Endothelial HIF2α suppresses retinal angiogenesis in neonatal mice by upregulating NOTCH signaling.

Prolyl hydroxylase domain (PHD) proteins are oxygen sensors that use intracellular oxygen as a substrate to hydroxylate hypoxia-inducible factor (HIF) α proteins, routing them for polyubiquitylation and proteasomal degradation. Typically, HIFα accumulation in hypoxic or PHD-deficient tissues leads to upregulated angiogenesis. Here, we report unexpected retinal phenotypes associated with endothelial cell (EC)-specific gene targeting of Phd2 (Egln1) and Hif2alpha (Epas1). EC-specific Phd2 disruption suppressed retinal angiogenesis, despite HIFα accumulation and VEGFA upregulation. Suppressed retinal angiogenesis was observed both in development and in the oxygen-induced retinopathy (OIR) model. On the other hand, EC-specific deletion of Hif1alpha (Hif1a), Hif2alpha, or both did not affect retinal vascular morphogenesis. Strikingly, retinal angiogenesis appeared normal in mice double-deficient for endothelial PHD2 and HIF2α. In PHD2-deficient retinal vasculature, delta-like 4 (DLL4, a NOTCH ligand) and HEY2 (a NOTCH target) were upregulated by HIF2α-dependent mechanisms. Inhibition of NOTCH signaling by a chemical inhibitor or DLL4 antibody partially rescued retinal angiogenesis. Taken together, our data demonstrate that HIF2α accumulation in retinal ECs inhibits rather than stimulates retinal angiogenesis, in part by upregulating DLL4 expression and NOTCH signaling.

CD147 Sparks Atherosclerosis by Driving M1 Phenotype and Impairing Efferocytosis.

BACKGROUND: Atherosclerosis is a globally prevalent chronic inflammatory disease with high morbidity and mortality. The development of atherosclerotic lesions is determined by macrophages. This study aimed to investigate the specific role of myeloid-derived CD147 (cluster of differentiation 147) in atherosclerosis and its translational significance. METHODS AND RESULTS: We generated mice with a myeloid-specific knockout of CD147 and mice with restricted CD147 overexpression, both in an apoE-deficient (ApoE-/-) background. Here, the myeloid-specific deletion of CD147 ameliorated atherosclerosis and inflammation. Consistent with our in vivo data, macrophages isolated from myeloid-specific CD147 knockout mice exhibited a phenotype shift from proinflammatory to anti-inflammatory macrophage polarization in response to lipopolysaccharide/IFN (interferon)-γ. These macrophages demonstrated a weakened proinflammatory macrophage phenotype, characterized by reduced production of NO and reactive nitrogen species derived from iNOS (inducible NO synthase). Mechanistically, the TRAF6 (tumor necrosis factor receptor-associated factor 6)-IKK (inhibitor of κB kinase)-IRF5 (IFN regulatory factor 5) signaling pathway was essential for the effect of CD147 on proinflammatory responses. Consistent with the reduced size of the necrotic core, myeloid-specific CD147 deficiency diminished the susceptibility of iNOS-mediated late apoptosis, accompanied by enhanced efferocytotic capacity mediated by increased secretion of GAS6 (growth arrest-specific 6) in proinflammatory macrophages. These findings were consistent in a mouse model with myeloid-restricted overexpression of CD147. Furthermore, we developed a new atherosclerosis model in ApoE-/- mice with humanized CD147 transgenic expression and demonstrated that the administration of an anti-human CD147 antibody effectively suppressed atherosclerosis by targeting inflammation and efferocytosis. CONCLUSIONS: Myeloid CD147 plays a crucial role in the growth of plaques by promoting inflammation in a TRAF6-IKK-IRF5-dependent manner and inhibiting efferocytosis by suppressing GAS6 during proinflammatory conditions. Consequently, the use of anti-human CD147 antibodies presents a complementary therapeutic approach to the existing lipid-lowering strategies for treating atherosclerotic diseases.

Oxygen-sensing mechanisms in development and tissue repair.

Under normoxia, hypoxia inducible factor (HIF) α subunits are hydroxylated by PHDs (prolyl hydroxylase domain proteins) and subsequently undergo polyubiquitylation and degradation. Normal embryogenesis occurs under hypoxia, which suppresses PHD activities and allows HIFα to stabilize and regulate development. In this Primer, we explain molecular mechanisms of the oxygen-sensing pathway, summarize HIF-regulated downstream events, discuss loss-of-function phenotypes primarily in mouse development, and highlight clinical relevance to angiogenesis and tissue repair.

Diversity, abundance, and expression of proteorhodopsin genes in the northern South China Sea.

Proteorhodopsins have been suggested as an important strategy among phototrophs to capture solar energy in marine environments. The goals of this study was to investigate the diversity of proteorhodopsin genes and to explore their abundance, distribution, and expression in the coastal surface waters of the northern South China Sea, one of the largest marginal seas of the western North Pacific Ocean. Using 21 metagenomes, we recovered proteorhodopsin genes from a wide range of prokaryotic taxa, and chlorophyll a contributed significantly to the community composition of proteorhodopsin-containing microbes. Most proteorhodopsin sequences were predicted to encode green light-absorbing proton pumps and green light-absorbing proteorhodopsin genes were more abundant than blue-absorbing ones. The variations in the conserved residues involved in ion pumping and several uncharacterized proteorhodopsins were observed. The gene abundance pattern of proteorhodopsin types were significantly influenced by the levels of total organic carbon and soluble reactive phosphorus. Gene expression analysis confirmed the importance of proteorhodopsin-based phototrophy and revealed different expressional patterns among major phyla. In tandem, we screened 2295 metagenome-assembled genomes to describe the taxonomic distribution of proteorhodopsins. Bacteroidota are the key lineages encoding proteorhodopsins, but proteorhodopsins were predicated from members of Proteobacteria, Marinisomatota, Myxococcota, Verrucomicrobiota and Thermoplasmatota. Our study expanded the diversity of proteorhodopsins and improve our understanding on the significance of proteorhodopsin-mediated phototrophy in the marine ecosystem.

Cell-derived nanovesicle-mediated drug delivery to the brain: Principles and strategies for vesicle engineering.

Developing strategies toward safe and effective drug delivery into the central nervous system (CNS) with improved targeting abilities and reduced off-target effects is crucial. CNS-targeted drug carriers made of synthetic molecules raise concerns about their biodegradation, clearance, immune responses, and neurotoxicity. Cell-derived nanovesicles (CDNs) have recently been applied in CNS-targeted drug delivery, because of their intrinsic stability, biocompatibility, inherent homing capability, and the ability to penetrate through biological barriers, including the blood-brain barrier. Among these CDNs, extracellular vesicles and exosomes are the most studied because their surface can be engineered and modified to cater to brain targeting. In this review, we focus on the application of CDNs in brain-targeted drug delivery to treat neurological diseases. We cover recently developed methods of exosome derivation and engineering, including exosome-like particles, hybrid exosomes, exosome-associated adeno-associated viruses, and envelope protein nanocages. Finally, we discuss the limitations and project the future development of the CDN-based brain-targeted delivery systems, and conclude that engineered CDNs hold great potential in the treatment of neurological diseases.

Exosome for mRNA delivery: strategies and therapeutic applications.

Messenger RNA (mRNA) has emerged as a promising therapeutic molecule with numerous clinical applications in treating central nervous system disorders, tumors, COVID-19, and other diseases. mRNA therapies must be encapsulated into safe, stable, and effective delivery vehicles to preserve the cargo from degradation and prevent immunogenicity. Exosomes have gained growing attention in mRNA delivery because of their good biocompatibility, low immunogenicity, small size, unique capacity to traverse physiological barriers, and cell-specific tropism. Moreover, these exosomes can be engineered to utilize the natural carriers to target specific cells or tissues. This targeted approach will enhance the efficacy and reduce the side effects of mRNAs. However, difficulties such as a lack of consistent and reliable methods for exosome purification and the efficient encapsulation of large mRNAs into exosomes must be addressed. This article outlines current breakthroughs in cell-derived vesicle-mediated mRNA delivery and its biomedical applications.

Yin-Yang: two sides of extracellular vesicles in inflammatory diseases.

The concept of Yin-Yang, originating in ancient Chinese philosophy, symbolizes two opposing but complementary forces or principles found in all aspects of life. This concept can be quite fitting in the context of extracellular vehicles (EVs) and inflammatory diseases. Over the past decades, numerous studies have revealed that EVs can exhibit dual sides, acting as both pro- and anti-inflammatory agents, akin to the concept of Yin-Yang theory (i.e., two sides of a coin). This has enabled EVs to serve as potential indicators of pathogenesis or be manipulated for therapeutic purposes by influencing immune and inflammatory pathways. This review delves into the recent advances in understanding the Yin-Yang sides of EVs and their regulation in specific inflammatory diseases. We shed light on the current prospects of engineering EVs for treating inflammatory conditions. The Yin-Yang principle of EVs bestows upon them great potential as, therapeutic, and preventive agents for inflammatory diseases.

Effects of combined microplastic and cadmium pollution on sorghum growth, Cd accumulation, and rhizosphere microbial functions.

The interaction between microplastics (MPs) and cadmium (Cd) poses a threat to agricultural soil environments, and their effects on plant growth and rhizosphere microbial community functions are not yet clear. In this study, energy sorghum was used as a test plant to investigate the effects of two types of MPs, polystyrene (PS) and polyethylene (PE), at different particle sizes (13 µm, 550 µm) and concentrations (0.1%, 1% w/w), and Cd, as well as their interactions, on the growth of sorghum in a soil-cultivation pot experiment. The results showed that the combined effects of MP and Cd pollution on the dry weight and Cd accumulation rate in sorghum varied depending on the type, concentration, and particle size of the MPs, with an overall trend of increasing stress from combined pollution with increasing Cd content and accumulation. High-throughput sequencing analysis revealed that combined MP and Cd pollution increased bacterial diversity, and the most significant increase was observed in the abundance-based coverage estimator (ACE), Shannon, and Sobs indices in the 13 µm 1% PS+Cd treatment group. Metagenomic analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways revealed that 19 groups of metabolic pathways, including microbial metabolism and methane metabolism, differed significantly under combined MP and Cd pollution. Hierarchical clustering results indicated that Cd treatment and combined MP and Cd treatment affected the abundances of sorghum rhizosphere soil nitrogen (N) and phosphorus (P) cycling genes and that the type of MP present was an important factor affecting N and P cycling genes. The results of this study provide a basis for exploring the toxic effects of combined MP and Cd pollution and for conducting soil environmental risk assessments.

Brain-derived extracellular vesicles: Potential diagnostic biomarkers for central nervous system diseases.

Extracellular vesicles (EVs) are membrane-enclosed nanovesicles secreted by cells into the extracellular space and contain functional biomolecules, e.g. signaling receptors, bioactive lipids, nucleic acids, and proteins, which can serve as biomarkers. Neurons and glial cells secrete EVs, contributing to various physiological and pathological aspects of brain diseases. EVs confer their role in the bidirectional crosstalk between the central nervous system (CNS) and the periphery owing to their distinctive ability to cross the unique blood-brain barrier (BBB). Thus, EVs in the blood, cerebrospinal fluid (CSF), and urine can be intriguing biomarkers, enabling the minimally invasive diagnosis of CNS diseases. Although there has been an enormous interest in evaluating EVs as promising biomarkers, the lack of ultra-sensitive approaches for isolating and detecting brain-derived EVs (BDEVs) has hindered the development of efficient biomarkers. This review presents the recent salient findings of exosomal biomarkers, focusing on brain disorders. We summarize highly sensitive sensors for EV detection and state-of-the-art methods for single EV detection. Finally, the prospect of developing advanced EV analysis approaches for the non-invasive diagnosis of brain diseases is presented.

Comparative study of female pelvic floor among undeformed high-resolution thin-sectional anatomical (visible human) images and MRI and ultrasound images.

PURPOSE: Using visible human, MRI and ultrasound images, we aim to provide an anatomical basis for the identification and diagnosis of pelvic floor structure and disease by ultrasound imaging. METHODS: One Chinese visible human (CVH) image, one American visible human image, 9 MRI images of normal volunteers, and 40 ultrasound images of normal volunteers or pelvic organ prolapse patients were used. Pelvic organs, pelvic floor muscles, and the connective tissue in CVH, VHP, MRI, and ultrasound images were selected for comparative study. RESULTS: We successfully identified the boundary of the anal sphincter complex, including the subcutaneous, superficial, and deep parts of the external anal sphincter, conjoined longitudinal muscles and internal anal sphincter; the levator ani muscle (LAM), including the internal and external parts of the pubovisceral muscle and the superficial and deep parts of the puborectal muscle; the urethral sphincter complex, including the urethral sphincter proper and the urethral compressor; and the perineal body, the rectoperineal muscle and superficial transverse perineal muscle. CONCLUSIONS: We successfully recognized and studied the location, subdivisions, 2D morphology and spatial relationships of the LAM, anal sphincter complex, urethral sphincter complex and perineal body in ultrasound images, thereby helping sonologists or clinicians accurately identify pelvic floor muscles and supporting structures in ultrasound images.

Preparation of functional geopolymers from municipal solid waste incineration fly ash: An approach combining experimental and computational simulation studies.

This study aims to evaluate the feasibility and safety of using municipal solid waste incineration fly ash (MSW-IFA) in the development of geopolymer-based solidification/stabilization (S/S) treatments. Geopolymers have garnered attention as a sustainable alternative to traditional cement, owing to their high strength, stability, and minimal CO2 emissions. In this study, a combination of experimental and simulation calculations was used to investigate the setting time, mechanical properties, environmental risks, hydration mechanisms and processes of municipal solid waste incineration fly ash-based polymeric functional cementitious materials (GFCM). The results demonstrate that the mechanical properties of GFCM are related to the changes in the mineral phases and the degree of compactness. Quantum chemical calculations indicate that the hydration products may be [Si(OH)4], [Al(OH)3(OH2)] and [Al(OH)4]-. It is possible that the heavy metals are embedded in the hydrated silica-aluminate by electrostatic interaction or chemisorption. Heavy metals may be embedded in hydrated silica-aluminate by electrostatic action or chemisorption. This study provides a feasible method for resource utilization and heavy metal stabilization mechanism of MSW-IFA.

Development and Experimental Study of Supercritical Flow Payload for Extravehicular Mounting on TZ-6.

This paper provides a detailed description of the development and experimental results of the supercritical flow experiment payload carried on the TZ-6 cargo spacecraft, as well as a systematic verification of the out-of-cabin deployment experiment. The technical and engineering indicators of the payload deployment experiment are analyzed, and the functional modules of the payload are shown. The paper provides a detailed description of the design, installation location, size, weight, temperature, illumination, pressure, radiation, control, command reception, telemetry data, downlink data, and experimental procedures for the out-of-cabin payload in the extreme conditions of space. The paper presents the annular liquid surface state and temperature oscillation signals obtained from the space experiment and conducts ground matching experiments to verify the results, providing scientific references for the design and condition setting of space experiments and comparisons for the experimental results to obtain the flow field structure under supercritical conditions. The paper provides a specific summary and discussion of the space fluid science experiment project, providing useful references for future long-term in-orbit scientific research using cargo spacecraft.

[Xixin Decoction regulates Th17/Treg balance and transcription factor expression in senescence-accelerated mouse-prone].

This study aims to investigate the effect of Xixin Decoction on the T helper 17 cell(Th17)/regulatory T cell(Treg) ba-lance of intestinal mucosa and the expression of related transcription factors in the senescence-accelerated mouse-prone 8(SAMP8) model. Fifty 14-week male mice of SAMP8 were randomized by the random number table method into model group, probiotics group, and high-, medium-, and low-dose Xixin Decoction groups, with 10 mice in each group. Ten 14-week male mice of senescence-acce-lerated mouse-resistant 1(SAMR1) served as control group. After 10 weeks of feeding, the mice were administrated with correspon-ding drugs for 10 weeks. Morris water maze test was carried out to examine the learning and memory abilities of mice. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the content of secretory immunoglobulin A(SIgA) in the intestinal mucosa, and flow cytometry to detect the percentage content of Th17 and Treg in the intestinal mucosa. Western blot was performed to determine the protein levels of retinoid-related orphan receptor gamma t(RORγt) and forkhead box p3(Foxp3) in the mouse colon tissue. Compared with control group, the escape latency of mice in model group was significantly prolonged(P<0.01), and the number of times of crossing the platform and the residence time in the target quadrant were significantly reduced within 60 s(P<0.01), intestinal mucosal SIgA content was significantly decreased(P<0.01), Th17 content was increased(P<0.05), Treg content was decreased(P<0.01), the expression of RORγt protein was increased and Foxp3 protein was decreased in colon(P<0.01). Compared with the model group, high-dose Xixin Decoction group improved the learning and memory ability(P<0.05 or P<0.01). Probiotics group and high-and medium-dose Xixin Decoction group increased the content of SIgA in intestinal mucosa(P<0.05 or P<0.01), decreased percentage content of Th17 and increased the percentage content of Treg in intestinal mucosa(P<0.05 or P<0.01). Furthermore, they down-regulated the protein level of RORγt and up-regulated the protein level of Foxp3 in the intestinal mucosa(P<0.01). In conclusion, Xixin Decoction may act on intestinal mucosal immune barrier, affect gut-brain information exchange, and improve the learning and memory ability of SAMP8 by promoting SIgA secretion and regulating the Th17/Treg balance and the expression of RORγt and Foxp3.

Analysis of genetic biomarkers, polymorphisms in ADME-related genes and their impact on pharmacotherapy for prostate cancer.

Prostate cancer (PCa) is a non-cutaneous malignancy in males with wide variation in incidence rates across the globe. It is the second most reported cause of cancer death. Its etiology may have been linked to genetic polymorphisms, which are not only dominating cause of malignancy casualties but also exerts significant effects on pharmacotherapy outcomes. Although many therapeutic options are available, but suitable candidates identified by useful biomarkers can exhibit maximum therapeutic efficacy. The single-nucleotide polymorphisms (SNPs) reported in androgen receptor signaling genes influence the effectiveness of androgen receptor pathway inhibitors and androgen deprivation therapy. Furthermore, SNPs located in genes involved in transport, drug metabolism, and efflux pumps also influence the efficacy of pharmacotherapy. Hence, SNPs biomarkers provide the basis for individualized pharmacotherapy. The pharmacotherapeutic options for PCa include hormonal therapy, chemotherapy (Docetaxel, Mitoxantrone, Cabazitaxel, and Estramustine, etc.), and radiotherapy. Here, we overview the impact of SNPs reported in various genes on the pharmacotherapy for PCa and evaluate current genetic biomarkers with an emphasis on early diagnosis and individualized treatment strategy in PCa.

Prunolactones A-G, proangiogenic isocoumarin derivatives with an unusual 6/6/6/6/6 spiropentacyclic skeleton from the endophytic fungus Phomopsis prunorum.

Seven novel isocoumarins, prunolactones A-G (1-7), featuring an unusual 6/6/6/6/6 spiropentacyclic skeleton, together with two biosynthetic precursors phomopsilactone (8) and methyl 3-epi-shikimate (9), were isolated from the endophytic fungus Phomopsis prunorum guided by UPLC-QTOF-MS and 1H NMR spectroscopic analytical techniques. Their structures including absolute configurations of 1-7 were elucidated based on extensive spectroscopic data, X-ray diffraction analysis, and ECD calculations. Biogenetically, compounds 1-7 are proposed to be derived from polyketide and shikimate pathways via key intermolecular Diels - Alder reactions. Compounds 2, 3, and 7 showed significant in vivo proangiogenic activity in transgenic zebrafish.

A Hybrid Scheme for Disaster-Monitoring Applications in Wireless Sensor Networks.

Disaster monitoring is a primary task for wireless sensor networks. Systems for the rapid reporting of earthquake information are a crucial aspect of disaster monitoring. Furthermore, during emergency rescue after a large earthquake, wireless sensor networks can provide pictures and sound information to save lives. Therefore, when accompanied by multimedia data flow, the alert and seismic data sent by the seismic monitoring nodes must be sufficiently fast. We present herein the architecture of a collaborative disaster-monitoring system that can obtain seismic data in a highly energy-efficient manner. In this paper, a hybrid superior node token ring MAC scheme is proposed for disaster monitoring in wireless sensor networks. This scheme consists of set-up and steady-state stages. A clustering approach was proposed for heterogeneous networks during the set-up stage. The proposed MAC operates in the duty cycle mode at the steady-state stage and is based on the virtual token ring of ordinary nodes, the polling all the superior nodes in one period, and alert transmissions with a low-power listening and shortened preamble approach during the sleep state. The proposed scheme can simultaneously satisfy the requirements of three types of data in disaster-monitoring applications. Based on embedded Markov chains, a model of the proposed MAC was developed and the mean queue length, mean cycle time, and mean upper bound of the frame delay were obtained. Using simulations under various conditions, the clustering approach performed better than the pLEACH approach, and the theoretical results of the proposed MAC were verified. We found that alerts and superior data have outstanding delay and throughput performances even under heavy traffic intensity, and the proposed MAC can provide a data rate of several hundred kb/s for superior and ordinary data. Considering all three types of data, the frame delay performances of the proposed MAC are better than those of the WirelessHART and DRX schemes, and the alert data of the proposed MAC have a maximum frame delay of 15 ms. These satisfy the application requirements of disaster monitoring.

Delta Infection After Vaccination Elicits Potent Neutralizing Immunity Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant extensively escape neutralizing antibodies by vaccines or infection. We assessed serum neutralizing activity in sera from Delta infection after vaccination and Delta infection only against SARS-CoV-2 Wuhan-Hu-1 (WA1), Beta, Delta, and Omicron. Sera from Delta infection only could neutralize WA1 and Delta but almost completely lost capacity to neutralize Beta and Omicron. However, Delta infection after vaccination resulted in a significant increase of serum neutralizing activity against WA1, Beta, and Omicron. This study demonstrates that breakthrough infection of Delta substantially induced high potency humoral immune response against the Omicron variant and other emerged variants.

[Xixin Decoction improves learning and memory ability of SAMP8 by enhancing neuroprotective effect and inhibiting neuroinflammation].

This study aimed to explore the possible effect of Xixin Decoction(XXD) on the learning and memory ability of Alzheimer's disease(AD) model senescence-accelerated mouse-prone 8(SAMP8) and the related mechanism in enhancing neuroprotective effect and reducing neuroinflammation. Forty SAMP8 were randomly divided into a model group(10 mL·kg~(-1)·d~(-1)), a probiotics group(0.39 g·kg~(-1)·d~(-1)), a high-dose group of XXD granules(H-XXD, 5.07 g·kg~(-1)·d~(-1)), a medium-dose group of XXD granules(M-XXD, 2.535 g·kg~(-1)·d~(-1)), and a low-dose group of XXD granules(L-XXD, 1.267 5 g·kg~(-1)·d~(-1)). Eight senescence-accelerated mouse-resistant 1(SAMR1) of the same age and strain were assigned to the control group(10 mL·kg~(-1)·d~(-1)). After ten weeks of intragastric administration, the Morris water maze was used to test the changes in spatial learning and memory ability of mice after treatment. Meanwhile, immunofluorescence staining was used to detect the positive expression of receptor for advanced glycation end products(AGER), Toll-like receptor 1(TLR1), and Toll-like receptor 2(TLR2) in the hippocampal CA1 region of mice. Western blot was employed to test the protein expression levels of silencing information regulator 2 related enzyme 1(SIRT1), AGER, TLR1, and TLR2 in the hippocampus of mice. Enzyme linked immunosorbent assay(ELISA) was applied to assess the levels of Aß_(1-42) in the hippocampus of mice and the levels of nuclear factor κB p65(NF-κB p65), NOD-like receptor protein 3(NLRP3), tumor necrosis factor-α(TNF-α), and interleukin-1ß(IL-1ß) in the serum and hippocampus of mice. Compared with the model group, XXD significantly improved the spatial learning and memory ability of SAMP8, increased the expression of neuroprotective factors in the hippocampus, decreased the levels of neuroinflammatory factors, and inhibited the expression of Aß_(1-42). In particular, H-XXD significantly increased the expression of SIRT1 in the hippocampus of mice, reduced the expression levels of NF-κB p65, NLRP3, TNF-α, and IL-1ß in the serum and hippocampus of mice, and decreased the expression of AGER, TLR1, and TLR2 in the hippocampus of mice(P<0.05 or P<0.01). XXD may improve the spatial learning and memory ability of AD model SAMP8 by enhancing the neuroprotective effect and inhibiting neuroinflammation.

Antibody and T-cellular response to COVID-19 booster vaccine in SARS-CoV-1 survivors.

The severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) survivors are more likely to produce a potent immune response to SARS-CoV-2 after booster vaccination. We assessed humoral and T cell responses against SARS-CoV-2 in previously vaccinated SARS-CoV-1 survivors and naïve healthy individuals (NHIs) after a booster Ad5-nCoV dose. Boosted SARS-CoV-1 survivors had a high neutralization of SARS-CoV-2 Wuhan-Hu-1 (WA1), Beta, and Delta but is limited to Omicron subvariants (BA.1, BA.2, BA.2.12.1, and BA.4/BA.5). Most boosted SARS-CoV-1 survivors had robust SARS-CoV-2-specific CD4+ and CD8+ T cell responses. While booster vaccination in NHIs elicited less or ineffective neutralization of WA1, Beta, and Delta, and none of them induced neutralizing antibodies against Omicron subvariants. However, they developed comparable SARS-CoV-2-specific T cell responses compared to boosted SARS-CoV-1 survivors. These findings suggest that boosted Ad5-nCoV would not elicit effective neutralizing antibodies against Omicron subvariants in SARS-CoV-1 survivors and NHIs but induced comparable robust T cell responses. Achieving a high antibody titer in SARS-CoV-1 survivors and NHIs is desirable to generate broad neutralization.

Developmental vascular pruning in neonatal mouse retinas is programmed by the astrocytic oxygen-sensing mechanism.

Vascular pruning is crucial for normal development, but its underlying mechanisms are poorly understood. Here, we report that retinal vascular pruning is controlled by the oxygen-sensing mechanism in local astrocytes. Oxygen sensing is mediated by prolyl hydroxylase domain proteins (PHDs), which use O2 as a substrate to hydroxylate specific prolyl residues on hypoxia inducible factor (HIF)-α proteins, labeling them for polyubiquitylation and proteasomal degradation. In neonatal mice, astrocytic PHD2 deficiency led to elevated HIF-2α protein levels, expanded retinal astrocyte population and defective vascular pruning. Although astrocytic VEGF-A was also increased, anti-VEGF failed to rescue vascular pruning. However, stimulation of retinal astrocytic growth by intravitreal delivery of PDGF-A was sufficient to block retinal vascular pruning in wild-type mice. We propose that in normal development, oxygen from nascent retinal vasculature triggers PHD2-dependent HIF-2α degradation in nearby astrocytic precursors, thus limiting their further growth by driving them to differentiate into non-proliferative mature astrocytes. The physiological limit of retinal capillary density may be set by astrocytes available to support their survival, with excess capillaries destined for regression.This article has an associated 'The people behind the papers' interview.