Immobile polyanionic backbone enables a 900-µm-thick electrode for compact energy storage with unprecedented areal capacitance.

Thickening of electrodes is crucial for maximizing the proportion of active components and thus improving the energy density of practical energy storage cells. Nevertheless, trade-offs between electrode thickness and electrochemical performance persist because of the considerably increased ion transport resistance of thick electrodes. Herein, we propose accelerating ion transport through thick and dense electrodes by establishing an immobile polyanionic backbone within the electrode pores; and as a proof of concept, gel polyacrylic electrolytes as such a backbone are in situ synthesized for supercapacitors. During charge and discharge, protons rapidly hop among RCOO- sites for oriented transport, fundamentally reducing the effects of electrode tortuosity and polarization resulting from concentration gradients. Consequently, nearly constant ion transport resistance per unit thickness is achieved, even in the case of a 900-µm-thick dense electrode, leading to unprecedented areal capacitances of 14.85 F cm-2 at 1 mA cm-2 and 4.26 F cm-2 at 100 mA cm-2. This study provides an efficient method for accelerating ion transport through thick and dense electrodes, indicating a significant solution for achieving high energy density in energy storage devices, including but not limited to supercapacitors.

Autophagy in chronic rhinosinusitis with or without nasal polyps.

Basic research on chronic rhinosinusitis (CRS) has advanced significantly in the past two decades, yet a comprehensive understanding of its pathogenic mechanisms remains elusive. Concurrently, there is a growing interest among scientists in exploring the involvement of autophagy in various human diseases, including tumors and inflammatory conditions. While the role of autophagy in asthma has been extensively studied in airway inflammatory diseases, its significance in CRS with or without nasal polyps (NPs), a condition closely linked to asthma pathophysiology, has also garnered attention, albeit with conflicting findings across studies. This review delves into the role of autophagy in CRS, suggesting that modulating autophagy to regulate inflammatory responses could potentially serve as a novel therapeutic target.

Comparation of fixed-ratio (IDegLira and iGlarLixi) versus free combination of basal insulin and glucagon-like peptide-1 receptor agonist for uncontrolled type 2 diabetes: A systematic review and network meta-analysis.

OBJECTIVE: This study aimed to evaluate the safety and efficacy of the fixed-ratio combination (FRC) and free combination of basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with type 2 diabetes mellitus (T2DM). METHODS: PubMed, Web of Science, Embase, The Cochrane Library, and four Chinese databases were searched for relevant studies from inception to April 13, 2023. Phase III clinical trials involving FRC or free combination in patients with uncontrolled T2DM were included. A network meta-analysis (NMA) was used to evaluate the effects of FRC and free combination. The Cochrane Collaboration's tool was used to evaluate the risk-of-bias. The primary outcomes were changes in hemoglobin A1c (HbA1c), body weight, and incident hypoglycemia. Secondary outcomes included changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP). This study was registered with PROSPERO (CRD42023409585). RESULTS: Forty-two trials with 23,619 patients were included in the NMA, and treatments were categorized as FRC, free combination and NOINSGLP (neither FRC nor free combination). The forest plots revealed comparable HbA1c control (mean difference (MD) = 0.07%, 95% confidence interval (CI): -0.17 to -0.30) between free combination and FRC. However, there were significant differences in the body weight (MD = -2.06 kg; 95% CI: -3.34 to -0.77), SBP (MD = -1.22 mmHg; 95% CI: -2.41 to -0.04), and DBP (MD = -1.09 mmHg; 95% CI: -1.94 to -0.24) between the two groups. CONCLUSIONS: In patients with uncontrolled T2DM, the safety and efficacy of FRC and free combination therapy were comparable. The use of FRC is justifiable in patients requiring free combination.

Fasting-induced RNF152 resensitizes gallbladder cancer cells to gemcitabine by inhibiting mTORC1-mediated glycolysis.

Abnormal mTORC1 activation by the lysosomal Ragulator complex has been implicated in cancer and glycolytic metabolism associated with drug resistance. Fasting upregulates RNF152 and mediates the metabolic status of cells. We report that RNF152 regulates mTORC1 signaling by targeting a Ragulator subunit, p18, and attenuates gemcitabine resistance in gallbladder cancer (GBC). We detected levels of RNF152 and p18 in tissues and undertook mechanistic studies using activators, inhibitors, and lentivirus transfections. RNF152 levels were significantly lower in GBC than in adjacent non-cancer tissues. Fasting impairs glycolysis, induces gemcitabine sensitivity, and upregulates RNF152 expression. RNF152 overexpression increases the sensitivity of GBC cells to gemcitabine, whereas silencing RNF152 has the opposite effect. Fasting-induced RNF152 ubiquitinates p18, resulting in proteasomal degradation. RNF152 deficiency increases the lysosomal localization of p18 and increases mTORC1 activity, to promote glycolysis and decrease gemcitabine sensitivity. RNF152 suppresses mTORC1 activity to inhibit glycolysis and enhance gemcitabine sensitivity in GBC.

Wide Linearity Range 3D Magnetic Sensor and Angular Position Detector Based on a Single FePt Spin-Orbit Torque Device.

Three-dimensional (3D) vector magnetic sensors play a significant role in a variety of industries, especially in the automotive industry, which enables the control of precise position, angle, and rotation of motion elements. Traditional 3D magnetic sensors integrate multiple sensors with their sensing orientations along the three coordinate axes, leading to a large size and inevitable nonorthogonal misalignment. Here, we demonstrate a wide linearity range 3D magnetic sensor utilizing a single L10-FePt Hall-bar device, whose sensitivity is 291 VA-1 T-1 in the z-axis and 27 VA-1 T-1 in the in-plane axis. Based on the spin-orbit torque-dominated magnetization reversal, the linear response of anomalous Hall resistance within a large linear range (±200 Oe) for the x, y, and z components of magnetic fields has been obtained, respectively. Typically, it exhibits a relatively lower magnetic noise level of 7.9 nV at 1 Hz than previous results, improving measurement resolution at the low frequency. Furthermore, we provide a straightforward approach for noncontact angular position detection based on a single Hall-bar device, which shows great potential for application in rotational motion control.

Targeting the cysteine biosynthesis pathway in microorganisms: Mechanism, structure, and drug discovery.

Owing to the global health crisis of resistant pathogenic infections, researchers are emphasizing the importance of novel prevention and control strategies. Existing antimicrobial drugs predominantly target a few pathways, and their widespread use has pervasively increased drug resistance. Therefore, it is imperative to develop new antimicrobial drugs with novel targets and chemical structures. The de novo cysteine biosynthesis pathway, one of the microbial metabolic pathways, plays a crucial role in pathogenicity and drug resistance. This pathway notably differs from that in humans, thereby representing an unexplored target for developing antimicrobial drugs. Herein, we have presented an overview of cysteine biosynthesis pathways and their roles in the pathogenicity of various microorganisms. Additionally, we have investigated the structure and function of enzymes involved in these pathways as well as have discussed drug design strategies and structure-activity relationships of the enzyme inhibitors. This review provides valuable insights for developing novel antimicrobials and offers new avenues to combat drug resistance.

Dual Defect Passivation at the Buried Interface for Printable Mesoscopic Perovskite Solar Cells with Reduced Open-Circuit Voltage Loss.

Numerous defects exist at the buried interface between the perovskite and adjacent electron transport layers in perovskite solar cells, resulting in severe non-radiative recombination and excessive open-circuit voltage (VOC) loss. Herein, a dual defect passivation strategy utilizing guanidine sulfate (GUA2SO4) as an interface modifier is first reported. On the one hand, the SO4 2- preferentially interacts with Pb-related defects, generating water-insoluble lead oxysalts complexes. Additionally, GUA+ diffuses into the perovskite and induces the formation of low-dimensional perovskite. These reactions effectively suppress trap states at the buried interface and perovskite boundaries in printable mesoscopic perovskite solar cells (p-MPSCs), thus increasing the carrier lifetime. Meanwhile, GUA2SO4 optimizes the interface energy band alignment, thus accelerating the charge extraction and transfer at the buried interface. This synergistic effect of trap passivation and interface energy band alignment modulation is strongly demonstrated by an increase in average VOC of 70 mV and the power conversion efficiency improvement from 17.51% to 18.70%. This work provides a novel approach to efficiently improve the performance of p-MPSCs through dual-targeted defect passivation at the buried interface.

Dynamic Profiling and Prediction of Antibody Response to SARS-CoV-2 Booster-Inactivated Vaccines by Microsample-Driven Biosensor and Machine Learning.

Knowledge of the antibody response to the third dose of inactivated SARS-CoV-2 vaccines is crucial because it is the subject of one of the largest global vaccination programs. This study integrated microsampling with optical biosensors to profile neutralizing antibodies (NAbs) in fifteen vaccinated healthy donors, followed by the application of machine learning to predict antibody response at given timepoints. Over a nine-month duration, microsampling and venipuncture were conducted at seven individual timepoints. A refined iteration of a fiber optic biolayer interferometry (FO-BLI) biosensor was designed, enabling rapid multiplexed biosensing of the NAbs of both wild-type and Omicron SARS-CoV-2 variants in minutes. Findings revealed a strong correlation (Pearson r of 0.919, specificity of 100%) between wild-type variant NAb levels in microsamples and sera. Following the third dose, sera NAb levels of the wild-type variant increased 2.9-fold after seven days and 3.3-fold within a month, subsequently waning and becoming undetectable after three months. Considerable but incomplete evasion of the latest Omicron subvariants from booster vaccine-elicited NAbs was confirmed, although a higher number of binding antibodies (BAbs) was identified by another rapid FO-BLI biosensor in minutes. Significantly, FO-BLI highly correlated with a pseudovirus neutralization assay in identifying neutralizing capacities (Pearson r of 0.983). Additionally, machine learning demonstrated exceptional accuracy in predicting antibody levels, with an error level of <5% for both NAbs and BAbs across multiple timepoints. Microsample-driven biosensing enables individuals to access their results within hours of self-collection, while precise models could guide personalized vaccination strategies. The technology's innate adaptability means it has the potential for effective translation in disease prevention and vaccine development.

A Critical Review on Room-Temperature Sodium-Sulfur Batteries: From Research Advances to Practical Perspectives.

Room-temperature sodium-sulfur (RT-Na/S) batteries are promising alternatives for next-generation energy storage systems with high energy density and high power density. However, some notorious issues are hampering the practical application of RT-Na/S batteries. Besides, the working mechanism of RT-Na/S batteries under practical conditions such as high sulfur loading, lean electrolyte, and low capacity ratio between the negative and positive electrode (N/P ratio), is of essential importance for practical applications, yet the significance of these parameters has long been disregarded. Herein, it is comprehensively reviewed recent advances on Na metal anode, S cathode, electrolyte, and separator engineering for RT-Na/S batteries. The discrepancies between laboratory research and practical conditions are elaborately discussed, endeavors toward practical applications are highlighted, and suggestions for the practical values of the crucial parameters are rationally proposed. Furthermore, an empirical equation to estimate the actual energy density of RT-Na/S pouch cells under practical conditions is rationally proposed for the first time, making it possible to evaluate the gravimetric energy density of the cells under practical conditions. This review aims to reemphasize the vital importance of the crucial parameters for RT-Na/S batteries to bridge the gaps between laboratory research and practical applications.

Room-Temperature Processed Annealing-Free Printable Carbon-Based Mesoscopic Perovskite Solar Cells with 17.34% Efficiency.

Carbon-based printable mesoscopic perovskite solar cells (MPSCs) have promising commercial development due to the use of easily scalable printing processes and low-cost carbon material electrodes. Simplifying the preparation process of MPSCs will undoubtedly contribute to their practical application. Here, we demonstrate that efficient and stable MPSCs can be prepared at room temperature without annealing by using low boiling point 2-methoxyethanol (2-ME) and strongly coordinated N-methyl-2-pyrrolidone (NMP) as a novel mixed solvent under the synergistic effect of ammonium chloride (NH4Cl). The results show that the 2-ME/NMP mixed solvent can generate an optimized coordination environment so that uniform nucleation and crystallization of perovskites in mesopores can be achieved at room temperature without annealing by forming uniform small-sized colloids in the precursor solution. Moreover, our work for the first time introduces NH4Cl as a crystallization modulator during a room-temperature annealing-free process, effectively regulating the crystallization behavior of perovskite in mesopores and obtaining high-quality perovskites. Finally, MPSCs prepared synergistically by a room-temperature annealing-free process based on a low boiling point 2-ME/NMP mixed solvent and NH4Cl modulator achieved a champion power conversion efficiency of 17.34% while demonstrating excellent long-term air stability for over half a year. This work provides a new approach to simplifying the preparation process of MPSCs and preparing efficient and stable MPSCs through a room-temperature annealing-free process.

Surplus fatty acid synthesis increases oxidative stress in adipocytes and lnduces lipodystrophy.

Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.

Dynamic palmitoylation of STX11 controls injury-induced fatty acid uptake to promote muscle regeneration.

Different types of cells uptake fatty acids in response to different stimuli or physiological conditions; however, little is known about context-specific regulation of fatty acid uptake. Here, we show that muscle injury induces fatty acid uptake in muscle stem cells (MuSCs) to promote their proliferation and muscle regeneration. In humans and mice, fatty acids are mobilized after muscle injury. Through CD36, fatty acids function as both fuels and growth signals to promote MuSC proliferation. Mechanistically, injury triggers the translocation of CD36 in MuSCs, which relies on dynamic palmitoylation of STX11. Palmitoylation facilitates the formation of STX11/SNAP23/VAMP4 SANRE complex, which stimulates the fusion of CD36- and STX11-containing vesicles. Restricting fatty acid supply, blocking fatty acid uptake, or inhibiting STX11 palmitoylation attenuates muscle regeneration in mice. Our studies have identified a critical role of fatty acids in muscle regeneration and shed light on context-specific regulation of fatty acid sensing and uptake.

Short-term antiplatelet versus anticoagulant therapy after left atrial appendage closure: a systematic review and meta-analysis.

This meta-analysis compared the efficacy and safety of different antithrombotic regimens after left atrial appendage closure (LAAC). PubMed, Embase, Medline, Cochrane Library databases were systematically searched from their inception to March 2023. Patients were divided into short-term oral anticoagulation (OAC) group and antiplatelet therapy (APT) group. The incidence of events were performed using RevMan 5.4. The events including device-related thrombus (DRT), ischemic stroke/systemic embolization (SE), major bleeding, any bleeding, any major adverse event and all-cause mortality. Subgroup analysis were based on OAC alone or OAC plus single antiplatelet therapy (SAPT) in OAC group. Oral anticoagulants include warfarin and direct oral anticoagulant (DOAC). Fourteen studies with 35,166 patients were included. We found that the incidence of DRT (OR = 0.49, 95% CI 0.36-0.66, P＜0.0001) and all-cause mortality (OR = 0.71, 95% CI 0.57-0.89, P = 0.002) were significantly lower in OAC group than APT group. However, there was no statistical differences in the incidence rates of ischemic stroke/SE (OR = 0.77, 95% CI 0.49-1.20, P = 0.25), major bleeding (OR = 0.84, 95% CI 0.55-1.27, P = 0.84), any bleeding (OR = 0.83, 95% CI 0.56-1.22, P = 0.34) and any major adverse event (OR = 0.56, 95% CI 0.30-1.03, P = 0.06) in the two groups. Subgroup analysis found that the incidence of DRT, all-cause mortality and any major adverse event in OAC monotherapy were lower than that in APT group (P＜0.05), but not statistically different from other outcome. The incidence of DRT, all-cause mortality, any major adverse event and any bleeding in DOAC were significantly better than APT group (P＜0.05). While warfarin only has better incidence of DRT than APT (P＜0.05), there was no statistical difference between the two groups in other outcome (P＞0.05). The incidence of DRT was significantly lower than APT group (P＜0.05), major bleeding were higher, and the rest of the outcome did not show any statistically significant differences(P＞0.05) when OAC plus SAPT. Based on the existing data, short-term OAC may be favored over APT for patients who undergo LAAC. DOAC monotherapy may be favored over warfarin monotherapy or OAC plus APT, when selecting anticoagulant therapies.

Proton is Essential or Not: A Fresh Look on Pseudocapacitive Energy Storage of PANI Composites.

Protonation has been considered essential for the pseudocapacitive energy storage of polyaniline (PANI) for years, as proton doping in PANI chains not only activates electron transport pathways, but also promotes the proceeding of redox reactions. Rarely has the ability for PANI of storing energy without protonation been investigated, and it remains uncertain whether PANI has pseudocapacitive charge storage properties in an alkaline electrolyte. Here, this work first demonstrates the pseudocapacitive energy storage for PANI without protonation using a PANI/graphene composite as a model material in an alkaline electrolyte. Using in situ Raman spectroscopy coupled with electrochemical quartz crystal microbalance (EQCM) measurements, this work determines the formation of -N= group over potential on a PANI chain and demonstrates the direct contribution of OH- in the nonprotonation type of oxidation reactions. This work finds that the PANI/graphene composite in an alkaline electrolyte has excellent cycling stability with a wider operation voltage of 1 V as well as a slightly higher specific capacitance than that in an acidic electrolyte. The findings provide a new perspective on pseudocapacitive energy storage of PANI-based composites, which will influence the selection of electrolytes for PANI materials and expand their application in energy storage fields.

Effectiveness and safety of short-term anticoagulant regimens after left atrial appendage occlusion: A systematic review and meta-analysis.

INTRODUCTION: Left atrial appendage occlusion (LAAO) provides an alternative for poor candidates of long-term oral anticoagulant (OAC) therapy; however, anticoagulant therapy after surgical procedures has limited use due to associated uncertainties. We aimed to evaluate the effectiveness and safety of the short-term use of direct oral anticoagulant (DOAC) and warfarin after LAAO. METHOD: Electronic databases such as PubMed, Embase, Medline, and Cochrane Library databases were searched up to November 11, 2022. Our study compared DOAC therapy and warfarin in patients after LAAO. A meta-analysis was conducted with the Review Manager software (version 5.4). RESULTS: The meta-analysis included 13 cohort studies with a total of 32,607 patients. Our findings indicated that the incidence of stroke/TIA/SE, peri-device leaks>5 mm, device-related thrombosis, and all-cause mortality were not significantly different between the two groups after LAAO (P > 0.05). The DOAC group had a significantly lower incidence of major bleeding (OR = 0.83, 95 % CI: 0.74-0.94, P = 0.003), any bleeding (OR = 0.34, 95 % CI: 0.23-0.51, P < 0.001), stroke/TIA/SE and major bleeding (OR = 0.57, 95 % CI: 0.34-0.95, P = 0.03), and any major adverse event (OR = 0.89, 95 % CI:0.82-0.97, P = 0.010) than the warfarin group. The subgroup analysis revealed that the rate of stroke/TIA/SE was similar in the two groups in terms of the different regions, follow-up time, study type, anticoagulant strategy, and bleeding risk. The incidence of major bleeding in the DOAC group was significantly lower than that in the warfarin group in North America, as well as at follow-up period ≤6 months, retrospective cohort, HAS-BLED average score ≥ 3. In addition, the risk of major bleeding was higher with the combination of OAC and single antiplatelet therapy (SAPT) than with OAC alone. Finally, in the North American region, retrospective cohort, and HAS-BLED average score ≥ 3, the incidence of any serious adverse event in the DOAC group was still significantly lower than that in the warfarin group. CONCLUSION: Compared to warfarin, DOAC reduced the risk of major bleeding and any serious adverse event in patients after LAAO. This advantage was particularly notable in North America and high-risk populations for bleeding. In addition, the incidence of device-related thrombosis, peri-device leaks, stroke/TIA/SE and all-cause mortality were similar in both groups. The risk of major bleeding was lower in patients taking OAC alone compared with those taking OAC plus SAPT, without increasing the risk of thrombosis.

Network of depressive symptoms before and after a diagnosis of chronic kidney disease.

OBJECTIVE: A diagnosis of chronic kidney disease (CKD) may increase the risk for depression. The network perspective focuses on dynamic relationships among individual symptoms, which could advance our understanding of the development of depression during the transition to a diagnosis of CKD. The aim of this study was to use network analysis to examine the longitudinal associations of depressive symptoms from before to after a diagnosis of CKD. METHOD: The analytic sample included 1,386 participants from the Chinese Health and Retirement Longitudinal Study. Participants were aged 45 years or older and reported a doctor's diagnosis of CKD in any wave of interviews between 2011 and 2018. Depressive symptoms were measured by the 10-item version of the Center for Epidemiological Studies Depression. Cross-lagged panel network analysis was conducted to examine relationships between symptoms at three time points: prediagnosis; onset of diagnosis, and postdiagnosis). RESULTS: After controlling for other symptoms and covariates, feeling unable to get going and less happiness at prediagnosis were the most predictive of other symptoms at the diagnosis of CKD. Feeling effortful to do everything and depressed mood at the diagnosis of CKD were the most predictive of other symptoms at postdiagnosis. CONCLUSIONS: Fatigue (i.e., feeling unable to get going, feeling effortful to do everything), less happiness, and depressed mood were central symptoms during the transition to a diagnosis of CKD. These findings highlight the benefits of identifying and managing these central symptoms to reduce the risk of activating other depressive symptoms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Correlation analysis of hypertension, traditional Chinese medicine constitution, and LPL gene polymorphism in the elderly in communities in Shanghai.

BACKGROUND: Research on the genetic mechanisms of hypertension has been a hot topic in the cardiovascular field. OBJECTIVE: To study the correlation between senile hypertension and traditional Chinese medicine (TCM) constitution and lipoprotein lipase (LPL) gene polymorphism and to provide the theoretical basis for TCM prevention and treatment of hypertension. METHODS: The elderly population in communities in Shanghai (hypertensive: 264 cases; non-hypertensive: 159 cases) was taken as the research object. Essential data and information on TCM constitution were collected. The LPL gene mutation was detected using the second-generation sequencing method. Statistical analysis was performed to clarify the relationship between hypertension and senile hypertension. The correlation of TCM constitution with risk factors and LPL gene polymorphisms was studied. RESULTS: The primary TCM constitutions in the hypertension group were phlegm-dampness constitution (51.52%), yin-deficiency constitution (17.42%), balanced constitution (15.53%), and yin-deficiency (9.43%). Logistic regression analysis showed that the phlegm-dampness constitution (P< 0.05, OR = 2.587) and yin-deficiency constitution (P< 0.01, OR = 2.693) were the risk constitutions of hypertension in the elderly. A total of 37 LPL gene mutation loci (SNP: 22; new discovery: 15) were detected in the LPL gene, and the mutation rates of rs254, rs255, rs3208305, rs316, rs11570891, rs328, rs11570893, and rs13702 were relatively high, which were 26.24%, 26.24%, 16.08%, 14.66%, 13.24%, 12.06%, and 10.64%. In the phlegm-dampness group, the proportion of rs254 CC type, rs255 TT type, and rs13702 TT type in the hypertensive group (77.21%, 77.21%, and 93.38%) was higher than that in the non-hypertensive group (56.41%, 56.41%, and 82.05%), The difference was statistically significant (P< 0.05). CONCLUSION: The phlegm-dampness constitution and yin-deficiency constitution are the risk factors of hypertension in the elderly; in the phlegm-dampness population, rs254 CC type, rs255 TT type, and rs13702 TT type are the risk factors for elderly hypertension.

Epidemiologic and Genomic Evidence for Zoonotic Transmission of SARS-CoV-2 among People and Animals on a Michigan Mink Farm, United States, 2020.

Farmed mink are one of few animals in which infection with SARS-CoV-2 has resulted in sustained transmission among a population and spillback from mink to people. In September 2020, mink on a Michigan farm exhibited increased morbidity and mortality rates due to confirmed SARS-CoV-2 infection. We conducted an epidemiologic investigation to identify the source of initial mink exposure, assess the degree of spread within the facility's overall mink population, and evaluate the risk of further viral spread on the farm and in surrounding wildlife habitats. Three farm employees reported symptoms consistent with COVID-19 the same day that increased mortality rates were observed among the mink herd. One of these individuals, and another asymptomatic employee, tested positive for SARS-CoV-2 by real-time reverse transcription PCR (RT-qPCR) 9 days later. All but one mink sampled on the farm were positive for SARS-CoV-2 based on nucleic acid detection from at least one oral, nasal, or rectal swab tested by RT-qPCR (99%). Sequence analysis showed high degrees of similarity between sequences from mink and the two positive farm employees. Epidemiologic and genomic data, including the presence of F486L and N501T mutations believed to arise through mink adaptation, support the hypothesis that the two employees with SARS-CoV-2 nucleic acid detection contracted COVID-19 from mink. However, the specific source of virus introduction onto the farm was not identified. Three companion animals living with mink farm employees and 31 wild animals of six species sampled in the surrounding area were negative for SARS-CoV-2 by RT-qPCR. Results from this investigation support the necessity of a One Health approach to manage the zoonotic spread of SARS-CoV-2 and underscores the critical need for multifaceted public health approaches to prevent the introduction and spread of respiratory viruses on mink farms.

ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS.

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 (ROBO1) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1-deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42.