiety at diagnosis is approximately halved for children in screening programs compared to the general community.3 The additional time provided for counseling, preparation for insulin therapy and education, delivered across time in the community or outpatient setting, may help reduce parental anxiety and smooth the transition to symptomatic T1D and insulin requirement.3,47 Screening also identifies children suitable for recruitment into clinical prevention trials, which include screening platforms such as T1D TrialNet, Type1Screen, Autoimmunity Screening for Kids (ASK), INNODIA and GPPAD (Global Platform for the Prevention of Diabetes).

Exhausted CD8 T cells (TEX) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGIT+KLRG1+ TEX with teplizumab therapy in type 1 diabetes (T1D), in the absence of treatment we found that the frequency of TIGIT+KLRG1+ TEX is stable within an individual but differs across individuals in both T1D and healthy control (HC) cohorts. This TIGIT+KLRG1+ CD8 TEX population shares an exhaustion-associated EOMES gene signature in HC, T1D, rheumatoid arthritis (RA), and cancer subjects, expresses multiple inhibitory receptors, and is hyporesponsive in vitro , together suggesting co-expression of TIGIT and KLRG1 may broadly define human peripheral exhausted cells. In HC and RA subjects, lower levels of EOMES transcriptional modules and frequency of TIGIT+KLRG1+ TEX were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and cytomegalovirus (CMV) seropositivity. Moreover, the frequency of TIGIT+KLRG1+ TEX was significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig). The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of TEX may be more effective in DR4 subjects and TEX may be indirectly influenced by cellular interactions that are blocked by abatacept.

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity.

Background Systems immunology approaches have proven invaluable in translational research settings. The current rate at which large-scale datasets are generated presents unique challenges and opportunities. Mining aggregates of these datasets could accelerate the pace of discovery, but new solutions are needed to integrate the heterogeneous data types with the contextual information that is necessary for interpretation. In addition, enabling tools and technologies facilitating investigators’ interaction with large-scale datasets must be developed in order to promote insight and foster knowledge discovery. Methods State of the art application programming was employed to develop an interactive web application for browsing and visualizing large and complex datasets. A collection of human immune transcriptome datasets were loaded alongside contextual information about the samples. Results We provide a resource enabling interactive query and navigation of transcriptome datasets relevant to human immunology research. Detailed information about studies and samples are displayed dynamically; if desired the associated data can be downloaded. Custom interactive visualizations of the data can be shared via email or social media. This application can be used to browse context-rich systems-scale data within and across systems immunology studies. This resource is publicly available online at [Gene Expression Browser Landing Page ( https://gxb.benaroyaresearch.org/dm3/landing.gsp )]. The source code is also available openly [Gene Expression Browser Source Code ( https://github.com/BenaroyaResearch/gxbrowser )]. Conclusions We have developed a data browsing and visualization application capable of navigating increasingly large and complex datasets generated in the context of immunological studies. This intuitive tool ensures that, whether taken individually or as a whole, such datasets generated at great effort and expense remain interpretable and a ready source of insight for years to come.

The yolk fatty-acid profiles of a range of species of insectivorous scincid lizards generally conform to a common pattern, typified by high proportions of linoleic acid (13.5-18.5% of total fatty acids), substantial proportions of alpha-linolenic acid (2.4-8.2%), and significant amounts of the long-chain polyunsaturated fatty acids, arachidonic (1.6-3.3%), eicosapentaenoic (0.7-1.2%) and docosahexaenoic (0.7-1.6%) acids. We characterised the fatty-acid compositions of ten prey taxa that are eaten by female skinks during vitellogenesis. Linoleic acid is the major polyunsaturated fatty acid in all prey, excepting Orthoptera where alpha-linolenic acid predominates. To varying extents, alpha-linolenic acid is present in all the prey items. Arachidonic acid forms over 1% of total fatty acids for six of the prey items. Four of the prey items contain eicosapentaenoic acid at over 1%. Most notably, docosahexaenoic acid is essentially absent from all the prey items. There is a general similarity between the fatty-acid profiles of prey and yolk, suggesting that the linoleic, alpha-linolenic, arachidonic and eicosapentaenoic acids required for egg formation can be supplied directly from the maternal diet. However, the docosahexaenoic acid of the egg lipids cannot derive from the diet and must, therefore, be formed by biosynthesis in the maternal liver, using dietary alpha-linolenic and eicosapentaenoic acids as precursors.

Eulamprus tympanum is a high-altitude viviparous lizard that was probably used to help define a Type I chorioallantoic placenta. In this article, we (1) describe the net transport of nutrients across the placenta of E. tympanum, and (2) compare placental uptake in E. tympanum with a previous study of Eulamprus quoyii, which occurs in warmer environments, to assess the potential importance of thermal regime on placentotrophy. Freshly ovulated eggs are \\documentclass{aastex} \\usepackage{amsbsy} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{bm} \\usepackage{mathrsfs} \\usepackage{pifont} \\usepackage{stmaryrd} \\usepackage{textcomp} \\usepackage{portland,xspace} \\usepackage{amsmath,amsxtra} \\usepackage[OT2,OT1]{fontenc} \\newcommand\\cyr{ \\renewcommand\\rmdefault{wncyr} \\renewcommand\\sfdefault{wncyss} \\renewcommand\\encodingdefault{OT2} \\normalfont \\selectfont} \\DeclareTextFontCommand{\\textcyr}{\\cyr} \\pagestyle{empty} \\DeclareMathSizes{10}{9}{7}{6} \\begin{document} \\landscape $$387.3\\pm 19.7$$ \\end{document} mg. There is a significant net uptake of water and a net loss of dry matter during development, so the dry neonate is only 84% the size of the dry egg. There is no significant change in the total ash or nitrogen in eggs during embryonic development, with the entire loss of dry matter being lipid. Almost the entire loss of lipid occurs in the triacylglycerol fraction, with no net change in phospholipids. A net increase in total cholesterol suggests that cholesterol is synthesised by the developing embryo. The lipid profile of eggs of E. tympanum reflects that of other species with simple placentae in having a relatively high proportion of triacylglycerol and little cholesterol. The fatty acid composition of eggs reflects that expected in the diet of E. tympanum. There is a preservation and some synthesis of arachidonic (20:4n-6) and docosahexaenoic (22:6n-3) acids in the phospholipid fraction during embryonic development. Despite there being no net uptake of ash, there is a net increase in calcium, potassium, sodium, and magnesium in the neonate compared with the egg. We conclude that E. tympanum, like E. quoyii, is predominantly lecithotrophic with little, if any, uptake of organic molecules but with significant uptake of some inorganic ions and water. In addition, there is no difference in placentotrophy correlated with differences in the environments inhabited by each species.