The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria–ER membranes

15 p.-4 fig.The protein alpha-synuclein (αSyn) plays a pivotal role in the pathogenesis of synucleinopathies, including Parkinson’s disease and multiple system atrophy, with growing evidence indicating that lipid dyshomeostasis is a key phenotype in these neurodegenerative disorders. Previously, we identified that αSyn localizes, at least in part, to mitochondria-associated endoplasmic reticulum membranes (MAMs), which are transient functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson’s disease and controls, as well as three less affected brain regions of Parkinson’s donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data reveal region- and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson’s disease. Some of these alterations, albeit to a lesser degree, are also observed in multiple system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn regulates phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. These findings support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications.This research was supported by the William N. and Bernice E. Bumpus Foundation (P.B is a recipient of the Early Career Investigator Innovation Award (WBBF CU22-0241), plus grants from the Fonds National de Recherche within the INTER program (INTER/LEIR/18/12719318) to PB and RK, and PEARL (FNR/P13/6682797) to RK, and the National Center for Excellence in Research on Parkinson’s disease (NCER-PD/11264123) program and by the European Union’s Horizon 2020 research and innovation program under Grant Agreement No 692320 (WIDESPREAD; CENTER-PD) to RK. This work was further supported by the US National Institutes of Health (NS107442, NS117583, NS111176, AG064596) to SP, (NS121826, NS133979) to UD, and (AG056387) to EAG, the DoD (W81XWH-22-1-0127) and the Parkinson Foundation to SP (PF-RCE-1948), the Ludwig Family Foundation (GT006761) to SP and PB, the Michael J Fox Foundation to CG-L (MJFOXFD CU18-0258), the Leir Foundation (GT006967) and Art2Cure to PB, CG-L, RK and SP.Peer reviewe

Empowering women in human immunodeficiency virus prevention.

Women comprise one-half of people infected with the human immunodeficiency virus in the world, and about 70% of them live in sub-Saharan Africa. Advancing, untreated HIV disease in women has resulted in substantial declines in fertility rates, life expectancy and infant mortality rates, and an increased burden of tuberculosis. Three decades into the pandemic, our knowledge of HIV acquisition in women remains sparse, as are options of what women can use to reduce their risk of acquiring HIV. Here, we describe the role of pre-HIV responses to venereal diseases and then discuss unwanted pregnancies, early perceptions of the HIV epidemic in setting prevention priorities, and the history of microbicide development. Opportunities to reduce HIV risk in women through sexual reproductive health services are highlighted. Women are key to turning the tide of the HIV pandemic. Microbicides provide an opportunity to ensure survival of women while addressing the power disparities that underpin women’s vulnerability to HIV.This article belongs to a special issue: Microbicides in Obstetrics and Gynaecology. Edited By Jagidesa Moodley

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Alzheimer’s Disease Genetics: A Dampened Microglial Response?

Alzheimer’s disease (AD) is a debilitating age-related neurodegenerative condition. Unbiased genetic studies have implicated a central role for microglia, the resident innate immune cells of the central nervous system, in AD pathogenesis. On-going efforts are clarifying the biology underlying these associations and the microglial pathways that are dysfunctional in AD. Several genetic risk factors converge to decrease the function of activating microglial receptors and increase the function of inhibitory receptors, resulting in a seemingly dampened microglial phenotype in AD. Moreover, many of these microglial proteins that are genetically associated with AD appear to interact and share pathways or regulatory mechanisms, presenting several points of convergence that may be strategic targets for therapeutic intervention. Here, we review some of these studies and their implications for microglial participation in AD pathogenesis. </jats:p

Abstract 1142: Activity and tolerability of combination of trastuzumab deruxtecan with the next generation PARP1-selective inhibitor AZD5305 in preclinical models

Abstract Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor, approved for HER2+ metastatic breast cancer. Clinically, T-DXd has demonstrated antitumor activity in both HER2+ and HER2-low cancers. Due to the role of PARP1 in resolution of DNA damage induced by topoisomerase I trapping, we tested the combination of the next generation PARP1-selective inhibitor AZD5305 with T-DXd. Methods: We evaluated the antiproliferative ability of the combination of T-DXd with AZD5305 in a panel of 27 breast cancer cell lines in an in vitro 7-day viability assay. The combination was also evaluated in vivo in two non-HRD HER2+ models, KPL4 (Breast) and NCI-N87 (Gastric) at doses of 3mg/kg and 10mg/kg Q3W for T-DXd combined with 0.01, 0.1, and 1 mg/kg QD of AZD5305. To evaluate the specificity of the combination activity in tumor cells (vs normal tissue), we further evaluated the combination in a human 2D in vitro bone marrow progenitor assay. Results: We found that the combination had enhanced in vitro cell killing activity over single agents in 8/27 of the models tested. The benefit was present in both Homologous Recombination Deficient (HRD) as well as Homologous Recombination proficient, suggesting it does not depend on HRD (as defined by mutations in DNA damage repair genes). Mechanistically, T-DXd activated PARP and the combination of T-DXd with AZD5305 abrogated PARP1 auto-parylation, leading to enhanced DNA damage (gH2AX, pRPA-S4/8) and cell death (cCasp3). In vivo, the combination was well tolerated and more active than monotherapy of either compound in both KPL4 (at 30 days the growth inhibition was 95% at 10mg/kg T-DXd, 10% at 1mg/kg AZD5305, and 100% TGI with 97% regression with T-DXd + AZD5305) and NCI-N87 (at 41 days TGI of 74% with 10mg/kg T-DXd, 47% with 1mg/kg AZD5305, and 100% TGI with 40% regression for T-DXd + AZD5305; p&amp;lt;0.0001). In an in vitro human bone marrow assay, the combination demonstrated modest enhancement over monotherapy activity (average Loewe Synergy Score of 3.1). We tested alternative doses and schedules of the combination in KPL4 in vivo. We found that reducing the dose of AZD5305 as low as 0.01mg/kg resulted in combination benefit (100% TGI with 78% regression for combination versus 0% TGI for monotherapy on day 30). Further, 7-day delay of 0.01mg/kg AZD5305 in combination with 10mg/kg T-DXd also provided greater activity (&amp;gt;100% TGI with 72% regression on day 30) vs. monotherapy T-DXd alone (95% TGI). Conclusions: These results suggest that T-DXd combined with the next generation PARP1 inhibitor AZD5305 is a potentially active combination, with preclinical activity demonstrated in HRD and HR proficient models. Further, the dose and scheduling may warrant exploration clinically to optimize therapeutic index. Citation Format: Yann Wallez, Theresa Proia, Elisabetta Leo, Laura Bradshaw, Zena Wilson, Joe’l Owusu, Azadeh Cheraghchi-Bashi-Astaneh, Anna Staniszewska, Mark O’Connor, Sabina Cosulich, Jerome Mettetal. Activity and tolerability of combination of trastuzumab deruxtecan with the next generation PARP1-selective inhibitor AZD5305 in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1142.</jats:p

Identification of 2 Novel Subtypes of Hepatitis C Virus Genotype 8 and a Potential New Genotype Successfully Treated With Direct Acting Antivirals.

Background: Hepatitis C virus (HCV) has high genetic diversity and is classified into 8 genotypes and >90 subtypes, with some endemic to specific world regions. This could compromise direct-acting antiviral efficacy and global HCV elimination. Methods: We characterized HCV subtypes "rare" in the United Kingdom (non-1a/1b/2b/3a/4d) by means of whole-genome sequencing via a national surveillance program. Genetic analyses to determine the genotype of samples with unresolved genotypes were undertaken by comparison with International Committee on Taxonomy of Viruses HCV reference sequences. Results: Two HCV variants were characterized as being closely related to the recently identified genotype (GT) 8, with >85% pairwise genetic distance similarity to GT8 sequences and within the typical intersubtype genetic distance range. The individuals infected by the variants were UK residents originally from Pakistan and India. In contrast, a third variant was only confidently identified to be more similar to GT6 compared with other genotypes across 6% of the genome and was isolated from a UK resident originally from Guyana. All 3 were cured with pangenotypic direct-acting antivirals (sofosbuvir-velpatasvir or glecaprevir-pibrentasvir) despite the presence of resistance polymorphisms in NS3 (80K/168E), NS5A (28V/30S/62L/92S/93S) and NS5B (159F). Conclusions: This study expands our knowledge of HCV diversity by identifying 2 new GT8 subtypes and potentially a new genotype

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease