The rockefeller university

During the last decade, the one drug-one target strategy has resulted to be inefficient in facing diseases with complex ethiology like Alzheimer's disease and many others. In this context, the multitarget paradigm has emerged as a promising strategy. Based on this consideration, we aim to develop novel molecules as promiscuous ligands acting in two or more targets at the same time. For such purpose, a new series of indolylpropyl-piperazinyl oxoethyl-benzamido piperazines were synthesized and evaluated as multitarget-directed drugs for the serotonin transporter (SERT) and acetylcholinesterase (AChE). The ability to decrease beta-amyloid levels as well as cell toxicity of all compounds were also measured. In vitro results showed that at least four compounds displayed promising activity against SERT and AChE. Compounds 18 and 19 (IC50 = 3.4 and 3.6 mu M respectively) exhibited AChE inhibition profile in the same order of magnitude as donepezil (DPZ, IC50 = 2.17 mu M), also displaying nanomolar affinity in SERT. Moreover, compounds 17 and 24 displayed high SERT affinities (IC50 = 9.2 and 1.9 nM respectively) similar to the antidepressant citalopram, and significant micromolar AChE activity at the same time. All the bioactive compounds showed a low toxicity profile in the range of concentrations studied. Molecular docking allowed us to rationalize the binding mode of the synthesized compounds in both targets. In addition, we also show that compounds 11 and 25 exhibit significant beta-amyloid lowering activity in a cell-based assay, 11 (50% inhibition, 10 mu M) and 25 (35% inhibition, 10 mu M). These results suggest that indolylpropyl benzamidopiperazines based compounds constitute promising leads for a multitargeted approach for Alzheimers disease. (C) 2020 Elsevier Masson SAS. All rights reserved.

Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles in 11 genes had previously been confirmed experimentally to be LoF. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes). The 41 dispensable olfactory receptor genes displayed a relaxation of selective constraints similar to that observed for other olfactory receptor genes. The 125 dispensable nonolfactory receptor genes also displayed a relaxation of selective constraints consistent with greater redundancy. Sixty-two of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Of the 179 LoF variants, 68 could be tested for two neutrality statistics, and 8 displayed robust signals of positive selection. These latter variants included a known FUT2 variant that confers resistance to intestinal viruses, and an APOL3 variant involved in resistance to parasitic infections. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival.

Depression is a leading cause of disability. Current pharmacological treatment of depression is insufficient, and development of improved treatments especially for treatment-resistant depression is desired. Understanding the neurobiology of antidepressant actions may lead to development of improved therapeutic approaches. Here, we demonstrate that dopamine D1 receptors in the dentate gyrus act as a pivotal mediator of antidepressant actions in mice. Chronic administration of a selective serotonin reuptake inhibitor (SSRI), fluoxetine, increases D1 receptor expression in mature granule cells in the dentate gyrus. The increased D1 receptor signaling, in turn, contributes to the actions of chronic fluoxetine treatment, such as suppression of acute stress-evoked serotonin release, stimulation of adult neurogenesis and behavioral improvement. Importantly, under severely stressed conditions, chronic administration of a D1 receptor agonist in conjunction with fluoxetine restores the efficacy of fluoxetine actions on D1 receptor expression and behavioral responses. Thus, our results suggest that stimulation of D1 receptors in the dentate gyrus is a potential adjunctive approach to improve therapeutic efficacy of SSRI antidepressants.

Therapeutic interventions in colorectal cancer are dependent on immune responses to dying epithelial cells that are modulated by specific members of the gut microbiota.

Dynamic trafficking of G protein-coupled receptors (GPCRs) out of cilia is mediated by the BBSome. In concert with its membrane recruitment factor, the small GTPase ARL6/BBS3, the BBSome ferries GPCRs across the transition zone, a diffusion barrier at the base of cilia. Here, we present the near-atomic structures of the BBSome by itself and in complex with ARL6(GTP), and we describe the changes in BBSome conformation induced by ARL6(GTP) binding. Modeling the interactions of the BBSome with membranes and the GPCR Smoothened (SMO) reveals that SMO, and likely also other GPCR cargoes, must release their amphipathic helix 8 from the membrane to be recognized by the BBSome.

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by the Bacille Calmette-Guerin (BCG) vaccine and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN-gamma immunity due to mutations of 15 genes controlling the production of or response to IFN-gamma. Since the first MSMD-causing mutations were reported in 1996, biallelic mutations in the genes encoding IFN-gamma receptor 1 (IFN-gamma R1) and IFN-gamma R2 have been reported in many patients of diverse ancestries. Surprisingly, mutations of the gene encoding the IFN-gamma cytokine itself have not been reported, raising the remote possibility that there might be other agonists of the IFN-gamma receptor. We describe 2 Lebanese cousins with MSMD, living in Kuwait, who are both homozygous for a small deletion within the IFNG gene (c.354_357del), causing a frameshift that generates a premature stop codon (p.T1191fs4*). The mutant allele is loss of expression and loss of function. We also show that the patients' herpesvirus Saimiri-immortalized T lymphocytes did not produce IFN-gamma, a phenotype that can be rescued by retrotransduction with WT IFNG cDNA. The blood T and NK lymphocytes from these patients also failed to produce and secrete detectable amounts of IFN-gamma. Finally, we show that human IFNG has evolved under stronger negative selection than IFNGIV or IFNGR2, suggesting that it is less tolerant to heterozygous deleterious mutations than IFNGIV or IFNGR2. This may account for the rarity of patients with autosomal-recessive, complete IFN-gamma deficiency relative to patients with complete IFN-gamma R1 and IFN-gamma R2 deficiencies.

Background There is a need for valid and reliable biomarkers in hidradenitis suppurativa (HS) for diagnosis and disease activity monitoring. Imaging-based biomarkers have the potential to fulfil this unmet need but no evaluation of analytical or clinical validity has yet been undertaken. Objectives To evaluate the analytical and clinical validity of sonographic epidermal thickness, Doppler ultrasound and dermal tunnel diameter in patients with HS. Methods Twenty-two participants with HS were recruited and underwent a total of 65 matched ultrasound and skin biopsies of lesional, perilesional and unaffected tissue. Ultrasound measurements were performed in triplicate with mean values used. Skin biopsies underwent immunohistochemistry as per previously published methods. Analytical validity was assessed in individual ultrasound-biopsy pairs (n= 65) by comparisons of sonographic variables with histological correlates. Clinical validity was assessed in individual patients (n= 22) by comparing measures of overall disease activity with sonographic outcomes. Results Epidermal thickness, dermal tunnel diameter and power Doppler intensity were assessed. Sonographic epidermal thickness and dermal tunnel diameter have high analytical validity with corresponding histological measurements. Power Doppler intensity demonstrated high correlation with dermal CD3(+)and CD11c(+)cell counts but not neutrophil elastase-positive cells. Power Doppler ultrasound has significant correlation with pain scores, abscess and nodule count, International HS Severity Scoring System score and number of draining tunnels. Conclusions Sonographic epidermal thickness and dermal tunnel diameter have acceptable levels of analytical validity in the assessment of HS lesions. Power Doppler intensity demonstrates acceptable clinical and analytical validity, suggesting it is a valid imaging-based biomarker in HS.