The rockefeller university

Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical for shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibited increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT-vSTR versus PFC-vSTR neuronal activity differentially regulated dendritic spine plasticity and social avoidance.

We have previously found that children heterozygous for IL4 variable-number tandem repeat (VNTR) (rs8179190) or IL4-33 (rs2070874) variants were at risk for severe malaria (SM), whereas homozygous children were protected suggesting a complex genetic control. Hence, to dissect this complex genetic control of IL4 VNTR and IL4-33, we performed further investigation by conditional logistic regression analysis and found a strong interaction between both markers (p<10(-6)). The best-fit model revealed three genotype combinations associated with different levels of SM risk. The highest risk (odds ratio (OR)=4.8, 95 % confidence interval (CI)= 2.0-11.5) was observed for subjects carrying at least one copy of both IL4-33 allele T and IL4 VNTR allele 1, who exhibited higher interleukin (IL)-4 plasma levels (p=0.007). Children homozygous for IL4 VNTR allele 2 had a lower SM risk as well as lower IL-4 plasma levels. Our findings indicate that the genetic interaction between these two IL-4 variants is a key factor of SM susceptibility, probably because of its direct role in IL-4 regulation.

Social insects present highly interesting and experimentally amenable systems for the study of disease transmission because they naturally live in dense groups of frequently interacting individuals. Using experimental inoculations of five trypanosomatid strains into groups of its natural host, the bumblebee Bombus terrestris, we investigate the effects of the initial parasite strain distribution across group members on the establishment and transmission success of the different strains to new hosts. For a given number of parasite strains circulating within a host group, transmission to new hosts was increased when the strains were initially inoculated as mixed infections (as opposed to separate single infections), presumably because mixed infections generally favored fast replicating strains. In contrast, separate single infections reduced transmission at least in part through a precedence effect, whereby weak strains appeared to persist by making their host unavailable to superinfection. These results suggest that host groups could benefit from 'compartmentalizing' infections by different parasite strains across different group members, which might be achieved in social insects, for example, by division of labor. (C) 2015 Elsevier B.V. All rights reserved.

Objectives: Streptococcus pneumoniae is becoming increasingly antibiotic resistant worldwide and new antimicrobials are urgently needed. Our aim was new chimeric phage endolysins, or lysins, with improved bactericidal activity by swapping the structural components of two pneumococcal phage lysozymes: Cpl-1 (the best lysin tested to date) and Cpl-7S. Methods: The bactericidal effects of four new chimeric lysins were checked against several bacteria. The purified enzymes were added at different concentrations to resuspended bacteria and viable cells were measured after 1 h. Killing capacity of the most active lysin, Cpl-711, was tested in a mouse bacteraemia model, following mouse survival after injecting different amounts (25-500 mu g) of enzyme. The capacity of Cpl-711 to reduce pneumococcal biofilm formation was also studied. Results: The chimera Cpl-711 substantially improved the killing activity of the parental phage lysozymes, Cpl-1 and Cpl-7S, against pneumococcal bacteria, including multiresistant strains. Specifically, 5 mu g/mL Cpl-711 killed >= 7.5 log of pneumococcal R6 strain. Cpl-711 also reduced pneumococcal biofilm formation and killed 4 log of the bacterial population at 1 mu g/mL. Mice challenged intraperitoneally with D39_IU pneumococcal strain were protected by treatment with a single intraperitoneal injection of Cpl-711 1 h later, resulting in about 50% greater protection than with Cpl-1. Conclusions: Domain swapping among phage lysins allows the construction of new chimeric enzymes with high bactericidal activity and a different substrate range. Cpl-711, the most powerful endolysin against pneumococci, offers a promising therapeutic perspective for the treatment of multiresistant pneumococcal infections.

During the past decade, advanced techniques in structural biology have provided atomic level information on the platelet integrin IIb3 activation mechanism that results in it adopting a high-affinity ligand-binding conformation(s). This review focuses on advances in imaging intact IIb3 in a lipid bilayer in the absence of detergent and new structural insights into the changes in the ligand-binding pocket with receptor activation and ligand binding. It concludes with descriptions of novel therapeutic IIb3 antagonists being developed based on an advanced knowledge of the receptor's structure.

Recent studies on T follicular helper (Tfh) cells have significantly advanced our understanding of T cell-dependent B cell responses. However, little is known about the early stage of Tfh cell commitment by dendritic cells (DCs), particularly by the conventional CD8 alpha(+) and CD8 alpha(-) DC subsets. We show that CD8 alpha(-) DCs localized at the interfollicular zone play a pivotal role in the induction of antigen-specific Tfh cells by upregulating the expression of Icosl and Ox40l through the non-canonical NF-kappa B signaling pathway. Tfh cells induced by CD8 alpha(-) DCs function as true B cell helpers, resulting in significantly increased humoral immune responses against various human pathogenic antigens, including Yersinia pestis LcrV, HIV Gag, and hepatitis B surface antigen. Our findings uncover a mechanistic role of CD8 alpha(-) DCs in the initiation of Tfh cell differentiation and thereby provide a rationale for investigating CD8 alpha(-) DCs in enhancing antigen-specific humoral immune responses for improving vaccines and therapeutics.

Background. Classic Kaposi sarcoma (cKS) is an inflammatory tumor caused by human herpesvirus 8 (HHV-8) commonly observed in elderly men of Mediterranean origin. We studied a Finnish family of 5 affected individuals in 2 generations. Except for atypical mycobacterial infection of the index case, the affected individuals did not have notable histories of infection. Methods.aEuro integral We performed genome and exome sequencing and mapped shared chromosomal regions to identify genetic predisposition in the family. Results.aEuro integral We identified 12 protein-coding candidate variants that segregated in the 3 affected cousins from whom we had samples. The affected mother of the index case was an obligatory carrier. Among the 12 candidates was a rare heterozygous substitution rs141331848 (c.1337C > T, p.Thr446Ile) in the DNA-binding domain of STAT4. The variant was not present in 242 Finnish control genomes or 180 additional regional controls. Activated T-helper cells from the HHV-8-negative variant carriers showed reduced interferon gamma production, compared with age and sex matched wild-type individuals. We screened STAT4 in additional 18 familial KS cases and the variant site from 56 sporadic KS cases but detected no pathogenic mutations. Conclusions.aEuro integral Our data suggest that STAT4 is a potential cKS-predisposition gene, but further functional and genetic validation is needed.

All life ends in death, but perhaps one of life's grander ironies is that it also depends on death. Cell-intrinsic suicide pathways, termed programmed cell death (PCD), are crucial for animal development, tissue homeostasis and pathogenesis. Originally, PCD was almost synonymous with apoptosis; recently, however, alternative mechanisms of PCD have been reported. Here, we provide an overview of several distinct PCD mechanisms, namely apoptosis, autophagy and necroptosis. In addition, we discuss the complex signals that emanate from dying cells, which can either trigger regeneration or instruct additional killing. Further advances in understanding the physiological roles of the various mechanisms of cell death and their associated signals will be important to selectively manipulate PCD for therapeutic purposes.

Autoimmunity is often familial, suggesting that inborn genetic variations might underlie its development. Curiously, autoimmunity has long been thought to be typically polygenic. Contrary to this prediction and consistent with growing discoveries of monogenic autoimmunity, Oftedal et al. discovered heterozygous dominant-negative AIRE mutations in patients with certain forms of autoimmunity.

Cells constantly adapt to various environmental changes and stresses. The way in which nutrient and stress levels in a cell feed back to control metabolism and growth are, unsurprisingly, extremely complex, as responding with great sensitivity and speed to the 'feast or famine, slack or stress' status of its environment is a central goal for any organism. The highly conserved target of rapamycin complex 1 (TORC1) controls eukaryotic cell growth and response to a variety of signals, including nutrients, hormones and stresses, and plays the key role in the regulation of autophagy. A lot of attention has been paid recently to the factors in this pathway functioning upstream of TORC1. In this Commentary, we focus on a major, newly discovered upstream regulator of TORC1 - the multiprotein SEA complex, also known as GATOR. We describe the structural and functional features of the yeast complex and its mammalian homolog, and their involvement in the regulation of the TORC1 pathway and TORC1-independent processes. We will also provide an overview of the consequences of GATOR deregulation in cancer and other diseases.