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Tuan Dinh Le,1,* Nga Thi Phi Nguyen,2,3,* Son Tien Nguyen,2,3 Hoa Thi Thanh Tran,4 Lan Thi Ho Nguyen,4 Hoang Huy Duong ,1 Ha Manh Nguyen ,4 Binh Nhu Do5,* 1Department of Internal Medicine, Thai Binh University of Medicine and Pharmacy, Thai Binh, Vietnam; 2Department of Endocrinology, Military Hospital 103, Ha Noi, Vietnam; 3Department of Rheumatology and Endocrinology, Vietnam Military Medical University, Ha Noi, Vietnam; 4The National Endocrinology Hospital, Ha Noi, Vietnam; 5Division of Military Science, Military Hospital 103, Ha Noi, Vietnam*These authors contributed equally to this workCorrespondence: Nga Thi Phi Nguyen; Binh Nhu Do Email ngabv103@yahoo.com.vn; nhubinh.do@vmmu.edu.vnIntroduction: To investigate effects of Sitagliptin on the enhancement of beta-cell function, reducing insulin resistance, serum glucagon like peptide-1 (GLP-1) concentrations and blood glucose in patients with type 2 diabetes mellitus (T2D) and suggest one of the underlying mechanisms on beta-cell function and insulin resistance.Patients and Methods: This was a cross-sectional and observational study in comparison to the control group. A study population of 44 newly diagnosed patients with T2D treated with Sitagliptin with a dose of 100 mg/day for 3 months was analyzed to compare 52 healthy participants. Indices for beta-cell function, peripheral insulin sensitivity, and insulin resistance were calculated with homeostasis model assessment 2 (HOMA2) calculator and compared. Serum GLP-1 concentrations were analyzed, and regression analysis was conducted to find the correlations between GLP-1 and beta-cell function and insulin resistance.Results: Newly diagnosed patients with T2D witnessed a significant reduction in beta-cell function, serum GLP-1 concentrations at the time of diagnosis. After treatment with Sitagliptin 100 mg/day, they achieved significant improvements in beta-cell function, peripheral insulin sensitivity and insulin resistance. Serum GLP-1 concentrations were increased significantly to those levels in the control group and correlated with peripheral insulin sensitivity and insulin resistance in patients whose beta-cell functions improved.Conclusion: Sitagliptin improved beta-cell function, insulin resistance and blood glucose in newly diagnosed patients with T2D. Meanwhile, Sitagliptin ameliorated serum GLP-1 concentrations, which contributed to the enhancement of beta-cell.Keywords: Sitagliptin, serum GLP-1 concentrations, beta-cell function, insulin resistance, newly diagnosed patients with type 2 diabetes mellitus

Inhibitors of voltage-gated sodium channels (Nav) have been used as anticonvulsants since the 1940s, while potassium channel activators have only been investigated more recently. We here describe the discovery of 2-amino-6-trifluoromethylthio-benzothiazole (SKA-19), a thioanalog of riluzole, as a potent, novel anticonvulsant, which combines the two mechanisms. SKA-19 is a use-dependent NaV channel blocker and an activator of small-conductance Ca2+-activated K+ channels. SKA-19 reduces action potential firing and increases medium afterhyperpolarization in CA1 pyramidal neurons in hippocampal slices. SKA-19 is orally bioavailable and shows activity in a broad range of rodent seizure models. SKA-19 protects against maximal electroshock-induced seizures in both rats (ED50 1.6 mg/kg i.p.; 2.3 mg/kg p.o.) and mice (ED50 4.3 mg/kg p.o.), and is also effective in the 6-Hz model in mice (ED50 12.2 mg/kg), Frings audiogenic seizure-susceptible mice (ED50 2.2 mg/kg), and the hippocampal kindled rat model of complex partial seizures (ED50 5.5 mg/kg). Toxicity tests for abnormal neurological status revealed a therapeutic index (TD50/ED50) of 6–9 following intraperitoneal and of 33 following oral administration. SKA-19 further reduced acute pain in the formalin pain model and raised allodynic threshold in a sciatic nerve ligation model. The anticonvulsant profile of SKA-19 is comparable to riluzole, which similarly affects NaV and KCa2 channels, except that SKA-19 has a ~4-fold greater duration of action owing to more prolonged brain levels. Based on these findings we propose that compounds combining KCa2 channel-activating and Nav channel-blocking activity exert broad-spectrum anticonvulsant and analgesic effects.

Hien Minh Nguyen,1 Minh Quang Dao2 1Department of Biochemistry, Thanh Nhan Hospital, Hanoi, Vietnam; 2Department of Oncology, Thanh Nhan Hospital, Hanoi, Vietnam Background: Detecting circulating tumor cells (CTCs) is a promising approach for evaluating the progression of occult metastases as well as the efficacy of treatment therapies among patients with breast cancer. A real-time reverse transcriptase polymerase chain reaction (RT-PCR) technique has been proposed for detecting CTCs due to its high sensitivity. In this study, we aimed to validate the RT-PCR technique for human mammaglobin (hMAM) mRNA detection among Vietnamese women with breast cancer. Patients and methods: Peripheral blood samples and breast cancer tissues from 43 patients suffering from breast cancer and 21 patients with fibroids were obtained. Real-time RT-PCR and gene sequencing techniques were employed to detect hMAM gene in CTCs of breast cancer cell lines and cancer tissues. Results: hMAM mRNA transcription was detected in 36 out of 43 (83.7%) breast cancer tissues and in blood of 23 out of 43 (53.5%) breast cancer patients, while it was detected in only 9.5% out of tissues and 0% of the blood of fibrosis patients. hMAM mRNA in the peripheral blood of breast cancer patients increased with tumor size, stage of cancer and distant metastasis (P0.05). Conclusion: The study highlighted the expression of hMAM mRNA in breast cancer cells and tissues. This reveals the overall picture of the replication of hMAM mRNA in breast cancer, suggesting the role of hMAM mRNA in breast cancer molecular pathology. Keywords: human mammaglobin mRNA, hMAM mRNA, breast cancer, circulating tumor cell, CTC, women, Vietnam

Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors., Competing Interests: Competing interests statement:E.C. received research funding under institutional SRA from Janssen Research and Development, Bayer Pharmaceuticals, KronosBio, Forma Pharmaceutics Foghorn, Gilead, Sanofi, AbbVie, MacrogGenics, Astra Zeneca, GSK, and K36. B.E.G., A.K.O., S.T., W.D.F., and J.S. are co-inventors on a patent covering this technology (WO2021150603A1). P.S.N. receives personal fees from Janssen, Bristol Myers Squibb, Pfizer, and Merck and grants from Janssen. The other authors declare no competing interests.

Non-resolving, chronic inflammation (inflammaging) is believed to play an important role in aging and age-related diseases. The goal of this study was to determine if inflammation induced by necroptosis arising from the liver plays a role in chronic liver disease (CLD) and liver cancer in mice fed a western diet (WD). Necroptosis was induced in liver using two knockin (KI) mouse models that overexpress genes involved in necroptosis (Ripk3 or Mlkl) specifically in liver (i.e., hRipk3-KI and hMlkl-KI mice). These mice and control mice (not overexpressing Ripk3 or Mlkl) were fed a WD (high in fat, sucrose, and cholesterol) starting at 2 months of age for 3, 6, and 12 months. Feeding the WD induced necroptosis in the control mice, which was further elevated in the hRipk3-KI and hMlkl-KI mice and was associated with a significant increase in inflammation in the livers of the hRipk3-KI and hMlkl-KI mice compared to control mice fed the WD. Overexpressing Ripk3 or Mlkl significantly increased steatosis and fibrosis compared to control mice fed the WD. Mice fed the WD for 12 months developed liver tumors (hepatocellular adenomas): 28% of the control mice developing tumors compared to 62% of the hRipk3-KI and hMlkl-KI mice. The hRipk3-KI and hMlkl-KI mice showed significantly more and larger tumor nodules. Our study provides the first direct evidence that inflammation induced by necroptosis arising from hepatocytes can lead to the progression of hepatic steatosis to fibrosis in obese mice that eventually results in an increased incidence in hepatocellular adenomas., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: This report presents a rare case of a dentigerous cyst (DC) associated with the maxillary right canine in a young child, successfully treated with marsupialization followed by enucleation., Presentation of Case: A 9-year-old girl was referred to a maxillofacial hospital after routine dental exam revealed a large lesion in maxilla. Radiograph showed a 5 × 6 cm unilocular radiolucent lesion in the right maxillary sinus, with destruction of the sinus and nasal cavity walls and displacement of the upper right canine into the floor of the right eye. Marsupialization was performed, and the patient was monitored every 6 months. Histology confirmed a dentigerous cyst lined with non-keratinized stratified cuboidal squamous epithelium. One-year post-surgery, the cyst had significantly reduced in size, and the canine had descended. A second surgery was performed to completely remove the cyst and the associated canine., Discussion: This case demonstrates the successful management of a large dentigerous cyst in a 9-year-old patient through staged treatment, initially with marsupialization, followed by complete cyst removal. The conservative approach allowed for the reduction of the cyst size and facilitated the natural descent of the displaced canine. Regular follow-up and timely surgical intervention were crucial in achieving a positive outcome and preventing recurrence., Conclusion: This case highlights the effectiveness of marsupialization in managing maxillary dentigerous cysts in young children., Competing Interests: Declaration of competing interest We declare there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Assessing disease progression among patients with uncontrolled hypertension is important for identifying opportunities for intervention., Objective: We aim to develop and validate 2 models, one to predict sustained, uncontrolled hypertension (≥2 blood pressure [BP] readings ≥140/90 mm Hg or ≥1 BP reading ≥180/120 mm Hg) and one to predict hypertensive crisis (≥1 BP reading ≥180/120 mm Hg) within 1 year of an index visit (outpatient or ambulatory encounter in which an uncontrolled BP reading was recorded)., Methods: Data from 142,897 patients with uncontrolled hypertension within Atrium Health Greater Charlotte in 2018 were used. Electronic health record-based predictors were based on the 1-year period before a patient's index visit. The dataset was randomly split (80:20) into a training set and a validation set. In total, 4 machine learning frameworks were considered: L2-regularized logistic regression, multilayer perceptron, gradient boosting machines, and random forest. Model selection was performed with 10-fold cross-validation. The final models were assessed on discrimination (C-statistic), calibration (eg, integrated calibration index), and net benefit (with decision curve analysis). Additionally, internal-external cross-validation was performed at the county level to assess performance with new populations and summarized using random-effect meta-analyses., Results: In internal validation, the C-statistic and integrated calibration index were 0.72 (95% CI 0.71-0.72) and 0.015 (95% CI 0.012-0.020) for the sustained, uncontrolled hypertension model, and 0.81 (95% CI 0.79-0.82) and 0.009 (95% CI 0.007-0.011) for the hypertensive crisis model. The models had higher net benefit than the default policies (ie, treat-all and treat-none) across different decision thresholds. In internal-external cross-validation, the pooled performance was consistent with internal validation results; in particular, the pooled C-statistics were 0.70 (95% CI 0.69-0.71) and 0.79 (95% CI 0.78-0.81) for the sustained, uncontrolled hypertension model and hypertensive crisis model, respectively., Conclusions: An electronic health record-based model predicted hypertensive crisis reasonably well in internal and internal-external validations. The model can potentially be used to support population health surveillance and hypertension management. Further studies are needed to improve the ability to predict sustained, uncontrolled hypertension., (© Hieu Minh Nguyen, William Anderson, Shih-Hsiung Chou, Andrew McWilliams, Jing Zhao, Nicholas Pajewski, Yhenneko Taylor. Originally published in JMIR Medical Informatics (https://medinform.jmir.org).)

Background: Diabetes is one of the leading causes of noncommunicable diseases worldwide. It is known to induce cardiovascular remodeling, which can result in a variety of complications, including a considerable increase in aortic stiffness. While studies in Western populations have explored these effects, data on Asians, mainly Vietnamese, are limited. This study aimed to assess aortic elasticity in type 2 diabetes mellitus (T2DM) patients compared to healthy individuals., Methods: This quantitative, cross-sectional study compared aortic elasticity indices between individuals with T2DM and healthy controls in Vietnam. Aortic elasticity indices were assessed for all participants using M-mode echocardiography., Results: A comparison between the healthy and T2DM groups revealed substantial differences in aortic elasticity indices. The aortic stiffness index (ASI) was significantly greater in the T2DM group than in the control group, with median values of 6.10 (3.64-12.47) and 3.79 (2.40-8.50), respectively (p = 0.003). Aortic strain (AS) was substantially lower in the T2DM group than in the control group, with median values of 8.21% (4.24-13.07) and 10.66% (6.01-18.23), respectively (p = 0.039). Furthermore, the median aortic compliance (AC, 10-2mm/mmHg) and aortic distensibility (AD, 10-3mmHg-1) in individuals with T2DM were 4.07 (2.28-7.44) and 3.08 (1.57-5.26), respectively, lower than those in the control group, with median values of 6.40 (3.08-10.75) and 5.33 (2.80-9.79). A longer diabetes duration was linked to a greater ASI (r = 0.43, p < 0.05), while the AS decreased (r = -0.37, p < 0.05)., Conclusions: Substantial variations in aorta elasticity indices were found in patients with T2DM using M-mode echocardiography. These differences highlight the impact of T2DM on vascular health. More research is needed to investigate the consequences of these discrepancies and their significance for clinical purposes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lung cancer stands out as a leading cause of death among various cancer types, highlighting the urgent need for effective anticancer drugs and the discovery of new compounds with potent therapeutic properties. Natural sources, such as the Conamomum genus, offer various bioactive compounds. Adunctin E (AE), a dihydrochalcone derived from Conamomum rubidum , exhibited several pharmacological activities, and its potential as an anticancer agent remains largely unexplored. Thus, this study aimed to elucidate its apoptotic-inducing effect and identify its molecular targets. The network pharmacology analysis led to the identification of 71 potential targets of AE against lung cancer. Subsequent gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway enrichment analyses revealed the involvement of these targets in cancer-associated signaling pathways. Notably, HSP90AA1, MAPK1, and PIK3CA emerged as key players in apoptosis. In silico molecular docking and dynamic simulations suggested a strong and stable interaction between AE and HSP90AA1. In vitro experiments further confirmed a significant apoptotic-inducing effect of AE on lung cancer cell lines A549 and H460. Furthermore, immunoblot analysis exhibited a substantial decrease in HSP90AA1 levels in response to AE treatment. These findings support the potential anticancer activity of AE through the HSP90AA1 mechanism, underscoring its promise as a novel compound worthy of further research and development for anti-lung cancer therapy.

Background: Xuan Lien Nature Reserve was established in 1999 to protect important habitats and wildlife in the northern part of the Annamites in Vietnam. While Xuan Lien is home to many threatened species, it has experienced a high level of human disturbance over the last decades. To document and provide baseline data on the status and distribution of the terrestrial vertebrate fauna community in the region, we conducted a systematic camera trapping survey in Xuan Lien Nature Reserve in 2023. The data collected during the survey will help design proper conservation measures to better conserve the remaining species., New Information: Our study investigates and updates the species richness of mid- to large-sized terrestrial vertebrates, thus providing essential information for developing conservation strategies in Xuan Lien Nature Reserve, Vietnam. As camera traps were set up in a grid-based design, our survey also generated the first-ever systematic data for terrestrial vertebrate fauna in the area. The study covers approximately 21,000 hectares (about 77% of the area), using 35 camera trap stations; each station consists of two cameras. In total, the final dataset consists of 6,276 trap nights, recording at least 46 species in 39 genera. The results suggest that Xuan Lien is a key stronghold for small carnivores, based on the diversity of such species groups in the Reserve. We failed to detect the previously documented Roosevelt's muntjac ( Muntiacusrooseveltorum Osgood, 1932) and we only documented a single record of the northern red muntjac ( Muntiacusvaginalis Boddaert, 1785). Our survey confirms the severity of overhunting and other anthropogenic threats to the mammal fauna, especially ungulates, in the Reserve., (Thanh Van Nguyen, Anh The Luu, Hung Viet Pham, Ha Manh Nguyen, Tam Anh Pham, Mai Thi Nguyen, Minh Duc Le, Anh Tuan Nguyen.)

Background: Afatinib, a second-generation epidermal growth factor receptor(EGFR) tyrosine kinase, has proven effective for non-small-cell lung cancer (NSCLC) patients with EGFR mutations through randomized controlled trials and real-world studies. Elderly patients exhibit unique characteristics in terms of physical condition and comorbidities, leading to differences in clinical practice for selecting the initial dosage and making dose adjustments compared to younger patients. This study aims to evaluate the effectiveness and adverse effects of first-line Afatinib treatment in elderly patients with NSCLC harboring EGFR mutations in Vietnam in a real-world context., Methods: We conducted a retrospective analysis of 135 patients, aged 65 years and older, across nine cancer centers in Vietnam. These patients, who harbored drug-sensitive EGFR mutations (excluding de novo T790M), received first-line Afatinib treatment between April 2018 and June 2022. The primary endpoints, time to treatment failure (TTF), and overall survival (OS) were assessed using the Kaplan-Meier method, and comparisons were conducted using the log-rank test. Secondary endpoints included the overall response rate (ORR) according to RECIST 1.1 and adverse effects as classified by CTCAE 4.0., Results: The median age was 71.2 years (SD ± 5.3). Comorbidities included cardiovascular disease (20.7%), diabetes (5.2%), chronic obstructive pulmonary disease (2.2%), and hepatitis B (0.7%). Common mutations constituted 71.9% of cases, with uncommon mutations representing 28.1%. Brain metastases were observed in 24.4% of patients. Initial treatment doses were 40 mg for 35.6% of patients and 30 mg for 62.2%. With a median follow-up of 34.3 months, the median TTF was 16.3 months (95% CI: 15.4-19.5), and the median OS was 32.9 months (95% CI: 28.9-37.5). Factors associated with decreased OS included poor performance status, current smoking, and the presence of uncommon mutations. The ORR was 77.8%, with a complete response of 11.1% and a disease control rate of 94.1%. The most common toxicities were dermatologic and mucosal, including diarrhea (55.6%), rash (48.9%), and stomatitis (40.7%), predominantly in grades 1 and 2. Initiating treatment at doses below 40 mg significantly reduced most toxicities compared to the 40 mg dose. The presence of brain metastases did not significantly affect ORR, TTF, or OS. Starting treatment at doses below 40 mg significantly lowered the response rate but did not impact TTF or OS., Conclusion: First-line treatment with Afatinib in elderly patients with NSCLC and EGFR mutations demonstrates significant efficacy and manageable toxicity in a Vietnamese multicenter real-life setting. The effectiveness of Afatinib was confirmed, with known and well-controlled adverse effects, supporting its use in this patient population.

This study effectively fabricated photocatalytic membranes (∼5 cm diameter) assembled by γ-AlOOH-PVA (BOP) decorated heterostructural ZIF-67/AgCl/Ag composites by combing seeded secondary growth and photoreduction methods. First, the ZIF-67-seeded BOP membrane was shaped in a petri dish, followed by submerging in a 2-methylimidazole ligand for secondary growth to obtain the BOP/ZIF-67 membrane. Next, AgCl/Ag was formulated on the membrane by dipping it in an AgNO 3 solution, followed by a photoreduction under visible LED light, resulting in a BOP/ZIF/AgCl/Ag membrane. The characterization showed that the membrane contained heterostructures of ZIF-67/AgCl/Ag anchored onto the BOP membrane. The BOP/ZIF/AgCl/Ag composite membranes exhibited enhanced light absorption and appeared the localized surface plasmon resonance (LSPR) of Ag 0 , giving it a bandgap energy of ∼2.10 eV. Photodegradation under visible LED light irradiation showed that the BOP/ZIF/AgCl/Ag membrane efficiently removed tetracycline (TC) and Rhodamine B dye (RhB) with corresponding degradation efficiency of ∼99% (90 min) and ∼95% (140 min), giving reaction rates of ∼0.046 min -1 and 0.019 min -1 , respectively. The photocatalytic mechanism and photodegradation pathways analyses provided insights into the degradations of organic pollutants. Significantly, the designed BOP/ZIF/AgCl/Ag membrane quickly recovered from the solution and was of good durability. The study provided an effective strategy for constructing heterostructural ZIF-67/AgCl/Ag composite membranes, which are efficient and eco-friendly photocatalyst materials., 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 Ltd. All rights reserved.)

Background: An association between driving pressure (∆P) and the outcomes of invasive mechanical ventilation (IMV) may exist. However, the effect of a sustained limitation of ∆P on mortality in patients with acute respiratory distress syndrome (ARDS), including patients with COVID-19 (COVID-19-related acute respiratory distress syndrome (C-ARDS)) undergoing IMV, has not been rigorously evaluated. The use of emulations of a target trial in intensive care unit research remains in its infancy. To inform future, large ARDS target trials, we explored using a target trial emulation approach to analyse data from a cohort of IMV adults with C-ARDS to determine whether maintaining daily ∆p<15 cm H 2 O (in addition to traditional low tidal volume ventilation (LTVV) (tidal volume 5-7 cc/PBW+plateau pressure (P plat ) ≤30 cm H 2 O), compared with LTVV alone, affects the 28-day mortality., Methods: To emulate a target trial, adults with C-ARDS requiring >24 hours of IMV were considered to be assigned to limited ∆P or LTVV. Lung mechanics were measured twice daily after ventilator setting adjustments were made. To evaluate the effect of each lung-protective ventilation (LPV) strategy on the 28-day mortality, we fit a stabilised inverse probability weighted marginal structural model that adjusted for baseline and time-varying confounders known to affect protection strategy use/adherence or survival., Results: Among the 92 patients included, 27 (29.3%) followed limited ∆P ventilation, 23 (25.0%) the LTVV strategy and 42 (45.7%) received no LPV strategy. The adjusted estimated 28-day survival was 47.0% (95% CI 23%, 76%) in the limited ∆P group, 70.3% in the LTVV group (95% CI 37.6%, 100%) and 37.6% (95% CI 20.8%, 58.0%) in the no LPV strategy group., Interpretation: Limiting ∆P may not provide additional survival benefits for patients with C-ARDS over LTVV. Our results help inform the development of future target trial emulations focused on evaluating LPV strategies, including reduced ∆P, in adults with ARDS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of this paper is to identify some of the characteristics of innovation and collective work in different fablab organizations. We first define fablabs through a review of literature, situating related questions in the field of ergonomics and focusing our point of view on individual and collective activity. Secondly, we show how the results of our qualitative analyses (performed on data from interviews and observations of fablab managers, users, and projects from 13 fablabs) reveal 3 main types of fablab organization: community-oriented fablabs, academic fablabs and industrial fablabs, in which different activities are carried out. Fablab activity depends on lab users and the type of design projects carried out. The discussion will focus on the fablab organization findings, including the links between design/innovation project work, collective work and evolving rules, and how all of these aspects might direct activity-centered ergonomics research and actions in the future., 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 Ltd. All rights reserved.)

In response to the escalating antibiotic resistance in multidrug-resistant pathogens, we propose an innovative phagemid-based capsid system to generate CRISPR-Cas13a-loaded antibacterial capsids (AB-capsids) for targeted therapy against multidrug-resistant Staphylococcus aureus. Our optimized phagemid system maximizes AB-capsid yield and purity, showing a positive correlation with phagemid copy number. Notably, an 8.65-fold increase in copy number results in a 2.54-fold rise in AB-capsid generation. Phagemids carrying terL-terS-rinA-rinB (prophage-encoded packaging site genes) consistently exhibit high packaging efficiency, and the generation of AB-capsids using lysogenized hosts with terL-terS deletion resulted in comparatively lower level of wild-type phage contamination, with minimal compromise on AB-capsid yield. These generated AB-capsids selectively eliminate S. aureus strains carrying the target gene while sparing non-target strains. In conclusion, our phagemid-based capsid system stands as a promising avenue for developing sequence-specific bactericidal agents, offering a streamlined approach to combat antibiotic-resistant pathogens within the constraints of efficient production and targeted efficacy., (© 2024. The Author(s).)

Phage therapy, the use of bacteriophages (phages) to treat bacterial infections, is regaining momentum as a promising weapon against the rising threat of multidrug-resistant (MDR) bacteria. This comprehensive review explores the historical context, the modern resurgence of phage therapy, and phage-facilitated advancements in medical and technological fields. It details the mechanisms of action and applications of phages in treating MDR bacterial infections, particularly those associated with biofilms and intracellular pathogens. The review further highlights innovative uses of phages in vaccine development, cancer therapy, and as gene delivery vectors. Despite its targeted and efficient approach, phage therapy faces challenges related to phage stability, immune response, and regulatory approval. By examining these areas in detail, this review underscores the immense potential and remaining hurdles in integrating phage-based therapies into modern medical practices.

Structure-based virtual screening is a key tool in early drug discovery, with growing interest in the screening of multi-billion chemical compound libraries. However, the success of virtual screening crucially depends on the accuracy of the binding pose and binding affinity predicted by computational docking. Here we develop a highly accurate structure-based virtual screen method, RosettaVS, for predicting docking poses and binding affinities. Our approach outperforms other state-of-the-art methods on a wide range of benchmarks, partially due to our ability to model receptor flexibility. We incorporate this into a new open-source artificial intelligence accelerated virtual screening platform for drug discovery. Using this platform, we screen multi-billion compound libraries against two unrelated targets, a ubiquitin ligase target KLHDC2 and the human voltage-gated sodium channel Na V 1.7. For both targets, we discover hit compounds, including seven hits (14% hit rate) to KLHDC2 and four hits (44% hit rate) to Na V 1.7, all with single digit micromolar binding affinities. Screening in both cases is completed in less than seven days. Finally, a high resolution X-ray crystallographic structure validates the predicted docking pose for the KLHDC2 ligand complex, demonstrating the effectiveness of our method in lead discovery., (© 2024. The Author(s).)

We investigate hydrogen sorption on open copper sites in various ligand coordinations of metal-organic frameworks (MOFs), including the triangular T(CuL 3 ) in MFU-4l, the linear L(CuL 2 ) in NU2100, and the paddlewheel P(CuL 4 ) 2 in HKUST-1 from an electronic structure perspective using DFT calculations. The ligand-field-induced splitting of d states and spd hybridizations in copper are thoroughly examined. The hybridization between Cu s, p, and d orbitals occurs in various forms to optimize the Coulomb repulsion of different ligand fields. Despite the Cu + oxidation state, which is typically conducive to strong Kubas interactions with hydrogen molecules, the vacant spd z 2 hybrid orbitals of the open copper site in the L(CuL 2 ) coordination are unsuitable for facilitating electron forward donation, thereby preventing effective hydrogen adsorption. In contrast, the vacant spd z 2 hybrid orbitals in the T(CuL 3 ) and P(CuL 4 ) 2 coordinations can engage in electron forward donations, forming bonding states between the Cu spd z 2 and H 2 σ bonding orbitals. The forward donation in the T(CuL 3 ) configuration is significantly stronger than in the P(CuL 4 ) 2 configuration due to both the lower energy of the vacant orbitals and the larger contributions of p and d z 2 characters to the hybrid orbital. Additionally, the occupied Cu pd xz / yz and pd x 2 - y 2 hybrid orbitals in the T(CuL 3 ) configuration promote electron back donation to the H 2 σ* antibonding orbital, leading to the formation of π bonding states. In the P(CuL 4 ) 2 coordination, the repulsion from the electron density distributed over the surrounding ligands prevents the H 2 molecule from approaching the copper center closely enough for the back donation to occur. The complete Kubas interaction, involving both forward and back electron donations, results in a large dihydrogen-copper binding energy of 37.6 kJ mol -1 in the T(CuL 3 ) coordination. In contrast, the binding energy of 10.6 kJ mol -1 in the P(CuL 4 ) 2 coordination is primarily driven by electrostatic interactions with a minor contribution of the Kubas-like forward donation interaction. This analysis highlights the pivotal role of coordination environments in determining the hydrogen sorption properties of MOFs., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Nature-based solutions (NBS) have been promoted as a holistic way to solve a variety of societal issues while benefiting biodiversity at the same time. To date, applications of NBS approaches that help ensure food security have yet been systematically reviewed. In this paper, we critically review the specific NBS for food security, highlighting their limitations, to provide recommendations that promote their applications for improving global food security. We accessed and evaluated publications on four different scholastic databases, and our systematic review of relevant materials indicated that many NBS approaches can be applied to enhance food security dimensions individually or together. However, there is a strong bias towards food availability, and not enough research has been done to link NBS with improvements in food access and utilization. Over 80 % of the reviewed papers were of short-term studies or without specific timeframes, and 25 % offered no information on the economic effectiveness of NBS. Environmental benefits of NBS were explicitly described in about 60 % of these papers, and biodiversity enhancement was measured in only about 10 %. We, therefore, recommend future applications of NBS to safeguard food security be shifted to food access and utilization with careful consultation with local communities to address their specific context, using indicators that are easily measured and managed. Systematic monitoring regimes and robust and diversified financial support systems are also equally important in efforts to successfully implement NBS. Moreover, environmental and societal benefits, especially water productivity and biodiversity, must be incorporated into the planning and design of NBS., Competing Interests: 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 article., (© 2024 The Authors. Published by Elsevier Ltd.)

Microglia are resident immune cells of the brain and regulate its inflammatory state. In neurodegenerative diseases, microglia transition from a homeostatic state to a state referred to as disease-associated microglia (DAM). DAM express higher levels of proinflammatory signaling molecules, like STAT1 and TLR2, and show transitions in mitochondrial activity toward a more glycolytic response. Inhibition of Kv1.3 decreases the proinflammatory signature of DAM, though how Kv1.3 influences the response is unknown. Our goal was to identify the potential proteins interacting with Kv1.3 during transition to DAM. We utilized TurboID, a biotin ligase, fused to Kv1.3 to evaluate potential interacting proteins with Kv1.3 via mass spectrometry in BV-2 microglia following TLR4-mediated activation. Electrophysiology, Western blotting, and flow cytometry were used to evaluate Kv1.3 channel presence and TurboID biotinylation activity. We hypothesized that Kv1.3 contains domain-specific interactors that vary during a TLR4-induced inflammatory response, some of which are dependent on the PDZ-binding domain on the C terminus. We determined that the N terminus of Kv1.3 is responsible for trafficking Kv1.3 to the cell surface and mitochondria (e.g., NUDC, TIMM50). Whereas, the C terminus interacts with immune signaling proteins in a lipopolysaccharide-induced inflammatory response (e.g., STAT1, TLR2, and C3). There are 70 proteins that rely on the C-terminal PDZ-binding domain to interact with Kv1.3 (e.g., ND3, Snx3, and Sun1). Furthermore, we used Kv1.3 blockade to verify functional coupling between Kv1.3 and interferon-mediated STAT1 activation. Overall, we highlight that the Kv1.3 potassium channel functions beyond conducting the outward flux of potassium ions in an inflammatory context and that Kv1.3 modulates the activity of key immune signaling proteins, such as STAT1 and C3., Competing Interests: Conflict of interest H. W. is an inventor on a University of California patent claiming PAP-1 for immunosuppression. This patent has been abandoned because of its short remaining patent life. The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) is becoming a growing public health concern. Diagnostic tests for determining the severity of HF often come with high costs and require specialized expertise, which makes it difficult to assess HF severity, especially in low-income countries or at primary healthcare facilities. Recently, red blood cell distribution width (RDW) has emerged as a promising, easily accessible marker associated with HF severity. The study aimed to assess changes in RDW levels in HF patients and the diagnostic value of RDW in detecting acute heart failure (AHF) among HF patients., Methods: We conducted a cross-sectional examination involving 351 participants divided into HF and non-HF cohorts. HF was defined and categorized according to the diagnostic and treatment guidelines for AHF and chronic heart failure (CHF) set forth by the European Society of Cardiology (2021). Univariate and multivariate analysis of factors associated with AHF was performed., Results: The study revealed that HF patients displayed higher median RDW levels (14.90% [13.70-17.00]) compared to non-HF individuals (13.00% [12.23-13.78]). RDW was notably elevated in HF patients with left ventricular ejection fraction < 50% compared to those with left ventricular ejection fraction ≥ 50%. ROC curve analysis of RDW for AHF detection identified a cutoff value of 13.85%, with a sensitivity of 86.05% and specificity of 47.18%, statistically significant at p < 0.001. RDW > 13.85% was identified as an independent risk factor for AHF in patients with HF, with odds ratios of 2.644 (95% CI, 1.190-5.875; p = 0.017)., Conclusion: The study revealed significant RDW variations in patients with CHF and AHF compared to the control group. These findings suggest that RDW could be a biomarker for detecting HF severity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Dang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In response to the escalating global threat of antimicrobial resistance, our laboratory has established a phagemid packaging system for the generation of CRISPR-Cas13a-antimicrobial capsids targeting methicillin-resistant Staphylococcus aureus (MRSA). However, a significant challenge arose during the packaging process: the unintentional production of wild-type phages alongside the antimicrobial capsids. To address this issue, the phagemid packaging system was optimized by strategically incorporated silent mutations. This approach effectively minimized contamination risks without compromising packaging efficiency. The study identified the indispensable role of phage packaging genes, particularly terL-terS, in efficient phagemid packaging. Additionally, the elimination of homologous sequences between the phagemid and wild-type phage genome was crucial in preventing wild-type phage contamination. The optimized phagemid-LSAB(mosaic) demonstrated sequence-specific killing, efficiently eliminating MRSA strains carrying target antibiotic-resistant genes. While acknowledging the need for further exploration across bacterial species and in vivo validation, this refined phagemid packaging system offers a valuable advancement in the development of CRISPR-Cas13a-based antimicrobials, shedding light on potential solutions in the ongoing battle against bacterial infections., (© 2024. The Author(s).)

The emergence of oxacillin-susceptible methicillin-resistant Staphylococcus aureus (OS-MRSA) has imposed further challenges to the clinical management of MRSA infections. When exposed to β-lactam antibiotics, these strains can easily acquire reduced β-lactam susceptibility through chromosomal mutations, including those in RNA polymerase (RNAP) genes such as rpoBC , which may then lead to treatment failure. Despite the increasing prevalence of such strains and the apparent challenges they pose for diagnosis and treatment, there is limited information available on the actual mechanisms underlying such chromosomal mutation-related transitions to reduced β-lactam susceptibility, as it does not directly associate with the expression of mecA . This study investigated the cellular physiology and metabolism of six missense mutants with reduced oxacillin susceptibility, each carrying respective mutations on RpoB H929P , RpoB Q645H , RpoC G950R , RpoC G498D , RpiA A64E , and FruB A211E , using capillary electrophoresis-mass spectrometry-based metabolomics analysis. Our results showed that rpoBC mutations caused RNAP transcription dysfunction, leading to an intracellular accumulation of ribonucleotides. These mutations also led to the accumulation of UDP-Glc/Gal and UDP-GlcNAc, which are precursors of UTP-associated peptidoglycan and wall teichoic acid. Excessive amounts of building blocks then contributed to the cell wall thickening of mutant strains, as observed in transmission electron microscopy, and ultimately resulted in decreased susceptibility to β-lactam in OS-MRSA., Importance: The emergence of oxacillin-susceptible methicillin-resistant Staphylococcus aureus (OS-MRSA) strains has created new challenges for treating MRSA infections. These strains can become resistant to β-lactam antibiotics through chromosomal mutations, including those in the RNA polymerase (RNAP) genes such as rpoBC , leading to treatment failure. This study investigated the mechanisms underlying reduced β-lactam susceptibility in four rpoBC mutants of OS-MRSA. The results showed that rpoBC mutations caused RNAP transcription dysfunction, leading to an intracellular accumulation of ribonucleotides and precursors of peptidoglycan as well as wall teichoic acid. This, in turn, caused thickening of the cell wall and ultimately resulted in decreased susceptibility to β-lactam in OS-MRSA. These findings provide insights into the mechanisms of antibiotic resistance in OS-MRSA and highlight the importance of continued research in developing effective treatments to combat antibiotic resistance., Competing Interests: The authors declare no conflict of interest.

This study is the first to investigate the chemical composition and antioxidant, anti-inflammatory, and cytotoxic activities of Peperomia leptostachya leaf oil. A yellow oil was obtained through hydro-distillation, with a yield of 0.1% ( w / w ). The GC-MS analysis revealed 66 compounds, constituting 99.6% of the oil. Sesquiterpene hydrocarbons predominated (70.4%), followed by monoterpene hydrocarbons (13.2%), oxygenated sesquiterpenes (12.4%), non-terpenic compounds (2.0%), and oxygenated monoterpenes (1.6%). Major constituents included germacrene D (25.1%), ( E )-caryophyllene (17.4%), bicyclogermacrene (6.6%), α -pinene (6.2%), and β -pinene (4.7%). The assessment of antioxidant capacity via 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging assay yielded a weak effect, with an IC 50 value > 100 µg/mL. The inhibition of lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells was quantified using the MTT assay, showing an IC 50 value of 15.15 ± 0.68 µg/mL. Furthermore, cytotoxic effects on SK-LU-1 cell line growth were evaluated using the sulforhodamine B assay, resulting in an IC 50 value of 37.45 ± 2.43 μg/mL. The anti-inflammatory activity was notable among the analyzed bioactivities of this oil. By employing a computational model, the predominant secondary metabolites in the essential oil were selected as candidates for interaction analysis with cyclooxygenase-2, an enzyme implicated in the inflammatory response. Our findings suggest that P. leptostachya leaf oil could serve as a potential source of natural compounds with prospective therapeutic effects in treating inflammatory conditions.

Background: During the COVID-19 pandemic, analytics and predictive models built on regional data provided timely, accurate monitoring of epidemiological behavior, informing critical planning and decision-making for health system leaders. At Atrium Health, a large, integrated healthcare system in the southeastern United States, a team of statisticians and physicians created a comprehensive forecast and monitoring program that leveraged an array of statistical methods., Methods: The program utilized the following methodological approaches: (i) exploratory graphics, including time plots of epidemiological metrics with smoothers; (ii) infection prevalence forecasting using a Bayesian epidemiological model with time-varying infection rate; (iii) doubling and halving times computed using changepoints in local linear trend; (iv) death monitoring using combination forecasting with an ensemble of models; (v) effective reproduction number estimation with a Bayesian approach; (vi) COVID-19 patients hospital census monitored via time series models; and (vii) quantified forecast performance., Results: A consolidated forecast and monitoring report was produced weekly and proved to be an effective, vital source of information and guidance as the healthcare system navigated the inherent uncertainty of the pandemic. Forecasts provided accurate and precise information that informed critical decisions on resource planning, bed capacity and staffing management, and infection prevention strategies., Conclusions: In this paper, we have presented the framework used in our epidemiological forecast and monitoring program at Atrium Health, as well as provided recommendations for implementation by other healthcare systems and institutions to facilitate use in future pandemics., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Chronic medical conditions (i.e., chronic widespread pain) may contribute to accelerated/accentuated aging, such that middle-aged individuals with comorbidities may actually show increased declines in physical, cognitive, and mental health compared to normal aging adults. We examined perceived stress, life stressors, and depression in adults with and without fibromyalgia, a chronic pain condition. Ninety-four participants (52% with fibromyalgia, 78% female) aged 50 to 93 were administered the Perceived Stress Scale, Social Readjustment Rating Scale, and Beck Depression Inventory. Hierarchical regression analyses were conducted: the predictor variables were age, gender, fibromyalgia status, depression, and fibromyalgia-depression interaction. The interaction term significantly predicted perceived stress, but not life stressors. Depression significantly predicted stress for Social Readjustment Rating Scale measures after controlling for covariates. Significant associations were found between perceived stress and life stressors in all participants. In addition, those with fibromyalgia were significantly more likely to report higher levels of stress above standardized scores on both the Perceived Stress Scale and the Social Readjustment Rating Scale. Finally, depressive symptoms played a more significant role than fibromyalgia status in predicting life stressors. Conclusions: These findings emphasize the importance of assessing different types of stress and stressors in individuals with chronic widespread pain and/or depression in mid-life and beyond to better treat individuals with these conditions.