The Hox Gene egl-5 Acts as a Terminal Selector for VD13 Development via Wnt Signaling

This work is licensed under a Creative Commons Attribution 4.0 International License.Nervous systems are comprised of diverse cell types that differ functionally and morphologically. During development, extrinsic signals, e.g., growth factors, can activate intrinsic programs, usually orchestrated by networks of transcription factors. Within that network, transcription factors that drive the specification of features specific to a limited number of cells are often referred to as terminal selectors. While we still have an incomplete view of how individual neurons within organisms become specified, reporters limited to a subset of neurons in a nervous system can facilitate the discovery of cell specification programs. We have identified a fluorescent reporter that labels VD13, the most posterior of the 19 inhibitory GABA (γ-amino butyric acid)-ergic motorneurons, and two additional neurons, LUAL and LUAR. Loss of function in multiple Wnt signaling genes resulted in an incompletely penetrant loss of the marker, selectively in VD13, but not the LUAs, even though other aspects of GABAergic specification in VD13 were normal. The posterior Hox gene, egl-5, was necessary for expression of our marker in VD13, and ectopic expression of egl-5 in more anterior GABAergic neurons induced expression of the marker. These results suggest egl-5 is a terminal selector of VD13, subsequent to GABAergic specification

The Immunoglobulin Superfamily Members syg-2 and syg-1 Regulate Neurite Development in C. elegans

Neurons form elaborate networks by guiding axons and dendrites to appropriate destinations. Neurites require information about the relative body axes during the initial projection from the cell body, and failure to receive or interpret those cues correctly can result in outgrowth errors. We identified a mutation in the Ig superfamily member syg-2 in a screen for animals with anterior/posterior (A/P) axon guidance defects. We found that syg-2 and its cognate Ig family member syg-1 appear to function in a linear genetic pathway to control the outgrowth of GABAergic axons. We determined that this pathway works in parallel to Wnt signaling. Specifically, mutations in syg-2 or syg-1 selectively affected the embryonically derived Dorsal D-type (DD) GABAergic neurons. We found no evidence that these mutations affected the Ventral D-type neurons (VD) that form later, during the first larval stage. In addition, mutations in syg-1 or syg-2 could result in the DD neurons forming multiple processes, becoming bipolar, rather than the expected pseudounipolar morphology. Given SYG-2′s essential function in synaptogenesis of the hermaphrodite-specific neurons (HSNs), we also examined DD neuron synapses in syg-2 mutants. We found syg-2 mutants had a decreased number of synapses formed, but synaptic morphology was largely normal. These results provide further evidence that the GABAergic motorneurons use multiple guidance pathways during development

Diurnal timing of nonmigratory movement by birds: the importance of foraging spatial scales

Timing of activity can reveal an organism's efforts to optimize foraging either by minimizing energy loss through passive movement or by maximizing energetic gain through foraging. Here, we assess whether signals of either of these strategies are detectable in the timing of activity of daily, local movements by birds. We compare the similarities of timing of movement activity among species using six temporal variables: start of activity relative to sunrise, end of activity relative to sunset, relative speed at midday, number of movement bouts, bout duration and proportion of active daytime hours. We test for the influence of flight mode and foraging habitat on the timing of movement activity across avian guilds. We used 64 570 days of GPS movement data collected between 2002 and 2019 for local (non‐migratory) movements of 991 birds from 49 species, representing 14 orders. Dissimilarity among daily activity patterns was best explained by flight mode. Terrestrial soaring birds began activity later and stopped activity earlier than pelagic soaring or flapping birds. Broad‐scale foraging habitat explained less of the clustering patterns because of divergent timing of active periods of pelagic surface and diving foragers. Among pelagic birds, surface foragers were active throughout all 24 hrs of the day while diving foragers matched their active hours more closely to daylight hours. Pelagic surface foragers also had the greatest daily foraging distances, which was consistent with their daytime activity patterns. This study demonstrates that flight mode and foraging habitat influence temporal patterns of daily movement activity of birds.We thank the Nature Conservancy, the Bailey Wildlife Foundation, the Bluestone Foundation, the Ocean View Foundation, Biodiversity Research Institute, the Maine Outdoor Heritage Fund, the Davis Conservation Foundation and The U.S. Department of Energy (DE‐EE0005362), and the Darwin Initiative (19-026), EDP S.A. ‘Fundação para a Biodiversidade’ and the Portuguese Foundation for Science and Technology (FCT) (DL57/2019/CP 1440/CT 0021), Enterprise St Helena (ESH), Friends of National Zoo Conservation Research Grant Program and Conservation Nation, ConocoPhillips Global Signature Program, Maryland Department of Natural Resources, Cellular Tracking Technologies and Hawk Mountain Sanctuary for providing funding and in-kind support for the GPS data used in our analyses

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Plakophilin-1 Protects Keratinocytes from Pemphigus Vulgaris IgG by Forming Calcium-Independent Desmosomes

Plakophilin-1 (PKP-1) is an armadillo family protein critical for desmosomal adhesion and epidermal integrity. In the autoimmune skin-blistering disease pemphigus vulgaris (PV), autoantibodies (IgG) target the desmosomal cadherin desmoglein 3 (Dsg3) and compromise keratinocyte cell–cell adhesion. Here, we report that enhanced expression of PKP-1 protects keratinocytes from PV IgG–induced loss of cell–cell adhesion. PKP-1 prevents loss of Dsg3 and other desmosomal proteins from cell–cell borders and prevents alterations in desmosome ultrastructure in keratinocytes treated with PV IgG. Using a series of Dsg3 chimeras and deletion constructs, we find that PKP-1 clusters Dsg3 with the desmosomal plaque protein desmoplakin in a manner dependent on the plakoglobin-binding domain of the Dsg3 tail. Furthermore, PKP-1 expression transforms desmosome adhesion from a calcium-dependent to a calcium-independent and hyperadhesive state. These results demonstrate that manipulating the expression of a single desmosomal plaque protein can block the pathogenic effects of PV IgG on keratinocyte adhesion

The Desmosome

Desmosomes are intercellular junctions that tether intermediate filaments to the plasma membrane. Desmogleins and desmocollins, members of the cadherin superfamily, mediate adhesion at desmosomes. Cytoplasmic components of the desmosome associate with the desmosomal cadherin tails through a series of protein interactions, which serve to recruit intermediate filaments to sites of desmosome assembly. These desmosomal plaque components include plakoglobin and the plakophilins, members of the armadillo gene family. Linkage to the cytoskeleton is mediated by the intermediate filament binding protein, desmoplakin, which associates with both plakoglobin and plakophilins. Although desmosomes are critical for maintaining stable cell–cell adhesion, emerging evidence indicates that they are also dynamic structures that contribute to cellular processes beyond that of cell adhesion. This article outlines the structure and function of the major desmosomal proteins, and explores the contributions of this protein complex to tissue architecture and morphogenesis

Children’s head motion during fMRI tasks is heritable and stable over time

Head motion during fMRI scans negatively impacts data quality, and as post-acquisition techniques for addressing motion become increasingly stringent, data retention decreases. Studies conducted with adult participants suggest that movement acts as a relatively stable, heritable phenotype that serves as a marker for other genetically influenced phenotypes. Whether these patterns extend downward to childhood has critical implications for the interpretation and generalizability of fMRI data acquired from children. We examined factors affecting scanner motion in two samples: a population-based twin sample of 73 participants (ages 7–12 years) and a case-control sample of 32 non-struggling and 78 struggling readers (ages 8–11 years), 30 of whom were scanned multiple times. Age, but not ADHD symptoms, was significantly related to scanner movement. Movement also varied as a function of task type, run length, and session length. Twin pair concordance for head motion was high for monozygotic twins and moderate for dizygotic twins. Cross-session test-retest reliability was high. Together, these findings suggest that children’s head motion is a genetically influenced trait that has the potential to systematically affect individual differences in BOLD changes within and across groups. We discuss recommendations for future work and best practices for pediatric neuroimaging. Keywords: Head motion, fMRI, Twin study, Repeated measures, Individual difference

Signaling Dependent and Independent Mechanisms in Pemphigus Vulgaris Blister Formation

<div><p>Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). Significant advances in our understanding of pemphigus pathomechanisms have been derived from the generation of pathogenic monoclonal Dsg3 antibodies. However, conflicting models for pemphigus pathogenicity have arisen from studies using either polyclonal PV patient IgG or monoclonal Dsg3 antibodies. In the present study, the pathogenic mechanisms of polyclonal PV IgG and monoclonal Dsg3 antibodies were directly compared. Polyclonal PV IgG cause extensive clustering and endocytosis of keratinocyte cell surface Dsg3, whereas pathogenic mouse monoclonal antibodies compromise cell-cell adhesion strength without causing these alterations in Dsg3 trafficking. Furthermore, tyrosine kinase or p38 MAPK inhibition prevents loss of keratinocyte adhesion in response to polyclonal PV IgG. In contrast, disruption of adhesion by pathogenic monoclonal antibodies is not prevented by these inhibitors either in vitro or in human skin explants. Our results reveal that the pathogenic activity of polyclonal PV IgG can be attributed to p38 MAPK-dependent clustering and endocytosis of Dsg3, whereas pathogenic monoclonal Dsg3 antibodies can function independently of this pathway. These findings have important implications for understanding pemphigus pathophysiology, and for the design of pemphigus model systems and therapeutic interventions.</p> </div

Loss of adhesion does not cause Dsg3 endocytosis.

<p>(<b>A</b>) The Dsg3 cytoplasmic domain was fused to the non-adhesive extracellular domain of the IL-2 receptor (IL2R) alpha chain. Carboxyl terminal deletion mutants were also generated to remove various Dsg3 cytoplasmic domains as illustrated. Immunoprecipitation and western blot analysis verified expression of each construct and demonstrated that deletion of the ICS domain abolished plakoglobin binding. (<b>B–I</b>) Antibody labeling of cells incubated at 4°C demonstrated that each of the chimeric IL2R polypeptides were delivered to the cell surface (B,D,F,H). After 6 h at 37°C, cell surface levels of IL-2R were significantly diminished (C). In contrast, the non-adhesive IL-2R-Dsg3_cyto was stable at the cell surface over the 6 hr time course (E). Deletion of the DTD and RUD domains resulted in more rapid loss of surface pools of the Dsg3 chimera (F–G, J), and further removal of the IPL and ICS domains enhanced this effect (H–I, J). (<b>J</b>) Quantitative analysis of cell surface levels remaining at 6 hr normalized to chimera levels at 0 h. IA, intracellular anchor; ICS, intracellular cadherin-like sequence; IPL, intracellular proline-rich linker; RUD, repeat unit domain; DTD, desmoglein terminal domain.</p