COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas.

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.

A close-in giant planet escapes engulfment by its star.

When main-sequence stars expand into red giants, they are expected to engulf close-in planets1-5. Until now, the absence of planets with short orbital periods around post-expansion, core-helium-burning red giants6-8 has been interpreted as evidence that short-period planets around Sun-like stars do not survive the giant expansion phase of their host stars9. Here we present the discovery that the giant planet 8 Ursae Minoris b10 orbits a core-helium-burning red giant. At a distance of only 0.5 AU from its host star, the planet would have been engulfed by its host star, which is predicted by standard single-star evolution to have previously expanded to a radius of 0.7 AU. Given the brief lifetime of helium-burning giants, the nearly circular orbit of the planet is challenging to reconcile with scenarios in which the planet survives by having a distant orbit initially. Instead, the planet may have avoided engulfment through a stellar merger that either altered the evolution of the host star or produced 8 Ursae Minoris b as a second-generation planet11. This system shows that core-helium-burning red giants can harbour close planets and provides evidence for the role of non-canonical stellar evolution in the extended survival of late-stage exoplanetary systems.

Benchmarking algorithms for single-cell multi-omics prediction and integration.

The development of single-cell multi-omics technology has greatly enhanced our understanding of biology, and in parallel, numerous algorithms have been proposed to predict the protein abundance and/or chromatin accessibility of cells from single-cell transcriptomic information and to integrate various types of single-cell multi-omics data. However, few studies have systematically compared and evaluated the performance of these algorithms. Here, we present a benchmark study of 14 protein abundance/chromatin accessibility prediction algorithms and 18 single-cell multi-omics integration algorithms using 47 single-cell multi-omics datasets. Our benchmark study showed overall totalVI and scArches outperformed the other algorithms for predicting protein abundance, and LS_Lab was the top-performing algorithm for the prediction of chromatin accessibility in most cases. Seurat, MOJITOO and scAI emerge as leading algorithms for vertical integration, whereas totalVI and UINMF excel beyond their counterparts in both horizontal and mosaic integration scenarios. Additionally, we provide a pipeline to assist researchers in selecting the optimal multi-omics prediction and integration algorithm.

Functional importance and divergence of plant apurinic/apyrimidinic endonucleases in somatic and meiotic DNA repair.

Apurinic/apyrimidinic (AP) sites are one of the most abundant DNA lesions and are mainly repaired by AP endonucleases (APEs). While most eukaryotic genomes encode two APEs, plants usually possess three APEs, namely APE1L, APE2, and ARP. To date, the biological relevance and functional divergence of plant APEs are unclear. Here, we show that the three plant APEs have ancient origins, with the APE1L clade being plant-specific. In Arabidopsis thaliana, simultaneously mutating APE1L and APE2, but not ARP alone or in combination with either APE1L or APE2, results in clear developmental defects linked to genotoxic stress. Genetic analyses indicated that the three plant APEs have different substrate preferences in vivo. ARP is mainly responsible for AP site repair, while APE1L and APE2 prefer to repair 3'-blocked single-stranded DNA breaks. We further determined that APEs play an important role in DNA repair and the maintenance of genomic integrity in meiotic cells. The ape1l ape2 double mutant exhibited a greatly enhanced frequency of sporulation 1 (SPO11-1)-dependent and SPO11-1-independent double-stranded DNA breaks. The DNA damage response (DDR) was activated in ape1l ape2 to trigger pollen abortion. Our findings suggest functional divergence of plant APEs and reveal important roles of plant APEs during vegetative and reproductive development.

ARHGAP15 promotes metastatic colonization in gastric cancer by suppressing RAC1-ROS pathway.

The molecular mechanism of tumor metastasis, especially how metastatic tumor cells colonize in a distant site, remains poorly understood. Here we reported that ARHGAP15, a Rho GTPase activating protein, enhanced gastric cancer (GC) metastatic colonization, which was quite different from its reported role as a tumor suppressor gene in other cancers. It was upregulated in metastatic lymph nodes and significantly associated with a poor prognosis. Ectopic expression of ARHGAP15 promoted metastatic colonization of gastric cancer cells in murine lungs and lymph nodes in vivo or protected cells from oxidative-related death in vitro. However, genetic downregulation of ARHGAP15 had the opposite effect. Mechanistically, ARHGAP15 inactivated RAC1 and then decreased intracellular accumulation of reactive oxygen species (ROS), thus enhancing the antioxidant capacity of colonizing tumor cells under oxidative stress. This phenotype could be phenocopied by inhibition of RAC1 or rescued by the introduction of constitutively active RAC1 into cells. Taken together, these findings suggested a novel role of ARHGAP15 in promoting gastric cancer metastasis by quenching ROS through inhibiting RAC1 and its potential value for prognosis estimation and targeted therapy.

The SHDRA syndrome-associated gene TMEM260 encodes a protein-specific O-mannosyltransferase.

Mutations in the TMEM260 gene cause structural heart defects and renal anomalies syndrome, but the function of the encoded protein remains unknown. We previously reported wide occurrence of O-mannose glycans on extracellular immunoglobulin, plexin, transcription factor (IPT) domains found in the hepatocyte growth factor receptor (cMET), macrophage-stimulating protein receptor (RON), and plexin receptors, and further demonstrated that two known protein O-mannosylation systems orchestrated by the POMT1/2 and transmembrane and tetratricopeptide repeat-containing proteins 1-4 gene families were not required for glycosylation of these IPT domains. Here, we report that the TMEM260 gene encodes an ER-located protein O-mannosyltransferase that selectively glycosylates IPT domains. We demonstrate that disease-causing TMEM260 mutations impair O-mannosylation of IPT domains and that TMEM260 knockout in cells results in receptor maturation defects and abnormal growth of 3D cell models. Thus, our study identifies the third protein-specific O-mannosylation pathway in mammals and demonstrates that O-mannosylation of IPT domains serves critical functions during epithelial morphogenesis. Our findings add a new glycosylation pathway and gene to a growing group of congenital disorders of glycosylation.

Oocytes orchestrate protein prenylation for mitochondrial function through selective inactivation of cholesterol biosynthesis in murine species.

Emerging research and clinical evidence suggest that the metabolic activity of oocytes may play a pivotal role in reproductive anomalies. However, the intrinsic mechanisms governing oocyte development regulated by metabolic enzymes remain largely unknown. Our investigation demonstrates that geranylgeranyl diphosphate synthase1 (Ggps1), the crucial enzyme in the mevalonate pathway responsible for synthesizing isoprenoid metabolite geranylgeranyl pyrophosphate from farnesyl pyrophosphate, is essential for oocyte maturation in mice. Our findings reveal that the deletion of Ggps1 that prevents protein prenylation in fully grown oocytes leads to subfertility and offspring metabolic defects without affecting follicle development. Oocytes that lack Ggps1 exhibit disrupted mitochondrial homeostasis and the mitochondrial defects arising from oocytes are inherited by the fetal offspring. Mechanistically, the excessive farnesylation of mitochondrial ribosome protein, Dap3, and decreased levels of small G proteins mediate the mitochondrial dysfunction induced by Ggps1 deficiency. Additionally, a significant reduction in Ggps1 levels in oocytes is accompanied by offspring defects when females are exposed to a high-cholesterol diet. Collectively, this study establishes that mevalonate pathway-protein prenylation is vital for mitochondrial function in oocyte maturation and provides evidence that the disrupted protein prenylation resulting from an imbalance between farnesyl pyrophosphate and geranylgeranyl pyrophosphate is the major mechanism underlying impairment of oocyte quality induced by high cholesterol.

Progesterone (P4) ameliorates cigarette smoke-induced chronic obstructive pulmonary disease (COPD).

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with high morbidity and mortality worldwide. Oxidative injury and mitochondrial dysfunction in the airway epithelium are major events in COPD progression. METHODS AND RESULTS: The therapeutic effects of Progesterone (P4) were investigated in vivo and in vitro in this study. In vivo, in a cigarette smoke (CS) exposure-induced COPD mouse model, P4 treatment significantly ameliorated CS exposure-induced physiological and pathological characteristics, including inflammatory cell infiltration and oxidative injury, in a dose-dependent manner. The c-MYC/SIRT1/PGC-1α pathway is involved in the protective function of P4 against CS-induced COPD. In vitro, P4 co-treatment significantly ameliorated H2O2-induced oxidative injury and mitochondrial dysfunctions by promoting cell proliferation, increasing mitochondrial membrane potential, decreasing ROS levels and apoptosis, and increasing ATP content. Moreover, P4 co-treatment partially attenuated H2O2-caused inhibition in Nrf1, Tfam, Mfn1, PGR-B, c-MYC, SIRT1, and PGC-1α levels. In BEAS-2B and ASM cells, the c-MYC/SIRT1 axis regulated P4's protective effects against H2O2-induced oxidative injury and mitochondrial dysfunctions. CONCLUSION: P4 activates the c-MYC/SIRT1 axis, ameliorating CS-induced COPD and protecting both airway epithelial cells and smooth muscle cells against H2O2-induced oxidative damage. PGC-1α and downstream mitochondrial signaling pathways might be involved.

Differential performance of RoseTTAFold in antibody modeling.

Antibodies are essential to life, and knowing their structures can facilitate the understanding of antibody-antigen recognition mechanisms. Precise antibody structure prediction has been a core challenge for a prolonged period, especially the accuracy of H3 loop prediction. Despite recent progress, existing methods cannot achieve atomic accuracy, especially when the homologous structures required for these methods are not available. Recently, RoseTTAFold, a deep learning-based algorithm, has shown remarkable breakthroughs in predicting the 3D structures of proteins. To assess the antibody modeling ability of RoseTTAFold, we first retrieved the sequences of 30 antibodies as the test set and used RoseTTAFold to model their 3D structures. We then compared the models constructed by RoseTTAFold with those of SWISS-MODEL in a different way, in which we stratified Global Model Quality Estimate (GMQE) into three different ranges. The results indicated that RoseTTAFold could achieve results similar to SWISS-MODEL in modeling most CDR loops, especially the templates with a GMQE score under 0.8. In addition, we also compared the structures modeled by RoseTTAFold, SWISS-MODEL and ABodyBuilder. In brief, RoseTTAFold could accurately predict 3D structures of antibodies, but its accuracy was not as good as the other two methods. However, RoseTTAFold exhibited better accuracy for modeling H3 loop than ABodyBuilder and was comparable to SWISS-MODEL. Finally, we discussed the limitations and potential improvements of the current RoseTTAFold, which may help to further the accuracy of RoseTTAFold's antibody modeling.

Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.

Transseptal approach versus retrograde aortic approach in mapping and ablation of ventricular arrhythmias from anterolateral papillary muscles.

INTRODUCTION: The anterior and lateral position of the anterolateral papillary muscle (ALPM) has found to be reached with better catheter stability and less mechanical bumping via the transseptal (TS) compared to the retrograde aortic (RA) approach. The aim of this study is to compare the TS and RA approaches on mapping and ablation of ventricular arrhythmias (VAs) arising from ALPMs. METHODS: Thirty-two patients with ALPM-VAs undergoing mapping and ablation via the TS approach were included and compared with 31 patients via the RA approach within the same period. Acute success was compared, as well as other outcomes including misinterpreted mapping results due to bumping, radiofrequency (RF) attempts, procedural time and success rate at 12-month follow-up. RESULTS: Acute success was achieved in more cases in the TS group (96.4% vs. 72.0%, p = .020). During activation mapping, bump-provoked premature ventricular complexes (PVCs) misinterpreted as clinical PVCs were more common in the RA group (30.0% vs. 58.3%, p = .036), leading to more RF attempts (3.5 ± 2.7 vs. 7.2 ± 6.8, p = .006). Suppression of VAs were finally achieved in the unsuccessful cases by changing to the alternative approach, but the procedural time was significantly less in the TS group (90.0 ± 33.0 vs. 113.7 ± 41.1 min, p = .027) with less need to change the approach, although follow-up success rates were similar (75.0% vs. 71.0%, p = .718). CONCLUSION: A TS rather than RA approach as the initial approach appears to facilitate mapping and ablation of ALPM-VAs, specifically by decreasing the possibility of misleading mapping results caused by bump-provoked PVC, and increase the acute success rate thereby.

Representation of obesity in contemporary atrial fibrillation ablation randomized controlled trials.

BACKGROUND: The prevalence and impact of obesity on outcomes of atrial fibrillation (AF) ablation randomized controlled trials (RCTs) have not been well studied. OBJECTIVE: To examine the proportion of participants with obesity enrolled in RCTs of AF ablation and outcomes of ablation when subgroup analysis of participants with obesity were available. METHODS: We systematically searched PubMed and EMBASE for AF ablation RCTs published between January 1, 2015 to May 31, 2022. When body mass index (BMI) data were available, normal distribution was assumed and a z score was used to estimate the proportion of obesity. Results categorized by BMI or body weight status were reviewed. Authors were contacted for additional information. RESULTS: Of 148 eligible RCTs with 30174 participants, 144 (97.30%) RCTs did not report the proportion of participants with obesity, while published information regarding BMI was available in 63.51%. Three trials excluded patients based on BMI. Using reported BMI, we estimated the proportion of participants with obesity varied greatly across these trials, ranging from 5.82%-71.9% (median 38.02%, interquartile 29.64%, 49.10%). Patients with obesity were represented in a greater proportion among trials conducted in North America (50.23%) and Asia (44.72%), compared to others (32.16%), p < .001. Subgroup analysis or analysis adjusting for BMI was reported in only 13 (8.78%) RCTs; four (30.77%) of these suggested that BMI or body weight might negatively affect primary outcomes. CONCLUSION: Obesity is a common comorbidity among AF patients. However, most AF ablation RCTs underreported the proportion of participants with obesity and its impact on the primary outcomes.

TTYH3 Promotes Cervical Cancer Progression by Activating the Wnt/ß-Catenin Signaling Pathway.

The role of tweety homolog 3 (TTYH3) has been studied in several cancers, including hepatocellular carcinoma, cholangiocarcinoma, and gastric cancer. The results showed that TTYH3 is highly expression in cervical cancer tissues and cells and high TTYH3 expression correlates with poor prognosis in patients with cervical cancer. TTYH3 markedly reduced the apoptosis rate and promoted proliferation, migration, and invasion. Silencing of TTYH3 has been shown to have an inhibitory effect on cervical cancer progression. Moreover, TTYH3 enhanced EMT and activated Wnt/ß-catenin signaling. Furthermore, TTYH3 knockdown inhibited the tumor growth in vivo. In conclusion, TTYH3 promoted cervical cancer progression by activating the Wnt/ß-catenin signaling.

TTYH3 is upregulated in cervical cancer tissue and cells.TTYH3 promotes cervical cancer cell proliferation.TTYH3 inhibits cervical cancer cell apoptosis.TTYH3 induces cervical cancer cell migration and invasion.TTYH3 activates the Wnt signaling in cervical cancer cell.

Management of Chronic Heart Failure in Dialysis Patients: A Challenging but Rewarding Path.

Chronic heart failure (CHF) is a common complication and cause of death in dialysis patients. Although several clinical guidelines and expert consensus on heart failure (HF) in the general population have been issued in China and abroad, due to abnormal renal function or even no residual renal function (RRF) in dialysis patients, the high number of chronic complications, as well as the specificity, variability, and limitations of hemodialysis (HD) and peritoneal dialysis (PD) treatments, there are significant differences between dialysis patients and the general population in terms of the treatment and management of HF. The current studies are not relevant to all dialysis-combined HF populations, and there is an urgent need for high-quality studies on managing HF in dialysis patients to guide and standardize treatment. After reviewing the existing guidelines and literature, we focused on the staging and diagnosis of HF, management of risk factors, pharmacotherapy, and dialysis treatment in patients on dialysis. Based on evidence-based medicine and clinical trial data, this report reflects new perspectives and future trends in the diagnosis and treatment of HF in dialysis patients, which will further enhance the clinicians' understanding of HF in dialysis patients.

Multi-order orbital angular momentum mode generators based on integrated long-period fiber gratings.

We propose integrated long-period fiber gratings (LPFGs) fabricated by a CO2 laser to realize a multi-channel and multi-order orbital angular momentum (OAM) mode generator. The integrated LPFG is inscribed on multiple surfaces of the few-mode fiber (FMF) by rotating the fiber in the opposite direction at an angle θ. By controlling the rotation angle, the number of integrated LPFGs can be set. The selected rotation angle is 43 ∘, which can integrate up to nine LPFGs, i.e., realizing that the number of channels for first-order orbital angular momentum (OAM) mode conversion is nine. The integrated LPFGs fabricated in this method allow a flexible design of channel spacing. In addition, the flexible selection of the integrated grating period achieves the simultaneous generation of multi-channel second-order and third-order OAM mode conversion. The multi-channel and multi-order OAM mode generators have important application in optical communication multiplexing systems and OAM sensing.

Magnetic tuning with minimal thermal drift in high-Q microspheres coated with magnetorheological polydimethylsiloxane.

Integration of whispering-gallery-mode (WGM) resonators with high-quality factors (Q) into advanced timing, oscillator, and sensing systems demands a platform that enables precise resonance frequency modulation. This study investigates the tuning characteristics of magnetorheological polydimethylsiloxane (MR-PDMS) coated microspheres (µ-spheres) employed as magnetic microresonators, achieving a Q value of 107 at the 1550 nm wavelength. Magnetic WGM resonators not only endow the device with magnetic adjustability but also markedly improve thermal resistance. Experimental findings reveal that the magnetic µ-sphere demonstrates a sensitivity of -32.53 MHz/mT, outperforming conventional magnetic WGM resonators. Furthermore, analysis of the temperature dependence shows a reduction in fluctuation to -2.85 MHz/K, thereby greatly enhancing the sensor's practical detection limit.

Mode conversion in graded-index few-mode fiber via hollow cylindrical long-period fiber gratings.

We demonstrate the realization of mode conversion using hollow cylindrical long-period fiber gratings (LPFGs) inscribed in graded-index few-mode fibers (FMFs) by a femtosecond laser. By precisely shaping the refractive index modulation into a hollow cylindrical structure, we enable efficient coupling from the fundamental mode to high-order modes (LP11, LP02, LP21, LP12, LP31, LP03, and LP22 modes). The method achieves high-efficiency and low-loss mode conversion across various mode groups, marking a first for graded-index FMFs with different grating periods. The influence of the hollow cylindrical LPFG radius on mode conversion efficiency and spectral characteristics is thoroughly investigated. Additionally, incorporating a linear polarizer allowed for distinguishing between LP modes within a mode group, enhancing the tunability of the mode converter. These mode conversion devices have significant potential for applications in mode gain equalization and mode scrambling for mode division multiplexing (MDM) systems.

Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors.

The comorbidity of autism spectrum disorder and anxiety is common, but the underlying circuitry is poorly understood. Here, Tmem74-/- mice showed autism- and anxiety-like behaviors along with increased excitability of pyramidal neurons (PNs) in the prelimbic cortex (PL), which were reversed by Tmem74 re-expression and chemogenetic inhibition in PNs of the PL. To determine the underlying circuitry, we performed conditional deletion of Tmem74 in the PNs of PL of mice, and we found that alterations in the PL projections to fast-spiking interneurons (FSIs) in the dorsal striatum (dSTR) (PLPNs-dSTRFSIs) mediated the hyperexcitability of FSIs and autism-like behaviors and that alterations in the PL projections to the PNs of the basolateral amygdaloid nucleus (BLA) (PLPNs-BLAPNs) mediated the hyperexcitability of PNs and anxiety-like behaviors. However, the two populations of PNs in the PL had different spatial locations, optogenetic manipulations revealed that alterations in the activity in the PL-dSTR or PL-BLA circuits led to autism- or anxiety-like behaviors, respectively. Collectively, these findings highlight that the hyperactivity of the two populations of PNs in the PL mediates autism and anxiety comorbidity through the PL-dSTR and PL-BLA circuits, which may lead to the development of new therapeutics for the autism and anxiety comorbidity.

Long-term survival of ischemic cardiomyopathy patients with severe left ventricular dysfunction after CABG vs heart transplantation: A single center retrospective analysis.

BACKGROUND: There are no guidelines on the surgical management for ischemic cardiomyopathy (ICM) patients with severe left ventricular dysfunction. The present study aims to assess the long-term survival of these patients treated with two different surgical techniques, coronary artery bypass grafting (CABG) and heart transplantation (HTx). METHODS: This retrospective study included 218 ICM patients with left ventricular ejection fraction (LVEF) ≤35% who underwent CABG (n = 106) and HTx (n = 112) from 2011 to 2021 in a single center. After propensity adjustment analysis each group consisted of 51 patients. Clinical characteristics were evaluated for all-cause follow-up mortality by the Cox proportional hazards regression model. A risk prediction model was generated from multivariable-adjusted Cox regression analysis and applied to stratify patients with different clinical risks. The long-term survival was estimated by Kaplan-Meier analysis for different surgery groups. RESULTS: Long-term survival was comparable between CABG and HTx groups. After being stratified into different risk subgroups according to risk predictors, the HTx group exhibited superior survival outcomes compared to the CABG group among the high-risk patients (67.8% vs 44.4%, 64.1% vs 38.9%, and 64.1% vs 33.3%, p = 0.047) at 12, 36, and 60 months respectively, while the survival was comparable between HTx and CABG groups among low-risk patients (87.0% vs 97.0%, 82.4% vs 97.0%, and 70.2% vs 91.6%, p = 0.11) at 12, 36, and 60 months respectively in the PSM cohort. CONCLUSION: Long-term survival in ICM patients with severe left ventricular dysfunction who received CABG or HTx was comparable in general. Nonetheless, a favorable outcome of HTx surgery compared to CABG was observed among high-risk patients.