Transcription factor ZmEREB97 regulates nitrate uptake in maize (Zea mays) roots.

Maize (Zea mays L.) has very strong requirements for nitrogen. However, the molecular mechanisms underlying the regulations of nitrogen uptake and translocation in this species are not fully understood. Here, we report that an APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factor ZmEREB97 functions as an important regulator in the N-signaling network in maize. Predominantly expressed and accumulated in main root and lateral root primordia, ZmEREB97 rapidly responded to nitrate treatment. By overlapping the analyses of differentially expressed genes and conducting a DAP-seq assay, we identified 1446 potential target genes of ZmEREB97. Among these, 764 genes were co-regulated in two lines of zmereb97 mutants. Loss of function of ZmEREB97 substantially weakened plant growth under both hydroponic and soil conditions. Physiological characterization of zmereb97 mutant plants demonstrated that reduced biomass and grain yield were both associated with reduced nitrate influx, decreased nitrate content and less N accumulation. We further demonstrated that ZmEREB97 directly targets and regulates the expression of six ZmNRT genes by binding to the GCC box-related sequences in gene promoters. Collectively, these data suggest that ZmEREB97 is a major positive regulator of the nitrate response and that it plays an important role in optimizing nitrate uptake, offering a target for improvement of nitrogen use efficiency in crops.

Global One Health index for zoonoses: A performance assessment in 160 countries and territories.

The One Health (OH) approach is used to control/prevent zoonotic events. However, there is a lack of tools for systematically assessing OH practices. Here, we applied the Global OH Index (GOHI) to evaluate the global OH performance for zoonoses (GOHI-Zoonoses). The fuzzy analytic hierarchy process algorithm and fuzzy comparison matrix were used to calculate the weights and scores of five key indicators, 16 subindicators, and 31 datasets for 160 countries and territories worldwide. The distribution of GOHI-Zoonoses scores varies significantly across countries and regions, reflecting the strengths and weaknesses in controlling or responding to zoonotic threats. Correlation analyses revealed that the GOHI-Zoonoses score was associated with economic, sociodemographic, environmental, climatic, and zoological factors. Additionally, the Human Development Index had a positive effect on the score. This study provides an evidence-based reference and guidance for global, regional, and country-level efforts to optimize the health of people, animals, and the environment.

DENND1A desensitizes granulosa cells to FSH by arresting intracellular FSHR transportation.

Polycystic ovary syndrome (PCOS) is a complex disorder. Genome-wide association studies (GWAS) have identified several genes associated with this condition, including DENND1A. DENND1A encodes a clathrin-binding protein that functions as a guanine nucleotide exchange factor involved in vesicular transport. However, the specific role of DENND1A in reproductive hormone abnormalities and follicle development disorders in PCOS remain poorly understood. In this study, we investigated DENND1A expression in ovarian granulosa cells (GCs) from PCOS patients and its correlation with hormones. Our results revealed an upregulation of DENND1A expression in GCs from PCOS cases, which was positively correlated with testosterone levels. To further explore the functional implications of DENND1A, we generated a transgenic mouse model overexpressing Dennd1a (TG mice). These TG mice exhibited subfertility, irregular estrous cycles, and increased testosterone production following PMSG stimulation. Additionally, the TG mice displayed diminished responsiveness to FSH, characterized by smaller ovary size, less well-developed follicles, and abnormal expressions of FSH-priming genes. Mechanistically, we found that Dennd1a overexpression disrupted the intracellular trafficking of follicle stimulating hormone receptor (FSHR), promoting its internalization and inhibiting recycling. These findings shed light on the reproductive role of DENND1A and uncover the underlying mechanisms, thereby contributing valuable insights into the pathogenesis of PCOS and providing potential avenues for drug design in PCOS treatment.

Vinpocetine represses the progression of nonalcoholic steatohepatitis in mice by mediating inflammasome components via NF-KB signaling / La vinpocetina reprime la progresión de la esteatohepatitis no alcohólica en ratones por mediación de los componentes del inflamasoma a través de la señalización NF-KB

Background: Inflammasome activation is known to be involved in nonalcoholic steatohepatitis (NASH). Vinpocetine is a derivative of vincamine and is reported to suppress the activation of inflammasome. Methods: This study explored the therapeutical potential of Vinpocetine on NASH. Mice were fed with a choline-deficient (MCD) or chow diet in the presence or absence of Vinpocetine for 8 weeks. H&E staining and biochemical assays were determined to evaluate the hepatic steatosis and fibrosis symptoms. In addition, primary hepatocytes and Kupffer cells were isolated and induced by MCD or lipopolysaccharides/cholesterol crystals with or without Vinpocetine. ELISAs, qPCR, and Western blotting were applied to determine the levels of NASH-related biomarkers in both in vivo mouse model and in vitro cell models. Results: Treatment of Vinpocetine did not cause observable side effects against and MCD-induced cells and mouse NASH model. However, treatment of Vinpocetine ameliorated hepatic steatosis and fibrosis and suppressed the levels of alanine transaminase and aspartate transferase in the mouse NASH model. In addition, treatment of Vinpocetine suppressed the mRNA and protein levels of inflammasome components both in vitro and in vivo. Conclusion: Vinpocetine suppressed NASH in mice by mediating inflammasome components via nuclear factor κB signaling. (AU)

Antecedentes: Se sabe que la activación del inflamasoma está implicada en la esteatohepatitis no alcohólica (EHNA). La vinpocetina es un derivado de la vincamina que, según los informes, suprime la activación del inflamasoma. Métodos: Este estudio exploró el potencial terapéutico de la vinpocetina en la EHNA. Durante 8 semanas se alimentó a ratones con una dieta deficiente en colina (MCD) o con una dieta chow en presencia o ausencia de vinpocetina. Se realizaron tinciones de H&E y ensayos bioquímicos para evaluar los síntomas de esteatosis hepática y fibrosis. Además, se aislaron hepatocitos primarios y células de Kupffer y se indujeron mediante MCD o cristales de lipopolisacáridos/colesterol con o sin vinpocetina. Se aplicaron ELISA, qPCR y Western blotting para determinar los niveles de biomarcadores relacionados con la EHNA tanto en el modelo de ratón in vivo como en los modelos celulares in vitro. Resultados: El tratamiento con vinpocetina no causó efectos secundarios observables contra las células y el modelo de ratón de EHNA inducidos por MCD. Sin embargo, el tratamiento con vinpocetina mejoró la esteatosis hepática y la fibrosis y suprimió los niveles de alanina transaminasa y de aspartato transferasa en el modelo de EHNA de ratón. Además, el tratamiento con vinpocetina suprimió los niveles de ARNm y proteínas de los componentes del inflamasoma tanto in vitro como in vivo. Conclusiones: La vinpocetina suprimió la EHNA en ratones por mediación de los componentes del inflamasoma a través de la señalización del factor nuclear κB. (AU)

Expression and prognostic significance of the PD-1/PD-L1 pathway in AIDS-related non-Hodgkin lymphoma.

OBJECTIVE: Immune tolerance and evasion play a critical role in virus-driven malignancies. However, the phenotype and clinical significance of programmed cell death 1 (PD-1) and its ligands, PD-L1 and PD-L2, in aggressive acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (AR-NHL) remain poorly understood, particularly in the Epstein-Barr virus (EBV)-positive subset. METHODS: We used in situ hybridization with EBV-encoded RNA (EBER) to assess the EBV status. We performed immunohistochemistry and flow cytometry analysis to evaluate components of the PD-1/PD-L1/L2 pathway in a multi-institutional cohort of 58 patients with AR-NHL and compared EBV-positive and EBV-negative cases. RESULTS: The prevalence of EBV+ in AR-NHL was 56.9% and was associated with a marked increase in the expression of PD-1/PD-L1/PD-L2 in malignant cells. Patients with AR-NHLs who tested positive for both EBER and PD-1 exhibited lower survival rates compared to those negative for these markers (47.4% vs. 93.8%, p = 0.004). Similarly, patients positive for both EBER and PD-L1 also demonstrated poorer survival (56.5% vs. 93.8%, p = 0.043). Importantly, PD-1 tissue-expression demonstrated independent prognostic significance for overall survival in multivariate analysis and was correlated to elevated levels of LDH (r = 0.313, p = 0.031), increased PD-1+ Tregs (p = 0.006), and robust expression of EBER (r = 0.541, p < 0.001) and PD-L1 (r = 0.354, p = 0.014) expression. CONCLUSIONS: These data emphasize the importance of PD-1-mediated immune evasion in the complex landscape of immune oncology in AR-NHL co-infected with EBV, and contribute to the diagnostic classification and possible definition of immunotherapeutic strategies for this unique subgroup.

PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion.

BACKGROUND: Despite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects and dysfunctions of CAR-T cells have limited the efficacy and clinical application of this promising approach. METHODS: In this study, we incorporated a short hairpin RNA cassette targeting PD-1 into a BCMA-CAR with an OX-40 costimulatory domain. The transduced PD-1KD BCMA CAR-T cells were evaluated for surface CAR expression, T-cell proliferation, cytotoxicity, cytokine production, and subsets when they were exposed to a single or repetitive antigen stimulation. Safety and efficacy were initially observed in a phase I clinical trial for RRMM patients. RESULTS: Compared with parental BCMA CAR-T cells, PD-1KD BCMA CAR-T cell therapy showed reduced T-cell exhaustion and increased percentage of memory T cells in vitro. Better antitumor activity in vivo was also observed in PD-1KD BCMA CAR-T group. In the phase I clinical trial of the CAR-T cell therapy for seven RRMM patients, safety and efficacy were initially observed in all seven patients, including four patients (4/7, 57.1%) with at least one extramedullary site and four patients (4/7, 57.1%) with high-risk cytogenetics. The overall response rate was 85.7% (6/7). Four patients had a stringent complete response (sCR), one patient had a CR, one patient had a partial response, and one patient had stable disease. Safety profile was also observed in these patients, with an incidence of manageable mild to moderate cytokine release syndrome and without the occurrence of neurological toxicity. CONCLUSIONS: Our study demonstrates a design concept of CAR-T cells independent of antigen specificity and provides an alternative approach for improving the efficacy of CAR-T cell therapy.

Bioinsecticide PA1b alleviates lipopolysaccharide-induced inflammation and impairment of bovine mammary epithelial cells.

Pea Albumin 1, subunit b (PA1b) is a 37 amino acid peptide. It was extracted from pea seeds and showed significant insecticidal activity against certain insects, such as the mosquitoes Culex pipiens and Aedes aegyptii, cereal weevils (genus Sitophilus), and certain species of aphids. Considering that pea seeds are regularly consumed by humans and mammals, PA1b is assumed to be a promising bioinsecticide with no allergenicity or toxicity to hosts. To clarify this aspect, PA1b was applied to bovine mammary epithelial cells challenged with lipopolysaccharide (LPS). The results revealed that LPS induced inflammatory cytokine tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL6) and monocyte chemoattractant protein 1 (MCP-1) secretion, while PA1b depressed these cytokines release via inhibiting NF-κB signaling activation. In addition, PA1b protected mammary epithelial cells from impairment caused by LPS, because it reduced cell membrane permeability and subsequently reconstructed mammary epithelial cell viability. Moreover, it inhibited cell apoptosis accompanied with alleviated oxidative stress. Furthermore, PA1b prevented opening of mitochondrial permeability transition pores, in turn up-regulated mitochondrial membrane potential and ATP production. Therefore, PA1b improved mitochondrial function, which contributed to re-construction of mammary epithelial cell viability. In conclusion, PA1b alleviates LPS-induced inflammation of bovine mammary epithelial cells via inhibiting NF-κB signaling activation and protects bovine mammary epithelial cells by improving mitochondrial function. PA1b is a good therapeutic survival factor for mammary epithelial cells.

Systematic optimization and evaluation of culture conditions for the construction of circulating tumor cell clusters using breast cancer cell lines.

BACKGROUND: Circulating tumor cell (CTC) clusters play a critical role in carcinoma metastasis. However, the rarity of CTC clusters and the limitations of capture techniques have retarded the research progress. In vitro CTC clusters model can help to further understand the biological properties of CTC clusters and their clinical significance. Therefore, it is necessary to establish reliable in vitro methodological models to form CTC clusters whose biological characteristics are very similar to clinical CTC clusters. METHODS: The assays of immunofluorescence, transmission electron microscopy, EdU incorporation, cell adhension and microfluidic chips were used. The experimental metastasis model in mice was used. RESULTS: We systematically optimized the culture methods to form in vitro CTC clusters model, and more importantly, evaluated it with reference to the biological capabilities of reported clinical CTC clusters. In vitro CTC clusters exhibited a high degree of similarity to the reported pathological characteristics of CTC clusters isolated from patients at different stages of tumor metastasis, including the appearance morphology, size, adhesive and tight junctions-associated proteins, and other indicators of CTC clusters. Furthermore, in vivo experiments also demonstrated that the CTC clusters had an enhanced ability to grow and metastasize compared to single CTC. CONCLUSIONS: The study provides a reliable model to help to obtain comparatively stable and qualified CTC clusters in vitro, propelling the studies on tumor metastasis.

Anaplastic and poorly differentiated thyroid carcinomas: genetic evidence of high-grade transformation from differentiated thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is the most advanced and aggressive thyroid cancer, and poorly differentiated thyroid carcinoma (PDTC) lacks anaplastic histology but has lost architectural and cytologic differentiation. Only a few studies have focused on the genetic relationship between the two advanced carcinomas and coexisting differentiated thyroid carcinomas (DTCs). In the present study, we investigated clinicopathologic features and genetic profiles in 57 ATC and PDTC samples, among which 33 cases had concomitant DTC components or DTC history. We performed immunohistochemistry for BRAF V600E, p53, and PD-L1 expression, Sanger sequencing for TERT promoter and RAS mutations, and fluorescence in situ hybridization for ALK and RET rearrangements. We found that ATCs and PDTCs shared similar gene alterations to their coexisting DTCs, and most DTCs were aggressive subtypes harboring frequent TERT promoter mutations. A significantly higher proportion of ATCs expressed p53 and PD-L1, and a lower proportion expressed PAX-8 and TTF-1, than the coexisting DTCs. Our findings provide more reliable evidence that ATCs and PDTCs are derived from DTCs.

LncRNA MRPL39 inhibits cell proliferation and migration by regulating miR-130/TSC1 axis in non-small cell lung cancer.

Currently, the effect of miR-130 on non-small cell lung cancer (NSCLC) remains controversial. In this study, the expression of miR-130 and lncRNA MRPL39 in tumor and non-tumor tissues of NSCLC patients was examined using real-time PCR (RT-PCR) and correlated with the prognosis of NSCLC. The phenotypic effects of miR-130 and MRPL39 on proliferation and migration of NSCLC cell line A549 cells were assessed through CCK-8 and Transwell assays with miR-130 mimic and MRPL39 (mitochondrial ribosomal protein L39) overexpressed plasmid transfection. StarBase/TargetScan analysis and dual-luciferase reporter gene assays were conducted to investigate the relationship between MRPL39, miR-130, and Tuberculosis sclerosis 1 (TSC1). MiR-130 was overexpressed, and MRPL39 was downregulated in NSCLC tissues and cells. Inhibition of miR-130 expression and overexpression of MRPL39 resulted in the inhibition of the viability and migration of A549 cells. MRPL39 is a potential upstream regulatory long non-coding RNA of miR-130, and its expression is negatively regulated by miR-130. TSC1 was identified as a target of miR-130, suppressing the antitumor effects of FGD5-AS1 silencing on GBM cells. After overexpression of MRPL39, the mRNA and protein levels of TSC1 in A549 cells significantly increased. However, after transfection with miR-130 mimic, the up-regulation of mRNA and protein was inhibited, leading to the suppression of cell proliferation and migration.

A survey of recent methods for addressing AI fairness and bias in biomedicine.

OBJECTIVES: Artificial intelligence (AI) systems have the potential to revolutionize clinical practices, including improving diagnostic accuracy and surgical decision-making, while also reducing costs and manpower. However, it is important to recognize that these systems may perpetuate social inequities or demonstrate biases, such as those based on race or gender. Such biases can occur before, during, or after the development of AI models, making it critical to understand and address potential biases to enable the accurate and reliable application of AI models in clinical settings. To mitigate bias concerns during model development, we surveyed recent publications on different debiasing methods in the fields of biomedical natural language processing (NLP) or computer vision (CV). Then we discussed the methods, such as data perturbation and adversarial learning, that have been applied in the biomedical domain to address bias. METHODS: We performed our literature search on PubMed, ACM digital library, and IEEE Xplore of relevant articles published between January 2018 and December 2023 using multiple combinations of keywords. We then filtered the result of 10,041 articles automatically with loose constraints, and manually inspected the abstracts of the remaining 890 articles to identify the 55 articles included in this review. Additional articles in the references are also included in this review. We discuss each method and compare its strengths and weaknesses. Finally, we review other potential methods from the general domain that could be applied to biomedicine to address bias and improve fairness. RESULTS: The bias of AIs in biomedicine can originate from multiple sources such as insufficient data, sampling bias and the use of health-irrelevant features or race-adjusted algorithms. Existing debiasing methods that focus on algorithms can be categorized into distributional or algorithmic. Distributional methods include data augmentation, data perturbation, data reweighting methods, and federated learning. Algorithmic approaches include unsupervised representation learning, adversarial learning, disentangled representation learning, loss-based methods and causality-based methods.

Artificial Vascular with Pressure-Responsive Property based on Deformable Microfluidic Channels.

In vitro blood vessel models are significant for disease modeling, drug assays, and therapeutic development. Microfluidic technologies allow to create physiologically relevant culture models reproducing the features of the in vivo vascular microenvironment. However, current microfluidic technologies are limited by impractical rectangular cross-sections and single or nonsynchronous compound mechanical stimuli. This study proposes a new strategy for creating round-shaped deformable soft microfluidic channels to serve as artificial in vitro vasculature for developing in vitro models with vascular physio-mechanical microenvironments. Endothelial cells seeded into vascular models are used to assess the effects of a remodeled in vivo mechanical environment. Furthermore, a 3D stenosis model is constructed to recapitulate the flow disturbances in atherosclerosis. Soft microchannels can also be integrated into traditional microfluidics to realize multifunctional composite systems. This technology provides new insights into applying microfluidic chips and a prospective approach for constructing in vitro blood vessel models.

Effects of different temperatures on Leiocassis longirostris gill structure and intestinal microbial composition.

Fish are poikilothermic vertebrates and their physiological activities are affected by water temperature. In recent years, extreme weather has occurred frequently, and temperature changes have adversely affected the growth of farmed fish. To explore the changes in gill tissue structure caused by changing the water temperature and the relationship between the intestinal microbiota and the Leiocassis longirostris host adaptation mechanism, gill tissue sections and intestinal microbial 16S rRNA amplicon sequencing were conducted under different temperature stress (low temperature 4 °C, normal temperature 26 °C and high temperature 32 °C). The results showed that heat stress and cold stress caused injury and swelling, terminal congestion, cell vacuolation, and necrosis of the gill tissue of L. longirostris. For intestinal microbiota, the abundances of Pseudomonadota and Bacillota increased at the cold stress, while the abundances of Fusobacteriota and Bacteroidota increased at the heat stress. The number of opportunistic bacteria, mainly Aeromonas and Acinetobacter, was the highest under cold stress. In addition, the richness of the intestinal microbiota decreased significantly at heat and cold stresses, while evenness increased. Prediction of intestinal microbiota function showed that most common functions, such as metabolism of cofactors and vitamins, energy metabolism and replication and repair, were decreased significantly at heat stress and cold stress, and phylogenetic relationship analysis revealed significant differences among the groups. In conclusion, the change of temperature altered the gill tissue structure, and affected the structure and homeostasis of the intestinal microbiota, thus affecting the survival time of L. longirostris, and cold stress had a greater effect than heat stress.

Novel copy number variations and phenotypes of infantile epileptic spasms syndrome.

We summarize the copy number variations (CNVs) and phenotype spectrum of infantile epileptic spasms syndrome (IESS) in a Chinese cohort. The CNVs were identified by genomic copy number variation sequencing. The CNVs and clinical data were analyzed. 74 IESS children with CNVs were enrolled. 35 kinds of CNVs were identified. There were 11 deletions and 5 duplications not reported previously in IESS, including 2 CNVs not reported in epilepsy. 87.8% were de novo, 9.5% were inherited from mother and 2.7% from father. Mosaicism occurred in one patient with Xq21.31q25 duplication. 16.2% (12/74) were 1p36 deletion, and 20.3% (15/74) were 15q11-q13 duplication. The age of seizure onset ranged from 17 days to 24 months. Seizure types included epileptic spasms, focal seizures, tonic seizures, and myoclonic seizures. All patients displayed developmental delay. Additional features included craniofacial anomaly, microcephaly, congenital heart defects, and hemangioma. 29.7% of patients were seizure-free for more than 12 months, and 70.3% still had seizures after trying 2 or more anti-seizure medications. In conclusion, CNVs is a prominent etiology of IESS. 1p36 deletion and 15q duplication occurred most frequently. CNV detection should be performed in patients with IESS of unknown causes, especially in children with craniofacial anomalies and microcephaly.

Expansion and improvement of ChinaMu by MuT-seq and chromosome-level assembly of the Mu-starter genome.

ChinaMu is the largest sequence-indexed Mutator (Mu) transposon insertional library in maize (Zea mays). In this study, we made significant improvements to the size and quality of the ChinaMu library. We developed a new Mu-tag isolation method Mu-Tn5-seq (MuT-seq). Compared to the previous method used by ChinaMu, MuT-seq recovered 1/3 more germinal insertions, while requiring only about 1/14 of the sequencing volume and 1/5 of the experimental time. Using MuT-seq, we identified 113,879 germinal insertions from 3,168 Mu-active F1 families. We also assembled a high-quality genome for the Mu-active line Mu-starter, which harbors the initial active MuDR element and was used as the pollen donor for the mutation population. Using the Mu-starter genome, we recovered 33,662 (15.6%) additional germinal insertions in 3,244 (7.4%) genes in the Mu-starter line. The Mu-starter genome also improved the assignment of 117,689 (54.5%) germinal insertions. The newly upgraded ChinaMu dataset currently contains 215,889 high-quality germinal insertions. These insertions cover 32,224 pan-genes in the Mu-starter and B73Ref5 genomes, including 23,006 (80.4%) core genes shared by the two genomes. As a test model, we investigated Mu insertions in the pentatricopeptide repeat (PPR) superfamily, discovering insertions for 92% (449/487) of PPR genes in ChinaMu, demonstrating the usefulness of ChinaMu as a functional genomics resource for maize.

Allelic reprogramming of chromatin states in human early embryos.

The reprogramming of parental epigenomes in human early embryos remains elusive. To what extent the characteristics of parental epigenomes are conserved between humans and mice is currently unknown. Here, we mapped parental haploid epigenomes using human parthenogenetic and androgenetic embryos. Human embryos have a larger portion of genome with parentally specific epigenetic states than mouse embryos. The allelic patterns of epigenetic states for orthologous regions are not conserved between humans and mice. Nevertheless, it is conserved that maternal DNA methylation and paternal H3K27me3 are associated with the repression of two alleles in humans and mice. In addition, for DNA-methylation-dependent imprinting, we report 19 novel imprinted genes and their associated germline differentially methylated regions. Unlike in mice, H3K27me3-dependent imprinting is not observed in human early embryos. Collectively, allele-specific epigenomic reprogramming is different in humans and mice.

Characteristics of the Hantaan virus complicated with SARS-CoV2 infection: A case series report.

Background: Coinfection poses a persistent threat to global public health due to its severe effect on individual-level infection risk and disease outcome. Coinfection of SARS-CoV2 with one or more pathogens has been documented. Nevertheless, this virus co-infected with the Hantaan virus (HTNV) is rarely reported. Case summary: Here, we presented three cases of HTNV complicated with SARS-CoV2 infection. Not only the conditions including general clinical manifestations, immune and inflammation parameters fluctuation presented in the single infection of HTNV or SARS-CoV2 can be found, but also the unexpected manifestations have attracted our attention that presented as more symptoms of HTNV infection including exudative changes in both lungs and an amount of bilateral pleural effusion as well as bilateral kidney enlargement rather than typical viral pneumonia in SARS-CoV2 infection. Fortunately, the conditions of patients gradually return to normal which is beneficial from the antiviral treatment, hemodialysis, and various supportive therapies including anti-inflammation, liver and gastric mucosa protection. Conclusion: Unexpected manifestations of coinfection patients present herein may be associated with multiple factors including virus load, competition or antagonism among antigens, and the susceptibility of target cells to the various pathogens, even though the pathogenesis of HTNV and SARS-CoV2 remains to be elucidated. Given that these two viruses have posed a profound influence on the socioeconomic, healthcare system worldwide, and the threat of coinfection to public health, it is warranted for clinicians, public health authorities, and infectious disease researchers to have a high index of consideration for patients co-infected with HTNV and SARS-CoV2.

Pharmacokinetics, Safety, and Tolerability of Tenapanor in Healthy Chinese and Caucasian Volunteers: A Randomized, Open-Label, Single-Center, Placebo-Controlled Phase 1 Study.

Background: Tenapanor is a locally acting selective sodium-hydrogen exchanger 3 inhibitor with the potential to treat sodium/phosphorus and fluid overload in various cardiac-renal diseases, which has been approved for constipation-predominant irritable bowel syndrome in the US. The pharmacokinetics (PK) of tenapanor and its metabolite tenapanor-M1 (AZ13792925), as well as the safety and tolerability of tenapanor, were investigated in healthy Chinese and Caucasian subjects. Methods: This randomized, open-label, single-center, placebo-controlled phase 1 study (https://www.chinadrugtrials.org.cn; CTR20201783) enrolled Chinese and Caucasian healthy volunteers into 4 parallel cohorts (3 cohorts for Chinese subjects, 1 cohort for Caucasian subjects). In each cohort, 15 subjects were expected to be included and received oral tenapanor (10 or 30 mg as single dose, or 50 mg as a single dose followed by a twice-daily repeated dose from Day 5 to 11, with a single dose in the morning on Day 11) or placebo in a 4 : 1 ratio. Results: 59 healthy volunteers received tenapanor 10 mg (n = 12 Chinese), 30 mg (n = 12 Chinese), or 50 mg (n = 12 (Chinese), n = 11 (Caucasian)) or placebo (n = 12, 3 per cohort). After single and twice-daily repeated doses, tenapanor plasma concentrations were all below the limit of quantitation; tenapanor-M1 appeared slowly in plasma. In single-ascending dose evaluation (10 to 50 mg) of Chinese subjects, the mean Cmax, AUC0-t, and AUC0-∞ of tenapanor-M1 increased with increasing dose level, and AUC0-t increased approximately dose proportionally. The Cmax accumulation ratio was 1.55 to 6.92 after 50 mg repeated dose in Chinese and Caucasian subjects. Exposure to tenapanor-M1 was generally similar between the Chinese and Caucasian subjects. Tenapanor was generally well-tolerated and the safety profile was similar between the Chinese and Caucasian participants receiving tenapanor 50 mg, as measured by vital signs, physical and laboratory examination, 12-lead ECG, and adverse events. No serious adverse event or adverse event leading to withdrawal occurred. Conclusion: Tenapanor was well-tolerated, with similar PK and safety profiles between Chinese and Caucasian subjects. This trial is registered with CTR20201783.

Improving Clinical Outcomes: Hightibialosteotomy Plate Placement Combined with Arthroscopic Surgery.

Objective: Our study aimed to investigate the clinical efficacy of hightibialosteotomy (HTO) posterior plate placement combined with arthroscopic surgery for degenerative injury of the posterior horn of the medial meniscus with poor force lines in the lower extremity, improve joint function or relieve pain. Methods: The case data of 98 patients with osteoarthritis of the knee admitted to the Department of Orthopedics in our hospital from January 2019 to January 2023 were selected for retrospective analysis. The patients were divided into 54 patients, each in the study group and the comparison group according to the different treatment regimens. The study group received hightibialosteotomy plate placement combined with arthroscopic surgery, while the comparison group underwent hightibialosteotomy plate placement alone. The differences in knee scores, knee Lysholm scores, Lysholm scores, Healthcare Security and Safety (HSS) scores, Tegner scores, Visual Analog Scale (VAS), lower extremity force lines, femorotibial angles, and tibial plateau were counted and compared between the two groups. Results: HSS knee function scores, Lysholm scores, and VAS scores of the study group were statistically significant compared with those of the comparison group at the final follow-up of patients, and the postoperative clinical outcomes improved significantly (P < .05). The differences in Hip-Knee-Ankle(HKA) angle andMedial-Pateral Tibial Angle (MPTA) of patients in the study group were statistically significant compared with the comparison group, and the increase in HKA (12.31±2.13)°, MPTA (11.84±2.32)° and lower limb force line was significantly improved (P < .05). Preoperatively, there was no statistically significant comparison between the visual analog scores of the knee joint in the study group and the comparison group. After surgery, the difference between the two groups was statistically significant (P < .05). The relative position of the mechanical axis of the lower limb through the tibial plateau, the femorotibial angle, and the posterior tibial plateau angle increased in patients after surgery, and the differences were statistically significant when compared with the preoperative period (P < .05). Both the tibial posterior displacement distance and the lateral knee gap opening were reduced compared with the preoperative period, and the differences were statistically significant (P < .05). Conclusion: Hightibialosteotomy after plate placement combined with arthroscopic surgery has better clinical efficacy in the early stage and can effectively treat the degenerative injury of the posterior horn of the medial meniscus with poor force lines in the lower limb, improve the joint function, and relieve the symptoms of patients.

Ultrahigh Energy Storage Density and Efficiency in Orthorhombic PLZST Antiferroelectric Ceramics via Composition Regulation.

PbZrO3-based antiferroelectric (AFE) ceramic materials have emerged as potential candidates for the next generation of high-energy multilayer ceramic capacitors (MLCCs) because of their distinctive characteristics of double hysteresis loops. The energy storage efficiency of orthorhombic AFE ceramics with ultrahigh storage density is relatively low, which hinders their practical application. In this study, the low efficiency limit of PLZST-based orthorhombic ceramics was overcome by precisely adjusting the Sn4+ content in the (Pb0.95Ca0.02La0.02)(Zr0.99-xSnxTi0.01)O3 AFE ceramics. On one hand, the addition of Sn4+ disrupts the original long-range dipole and improves the rapid response of polarization reversal under the applied voltage. As a result, the difference in electric hysteresis under an electric field is reduced, leading to a significant improvement in energy storage efficiency. On the other hand, increasing the Sn4+ content suppresses the formation of oxygen vacancies, inhibiting grain growth and strengthening grain bonding. This results in ceramics with a high breakdown field strength. Ultimately, the resulting PLCZST ceramics reveal an expressively improved recoverable energy density of 10.2 J cm-3 together with a high energy efficiency of 91.4% under a high applied electric field of 560 kV cm-1. The present study demonstrates the tunability of performance in orthorhombic PLZST AFE ceramics, thereby introducing a ceramic material with exceptional energy storage capabilities for MLCC applications.