Tetanus toxin is internalized by a sequential clathrin-dependent mechanism initiated within lipid microdomains and independent of epsin1

Ligand–receptor complexes are internalized by a variety of endocytic mechanisms. Some are initiated within clathrin-coated membranes, whereas others involve lipid microdomains of the plasma membrane. In neurons, where alternative targeting to short- or long-range trafficking routes underpins the differential processing of synaptic vesicle components and neurotrophin receptors, the mechanism giving access to the axonal retrograde pathway remains unknown. To investigate this sorting process, we examined the internalization of a tetanus neurotoxin fragment (TeNT HC), which shares axonal carriers with neurotrophins and their receptors. Previous studies have shown that the TeNT HC receptor, which comprises polysialogangliosides, resides in lipid microdomains. We demonstrate that TeNT HC internalization also relies on a specialized clathrin-mediated pathway, which is independent of synaptic vesicle recycling. Moreover, unlike transferrin uptake, this AP-2–dependent process is independent of epsin1. These findings identify a pathway for TeNT, beginning with the binding to a lipid raft component (GD1b) and followed by dissociation from GD1b as the toxin internalizes via a clathrin-mediated mechanism using a specific subset of adaptor proteins

Rab27a Regulates the Peripheral Distribution of Melanosomes in Melanocytes

Rab GTPases are regulators of intracellular membrane traffic. We report a possible function of Rab27a, a protein implicated in several diseases, including Griscelli syndrome, choroideremia, and the Hermansky-Pudlak syndrome mouse model, gunmetal. We studied endogenous Rab27a and overexpressed enhanced GFP-Rab27a fusion protein in several cultured melanocyte and melanoma-derived cell lines. In pigmented cells, we observed that Rab27a decorates melanosomes, whereas in nonpigmented cells Rab27a colocalizes with melanosome-resident proteins. When dominant interfering Rab27a mutants were expressed in pigmented cells, we observed a redistribution of pigment granules with perinuclear clustering. This phenotype is similar to that observed by others in melanocytes derived from the ashen and dilute mutant mice, which bear mutations in the Rab27a and MyoVa loci, respectively. We also found that myosinVa coimmunoprecipitates with Rab27a in extracts from melanocytes and that both Rab27a and myosinVa colocalize on the cytoplasmic face of peripheral melanosomes in wild-type melanocytes. However, the amount of myosinVa in melanosomes from Rab27a-deficient ashen melanocytes is greatly reduced. These results, together with recent data implicating myosinVa in the peripheral capture of melanosomes, suggest that Rab27a is necessary for the recruitment of myosinVa, so allowing the peripheral retention of melanosomes in melanocytes

COVID-19 in Pregnancy in Scotland (COPS):protocol for an observational study using linked Scottish national data

Funding: EAVE II funded by the Medical Research Council (MR/R008345/1) with the support of BREATHE - The Health Data Research Hub for Respiratory Health [MC_PC_19004], which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. Additional support has been provided through the Scottish Government DG Health and Social Care. COPS receive additional funding from Tommy’s charity (1060508; SC039280). SJS is supported by Wellcome Trust (209560/Z/17/Z).Introduction The effects of SARS-CoV-2 in pregnancy are not fully delineated. We will describe the incidence of COVID-19 in pregnancy at population level in Scotland, in a prospective cohort study using linked data. We will determine associations between COVID-19 and adverse pregnancy, neonatal and maternal outcomes and the proportion of confirmed cases of SARS-CoV-2 infection in neonates associated with maternal COVID-19. Methods and analysis Prospective cohort study using national linked data sets. We will include all women in Scotland, UK, who were pregnant on or became pregnant after, 1 March 2020 (the date of the first confirmed case of SARS-CoV-2 infection in Scotland) and all births in Scotland from 1 March 2020 onwards. Individual-level data will be extracted from data sets containing details of all livebirths, stillbirth, terminations of pregnancy and miscarriages and ectopic pregnancies treated in hospital or attending general practice. Records will be linked within the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) platform, which includes primary care records, virology and serology results and details of COVID-19 Community Hubs and Assessment Centre contacts and deaths. We will perform analyses using definitions for confirmed, probable and possible COVID-19 and report serology results (where available). Outcomes will include congenital anomaly, miscarriage, stillbirth, termination of pregnancy, preterm birth, neonatal infection, severe maternal disease and maternal deaths. We will perform descriptive analyses and appropriate modelling, adjusting for demographic and pregnancy characteristics and the presence of comorbidities. The cohort will provide a platform for future studies of the effectiveness and safety of therapeutic interventions and immunisations for COVID-19 and their effects on childhood and developmental outcomes. Ethics and dissemination COVID-19 in Pregnancy in Scotland is a substudy of EAVE II(, which has approval from the National Research Ethics Service Committee. Findings will be reported to Scottish Government, Public Health Scotland and published in peer-reviewed journals.Publisher PDFPeer reviewe

Endophilin drives the fast mode of vesicle retrieval in a ribbon synapse

Compensatory endocytosis of exocytosed membrane and recycling of synaptic vesicle components is essential for sustained synaptic transmission at nerve terminals. At the ribbon-type synapse of retinal bipolar cells, manipulations expected to inhibit the interactions of the clathrin adaptor protein complex (AP2) affect only the slow phase of endocytosis (τ = 10-15 s), leading to the conclusion that fast endocytosis (τ = 1-2 s) occurs by a mechanism that differs from the classical pathway of clathrin-coated vesicle retrieval from the plasma membrane. Here we investigate the role of endophilin in endocytosis at this ribbon synapse. Endophilin A1 is a synaptically enriched N-BAR domain-containing protein, suggested to function in clathrin-mediated endocytosis. Internal dialysis of the synaptic terminal with dominant-negative endophilin A1 lacking its linker and Src homology 3 (SH3) domain inhibited the fast mode of endocytosis, while slow endocytosis continued. Dialysis of a peptide that binds endophilin SH3 domain also decreased fast retrieval. Electron microscopy indicated that fast endocytosis occurred by retrieval of small vesicles in most instances. These results indicate that endophilin is involved in fast retrieval of synaptic vesicles occurring by a mechanism that can be distinguished from the classical pathway involving clathrin-AP2 interactions

Cohort Profile: the COVID-19 in Pregnancy in Scotland (COPS) dynamic cohort of pregnant women to assess effects of viral and vaccine exposures on pregnancy

Funding: EAVE II is funded by the Medical Research Council (MR/R008345/1) with the support of BREATHE—the Health Data Research Hub for Respiratory Health [MC_PC_19004] which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. Additional EAVE II support has been provided through the Scottish Government DG Health and Social Care. COPS receive additional funding from Tommy’s Charity (Charity number 1060508; SC039280) and is supported by Sands (Charity number 299679). S.J.S. is supported by the Wellcome Trust (209560/Z/17/Z). S.V.K. acknowledges funding from an NRS Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_00022/2) and the Scottish Government Chief Scientist Office (SPHSU17). B.A. was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No.813546, the Baily Thomas Charitable Fund, the Data Driven Innovation and the UK Economic and Social Research Council (ES/N018877/1) during the course of this work.Publisher PDFPeer reviewe

Author Correction:SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland

Population-level data on COVID-19 vaccine uptake in pregnancy and SARS-CoV-2 infection outcomes are lacking. We describe COVID-19 vaccine uptake and SARS-CoV-2 infection in pregnant women in Scotland, using whole-population data from a national, prospective cohort. Between the start of a COVID-19 vaccine program in Scotland, on 8 December 2020 and 31 October 2021, 25,917 COVID-19 vaccinations were given to 18,457 pregnant women. Vaccine coverage was substantially lower in pregnant women than in the general female population of 18−44 years; 32.3% of women giving birth in October 2021 had two doses of vaccine compared to 77.4% in all women. The extended perinatal mortality rate for women who gave birth within 28 d of a COVID-19 diagnosis was 22.6 per 1,000 births (95% CI 12.9−38.5; pandemic background rate 5.6 per 1,000 births; 452 out of 80,456; 95% CI 5.1−6.2). Overall, 77.4% (3,833 out of 4,950; 95% CI 76.2−78.6) of SARS-CoV-2 infections, 90.9% (748 out of 823; 95% CI 88.7−92.7) of SARS-CoV-2 associated with hospital admission and 98% (102 out of 104; 95% CI 92.5−99.7) of SARS-CoV-2 associated with critical care admission, as well as all baby deaths, occurred in pregnant women who were unvaccinated at the time of COVID-19 diagnosis. Addressing low vaccine uptake rates in pregnant women is imperative to protect the health of women and babies in the ongoing pandemic

SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland

Population-level data on COVID-19 vaccine uptake in pregnancy and SARS-CoV-2 infection outcomes are lacking. We describe COVID-19 vaccine uptake and SARS-CoV-2 infection in pregnant women in Scotland, using whole-population data from a national, prospective cohort. Between the start of a COVID-19 vaccine program in Scotland, on 8 December 2020 and 31 October 2021, 25,917 COVID-19 vaccinations were given to 18,457 pregnant women. Vaccine coverage was substantially lower in pregnant women than in the general female population of 18-44 years; 32.3% of women giving birth in October 2021 had two doses of vaccine compared to 77.4% in all women. The extended perinatal mortality rate for women who gave birth within 28 d of a COVID-19 diagnosis was 22.6 per 1,000 births (95% CI 12.9-38.5; pandemic background rate 5.6 per 1,000 births; 452 out of 80,456; 95% CI 5.1-6.2). Overall, 77.4% (3,833 out of 4,950; 95% CI 76.2-78.6) of SARS-CoV-2 infections, 90.9% (748 out of 823; 95% CI 88.7-92.7) of SARS-CoV-2 associated with hospital admission and 98% (102 out of 104; 95% CI 92.5-99.7) of SARS-CoV-2 associated with critical care admission, as well as all baby deaths, occurred in pregnant women who were unvaccinated at the time of COVID-19 diagnosis. Addressing low vaccine uptake rates in pregnant women is imperative to protect the health of women and babies in the ongoing pandemic. [Abstract copyright: © 2022. The Author(s).

A New Population of High Redshift, Dusty Lyman-Alpha Emitters and Blobs Discovered by WISE

We report a new technique to select 1.6<z<4.6 dusty Lyman-alpha emitters (LAEs), over a third of which are `blobs' (LABs) with emission extended on scales of 30-100kpc. Combining data from the NASA Wide-field Infrared Survey Explorer (WISE) mission with optical spectroscopy from the W.M. Keck telescope, we present a color criteria that yields a 78% success rate in identifying rare, dusty LAEs of which at least 37% are LABs. The objects have a surface density of only ~0.1 per square degree, making them rare enough that they have been largely missed in narrow surveys. We measured spectroscopic redshifts for 92 of these WISE-selected, typically radio-quiet galaxies and find that the LAEs (LABs) have a median redshift of 2.3 (2.5). The WISE photometry coupled with data from Herschel reveals that these galaxies have extreme far-infrared luminosities (L_IR>10^{13-14}L_sun) and warm colors, typically larger than submillimeter-selected galaxies (SMGs) and dust-obscured galaxies (DOGs). These traits are commonly associated with the dust being energized by intense AGN activity. We hypothesize that the combination of spatially extended Lyman-alpha, large amounts of warm IR-luminous dust, and rarity (implying a short-lived phase) can be explained if the galaxies are undergoing strong `feedback' transforming them from an extreme dusty starburst to a QSO.Comment: Submitted to ApJ Letters, 6 pages, 4 figures. Comments welcom