Pathogen protein modularity enables elaborate mimicry of a host phosphatase.

Pathogens produce diverse effector proteins to manipulate host cellular processes. However, how functional diversity is generated in an effector repertoire is poorly understood. Many effectors in the devastating plant pathogen Phytophthora contain tandem repeats of the "(L)WY" motif, which are structurally conserved but variable in sequences. Here, we discovered a functional module formed by a specific (L)WY-LWY combination in multiple Phytophthora effectors, which efficiently recruits the serine/threonine protein phosphatase 2A (PP2A) core enzyme in plant hosts. Crystal structure of an effector-PP2A complex shows that the (L)WY-LWY module enables hijacking of the host PP2A core enzyme to form functional holoenzymes. While sharing the PP2A-interacting module at the amino terminus, these effectors possess divergent C-terminal LWY units and regulate distinct sets of phosphoproteins in the host. Our results highlight the appropriation of an essential host phosphatase through molecular mimicry by pathogens and diversification promoted by protein modularity in an effector repertoire.

Genome-Wide Genetic Associations Prioritize Evaluation of Causal Mechanisms of Atherosclerotic Disease Risk.

OBJECTIVE: The goal of this review is to discuss the implementation of genome-wide association studies to identify causal mechanisms of vascular disease risk. APPROACH AND RESULTS: The history of genome-wide association studies is described, the use of imputation and the creation of consortia to conduct meta-analyses with sufficient power to arrive at consistent associated loci for vascular disease. Genomic methods are described that allow the identification of causal variants and causal genes and how they impact the disease process. The power of single-cell analyses to promote genome-wide association studies of causal gene function is described. CONCLUSIONS: Genome-wide association studies represent a paradigm shift in the study of cardiovascular disease, providing identification of genes, cellular phenotypes, and disease pathways that empower the future of targeted drug development.

The effect of TRIM5 variants on the susceptibility to HIV-1 infection and disease progression in the Polish population.

BACKGROUD: Tripartite motif containing 5α protein is a factor contributing to intracellular defense mechanisms against human immunodeficiency virus-1 (HIV-1) infection. The studies of TRIM5 variants effects on the risk of HIV-1 infection and the clinical course of disease provided inconclusive results in different ethnic groups. The aim of this study was to investigate the influence of TRIM5 variants on susceptibility to HIV-1 infection and clinical parameters among Polish HIV-1-infected patients. MATERIALS & METHODS: In our study, we investigated 301 HIV-1-infected patients and 186 age-matched seronegative controls. Seven variants of the TRIM5 gene (rs7127617, rs3824949, rs3740996, rs11601507, rs10838525, rs11038628, and rs28381981) were genotyped using both sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques. RESULTS AND CONCLUSIONS: The frequencies of rs7127617 TT genotype and T allele occurrence were lower in HIV-1-infected subjects compared to controls (0.14 vs. 0.26 for T/T genotype and 0.45 vs. 0.54 for T allele), suggesting their possible protective effect (p = 0.005 and p = 0.007, respectively). Heterozygosity and presence of the T allele at rs3740996 were enriched in controls compared to HIV-1-infected group (0.19 vs. 0.12 for C/T genotype and 0.11 vs. 0.07 for T allele; p = 0.03 and p = 0.02, respectively). Moreover, rs3824949 CC genotype carriers had a lower viral load than patients bearing rs3824949 GG/CG genotypes (4.0 vs. 4.6 log copies/mL; p = 0.049); however, none of the variants affected CD4+ cell count. In conclusion, our data confirm the role of TRIM5 variants in the HIV-1 transmission and the clinical course of HIV-1 infection. The presence of rs7127617 TT genotype and T allele seems to protect against HIV-1 transmission in examined population.

Genome-wide analyses in Lyme borreliosis: identification of a genetic variant associated with disease susceptibility and its immunological implications.

BACKGROUND: Genetic variation underly inter-individual variation in host immune responses to infectious diseases, and may affect susceptibility or the course of signs and symptoms. METHODS: We performed genome-wide association studies in a prospective cohort of 1138 patients with physician-confirmed Lyme borreliosis (LB), the most common tick-borne disease in the Northern hemisphere caused by the bacterium Borrelia burgdorferi sensu lato. Genome-wide variants in LB patients-divided into a discovery and validation cohort-were compared to two healthy cohorts. Additionally, ex vivo monocyte-derived cytokine responses of peripheral blood mononuclear cells to several stimuli including Borrelia burgdorferi were performed in both LB patient and healthy control samples, as were stimulation experiments using mechanistic/mammalian target of rapamycin (mTOR) inhibitors. In addition, for LB patients, anti-Borrelia antibody responses were measured. Finally, in a subset of LB patients, gene expression was analysed using RNA-sequencing data from the ex vivo stimulation experiments. RESULTS: We identified a previously unknown genetic variant, rs1061632, that was associated with enhanced LB susceptibility. This polymorphism was an eQTL for KCTD20 and ETV7 genes, and its major risk allele was associated with upregulation of the mTOR pathway and cytokine responses, and lower anti-Borrelia antibody production. In addition, we replicated the recently reported SCGB1D2 locus that was suggested to have a protective effect on B. burgdorferi infection, and associated this locus with higher Borrelia burgdorferi antibody indexes and lower IL-10 responses. CONCLUSIONS: Susceptibility for LB was associated with higher anti-inflammatory responses and reduced anti-Borrelia antibody production, which in turn may negatively impact bacterial clearance. These findings provide important insights into the immunogenetic susceptibility for LB and may guide future studies on development of preventive or therapeutic measures. TRIAL REGISTRATION: The LymeProspect study was registered with the International Clinical Trials Registry Platform (NTR4998, registration date 2015-02-13).

Restless nights when sick: ectoparasite infections alter rest-activity cycles of diurnal fish hosts.

Circadian rhythms are timekeeping mechanisms responsible for an array of biological processes. Disruption of such cycles can detrimentally affect animal health. Circadian rhythms are critical in the co-evolution of host­parasite systems, as synchronization of parasite rhythms to the host can influence infection dynamics and transmission potential. This study examines the circadian rhythms in behaviour and activity of a model fish species (Poecilia reticulata) in isolation and in shoals, both when uninfected and infected with an ectoparasite (Gyrodactylus turnbulli). Additionally, the rhythmical variance of parasite activity under different light conditions as well as rhythmical variance in parasite transmissibility was explored. Overall, infection alters the circadian rhythm of fish, causing nocturnal restlessness. Increased activity of gyrodactylids on the host's skin at night could potentially contribute to this elevated host activity. Whilst migration of gyrodactylids across the host's skin may have caused irritation to the host resulting in nocturnal restlessness, the disruption in guppy activity rhythm caused by the expression of host innate immunity cannot be excluded. We discuss the wider repercussions such behavioural responses to infection have for host health, the implications for animal behaviour studies of diurnal species as well as the application of chronotherapeutic approaches to aquaculture.

Temporal patterns in coral disease prevalences at Thudufushi Island, Maldives, 2010-2022.

Coral reefs are lately suffering a fast decline in biodiversity due to the coupled effect of climate change and disease outbreaks, which in recent decades have been reported with higher frequency and shorter intervals. Limited studies have been conducted on coral diseases in the Maldives resulting in the impossibility of assessing the temporal trend in their dynamics. In this context, we evaluated the change in the distribution, prevalence, and host range of 4 diseases, namely black band disease (BBD), brown band disease (BrB), skeletal eroding band (SEB) and white syndrome (WS), in the reef system around Thudufushi Island after an interval of 12 yr since the last assessment. In this period, the overall disease prevalence increased, except for BrB, with SEB showing the most severe increase in 2022 in comparison to 2010. The overall average prevalence of coral diseases is approximately 2%, indicating an increase of about 0.7% since 2010. Diseased coral colonies were found in all the investigated sites, with the east site being the most affected and SEB emerging as the most prevalent disease across all the investigated sites. The affected colonies belong to 13 genera, with Psammocora genus showing the highest overall mean disease prevalence. This study depicted a basic temporal trend in disease prevalence that confirms an increase in coral diseases in the region and calls for a dedicated national monitoring protocol to better understand and predict future coral disease dynamics at regional scales.

On the effect heterogeneity of established disease susceptibility loci for Alzheimer's disease across different genetic ancestries.

INTRODUCTION: Genome-wide association studies have identified numerous disease susceptibility loci (DSLs) for Alzheimer's disease (AD). However, only a limited number of studies have investigated the dependence of the genetic effect size of established DSLs on genetic ancestry. METHODS: We utilized the whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) including 35,569 participants. A total of 25,459 subjects in four distinct populations (African ancestry, non-Hispanic White, admixed Hispanic, and Asian) were analyzed. RESULTS: We found that nine DSLs showed significant heterogeneity across populations. Single nucleotide polymorphism (SNP) rs2075650 in translocase of outer mitochondrial membrane 40 (TOMM40) showed the largest heterogeneity (Cochran's Q = 0.00, I2 = 90.08), followed by other SNPs in apolipoprotein C1 (APOC1) and apolipoprotein E (APOE). Two additional loci, signal-induced proliferation-associated 1 like 2 (SIPA1L2) and solute carrier 24 member 4 (SLC24A4), showed significant heterogeneity across populations. DISCUSSION: We observed substantial heterogeneity for the APOE-harboring 19q13.32 region with TOMM40/APOE/APOC1 genes. The largest risk effect was seen among African Americans, while Asians showed a surprisingly small risk effect.

Embryonic Amoxicillin Exposure Has Limited Impact on Liver Development but Increases Susceptibility to NAFLD in Zebrafish Larvae.

Amoxicillin is commonly used in clinical settings to target bacterial infection and is frequently prescribed during pregnancy. Investigations into its developmental toxicity and effects on disease susceptibility are not comprehensive. Our present study examined the effects of embryonic amoxicillin exposure on liver development and function, especially the effects on susceptibility to non-alcoholic fatty liver disease (NAFLD) using zebrafish as an animal model. We discovered that embryonic amoxicillin exposure did not compromise liver development, nor did it induce liver toxicity. However, co-treatment of amoxicillin and clavulanic acid diminished BESP expression, caused bile stasis and induced liver toxicity. Embryonic amoxicillin exposure resulted in elevated expression of lipid synthesis genes and exacerbated hepatic steatosis in a fructose-induced NAFLD model, indicating embryonic amoxicillin exposure increased susceptibility to NAFLD in zebrafish larvae. In summary, this research broadens our understanding of the risks of amoxicillin usage during pregnancy and provides evidence for the impact of embryonic amoxicillin exposure on disease susceptibility in offspring.

Targeting Disease Susceptibility Genes in Wheat Through wide Hybridization with Maize Expressing Cas9 and Guide RNA.

Two genes (TaHRC and Tsn1) conferring susceptibility to Fusarium head blight and tan spot, Septoria nodorum blotch, and spot blotch in wheat were targeted through wide hybridization with maize expressing Cas9 and guide RNA (gRNA). For each gene, two target sites were selected and corresponding gRNA expression cassettes were synthesized and cloned into a binary vector carrying the CRISPR/Cas9-mediated genome editing machinery. The constructed binary vectors were used to transform the hybrid maize Hi-II through an Agrobacterium-mediated approach to generate T0 and T1 plants, which were used to cross with wheat variety Dayn for targeting Tsn1 or the susceptible allele (TaHRC-S) of TaHRC as well as with the near-isogenic line (Day-Fhb1) of Dayn for targeting the resistant allele (TaHRC-R) of TaHRC. Haploid embryos were rescued in vitro from the wide crosses to generate haploid plants. PCR amplification and sequencing indicated that 15 to 33% of the haploid plants contained the target gene with mutations at the target sites. This wheat × maize hybridization combined with genome editing approach provides a useful alternative tool, not only for targeting susceptibility genes to improve disease resistance without regulatory issues, but also for understanding gene function in wheat. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Dietary, Cultural, and Pathogens-Related Selective Pressures Shaped Differential Adaptive Evolution among Native Mexican Populations.

Native American genetic ancestry has been remarkably implicated with increased risk of diverse health issues in several Mexican populations, especially in relation to the dramatic changes in environmental, dietary, and cultural settings they have recently undergone. In particular, the effects of these ecological transitions and Westernization of lifestyles have been investigated so far predominantly on Mestizo individuals. Nevertheless, indigenous groups, rather than admixed Mexicans, have plausibly retained the highest proportions of genetic components shaped by natural selection in response to the ancient milieu experienced by Mexican ancestors during their pre-Columbian evolutionary history. These formerly adaptive variants have the potential to represent the genetic determinants of some biological traits that are peculiar to Mexican people, as well as a reservoir of loci with possible biomedical relevance. To test such a hypothesis, we used genome-wide genotype data to infer the unique adaptive evolution of Native Mexican groups selected as reasonable descendants of the main pre-Columbian Mexican civilizations. A combination of haplotype-based and gene-network analyses enabled us to detect genomic signatures ascribable to polygenic adaptive traits plausibly evolved by the main genetic clusters of Mexican indigenous populations to cope with local environmental and/or cultural conditions. Some of these adaptations were found to play a role in modulating the susceptibility/resistance of these groups to certain pathological conditions, thus providing new evidence that diverse selective pressures have contributed to shape the current biological and disease-risk patterns of present-day Native and Mestizo Mexican populations.

Exposure, Susceptibility, and Recovery: A Framework for Examining the Intersection of the Social and Physical Environments and Infectious Disease Risk.

Despite well-documented evidence that structurally disadvantaged populations are disproportionately affected by infectious diseases, our understanding of the pathways that connect structural disadvantage to the burden of infectious diseases is limited. We propose a conceptual framework to facilitate more rigorous examination and testing of hypothesized mechanisms through which social and environmental factors shape the burden of infectious diseases and lead to persistent inequities. Drawing upon the principles laid out by Link and Phelan in their landmark paper on social conditions (J Health Soc Behav. 1995;(spec no.):80-94), we offer an explication of potential pathways through which structural disadvantage (e.g., racism, sexism, and economic deprivation) operates to produce infectious disease inequities. Specifically, we describe how the social environment affects an individual's risk of infectious disease by 1) increasing exposure to infectious pathogens and 2) increasing susceptibility to infection. This framework will facilitate both the systematic examination of the ways in which structural disadvantage shapes the burden of infectious disease and the design of interventions that can disrupt these pathways.

DSP: database of disease susceptibility genes in plants.

Host-pathogen interaction is the most crucial factor that evokes the host immune system to fight against pathogens. In contrast to specialized immune cells present in humans and animals, plants have disease resistance (R-) and disease susceptibility (S-) genes. R-genes confer disease resistance and are generally introgressed from wild crop relatives to cultivated crops. S-genes, on the other hand, assist pathogens in establishing contact, displaying counter-defense measures, and spreading the infection. To achieve resistance in a variety of crops, researchers are now focusing on the identification, silencing, editing, or elimination of crucial S-genes. To aid in this field, we created the first curated database of disease susceptibility genes in plants (DSP), with the simple and advanced search tool that allows researchers to restrict the query and mining of specified hits. SSR marker identification and primer designing could be performed with the help of MISA and Primer3 software, respectively. The DSP database is available at http://45.248.163.60/bic/sgenos/ and http://14.139.62.220/sgenos/ .

The immunogenetics of COVID-19.

The worldwide coronavirus disease 2019 pandemic was sparked by the severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) that first surfaced in December 2019 (COVID-19). The effects of COVID-19 differ substantially not just between patients individually but also between populations with different ancestries. In humans, the human leukocyte antigen (HLA) system coordinates immune regulation. Since HLA molecules are a major component of antigen-presenting pathway, they play an important role in determining susceptibility to infectious disease. It is likely that differential susceptibility to SARS-CoV-2 infection and/or disease course in COVID-19 in different individuals could be influenced by the variations in the HLA genes which are associated with various immune responses to SARS-CoV-2. A growing number of studies have identified a connection between HLA variation and diverse COVID-19 outcomes. Here, we review research investigating the impact of HLA on individual responses to SARS-CoV-2 infection and/or progression, also discussing the significance of MHC-related immunological patterns and its use in vaccine design.

Association of blood group with COVID-19 disease susceptibility and severity in Saudi Arabia.

BACKGROUND: Novel SARS-CoV-2 (COVID-19) virus has rapidly spread worldwide and was declared a pandemic, making identifying and prioritizing individuals most at risk a critical challenge. The literature describes an association between blood groups and the susceptibility to various viral infections and their severity. Knowing if a specific blood group has more susceptibility to COVID-19 may help improve understanding the pathogenesis and severity of the disease. We aimed to assess the association between ABO/RhD and COVID-19 susceptibility and severity, and to compare results with similar studies in Saudi Arabia. STUDY DESIGN AND METHODS: This study was conducted between March and October 2021 on 600 patients confirmed positive for COVID-19 infection. Patients' data were collected and analyzed. As a control, 8423 healthy blood donors were enrolled as a sample representative of the population for blood group distribution. RESULTS: More individuals had blood group B in the COVID-19 group in comparison with the control group (24.2% vs. 18%), The opposite was observed among individuals of group O (39.5% vs. 47.3%). The B blood group was predictive of higher risk of mortality. No significant difference in the distribution of RhD was observed between the COVID-19 and the control groups. Neither ABO nor RhD was significantly associated with the severity of COVID-19. DISCUSSION: Although there was no significant association with the disease severity, the B blood group may be associated with a higher risk for COVID-19 infection. Further studies with a larger sample size are necessary to evaluate this correlation.

Twenty-four hour pattern of childhood febrile seizures substantiated by time series meta-analysis: Circadian medicine perspectives.

Major objectives of this work were to: (1) substantiate the 24-hour pattern in the occurrence of childhood febrile seizures (CFSs) by a novel time series meta-analysis of past reported time-of-day data and (2) discuss its potential circadian rhythm-dependencies. Comprehensive search of the published literature retrieved eight articles that met inclusion criteria. Three investigations were conducted in Iran, two in Japan, and one each in Finland, Italy, and South Korea, representing a total of 2461 mostly simple febrile seizures of children who were on average about 2 years of age. Population-mean cosinor analysis validated (p < .001) a 24-hour pattern in the onset of CFSs, with an approximate four-fold difference in the proportion of children expressing seizures at its peak at 18:04 h (95% confidence interval: 16:40-19:07 h) vs trough at 06:00 h, in the absence of meaningful time-of-day differences in mean body temeprarure. The CFS time-of-day pattern likely derives from the actions of multiple circadian rhythms, particularly the cytokines that comprise the pyrogenic inflammatory pathway and melatonin that influences the excitation level of central neurons and helps regulate body temperature. Past laboratory animal and patient investigations document that the vulnerability to a seizure by a provoking trigger of the same intensity is not the same but different in a predictable-in-time manner during the 24 h as a circadian susceptibility/resistance rhythm. Knowledge of the marked disparity in the time-of-day risk of CFSs can be translated into improved prevention, particularly during the late afternoon and early evening when highest, through proper timing of prophylactic interventions.

Epigenome-wide methylation haplotype association analysis identified HLA-DRB1, HLA-DRB5 and HLA-DQB1 as risk factors for rheumatoid arthritis.

The aim of this study was to compare nonrandom associations between physically adjacent single methylation polymorphism loci among rheumatoid arthritis (RA) and normal subjects for investigating RA-risk methylation haplotypes (meplotype). With 354 ACPA-positive RA patients and 335 normal controls selected from a case-control study based on Swedish population, we conducted the first RA epigenome-wide meplotype association study using our software EWAS2.0, mainly including (i) converted the ß value to methylation genotype (menotype) data, (ii) identified methylation disequilibrium (MD) block, (iii) calculated frequent of each meplotypes in MD block and performed case-control association test and (iv) screened for RA-risk meplotypes by odd ratio (OR) and p-values. Ultimately, 545 meplotypes on 334 MD blocks were identified significantly associated with RA (p-value < .05). These meplotypes were mapped to 329 candidate genes related to RA. Subsequently, combined with gene optimization, eight RA-risk meplotypes were identified on three risk genes: HLA-DRB1, HLA-DRB5 and HLA-DQB1. Our results reported the relationship between DNA methylation pattern on HLA-DQB1 and the risk of RA for the first time, demonstrating the co-demethylation of 'cg22984282' and 'cg13423887' on HLA-DQB1 gene (meplotype UU, p-value = 2.90E - 6, OR = 1.68, 95% CI = [1.35, 2.10]) may increase the risk of RA. Our results demonstrates the potential of methylation haplotype analysis to identify RA-related genes from a new perspective and its applicability to the study of other disease.

Major depressive disorders increase the susceptibility to self-reported infections in two German cohort studies.

INTRODUCTION: In several claims-based studies, major depressive disorder (MDD) has been associated with increased risk of hospitalization due to acute infections. It remains unclear if this is a causal effect, and if it generalizes to an increased susceptibility to infections. METHODS: We used data of the BiDirect (n = 925) and the HaBIDS (n = 1007) cohort studies to estimate the effect of MDD on self-reported infections, which were assessed with identical infection susceptibility questionnaires in both studies. We used the Center for Epidemiologic Studies Depression Scale (CES-D) to examine if there was a dose-response relationship between depressive symptom severity and self-reported infections. RESULTS: BiDirect participants with MDD diagnosis (48%) had a higher risk of lower respiratory tract infections (incidence rate ratio 1.32, 95% confidence interval [1.00-1.75]), gastrointestinal infections (1.68 [1.30-2.16]) and fever (1.48 [1.11-1.98]) after adjusting for confounders identified by a directed acyclic graph approach. There was a dose-response relationship, i.e. individuals with higher CES-D scores reported more infections. Effect sizes were similar in HaBIDS (4% individuals with MDD). CONCLUSION: We found increased risks of mild infections in patients with MDD diagnosis and a dose-response relationship between depressive symptom severity and infection frequency. While causal immunological pathways remain unclear, the results of our study might contribute to a change in prevention strategies, e.g. by recommending vaccination against influenza and S. pneumoniae to MDD patients because observed effect sizes in our study are similar to those of patients with cardiovascular and metabolic diseases for which the respective vaccinations are recommended.

Factor H-Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy.

BACKGROUND: C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H-related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear. METHODS: Using in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant's association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population. RESULTS: Duplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome. CONCLUSIONS: Our findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G.

A Novel Soluble ACE2 Protein Provides Lung and Kidney Protection in Mice Susceptible to Lethal SARS-CoV-2 Infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2) as a main receptor to enter target cells. The goal of this study was to demonstrate the preclinical efficacy of a novel soluble ACE2 protein with increased duration of action and binding capacity in a lethal mouse model of COVID-19. METHODS: A human soluble ACE2 variant fused with an albumin binding domain (ABD) was linked via a dimerization motif hinge-like 4-cysteine dodecapeptide (DDC) to improve binding capacity to SARS-CoV-2. This novel soluble ACE2 protein (ACE2-1-618-DDC-ABD) was then administered intranasally and intraperitoneally to mice before intranasal inoculation of SARS-CoV-2 and then for two additional days post viral inoculation. RESULTS: Untreated animals became severely ill, and all had to be humanely euthanized by day 6 or 7 and had pulmonary alveolar hemorrhage with mononuclear infiltrates. In contrast, all but one mouse infected with a lethal dose of SARS-CoV-2 that received ACE2-1-618-DDC-ABD survived. In the animals inoculated with SARS-CoV-2 that were untreated, viral titers were high in the lungs and brain, but viral titers were absent in the kidneys. Some untreated animals, however, had variable degrees of kidney proximal tubular injury as shown by attenuation of the proximal tubular brush border and increased NGAL and TUNEL staining. Viral titers in the lung and brain were reduced or nondetectable in mice that received ACE2-1-618-DDC-ABD, and the animals developed only moderate disease as assessed by a near-normal clinical score, minimal weight loss, and improved lung and kidney injury. CONCLUSIONS: This study demonstrates the preclinical efficacy of a novel soluble ACE2 protein, termed ACE2-1-618-DDC-ABD, in a lethal mouse model of SARS-CoV-2 infection that develops severe lung injury and variable degrees of moderate kidney proximal tubular injury.

Association between GABRG2 Gene Single Nucleotide Polymorphisms and Susceptibility to Ischemic Stroke in a Chinese Population.

BACKGROUND: Current evidence suggests that Gamma-aminobutyric acid (GABA) receptors are associated with the occurrence and progression of cerebrovascular diseases. The present study investigated the association between single nucleotide polymorphisms (SNPs) in the Gamma-aminobutyric acid type A receptor gamma2 subunit (GABRG2) gene and ischemic stroke (IS). METHODS: A total of 120 healthy volunteers and 187 patients with IS were recruited. Patients underwent complete neurological assessment and classification with the National Institute of Health Stroke Scale (NIHSS) and the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to analyze SNP sites in 4 different regions (rs211037, rs418210, rs211035, and rs424740) of the GABRG2 gene. SHEsis online platform was used to assess SNP allele and genotype frequencies. Multivariate logistic regression analysis was performed to identify the risk factors for IS. RESULTS: Univariate analysis showed that the T allele and TT genotype distribution for rs211037 were significantly more frequent in the IS group compared to controls (pallele = 0.01, odds ratio (OR) = 1.673, 95% confidence intervals (CI), 1.119-2.500, pgenotype = 0.03). Furthermore, multivariate logistic regression analysis revealed the TT genotype for rs211037 was an independent risk factor for IS (p = 0.017, OR = 1.925, 95% CI, 1.122-3.303). Age was also found to be an independent risk factor, and the older the age, the higher the risk of IS (p = 0.001, OR = 1.047, 95% CI, 1.020-1.073). Finally, subgroup analysis revealed that patients with the rs211037 TT genotype were associated with a higher NIHSS score (p = 0.03), and that large-artery atherosclerosis (LAA) subtype was predominant in patients with the rs211037 TT genotype (p = 0.042). CONCLUSIONS: These findings suggest the rs211037 polymorphism in the GABRG2 gene is an independent risk factor for IS in the Chinese population. GABRG2 could thus be a potential biomarker to assess the risk of IS.