Exposure modality influences viral kinetics but not respiratory outcome of COVID-19 in multiple nonhuman primate species.

The novel coronavirus SARS-CoV-2 emerged in late 2019, rapidly reached pandemic status, and has maintained global ubiquity through the emergence of variants of concern. Efforts to develop animal models have mostly fallen short of recapitulating severe disease, diminishing their utility for research focusing on severe disease pathogenesis and life-saving medical countermeasures. We tested whether route of experimental infection substantially changes COVID-19 disease characteristics in two species of nonhuman primates (Macaca mulatta; rhesus macaques; RM, Chlorocebus atheiops; African green monkeys; AGM). Species-specific cohorts were experimentally infected with SARS-CoV-2 by either direct mucosal (intratracheal + intranasal) instillation or small particle aerosol in route-discrete subcohorts. Both species demonstrated analogous viral loads in all compartments by either exposure route although the magnitude and duration of viral loading was marginally greater in AGMs than RMs. Clinical onset was nearly immediate (+1dpi) in the mucosal exposure cohort whereas clinical signs and cytokine responses in aerosol exposure animals began +7dpi. Pathologies conserved in both species and both exposure modalities include pulmonary myeloid cell influx, development of pleuritis, and extended lack of regenerative capacity in the pulmonary compartment. Demonstration of conserved pulmonary pathology regardless of species and exposure route expands our understanding of how SARS-CoV-2 infection may lead to ARDS and/or functional lung damage and demonstrates the near clinical response of the nonhuman primate model for anti-fibrotic therapeutic evaluation studies.

Complementary antibody lineages achieve neutralization breadth in an HIV-1 infected elite neutralizer.

Broadly neutralizing antibodies (bNAbs) have remarkable breadth and potency against most HIV-1 subtypes and are able to prevent HIV-1 infection in animal models. However, bNAbs are extremely difficult to induce by vaccination. Defining the developmental pathways towards neutralization breadth can assist in the design of strategies to elicit protective bNAb responses by vaccination. Here, HIV-1 envelope glycoproteins (Env)-specific IgG+ B cells were isolated at various time points post infection from an HIV-1 infected elite neutralizer to obtain monoclonal antibodies (mAbs). Multiple antibody lineages were isolated targeting distinct epitopes on Env, including the gp120-gp41 interface, CD4-binding site, silent face and V3 region. The mAbs each neutralized a diverse set of HIV-1 strains from different clades indicating that the patient's remarkable serum breadth and potency might have been the result of a polyclonal mixture rather than a single bNAb lineage. High-resolution cryo-electron microscopy structures of the neutralizing mAbs (NAbs) in complex with an Env trimer generated from the same individual revealed that the NAbs used multiple strategies to neutralize the virus; blocking the receptor binding site, binding to HIV-1 Env N-linked glycans, and disassembly of the trimer. These results show that diverse NAbs can complement each other to achieve a broad and potent neutralizing serum response in HIV-1 infected individuals. Hence, the induction of combinations of moderately broad NAbs might be a viable vaccine strategy to protect against a wide range of circulating HIV-1 viruses.

Prevalence and prognosis of malignancy in THSD7A-associated membranous nephropathy: a systematic literature review and clinical case study.

BACKGROUND: This study aims to investigate the incidence and prognosis of malignancy in individuals with thrombospondin type-1 domain-containing 7A (THSD7A)-associated membranous nephropathy (MN). METHODS: First, we performed a systematic literature review of prevalence of malignancy in THSD7A-associated MN. Then, we conducted a retrospective analysis of 454 patients diagnosed with MN through renal biopsy at our hospital between January 2016 and December 2020. We assessed the presence of serum anti-THSD7A antibodies and performed immunohistochemical staining of renal tissue for THSD7A. Subsequently, we followed patients with THSD7A-associated MN for a minimum of 3-5 years, collecting their clinical, pathological characteristics, and prognosis. Additionally, we conducted a literature review on patients with THSD7A-associated MN in conjunction with malignancy. RESULTS: We identified a total of nine articles containing comprehensive data on THSD7A-associated MN and malignancy. Among 235 patients with THSD7A-positive MN, 36 individuals had concurrent malignancies, resulting in a malignancy prevalence of 13.3% (95% CI: 8.9-17.7%). In our center, we followed up with 15 patients diagnosed with THSD7A-associated MN and observed three cases of concomitant tumors: two cases of lung adenocarcinoma and one case of small cell lung cancer with multiple metastases. The prevalence of malignancy in our cohort was 20%. Notably, we detected positive THSD7A staining in both renal and lung cancer tissues in one patient with small cell lung cancer. CONCLUSIONS: Patients with THSD7A-associated MN should undergo vigilant follow-up assessments, with a particular focus on actively seeking potential tumorigenic lesions to prevent misdiagnosis or oversight.

Prevalence and immunopathologic characteristics of seropositive and seronegative hepatitis B virus-associated membranous nephropathy: a retrospective study of 420 biopsy-proven cases.

BACKGROUND: This retrospective study aims to investigate the prevalence and immunopathologic characteristics of seropositive and seronegative hepatitis B virus-associated membranous nephropathy (HBV-MN). METHODS: Clinicopathologic and serologic records of 420 patients with histologically confirmed HBV-MN between January 2014 and July 2021 were examined to determine the prevalence of seropositive and seronegative HBV-MN. Serum anti-PLA2R antibody testing was conducted on 280 patients with HBV-associated membranous nephropathy (HBV-MN) from August 2018 to July 2021. Immunopathologic characteristics of HBV-MN patients and anti-PLA2R antibody positivity were analyzed. RESULTS: Among 420 pathologically confirmed HBV-MN patients, 230 (54.8%) were seropositive for HBV. The seropositive group exhibited higher blood creatinine values and incidence of liver function abnormalities than the seronegative group (p < .05). Serum anti-PLA2R antibody testing on 280 HBV-MN patients revealed a total positive rate of 44.6%, with the seronegative group showing a significantly higher rate (62.6%) compared to the seropositive group (32.1%) (p < .01). The anti-PLA2R antibody-positive group displayed higher levels of urine protein (p < .05), serum cholesterol (p < .01), and IgG4 subtypes (p < .05) compared to the negative group. Additionally, the positive group had significantly lower levels of serum albumin and IgG than the negative group (p < .01). CONCLUSIONS: This comprehensive study reveals a significantly higher prevalence of seronegative HBV-MN than previously thought. The blood creatinine values and incidence of liver function abnormalities was higher in the serology-positive group than in the serology-negative group. Notably, the seronegative group displayed a higher positive rate of anti-PLA2R antibodies compared to the seropositive group, indicating distinctive clinical and immunopathologic features.

Selection of HIV Envelope Strains for Standardized Assessments of Vaccine-Elicited Antibody-Dependent Cellular Cytotoxicity-Mediating Antibodies.

Antibody-dependent cellular cytotoxicity (ADCC) has been correlated with reduced risk of human immunodeficiency virus type 1 (HIV-1) infection in several preclinical vaccine trials and in the RV144 clinical trial, indicating that this is a relevant antibody function to study. Given the diversity of HIV-1, the breadth of vaccine-induced antibody responses is a critical parameter to understand if a universal vaccine is to be realized. Moreover, the breadth of ADCC responses can be influenced by different vaccine strategies and regimens, including adjuvants. Therefore, to accurately evaluate ADCC and to compare vaccine regimens, it is important to understand the range of HIV Envelope (Env) susceptibility to these responses. These evaluations have been limited because of the complexity of the assay and the lack of a comprehensive panel of viruses for the assessment of these humoral responses. Here, we used 29 HIV-1 infectious molecular clones (IMCs) representing different Envelope subtypes and circulating recombinant forms to characterize susceptibility to ADCC from antibodies in plasma from infected individuals, including 13 viremic individuals, 10 controllers, and six with broadly neutralizing antibody responses. We found in our panel that ADCC susceptibility of the IMCs in our panel did not cluster by subtype, infectivity, level of CD4 downregulation, level of shedding, or neutralization sensitivity. Using partitioning around medoids (PAM) clustering to distinguish smaller groups of IMCs with similar ADCC susceptibility, we identified nested panels of four to eight IMCs that broadly represent the ADCC susceptibility of the entire 29-IMC panel. These panels, together with reagents developed to specifically accommodate circulating viruses at the geographical sites of vaccine trials, will provide a powerful tool to harmonize ADCC data generated across different studies and to detect common themes of ADCC responses elicited by various vaccines. IMPORTANCE Antibody-dependent cellular cytotoxicity (ADCC) responses were found to correlate with reduced risk of infection in the RV144 trial of the only human HIV-1 vaccine to show any efficacy to date. However, reagents to understand the breadth and magnitude of these responses across preclinical and clinical vaccine trials remain underdeveloped. In this study, we characterize HIV-1 infectious molecular clones encoding 29 distinct Envelope strains (Env-IMCs) to understand factors that impact virus susceptibility to ADCC and use statistical methods to identify smaller nested panels of four to eight Env-IMCs that accurately represent the full set. These reagents can be used as standardized reagents across studies to fully understand how ADCC may affect efficacy of future vaccine studies and how studies differ in the breadth of responses developed.

The pigtail macaque (Macaca nemestrina) model of COVID-19 reproduces diverse clinical outcomes and reveals new and complex signatures of disease.

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 disease, has killed over five million people worldwide as of December 2021 with infections rising again due to the emergence of highly transmissible variants. Animal models that faithfully recapitulate human disease are critical for assessing SARS-CoV-2 viral and immune dynamics, for understanding mechanisms of disease, and for testing vaccines and therapeutics. Pigtail macaques (PTM, Macaca nemestrina) demonstrate a rapid and severe disease course when infected with simian immunodeficiency virus (SIV), including the development of severe cardiovascular symptoms that are pertinent to COVID-19 manifestations in humans. We thus proposed this species may likewise exhibit severe COVID-19 disease upon infection with SARS-CoV-2. Here, we extensively studied a cohort of SARS-CoV-2-infected PTM euthanized either 6- or 21-days after respiratory viral challenge. We show that PTM demonstrate largely mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, including CD4+ T cells that upregulate CD8 and express cytotoxic molecules, as well as virus-targeting T cells that were predominantly CD4+. We also noted increases in inflammatory and coagulation markers in blood, pulmonary pathologic lesions, and the development of neutralizing antibodies. Together, our data demonstrate that SARS-CoV-2 infection of PTM recapitulates important features of COVID-19 and reveals new immune and viral dynamics and thus may serve as a useful animal model for studying pathogenesis and testing vaccines and therapeutics.

Effects of Insulin-degrading enzyme on the proliferation of swine Sertoli cells.

Sertoli cells, the only somatic cells in testis seminiferous tubules, provide a supporting microenvironment for male germ cells and play essential roles in spermatogenesis. The insulin-degrading enzyme (IDE), a ubiquitous zinc peptidase of the inverzincin family, plays crucial role in sperm production, as IDE-knockout mice presented decreased testis weight and impaired sperm viability and morphology. However, whether and how IDE affects swine Sertoli cell proliferation remains unclear. Thus, in the present study, we aimed to evaluate the effects of IDE on the proliferation of swine Sertoli cells, as well as its underlying molecular mechanism. After knocking down IDE expression with small interfering RNA transfection, we analyzed the proliferation of swine Sertoli cells as well as the expression of related regulatory factors (WT1, ERK, and AKT). The results showed that IDE knockdown promoted swine Sertoli cell proliferation and increased WT1 expression, possibly through activating ERK and AKT. Overall, our findings suggest that IDE may be involved in male reproduction by regulating Sertoli cell proliferation, which provides new information to better understand the regulatory mechanisms of swine Sertoli cells and improve the reproductive traits of male pigs.

Marked variations in gut microbial diversity, functions, and disease risk between wild and captive alpine musk deer.

Maintaining a healthy status is crucial for the successful captive breeding of endangered alpine musk deer (Moschus chrysogaster, AMD), and captive breeding programs are beneficial to the ex-situ conservation and wild population recovery of this species. Meanwhile, the gut microbiota is essential for host health, survival, and environmental adaptation. However, changes in feeding environment and food can affect the composition and function of gut microbiota in musk deer, ultimately impacting their health and adaptation. Therefore, regulating the health status of wild and captive AMD through a non-invasive method that targets gut microbiota is a promising approach. Here, 16S rRNA gene sequencing was employed to reveal the composition and functional variations between wild (N = 23) and captive (N = 25) AMD populations. The results indicated that the gut microbiota of wild AMD exhibited significantly higher alpha diversity (P < 0.001) and greater abundance of the phylum Firmicutes, as well as several dominant genera, including UCG-005, Christensenellaceae R7 group, Monoglobus, Ruminococcus, and Roseburia (P < 0.05), compared to captive AMD. These findings suggest that the wild AMD may possess more effective nutrient absorption and utilization, a more stable intestinal microecology, and better adaption to the complex natural environment. The captive individuals displayed higher metabolic functions with an increased abundance of the phylum Bacteroidetes and certain dominant genera, including Bacteroides, Rikenellaceae RC9 gut group, NK4A214 group, and Alistipes (P < 0.05), which contributed to the metabolic activities of various nutrients. Furthermore, captive AMD showed a higher level of 11 potential opportunistic pathogens and a greater enrichment of disease-related functions compared to wild AMD, indicating that wild musk deer have a lower risk of intestinal diseases and more stable intestinal structure in comparison to captive populations. These findings can serve as a valuable theoretical foundation for promoting the healthy breeding of musk deer and as a guide for evaluating the health of wild-released and reintroduced musk deer in the future. KEY POINTS: • Wild and captive AMD exhibit contrasting gut microbial diversity and certain functions. • With higher diversity, certain bacteria aid wild AMD's adaptation to complex habitats. • Higher potential pathogens and functions increase disease risk in captive AMD.

Atrial fibrillation is not an independent determinant of 28-day mortality among critically III sepsis patients.

This study was conducted to investigate the relationship between atrial fibrillation and the clinical prognosis of patients with sepsis in intensive care unit. A total of 21,538 sepsis patients were enrolled in the study based on the Medical Information Mart for Intensive Care IV database, of whom 6,759 had AF. Propensity score matching was used to compare the clinical characteristics and outcomes of patients with and without AF. Besides, the inverse probability of treatment weighting, univariate and multivariate Cox regression analyzes were performed. Of the 21,538 patients, 31.4% had AF. The prevalence of AF increased in a step-by-step manner with growing age. Patients with AF were older than those without AF. After PSM, 11,180 patients remained, comprising 5,790 matched pairs in both groups. In IPTW, AF was not associated with 28-day mortality [hazard ratio (HR), 1.07; 95% confidence interval (CI), 0.99-1.15]. In Kaplan-Meier analysis, it was not observed difference of 28-day mortality between patients with and without AF. AF could be associated with increased ICU LOS, hospital LOS and need for mechanical ventilation; however, it does not remain an independent short-term predictor of 28-day mortality among patients with sepsis after PSM with IPTW and multivariate analysis.

Recognition of Ellipsoid-like Herbaceous Tibetan Medicinal Materials Using DenseNet with Attention and ILBP-Encoded Gabor Features.

Tibetan medicinal materials play a significant role in Tibetan culture. However, some types of Tibetan medicinal materials share similar shapes and colors, but possess different medicinal properties and functions. The incorrect use of such medicinal materials may lead to poisoning, delayed treatment, and potentially severe consequences for patients. Historically, the identification of ellipsoid-like herbaceous Tibetan medicinal materials has relied on manual identification methods, including observation, touching, tasting, and nasal smell, which heavily rely on the technicians' accumulated experience and are prone to errors. In this paper, we propose an image-recognition method for ellipsoid-like herbaceous Tibetan medicinal materials that combines texture feature extraction and a deep-learning network. We created an image dataset consisting of 3200 images of 18 types of ellipsoid-like Tibetan medicinal materials. Due to the complex background and high similarity in the shape and color of the ellipsoid-like herbaceous Tibetan medicinal materials in the images, we conducted a multi-feature fusion experiment on the shape, color, and texture features of these materials. To leverage the importance of texture features, we utilized an improved LBP (local binary pattern) algorithm to encode the texture features extracted by the Gabor algorithm. We inputted the final features into the DenseNet network to recognize the images of the ellipsoid-like herbaceous Tibetan medicinal materials. Our approach focuses on extracting important texture information while ignoring irrelevant information such as background clutter to eliminate interference and improve recognition performance. The experimental results show that our proposed method achieved a recognition accuracy of 93.67% on the original dataset and 95.11% on the augmented dataset. In conclusion, our proposed method could aid in the identification and authentication of ellipsoid-like herbaceous Tibetan medicinal materials, reducing errors and ensuring the safe use of Tibetan medicinal materials in healthcare.

Reducing the Ir-O Coordination Number in Anodic Catalysts based on IrOx Nanoparticles towards Enhanced Proton-exchange-membrane Water Electrolysis.

Due to the robust oxidation conditions in strong acid oxygen evolution reaction (OER), developing an OER electrocatalyst with high efficiency remains challenging in polymer electrolyte membrane (PEM) water electrolyzer. Recent theoretical research suggested that reducing the coordination number of Ir-O is feasible to reduce the energy barrier of the rate-determination step, potentially accelerating the OER. Inspired by this, we experimentally verified the Ir-O coordination number's role at model catalysts, then synthesized low-coordinated IrOx nanoparticles toward a durable PEM water electrolyzer. We first conducted model studies on commercial rutile-IrO2 using plasma-based defect engineering. The combined in situ X-ray absorption spectroscopy (XAS) analysis and computational studies clarify why the decreased coordination numbers increase catalytic activity. Next, under the model studies' guidelines, we explored a low-coordinated Ir-based catalyst with a lower overpotential of 231 mV@10 mA cm-2 accompanied by long durability (100 h) in an acidic OER. Finally, the assembled PEM water electrolyzer delivers a low voltage (1.72 V@1 A cm-2 ) as well as excellent stability exceeding 1200 h (@1 A cm-2 ) without obvious decay. This work provides a unique insight into the role of coordination numbers, paving the way for designing Ir-based catalysts for PEM water electrolyzers.

Comparative analysis of gut microbial composition and potential functions in captive forest and alpine musk deer.

Gut microbiota forms a unique microecosystem and performs various irreplaceable metabolic functions for ruminants. The gut microbiota is important for host health and provides new insight into endangered species conservation. Forest musk deer (FMD) and alpine musk deer (AMD) are typical small ruminants, globally endangered due to excessive hunting and habitat loss. Although nearly 60 years of captive musk deer breeding has reduced the hunting pressure in the wild, fatal gastrointestinal diseases restrict the growth of captive populations. In this study, 16S rRNA high-throughput sequencing revealed the differences in gut microbiota between FMD and AMD based on 166 fecal samples. The alpha diversity was higher in FMD than in AMD, probably helping FMD adapt to different and wider habitats. The ß-diversity was higher between adult FMD and AMD than juveniles and in winter than late spring. The phylum Firmicutes and the genera Christensenellaceae R7 group, Ruminococcus, Prevotellaceae UCG-004, and Monoglobus were significantly higher in abundance in FMD than in AMD. However, the phylum Bacteroidetes and genera Bacteroides, UCG-005, Rikenellaceae RC9 gut group, and Alistipes were significantly higher in AMD than FMD. The expression of metabolic functions was higher in AMD than in FMD, a beneficial pattern for AMD to maintain higher energy and substance metabolism. Captive AMD may be at higher risk of intestinal diseases than FMD, with higher relative abundances of most opportunistic pathogens and the expression of disease-related functions. These results provide valuable data for breeding healthy captive musk deer and assessing their adaptability in the wild. KEY POINTS: • Alpha diversity of gut microbiota was higher in FMD than that in AMD • Expression of metabolic and disease-related functions was higher in AMD than in FMD.

Identification of imprinted genes in the skeletal muscle of newborn piglets by high-throughput sequencing.

Imprinted genes - exhibiting parent-specific transcription - play essential roles in the process of mammalian development and growth. Skeletal muscle growth is crucial for meat production. To further understand the role of imprinted genes during the porcine skeletal muscle growth, DNA-seq and RNA-seq were used to explore the characteristics of imprinted genes from porcine reciprocal crosses. A total of 584 545 single-nucleotide variations were discovered in the DNA-seq data of F0 parents, heterozygous in two pig breeds (Yorkshire and Min pigs) but homozygous in each breed. These single-nucleotide variations were used to determine the allelic-specific expression in F1 individuals. Finally, eight paternal expression sites and three maternal expression sites were detected, whereas two paternally expressed imprinted genes (NDN and IGF2) and one maternally expressed imprinted gene (H1-3) were validated by Sanger sequencing. DNA methylation regulates the expression of imprinted genes, and all of the identified imprinted genes in this study were predicted to possess CpG islands. PBX1 and YY1 binding motifs were discovered in the promoter regions of all three imprinted genes, which were candidate elements regulating the transcription of imprinted genes. For these identified imprinted genes, IGF2 and NDN promoted muscle growth whereas H1-3 inhibited cell proliferation, corroborating the 'parental conflict' theory that paternally expressed imprinted genes assisted descendants' growth whereas maternally expressed imprinted genes inhibited it. This study discovered porcine imprinted genes in skeletal muscle and was the first to reveal that H1-3 was expressed by the maternal allele to our knowledge. Our findings provided valuable resources for the potential utilization of imprinted genes in pig breeding.

Genome-wide association study revealed ABCD4 on SSC7 and GREB1L and MIB1 on SSC6 as crucial candidate genes for rib number in Beijing Black pigs.

As one of the few animals with variation in the number of rib pairs (RIB), the pig is a good model to study the mechanism of RIB regulation. Quantitative trait loci (QTL) for porcine RIB are present on Sus scrofa chromosome 7 (SSC7). Although several candidate genes exist in this QTL region on SSC7, the causal gene has yet to be verified. Beijing Black pig with 14-17 RIB is a good population for candidate gene mining and 1104 individuals were genotyped using the Illumina Porcine 50K BeadChip. A total of 14 SNPs from 95.49 to 97.78 Mb on SSC7 showed genome-wide significant association with RIB. On SSC7, a locuszoom plot using pairwise linkage disequilibrium displayed the narrowest linkage region encompassing only two genes, ABCD4 and VRTN. In mice, a transcriptome expression profile was obtained using three embryos at E9.5 (the critical period for rib formation). ABCD4 was highly expressed, but no expression of VRTN was detected. On SSC6, there were four genome-wide significant SNPs from 106.42 to 106.92 Mb associated with RIB. GREB1L and MIB1, in this region, were regarded as novel candidate genes. These results revealed a crucial candidate causal gene on SSC7 and novel genes on SSC6 for rib number and provided interesting new insights into its genetic basis.

Gap between risk factors and prevention strategies? A nationwide survey of fall prevention among medical and surgical patients.

AIMS: This study aimed to determine the extent to which nurses report assessing evidence-based falls risk factors and implementing targeted prevention for medical and surgical patients in China. DESIGN: This study was a national online survey. METHODS: The respondents were registered nurses working in medical and surgical units in 662 Chinese hospitals. The data concerning the falls risk factor assessments and targeted interventions implemented by nurses were collected online by the Nursing Management Committee of the Chinese Nursing Association in China in 2019. RESULTS: In total, 68 527 valid questionnaires were returned (95.0%). In medical and surgical units, nurses were most likely to report assessing balance, mobility and strength (81.6%) and orthostatic hypotension (76.4%) in falls patients and least likely to report assessing continence (61.3%) and feet and footwear (55.8%). Ensuring the use of appropriate footwear (79.3%) and managing syncope, dizziness and vertigo (73.8%) were the most common multiple interventions, while managing postural hypotension (48.8%) and cognitive impairment (48.4%) was the least common. Nine falls risk factors with clearly matched multifactorial interventions were identified in medical and surgical units (68.2%-97.1%). CONCLUSIONS: The implementation of multifactorial interventions in medical and surgical wards is inconsistent as reported by nurses in medical and surgical wards. Throughout China, nurses are generally concerned about falls risk factors and prevention for their patients; however, limited attention has been focused on continence, feet and footwear assessment and the management of cognitive impairment. Evidence-based falls prevention should be further tailored to the specific risk factors of each patient. IMPACT: Best practice guidelines for falls prevention in hospitals have been developed and published, and it is important for nurses to use these guidelines to guide practice. Our findings identify that in routine care, healthcare providers and hospitals can prevent falls.

Scoparone alleviates Ang II-induced pathological myocardial hypertrophy in mice by inhibiting oxidative stress.

Long-term poorly controlled myocardial hypertrophy often leads to heart failure and sudden death. Activation of ras-related C3 botulinum toxin substrate 1 (RAC1) by angiotensin II (Ang II) plays a pivotal role in myocardial hypertrophy. Previous studies have demonstrated that scoparone (SCO) has beneficial effects on hypertension and extracellular matrix remodelling. However, the function of SCO on Ang II-mediated myocardial hypertrophy remains unknown. In our study, a mouse model of myocardial hypertrophy was established by Ang II infusion (2 mg/kg/day) for 4 weeks, and SCO (60 mg/kg bodyweight) was administered by gavage daily. In vitro experiments were also performed. Our results showed that SCO could alleviate Ang II infusion-induced cardiac hypertrophy and fibrosis in mice. In vitro, SCO treatment blocks Ang II-induced cardiomyocyte hypertrophy, cardiac fibroblast collagen synthesis and differentiation to myofibroblasts. Meanwhile, we found that SCO treatment blocked Ang II-induced oxidative stress in cardiomyocytes and cardiac fibroblasts by inhibiting RAC1-GTP and total RAC1 in vivo and in vitro. Furthermore, reactive oxygen species (ROS) burst by overexpression of RAC1 completely abolished SCO-mediated protection in cardiomyocytes and cardiac fibroblasts in vitro. In conclusion, SCO, an antioxidant, may attenuate Ang II-induced myocardial hypertrophy by suppressing of RAC1 mediated oxidative stress.

Diverse antiviral IgG effector activities are predicted by unique biophysical antibody features.

BACKGROUND: The critical role of antibody Fc-mediated effector functions in immune defense has been widely reported in various viral infections. These effector functions confer cellular responses through engagement with innate immune cells. The precise mechanism(s) by which immunoglobulin G (IgG) Fc domain and cognate receptors may afford protection are poorly understood, however, in the context of HIV/SHIV infections. Many different in vitro assays have been developed and utilized to measure effector functions, but the extent to which these assays capture distinct antibody activities has not been fully elucidated. RESULTS: In this study, six Fc-mediated effector function assays and two biophysical antibody profiling assays were performed on a common set of samples from HIV-1 infected and vaccinated subjects. Biophysical antibody profiles supported robust prediction of diverse IgG effector functions across distinct Fc-mediated effector function assays. While a number of assays showed correlated activities, supervised machine learning models indicated unique antibody features as primary contributing factors to the associated effector functions. Additional experiments established the mechanistic relevance of relationships discovered using this unbiased approach. CONCLUSIONS: In sum, this study provides better resolution on the diversity and complexity of effector function assays, offering a clearer perspective into this family of antibody mechanisms of action to inform future HIV-1 treatment and vaccination strategies.

Correction: HIV-1 envelope glycan modifications that permit neutralization by germline-reverted VRC01-class broadly neutralizing antibodies.

[This corrects the article DOI: 10.1371/journal.ppat.1007431.].

Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.

The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man5-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man5-enriched CH505.N279K.G458Y.SOSIP.664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategy to initiate and mature the CH235 bnAb lineage.

Correction: Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies.

[This corrects the article DOI: 10.1371/journal.ppat.1008026.].