Local lung hypoxia determines epithelial fate decisions during alveolar regeneration.

After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), drives Notch signalling and Krt5pos basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5pos basal-like state. Activated murine Krt5pos LNEPs and diseased human AEC2s upregulate strikingly similar core pathways underlying migration and squamous metaplasia. While robust, HIF1α-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1α deletion or enhanced Wnt/β-catenin activity in Sox2pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair

Profiling human breast epithelial cells using single cell RNA sequencing identifies cell diversity.

Breast cancer arises from breast epithelial cells that acquire genetic alterations leading to subsequent loss of tissue homeostasis. Several distinct epithelial subpopulations have been proposed, but complete understanding of the spectrum of heterogeneity and differentiation hierarchy in the human breast remains elusive. Here, we use single-cell mRNA sequencing (scRNAseq) to profile the transcriptomes of 25,790 primary human breast epithelial cells isolated from reduction mammoplasties of seven individuals. Unbiased clustering analysis reveals the existence of three distinct epithelial cell populations, one basal and two luminal cell types, which we identify as secretory L1- and hormone-responsive L2-type cells. Pseudotemporal reconstruction of differentiation trajectories produces one continuous lineage hierarchy that closely connects the basal lineage to the two differentiated luminal branches. Our comprehensive cell atlas provides insights into the cellular blueprint of the human breast epithelium and will form the foundation to understand how the system goes awry during breast cancer

Hidden giants in JWST's PEARLS: An ultra-massive z=4.26 sub-millimeter galaxy that is invisible to HST

We present a multi-wavelength analysis using SMA, JCMT, NOEMA, JWST, HST, and SST of two dusty strongly star-forming galaxies, 850.1 and 850.2, seen through the massive cluster lens A1489. These SMA-located sources both lie at z=4.26 and have bright dust continuum emission, but 850.2 is a UV-detected Lyman-break galaxy, while 850.1 is undetected at <2um, even with deep JWST/NIRCam observations. We investigate their stellar, ISM, and dynamical properties, including a pixel-level SED analysis to derive sub-kpc-resolution stellar-mass and Av maps. We find that 850.1 is one of the most massive and highly obscured, Av~5, galaxies known at z>4 with M*~10^11.8 Mo (likely forming at z>6), and 850.2 is one of the least massive and least obscured, Av~1, members of the z>4 dusty star-forming population. The diversity of these two dust-mass-selected galaxies illustrates the incompleteness of galaxy surveys at z>3-4 based on imaging at <2um, the longest wavelengths feasible from HST or the ground. The resolved mass map of 850.1 shows a compact stellar mass distribution, Re(mass)~1kpc, but its expected evolution to z~1.5 and then z~0 matches both the properties of massive, quiescent galaxies at z~1.5 and ultra-massive early-type galaxies at z~0. We suggest that 850.1 is the central galaxy of a group in which 850.2 is a satellite that will likely merge in the near future. The stellar morphology of 850.1 shows arms and a linear bar feature which we link to the active dynamical environment it resides within.Comment: Submitted to ApJ, comments welcome

Hidden Giants in JWST's PEARLS: An Ultramassive z = 4.26 Submillimeter Galaxy that Is Invisible to HST

We present a multiwavelength analysis using the Submillimeter Array (SMA), James Clerk Maxwell Telescope, NOEMA, JWST, the Hubble Space Telescope (HST), and the Spitzer Space Telescope of two dusty strongly star-forming galaxies, 850.1 and 850.2, seen through the massive cluster lens A 1489. These SMA-located sources both lie at z = 4.26 and have bright dust continuum emission, but 850.2 is a UV-detected Lyman-break galaxy, while 850.1 is undetected at ≲ 2 μm, even with deep JWST/NIRCam observations. We investigate their stellar, interstellar medium, and dynamical properties, including a pixel-level spectral energy distribution analysis to derive subkiloparsec-resolution stellar-mass and A V maps. We find that 850.1 is one of the most massive and highly obscured, A V ∼ 5, galaxies known at z > 4 with M * ∼1011.8 M ⊙ (likely forming at z > 6), and 850.2 is one of the least massive and least obscured, A V ∼ 1, members of the z > 4 dusty star-forming population. The diversity of these two dust-mass-selected galaxies illustrates the incompleteness of galaxy surveys at z ≳ 3–4 based on imaging at ≲ 2 μm, the longest wavelengths feasible from HST or the ground. The resolved mass map of 850.1 shows a compact stellar-mass distribution, Remass ∼1 kpc, but its expected evolution means that it matches both the properties of massive, quiescent galaxies at z ∼ 1.5 and ultramassive early-type galaxies at z ∼ 0. We suggest that 850.1 is the central galaxy of a group in which 850.2 is a satellite that will likely merge in the near future. The stellar morphology of 850.1 shows arms and a linear bar feature that we link to the active dynamical environment it resides within

Unintended knowledge learnt in primary science practical lessons

This study explored the different kinds of unintended learning in primary school practical science lessons. In this study, unintended learning has been defined as student learning that was found to occur that was not included in the teachers learning objectives for that specific lesson. A total of 22 lessons, taught by five teachers in Korean primary schools with 10- to 12-year-old students, were audio-and video recorded. Pre-lesson interviews with the teachers were conducted to ascertain their intended learning objectives. Students were asked to write short memos after the lesson about what they learnt. Post-lesson interviews with students and teachers were undertaken. What emerged was that there were three types of knowledge that students learnt unintentionally: factual knowledge gained by phenomenon-based reasoning, conceptual knowledge gained by relation- or model-based reasoning, and procedural knowledge acquired by practice. Most unintended learning found in this study fell into the factual knowledge and only a few cases of conceptual knowledge were found. Cases of both explicit procedural knowledge and implicit procedural knowledge were found. This study is significant in that it suggests how unintended learning in practical work can be facilitated as an educative opportunity for meaningful learning by exploring what and how students learnt

What Electrophysiology Tells Us About Alzheimer’s Disease::A Window into the Synchronization and Connectivity of Brain Neurons

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer’s disease (AD), despite a surge in recent validated evidence. This Position Paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity reflecting thalamocortical and cortico-cortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Recruited Monocytes and Type 2 Immunity Promote Lung Regeneration following Pneumonectomy

To investigate the role of immune cells in lung regeneration, we used a unilateral pneumonectomy model that promotes the formation of new alveoli in the remaining lobes. Immunofluorescence and single-cell RNA sequencing found CD115+ and CCR2+ monocytes and M2-like macrophages accumulating in the lung during the peak of type 2 alveolar epithelial stem cell (AEC2) proliferation. Genetic loss of function in mice and adoptive transfer studies revealed that bone marrow-derived macrophages (BMDMs) traffic to the lung through a CCL2-CCR2 chemokine axis and are required for optimal lung regeneration, along with Il4ra-expressing leukocytes. Our data suggest that these cells modulate AEC2 proliferation and differentiation. Finally, we provide evidence that group 2 innate lymphoid cells are a source of IL-13, which promotes lung regeneration. Together, our data highlight the potential for immunomodulatory therapies to stimulate alveologenesis in adults

Low Serum Bicarbonate and Kidney Function Decline: The Multi-Ethnic Study of Atherosclerosis (MESA)

BackgroundAmong populations with established chronic kidney disease (CKD), metabolic acidosis is associated with more rapid progression of kidney disease. The association of serum bicarbonate concentrations with early declines in kidney function is less clear.Study designRetrospective cohort study.Setting &amp; participants5,810 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with a baseline estimated glomerular filtration rate (eGFR) &gt; 60mL/min/1.73 m(2) using the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation.PredictorsSerum bicarbonate concentrations.OutcomesRapid kidney function decline (eGFR decline &gt; 5% per year) and incident reduced eGFR (eGFR &lt; 60mL/min/1.73 m(2) with minimum rate of eGFR loss of 1 mL/min/1.73 m(2) per year).ResultsAverage bicarbonate concentration was 23.2 ± 1.8mEq/L. 1,730 (33%) participants had rapid kidney function decline, and 487 had incident reduced eGFR during follow-up. Each 1-SD lower baseline bicarbonate concentration was associated with 12% higher adjusted odds of rapid kidney function decline (95% CI, 6%-20%) and higher risk of incident reduced eGFR (adjusted incidence rate ratio, 1.11; 95% CI, 1.03-1.20) in models adjusting for demographics, baseline eGFR, albuminuria, and CKD risk factors. The OR for the associations of bicarbonate level &lt; 21 mEq/L relative to 23-24 mEq/L was 1.35 (95% CI, 1.05-1.73) for rapid kidney function decline, and the incidence rate ratio was 1.16 (95% CI, 0.83-1.62) for incident reduced eGFR.LimitationsCause of metabolic acidosis cannot be determined in this study.ConclusionsLower serum bicarbonate concentrations are associated independently with rapid kidney function decline independent of eGFR or albuminuria in community-living persons with baseline eGFR &gt; 60 mL/min/1.73 m(2). If confirmed, our findings suggest that metabolic acidosis may indicate either early kidney disease that is not captured by eGFR or albuminuria or may have a causal role in the development of eGFR &lt; 60 mL/min/1.73 m(2)