The rockefeller university

Coronavirus disease (COVID-19), caused by the virus SARS-CoV-2, is already responsible for more than 4.3 million confirmed cases and 295,000 deaths worldwide as of May 15, 2020. Ongoing efforts to control the pandemic include the development of peptide-based vaccines and diagnostic tests. In these approaches, HLA allelic diversity plays a crucial role. Despite its importance, current knowledge of HLA allele frequencies in South America is very limited. In this study, we have performed a literature review of datasets reporting HLA frequencies of South American populations, available in scientific literature and/or in the Allele Frequency Net Database. This allowed us to enrich the current scenario with more than 12.8 million data points. As a result, we are presenting updated HLA allelic frequencies based on country, including 91 alleles that were previously thought to have frequencies either under 5% or of an unknown value. Using alleles with an updated frequency of at least >= 5% in any South American country, we predicted epitopes in SARS-CoV-2 proteins using NetMHCpan (I and II) and MHC flurry. Then, the best predicted epitopes (class-I and -II) were selected based on their binding to South American alleles (Coverage Score). Class II predicted epitopes were also filtered based on their three-dimensional exposure. We obtained 14 class-I and four class-II candidate epitopes with experimental evidence (reported in the Immune Epitope Database and Analysis Resource), having good coverage scores for South America. Additionally, we are presenting 13 HLA-I and 30 HLA-II novel candidate epitopes without experimental evidence, including 16 class-II candidates in highly exposed conserved areas of the NTD and RBD regions of the Spike protein. These novel candidates have even better coverage scores for South America than those with experimental evidence. Finally, we show that recent similar studies presenting candidate epitopes also predicted some of our candidates but discarded them in the selection process, resulting in candidates with suboptimal coverage for South America. In conclusion, the candidate epitopes presented provide valuable information for the development of epitope-based strategies against SARS-CoV-2, such as peptide vaccines and diagnostic tests. Additionally, the updated HLA allelic frequencies provide a better representation of South America and may impact different immunogenetic studies.

Mendelian susceptibility to mycobacterial diseases (MSMD; Online Mendelian Inheritance in Man, OMIM #209950) is an inborn error of immunity (IEI) characterized by extreme susceptibility to invasive infections sustained by poorly virulent mycobacteria, including Mycobacterium bovis, bacillus Calmette-Guérin (BCG) vaccines, and environmental mycobacteria [1,2,3,4]. M. tuberculosis may also be involved in rare cases [5]. Many genes involved in interferon (IFN)-γ production (IL12B, IL12RB1, IL12RB2, IL23R, TYK2, ISG15, RORC), in response to IFN-γ (IFN-γR1, IFN-γR2, STAT1, JAK1, CYBB), both (IRF8, SPPL2A, NEMO) or IFN-γ itself are responsible for MSDM [4,5,6,7,8]. The clinical features depend on the genotype and the residual activity of IFN-γ.

Fanconi anaemia (FA) is a genetic disorder due to mutations in any of the 22FANCgenes (FANCA-FANCW) and has high phenotypic variation. Siblings may have similar clinical outcome because they share the same variants; however, such association has not been reported. We present the detailed phenotype and clinical course of 25 sibling sets with FA from two institutions. Haematological progression significantly correlated between siblings, which was confirmed in an additional 55 sibling pairs from the International Fanconi Anemia Registry. Constitutional abnormalities were not concordant, except for a moderate degree of concordance in kidney abnormalities and microcephaly.

Infection by malaria parasites triggers dynamic immune responses leading to diverse symptoms and pathologies; however, the molecular mechanisms responsible for these reactions are largely unknown. We performed Trans-species Expression Quantitative Trait Locus analysis to identify a large number of host genes that respond to malaria parasite infections. Here we functionally characterize one of the host genes called receptor transporter protein 4 (RTP4) in responses to malaria parasite and virus infections. RTP4 is induced by type I IFN (IFN-I) and binds to the TANK-binding kinase (TBK1) complex where it negatively regulates TBK1 signaling by interfering with expression and phosphorylation of both TBK1 and IFN regulatory factor 3. Rtp4(-/-) mice were generated and infected with malaria parasite Plasmodiun berghei ANKA. Significantly higher levels of IFN-I response in microglia, lower parasitemia, fewer neurologic symptoms, and better survival rateswere observed in Rtp4(-/-) than in wild-type mice. Similarly, RTP4 deficiency significantly reduced West Nile virus titers in the brain, but not in the heart and the spleen, of infected mice, suggesting a specific role for RTP4 in brain infection and pathology. This study reveals functions of RTP4 in IFN-I response and a potential target for therapy in diseases with neuropathology.

Melanin-concentrating hormone (MCH) is a neuropeptide primarily transcribed in the lateral hypothalamus (LH), with vast projections to many areas throughout the central nervous system that play an important role in motivated behaviors and drug use. Anatomical, pharmacological and genetic studies implicate MCH in mediating the intake and reinforcement of commonly abused substances, acting by influencing several systems including the mesolimbic dopaminergic system, glutamatergic as well as GABAergic signaling and being modulated by inflammatory neuroimmune pathways. Further support for the role of MCH in controlling behavior related to drug use will be discussed as it relates to cerebral ventricular volume transmission and intracellular molecules including cocaine- and amphetamine-regulated transcript peptide, dopamine- and cAMP-regulated phosphoprotein 32 kDa. The primary goal of this review is to introduce and summarize current literature surrounding the role of MCH in mediating the intake and reinforcement of commonly abused drugs, such as alcohol, cocaine, amphetamine, nicotine and opiates.

Autologous stem cell transplantation (ASCT) remains the standard of care for transplantation-eligible patients with multiple myeloma (MM). Bortezomib with lenalidomide and dexamethasone (VRD) is the most common triplet regimen for newly diagnosed MM in the United States. Carfilzomib with lenalidomide and dexamethasone (KRD) has shown promising efficacy and may supplant VRD. We compared stem cell yields and autograft minimal residual disease (MRD)-negativity after VRD and KRD induction. Deeper responses (ie, very good partial response or better) were more common with KRD. Precollection bone marrow (BM) cellularity, interval from the end of induction therapy to start of stem cell collection, and method of stem cell mobilization were similar for the 2 cohorts. Days to complete collection was greater with KRD (2.2 days, versus 1.81 days with VRD), which more often required >= 3 days of apheresis. Precollection viable CD34(+) cell content was greater with VRD, as was collection yield (11.11 x 10(6), versus 9.19 x 10(6) with KRD). Collection failure (defined as <2 x 10(6) CD34(+) cells/kg) was more frequent with KRD (5.4% versus .7% with VRD). The difference in stem cell yield between VRD and KRD is associated with the degree of lenalidomide exposure. Age >= 70 years predicted poorer collection for both cohorts. Stem cell autograft purity/MRD-negativity was higher with KRD (81.4%, versus 57.1% with VRD). For both cohorts, MRD-negativity was attained in a larger fraction of autografts than in precollection BM. For patients proceeding to ASCT, the time to neutrophil/platelet engraftment was comparable in the 2 study arms. In summary, our data demonstrate that KRD induces deeper clinical responses and greater autograft purity than VRD without compromising stem cell yield or post-transplantation engraftment kinetics. (C) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Bacterial natural products have inspired the development of numerous antibiotics in use today. As resistance to existing antibiotics has become more prevalent, new antibiotic lead structures and activities are desperately needed. An increasing number of natural product biosynthetic gene clusters, to which no known molecules can be assigned, are found in genome and metagenome sequencing data. Here we access structural information encoded in this underexploited resource using a synthetic-bioinformatic natural product (syn-BNP) approach, which relies on bioinformatic algorithms followed by chemical synthesis to predict and then produce small molecules inspired by biosynthetic gene clusters. In total, 157 syn-BNP cyclic peptides inspired by 96 nonribosomal peptide synthetase gene clusters were synthesized and screened for antibacterial activity. This yielded nine antibiotics with activities against ESKAPE pathogens as well as Mycobacterium tuberculosis. Not only are antibiotic-resistant pathogens susceptible to many of these syn-BNP antibiotics, but they were also unable to develop resistance to these antibiotics in laboratory experiments. Characterized modes of action for these antibiotics include cell lysis, membrane depolarization, inhibition of cell wall biosynthesis, and ClpP protease dysregulation. Increasingly refined syn-BNP-based explorations of biosynthetic gene clusters should allow for more rapid identification of evolutionarily inspired bioactive small molecules, in particular antibiotics with diverse mechanism of actions that could help confront the imminent crisis of antimicrobial resistance.

Emergence of resistance is a major factor limiting the efficacy of molecularly targeted anticancer drugs. Understanding the specific mutations, or other genetic or cellular changes, that confer drug resistance can help in the development of therapeutic strategies with improved efficacies. Here, we outline recent progress in understanding chemotype-specific mechanisms of resistance and present chemical strategies, such as designing drugs with distinct binding modes or using proteolysis targeting chimeras, to overcome resistance. We also discuss how targeting multiple binding sites with bifunctional inhibitors or identifying collateral sensitivity profiles can be exploited to limit the emergence of resistance. Finally, we highlight how incorporating analyses of resistance early in drug development can help with the design and evaluation of therapeutics that can have long-term benefits for patients.