Two conserved epigenetic regulators prevent healthy ageing.

It has long been assumed that lifespan and healthspan correlate strongly, yet the two can be clearly dissociated1-6. Although there has been a global increase in human life expectancy, increasing longevity is rarely accompanied by an extended healthspan4,7. Thus, understanding the origin of healthy behaviours in old people remains an important and challenging task. Here we report a conserved epigenetic mechanism underlying healthy ageing. Through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing Caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behavioural deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases8,9 shows that expression of the human orthologues of these C. elegans regulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer's disease. Furthermore, ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. Thus our genome-wide RNA-interference screen in C. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.

KLF10/CBS increases the sensitivity of gastric carcinoma cells to methionine restriction by promoting sulfur transfer pathway.

Gastric cancer metastasis is a major cause of poor prognosis. Our previous research showed that methionine restriction (MR) lowers the invasiveness and motility of gastric carcinoma. In this study, we investigated the particular mechanisms of MR on gastric carcinoma metastasis. In vitro, gastric carcinoma cells (AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45) were grown in an MR medium for 24 h. In vivo, BALB/c mice were given a methionine-free (Met-) diet. Transwell assays were used to investigate cell invasion and migration. The amounts of Krüppel like factor 10 (KLF10) and cystathionine ß-synthase (CBS) were determined using quantitative real-time PCR and Western blot. To determine the relationship between KLF10 and CBS, chromatin immunoprecipitation and a dual-luciferase reporter experiment were used. Hematoxylin-eosin staining was used to detect lung metastasis. Liquid chromatography-mass spectrometry was used to determine cystathionine content. MR therapy had varying effects on the invasion and migration of gastric carcinoma cells AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45. KLF10 was highly expressed in AGS cells but poorly expressed in KATO III cells. KLF10 improved MR's ability to prevent gastric carcinoma cell invasion and migration. In addition, KLF10 may interact with CBS, facilitating transcription. Further detection revealed that inhibiting the KLF10/CBS-mediated trans-sulfur pathway lowered Met-'s inhibitory effect on lung metastasis development. KLF10 transcription activated CBS, accelerated the trans-sulfur pathway, and increased gastric carcinoma cells' susceptibility to MR.

Methionine restriction attenuates the migration and invasion of gastric cancer cells by inhibiting nuclear p65 translocation through TRIM47.

The prevention and treatment of gastric cancer has been the focus and difficulty of medical research. We aimed to explore the mechanism of inhibiting migration and invasion of gastric cancer cells by methionine restriction (MR). The human gastric cancer cell lines AGS and MKN45 cultured with complete medium (CM) or medium without methionine were used for in vitro experiments. MKN45 cells were injected tail vein into BALB/c nude mice and then fed with normal diet or methionine diet for in vivo experiments. MR treatment decreased cell migration and invasion, increased E-cadherin expression, decreased N-cadherin and p-p65 expressions, and inhibited nuclear p65 translocation of AGS and MKN45 cells when compared with CM group. MR treatment increased IκBα protein expression and protein stability, and decreased IκBα protein ubiquitination level and TRIM47 expression. TRIM47 interacted with IκBα protein, and overexpression of TRIM47 reversed the regulatory effects of MR. TRIM47 promoted lung metastasis formation and partially attenuated the effect of MR on metastasis formation in vivo compared to normal diet group mice. MR reduces TRIM47 expression, leads to the degradation of IκBα, and then inhibits the translocation of nuclear p65 and the migration and invasion of gastric cancer cells.

Identification of Coupled Landau and Anomalous Resonances in Space Plasmas.

Wave-particle resonance, a ubiquitous process in the plasma universe, occurs when resonant particles observe a constant wave phase to enable sustained energy transfer. Here, we present spacecraft observations of simultaneous Landau and anomalous resonances between oblique whistler waves and the same group of protons, which are evidenced, respectively, by phase-space rings in parallel-velocity spectra and phase-bunched distributions in gyrophase spectra. Our results indicate the coupling between Landau and anomalous resonances via the overlapping of the resonance islands.

Bone marrow mesenchymal stem cell-derived exosomal miR-221-3p promotes angiogenesis and wound healing in diabetes via the downregulation of forkhead box P1.

AIM: Impaired wound healing in patients with diabetes can develop into nonhealing ulcerations. Because bone marrow mesenchymal stem cells (BMSCs) exosomes can promote wound healing, this study aims to investigate the mechanism of BMSCs-isolated exosomal miR-221-3p in angiogenesis and diabetic wound healing. METHODS: To mimic diabetes in vitro, human umbilical vein endothelial cells (HUVECs) were subjected to high glucose (HG). Exosomes were derived from BMSCs and identified by transmission electron microscopy (TEM), western blot analysis and dynamic light scattering (DLS). The ability to differentiate BMSCs was assessed via Oil red O staining, alkaline phosphatase (ALP) staining and alizarin red staining. The ability to internalise PKH26-labelled exosomes was assessed using confocal microscopy. Migration, cell viability and angiogenesis were tested by scratch, MTT and tube formation assays separately. The miRNA and protein levels were analysed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) or western blotting. The relationship among miR-221-3p, FOXP1 and SPRY1 was determined using the dual-luciferase reporter, ChIP and RIP assays. RESULTS: Exosomal miR-221-3p was successfully isolated from BMSCs and delivered into HUVECs. HG was found to suppress the angiogenesis, cell viability and migration of HUVECs and exosomal miR-221-3p separated from BMSCs inhibited the above phenomenon. FOXP1 could transcriptionally upregulate SPRY1, and the silencing of FOXP1 reversed the HG-stimulated angiogenesis inhibition, cell viability and migration in HUVECs via the downregulation of SPRY1. Meanwhile, miR-221-3p directly targeted FOXP1 and the overexpression of FOXP1 reversed the positive effect of exosomal miR-221-3p on HUVEC angiogenesis. CONCLUSION: Exosomal miR-221-3p isolated from BMSCs promoted angiogenesis in diabetic wounds through the mediation of the FOXP1/SPRY1 axis. Furthermore, the findings of this study can provide new insights into probing strategies against diabetes.

Satisfactory Tensile Strength and Strain of Recyclable Polyurethane with a Trimaleimide Structure for Thermal Self-Healing and Anticorrosive Coatings.

Bismaleimide (BMI) is often used as the cross-linking reagent in Diels-Alder (D-A)-type intrinsic self-healing materials (DISMs) to promote the connectivity of damaged surfaces based on reversible D-A bond formation on the molecular scale. Until now, although DISMs have exhibited great potential in the applications of various sensors, electronic skin, and artificial muscles, it is still difficult to prepare DISMs with satisfactory self-healing abilities and high tensile strengths and strains at the same time, thus largely limiting their applications in self-healing anticorrosive coatings. Herein, symmetrical trimaleimide (TMI) was successfully synthesized, and trimaleimide-structured D-A self-healing polyurethane (TMI-DA-PU) was prepared via the reversible D-A reaction (cycloaddition of furan and maleimide). As a DISM, TMI-DA-PU exhibits apparently higher self-healing efficiency (98.7%), tensile strength (25.4 MPa), and strain (1378%) compared to bismaleimide-structured D-A self-healing polyurethane (BMI-DA-PU) (self-healing efficiency, 90.2%; tensile strength, 19.3 MPa; strain, 1174%). In addition, TMI-DA-PU shows a high recycling efficiency (>95%) after 4 cycles of recycling. A series of characterizations indicate that TMI provides more monoene rings as the self-healing sites, forms denser cross-linked structures compared to BMI, and is, thus, more appropriate to be used for DISM applications. Moreover, the barrier abilities of coatings can be semi-quantitatively expressed by the impedance value at 0.01 Hz (|Z|0.01 Hz). The |Z|0.01 Hz value of the TMI-DA-PU coating is 3.93 × 109 Ω cm2 on day 0, which is significantly higher than that of the BMI-DA-PU coating (6.76 × 108 Ω cm2 on day 0), indicating that the denser rigid cross-linked structure of TMI results in the small porosity in the TMI-DA-PU coating, thus effectively improving the anticorrosion performance. The construction of DISMs with the structure of TMI demonstrates immense potential in self-healing anticorrosive coatings.

Global, regional, and national burden of thalassemia during 1990-2019: A systematic analysis of the Global Burden of Disease Study 2019.

INTRODUCTION: Thalassemia represents a significant public health challenge globally. However, the global burden of thalassemia and the disparities associated with it remain poorly understood. Our study aims to uncover the long-term spatial and temporal trends in thalassemia at global, regional, and national levels, analyze the impacts of age, time periods, and birth cohorts, and pinpoint the global disparities in thalassemia burden. METHODS: We extracted data on the thalassemia burden from the Global Burden of Disease Study (GBD) 2019. We employed a joinpoint regression model to assess temporal trends in thalassemia burden and an age-period-cohort model to evaluate the effects of age, period, and cohort on thalassemia mortality. RESULTS: From 1990 to 2019, the number of thalassemia incident cases, prevalent cases, mortality cases, and disability-adjusted life years (DALYs) decreased by 20.9%, 3.1%, 38.6%, and 43.1%, respectively. Age-standardized rates of incidence, prevalence, mortality, and DALY declined across regions with high, high-middle, middle, and low-middle sociodemographic index (SDI), yet remained the highest in regions with low SDI and low-middle SDI as well as in Southeast Asia, peaking among children under five years of age. The global prevalence rate was higher in males than in females. The global mortality rate showed a consistent decrease with increasing age. CONCLUSION: The global burden of thalassemia has significantly declined, yet notable disparities exist in terms of gender, age groups, periods, birth cohorts, SDI regions, and GBD regions. Systemic interventions that include early screening, genetic counseling, premarital health examinations, and prenatal diagnosis should be prioritized in regions with low, and low-middle SDI, particularly in Southeast Asia. Future population-based studies should focus specifically on thalassemia subtypes and transfusion requirements, and national registries should enhance data capture through newborn screening.

Rational Design and Synthesis of Fe-Doped Co-Based Coordination Polymer Composite Photocatalysts for the Degradation of Norfloxacin and Ciprofloxacin.

The solar light-responsive Fe-doped Co-based coordination polymer (Fe@Co-CP) photocatalyst was synthesized under mild conditions. [Co(4-padpe)(1,3-BDC)]n (Co-CP) was first constructed using mixed ligands through the hydrothermal method. Then, Fe was introduced into the Co-CP framework to achieve the enhanced photocatalytic activity. The optimal Fe@Co-CP-2 exhibited excellent catalytic degradation performance for norfloxacin and ciprofloxacin under sunlight irradiation without auxiliary oxidants, and the degradation rates were 91.25 and 92.66% in 120 min. These excellent photocatalytic properties were ascribed to the generation of the Fe-O bond, which not only enhanced the light absorption intensity but also accelerated the separation efficiency of electrons and holes, and hence significantly improved the photocatalytic property of the composites. Meanwhile, Fe@Co-CP-2 displayed excellent stability and reusability. In addition, the degradation pathways and intermediates of antibiotic molecules were effectively analyzed. The free radical scavenging experiment and ESR results confirmed that •OH, •O2-, and h+ active species were involved in the catalytic degradation reaction; the corresponding mechanisms were deeply investigated. This study provides a fresh approach for constructing Fe-doped Co-CP-based composite materials as photocatalysts for degradation of antibiotic contaminants.

Delays in Multiple Sclerosis diagnosis (DIMES): protocol for a multicentre, observational study of multiple sclerosis diagnostic pathways in the United Kingdom and Republic of Ireland.

BACKGROUND: Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. Accumulating evidence indicates early diagnosis and early treatment improves long-term outcomes. However, the MS diagnostic pathway is increasingly complex, and delays may occur at several stages. Factors causing delays remain understudied. We aim to quantify the time taken for MS to be diagnosed, and characterise the diagnostic pathway and initial care provided, in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: Delays In MultiplE Sclerosis diagnosis (DIMES) in the UK and ROI is a multicentre, observational, retrospective study that will be conducted via the Neurology and Neurosurgery Interest Group (NANSIG) collaborative network. Any hospital in the UK and ROI providing an MS diagnostic service is eligible to participate. Data on consecutive individuals newly diagnosed with MS between 1st July 2022 and 31st December 2022 will be collected. The primary outcomes are 1) time from symptoms/signs prompting referral to neurology, to MS diagnosis; and 2) time from referral to neurology for suspected MS, to MS diagnosis. Secondary outcomes include: MS symptoms, referring specialties, investigations performed, neurology appointments, functional status, use of disease modifying treatments, and support at diagnosis including physical activity, and follow up. Demographic characteristics of people newly diagnosed with MS will be summarised, adherence to quality standards summarised as percentages, and time-to-event variables presented with survival curves. Multivariable models will be used to investigate the association of demographic and clinical factors with time to MS diagnosis, as defined in our primary outcomes. DISCUSSION: DIMES aims to be the largest multicentre study of the MS diagnostic pathway in the UK and ROI. The proposed data collection provides insights that cannot be provided from contemporary registries, and the findings will inform approaches to MS services nationally in the future.

Management and outcome of intracranial fungal infections in children and adults in Africa: a scoping review.

INTRODUCTION: Intracranial fungal infections' (IcFIs) varying clinical manifestations lead to difficulties in diagnosis and treatment. African populations are disproportionately affected by the high burden of the disease. There is a lack of clarity as to the diagnostic and treatment modalities employed across the continent. In this review, we aim to detail the management, and outcome of IcFIs across Africa. METHODS: This scoping review was conducted using the Arksey and O'Malley framework. MEDLINE, EMBASE, Cochrane Library, African Index Medicus, and African Journals Online were searched for relevant articles from database inception to August 10th, 2021. The Preferred Reporting Items for Systematic Review and Meta-Analysis extension for Scoping Reviews guidelines were used to report the findings of the review. RESULTS: Of the 5,779 records identified, 131 articles were included. The mean age was 35.6 years, and the majority (56.4%) were males. The majority (n = 8,433/8,693, 97.0%) of IcFIs presented as a meningitis, the most common communicable predisposing factor of IcFIs was HIV/AIDS (n = 7,815/8,693, 89.9%), and the most common non-communicable risk factor was diabetes mellitus (n = 32/8,693, 0.4%). Cryptococcus species was the most common (n = 8,428/8,693, 97.0%) causative organism. The most commonly used diagnostic modality was cerebrospinal (CSF) cultures (n = 4,390/6,830, 64.3%) for diffuse IcFIs, and MRI imaging (n = 12/30, 40%) for focal IcFIs. The most common treatment modality was medical management with antifungals only (n = 4,481/8,693, 51.6%). The most commonly used antifungal agent in paediatric, and adult patients was amphotericin B and fluconazole dual therapy (51.5% vs 44.9%). The overall mortality rate was high (n = 3,475/7,493, 46.3%), and similar for both adult and paediatric patients (47.8% vs 42.1%). CONCLUSION: Most IcFIs occurred in immunosuppressed individuals, and despite the new diagnostic techniques, CSF culture was mostly used in Africa. Antifungals regimens used was similar between children and adults. The outcome of IcFIs in Africa was poor for both paediatric and adult patients.

Endoplasmic reticulum stress-mediated autophagy alleviates lipopolysaccharide-induced nucleus pulposus cell pyroptosis by inhibiting CHOP signaling in vitro.

Pyroptosis, a newly discovered pro-inflammatory programmed necrosis of cells, serves as an initiating and promoting event that leads to intervertebral disc (IVD) degeneration (IDD). Endoplasmic reticulum stress (ERS) and autophagy are vital regulatory mechanisms of cellular homeostasis, which is also closely related to IDD. However, the role and relationship of ERS and autophagy in the pyroptosis of nucleus pulposus cell (NPC) are not well understood. In this research, we aimed to elucidate the role and mechanism of ERS-C/EBP homologous protein (CHOP) in lipopolysaccharide (LPS)-induced cell pyroptosis and determine its interaction with autophagy. ERS and autophagy inducers or inhibitors were used or not in the preconditioning of rat NPCs. Cell viability, pyroptosis-related protein expression, caspase-1 activity assay, and enzyme-linked immunosorbent assay were performed to observe rat NPC pyroptosis after the treatment of LPS. Activation of the ERS pathway and autophagy were assessed by quantitative real-time PCR, western blot analyses, and immunofluorescence staining assay to classify the molecular mechanisms. Our results showed that LPS stimulation induced NPC pyroptosis with concomitant activation of the ERS-CHOP pathway and initiated autophagy. Activation of the ERS-CHOP pathway exacerbated rat NPC pyroptosis, whereas autophagy inhibited cell pyroptosis. LPS-induced cell pyroptosis and CHOP upregulation were negatively regulated by autophagy. LPS-induced autophagy was depressed by the ERS inhibitor but aggravated by the ERS inducer. Taken together, our findings suggested that LPS induced NPC pyroptosis by activating ERS-CHOP signaling and ERS mediated LPS-induced autophagy, which in turn alleviated NPC pyroptosis by inhibiting CHOP signaling.

Focal ischemic myocardial fibrosis assessed by late gadolinium enhancement cardiovascular magnetic resonance in patients with hypertrophic cardiomyopathy.

BACKGROUND: In patients with hypertrophic cardiomyopathy (HCM), ischemic myocardial fibrosis assessed by late gadolinium enhancement (I-LGE) using cardiovascular magnetic resonance (CMR) have been reported. However, the clinical significance of I-LGE has not been completely understood. We aim to evaluate the I-LGE differ phenotypically from HCM without LGE or nonischemic myocardial fibrosis assessed by late gadolinium enhancement (NI-LGE) in the left ventricle (LV). METHODS: The patients with HCM whom was underwent CMR were enrolled, using cine cardiac magnetic resonance to evaluate LV function and LGE to detect the myocardial fibrosis. Three groups were assorted: 1) HCM without LGE; 2) HCM with LGE involved the subendocardial layer was defined as I-LGE; 3) HCM with LGE not involved the subendocardial layer was defined as NI-LGE. RESULTS: We enrolled 122 patients with HCM in the present study. LGE was detected in 58 of 122 (48%) patients with HCM, and 22 (18%) of patients reported I-LGE. HCM with I-LGE had increased higher left ventricular mass index (LVMI) (P < 0.0001) than HCM with NI-LGE or without LGE. In addition, HCM with I-LGE had a larger LV end- systolic volume (P = 0.045), lower LV ejection fraction (LVEF) (P = 0.026), higher LV myocardial mass (P < 0.001) and thicker LV wall (P < 0.001) more than HCM without LGE alone. The I-LGE were significantly associated with LVEF (OR: 0.961; P = 0.016), LV mass (OR: 1.028; P < 0.001), and maximal end-diastolic LVWT (OR: 1.567; P < 0.001). On multivariate analysis, LVEF (OR: 0.948; P = 0.013) and maximal end-diastolic LVWT (OR: 1.548; P = 0.001) were associated with higher risk for I-LGE compared to HCM without LGE. Noticeably, the maximal end-diastolic LVWT (OR: 1.316; P = 0.011) was the only associated with NI-LGE compared to HCM without LGE. CONCLUSIONS: I-LGE is not uncommon in patients with HCM. HCM with I-LGE was associated with significant LV hypertrophy, extensive LGE and poor LV ejection fraction. We should consider focal ischemic myocardial fibrosis when applying LGE to risk stratification for HCM.

A potential role for inflammatory cytokines in a rare late-onset capsular block syndrome: a case report.

BACKGROUND: Late-onset capsule block syndrome (CBS) is a rare complication of cataract phacoemulsification and the implantation of a posterior chamber intraocular lens (PCIOL), which manifests six months to years after surgery. The hallmark of CBS is the formation of an opaque liquid substance between the implanted intraocular lens (IOL) and the posterior capsule. However, its pathogenesis remains unclear. CASE PRESENTATION: A 64-year-old female patient with chronic angle-closure glaucoma (axis length < 21 mm) underwent trabeculectomy surgery combined with phacoemulsification and PCIOL. After a 4-year follow-up, a decline in visual acuity occurred in her right eye due to the location of opaque fluid in the visual axis and distension of the capsular bag. The initial course of action was to release the trapped fluid. Neodymium: yttrium-aluminum-garnet (Nd: YAG) laser capsulotomy could not be employed due to her non-dilating pupil and high extension of the posterior capsule. Subsequently, anterior capsule peeling and anterior segment vitrectomy surgery were performed. The depth of the anterior chamber (ACD), the distance between the face of the retro-IOL and the posterior capsule, the best-corrected visual acuity (BCVA), and the visual quality (VQ) were measured both before and after surgery. Inflammatory cytokine levels in the opaque substances (OS) trapped between the PCIOL and the posterior capsule were assessed using a flow cytometer and compared to normal statistical data in aqueous humor. After surgery, the patient experienced a significant improvement in BCVA and VQ. The distance between the face of the retro-IOL and the posterior capsule was on the verge of disappearing. However, ACD did not differ between pre- and post-operatively. Interleukin-8 (IL-8) and basic fibroblast growth factor (BFGF) concentrations were higher in the OS than in aqueous humor, especially in the former. However, the concentration of vascular cell adhesion molecule (VCAM) in the OS was lower than in aqueous humor. CONCLUSIONS: Anterior segment vitrectomy surgery proved to be a successful treatment for late-onset CBS, presenting a challenging case. In the human lens, inflammatory cytokines originating from the opaque substances may contribute to abnormal metabolism in the sealed area, a consequence of late-onset CBS.

Small non-coding RNAome changes during human chondrocyte senescence as potential epigenetic targets in age-related osteoarthritis.

Chondrocyte senescence is a decisive component of age-related osteoarthritis, however, the function of small noncoding RNAs (sncRNAs) in chondrocyte senescence remains underexplored. Human hip joint cartilage chondrocytes were cultivated up to passage 4 to induce senescence. RNA samples were extracted and then analyzed using small RNA sequencing and qPCR. ß-galactosidase staining was used to detect the effect of sncRNA on chondrocyte aging. Results of small RNA sequencing showed that 279 miRNAs, 136 snoRNAs, 30 snRNAs, 102 piRNAs, and 5 rasiRNAs were differentially expressed in senescent chondrocytes. The differential expression of 150 sncRNAs was further validated by qPCR. Transfection of sncRNAs and ß-galactosidase staining were also performed to further revealed that hsa-miR-135b-5p, SNORA80B-201, and RNU5E-1-201 have the function to restrain chondrocyte senescence, while has-piR-019102 has the function to promote chondrocyte senescence. Our data suggest that sncRNAs have therapeutic potential as novel epigenetic targets in age-related osteoarthritis.

Conventional High-Dose vs Low-Dose Hyaluronidase for Skin Necrosis after Hyaluronic Acid Fillers: A Systematic Review and Pilot Meta-Analysis.

BACKGROUND: Hyaluronidase remains the mainstay treatment for skin necrosis due to vascular occlusion after hyaluronic acid (HA) dermal fillers. There is wide variability in protocols for the administration of hyaluronidase. Most protocols, however, lack strong evidence regarding hyaluronidase dosages. METHODS: We conducted a systematic review and pilot meta-analysis, searching four international databases from inception until December 2023 for clinical studies reporting on two or more patients receiving hyaluronidase for skin necrosis after hyaluronic acid fillers. Random-effects (DerSimonian and Laird) meta-analyses were conducted. The primary outcome was the pooled proportion of complete scar resolution. We rated intra-study risk of bias using the Joanna Briggs Institute checklists and assessed the certainty of evidence using the GRADE approach. RESULTS: We included 15 studies totaling 223 patients. The pooled proportion of complete scar resolution after hyaluronidase administration was 77.8% (95%-CI: 65.5% to 86.6%, pegger = 0.093, low certainty). Patients treated with high doses of hyaluronidase (>500 international units [IUs]) had lower rates of resolution of 69.6% (95%-CI: 41.2% to 88.3%) compared to those treated with low doses (500IU or less) that had 88.1% rate of resolution (95%-CI: 86.0% to 96.2%), though not statistically significant (p= 0.18). The use of adjunct therapies did not have a statistically significant effect on outcomes. CONCLUSION: A higher proportion of patients receiving low doses (500IU or less) (88.1%) had complete scar resolution compared to patients receiving high doses (69.7%), though not statistically significant (p=0.18). Future studies should provide more granular details on their protocols to benefit the formulation of evidence-based guidelines in future. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PROTOCOL REGISTRATION: CRD42024538661.

The global prevalence of highly pathogenic avian influenza A (H5N8) infection in birds: A systematic review and meta-analysis.

The zoonotic pathogen avian influenza A H5N8 causes enormous economic losses in the poultry industry and poses a serious threat to the public health. Here, we report the first systematic review and meta-analysis of the worldwide prevalence of birds. We filtered 45 eligible articles from seven databases. A random-effects model was used to analyze the prevalence of H5N8 in birds. The pooled prevalence of H5N8 in birds was 1.6%. In the regions, Africa has the highest prevalence (8.0%). Based on the source, village (8.3%) was the highest. In the sample type, the highest prevalence was organs (79.7%). In seasons, the highest prevalence was autumn (28.1%). The largest prevalence in the sampling time was during 2019 or later (7.0%). Furthermore, geographical factors also were associated with the prevalence. Therefore, we recommend site-specific prevention and control tools for this strain in birds and enhance the surveillance to reduce the spread of H5N8.

UCMSCs-derived exosomal circHIPK3 promotes ulcer wound angiogenesis of diabetes mellitus via miR-20b-5p/Nrf2/VEGFA axis.

AIMS: Experiments confirmed that circular RNAs contributed to the pathogenesis of diabetic foot ulcers (DFUs). CircHIPK3 was upregulated in type 2 diabetes mellitus (T2DM), but its role in DFU remained unknown. Our study aimed to investigate the regulatory functions of exosomal circHIPK3 and its potential mechanisms in DFU. METHODS: Exosomal size and distribution, marker proteins, and circHIPK3 levels were evaluated by transmission electron microscope, ExoView R200, western blot, and qRT-PCR. Flow cytometry, MTT, Wound healing assays, and tube formation assays were used to assess the roles of exosomal circHIPK3 in high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs). The relationships between Nrf2/VEGFA/circHIPK3 and miR-20b-5p, and between Nrf2 and VEGFA were determined by luciferase reporter assay and RNA immunoprecipitation. We used cell and mice models to investigate the mechanisms of exosomal circHIPK3 under diabetic conditions. RESULTS: CircHIPK3 was significantly upregulated in exo-circHIPK3 rather than exo-vector. Exo-circHIPK3 remarkably inhibited cell apoptosis but promoted cell proliferation, migration, and tube formation in HG-treated HUVECs. Luciferase reporter and RIP assays showed that miR-20b-5p targeted and inhibited Nrf2 and VEGFA, and circHIPK3 acted as a ceRNA of miR-20b-5p to inhibit the binding to its downstream genes Nrf2 and VEGFA. Mechanistically, circHIPK3 promoted cell proliferation, migration, and angiogenesis via downregulating miR-20b-5p to upregulate Nrf2 and VEGFA. However, the overexpressed miR-20b-5p could abolish the promoting effects of circHIPK3 overexpression on cell proliferation, migration, and tube formation under HG conditions. CONCLUSION: UCMSCs-derived exosomal circHIPK3 protected HG-treated HUVECs via miR-20b-5p/Nrf2/VEGFA axis. The exosomal circHIPK3 might be a therapeutic candidate to treat DFU.

Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state.

Kindlin-1, -2, and -3 directly bind integrin ß cytoplasmic tails to regulate integrin activation and signaling. Despite their functional significance and links to several diseases, structural information on full-length kindlin proteins remains unknown. Here, we report the crystal structure of human full-length kindlin-3, which reveals a novel homotrimer state. Unlike kindlin-3 monomer, which is the major population in insect and mammalian cell expression systems, kindlin-3 trimer does not bind integrin ß cytoplasmic tail as the integrin-binding pocket in the F3 subdomain of 1 protomer is occluded by the pleckstrin homology (PH) domain of another protomer, suggesting that kindlin-3 is auto-inhibited upon trimer formation. This is also supported by functional assays in which kindlin-3 knockout K562 erythroleukemia cells reconstituted with the mutant kindlin-3 containing trimer-disrupting mutations exhibited an increase in integrin-mediated adhesion and spreading on fibronectin compared with those reconstituted with wild-type kindlin-3. Taken together, our findings reveal a novel mechanism of kindlin auto-inhibition that involves its homotrimer formation.

LncRNA GNAS-AS1 knockdown inhibits keloid cells growth by mediating the miR-188-5p/RUNX2 axis.

Keloid is a common dermis tumor, occurring repeatedly, affecting the quality of patients' life. Long non-coding RNAs (lncRNAs) have crucial regulatory capacities in skin scarring formation and subsequent scar carcinogenesis. The intention of this study was to investigate the mechanism and function of GNAS antisense-1 (GNAS-AS1) in keloids. Clinical samples were collected to evaluate the expression of GNAS-AS1, RUNX2, and miR-188-5p by qRT-PCR. The proliferation, migration, and invasion of HKF cells were detected by CCK-8, wound healing, and Transwell assays. The expression levels of mRNA and protein were examined through qRT-PCR and Western blot assay. Luciferase reporter assay was used to identify the binding relationship among GNAS-AS1, miR-188-5p, and Runt-related transcription factor 2 (RUNX2). GNAS-AS1 and RUNX2 expressions were remarkably enhanced, and miR-188-5p expression was decreased in keloid clinical tissues and HKF cells. GNAS-AS1 overexpression promoted cells proliferation, migration, and invasion, while GNAS-AS1 knockdown had the opposite trend. Furthermore, overexpression of GNAS-AS1 reversed the inhibitory effect of 5-FU on cell proliferation, migration, and invasion. MiR-188-5p inhibition or RUNX2 overexpression could enhance the proliferation, migration, and invasion of HKF cells. GNAS-AS1 targeted miR-188-5p to regulate RUNX2 expression. In addition, the inhibition effects of GNAS-AS1 knockdown on HKF cells could be reversed by inhibition of miR-188-5p or overexpression of RUNX2, while RUNX2 overexpression eliminated the suppressive efficaciousness of miR-188-5p mimics on HKF cells growth. GNAS-AS1 knockdown could regulate the miR-188-5p/RUNX2 signaling axis to inhibit the growth and migration in keloid cells. It is suggested that GNAS-AS1 may become a new target for the prevention and treatment of keloid.

Coexistence of Synechococcus and Microcystis Blooms in a Tropical Urban Reservoir and Their Links with Microbiomes.

Bacteria play a crucial role in driving ecological processes in aquatic ecosystems. Studies have shown that bacteria-cyanobacteria interactions contributed significantly to phytoplankton dynamics. However, information on the contribution of bacterial communities to blooms remains scarce. Here, we tracked changes in the bacterial community during the development of a cyanobacterial bloom in an equatorial estuarine reservoir. Two forms of blooms were observed simultaneously corresponding to the lotic and lentic characteristics of the sampling sites where significant spatial variabilities in physicochemical water quality, cyanobacterial biomass, secondary metabolites, and cyanobacterial/bacterial compositions were detected. Microcystis dominated the upstream sites during peak periods and were succeeded by Synechococcus when the bloom subsided. For the main body of the reservoir, a mixed bloom featuring coccoid and filamentous cyanobacteria (Microcystis, Synechococcus, Planktothricoides, Nodosilinea, Raphidiopsis, and Prochlorothrix) was observed. Concentrations of the picocyanobacteria Synechococcus remained high throughout the study, and their positive correlations with cylindrospermopsin and anatoxin-a suggested that they could produce cyanotoxins, which pose more damaging impacts than previously supposed. Succession of different cyanobacteria (Synechococcus and Microcystis) following changes in nutrient composition and ionic strength was demonstrated. The microbiomes associated with blooms were unique to the dominant cyanobacteria. Generic and specialized bloom biomarkers for the Microcystis and downstream mixed blooms were also identified. Microscillaceae, Chthoniobacteraceae, and Roseomonas were the major heterotrophic bacteria associated with Microcystis bloom, whereas Phycisphaeraceae and Methylacidiphilaceae were the most prominent groups for the Synechococcus bloom. Collectively, bacterial community can be greatly deviated by the geological condition, monsoon season, cyanobacterial density, and dominant cyanobacteria.