Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3

INTRODUCTION: Involution of the mammary gland is a complex process of controlled apoptosis and tissue remodelling. The aim of the project was to identify genes that are specifically involved in this process. METHODS: We used Affymetrix oligonucleotide microarrays to perform a detailed transcript analysis on the mechanism of controlled involution after withdrawal of the pups at day seven of lactation. Some of the results were confirmed by semi-quantitative reverse transcriptase polymerase chain reaction, Western blotting or immunohistochemistry. RESULTS: We identified 145 genes that were specifically upregulated during the first 4 days of involution; of these, 49 encoded immunoglobulin genes. A further 12 genes, including those encoding the signal transducer and activator of transcription 3 (STAT3), the lipopolysaccharide receptor (CD14) and lipopolysaccharide-binding protein (LBP), were involved in the acute-phase response, demonstrating that the expression of acute-phase response genes can occur in the mammary gland itself and not only in the liver. Expression of LBP and CD14 was upregulated, at both the RNA and protein level, immediately after pup withdrawal; CD14 was strongly expressed in the luminal epithelial cells. Other genes identified suggested neutrophil activation early in involution, followed by macrophage activation late in the process. Immunohistochemistry and histological staining confirmed the infiltration of the involuting mammary tissue with neutrophils, plasma cells, macrophages and eosinophils. CONCLUSION: Oligonucleotide microarrays are a useful tool for identifying genes that are involved in the complex developmental process of mammary gland involution. The genes identified are consistent with an immune cascade, with an early acute-phase response that occurs in the mammary gland itself and resembles a wound healing process

A novel primary cilium‐mediated mechanism through which osteocytes regulate metastatic behavior of both breast and prostate cancer cells

Bone metastases are a common cause of suffering in breast and prostate cancer patients, however, the interaction between bone cells and cancer cells is poorly understood. Using a series of co-culture, conditioned media, human cancer spheroid, and organ-on-a-chip experiments, this study reveals that osteocytes suppress cancer cell proliferation and increase migration via tumor necrosis factor alpha (TNF-α) secretion. This action is regulated by osteocyte primary cilia and associated intraflagellar transport protein 88 (IFT88). Furthermore, it shows that cancer cells block this mechanism by secreting transforming growth factor beta (TGF-β), which disrupts osteocyte cilia and IFT88 gene expression. This bi-directional crosstalk signaling between osteocytes and cancer cells is common to both breast and prostate cancer. This study also proposes that osteocyte inhibition of cancer cell proliferation decreases as cancer cells increase, producing more TGF-β. Hence, a positive feedback loop develops accelerating metastatic tumor growth. These findings demonstrate the importance of cancer cell-osteocyte signaling in regulating breast and prostate bone metastases and support the development of therapies targeting this pathway

A single-center, observational study of 607 children & young people presenting with Differences in Sex Development (DSD)

Context Differences in sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family and developing a management plan are important. Objective We aimed to better understand the presentation and prevalence of pediatric DSD. Design A retrospective, observational cohort study was undertaken of all children and young people (CYP) referred to a DSD multi-disciplinary team over 25 years (1995-2019). Setting A single tertiary paediatric center. Participants In total, 607 CYP (520 regional referrals) were included. Main Outcome Measures Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. Results Amongst the three major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45, X/46, XY mosaicism), 46, XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46, XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or herniae. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46, XY children, usually due to complex associated features (46, XY girls, 8.3%; 46, XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6,347 births, and 1 in 5,101 overall throughout childhood. Conclusions DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care

Special Supplemental Nutrition Program for Women, Infants, and Children Participant Grocery Store Purchases during the COVID-19 Pandemic in North Carolina

Background: Families participating in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) experienced barriers to accessing healthy food during the COVID-19 pandemic, but we do not yet understand how WIC participant food purchases shifted during the pandemic. Objectives: We aimed to describe the association between the initial shock of the pandemic in March 2020 and WIC shoppers’ food purchases and changes in purchases before and during the pandemic at a top grocery chain and examine differences in these relationships by duration of WIC use. Methods: We used longitudinal food transaction data from WIC shoppers (n = 2,989,116 shopper-month observations from 175,081 unique WIC shoppers) from 496 stores in a top grocery store chain in North Carolina between October 2019 and May 2021. We used an interrupted time series design to describe the following: 1) the relationship between the initial shock of the pandemic and WIC shopper food purchases and 2) differences in purchases before and during the pandemic. To assess differences in purchases between shoppers consistently using WIC electronic benefit transfer (EBT) cards and shoppers starting or stopping WIC EBT use during the pandemic, we used models stratified by WIC group. Primary outcomes were share (%) of total calories purchased from fruits, vegetables, nuts, and legumes (FV), processed foods, and sugar-sweetened beverages (SSBs). Results: We observed small decreases in the share of total calories from FV (−0.4%) and small increases in the share of calories from processed food (1.1%) and SSBs (0.5%) purchased at this retailer when comparing the pre and post March 2020 periods. Compared with shoppers that started or stopped using WIC benefits during the pandemic, shoppers that used WIC benefits consistently had slightly higher FV and lower processed food and SSB purchases at this retailer. Conclusions: Future studies should examine whether additional supports for nutrient-dense food choices may be needed for families with low incomes in public health emergencies

Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2–host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype

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

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 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