Search

Chin-Hsiu Yu,1 Ya-Ai Cheng,2 Ru-Yih Chen,3 Yu-Lung Wu,4 Min-Hsi Lin5 1Department of Information Engineering, I-Shou University, Kaohsiung, Taiwan; 2Department of Healthcare Administration, I-Shou University, Kaohsiung, Taiwan; 3Department of Family Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 4Department of Information Management, I-Shou University, Kaohsiung, Taiwan; 5Division of Chest Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, TaiwanCorrespondence: Ru-Yih Chen Department of Family MedicineKaohsiung Veterans General Hospital, No. 386, Dazhong 1st Road, Zuoying District, Kaohsiung City 813414, Taiwan (R.O.C.)Tel +886-7-346-8236Fax +886-7-342-2288Email louie0812@gmail.comPurpose: To explore whether antineoplastic treatment can improve overall survival (OS) in older patients with metastatic non-small-cell lung cancer (mNSCLC).Patients and Methods: Using the cancer registry database of a tertiary medical center in Taiwan, we followed patients 65 years old and above with pathologically proved mNSCLC. Chi-square test and Cox regression were used to analyze differences in clinical characteristics, the treatments they received, and factors predicting survival. Kaplan–Meier survival analysis was used to analyze OS differences.Results: A total of 542 older patients were diagnosed with mNSCLC from 2011 to 2017. Multivariate Cox regression showed that patients receiving targeted therapy (TT) alone, chemotherapy (CT) alone, and crossover (CO) treatment were at significantly less risk of short OS [hazard ratio (HR) 0.351, 95% confidence interval (CI), 0.257– 0.479; HR 0.517, CI 0.376– 0.711; and HR 0.544, CI 0.373– 0.792, respectively]. Patients at significantly increased risk of short OS were those aged ≥ 85 years and those assigned poorer Eastern Cooperative Oncology Group Performance Status (ECOG-PS) scores (HR 1.513, CI 1.135– 2.017, and HR 2.854, CI 2.188– 3.724, respectively). The result of Kaplan–Meier survival analysis of 418 patients with ECOG-PS scores 0– 2 suggested that patients who received antineoplastic treatments had a significantly better median OS than those receiving supportive care (SC), those receiving TT having the best result (SC, 4.00 months; TT, 21.17 months; CT, 12.83 months; CO, 15.83 months, P< 0.001).Conclusion: Antineoplastic treatments, especially TT, can improve OS for selected older patients with mNSCLC.Keywords: chemotherapy, targeted therapy, crossover treatment, stage IV lung cancer, older patient, survival

OBJECTIVE: To study the effects and possible mechanisms of effective composite of Naodesheng (NDS) on permanent cerebral ischemia-induced injury in rats. METHODS: Male Sprague-Dawley rats: with middle cerebral artery occlusion (MCAO) were established with the modified suture method, and they were randomly divided into the following groups: the sham-operated group, the model group, the Nimodipine group (0.012 g/kg), the NDS group (1.075 g/kg), the total extracts group (0.23 g/kg), the high-dose NEC group (0.07 g/kg), the middle-dose NEC group (0.02 g/kg), and the low-dose NEC group (0.007 g/kg). The aforesaid medicines were administered at the 2nd, 4th, and 24th h after focal cerebral ischemia, and the infarction size and water content in the brain were evaluated at the 26th h after MCAO. Then, after oral administration once daily for 7 successive days, the changes in the degree of neurological deficit, oxidative stress, and apoptosis were measured on the 7th day. RESULTS: NEC could significantly reduce the infarction size after focal cerebral ischemia, and slightly relieve water content in the brain, significantly alleviate neurological function impairment, increase the levels of superoxide dismutase (SOD) and adenosine triphosphate enzyme (ATPase) activity, and decrease the content of malondialdehyde (MDA). NEC could also extenuate Bax and caspase-3 expression in the hippocampus tissue of the ischemic region. As compared with the three NEC treated groups, the high-dose NEC showed better efficacy. CONCLUSIONS: NEC could significantly reduce brain injury induced by ischemia;: its mechanism was closely associated with hindering oxidative stress and apoptosis. The effective composite-guided methodology is a feasible tool to improve the neuro-protective properties of the Chinese medicine guided prescription NDS against focal cerebral ischemia in rats. [ABSTRACT FROM AUTHOR]

The green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), inhibits the development and progression of prostate cancer in TRAMP mice and in men. We examined the effects of EGCG on LNCaP human prostate cancer sublines 104-S, 104-R1 and R1Ad representing different progression stages of prostate cancer. EGCG suppressed cell proliferation, prostate specific antigen (PSA) expression, and AR transcriptional activity in the different LNCaP sublines. Intraperitoneal administration of EGCG also suppressed the growth of relapsing R1Ad tumors and decreased tumor-derived serum PSA. Effects of EGCG on tumor PSA expression have the potential to affect accurate monitoring of patient tumor burden by serum PSA measurements. [ABSTRACT FROM AUTHOR]

Objective: We investigated white sponge nevus (WSN) in a Chinese family, and tried to find new mutation and demonstrated that this mutation is the causative mutation for WSN in this family and this condition affects a functionally important segment of the keratin 4 protein. Materials and methods: We studied the affected family with the 32-year-old female patient, her mother, her younger sister and her daughter. Pathologic examinations were performed. DNA was extracted from peripheral blood lymphocytes, K4 and K13 genes were amplified by polymerase chain reaction (PCR) and sequenced. Results: Direct sequencing of PCR products revealed two new mutations in the keratin 4 gene, the heterozygous missense mutation 1829G→A in exon 2B, and 2324A→G in non-coding region. No any mutation was found in the keratin 13 gene. Conclusions: We found two new mutations in the keratin 4, which may be related with the development of WSN. [ABSTRACT FROM AUTHOR]

Measles is vaccine-preventable extremely contagious disease caused by the measles virus. High vaccination coverage is needed to prevent outbreaks of disease. Although molecular surveillance of measles is critical to characterize outbreaks and track viral evolution, few whole-genome sequences of measles virus from West Africa are available despite continual outbreaks in the region. Using VirCapSeq-VERT, an enhanced and comprehensive metagenomic sequencing technique that allows for simultaneous identification of all vertebrate viruses, 23 wild-type near-complete genomes of measles virus from across Mali were obtained from samples collected between January 2012 to October 2022. Other febrile rash illnesses were also identified by VirCapSeq-VERT, demonstrating the advantage of using broad detection agnostic methods when the clinical diagnosis is unclear. Whereas one measles virus sequence was consistent with measles vaccine-associated rash illness (VARI), the remaining 38 were classified within the B3.1 genotype. Broad surveillance throughout Mali reveals regional measles virus transmission across West and Central Africa into Mali, while local clinical testing in Bamako shows stable sequence conservation within genotype B3.1 evolving from Nigerian sequences. The genomic information generated in this study is critical in addressing the lack of whole genome sequences available in West Africa and these findings show the importance of phylogenetically tracking measles outbreaks given recent increases in measles cases globally., Competing Interests: Declaration of competing interest Any competing interests was declared. All authors read and approved final version., (Copyright © 2024. Published by Elsevier B.V.)

Ethnopharmacological Relevance: According to the theory of traditional Chinese medicine, Graves' disease (GD) is called 'Ying Bing', which is a kind of goiter. Haizao Yuhu decoction, originated from the medical book of the Ming Dynasty 'Waikezhengzong', is a classic Chinese herbal formula for the treatment of 'Ying Bing' for more than 400 years. Pingkang granules, modified from the Chinese herbal formula Haizao Yuhu decoction specialized in GD, has shown effectiveness in several single-centre studies. However, high-quality clinical evidence for the management of GD using Pingkang granules remains insufficient., Aim of the Study: To obtain high-quality medical evidence for the treatment of GD with Pingkang granules through randomized controlled clinical trial., Materials and Methods: A multicentre, randomized, double-blinded, placebo-controlled clinical trial was designed. A total of 186 patients with Graves' hyperthyroidism from five medical centers were randomly assigned to receive methimazole [MMI] and Pingkang granules placebo (group A), MMI and Pingkang granules (group B), or MMI placebo and Pingkang granules (group C) in a 1:1:1 ratio for 12 weeks. The primary clinical outcomes were serum free triiodothyronine (FT 3 ) and free thyroxine (FT 4 ) levels from baseline until the end of the research. Secondary clinical outcomes included serum thyrotrophin receptor antibody (TRAb) levels at 4- and 12-weeks post-intervention, thyroid volume, peak systolic velocity of the superior thyroid artery (STA-PSV), 39-item version of Thyroid-Related Patient-Reported Outcome (ThyPRO39) scores, and safety assessment included blood routine, liver and kidney function tests from baseline to the endpoint., Results: 150 patients were included in the full analysis set for efficacy analysis, including 48, 50, and 52 in groups A, B, and C, respectively. At the endpoint, three regimens significantly reduced serum FT 3 levels (group A, p=0.0027; group B, p < 0.0001; group C, p=0.0028) and FT 4 levels (group A, p < 0.0001; group B, p < 0.0001; group C, p < 0.0001), and the combination of MMI and Pingkang granules markedly reduced serum TRAb levels (p = 0.0014). The thyroid volume in group A was significantly larger than that at baseline at week 12 (p=0.0370), and there were no statistically significant differences in the thyroid volume among groups at week 4 (p=0.7485) and 12 (p=0.1333). STA-PSV values in group B were significantly higher than those in group A at week 4 (p=0.0409). The STA-PSV levels in groups A (p < 0.0001) and C (p=0.0025) were significantly lower than those at baseline at week 4, and STA-PSV levels in all groups were significantly lower than those at baseline at week 12 (group A, p=0.0095; group B, p=0.0138; group C, p=0.0423). Pingkang granule monotherapy significantly ameliorated symptoms related to hyperthyroidism (p < 0.0001), eye (p=0.0490), tiredness (p < 0.0001), cognition (p < 0.0001), depression (p=0.0478), and susceptibility (p=0.0052). No severe adverse events were reported in either group or three regimens showed similar safety., Conclusions: Pingkang granules significantly reduced serum FT 3 , FT 4 and STA-PSV levels, improved ThyPRO39 scores, and lowered serum TRAb levels when combined with MMI in patients with Grave's hyperthyroidism., Competing Interests: Declaration of competing interest This study was supported by the Project of Clinical Center (Traditional Chinese Medicine) of Endocrinology and Metabolism Disease of Shenyang (Grant Number SKF201875), the Traditional Chinese Medicine Clinical Discipline and Specialty Capacity Construction Project of Liaoning Province (Grant Number LNZYXZK201902). All the authors declare no conflicts of interest associated with this research and the study received no financial support that could have influenced its outcomes., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

KDM7A, a histone demethylase implicated in cancer proliferation, metastasis, and drug resistance, represents a crucial therapeutic target. Utilizing "mcule.com" for virtual screening of 100,000 compounds from the ZINC database, we identified 12 compounds with high affinity for KDM7A, with compound 4 emerging as the leading candidate for effectively inhibiting KDM7A's demethylase activity. Analysis of the GTRD database, the Breast Cancer Gene Expression Miner website, and recent studies highlighted MKRN1, a gene associated with cell proliferation and drug resistance, as a key intersecting factor. Compared to 2,4-pyridine dicarboxylic acid, compound 4 significantly reduced breast cancer stem cells and induced G1 phase cell cycle arrest. Mechanistically, compound 4 inhibited KDM7A's binding to H3K27me3, decreased MKRN1 transcription, and increased the levels of cell cycle regulators p16, p21, and p27, while reducing stem cell markers ALDH1A1, CD44, and CD133. These findings suggest that compound 4 could serve as a promising lead for selective KDM7A-targeting drugs. Additionally, this study is the first to demonstrate MKRN1 as a downstream gene of KDM7A, showing significant inhibitory effects in both taxol-resistant and drug-sensitive triple-negative breast cancer (TNBC) cells. This research offers new insights into the anticancer mechanisms of KDM7A inhibitors and underscores KDM7A's potential as a therapeutic target against TNBC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Environmental enteric dysfunction (EED), a small intestinal disorder found at a high prevalence in stunted children, is associated with gut mucosal barrier disruption and decreased absorptive capacity due to reduced intact small intestinal villi 1-4 . To test the hypothesis that intergenerational transmission of a perturbed small intestinal microbiota contributes to undernutrition by inducing EED 5 , we characterized two consortia of bacterial strains cultured from duodenal aspirates from stunted Bangladeshi children with EED - one of which induced local and systemic inflammation in gnotobiotic female mice. Offspring of dams that received this inflammatory consortium exhibited immunologic changes along their gut that phenocopied features of EED in children. Single nucleus plus bulk RNA-sequencing revealed alterations in inter-cellular signaling pathways related to intestinal epithelial cell renewal, barrier integrity and immune function while analyses of cerebral cortex disclosed alterations in glial- and endothelial-neuronal signaling pathways that regulate neural growth/axonal guidance, angiogenesis and inflammation. Analysis of ultrasonic vocalization calls in gnotobiotic P5-P9 pups indicated increased arousal and perturbed neurodevelopment in the offspring of dams harboring the inflammation-inducing consortium. Cohousing experiments and follow-up screening of candidate disease-promoting bacterial isolates identified a strain typically found in the oral microbiota ( Campylobacter concisus ) as a contributor to enteropathy. Given that fetal growth was also impaired in the dams with the consortium that induced enteropathy, this preclinical model allows the effects of the human small intestinal microbiota on both pre- and postnatal development to be ascertained, setting the stage for identification of small intestinal microbiota-targeted therapeutics for (intergenerational) undernutrition., Competing Interests: Competing Interests - D.R. and A.O. are co-founders of Phenobiome Inc., a company pursuing development of computational tools for predictive phenotype profiling of microbial communities.

The escalating obesity epidemic and aging population have propelled metabolic dysfunction-associated steatohepatitis (MASH) to the forefront of public health concerns. The activation of FXR shows promise to combat MASH and its detrimental consequences. However, the specific alterations within the MASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse MASH samples, we identified central perturbations within the MASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and open-source human datasets, we determined that hepatic FXR activation effectively ameliorated MASH by reversing the dysregulated metabolic and inflammatory networks implicated in MASH pathogenesis. This mitigation encompassed resolving fibrosis and reducing immune infiltration. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of MASH at a transcriptional level and highlights the complex interplay between FXR activation and both MASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Purpose: As they are effective and well tolerated, aminopenicillins are still the cornerstone for the treatment of enterococcal infections. Current treatment guidelines for infective endocarditis (IE) recommend combination treatments, which carry a higher risk of adverse effects and are based on limited in vitro and experimental data. The aim of this study was therefore to evaluate the treatments of enterococcal IE in real-life practice., Methods: A total of 4121 episodes of enterococcal bloodstream infections, occurring between 1994 and 2019, were screened for the evidence of IE. Baseline characteristics, risk factors for complicated infections and treatment information were assessed and analyzed using Cox regression analysis., Results: Overall, 80 (3.9%) IE episodes were identified of which 78 were included in the final analysis. Treatment regimens in our cohort comprised aminopenicillin-monotherapy (n = 20), teicoplanin-monotherapy (n = 26), other monotherapies (OMT) (n = 8), as well as combinations of ampicillin plus daptomycin (n = 8), ampicillin plus gentamicin (n = 4) or other combinations (n = 9). Overall mortality at 28-days was low (9 of 75) and increased to (19 of 75) after 6-months. Frequency of moderate to severe valve regurgitation (p = 0.89), or signs of uncontrolled infection (p = 0.5) and vegetation size ≥ 10 mm (p = 0.11) were similar in the treatment groups. None of the treatment groups was associated with increased hazard for IE-related mortality., Conclusions: This retrospective study complements previous evidence, demonstrating that monotherapy regimens may be a suitable and effective option for the treatment of IE and supports the need for a prospective evaluation of aminopenicillin-monotherapy for initial and subsequent therapy in these patients., (© 2024. The Author(s).)

Introduction: The course of maternal antiviral prophylaxis to prevent mother-to-child transmission of hepatitis B virus (HBV-MTCT) varies greatly, and it has not been demonstrated in a randomized controlled study., Methods: In this multicenter, open-label, randomized controlled trial, eligible pregnant women with HBV DNA of 5.3-9.0 log 10 IU/mL who received tenofovir alafenamide fumarate (TAF) from the first day of 33 gestational weeks to delivery (expected 8 week) or to 4 weeks postpartum (expected 12 week) were randomly enrolled at a 1:1 ratio and followed until 6 months postpartum. All infants received standard immunoprophylaxis (hepatitis B immunoglobulin and vaccine). The primary end point was the safety of mothers and infants. The secondary end point was the HBV-MTCT rate of infants at the age of 7 months., Results: Among 119 and 120 intention-to-treat pregnant women, 115 and 116 women were followed until delivery, and 110 and 112 per-protocol mother-infant dyads in 2 groups completed the study. Overall, TAF was well tolerated, no one discontinued the therapy due to adverse events (0/239, 0%, 95% confidence interval [CI] 0%-1.6%), and no infant had congenital defects or malformations at delivery (0/231, 0%, 95% CI 0%-1.6%). The infants' physical development at birth (n = 231) and at 7 months (n = 222) was normal. Furthermore, 97.0% (224/231, 95% CI 93.9%-98.5%) of women achieved HBV DNA <5.3 log 10 IU/mL at delivery. The intention-to-treat and per-protocol infants' HBV-MTCT rates were 7.1% (17/239, 95% CI 4.5%-11.1%) and 0% (0/222, 95% CI 0%-1.7%) at the age of 7 months. Comparatively, 15.1% (18/119, 95% CI 9.8%-22.7%) vs 18.3% (22/120, 95% CI 12.4%-26.2%) of women in the 2 groups had mildly elevated alanine aminotransferase levels at 3 months and 6 months postpartum, respectively ( P = 0.507); notably, no one experienced alanine aminotransferase flare (0% [0/119, 95% CI 0%-3.1%] vs 0% [0/120, 0%-3.1%])., Discussion: Maternal TAF prophylaxis to prevent HBV-MTCT is generally safe and effective, and expected 8-week prenatal duration is feasible. ClinicalTrials.gov , NCT04850950., (Copyright © 2024 by The American College of Gastroenterology.)

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high mortality and drug resistance and no targeted drug available at present. Compound 4 , a staurosporine alkaloid derived from Streptomyces sp. NBU3142 in a marine sponge, exhibits potent anti-TNBC activity. This research investigated its impact on MDA-MB-231 cells and their drug-resistant variants. The findings highlighted that compound 4 inhibits breast cancer cell migration, induces apoptosis, arrests the cell cycle, and promotes cellular senescence in both regular and paclitaxel-resistant MDA-MB-231 cells. Additionally, this study identified mitogen-activated protein kinase kinase kinase 11 (MAP3K11) as a target of compound 4 , implicating its role in breast tumorigenesis by affecting cell proliferation, migration, and cell cycle progression.

Globally, severe acute malnutrition (SAM), defined as a weight-for-length z -score more than three SDs below a reference mean (WLZ < -3), affects 14 million children under 5 years of age. Complete anthropometric recovery after standard, short-term interventions is rare, with children often left with moderate acute malnutrition (MAM; WLZ -2 to -3). We conducted a randomized controlled trial (RCT) involving 12- to 18-month-old Bangladeshi children from urban and rural sites, who, after initial hospital-based treatment for SAM, received a 3-month intervention with a microbiome-directed complementary food (MDCF-2) or a calorically more dense, standard ready-to-use supplementary food (RUSF). The rate of WLZ improvement was significantly greater in MDCF-2-treated children ( P = 8.73 × 10 -3 ), similar to our previous RCT of Bangladeshi children with MAM without antecedent SAM ( P = 0.032). A correlated meta-analysis of plasma levels of 4520 proteins in both RCTs revealed 215 positively associated with WLZ (largely representing musculoskeletal and central nervous system development) and 44 negatively associated (primarily related to immune activation). Moreover, the positively associated proteins were significantly enriched by MDCF-2 ( q = 1.1 × 10 -6 ). Characterizing the abundances of 754 bacterial metagenome-assembled genomes in serially collected fecal samples disclosed the effects of acute rehabilitation for SAM on the microbiome and how, during treatment for MAM, specific strains of Prevotella copri function at the intersection between MDCF-2 glycan metabolism and anthropometric recovery. These results provide a rationale for further testing the generalizability of MDCF efficacy and for identifying biomarkers to define treatment responses.

Background: Cervical spinal cord injury usually results in cardiorespiratory dysfunctions due to interruptions of the bulbospinal pathways innervating the cervical phrenic motoneurons and thoracic sympathetic preganglionic neurons., Purpose: The present study aimed to evaluate the therapeutic effects of adrenergic agents on systemic and spinal hemodynamics during acute cervical spinal cord injury., Study Design: In vivo animal study., Methods: The cardiorespiratory function and spinal cord blood flow and oxygenation level were monitored in response to cervical spinal cord contusion and intravenous infusion of three types of adrenergic agents (phenylephrine, dobutamine, and norepinephrine)., Results: Cervical spinal cord contusion resulted in immediate reduction of respiratory airflow, arterial blood pressure, and spinal cord blood flow. The arterial blood pressure and spinal cord blood flow remained lower than the preinjury value in contused animals infused with saline at 60 min postinjury. Infusion of phenylephrine (500, 1000, and 2000 μg/kg) and norepinephrine (125, 250, and 500 μg/kg) significantly increased the arterial blood pressure, while only norepinephrine augmented the spinal cord blood flow. Conversely, dobutamine (1000 and 2000 μg/kg) reduced both arterial blood pressure and spinal cord blood flow. Notably, administration of adrenergic agents tended to increase spinal cord hemorrhage in contused animals., Conclusions: Infusion of norepinephrine can effectively maintain the blood pressure and improve spinal cord blood flow during acute spinal cord injury., Clinical Significance: Norepinephrine may be a superior medicine for hemodynamic management; however, the potential hemorrhage should be considered when utilizing the vasopressor to regulate systemic and spinal hemodynamics at the acute injured stage., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Systemic viral infection of insects typically begins with the primary infection of midgut epithelial cells (enterocytes) and subsequent transit of the progeny virus in an apical-to-basal orientation into the hemocoel. For insect-vectored viruses, an oppositely oriented process (basal-to-apical transit) occurs upon secondary infection of salivary glands and is necessary for virus transmission to non-insect hosts. To examine this inversely oriented virus transit in these polarized tissues, we assessed the intracellular trafficking of two model viral envelope proteins (baculovirus GP64 and vesicular stomatitis virus G) in the midgut and salivary gland cells of the model insect, Drosophila melanogaster . Using fly lines that inducibly express either GP64 or VSV G, we found that each protein, expressed alone, was trafficked basally in midgut enterocytes. In salivary gland cells, VSV G was trafficked apically in most but not all cells, whereas GP64 was consistently trafficked basally. We demonstrated that a YxxØ motif present in both proteins was critical for basal trafficking in midgut enterocytes but dispensable for trafficking in salivary gland cells. Using RNAi, we found that clathrin adaptor protein complexes AP-1 and AP-3, as well as seven Rab GTPases, were involved in polarized VSV G trafficking in midgut enterocytes. Our results indicate that these viral envelope proteins encode the requisite information and require no other viral factors for appropriately polarized trafficking. In addition, they exploit tissue-specific differences in protein trafficking pathways to facilitate virus egress in the appropriate orientation for establishing systemic infections and vectoring infection to other hosts., Importance: Viruses that use insects as hosts must navigate specific routes through different insect tissues to complete their life cycles. The routes may differ substantially depending on the life cycle of the virus. Both insect pathogenic viruses and insect-vectored viruses must navigate through the polarized cells of the midgut epithelium to establish a systemic infection. In addition, insect-vectored viruses must also navigate through the polarized salivary gland epithelium for transmission. Thus, insect-vectored viruses appear to traffic in opposite directions in these two tissues. In this study, we asked whether two viral envelope proteins (VSV G and baculovirus GP64) alone encode the signals necessary for the polarized trafficking associated with their respective life cycles. Using Drosophila as a model to examine tissue-specific polarized trafficking of these viral envelope proteins, we identified one of the virus-encoded signals and several host proteins associated with regulating the polarized trafficking in the midgut epithelium., Competing Interests: The authors declare no conflict of interest.

Jumonji domain-containing protein D3 (JMJD3) is a 2-oxoglutarate-dependent dioxygenase that specifically removes transcriptional repression marks di- and tri-methylated groups from lysine 27 on histone 3 (H3K27me2/3). The erasure of these marks leads to the activation of some associated genes, thereby influencing various biological processes, such as development, differentiation, and immune response. However, comprehensive descriptions regarding the relationship between JMJD3 and inflammation are lacking. Here, we provide a comprehensive overview of JMJD3, including its structure, functions, and involvement in inflammatory pathways. In addition, we summarize the evidence supporting JMJD3's role in several inflammatory diseases, as well as the potential therapeutic applications of JMJD3 inhibitors. Additionally, we also discuss the challenges and opportunities associated with investigating the functions of JMJD3 and developing targeted inhibitors and propose feasible solutions to provide valuable insights into the functional exploration and discovery of potential drugs targeting JMJD3 for inflammatory diseases., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 The Author(s).)

While certain members of ubiquitin-coupled enzymes (E2s) have garnered attention as potential therapeutic targets across diverse diseases, research progress on Ubiquitin-Conjugating Enzyme 5 (UBC5)-a pivotal member of the E2s family involved in crucial cellular processes such as apoptosis, DNA repair, and signal transduction-has been relatively sluggish. Previous findings suggest that UBC5 plays a vital role in the ubiquitination of various target proteins implicated in diseases and homeostasis, particularly in various cancer types. This review comprehensively introduces the structure and biological functions of UBC5, with a specific focus on its contributions to the onset and advancement of diverse diseases. It suggests that targeting UBC5 holds promise as a therapeutic approach for disease therapy. Recent discoveries highlighting the high homology between UBC5, UBC1, and UBC4 have provided insight into the mechanism of UBC5 in protein degradation and the regulation of cellular functions. As our comprehension of the structural distinctions among UBC5 and its homologues, namely UBC1 and UBC4, advances, our understanding of UBC5's functional significance also expands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Superior mesenteric artery syndrome (SMAS) is a rare condition, for which laparoscopic surgery was successfully performed safely and with long-term efficacy., Methods: This single center retrospective clinical study comprised 66 patients with SMAS, surgically treated between January 2010 and January 2020, who were allocated to three different surgical groups according to their medical history and symptoms (Laparoscopic duodenojejunostomy, n  = 35; Gastrojejunostomy, n  = 16; Duodenojejunostomy plus gastrojejunostomy, n  = 15). Patient demographics, surgical data and postoperative outcomes were retrieved from the medical records., Results: All operations were successfully completed laparoscopically, and with a median follow-up of 65 months, the overall symptom score was significantly reduced from 32 to 8 ( p  < 0.0001) and the BMI was increased from 17.2 kg/m 2 to 21.8 kg/m 2 ( p  < 0.0001)., Conclusions: When conservative measures failed in the treatment of SMAS, laparoscopic surgery proved to be a safe and effective method. The specific surgical technique was selected according to the history and symptoms of each individual patient. To our knowledge, this study represents the largest number of laparoscopic procedures at a single center for the treatment of superior mesenteric artery syndrome.

Background and Aims: Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α., Methods: In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m 2 , subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored., Results: As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment., Conclusions: TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB., (© 2024. The Author(s).)

Two novel rod-shaped, strictly aerobic, non-motile and Gram-stain-negative bacterial strains, designated SDUM040013 T and SDUM040014 T , were isolated from kelp seedlings in Weihai, PR China. Cells of strain SDUM040013 T were 0.3-0.4 µm wide and 0.8-1.8 µm long, catalase-positive and oxidase-positive. Growth of SDUM040013 T was observed at 0-37 °C (optimum, 28-30 °C) and pH 5.5-9 (optimum, pH 8.0) and in the presence of 1-8 % (w/v) NaCl (optimum, 2 %). The DNA G+C content of strain SDUM040013 T was 50.5 %. Strain SDUM040013 T showed the highest 16S rRNA gene sequence similarity (97.1 %) to Gilvimarinus chinensis . Cells of strain SDUM040014 T were 0.4-0.5 µm wide and 1.0-1.4 µm long, catalase-positive and oxidase-positive. Growth of SDUM040014 T was observed at 4-40 °C (optimum, 28-30 °C) and pH 5.5-9 (optimum, pH 8.5) and in the presence of 0-8 % (w/v) NaCl (optimum, 2 %). The DNA G+C content of strain SDUM040014 T was 56.5 %. Strain SDUM040014 T showed the highest 16S rRNA gene sequence similarity (96.2%) to Gilvimarinus polysaccharolyticus . The isoprenoid quinone of both strains was Q-8 and the predominant fatty acids were summed feature 3 (C 16 : 1  ω 7 c and/or C 16 : 1  ω 6 c ), summed feature 8 (C 18 : 1  ω 7 c ) and C 16 : 0 . Diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine were the major polar lipids. Given these phenotypic and chemotaxonomic properties, as well as phylogenetic data, strains SDUM040013 T and SDUM040014 T were considered to represent two novel species of the genus Gilvimarinus , for which the names Gilvimarinus gilvus sp. nov. and Gilvimarinus algae sp. nov. are proposed. The type strains are SDUM040013 T (=KCTC 8123 T =MCCC 1H01413 T ) and SDUM040014 T (=KCTC 8124 T =MCCC 1H01414 T ), respectively.

Introduction: Data on the management of patients aged more than 85 years with chronic hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequential infections are lacking., Methods: The current study described the management of an older couple aged more than 85 years with these above-mentioned two diseases treated with 12 weeks of sofosbuvir/velpatasvir (Epclusa ® ) and 5 days of nirmatrelvir/ritonavir (Paxlovid ® ) sequentially. The effectiveness and safety profiles were closely monitored during therapy and till 9 months posttreatment., Results: In late March 2023, the husband with the main complaint of repeated gingival bleeding and asymptomatic wife were 86 and 85 years old, and had HCV RNA levels of 91,800 and 6,630,000 IU/mL, respectively. On the fourth day of sofosbuvir/velpatasvir treatment, the husband had a moderate headache, and the wife had severe headache and moderate fever and dizziness. We then found that their SARS-CoV-2 test results were positive. After careful consideration, the expert panel decided to treat the couple with oral nirmatrelvir/ritonavir (300 mg/100 mg, twice daily) beginning on the fifth day of sofosbuvir/velpatasvir treatment for 5 days. During the 5 days of nirmatrelvir/ritonavir treatment, the patient's symptoms and signs gradually improved, and the patient was negative for SARS-CoV-2 RNA on the fifth day of nirmatrelvir/ritonavir therapy. Meanwhile, the husband's HCV RNA was not detectable after one week of sofosbuvir/velpatasvir treatment till posttreatment month 9, and his ALT level was normal beginning at week 1 of sofosbuvir/velpatasvir treatment. Moreover, the wife's HCV RNA was not detectable after week 4 of sofosbuvir/velpatasvir treatment till posttreatment month 9. Notably, no other symptoms or signs occurred during the treatment or follow-up period, and other serum biochemical parameters remained stable until 9 months after the discontinuation of sofosbuvir/velpatasvir treatment., Conclusion: The older couple aged more than 85 years with chronic HCV and SARS-CoV-2 sequential infection were safely cured by the sofosbuvir/velpatasvir and nirmatrelvir/ritonavir sequential treatment., Discussion: This study suggested that old age should not be a barrier to HCV/SARS-CoV-2 treatment. Given that the proportion of older HCV-infected patients is increasing, clinical trials of direct-acting antiviral agents should include older HCV-infected individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zeng, Lv, Chen and Pan.)

Atmospheric nitrogen (N) deposition could affect the structure and function of terrestrial plants. Non-N 2 -fixing lichens are used to monitor atmospheric N deposition because they rely on the deposited inorganic N ( i.e ., ammonium and nitrate) as N sources. However, the uptake capacities of lichen on ammonium and nitrate remain unclear, which hinders the application of lichen N content to accurate bioindication of atmospheric N deposition levels. We investigated ammonium and nitrate uptake capacities of Cladonia rangiferina , which was treated with ammonium alone, nitrate alone, and ammonium and nitrate mixture solutions with different mixing ratios under light and dark conditions. The results showed that N uptake rates increased with ammonium and nitrate concentrations in solutions and generally followed the Michaelis-Menten saturation kinetics. Ammonium uptake of C. rangiferina showed higher values of affinity, and was more efficient than the nitrate uptake. Both rates and amounts of nitrate uptake decreased with increasing ratios of ammonium to nitrate in solutions, while ammonium uptake showed no substantial variations, indicating an inhibition of ammonium on nitrate uptake capability. The darkness significantly decreased the maximum uptake rate and efficiency of nitrate, but had much weaker effects on lichen ammonium uptake. These findings highlight the preference of lichen on ammonium as a key N uptake strategy. It is thus necessary to consider the main types of atmospheric inorganic N deposition when using lichens to monitor atmospheric N pollution levels and evaluate N deposition based on lichen ecophysiology.

Environmental enteric dysfunction (EED) is a subclinical syndrome of altered small intestinal function postulated to be an important contributor to childhood undernutrition. The role of small intestinal bacterial communities in the pathophysiology of EED is poorly defined due to a paucity of studies where there has been a direct collection of small intestinal samples from undernourished children. Sixty-three members of a Pakistani cohort identified as being acutely malnourished between 3 and 6 months of age and whose wasting (weight-for-length Z -score [WLZ]) failed to improve after a 2-month nutritional intervention underwent esophagogastroduodenoscopy (EGD). Paired duodenal luminal aspirates and duodenal mucosal biopsies were obtained from 43 children. Duodenal microbiota composition was characterized by sequencing bacterial 16S rRNA gene amplicons. Levels of bacterial taxa (amplicon sequence variants [ASVs]) were referenced to anthropometric indices, histopathologic severity in biopsies, expression of selected genes in the duodenal mucosa, and fecal levels of an immunoinflammatory biomarker (lipocalin-2). A "core" group of eight bacterial ASVs was present in the duodenal samples of 69% of participants. Streptococcus anginosus was the most prevalent, followed by Streptococcus sp., Gemella haemolysans , Streptococcus australis , Granulicatella elegans , Granulicatella adiacens, and Abiotrophia defectiva . At the time of EGD, none of the core taxa were significantly correlated with WLZ. Statistically significant correlations were documented between the abundances of Granulicatella elegans and Granulicatella adiacens and the expression of duodenal mucosal genes involved in immune responses (dual oxidase maturation factor 2, serum amyloid A, and granzyme H). These results suggest that a potential role for members of the oral microbiota in pathogenesis, notably Streptococcus , Gemella, and Granulicatella species, warrants further investigation.IMPORTANCEUndernutrition among women and children is a pressing global health problem. Environmental enteric dysfunction (EED) is a disease of the small intestine (SI) associated with impaired gut mucosal barrier function and reduced capacity for nutrient absorption. The cause of EED is ill-defined. One emerging hypothesis is that alterations in the SI microbiota contribute to EED. We performed a culture-independent analysis of the SI microbiota of a cohort of Pakistani children with undernutrition who had failed a standard nutritional intervention, underwent upper gastrointestinal tract endoscopy, and had histologic evidence of EED in their duodenal mucosal biopsies. The results revealed a shared group of bacterial taxa in their duodenums whose absolute abundances were correlated with levels of the expression of genes in the duodenal mucosa that are involved in inflammatory responses. A number of these bacterial taxa are more typically found in the oral microbiota, a finding that has potential physiologic and therapeutic implications., Competing Interests: The authors declare no conflict of interest.

Licorice ( Glycyrrhiza glabra ) is a plant of the genus Glycyrrhiza in the family Fabaceae / Leguminosae and is a renowned natural herb with a long history of medicinal use dating back to ancient times. Glycyrrhizin (GLY), the main active component of licorice, serves as a widely utilized therapeutic agent in clinical practice. GLY exhibits diverse medicinal properties, including anti-inflammatory, antibacterial, antiviral, antitumor, immunomodulatory, intestinal environment maintenance, and liver protection effects. However, current research primarily emphasizes GLY's antiviral activity, while providing limited insight into its antibacterial properties. GLY demonstrates a broad spectrum of antibacterial activity via inhibiting the growth of bacteria by targeting bacterial enzymes, impacting cell membrane formation, and altering membrane permeability. Moreover, GLY can also bolster host immunity by activating pertinent immune pathways, thereby enhancing pathogen clearance. This paper reviews GLY's inhibitory mechanisms against various pathogenic bacteria-induced pathological changes, its role as a high-mobility group box 1 inhibitor in immune regulation, and its efficacy in combating diseases caused by pathogenic bacteria. Furthermore, combining GLY with other antibiotics reduces the minimum inhibitory concentration, potentially aiding in the clinical development of combination therapies against drug-resistant bacteria. Sources of information were searched using PubMed, Web of Science, Science Direct, and GreenMedical for the keywords "licorice", "Glycyrrhizin", "antibacterial", "anti-inflammatory", "HMGB1", and combinations thereof, mainly from articles published from 1979 to 2024, with no language restrictions. Screening was carried out by one author and supplemented by others. Papers with experimental flaws in their experimental design and papers that did not meet expectations (antifungal papers, etc.) were excluded.

Background: RNA interference (RNAi) is the sequence-dependent suppression of gene expression by double-stranded RNA (dsRNA). This is a promising strategy for the control of insect pests because dsRNA can be rationally designed to maximize efficacy and biosafety, the latter by using sequences that are found in target pests but are safe for non-target insects. However, this has yet to be optimized in aphids, destructive sap-sucking pests that also transmit plant viruses. We used the green peach aphid (Myzus persicae) as a case study to optimize the efficiency of RNAi by applying a novel fusion dsRNA design., Results: Comparative transcriptomics revealed a number of genes that are induced in feeding aphids, and eight candidate genes were chosen as RNAi targets. To improve RNAi efficiency, our fusion dsRNA design approach combined optimal gene fragments (highly conserved in several aphid species but with less homology in beneficial insects such as the predator ladybeetle Propylea japonica) from three candidate genes. We compared this RNAi-based biological control approach with conventional chemical control using imidacloprid. We found that the fusion dsRNA strategy inhibited the aphid population to a significantly greater extent than single-target RNAi and did not affect ladybeetle fitness, allowing an additive effect between RNAi and natural predation, whereas imidacloprid was harmful to aphids and ladybeetles., Conclusion: Our fusion dsRNA design approach enhances the ability of RNAi to control aphids without harming natural predators. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Although certain members of the Ubiquitin-specific peptidases (USPs) have been recognized as promising therapeutic targets for various diseases, research progress regarding USP21 has been relatively sluggish in its early stages. USP21 is a crucial member of the USPs subfamily, involved in diverse cellular processes such as apoptosis, DNA repair, and signal transduction. Research findings from the past decade demonstrate that USP21 mediates the deubiquitination of multiple well-known target proteins associated with critical cellular processes relevant to both disease and homeostasis, particularly in various cancers.This reviewcomprehensively summarizes the structure and biological functions of USP21 with an emphasis on its role in tumorigenesis, and elucidates the advances on the discovery of tens of small-molecule inhibitors targeting USP21, which suggests that targeting USP21 may represent a potential strategy for cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Mutations in progranulin ( GRN ) cause frontotemporal dementia ( GRN -FTD) due to deficiency of the pleiotropic protein progranulin. GRN -FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN -FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn -/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn -/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.

Several brainstem nuclei degenerate in Parkinson's disease (PD). In addition to the well-characterized dopaminergic neurons of the substantia nigra pars compacta (SNc), the cholinergic neurons of the pedunculopontine nucleus (PPN) also degenerate in PD. One leading hypothesis of selective vulnerability is that pacemaking activity and the activation of low-threshold L-type calcium current are major contributors to tonic calcium load and cellular stress in SNc dopaminergic neurons. However, it is not yet clear whether the vulnerable PPN cholinergic neurons share this property. Therefore, we used two-photon dendritic calcium imaging and whole-cell electrophysiology to evaluate the role of L-type calcium channels in tonic and phasic dendritic calcium signals in PPN and SNc neurons. In addition, we investigated N- and P/Q-type calcium channel regulation of firing properties and dendritic calcium in PPN neurons. We found that blocking L-type channels reduces tonic firing rate and dendritic calcium levels in SNc neurons. By contrast, the tonic calcium load in PPN neurons did not depend on L-, N- or P/Q-type channels. However, we found that blocking either L-type (with nifedipine) or N- and P/Q-type (with omega-conotoxin MVIIC) channels reduces phasic calcium influx in PPN dendrites. Together, these findings show that L-type calcium channels play different roles in the activity of SNc and PPN neurons, and suggest that low-threshold L-type channels are not responsible for tonic calcium levels in PPN cholinergic neurons and are therefore not likely to be a source of selective vulnerability in these cells., (© 2024 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Microbiota-directed complementary food (MDCF) formulations have been designed to repair the gut communities of malnourished children. A randomized controlled trial demonstrated that one formulation, MDCF-2, improved weight gain in malnourished Bangladeshi children compared to a more calorically dense standard nutritional intervention. Metagenome-assembled genomes from study participants revealed a correlation between ponderal growth and expression of MDCF-2 glycan utilization pathways by Prevotella copri strains. To test this correlation, here we use gnotobiotic mice colonized with defined consortia of age- and ponderal growth-associated gut bacterial strains, with or without P. copri isolates closely matching the metagenome-assembled genomes. Combining gut metagenomics and metatranscriptomics with host single-nucleus RNA sequencing and gut metabolomic analyses, we identify a key role of P. copri in metabolizing MDCF-2 glycans and uncover its interactions with other microbes including Bifidobacterium infantis. P. copri-containing consortia mediated weight gain and modulated energy metabolism within intestinal epithelial cells. Our results reveal structure-function relationships between MDCF-2 and members of the gut microbiota of malnourished children with potential implications for future therapies., (© 2024. The Author(s).)

Guaico Culex virus (GCXV) is a newly identified segmented Jingmenvirus from Culex spp. mosquitoes in Central and South America. The genome of GCXV is composed of four or five single-stranded positive RNA segments. However, the infection kinetics and transmission capability of GCXV in mosquitoes remain unknown. In this study, we used reverse genetics to rescue two GCXVs (4S and 5S) that contained four and five RNA segments, respectively, in C6/36 ​cells. Further in vitro characterization revealed that the two GCXVs exhibited comparable replication kinetics, protein expression and viral titers. Importantly, GCXV RNAs were detected in the bodies, salivary glands, midguts and ovaries of Culex quinquefasciatus at 4-10 days after oral infection. In addition, two GCXVs can colonize Cx. quinquefasciatus eggs, resulting in positive rates of 15%-35% for the second gonotrophic cycle. In conclusion, our results demonstrated that GCXVs with four or five RNA segments can be detected in Cx. quinquefasciatus eggs during the first and second gonotrophic cycles after oral infection., Competing Interests: Conflict of interest Prof. Cheng-Feng Qin is an Editorial Board member for Virologica Sinica and was not involved in the editorial review or the decision to publish this article. All the authors declare no competing interests., (Copyright © 2024 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

The Orthopoxvirus genus, especially variola virus (VARV), monkeypox virus (MPXV), remains a significant public health threat worldwide. The development of therapeutic antibodies against orthopoxviruses is largely hampered by the high cost of antibody engineering and manufacturing processes. mRNA-encoded antibodies have emerged as a powerful and universal platform for rapid antibody production. Herein, by using the established lipid nanoparticle (LNP)-encapsulated mRNA platform, we constructed four mRNA combinations that encode monoclonal antibodies with broad neutralization activities against orthopoxviruses. In vivo characterization demonstrated that a single intravenous injection of each LNP-encapsulated mRNA antibody in mice resulted in the rapid production of neutralizing antibodies. More importantly, mRNA antibody treatments showed significant protection from weight loss and mortality in the vaccinia virus (VACV) lethal challenge mouse model, and a unique mRNA antibody cocktail, Mix2a, exhibited superior in vivo protection by targeting both intracellular mature virus (IMV)-form and extracellular enveloped virus (EEV)-form viruses. In summary, our results demonstrate the proof-of-concept production of orthopoxvirus antibodies via the LNP-mRNA platform, highlighting the great potential of tailored mRNA antibody combinations as a universal strategy to combat orthopoxvirus as well as other emerging viruses., (© 2024. The Author(s).)

Background: Children with unilateral cerebral palsy (UCP) are encouraged to participate in the regular school curriculum. However, even when using the less-affected hand for handwriting, children with UCP still experience handwriting difficulties. Visual-motor integration (VMI) is a predictor of handwriting quality. Investigating VMI in children with UCP is important but still lacking. Conventional paper-based VMI assessments is subjective and use all-or-nothing scoring procedures, which may compromise the fidelity of VMI assessments. Moreover, identifying important shapes that are predictive of VMI performance might benefit clinical decision-making because different geometric shapes represent different developmental stepping stones of VMI. Therefore, a new computer-aided measure of VMI (the CAM-VMI) was developed to investigate VMI performance in children with UCP and to identify shapes important for predicting their VMI performance., Methods: Twenty-eight children with UCP and 28 typically-developing (TD) children were recruited. All participants were instructed to complete the CAM-VMI and Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI). The test items of the CAM-VMI consisted of nine simple geometric shapes related to writing readiness. Two scores of the CAM-VMI, namely, Error and Effort, were obtained by image registration technique. The performances on the Beery-VMI and the CAM-VMI of children with UCP and TD children were compared by independent t-test. A series of stepwise regression analyses were used to identify shapes important for predicting VMI performance in children with UCP., Results: Significant group differences were found in both the CAM-VMI and the Beery-VMI results. Furthermore, Error was identified as a significant aspect for predicting VMI performance in children with UCP. Specifically, the square item was the only significant predictor of VMI performance in children with UCP., Conclusions: This study was a large-scale study that provided direct evidence of impaired VMI in school-aged children with UCP. Even when using the less-affected hand, children with UCP could not copy the geometric shapes as well as TD children did. The copied products of children with UCP demonstrated poor constructional accuracy and inappropriate alignment. Furthermore, the predictive model suggested that the constructional accuracy of a copied square is an important predictor of VMI performance in children with UCP., (© 2024. The Author(s).)

RNA-binding proteins (RBPs) are kinds of proteins with either singular or multiple RNA-binding domains (RBDs), and they can assembly into ribonucleic acid-protein complexes, which mediate transportation, editing, splicing, stabilization, translational efficiency, or epigenetic modifications of their binding RNA partners, and thereby modulate various physiological and pathological processes. CUG-BP, Elav-like family 1 (CELF1) is a member of the CELF family of RBPs with high affinity to the GU-rich elements in mRNA, and thus exerting control over critical processes including mRNA splicing, translation, and decay. Mounting studies support that CELF1 is correlated with occurrence, genesis and development and represents a potential therapeutical target for these malignant diseases. Herein, we present the structure and function of CELF1, outline its role and regulatory mechanisms in varieties of homeostasis and diseases, summarize the identified CELF1 regulators and their structure-activity relationships, and prospect the current challenges and their solutions during studies on CELF1 functions and corresponding drug discovery, which will facilitate the establishment of a targeted regulatory network for CELF1 in diseases and advance CELF1 as a potential drug target for disease therapy., (© 2024. The Author(s).)

Four new iridoid glycosides ( 1 - 4 ), rehmaglutosides L-O, were isolated from the air-dried roots of Rehmannia glutinosa . Their structures were established from the spectroscopic data obtained and by chemical evidence. The known mellittoside ( 5 ) and ajugol ( 6 ) were also obtained in the current investigation, and the structure of mellittoside was unequivocally defined using X-ray diffraction data. Compounds 1 - 6 were tested for their cytotoxicity against five human tumor cell lines and proliferation effects on Lactobacillus Reuteri .