The rockefeller university

The behavioral response to antidepressants is closely associated with physiological changes in the function of neurons in the hippocampal dentate gyrus (DG). Parvalbumin interneurons are a major class of GABAergic neurons, essential for DG function, and are involved in the pathophysiology of several neuropsychiatric disorders. However, little is known about the role(s) of these neurons in major depressive disorder or in mediating the delayed behavioral response to antidepressants. Here we show, in mice, that hippocampal parvalbumin interneurons express functionally silent serotonin 5A receptors, which translocate to the cell membrane and become active upon chronic, but not acute, treatment with a selective serotonin reuptake inhibitor (SSRI). Activation of these serotonergic receptors in these neurons initiates a signaling cascade through which Gi-protein reduces cAMP levels and attenuates protein kinase A and protein phosphatase 2A activities. This results in increased phosphorylation and inhibition of Kv3.1 beta channels, and thereby reduces the firing of the parvalbumin neurons. Through the loss of this signaling pathway in these neurons, conditional deletion of the serotonin 5A receptor leads to the loss of the physiological and behavioral responses to chronic antidepressants.

The IgG Fc domain has the capacity to interact with diverse types of receptors, including the neonatal Fc receptor (FcRn) and Fc gamma receptors (Fc gamma Rs), which confer pleiotropic biological activities. Whereas FcRn regulates IgG epithelial transport and recycling, Fc effector activities, such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis, are mediated by Fc gamma Rs, which upon cross-linking transduce signals that modulate the function of effector leukocytes. Despite the well-defined and nonoverlapping functional properties of FcRn and Fc gamma Rs, recent studies have suggested that Fc ?Rs mediate transplacental IgG transport, as certain Fc glycoforms were reported to be enriched in fetal circulation. To determine the contribution of Fc gamma Rs and FcRn to the maternal-fetal transport of IgG, we characterized the IgG Fc glycosylation in paired maternal-fetal samples from patient cohorts from Uganda and Nicaragua. No differences in IgG1 Fc glycan profiles and minimal differences in IgG2 Fc glycans were noted, whereas the presence or absence of galactose on the Fc glycan of IgG1 did not alter Fc gamma RIIIa or FcRn bind-ing, half-life, or their ability to deplete target cells in Fc gamma R/FcRn humanized mice. Modeling maternal-fetal transport in Fc gamma/FcRn humanized mice confirmed that only FcRn contributed to trans-placental transport of IgG; IgG selectively enhanced for FcRn binding resulted in enhanced accumulation of maternal antibody in the fetus. In contrast, enhancing Fc gamma RIIIa binding did not result in en-hanced maternal-fetal transport. These results argue against a role for Fc gamma Rs in IgG transplacental transport, suggesting Fc engineering of maternally administered antibody to enhance only FcRn binding as a means to improve maternal-fetal transport of IgG.

Elucidating the physiological binding partners of histone post-translational modifications (hPTMs) is key to understanding fundamental epigenetic regulatory pathways. Determining such interactomes will enable the study of how perturbations of these interactions affect disease. Here we use a synthetic biology approach to set a series of hPTM-controlled photo-affinity traps in native chromatin. Using quantitative proteomics, the local interactomes of these chemically customized chromatin landscapes are determined. We show that the approach captures transiently interacting factors such as methyltransferases and demethylases, as well as previously reported and novel hPTM reader proteins. We also apply this in situ proteomics approach to a recently disclosed cancer-associated histone mutation, H3K4M, revealing a number of perturbed interactions with the mutated tail. Collectively our studies demonstrate that modifying and interrogating native chromatin with chemical precision is a powerful tool for exploring epigenetic regulation and dysregulation at the molecular level. Proteins that interact with histone post-translational modifications have now been identified using an approach based on split-intein mediated histone semisynthesis. Histone modifications and disease-relevant mutations were installed into native chromatin with an adjacent photocross-linker to enable in situ cross-linking. This strategy enabled the determination of chromatin-relevant interactomes and represents a powerful tool for exploring epigenetic regulation and dysregulation at the molecular level.

The HIV-1 Vpr accessory protein induces ubiquitin/proteasome-dependent degradation of many cellular proteins by recruiting them to a cullin4A-DDB1-DCAF1 complex. In so doing, Vpr enhances HIV-1 gene expression and induces (G2/M) cell cycle arrest. However, the identities of Vpr target proteins through which these biological effects are exerted are unknown. We show that a chromosome periphery protein, CCDC137/cPERP-B, is targeted for depletion by HIV-1 Vpr, in a cullin4A-DDB1-DCAF1 dependent manner. CCDC137 depletion caused G2/M cellcycle arrest, while Vpr-resistant CCDC137 mutants conferred resistance to Vpr-induced G2/M arrest. CCDC137 depletion also recapitulated the ability of Vpr to enhance HIV-1 gene expression, particularly in macrophages. Our findings indicate that Vpr promotes cell-cycle arrest and HIV-1 gene expression through depletion of CCDC137.

Background Due to the affordability of whole-genome sequencing, the genetic association design can now address rare diseases. However, some common statistical association methods only consider homozygosity mapping and need several criteria, such as sliding windows of a given size and statistical significance threshold setting, such asP-value < 0.05 to achieve good power in rare disease association detection. Methods Our region-specific method, called expanded maximal segmental score (eMSS), convertsp-values into continuous scores based on the maximal segmental score (MSS) (Lin et al., 2014) for detecting disease-associated segments. Our eMSS considers the whole genome sequence data, not only regions of homozygosity in candidate genes. Unlike sliding window methods of a given size, eMSS does not need predetermined parameters, such as window size or minimum or maximum number of SNPs in a segment. The performance of eMSS was evaluated by simulations and real data analysis for autosomal recessive diseases multiple intestinal atresia (MIA) and osteogenesis imperfecta (OI), where the number of cases is extremely small. For the real data, the results by eMSS were compared with a state-of-the-art method, HDR-del (Imai et al., 2016). Results Our simulation results show that eMSS had higher power as the number of non-causal haplotype blocks decreased. The type I error for eMSS under different scenarios was well controlled,p< 0.05. For our observed data, the bone morphogenetic protein 1 (BMP1) gene on chromosome 8, the Violaxanthin de-epoxidase-related chloroplast (VDR) gene on chromosome 12 associated with OI, and the tetratricopeptide repeat domain 7A (TTC7A) gene on chromosome 2 associated with MIA have previously been identified as harboring the relevant pathogenic mutations. Conclusions When compared to HDR-del, our eMSS is powerful in analyzing even small numbers of recessive cases, and the results show that the method can further reduce numbers of candidate variants to a very small set of susceptibility pathogenic variants underlying OI and MIA. When we conduct whole-genome sequence analysis, eMSS used 3/5 the computation time of HDR-del. Without additional parameters needing to be set in the segment detection, the computational burden for eMSS is lower compared with that in other region-specific approaches.

Opioid use disorder (OUD) is a chronic, relapsing disease. Genetic variability, dysregulated stress system response, and history of opioid experimentation or escalating exposure all contribute to the likelihood of developing OUD, which produces complex brain changes that make it difficult to stop opioid use. Understanding the neurobiology of OUD helps nurses anticipate the behaviors of patients with OUD and approach them with empathy. Here, the authors discuss the pathophysiology of OUD, available screening tools, medical treatments, and behavioral interventions that have demonstrated efficacy in reducing substance use.

Background Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder (PID) affecting NADPH oxidase activity. The rarest form of the disease is considered to be caused by NCF2 gene bi-allelic variant. Here, we report the clinical and molecular characterization of a patient presenting with early-onset severe disease due to bi-allelic NCF2 variant. Methods Gene mutational analysis was performed by whole-exome and Sanger sequencing. Results The patient presented with a history of fever and rash since the age of 1 month, followed by destructive osteomyelitis and necrotizing lymphadenopathy. The patient received the Bacillus Calmette-Guerin (BCG) vaccine at birth; she was subsequently diagnosed with disseminated BCG infection. Whole-exome sequencing identified a private (unreported) homozygous variant in NCF2 (c.290C > A) that results in a nonconservative change, p.Ala97Asp, in the p67(phox) protein. The variant is located in the third helix of the TRP domain, which is crucial for the binding of GTPase RAC2 to the NADPH oxidase complex. Conclusion We identified a novel NCF2 variant located in the region interacting with RAC2 that is linked to a severe and early CGD phenotype in the setting of disseminated BCG infection. Our findings support postponing BCG vaccination until 6-12 months of age and after PID assessment.

Here a group of leaders in the field define our current understanding of 'trained immunity', which refers to the memory-type responses that occur in the innate immune system. The authors discuss our current understanding of the key epigenetic and metabolic processes involved in trained immunity and consider its relevance in immune-mediated diseases and cancer. Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.

Host microRNA (miRNA) dependency is a hallmark of the human pathogen hepatitis C virus (HCV) and was also described for the related pestiviruses, which are important livestock pathogens. The liver-specific miR-122 binds within the HCV 5 ' untranslated region (UTR), whereas the broadly expressed let-7 and miR-17 families bind two sites (S1 and S2, respectively) in the pestiviral 3 ' UTR. Here, we dissected the mechanism of miRNA dependency of the pestivirus bovine viral diarrhea virus (BVDV). Argonaute 2 (AGO2) and miR-17 binding were essential for viral replication, whereas let-7 binding was mainly required for full translational efficiency. Furthermore, using seed site randomized genomes and evolutionary selection experiments, we found that tropism could be redirected to different miRNAs. AGO cross-linking and immunoprecipitation (CLIP) experiments and miRNA antagonism demonstrated that these alternative variants bound and depended on the corresponding miRNAs. Interestingly, we also identified miRNA-independent variants that were obtained through acquisition of compensatory mutations near the genomic 3 ' terminus. Rescue experiments demonstrated that miRNA binding and 3 ' mutagenesis contribute to replication through mutually exclusive mechanisms. Altogether, our findings suggest that pestiviruses, although capable of miRNA-independent replication, took advantage of miRNAs as essential host factors, suggesting a favorable path during evolutionary adaptation.