Differentiation Factor Research Articles

Transcriptional dynamics orchestrating the development and integration of neurons born in the adult hippocampus.

The adult hippocampus generates new granule cells (aGCs) with functional capabilities that convey unique forms of plasticity to the preexisting circuits. While early differentiation of adult radial glia-like cells (RGLs) has been studied extensively, the molecular mechanisms guiding the maturation of postmitotic neurons remain unknown. Here, we used a precise birthdating strategy to study aGC differentiation using single-nuclei RNA sequencing. Transcriptional profiling revealed a continuous trajectory from RGLs to mature aGCs, with multiple immature stages bearing increasing levels of effector genes supporting growth, excitability, and synaptogenesis. Analysis of differential gene expression, pseudo-time trajectory, and transcription factors (TFs) revealed critical transitions defining four cellular states: quiescent RGLs, proliferative progenitors, immature aGCs, and mature aGCs. Becoming mature aGCs involved a transcriptional switch that shuts down pathways promoting cell growth, such SoxC TFs, to activate programs that likely control neuronal homeostasis. aGCs overexpressing Sox4 or Sox11 remained immature. Our results unveil precise molecular mechanisms driving adult RGLs through the pathway of neuronal differentiation.

Fibroblast Smad7 Induction Protects the Remodeling Pressure-Overloaded Heart.

Cardiac fibroblast activation contributes to adverse remodeling, fibrosis, and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-β (transforming growth factor-β)/Smad (small mother against decapentaplegic)-3 activation protects the pressure-overloaded heart by preserving the matrix, sustained TGF-β activation is deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF-β response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. We hypothesized that Smad7, an inhibitory Smad that restrains TGF-β signaling, may be induced in the pressure-overloaded myocardium and may regulate fibrosis, remodeling, and dysfunction. The effects of myofibroblast-specific Smad7 loss were studied in a mouse model of transverse aortic constriction, using echocardiography, histological analysis, and molecular analysis. Proteomic studies in S7KO (Smad7 knockout) and overexpressing cells were used to identify fibroblast-derived mediators modulated by Smad7. In vitro experiments using cultured cardiac fibroblasts, fibroblasts populating collagen lattices, and isolated macrophages were used to dissect the molecular signals responsible for the effects of Smad7. Following pressure overload, Smad7 was upregulated in cardiac myofibroblasts. TGF-β and angiotensin II stimulated fibroblast Smad7 upregulation via Smad3, whereas GDF15 (growth differentiation factor 15) induced Smad7 through GFRAL (glial cell line-derived neurotrophic factor family receptor α-like). MFS7KO (myofibroblast-specific S7KO) mice had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to transverse aortic constriction. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased MMP (matrix metalloproteinase)-2 activity and collagen denaturation. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins and markedly increases MMP2 secretion. In contrast, Smad7 overexpression reduced MMP2 levels. In fibroblasts populating collagen lattices, the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Macrophage activation involved the combined effects of the fibroblast-derived matricellular proteins CD5L (CD5 antigen-like), SPARC (secreted protein acidic and rich in cysteine), CTGF (connective tissue growth factor), ECM1 (extracellular matrix protein 1), and TGFBI (TGFB induced). The antifibrotic effects of Smad7 in the pressure-overloaded heart protect from dysfunction and involve not only reduction in collagen deposition but also suppression of MMP2-mediated matrix denaturation and paracrine effects that suppress macrophage activation through inhibition of matricellular proteins.

Safety and efficacy of deoxycytidine/deoxythymidine combination therapy in POLG-related disorders: 6-month interim results of an open-label, single arm, phase 2 trial

DNA polymerase gamma (POLG)-related disorders are a group of rare neurodegenerative mitochondrial diseases caused by pathogenic variants in POLG, the gene encoding POLG. Patients may experience a range of signs and symptoms, including seizures, vision loss, myopathy, neuropathy, developmental impairment or regression, and liver failure. The diseases follow a progressive, degenerative course, with most affected individuals dying within 3 months-12 years of diagnosis. At present, there are no effective treatments for POLG-related disorders. In this study we report the interim 6-month data from a long term open-label, single arm phase 2 trial, in which we assessed the safety and efficacy of combination therapy with deoxycytidine and deoxythymidine (dC/dT) in children with POLG-related disorders. dC/dT was given enterally in powder form, dissolved in water. The primary outcome measures included Newcastle Mitochondrial Disease Scale (NMDS) score, serum growth differentiation factor 15 (GDF-15; a biomarker of mitochondrial dysfunction), electroencephalography (EEG), seizure diary, and blood and urine tests to assess end organ and mitochondrial function. Secondary outcome measures included recording of all adverse events to evaluate the safety of the intervention. The trial is registered with ClinicalTrials.gov, NCT04802707 (https://clinicaltrials.gov/ct2/show/NCT04802707). Data were collected from 14 October, 2021 to 13 December,2023. We present 6-month interim data from the first ten people with POLG-related disorders enrolled in the trial, six with Alpers-Huttenlocher syndrome, two with ataxia-neuropathy spectrum, and two who do not fit into a classical POLG-related phenotype. During the 6 months of treatment, NMDS score improved from a mean of 27.3at baseline to 20.7at 6 months (estimated difference 6.0; 95% CI 2.5-∞). GDF-15 values remained stable or decreased in all patients; the mean decreased from 1031pg/ml to 729pg/ml (estimated difference 200; 95% CI 12-∞). 8/10 patients had abnormal baseline EEG; improvement in EEG was seen in 5 of these 8. There were no significant changes in other blood and urine testing. Regarding adverse events, two patients experienced diarrhea that spontaneously resolved. dC/dT is a promising treatment option for people with POLG-related disorders. Further research is needed to assess the long-term safety and efficacy in POLG-related disorders, as well as safety and efficacy in other mitochondrial DNA depletion disorders. This study was primarily funded by the Liam Foundation, with additional funding from the Savoy Foundation, Grand Défi Pierre Lavoie Foundation, and Fonds de Recherche du Québec - Santé.

Discovery of crucial cytokines associated with deep vein thrombus formation by protein array analysis

BackgroundExpanding the number of biomarkers is imperative for studying the etiology and improving venous thromboembolism prediction. In this study, we aimed to identify promising biomarkers or targeted therapies to improve the detection accuracy of early-stage deep vein thrombosis (DVT) or reduce complications.MethodsQuantibody Human Cytokine Antibody Array 440 (QAH-CAA-440) was used to screen novel serum-based biomarkers for DVT/non-lower extremity DVT (NDVT). Differentially expressed proteins in DVT were analyzed using bioinformatics methods and validated using a customized array. Diagnostic accuracy was calculated using receiver operating characteristics, and machine learning was applied to establish a biomarker model for evaluating the identified targets. Twelve targets were selected for validation.ResultsCytokine profiling was conducted using a QAH-CAA-440 (RayBiotech, USA) quantimeter array. Cross-tabulation analysis with Venn diagrams identified common differential factors, leading to the selection of 12 cytokines for validation based on their clinical significance. These 12 biomarkers were consistent with the results of previous array analysis: FGF-6 (AUC = 0.956), Galectin-3 (AUC = 0.942), EDA-A2 (AUC = 0.933), CHI3L1 (AUC = 0.911), IL-1 F9 (AUC = 0.898), Dkk-4 (AUC = 0.88), IG-H3 (AUC = 0.876), IGFBP (AUC = 0.858), Gas-1 (AUC = 0.858), Layilin (AUC = 0.849), ULBP-2 (AUC = 0.813)and FGF-9 (AUC = 0.773). These cytokines are expected to serve as biomarkers, targets, or therapeutic targets to differentiate DVT from NDVT.ConclusionsEDA-A2, FGF-6, Dkk-4, IL-1 F9, Galentin-3, Layilin, Big-h3, CHI3L1, ULBP-2, Gas-1, IGFBP-5, and FGF-9 are promising targets for DVT diagnosis and treatment.

Association between eating speed and atherosclerosis in relation to growth differentiation factor-15 levels in older individuals in a cross-sectional study

Although fast eating speed has been associated with cardiovascular risk factors, no studies have reported an association between fast eating speed and atherosclerosis as evaluated by carotid intima–media thickness (CIMT). Rapid glucose ingestion is known to cause glucose spikes, which may accelerate atherogenesis and increase levels of growth differentiation factor 15 (GDF-15). Therefore, GDF-15 levels may influence the association between fast eating speed and atherosclerosis. To evaluate the association between eating speed and atherosclerosis in relation to GDF-15, this cross-sectional study analyzed 742 Japanese aged 60–69 years. They were required to have normal thyroid hormone levels, because both GDF-15 levels and atherosclerosis (CIMT ≥ 1.1 mm) can be influenced by thyroid dysfunction. Participants were stratified by the median GDF-15 level. A significant positive association was observed between fast eating speed and atherosclerosis, but only among participants with a high GDF-15 level: the sex- and age-adjusted odds ratios (95% confidence intervals) were 1.95 (1.09, 3.48) in participants with a high GDF-15 level, and 0.83 (0.37, 1.88) in those with a low GDF-15 level. This association remained even after further adjustment for thyroid function and metabolic factors. Serum concentrations of GDF-15 may mediate the association between fast eating speed and atherosclerosis.

Social Epidemiology of Early Initiation of Electronic and Conventional Cigarette Use in Early to Middle Adolescents.

Early initiation of tobacco use among adolescents is a significant public health concern. While there is extensive research on overall tobacco use, much of it focuses on initiation in late adolescence, uses cross-sectional designs, and lacks specific exploration of electronic versus conventional cigarette use. This study aims to investigate social determinants influencing the early initiation of electronic and conventional cigarette use among U.S. adolescents. We utilized data from the Adolescent Brain Cognitive Development (ABCD) study, which follows a cohort of tobacco-naïve children from age nine through age 16. The social determinants examined included household income, parental education, financial difficulties, racial/ethnic minority status, family structure, neighborhood income, and gender minority status. Structural equation models were employed to assess associations between these determinants and early initiation of electronic and conventional cigarette use. Male gender was associated with a higher likelihood of conventional cigarette use, while the risk of early initiation of electronic cigarette use was similar across genders. White adolescents were at a higher risk of conventional cigarette use; however, the risk for electronic cigarette use was comparable across White and non-White groups. Financial difficulties were linked to an increased likelihood of early initiation of conventional cigarette use but not electronic cigarette use. Higher household income was associated with a reduced risk of initiating conventional cigarettes but did not significantly impact electronic cigarette use. Adolescents from married families were less likely to initiate electronic cigarette use. No significant effects were found for parental education or neighborhood income on the initiation of either type of cigarette use. Age did not significantly affect the initiation of either cigarette type, and gender minority status was marginally associated with early initiation of conventional cigarette use. The social patterning of electronic cigarette use differs from that of conventional cigarette use, suggesting that distinct tobacco products do not pose a uniform risk across all adolescents. This study underscores the importance of tailored prevention efforts that address the unique challenges associated with early initiation of electronic and conventional cigarette use among adolescents. The differential risk factors identified suggest targeted prevention strategies for conventional cigarette use, focusing on financial difficulties, household income, and gender-specific interventions. In contrast, prevention efforts for electronic cigarette use may require broader, more inclusive approaches that address all adolescents, regardless of their background. Comprehensive universal screening for electronic cigarette use and targeted screening for conventional cigarette use among adolescents are recommended.

Distinct prophage gene profiles of Staphylococcus aureus strains from atopic dermatitis patients and healthy individuals.

Through a nuanced exploration of Staphylococcus aureus strains obtained from atopic dermatitis (AD) patients and healthy controls (HE), our research unveils pivotal genetic determinants influencing their pathogenic associations. Utilizing a random forest classifier, we illuminate distinct marker genes, with phage holin emerging as a critical differential factor, revealing the profound impact of prophages on genetic and pathogenic profiles. HE strains exhibited a diverse gene content, notably shaped by unique, heightened prophages. Conversely, AD strains emphasized a pronounced enrichment of virulence factors within prophages, signifying their key role in AD pathogenesis. This work crucially highlights prophages as central architects of the genetic and functional attributes of S. aureus strains, providing vital insights into pathogenic mechanisms and phenotypic variations, thereby paving the way for targeted AD therapeutic approaches and management strategies by demystifying specific genetic and pathogenic mechanisms.

Proximal and distant expression of growth differentiation factor 15 (GDF15) correlate with neurological deficit following experimental ischemic stroke.

Growth differentiation factor 15 (GDF15) has emerged as a promising biomarker in cerebro-cardiovascular disease, particularly in acute and chronic inflammatory stress situations. However, understanding the origins, targets and functions of GDF15 in clinical situations, such as ischemic stroke, remains a complex challenge. This study aims to assess the sources of GDF15 production following an experimental ischemic stroke. Adult male Wistar rats underwent cerebral embolization through microspheres injection into the left or right internal carotid artery. Two hours post-surgery, GDF15 expression was analyzed in the brain, blood, lungs, liver and heart using quantitative RT-PCR and Western blotting. Stroke model induced large cerebral infarcts accompanied by severe neurological deficits. GDF15 gene expression exhibited a substantial increase in the ipsilateral cortex and cerebellum, with a lesser extent in the contralateral cortex. Regarding GDF15 protein expression, proGDF15 levels were elevated in the 3 aforementioned organs mentioned and the heart. However, the mature form of GDF15 was exclusively present and increased in the heart. Finally, the expression of GDF15 expression was correlated with the neurological deficit score. Our findings suggest that both the GDF15 gene and pro-protein are expressed in the ischemic brain after a stroke, while only its mature form is expressed remotely in in the heart. The impact of increased GDF15 in the heart following a stroke remains to be established. This is particularly relevant in understanding its relationships with poor neurological outcomes, determining whether it may contribute to stroke-induced cardiac dysfunction.

NR2F1 overexpression alleviates trophoblast cell dysfunction by inhibiting GDF15/MAPK axis in preeclampsia.

Abnormal functions of trophoblast cells are associated with the pathogenesis of preeclampsia (PE). Nuclear receptor subfamily 2 group F member 1 (NR2F1) acts as a transcriptionally regulator in many diseases, but its role in PE remains unknown. Hypoxia/reoxygenation (H/R)-stimulated HTR-8/SVneo cells were used to mimic PE injury in vitro. NR2F1 overexpression alleviated trophoblast apoptosis, as evidenced by the decreased number of TUNEL-positive cells and the downregulation of caspase 3 and caspase 9 expression in cells. NR2F1 overexpression increased the invasion and migration ability of HTR-8/SVneo cells, accompanied by increased protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. mRNA-seq was applied to explore the underlying mechanism of NR2F1, identifying growth differentiation factor 15 (GDF15) as the possible downstream effector. Dual-luciferase reporter, ChIP-qPCR, and DNA pull-down assays confirmed that NR2F1 bound to the promoter of GDF15 and transcriptionally inhibited its expression. GDF15 overexpression increased apoptosis and decreased the ability of invasion and migration in HTR-8/SVneo cells expressing NR2F1. MAPK pathway was involved in the regulation of PE. Administration of p38 inhibitor, ERK inhibitor, and JNK inhibitor reversed the effect of simultaneous overexpression NR2F1 and GDF15 on trophoblast apoptosis, invasion, and migration. Our findings demonstrated that NR2F1 overexpression inhibited trophoblast apoptosis and promoted trophoblast invasion and migration. NR2F1 might negatively regulate GDF15 expression by binding to its promoter region, which further inhibited MAPK signaling pathway in PE. Our study highlights that NR2F1 might sever as a potential target in PE.

Screening of <em>FecLL</em> prolific allele of the <em>B4GALNT2</em> gene in Algerian sheep populations

Background: Research on the main genes controlling prolificacy in sheep, also known as fecundity genes (Fec genes), has highlighted the mechanisms involved in ewe fertility and the genetic improvement of prolificacy. The gene, FecL/B4GALNT2 (beta-1,4-N-acetyl-galactosaminyl transferase 2) and its prolific allele FecLL, which segregate in French Lacaune sheep and some local sheep breeds in Morocco and Tunisia, were found to influence ovarian function. However, their action differs from that of other major genes discovered previously, such as: FecX/BMP15 (bone morphogenetic protein 15); FecG/GDF9 (growth differentiation factor 9); and FecB/BMPR1B (bone morphogenetic protein receptor type 1B). The latter act in the bone morphogenetic protein (BMP) signalling pathway. Aim: The objective of this study is to investigate the segregation of the FecLL allele in Algerian sheep populations. Methods: A total of 338 animals from 12 breeds were genotyped using the PCR-RFLP technique. Results: Our results revealed the presence of FecLL in the Algerian D’man sheep population. Among the genotyped D’man sheep, 21% were carriers of the mutation in the heterozygous state. The frequency of the FecLL allele in the Algerian D’man population (0.11) is close to what is observed in Lacaune sheep and remains relatively low compared to Moroccan (0.58) and Tunisian (0.65) D’man sheep. Conclusions: The FecLL allele, which is shared by the French Lacaune population and the North African D’man populations, could indicate the ancestral origin of the mutation in B4GALNT2 or the occurrence of an ancient introgression event to improve prolificacy. Managing this mutation in Algerian D’man flocks could help improve the numerical productivity of D’man sheep in Algeria.

Serum growth differentiation factor 15 as a biomarker for malnutrition in patients with acute exacerbation of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that often coexists with malnutrition during acute exacerbation (AECOPD) and significantly affects the prognosis. Previous studies have shown that growth differentiation factor 15 (GDF15) levels promote appetite suppression, weight loss, and muscle weakness, and are markedly high in peripheral blood following inflammatory stimulation. However, it is still unknown whether serum GDF15 levels can be used to predict malnutrition in patients with AECOPD. A total of 142 patients admitted to the Department of Respiratory Medicine at Anshun People's Hospital between December 2022 and August 2023 were selected for this study. The participants were divided into two groups: malnutrition group (n = 44) and non-malnutrition group (n = 98) based on a body mass index (BMI) < 18.5 kg/m2, according to the Global Leadership Initiative on Malnutrition (GLIM) criteria. Serum GDF15 levels were measured using the enzyme-linked immunosorbent assay (ELISA) and compared between the two groups. Spearman correlation analysis was used to examine the association between serum GDF15 levels, baseline data, and clinical indicators. Binary logistic regression was used to identify the independent risk factors for AECOPD combined with malnutrition. The predictive value of serum GDF15, albumin (ALB), and a combination of these was evaluated to identify malnutrition in patients with AECOPD using a receiver operating characteristic (ROC) curve. Serum GDF15 levels in patients with malnutrition and AECOPD were significantly higher than those in patients without malnutrition, whereas the serum ALB levels were significantly lower than those in patients without malnutrition (p < 0.001). Moreover, serum GDF15 levels were negatively correlated with BMI (r = -0.562, p < 0.001), mid-arm circumference (r = -0.505, p < 0.001), calf circumference (r = -0.490, p < 0.001), total protein (r = -0.486, p < 0.001), ALB (r = -0.445, p < 0.001), and prognostic nutritional index (r = -0.276, p = 0.001), and positively correlated with C-reactive protein (r = 0.318, p < 0.001), COPD assessment test score (r = 0.286, p = 0.001), modified medical research council classification (r = 0.310, p < 0.001), and global initiative for chronic obstructive pulmonary disease grade (r = 0.177, p = 0.035). Furthermore, serum GDF15 levels were an independent risk factor for malnutrition in patients with AECOPD (OR = 1.010, 95% CI, 1.003∼1.016). The optimal cut-off value of serum GDF15 level was 1,092.885 pg/mL, with a sensitivity of 65.90% and a specificity of 89.80%, while the serum ALB level was 36.15 g/L, with a sensitivity of 86.40% and a specificity of 65.00%, as well as a combined sensitivity of 84.10% and a specificity of 73.90%. Serum GDF15 and serum ALB levels had a good predictive ability (AUC = 0.856, AUC = 0.887), and the ROC revealed a greater combined prediction value for the two (AUC = 0.935). Serum GDF15 levels could be used as a potential biomarker in the prediction of malnutrition in patients with AECOPD, offering a guidance for future clinical evaluation of malnutrition.

Insight into IL-5 as a Potential Target for the Treatment of Allergic Diseases.

Interleukin-5 functions as a B-cell differentiation factor, but more importantly, in the context of this review, it plays a variety of roles in eosinophil biology, including eosinophil differentiation and maturation in the bone marrow, and facilitates eosinophil migration to tissue sites, usually in the context of an allergic reaction. Given the availability of selective anti-IL-5 drugs such as mepolizumab and reslizumab, as well as the IL-5 receptor antagonist benralizumab, it is worth investigating whether they could be used in some cases of allergic disease. Asthma has a well-documented involvement of IL-5 in its pathophysiology and has clear benefits in the case of anti-IL-5 therapy; therefore, current knowledge is presented to provide a reference point for the study of less-described diseases such as atopic dermatitis, chronic rhinosinusitis, chronic spontaneous urticaria, and its association with both IL-5 and anti-IL-5 treatment options. We then review the current literature on these diseases, explain where appropriate potential reasons why anti-IL-5 treatments are ineffective, and then point out possible future directions for further research.

Sensing and guiding cell-state transitions by using genetically encoded endoribonuclease-mediated microRNA sensors.

Precisely sensing and guiding cell-state transitions via the conditional genetic activation of appropriate differentiation factors is challenging. Here we show that desired cell-state transitions can be guided via genetically encoded sensors, whereby endogenous cell-state-specific miRNAs regulate the translation of a constitutively transcribed endoribonuclease, which, in turn, controls the translation of a gene of interest. We used this approach to monitor several cell-state transitions, to enrich specific cell types and to automatically guide the multistep differentiation of human induced pluripotent stem cells towards a haematopoietic lineage via endothelial cells as an intermediate state. Such conditional activation of gene expression is durable and resistant to epigenetic silencing and could facilitate the monitoring of cell-state transitions in physiological and pathological conditions and eventually the 'rewiring' of cell-state transitions for applications in organoid-based disease modelling, cellular therapies and regenerative medicine.

Associations of Epigenetic Age Estimators With Cognitive Function Trajectories in the Women's Health Initiative Memory Study.

Epigenetic age estimators indicating faster/slower biological aging vs chronological age independently associate with several age-related outcomes; however, longitudinal associations with cognitive function are understudied. We examined associations of epigenetic age estimators with cognitive function measured annually. This longitudinal study consisted of older women enrolled in the Women's Health Initiative Memory Study with DNA methylation (DNAm) collected at baseline (1995-1998) from 3 ancillary studies and were followed up to 13 years. Global cognitive function was measured annually by Modified Mini-Mental State Examination (3MS; baseline-2007) and by modified Telephone Interview for Cognitive Status (TICS-m, 2008-2021). We calculated 5 epigenetic age estimators: extrinsic AgeAccel, intrinsic AgeAccel, AgeAccelPheno, AgeAccelGrim2, Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE), and AgeAccelGrim2 components (DNA-based plasma protein surrogates). We estimated longitudinal epigenetic age estimator-cognitive function associations using linear mixed-effects models containing age, education, race or ethnicity, and subsequently alcohol, smoking, body mass index, and comorbidities. We examined effect modification by APOE ε4 carriage. A total of 795 participants were enrolled. The mean baseline age was 70.8 ± 4 years (10.7% Black, 3.9% Hispanic or Latina, 85.4% White), A 1-SD (0.12) increment in DunedinPACE associated with faster annual declines in TICS-m scores in minimally adjusted (β = -0.118, 95% CI -0.202 to -0.034; p = 0.0006) and fully adjusted (β = -0.123, 95% CI -0.211 to -0.036; p = 0.006) models. AgeAccelPheno associated with faster annual declines in TICS-m with minimal adjustment (β = -0.091, 95% CI -0.176 to -0.006; p = 0.035) but not with full adjustment. No other epigenetic age estimators associated with changes in 3MS or TICS-m. Higher values of DNAm-based surrogates of growth differentiation factor 15, beta-2 microglobulin, Cystatin C, tissue inhibitor metalloproteinase 1, and adrenomedullin associated with faster annual declines in 3MS and TICS-m. Higher DNAm log A1c associated with faster annual declines in TICS-m only. DunedinPACE associated with faster annual declines in 3MS among APOE ε4 carriers but not among noncarriers (p-interaction = 0.020). Higher DunedinPACE associated with faster declines in TICS-m and 3MS scores among APOE ε4 carriers. DunedinPACE may help identify older women at risk of future cognitive decline. Limitations include the ancillary studies that collected epigenetic data not designed to study epigenetics and cognitive function. We examined epigenetic age estimators with global cognitive function and not specific cognitive domains. Findings may not generalize to men and more diverse populations.

Longitudinal Assessment of Blood-Based Inflammatory, Neuromuscular, and Neurovascular Biomarker Profiles in Intensive Care Unit-Acquired Weakness: A Prospective Single-Center Cohort Study.

The diagnosis of intensive care unit (ICU)-acquired weakness (ICUAW) and critical illness neuromyopathy (CINM) is frequently hampered in the clinical routine. We evaluated a novel panel of blood-based inflammatory, neuromuscular, and neurovascular biomarkers as an alternative diagnostic approach for ICUAW and CINM. Patients admitted to the ICU with a Sequential Organ Failure Assessment score of ≥ 8 on 3 consecutive days within the first 5 days as well as healthy controls were enrolled. The Medical Research Council Sum Score (MRCSS) was calculated, and motor and sensory electroneurography (ENG) for assessment of peripheral nerve function were performed at days 3 and 10. ICUAW was defined by an MRCSS < 48 and CINM by pathological ENG alterations, both at day 10. Blood samples were taken at days 3, 10, and 17 for quantitative analysis of 18 different biomarkers (white blood cell count, C-reactive protein, procalcitonin, C-terminal agrin filament, fatty-acid-binding protein 3, growth and differentiation factor 15, syndecan 1, troponin I, interferon-γ, tumor necrosis factor-α, interleukin-1α [IL-1α], IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, and monocyte chemoattractant protein 1). Results of the biomarker analysis were categorized according to the ICUAW and CINM status. Clinical outcome was assessed after 3 months. Between October 2016 and December 2018, 38 critically ill patients, grouped into ICUAW (18 with and 20 without) and CINM (18 with and 17 without), as well as ten healthy volunteers were included. Biomarkers were significantly elevated in critically ill patients compared to healthy controls and correlated with disease severity and 3-month outcome parameters. However, none of the biomarkers enabled discrimination of patients with and without neuromuscular impairment, irrespective of applied classification. Blood-based biomarkers are generally elevated in ICU patients but do not identify patients with ICUAW or CINM. ClinicalTrials.gov identifier: NCT02706314.

Spatio-temporal Evolution and Driving Factors of Ecological Environment Quality in the Huaihe River Basin Based on RSEI

Clarifying the spatio-temporal evolution of the ecological environment quality of a watershed and its response to the natural environment and human factors are crucial for policy implementation in the ecological environment of the watershed. Using the Google earth engine（GEE） to establish a remote sensing ecological index （RSEI）, the spatio-temporal changes in the ecological environment quality of the Huaihe River Basin from 2002 to 2022 were evaluated combined with trend analysis, variation coefficient, and Hurst index. The main driving factors of spatial differentiation of RSEI were explored using the geographic detector. The results showed that： ① In the past 21 years, RSEI of the Huaihe River Basin had generally improved, but it showed a gradual upward-downward trend. Overall, the area of poor and less poor grades decreased, the area of medium grades increased, and the area of good and excellent grades increased. The improved area accounted for 55.93%, and the degraded area accounted for 22.01%. ② In terms of spatial distribution, RSEI gradually deteriorated from east to west （except in the northwest and southwest marginal mountainous areas）. The stability was better in the east and worse in the western and central areas. In the future, the ecological quality change in the basin was prone to be anti-sustainable and mainly improved. ③ Factor detection results showed that the spatial differentiation of RSEI in the basin was mainly driven by vegetation factors, followed by altitude. The interaction between two factors enhanced the driving force for RSEI spatial differentiation, in which the interaction between vegetation factor and elevation had the strongest driving force for RSEI spatial differentiation, reaching 86.3%.

Variation Characteristics and Source Analysis of Atmospheric Ozone Pollution in Guanzhong Region

Guanzhong urban agglomeration has a good development foundation and great development potential, and it has a unique strategic position in the national all-round opening up pattern. In recent years, the problem of near-surface ozone （O3） in the Guanzhong Region has become increasingly prominent, which has become a bottleneck affecting the continuous improvement of air quality. In order to effectively prevent and control O3 pollution, this study analyzed the characteristics of annual, monthly, and daily changes in O3 concentration in the Guanzhong Region based on the environmental monitoring data from 2018 to 2021. A geo-detector was used to study the driving factors of the spatial differentiation of O3 concentration, and the sources of O3 were analyzed using a backward trajectory model and emission inventory construction. The results showed that the daily and monthly variation in O3 concentration in the Guanzhong Region were unimodal. The daily maximum value appeared at 15：00, the minimum value appeared at 07：00, the peak value of the monthly average appeared in June, and the valley value appeared in December. The O3 concentration was highest in summer, followed by that in spring, and the lowest in winter. The days of O3 exceeding the standard showed mainly mild pollution, and moderate and above pollution showed a trend of decreasing first and then increasing. The O3 concentration in the Guanzhong Region was mainly closely related to precursors and meteorological factors, and the explanatory power of the interaction of each factor was significantly greater than that of any single factor. The regional transport of O3 concentration in the Guanzhong Region was mainly affected by easterly airflow, followed by the northwest direction, with the potential source areas located mainly in Henan Province and Hubei Province. The main local sources of volatile organic compounds （VOCs） were solvent use sources, process sources, and mobile sources, and the main emission sources of nitrogen oxides （NOx） were mobile sources and industrial production combustion sources. The research results have a guiding significance for O3 joint prevention and control in the Guanzhong Region.

Growth Differentiation Factor 15 as a Biomarker of Cardiovascular Risk in Chronic Musculoskeletal Pain.

It is unknown whether growth differentiation factor 15 (GDF-15) is associated with chronic musculoskeletal pain (CMP) and whether or not its association with incident cardiovascular disease (CVD) changes according to CMP status. In total, 1957 randomly selected adults aged ≥65 years without prior CVD were followed up between 2015 and 2023. CMP was classified according to its intensity, frequency, and interference with daily activities. The association between GDF-15 levels and CMP was assessed using linear models with progressive inclusion of potential confounders, whereas the association between GDF-15 and CVD risk was evaluated with Cox proportional hazard models with similar adjustment and interaction terms between GDF-15 and CMP. The incremental predictive performance of GDF-15 over standard predictors was evaluated using discrimination and risk reclassification metrics. GDF-15 concentrations were 6.90% (95% confidence interval [CI]: 2.56; 11.25) higher in individuals with CMP, and up to 8.89% (4.07; 15.71) and 15.79% (8.43; 23.16) higher in those with ≥3 CMP locations and interfering pain. These increased levels were influenced by a higher prevalence of cardiometabolic risk factors, functional impairments, depressive symptoms, and greater levels of inflammation in individuals with CMP. In fully adjusted models, a twofold increase in GDF-15 was associated with a 1.49 increased risk (95% CI: 1.08; 2.05) of a CVD event in individuals with CMP, but not among those without CMP (1.02 [0.77; 1.35]); p-interaction 0.041. Adding GDF-15 to models including the Framingham Risk Score improved predictive performance among individuals with CMP. We provide evidence that GDF-15 could serve as a biomarker to assess CMP, as well as to predict CVD incidence in individuals with CMP.

The Accusatives in the Commentaries of Al-Durra Al-Alfiya by Ibn Al-Muati and Ibn Al-Khabbaz

The research elucidates the permissibility of placing the object first to convey the meaning, as the notion that the pear is eaten comes to mind first. The study delves into the issue of whether the verb can extend to encompass inclusion, involving both the deaf and others, suggesting that it has extended to inclusion in the sentence when it is a type of inclusion, as well as in instances of returning and walking The research asserts that the circumstantial accusative is in the accusative case because it resembles the direct object, being an adjunct. As Sibawayh stated: "The chapter on what is in the accusative among nouns that are neither adjectives nor verbal nouns, because it denotes the state in which the action occurs, thus it is in the accusative as it functions as an object. Some Arabs say: 'I spoke to him, his mouth to my mouth,' as if to say: 'I spoke to him, and this was his state.' Hence, it is the accusative because it describes the state in which the action occurred The research underscores the importance of the representation adopted by the author and the commentator, demonstrating that the object must fulfill three conditions: it must be a noun, it must occur after a clause containing a verb or a word conveying the meaning of a verb and its particles, or it must follow the conjunction "و" indicating association, which signifies accompaniment. Thus, the object actually serves as a noun adjunct to the conjunction"و" denoting association. The study concludes that advancing transmission and analogy in differentiation is permissible. Regarding analogy, this is because the factor in differentiation falls into two categories: one being a solid noun and the other a transitive verb, with the differentiating factor being transitive.

Differentiation of glioma and solitary brain metastasis: a multi-parameter magnetic resonance imaging study using histogram analysis

BackgroundDifferentiation of glioma and solitary brain metastasis (SBM), which requires biopsy or multi-disciplinary diagnosis, remains sophisticated clinically. Histogram analysis of MR diffusion or molecular imaging hasn’t been fully investigated for the differentiation and may have the potential to improve it.MethodsA total of 65 patients with newly diagnosed glioma or metastases were enrolled. All patients underwent DWI, IVIM, and APTW, as well as the T1W, T2W, T2FLAIR, and contrast-enhanced T1W imaging. The histogram features of apparent diffusion coefficient (ADC) from DWI, slow diffusion coefficient (Dslow), perfusion fraction (frac), fast diffusion coefficient (Dfast) from IVIM, and MTRasym@3.5ppm from APTWI were extracted from the tumor parenchyma and compared between glioma and SBM. Parameters with significant differences were analyzed with the logistics regression and receiver operator curves to explore the optimal model and compare the differentiation performance.ResultsHigher ADCkurtosis (P = 0.022), frackurtosis (P<0.001),and fracskewness (P<0.001) were found for glioma, while higher (MTRasym@3.5ppm)10 (P = 0.045), frac10 (P<0.001),frac90 (P = 0.001), fracmean (P<0.001), and fracentropy (P<0.001) were observed for SBM. frackurtosis (OR = 0.431, 95%CI 0.256–0.723, P = 0.002) was independent factor for SBM differentiation. The model combining (MTRasym@3.5ppm)10, frac10, and frackurtosis showed an AUC of 0.857 (sensitivity: 0.857, specificity: 0.750), while the model combined with frac10 and frackurtosis had an AUC of 0.824 (sensitivity: 0.952, specificity: 0.591). There was no statistically significant difference between AUCs from the two models. (Z = -1.14, P = 0.25).ConclusionsThe frac10 and frackurtosis in enhanced tumor region could be used to differentiate glioma and SBM and (MTRasym@3.5ppm)10 helps improving the differentiation specificity.