LRH-1 mitigates intestinal inflammatory disease by maintaining epithelial homeostasis and cell survival.

Epithelial dysfunction and crypt destruction are defining features of inflammatory bowel disease (IBD). However, current IBD therapies targeting epithelial dysfunction are lacking. The nuclear receptor LRH-1 (NR5A2) is expressed in intestinal epithelium and thought to contribute to epithelial renewal. Here we show that LRH-1 maintains intestinal epithelial health and protects against inflammatory damage. Knocking out LRH-1 in murine intestinal organoids reduces Notch signaling, increases crypt cell death, distorts the cellular composition of the epithelium, and weakens the epithelial barrier. Human LRH-1 (hLRH-1) rescues epithelial integrity and when overexpressed, mitigates inflammatory damage in murine and human intestinal organoids, including those derived from IBD patients. Finally, hLRH-1 greatly reduces disease severity in T-cell-mediated murine colitis. Together with the failure of a ligand-incompetent hLRH-1 mutant to protect against TNFα-damage, these findings provide compelling evidence that hLRH-1 mediates epithelial homeostasis and is an attractive target for intestinal disease

Identification of an env-defective HIV-1 mutant capable of spontaneous reversion to a wild-type phenotype in certain T-cell lines

BACKGROUND: Attempts to eradicate HIV from cellular reservoirs are vital but depend on a clear understanding of how viral variants are transmitted and survive in the different cell types that constitute such reservoirs. Mutations in the env gene of HIV may be able to exert a differential influence on viral transmission ability in regard to cell-free and cell-associated viral forms. METHODS: The ability of HIV containing an env G367R mutation in cell-free and cell-associated viruses to cause infection and to revert to wild-type was measured using several T cell lines. To determine factors that might potentially influence the reversion of G367R, we studied each of entry inhibitors, inhibitors of cellular endocytosis, and modulators of cell growth and activation. RESULTS: We demonstrate that an HIV-1 variant containing a G367R substitution within the CD4 binding site of gp120 was non-infectious as free virus in culture but was infectious when infected cells were co-cultured with certain T cell lines or when cells were transfected by a relevant proviral plasmid. Differences in viral infectivity by cell-associated G367R viruses were determined by the type of target cell employed, regardless which type of donor cell was used. Reversion was slowed or inhibited by entry inhibitors and by inhibitors of cellular endocytosis. Interleukin 2 was able to block G367R reversion in only one of the T cell lines studied but not in the other, while phorbol 12-myristate 13-acetate (PMA) inhibited G367R reversion in all the T cell lines. CONCLUSIONS: Env-defective HIV may have a different phenotype as cell-free versus cell-associated virus. The persistence of defective forms can potentially lead to the emergence of virulent forms. The heterogeneity of cell types that constitute the HIV reservoir can contribute to viral variability, even among similar types of cells. This is the first demonstration of a mutation in the HIV envelope, i.e. G367R, that can compromise infection by cell-free virus but less severely by cell-associated virus and that does so in a cell type-dependent manner

Comparative biochemical analysis of HIV-1 subtype B and C integrase enzymes

<p>Abstract</p> <p>Background</p> <p>Integrase inhibitors are currently being incorporated into highly active antiretroviral therapy (HAART). Due to high HIV variability, integrase inhibitor efficacy must be evaluated against a range of integrase enzymes from different subtypes.</p> <p>Methods</p> <p>This study compares the enzymatic activities of HIV-1 integrase from subtypes B and C as well as susceptibility to various integrase inhibitors <it>in vitro</it>. The catalytic activities of both enzymes were analyzed in regard to each of 3' processing and strand transfer activities both in the presence and absence of the integrase inhibitors raltegravir (RAL), elvitegravir (EVG), and MK-2048.</p> <p>Results</p> <p>Our results show that integrase function is similar with enzymes of either subtype and that the various integrase strand transfer inhibitors (INSTIs) that were employed possessed similar inhibitory activity against both enzymes.</p> <p>Conclusion</p> <p>This suggests that the use of integrase inhibitors against HIV-1 subtype C will result in comparable outcomes to those obtained against subtype B infections.</p

A practical graphitic carbon nitride (g-C₃N₄)based fluorescence sensor for the competitive detection of trithiocyanuric acid and mercury ions

[EN] A fluorescent sensor for the detection of trithiocyanuric acid (TCA) and Hg was developed based on competitive interactions: non-covalent stacking between g-CN and TCA vs coordinative interaction between TCA and Hg. Electrostatic simulations were used to evaluate the interactions and help describe the detection mechanism. Moreover, normalized 2D fluorescence contour plots have been used to understand the fluorescence phenomenon. When TCA was added into a g-CN nanosheet solution free of Hg, TCA interacted with g-CN nanosheets via hydrogen bonding and π-π interactions, resulting in fluorescence quenching of the g-CN nanosheets. However, upon the addition of Hg, the fluorescence of the TCA-g-CN nanosheet hybrid system was restored, due to coordination of Hg with TCA through the S atoms, breaking the TCA-g-CN stacking interaction. Our results provide a new approach for the design of multifunctional nanosensors suitable for the detection of environmental pollutants.The present work is supported by the National Natural Science Foundation of China (No. 21607044), the Natural Science Foundation of Hebei Province (No. B2017502069) and the Fundamental Research Funds for the Central Universities (No. 2018MS113). All data sup-porting this study are provided as supplementary information accom-panying this paper. T.D.J. wishes to thank the Royal Society for a Wolfson Research Merit Award

Hereditary Sensory and Autonomic Neuropathy: Case Report and Discussion

Abstract Hereditary sensory and autonomic neuropathies (HSAN) are a diverse group of diseases involving the peripheral nervous system. Patients present with profound distal sensory loss and variable degrees of autonomic disturbances. Multiple subtypes have been defined based on clinical symptoms and genetic testing. We present a case report of a nine month-old female with recurrent hand lesions and an absent response to noxious stimuli who was ultimately diagnosed with HSAN. A review of the literature and discussion of the pathogenetic mechanisms, current treatment, and future therapies for HSAN are also provided. Introduction Hereditary Sensory and Autonomic Neuropathies (HSAN) comprise a heterogeneous group of disorders involving the peripheral nervous system. The first description of these conditions was made in 1852 with a report of three brothers with neurotrophic plantar ulcers HSANs can be broadly subdivided based on mode of inheritance into autosomal dominant forms, with either juvenile or adultonset, and autosomal recessive forms with congenital or early childhood onset Case Report A nine month-old female was brought in to the Emergency Department for evaluation of rapidly progressive skin lesions on the hands and a small resolving vesicular lesion on the tip of the tongue. The patient&apos;s mother reported first noticing a small, red bump on the left thumb that grew and turned black over the course of one day. Small blisters were also noted on other fingers. Aside from these lesions, the patient&apos;s mother reported no other symptoms. The patient was born full-term and had met gross motor milestones. Physical examination revealed a 2 x 1 cm black, well-demarcated eschar on the volar surface of the left thumb ( Initial differential diagnosis included herpetic whitlow with associated Herpes Simplex Virus (HSV) infection, gingivostomatitis, ecthyma, bullous impetigo, pyoderma gangrenosum, vasculitis, spider bite, or anthrax. The patient was placed in isolation and started on intravenous antibiotics and acyclovir empirically. A HSV/varicella zoster virus direct fluorescent antibody test was performed on the Journal of Clinical &amp; Medical Case Reports Case Report Open Acces

Novel TNF Receptor-1 Inhibitors Identified as Potential Therapeutic Candidates for Traumatic Brain Injury

Background: Traumatic brain injury (TBI) begins with the application of mechanical force to the head or brain, which initiates systemic and cellular processes that are hallmarks of the disease. The pathological cascade of secondary injury processes, including inflammation, can exacerbate brain injury-induced morbidities and thus represents a plausible target for pharmaceutical therapies. We have pioneered research on post-traumatic sleep, identifying that injury-induced sleep lasting for 6 h in brain-injured mice coincides with increased cortical levels of inflammatory cytokines, including tumor necrosis factor (TNF). Here, we apply post-traumatic sleep as a physiological bio-indicator of inflammation. We hypothesized the efficacy of novel TNF receptor (TNF-R) inhibitors could be screened using post-traumatic sleep and that these novel compounds would improve functional recovery following diffuse TBI in the mouse. Methods: Three inhibitors of TNF-R activation were synthesized based on the structure of previously reported TNF CIAM inhibitor F002, which lodges into a defined TNFR1 cavity at the TNF-binding interface, and screened for in vitro efficacy of TNF pathway inhibition (IκB phosphorylation). Compounds were screened for in vivo efficacy in modulating post-traumatic sleep. Compounds were then tested for efficacy in improving functional recovery and verification of cellular mechanism. Results: Brain-injured mice treated with Compound 7 (C7) or SGT11 slept significantly less than those treated with vehicle, suggesting a therapeutic potential to target neuroinflammation. SGT11 restored cognitive, sensorimotor, and neurological function. C7 and SGT11 significantly decreased cortical inflammatory cytokines 3 h post-TBI. Conclusions: Using sleep as a bio-indicator of TNF-R-dependent neuroinflammation, we identified C7 and SGT11 as potential therapeutic candidates for TBI

A Study of Joinpoint Models for Longitudinal Data

In many medical studies, data are collected simultaneously on multiple biomarkers from each individual. Levels of these biomarkers are measured periodically over certain time duration, giving rise to longitudinal trajectories. The subjects under study may also be subject to dropout due to several competing causes, the likelihood of which may be affected by the levels of these biomarkers. In this dissertation, we investigate flexible Bayesian modeling of such data, taking into account any available covariate information as well as possible censoring of the drop-out times. We propose joint models for multiple biomarkers with multiple causes of dropout. Our proposed models allow the trajectories to have multiple joinpoints, the locations of which are estimated from the data. We explore two ways of modeling longitudinal data incorporating the dropout information. Dirichlet process priors are used to make the models robust to misspecication. The Dirichlet process also leads to a natural clustering of subjects with similar trajectories, which can be of importance in efficiently estimating the joinpoints. Efficient Markov chain Monte Carlo algorithms are developed for fitting the proposed models. The performance of all the methods is investigated through simulation studies. One of the proposed models is seen to give rise to improved estimates of individual trajectories. Data from ACTG 398 study is used to illustrate the applicability of that model