Covalent Organic Frameworks as Single-Site Photocatalysts for Solar-to-Fuel Conversion.

Single-site photocatalysts (SSPCs) are well-established as potent platforms for designing innovative materials to accomplish direct solar-to-fuel conversion. Compared to classical inorganic porous materials, such as zeolites and silica, covalent organic frameworks (COFs)─an emerging class of porous polymers that combine high surface areas, structural diversity, and chemical stability─are attractive candidates for SSPCs due to their molecular-level precision and intrinsic light harvesting ability, both amenable to structural engineering. In this Perspective, we summarize the design concepts and state-of-the-art strategies for the construction of COF SSPCs, and we review the development of COF SSPCs and their applications in solar-to-fuel conversion from their inception. Underlying pitfalls concerning photocatalytic characterization are discussed, and perspectives for the future development of this burgeoning field are given.

White matter alterations and their associations with biomarkers and behavior in subjective cognitive decline individuals: a fixel-based analysis.

BACKGROUND: Subjective cognitive decline (SCD) is an early stage of dementia linked to Alzheimer's disease pathology. White matter changes were found in SCD using diffusion tensor imaging, but there are known limitations in voxel-wise tensor-based methods. Fixel-based analysis (FBA) can help understand changes in white matter fibers and how they relate to neurodegenerative proteins and multidomain behavior data in individuals with SCD. METHODS: Healthy adults with normal cognition were recruited in the Northeastern Taiwan Community Medicine Research Cohort in 2018-2022 and divided into SCD and normal control (NC). Participants underwent evaluations to assess cognitive abilities, mental states, physical activity levels, and susceptibility to fatigue. Neurodegenerative proteins were measured using an immunomagnetic reduction technique. Multi-shell diffusion MRI data were collected and analyzed using whole-brain FBA, comparing results between groups and correlating them with multidomain assessments. RESULTS: The final enrollment included 33 SCD and 46 NC participants, with no significant differences in age, sex, or education between the groups. SCD had a greater fiber-bundle cross-section than NC (pFWE < 0.05) at bilateral frontal superior longitudinal fasciculus II (SLFII). These white matter changes correlate negatively with plasma Aß42 level (r = -0.38, p = 0.01) and positively with the AD8 score for subjective cognitive complaints (r = 0.42, p = 0.004) and the Hamilton Anxiety Rating Scale score for the degree of anxiety (Ham-A, r = 0.35, p = 0.019). The dimensional analysis of FBA metrics and blood biomarkers found positive correlations of plasma neurofilament light chain with fiber density at the splenium of corpus callosum (pFWE < 0.05) and with fiber-bundle cross-section at the right thalamus (pFWE < 0.05). Further examination of how SCD grouping interacts between the correlations of FBA metrics and multidomain assessments showed interactions between the fiber density at the corpus callosum with letter-number sequencing cognitive score (pFWE < 0.01) and with fatigue to leisure activities (pFWE < 0.05). CONCLUSION: Based on FBA, our investigation suggests white matter structural alterations in SCD. The enlargement of SLFII's fiber cross-section is linked to plasma Aß42 and neuropsychiatric symptoms, which suggests potential early axonal dystrophy associated with Alzheimer's pathology in SCD. The splenium of the corpus callosum is also a critical region of axonal degeneration and cognitive alteration for SCD.

A Systematic Review and Quality Assessment of Cardiovascular Disease-Specific Health-Related Quality-of-Life Instruments Part I: Instrument Development and Content Validity.

OBJECTIVES: Health-related quality-of-life (HRQoL) instruments for cardiovascular diseases (CVD) have been commonly used to measure important patient-reported outcomes (PROs) in clinical trials and practices. This study aimed at systematically identifying and assessing the content validity of CVD-specific HRQoL instruments in clinical studies. METHODS: The research team searched Cumulative Index to Nursing and Allied Health Literature, Embase, and PubMed from inception to January 20, 2022. The research team included studies that reported the development and content validity for CVD-specific instruments. Two reviewers independently assessed the methodological quality using the Consensus-based Standards for the Selection of Health Measurement Instruments methods on evaluating content validity of PROs. Content analysis was used to categorize the items included in the instruments. RESULTS: The research team found 69 studies reporting the content validity of 40 instruments specifically developed for CVD. Fourteen (35.0%) were rated "sufficient" with very low to moderate quality of evidence. For PRO development, all instruments were rated "doubtful" or "inadequate." Twenty-eight (70.0%) instruments cover the core concepts of HRQoL. CONCLUSIONS: The quality of development and content validity vary among existing CVD-specific instruments. The evidence on the content validity should be considered when choosing a HRQoL instrument in CVD clinical studies and health economic evaluations.

Complete genome sequence of a novel amalgavirus in sponge gourd, Luffa cylindrica.

A novel monopartite dsRNA virus, tentatively named "sponge gourd amalgavirus 1" (SGAV1), was discovered by high-throughput sequencing in sponge gourd (Luffa cylindrica) displaying mosaic symptoms in Jiashan County, Zhejiang Province, China. The genome of SGAV1 is 3,447 nucleotides in length and contains partially overlapping open reading frames (ORFs) encoding a putative replication factory matrix-like protein and a fusion protein, respectively. The fusion protein of SGAV1 shares 57.07% identity with the homologous protein of salvia miltiorrhiza amalgavirus 1 (accession no. DAZ91057.1). Phylogenetic analysis based on the RNA-dependent RNA polymerase (RdRp) protein suggests that SGAV1 belongs to the genus Amalgavirus of the family Amalgaviridae. Moreover, analysis of SGAV1-derived small interfering RNAs indicated that SGAV1 was actively replicating in the host plant. Semi-quantitative RT-PCR showed higher levels of SGAV1 expression in leaves than in flowers and fruits. This is the first report of a novel amalgavirus found in sponge gourd in China.

Network meta-analysis of probiotics, prebiotics, and synbiotics for the treatment of chronic constipation in adults.

OBJECTIVE: To compare the outcomes associated with the use of probiotics, prebiotics, and synbiotics for the treatment of chronic constipation in adults. METHODS: We searched eight electronic databases from database inception to July 11, 2023, to identify randomized controlled trials (RCTs) that report efficacy and safety for the treatment of chronic constipation. The risk of bias in the included RCTs was evaluated according to the Cochrane tool, and the certainty of the evidence was assessed using the Confidence in Network Meta-Analysis framework. The analysis was conducted using R version 4.3.0. RESULTS: Out of the 37 RCTs, a total of 21 different types of interventions were reported, involving 3,903 patients. This NMA demonstrated that both prebiotics and synbiotics resulted in an increase in frequency of stool movements per week. Compared to placebo, lactulose (Mean difference [MD] = 3.39, 95% Confdence interval [CI] [1.13, 5.65], moderate certainty), mix2 (consisting of Lactulose and Bacillus coagulans) (MD = 3.63, 95% CI [1.37, 5.89], moderate certainty), mix6 (consisting of Lactulose and Bifidobacterium coagulans) (MD = 4.30, 95% CI [1.04, 7.54], low certainty), and mix7 (consisting of Lactulose, Bifidobacterium subtilis, and Enterococcus faecium) (MD = 4.58, 95% CI [1.35, 7.78], moderate certainty) exhibited a significant effect. Notably, mix7 demonstrated the highest probability of being the most effective intervention (94.8%). Furthermore, when compared to L. plantarum, four probiotics and two synbiotics showed significant advantages in the Patient Assessment of Constipation Symptoms (PAC-SYM) score. L. reuteri (MD = -13.74, 95% CI [-22.20, -4.66], very low certainty) exhibited a significant effect in improving the Patient Assessment of Constipation Quality of Life (PAC-QoL) score. In terms of safety, there were no statistically significant differences between the intervention and control groups in all adverse event analyses. CONCLUSIONS: Moderate to very low evidence supports the use of lactulose and synbiotics to increase the number of weekly stool movements in patients, particularly highlighting the significant impact of synbiotics in increasing the number of weekly stool movements in patients with constipation. The use of L. paracasei showed improvements in PAC-SYM scores, while L. reuteri demonstrated enhancements in PAC-QoL scores.

Intravenous immunoglobulin for treatment of hospitalized COVID-19 patients: an evidence mapping and meta-analysis.

BACKGROUND: The clinical efficacy and safety of intravenous immunoglobulin (IVIg) treatment for COVID-19 remain controversial. This study aimed to map the current status and gaps of available evidence, and conduct a meta-analysis to further investigate the benefit of IVIg in COVID-19 patients. METHODS: Electronic databases were searched for systematic reviews/meta-analyses (SR/MAs), primary studies with control groups, reporting on the use of IVIg in patients with COVID-19. A random-effects meta-analysis with subgroup analyses regarding study design and patient disease severity was performed. Our outcomes of interest determined by the evidence mapping, were mortality, length of hospitalization (days), length of intensive care unit (ICU) stay (days), number of patients requiring mechanical ventilation, and adverse events. RESULTS: We included 34 studies (12 SR/MAs, 8 prospective and 14 retrospective studies). A total of 5571 hospitalized patients were involved in 22 primary studies. Random-effects meta-analyses of very low to moderate evidence showed that there was little or no difference between IVIg and standard care or placebo in reducing mortality (relative risk [RR] 0.91; 95% CI 0.78-1.06; risk difference [RD] 3.3% fewer), length of hospital (mean difference [MD] 0.37; 95% CI - 2.56, 3.31) and ICU (MD 0.36; 95% CI - 0.81, 1.53) stays, mechanical ventilation use (RR 0.92; 95% CI 0.68-1.24; RD 2.8% fewer), and adverse events (RR 0.98; 95% CI 0.84-1.14; RD 0.5% fewer) of patients with COVID-19. Sensitivity analysis using a fixed-effects model indicated that IVIg may reduce mortality (RR 0.76; 95% CI 0.60-0.97), and increase length of hospital stay (MD 0.68; 95% CI 0.09-1.28). CONCLUSION: Very low to moderate certainty of evidence indicated IVIg may not improve the clinical outcomes of hospitalized patients with COVID-19. Given the discrepancy between the random- and fixed-effects model results, further large-scale and well-designed RCTs are warranted.

Optimal cut-offs of depression screening tools during the COVID-19 pandemic: a systematic review.

BACKGROUND: Studies have reported an increase in the prevalence of depression during the COVID-19 pandemic. The accuracy of screening tools may change with the prevalence and distribution of a disease in a population or sample: the "Spectrum Effect". METHODS: First, we selected commonly used screening tools and developed search strategies for the inclusion of original studies during the pandemic. Second, we searched PsycINFO, EMBASE, and MEDLINE from March 2020 to September 2022 to obtain original studies that investigated the accuracy of depression screening tools during the pandemic. We then searched these databases to identify meta-analyses summarizing the accuracy of these tools conducted before the pandemic and compared the optimal cut-offs for depression screening tools during the pandemic with those before. RESULT: Four original studies evaluating the optimal cut-offs for four screening tools (Beck Depression Inventory [BDI-II], Hospital Anxiety and Depression Scale-Depression [HADS-D], Patient Health Questionnaire-9 [PHQ-9], and Geriatric Depression Scale-4 [GDS-4]) were published during the pandemic. Four meta-analyses summarizing these tools before the pandemic. We found that the optimal cut-off of BDI-II was 14 during the pandemic (23.8% depression prevalence, screening patients with Type 2 diabetes) and 14.5 before the pandemic (17.6% depression prevalence, screening psychiatric, primary care, and healthy populations); HADS-D was 10 during the pandemic (23.8% depression prevalence, screening patients with type 2 diabetes) and 7 before the pandemic (15.0% depression prevalence, screening medically ill patients); PHQ-9 was 11 during the pandemic (14.5% depression prevalence, screening university students) and 8 before the pandemic (10.9% depression prevalence, screening the unrestricted population), and GDS-4 was 1.8 during the pandemic (29.0% depression prevalence, screening adults seen in a memory clinic setting) and 3 before the pandemic (18.5% depression prevalence, screening older adults). CONCLUSION: The optimal cut-off for different screening tools may be sensitive to changes in study populations and reference standards. And potential spectrum effects that should be considered in post-COVID time which aiming to improve diagnostic accuracy.

Potential therapeutic targets of the JAK2/STAT3 signaling pathway in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its propensity for metastasis and poor prognosis. TNBC evades the body's immune system recognition and attack through various mechanisms, including the Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. This pathway, characterized by heightened activity in numerous solid tumors, exhibits pronounced activation in specific TNBC subtypes. Consequently, targeting the JAK2/STAT3 signaling pathway emerges as a promising and precise therapeutic strategy for TNBC. The signal transduction cascade of the JAK2/STAT3 pathway predominantly involves receptor tyrosine kinases, the tyrosine kinase JAK2, and the transcription factor STAT3. Ongoing preclinical studies and clinical research are actively investigating this pathway as a potential therapeutic target for TNBC treatment. This article comprehensively reviews preclinical and clinical investigations into TNBC treatment by targeting the JAK2/STAT3 signaling pathway using small molecule compounds. The review explores the role of the JAK2/STAT3 pathway in TNBC therapeutics, evaluating the benefits and limitations of active inhibitors and proteolysis-targeting chimeras in TNBC treatment. The aim is to facilitate the development of novel small-molecule compounds that target TNBC effectively. Ultimately, this work seeks to contribute to enhancing therapeutic efficacy for patients with TNBC.

Extended culture of 2D gastruloids to model human mesoderm development.

Micropatterned human pluripotent stem cells (hPSCs) treated with BMP4 (2D gastruloids) are among the most widely used stem cell models for human gastrulation. Due to its simplicity and reproducibility, this system is ideal for high throughput quantitative studies of tissue patterning and has led to many insights into the mechanisms of mammalian gastrulation. However, 2D gastruloids have only been studied up to 48h. Here we extended this system to 96h. We discovered a phase of highly reproducible morphogenesis during which directed migration from the primitive streak-like region gives rise to a mesodermal layer beneath an epiblast-like layer. Multiple types of mesoderm arise with striking spatial organization including lateral mesoderm-like cells on the colony border and paraxial mesoderm-like further inside the colony. Single cell transcriptomics showed strong similarity of these cells to mesoderm in human and non-human primate embryos. However, our data suggest that the annotation of the reference human embryo may need to be revised. This illustrates that extended culture of 2D gastruloids provides a powerful model for human mesoderm differentiation and morphogenesis.

Enhancing trabecular CT scans based on deep learning with multi-strategy fusion.

Trabecular bone analysis plays a crucial role in understanding bone health and disease, with applications like osteoporosis diagnosis. This paper presents a comprehensive study on 3D trabecular computed tomography (CT) image restoration, addressing significant challenges in this domain. The research introduces a backbone model, Cascade-SwinUNETR, for single-view 3D CT image restoration. This model leverages deep layer aggregation with supervision and capabilities of Swin-Transformer to excel in feature extraction. Additionally, this study also brings DVSR3D, a dual-view restoration model, achieving good performance through deep feature fusion with attention mechanisms and Autoencoders. Furthermore, an Unsupervised Domain Adaptation (UDA) method is introduced, allowing models to adapt to input data distributions without additional labels, holding significant potential for real-world medical applications, and eliminating the need for invasive data collection procedures. The study also includes the curation of a new dual-view dataset for CT image restoration, addressing the scarcity of real human bone data in Micro-CT. Finally, the dual-view approach is validated through downstream medical bone microstructure measurements. Our contributions open several paths for trabecular bone analysis, promising improved clinical outcomes in bone health assessment and diagnosis.

Age-Related Macular Degeneration Choroidal Vascular Distribution Characteristics Based on Indocyanine Green Angiography.

Purpose: The purpose of this study was to present our findings of the distribution pattern of choroidal arteries and large veins in patients with age-related macular degeneration (AMD) using indocyanine green angiography (ICGA). Methods: A retrospective analysis was conducted on 980 patients who underwent ICGA at The Second Affiliated Hospital of Xi'an Jiaotong University from 2017 to 2023, including 240 patients with AMD. Secondary image processing was applied to the angiographic videos to obtain posterior distribution maps of choroidal arteries and large veins. Differences between different distribution patterns regarding age, gender, eye laterality, and circulation time were compared. We also conducted a comparison of choroidal vascular distribution characteristics between patients with AMD and patients with diabetic retinopathy (DR) and provided a summary of choroidal vascular distribution patterns in AMD. Results: The filling patterns of choroidal arteries can be classified into the invisible trunk arteries type, the partially masked trunk arteries type, and the exposed trunk arteries type. The vascular topography of the large choroidal vein can be classified into the watershed type, the non-watershed type, and the unknown type, further divided into six subtypes. The distribution patterns of choroidal arteries and veins were significantly correlated with age (P < 0.001). Left eye, older age, and the exposed trunk arteries type were independent risk factors for non-watershed large choroidal vein (P < 0.05). The non-watershed type was the main characteristic of the venous phase in AMD. Conclusions: The distribution characteristics of the arterial and venous patterns in AMD suggest atrophy of the small blood vessels in the choroid and insufficient perfusion pressure of the blood flow.

Downsizing Porphyrin Covalent Organic Framework Particles Using Protected Precursors for Electrocatalytic CO2 Reduction.

Covalent organic frameworks (COFs) are promising electrocatalyst platforms owing to their designability, porosity, and stability. Recently, COFs with various chemical structures are developed as efficient electrochemical CO2 reduction catalysts. However, controlling the morphology of COF catalysts remains a challenge, which can limit their electrocatalytic performance. Especially, while porphyrin COFs show promising catalytic properties, their particle size is mostly large and uncontrolled because of the severe aggregation of crystallites. In this work, a new synthetic methodology for rationally downsized COF catalyst particles is reported, where a tritylated amine is employed as a novel protected precursor for COF synthesis. Trityl protection provides high solubility to a porphyrin precursor, while its deprotection proceeds in situ under typical COF synthesis conditions. Subsequent homogeneous nucleation and colloidal growth yield smaller COF particles than a conventional synthesis, owing to suppressed crystallite aggregation. The downsized COF particles exhibit superior catalytic performance in electrochemical CO2 reduction, with higher CO production rate and faradaic efficiency compared to conventional COF particles. The improved performance is attributed to the higher contact area with a conductive agent. This study reveals particle size as an important factor for the evaluation of COF electrocatalysts and provides a strategy to control it.

Electron transfer mediated photo-Fenton-like synergistic catalysis of Fe,Cu-doped MIL-101 coupled with Ag3PO4: Quantitative evaluation and DFT calculations.

Widespread use of tetracycline (TC) results in its persistent residue and bioaccumulation in aquatic environments, posing a high toxicity to non-target organisms. In this study, a bimetal-doped composite material Ag3PO4/MIL-101(Fe,Cu) has been designed for the treatment of TC in aqueous solutions. As the molar ratio of Fe/Cu in composite is 1:1, the obtained material AP/MFe1Cu1 is placed in an aqueous environment under visible light irradiation in the presence of 3 mM peroxydisulfate (PDS), which forms a photo-Fenton-like catalytic system that can completely degrade TC (10 mg/L) within 60 min. Further, the degradation rate constant (0.0668 min-1) is 5.66 and 7.34 times higher than that of AP/MFe and AP/MCu, respectively, demonstrating a significant advantage over single metal-doped catalysts. DFT calculations confirm the strong adsorption capacity and activation advantage of PDS on the composite surface. Therefore, the continuous photogenerated electrons (e-) accelerate the activation of PDS and the production of SO4•-, resulting in the stripping of abundant photogenerated h + for TC oxidation. Meanwhile, the internal circulation of FeⅢ/FeⅡ and CuⅡ/CuⅢ in composite also greatly enhances the photo-Fenton-like catalytic stability. According to the competitive dynamic experiments, SO4•- have the greatest contribution to TC degradation (58.93%), followed by 1O2 (23.80%). The degradation intermediates (products) identified by high-performance liquid chromatography-mass spectrometry (HPLC/MS) technique indicate the involvement of various processes in TC degradation, such as dehydroxylation, deamination, N-demethylation, and ring opening. Furthermore, as the reaction proceeds, the toxicity of the intermediates produced during TC degradation gradually decreases, which can ensure the safety of the aquatic ecosystem. Overall, this work reveals the synergy mechanism of PDS catalysis and photocatalysis, as well as provides technical support for removal of TC-contaminated wastewater.

Structural characterization and improves cognitive disorder in ageing mice of a glucomannan from Dendrobium huoshanense.

In the present work, a neutral polysaccharide (DHP-2W) with attenuating cognitive disorder was identified from Dendrobium huoshanense and its structure was clarified. The polysaccharide was successfully purified from D. huoshanense by column chromatography and its activity was evaluated. With a molecular weight of 508.934kDa, this polysaccharide is composed of mannose and glucose at a molar ratio of 75.81: 24.19. Structural characterization revealed that DHP-2W has a backbone consisting of 4)-ß-D-Manp-(1 and 4)-ß-D-Glcp-(1. In vivo experiments revealed that DHP-2W improved cognitive disorder in D-galactose treated mice and relieved oxidative stress and inflammation. DHP-2W attenuates D-galactose-induced cognitive disorder by inhibiting the BCL2/BAX/CASP3 pathway and activating the AMPK/SIRT pathway, thereby inhibiting apoptosis. Furthermore, DHP-2W had a significant effect on regulating the serum levels of Flavin adenine dinucleotide, Shikimic acid, and Kynurenic acid in aged mice. These, in turn, had a positive impact on AMPK/SIRT1 and BCL2/BAX/CASP3, resulting in protective effects against cognitive disorder.

Comparative study on physicochemical properties and hypoglycemic activities of intracellular and extracellular polysaccharides from submerged fermentation of Morchella esculenta.

The structural characteristic, physicochemical properties and structure-hypoglycemic activity relationship of intracellular (IPS) and extracellular (EPS) from submerged fermentation of Morchella esculenta were systematically compared and assessed. Both IPS and EPS were neutral, with a triple-helical conformation, and composed of galactose, glucose and mannose monosaccharides in different molar ratios. The molecular weight and particle size of IPS were higher than those of EPS. FTIR and SEM showed that the main functional group absorption peak intensity, glycosidic bond type and surface morphology of the two polysaccharides differed. Analysis of rheological and thermal properties revealed that the viscosity of IPS was higher than that of EPS, while thermal stability of EPS was greater than that of IPS. Hypoglycemic activity analysis in vitro showed that both IPS and EPS were non-competitive inhibitors of α-amylase and α-glucosidase. EPS showed strong digestive enzyme inhibitory activity due to its higher sulphate content and molar ratio of galactose, lower Mw and particle size. Meanwhile, with its higher Mw and apparent viscosity, IPS showed stronger glucose adsorption capacity and glucose diffusion retardation. These results indicate that IPS and EPS differed considerably in structure and physicochemical properties, which ultimately led to differences in hypoglycemic activity. These results not only suggested that IPS and EPS has the potential to be functional foods or hypoglycemic drugs, but also provided a new target for the prevention and treatment of diabetes with natural polysaccharides.

Time-integrated BMP signaling determines fate in a stem cell model for early human development.

How paracrine signals are interpreted to yield multiple cell fate decisions in a dynamic context during human development in vivo and in vitro remains poorly understood. Here we report an automated tracking method to follow signaling histories linked to cell fate in large numbers of human pluripotent stem cells (hPSCs). Using an unbiased statistical approach, we discover that measured BMP signaling history correlates strongly with fate in individual cells. We find that BMP response in hPSCs varies more strongly in the duration of signaling than the level. However, both the level and duration of signaling activity control cell fate choices only by changing the time integral. Therefore, signaling duration and level are interchangeable in this context. In a stem cell model for patterning of the human embryo, we show that signaling histories predict the fate pattern and that the integral model correctly predicts changes in cell fate domains when signaling is perturbed. Our data suggest that mechanistically, BMP signaling is integrated by SOX2.

Endogenous FGFs drive ERK-dependent cell fate patterning in 2D human gastruloids.

The role of FGF is the least understood of the morphogens driving mammalian gastrulation. Here we investigated the function of FGF in a stem cell model for human gastrulation known as a 2D gastruloid. We found a ring of FGF-dependent ERK activity that closely follows the emergence of primitive streak (PS)-like cells but expands further inward. We showed that this ERK activity pattern is required for PS-like differentiation and that loss of PS-like cells upon FGF receptor inhibition can be rescued by directly activating ERK. We further demonstrated that the ERK-ring depends on localized activation of basally localized FGF receptors (FGFR) by endogenous FGF gradients. We confirm and extend previous studies in analyzing expression of FGF pathway components, showing the main receptor to be FGFR1 and the key ligands FGF2/4/17, similar to the human and monkey embryo but different from the mouse. In situ hybridization and scRNA-seq revealed that FGF4 and FGF17 expression colocalize with the PS marker TBXT but only FGF17 is maintained in nascent mesoderm and endoderm. FGF4 and FGF17 reduction both reduced ERK activity and differentiation to PS-like cells and their derivatives, indicating overlapping function. Thus, we have identified a previously unknown role for FGF-dependent ERK signaling in 2D gastruloids and possibly the human embryo, driven by a mechanism where FGF4 and FGF17 signal through basally localized FGFR1 to induce PS-like cells.

Dendrobium huoshanense in the treatment of ulcerative colitis: Network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium huoshanense C. Z. Tang et S. J. Cheng (DH) is a traditional medicinal herb with a long history of medicinal use. DH has been recorded as protecting the gastrointestinal function. Modern pharmacology research shows that DH regulates intestinal flora, intestinal mucosal immunity, gastrointestinal peristalsis and secretion of digestive juices. At the same time, some studies have shown that DH has a good therapeutic effect on ulcerative colitis, but its mechanism of action has not been fully elucidated. AIMS OF THIS STUDY: To investigate the mechanism and effect of Dendrobium huoshanense C. Z. Tang et S. J. Cheng (DH) in the treatment of ulcerative colitis (UC) by combining network pharmacology and in vivo experimental validation. METHODS: A network pharmacology approach was used to perform component screening, target prediction, PPI network interaction analysis, GO and KEGG enrichment analysis to initially predict the mechanism of DH treatment for UC. Then, the mechanism was validated with the UC mouse model induced by 3% DSS. RESULTS: Based on the network pharmacological analysis, a comprehensive of 101 active components were identified, with 19 of them potentially serving as the crucial elements in DH's effectiveness against UC treatment. Additionally, the study revealed 314 potential core therapeutic targets along with the top 5 key targets: SRC, STAT3, AKT1, HSP90AA1, and PIK3CA. In experiments conducted on live mice with UC, DH was found to decrease the levels of IL-6 and TNF-α in the blood, while increasing the levels of IL-10 and TGF-ß. This led to notable improvements in colon length, injury severity, and an up-regulation of SRC, STAT3, HSP90AA1, PIK3CA, p-AKT1 and PI3K/AKT signaling pathway expression in the colon tissue. CONCLUSIONS: In this study, the active components and main targets of DH for UC treatment were initially forecasted, and the potential mechanism was investigated through network pharmacology. These findings offer an experimental foundation for the clinical utilization of DH.

CRF08_BC subtype is more prone to ART failure and new-generation NNRTI-resistance under long-term first-line ART.

OBJECTIVE: To investigate the characteristics of drug resistance mutations (DRMs) and their contextual influence on drug susceptibility in CRF07_BC and CRF_08BC subtypes. METHODS: Patients with virological failure were genotyped using phylogenetic analysis. DRMs and susceptibility to antiretroviral drugs were analysed using the Stanford University HIV Drug Resistance Database. RESULTS: Six HIV subtypes were identified among 1296 successfully amplified sequences, with the CRF07_BC subtype prevailing at a rate of 91.7%, followed by CRF08_BC. Overall, the CRF07_BC and CRF08_BC subtypes were similar in the distribution and frequency of DRMs, the most common DRMs were K103N and M184V. However, among patients with antiretroviral therapy duration of ≥3 y who developed resistance, CRF08_BC exhibited a higher mutation frequency at sites 184, 138, 221, and 188 (Chi-square test, P < 0.05), and compared with CRF07_BC, patients with CRF08_BC had higher prevalence of abacavir, emtricitabine, lamivudine, doravirine, etravirine, and rilpivirine resistance. Moreover, there was an increased prevalence of cross-resistance between efavirenz/nevirapine and new-generation NNRTIs in patients with CRF08_BC; doravirine (r = 1.0), rilpivirine (r = 0.93), and etravirine (r = 0.86) resistance highly correlated with efavirenz/nevirapine. CONCLUSIONS: The present study provides valuable insights into the profile of DRMs and resistance patterns in patients with CRF07_BC and CRF08_BC experiencing treatment failure in Butuo. These findings have the potential to contribute to future strategies for HIV control and treatment.