Targets For Intervention Research Articles

Genomic Insights into Blood Pressure Regulation: Exploring Ion Channel and Transporter Gene Variations in Jordanian Hypertensive Individuals.

Background and Objectives: Hypertension (HTN) constitutes a significant global health burden, yet the specific genetic variant responsible for blood pressure regulation remains elusive. This study investigates the genetic basis of hypertension in the Jordanian population, focusing on gene variants related to ion channels and transporters, including KCNJ1, WNK1, NPPA, STK39, LUC7L2, NEDD4L, NPHS1, BDKRB2, and CACNA1C. Materials and Methods: This research involved 200 hypertensive patients and 224 healthy controls. Whole blood samples were collected from each participant, and genomic DNA was extracted. The genetic distribution of the polymorphisms was analyzed. The haplotype frequencies were investigated using the SNPStats web tool, and the genotype and allele frequencies of the studied variants were assessed using the χ2 test. Results: Sixteen single nucleotide polymorphisms (SNPs) from nine genes were evaluated. A significant association was observed between the rs880054 variant of the WNK1 gene and hypertension susceptibility, with the T allele elevating the risk of hypertension. This association remained important in the codominant model (p = 0.049) and the dominant model (p = 0.029). In addition, rs880054 was associated with clinical characteristics such as triglyceride levels and cerebrovascular accidents (p-value > 0.05). Conclusions: Our findings reveal a significant link between the rs880054 SNP and an increased hypertension risk, suggesting that variations in WNK1 may be crucial in regulating blood pressure. This study provides new insights into the genetic factors contributing to hypertension and highlights the potential of WNK1 as a target for future therapeutic interventions.

Upregulating lncRNA GUSBP11 protects chondrocytes from IL-1β-induced inflammatory damage via inhibiting miR-122-5p.

Studies have demonstrated that several lncRNAs exhibit abnormal expression levels in patients suffering from osteoarthritis, and in-depth investigation of these aberrantly expressed lncRNAs may pave the way for innovative therapeutic strategies targeting OA. The aim of this study was to examine the expression of glucuronidase beta pseudogene 11 (GUSBP11) in OA patients and to elucidate its potential molecular mechanism. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to detect GUSBP11 levels on cartilage tissues and serum samples obtained from OA patients. To establish an in vitro OA cell model, interleukin-1β (IL-1β) was utilized to induce CHON-001 and ATDC5 cell lines. Cell counting kit-8 (CCK-8) assay and flow cytometry were performed to evaluate cell viability and apoptosis, and enzyme-linked immunosorbent assay (ELISA) was employed to qualify the levels of inflammatory factors. StarBase database predicted that miR-122-5p was the target gene of GUSBP11. Subsequently, luciferase reporter genes were conducted to validate this interaction. Potential target genes of miR-122-5p were predicted, followed by gene function annotation and correlation analysis of these targets. Our findings revealed that GUSBP11 expression was markedly decreased in both the cartilage tissues and serum of OA patients. Diminished levels of GUSBP11 showed high diagnostic accuracy for OA. In the IL-1β-induced OA cell model, GUSBP11 expression was notably reduced, leading to decreased cell viability, an increase in apoptotic cells, and elevated levels of inflammatory factors. Up-regulation of GUSBP11 significantly ameliorated these adverse effects. Luciferase reporter genes confirmed the interaction between GUSBP11 and miR-122-5p, indicating that an increase in miR-122-5p drastically inhibited cell viability while promoting apoptosis and inflammation. In conclusion, within the context of the in vitro OA cell model, GUSBP11 appears to exacerbate IL-1β-induced chondrocyte inflammation through the up-regulation of miR-122-5p. This underscores the potential of GUSBP11 as a novel target and avenue for therapeutic intervention in the treatment of OA.

Contribution of neuroimaging to the understanding of social cognition in epilepsy.

This narrative review aims to identify and summarize existing research to better understand the pathophysiological and neuroanatomical bases of social cognition deficits in people with epilepsy. The neuroanatomical basis of social cognition was primarily examined in healthy subjects. In healthy individuals, social cognition is supported by a complex network of interconnected brain regions. Facial emotion recognition relies on a distributed set of structures, including the occipitotemporal neocortex, the temporoparietal and prefrontal areas, and the putamen with a pivotal role of the amygdala. Theory of mind primarily involves the dorsal medial prefrontal cortex and temporoparietal junction, while empathy engages the anterior insular and cingulate cortices. In people with epilepsy, most functional neuroimaging studies have focused on facial emotion recognition, primarily in patients with temporal lobe epilepsy. Nevertheless, across various domains of social cognition, abnormal activations and disrupted connectivity within social cognition networks are consistently observed, regardless of the focus location. Aberrant connectivity has also been noted in the few studies involving patients with generalized epilepsy. In focal epilepsy, the amygdala remains a central region for facial emotion recognition, irrespective of whether the epilepsy is localized to the temporal or frontal lobes. For theory of mind studies, regions typically identified in healthy individuals, such as the medial prefrontal cortex, exhibit either hyperactivation or reduced activation in people with focal epilepsy, complicating interpretation. In the domain of empathy, a study involving patients with idiopathic generalized epilepsy reported decreased activation in core regions commonly identified in healthy individuals, particularly the anterior cingulate cortex and anterior insula. The limited data available in the literature suggest that key regions shared between social cognition and epilepsy networks consistently contribute to these disruptions and may serve as potential targets for future neuromodulation interventions.

Neural deterioration and compensation in visual short-term memory among individuals with amnestic mild cognitive impairment.

Visual short-term memory (VSTM) is a critical indicator of Alzheimer's disease (AD), but whether its neural substrates could adapt to early disease progression and contribute to cognitive resilience in amnestic mild cognitive impairment (aMCI) has been unclear. Fifty-five aMCI patients and 68 normal controls (NC) performed a change-detection task and underwent multimodal neuroimaging scanning. Among the atrophic brain regions in aMCI, VSTM performance correlated with the volume of the right prefrontal cortex (PFC) but not the medial temporal lobe (MTL), and this correlation was mainly present in patients with greater MTL atrophy. Furthermore, VSTM was primarily correlated with frontal structural connectivity in aMCI but was correlated with more distributed frontal and MTL connectivity in NC. This study provided evidence on neural adaptation in the precursor stages of AD, highlighting the compensatory role of PFC as MTL deteriorated and suggesting potential targets in early intervention for cognitive preservation. Atrophic left medial temporal lobe (MTL) no longer correlated with visual short-term memory (VSTM) in amnestic mild cognitive impairment (aMCI). Atrophic right middle frontal area continued to correlate with VSTM in aMCI. Frontal brain-behavior correlation was mainly present in the aMCI subgroup with greater medial temporal lobe (MTL) atrophy. Reliance of VSTM on frontal connectivity increased in compensation for MTL dysfunction.

Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models.

Background/Objectives: Charcot first described ALS in 1869, but the specific mechanisms that mediate the disease pathology are still not clear. Intense research efforts have provided insight into unique neuroanatomical regions, specific neuronal populations and genetic associations for ALS and other neurodegenerative diseases; however, the experimental results also suggest a convergence of these events to common toxic pathways. We propose that common toxic pathways can be therapeutically targeted, and this intervention will be effective in slowing progression and improving patient quality of life. Here, we focus on understanding the role of IL6 trans-signaling in ALS disease processes. Methods: We leveraged unique mouse models of IL6 trans-signaling that we developed that recapitulate the production of active sIL6R in a genotypic and quantitative fashion observed in humans. Given that the SOD1 transgenic mouse is one of the most highly studied and characterized models of ALS, we bred SOD1G93A mice with IL6R trans-signaling mice to determine how enhanced trans-signaling influenced symptom onset and pathological processes, including neuromuscular junction (NMJ) denervation, glial activation and motoneuron (MN) survival. Results: The results indicate that in animals with enhanced trans-signaling, symptom onset and pathological processes were accelerated, suggesting a role in disease modification. Administration of an IL6R functional blocking antibody failed to alter accelerated symptom onset and disease progression. Conclusions: Future work to investigate the site-specific influence of enhanced IL6 trans-signaling and the tissue-specific bioavailability of potential therapeutics will be necessary to identify targets for precise therapeutic interventions that may limit disease progression in the 60% of ALS patients who inherit the common Il6R Asp358Ala variant.

GPX8 as a potential prognostic marker in gastric and colorectal cancer.

Gastric and colorectal cancers are common malignancies with high incidence and mortality worldwide. Early detection and individualized treatment are crucial to improving patient outcomes. Glutathione peroxidase-8 (GPX8), a member of the glutathione peroxidase family, emerges as a potential target for intervention in the treatment of various cancers. This study investigated the potential of GPX8 as a prognostic marker in patients with gastric and colorectal adenocarcinoma. The study employed a multi-omics approach to analyze GPX8 expression in both tumor and adjacent normal tissue of stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD) and rectum adenocarcinoma patients. The Cancer Genome Atlas database was used to download the microarray data of GPX8 and clinical information for cancer patients. The TIMER database and TNMplot database were used to systematically evaluate the association of GPX8 with tumor-infiltrating lymphocytes in adenocarcinoma. Immunohistochemistry is used to detect GPX8 expression in clinical tumors and adjacent normal tissues. Univariate Cox analysis was performed to explore the relationship between GPX8 expression, immune cell levels, and the prognosis in cancer patients. GPX8 was significantly upregulated in tumor tissue and was associated with a poor prognosis in STAD and COAD patients. Furthermore, high GPX8 expression was found to be correlated with a higher degree of CD4+ T cell-infiltrating in COAD and neutrophil-infiltrating in STAD, indicating that GPX8 may play a role in immune evasion in cancer progression. This study highlights the potential of GPX8 as a prognostic marker in STAD and COAD, providing valuable insight into the development of personalized treatment strategies for cancer patients.

CXCR3 inhibition ameliorates mitochondrial function to restrict oxidative damage via NCOA4-mediated ferritinophagy and improves the gut microbiota in mice.

Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy contributes to maintain intracellular iron balance by regulating ferritin degradation, which is essential for redox homeostasis. CXC-motif chemokine receptor 3 (CXCR3) is involved in the regulation of oxidative stress and autophagy. However, its role in modulating intestinal oxidative damage through ferritinophagy and the gut microbiota remains unclear. In this study, the impact of CXCR3 inhibition on intestine oxidative damage, ferritinophagy, and the gut microbiota, as well as mitochondrial quality control was investigated both in vivo and in vitro. The results show that CXCR3 inhibition by AMG487 relieves Diquat-induced intestinal damage, enhances the expression of tight junction proteins, and enhances antioxidant capacity in mice. Simultaneously, CXCR3 inhibition improves gut microbiota composition, and promotes NCOA4-mediated ferritinophagy. Mechanistically, the effects of CXCR3 inhibition on ferritinophagy are explored in IPEC-J2 cells. Co-localization and interaction between CXCR3 and NCOA4 were observed. Downregulation of NCOA4-medicated ferritinophagy leads to increase the expression of tight junction proteins, reduces iron levels, restricts ROS accumulation, and enhances GPX4 expression. Moreover, CXCR3 suppression facilitates mitochondrial biogenesis and mitochondrial fusion, increases antioxidative capacity, as well as resulting in elevation of tight junction proteins. These findings suggest that CXCR3 inhibition reverses Diquat-induced intestinal oxidative damage, enhances mitochondrial function, and improves gut microbiota composition by elevating NCOA4-medicated ferritinophagy, which implies that CXCR3 may serve as a potential therapeutic intervention targeting iron metabolism for treating intestinal diseases.

Risk factors for acquired weakness in intensive care unit patients: An umbrella review.

This umbrella review aims to summarize and synthesize the evidence on risk factors related to intensive care unit-acquired weakness in systematic reviews to create prevention strategies and intervention measures for intensive care unit-acquired weakness. Eight databases were searched systematically from inception to 1st November 2023. Two researchers independently screened and extracted data based on predefined inclusion and exclusion criteria. The methodological quality, risk of bias and certainty of evidence of reviews included were evaluated using version 2 of the Measurement Tool for Evaluation System Review (AMSTAR-2) and the Risk of Bias in Systematic Reviews (ROBIS), and the Grading of Recommendations Assessment, Development and Evaluation(GRADE) respectively. This review included 10 systematic reviews, reporting a total of 42 factors and 22 associations with meta-analysis. Overall, among these associations, the methodological and evidence quality of the majority ofstudies was rated as low or extremely low. Most systematic reviews and/or meta-analyses exhibited a high risk of bias. This umbrella review comprehensively summarized the risk factors related to intensive care unit-acquired weakness and evaluated the methodological quality, risk of bias, and evidence quality of reviews included. Future studies with high-quality research such as cohort studies are needed, to better update and synthesize the risk factors of intensive care unit-acquired weakness. Inconsistent or even contradictory findings exist among multiple systematic reviews regarding intensive care unit-acquired weakness. The present study offers a comprehensive and readily comprehensible overview of the risk factors linked to intensive care unit-acquired weakness, which is conducive to develop assessment tools for the condition and identify intervention targets.

Identification of Potential Intervention Targets Involved in Prior Exercise that Attenuates Peripheral Neuropathic Pain by Integrating Transcriptome and Whole-genome Bisulfite Sequencing Analyses.

Changes in DNA methylation and subsequent alterations in gene expression have opened a new direction in research related to the pathogenesis of peripheral neuropathic pain (PNP). This study aimed to reveal epigenetic perturbations underlying DNA methylation in the dorsal root ganglion (DRG) of rats with peripheral nerve injury in response to prior exercise and identify potential target genes involved. Male Sprague-Dawley rats were divided into three groups, namely, chronic constriction injury (CCI) of the sciatic nerve, CCI with prior 6-week swimming training (CCI_Ex), and sham operated (Sham). Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were used as the main observation indicators to evaluate behavioral changes associated with pain. In this study, 6-week swimming training before CCI prevented later chronic pain. In particular, CCI rats with prior exercise showed a significant increase in the MWT and TWL of the injured lateral hind paw compared with CCI rats without exercise on days 14, 21, and 28 after CCI. Whole-genome bisulfite sequencing from the injured lumbar (L4-L6) DRGs on the 28th day after surgery was detected. We also generated DNA methylation maps of the two comparisons (sham group vs. CCI and CCI groups vs. CCI_Ex group), and 396 overlapping differentially methylated region-related genes were found between the two comparisons. Moreover, we integrated RNA sequencing to understand the mechanism by which differential DNA methylation after CCI may influence gene expression. Finally, Ryr1 and Xirp2 were identified through association analysis of two omics and quantitative reverse-transcription polymerase chain reaction, respectively. The methylation levels of Ryr1 and Xirp2 were upregulated with a corresponding increase in their mRNA expression in the DRGs of CCI rats, whereas prior exercise downregulated Ryr1 methylation and restore its expression level. Functional enrichment analysis of both omics found that the calcium signaling pathway was significantly enriched. Therefore, the potential intervention targets (Ryr1 and Xirp2) in L4-L6 DRGs may be involved in prior exercise that attenuates PNP induced by CCI. This study provides crucial insights into the epigenetic regulation of PNP responses to prior exercise.

Characteristics and Clinical Outcomes of Women with Polycystic Ovary Syndrome After Bariatric Surgery.

Polycystic ovary syndrome (PCOS) commonly co-occurs with obesity, medical comorbidities, and psychiatric symptoms. Bariatric surgery is an effective treatment for co-occurring obesity and PCOS. While the incidence of PCOS declines substantially after bariatric surgery, the condition is still present for a subset of women. Examining characteristics and clinical outcomes of those with and without PCOS post-surgery may underscore potential risk factors or intervention targets. Individuals up to four years after bariatric surgery were invited to participate in this cross-sectional survey study, which included validated measures of depression, anxiety, eating disorder pathology, and quality of life. Post-surgical weight outcomes, medical comorbidities, and mental health treatment engagement were also assessed. Regression analyses were performed to examine differences in outcomes between those with and without a PCOS diagnosis after bariatric surgery. Of the 657 female (sex assigned at birth) participants who underwent bariatric surgery, 7% (n = 46) reported having a current diagnosis of PCOS. All females identified as women. Women with PCOS were significantly younger (p < 0.001) and were more likely to endorse migraines (p < 0.007) and loss of control (LOC) eating episodes (< 0.001) since undergoing surgery. Additionally, 47.8% of women with PCOS endorsed clinically significant anxiety, compared to 25.7% of women without PCOS(p = 0.03). There were no differences in other demographic, psychiatric, or medical characteristics. Despite thelow prevalence of PCOS diagnoses in the four years after bariatric surgery, this subpopulation may be particularly susceptible to migraines, disinhibited eating behavior, and anxiety, although weight and cardiometabolic outcomes were comparable to those without adiagnosis ofPCOS post-surgically.

Homocysteine Metabolites, Endothelial Dysfunction, and Cardiovascular Disease.

Atherosclerosis is accompanied by inflammation that underlies cardiovascular disease (CVD) and its vascular manifestations, including acute stroke, myocardial infarction, and peripheral artery disease, the leading causes of morbidity/mortality worldwide. The monolayer of endothelial cells formed on the luminal surface of arteries and veins regulates vascular tone and permeability, which supports vascular homeostasis. Endothelial dysfunction, the first step in the development of atherosclerosis, is caused by mechanical and biochemical factors that disrupt vascular homeostasis and induce inflammation. Together with increased plasma levels of low-density lipoprotein (LDL), diabetes, hypertension, cigarette smoking, infectious microorganisms, and genetic factors, epidemiological studies established that dysregulated metabolism of homocysteine (Hcy) causing hyperhomocysteinemia (HHcy) is associated with CVD. Patients with severe HHcy exhibit severe CVD and die prematurely due to vascular complications. Biochemically, HHcy is characterized by elevated levels of Hcy and related metabolites such as Hcy-thiolactone and N-Hcy-protein, seen in genetic and nutritional deficiencies in Hcy metabolism in humans and animals. The only known source of Hcy in humans is methionine released in the gut from dietary protein. Hcy is generated from S-adenosylhomocysteine (AdoHcy) and metabolized to cystathionine by cystathionine β-synthase (CBS) and to Hcy-thiolactone by methionyl-tRNA synthetase. Hcy-thiolactone, a chemically reactive thioester, modifies protein lysine residues, generating N-homocysteinylated (N-Hcy)-protein. N-Hcy-proteins lose their normal native function and become cytotoxic, autoimmunogenic, proinflammatory, prothrombotic, and proatherogenic. Accumulating evidence, discussed in this review, shows that these Hcy metabolites can promote endothelial dysfunction, CVD, and stroke in humans by inducing pro-atherogenic changes in gene expression, upregulating mTOR signaling, and inhibiting autophagy through epigenetic mechanisms involving specific microRNAs, histone demethylase PHF8, and methylated histone H4K20me1. Clinical studies, also discussed in this review, show that cystathionine and Hcy-thiolactone are associated with myocardial infarction and ischemic stroke by influencing blood clotting. These findings contribute to our understanding of the complex mechanisms underlying endothelial dysfunction, atherosclerosis, CVD, and stroke and identify potential targets for therapeutic intervention.

Changes in Lysine Methylation Contribute to the Cytotoxicity of Curcumin in Colon Cancer Cells.

Epigenetic abnormalities play a critical role in colon carcinogenesis, making them a promising target for therapeutic interventions. In this study, we demonstrated that curcumin reduces colon cancer cell survival and that a decrease in lysine methylation was involved in such an effect. This correlated with the downregulation of methyltransferases EZH2, MLL1, and G9a, in both wild-type p53 (wtp53) HCT116 cells and mutant p53 (mutp53) SW480 cells, as well as SET7/9 specifically in wtp53 HCT116 cells. The effects induced by curcumin were more pronounced in wtp53 cells, where it induced a stronger apoptosis and ferroptosis. Interestingly, curcumin also reduced mutp53 expression, suggesting that it could enhance the efficacy of other therapies, particularly in overcoming drug resistance mechanisms associated with mutp53. For instance, in this study, we show that curcumin sensitized SW480 cells to SET7/9 inhibition by sinefungin, further supporting its potential as a combinatorial therapeutic agent. However, although to a lesser extent, curcumin also impaired cell survival in HCT 116 p53 null cells, suggesting that other molecular pathways or factors, beyond p53, may be involved in curcumin-induced cytotoxicity.

Expression level of miR-548aa in tissue samples of patients with colorectal cancer.

The pathogenesis of colorectal cancer (CRC) is influenced by various risk factors, and genetic alterations in progression of colon polyps. The expression patterns of microRNA-548 (miR-548) in colorectal tissues have been sufficiently characterized. The aim of this study is to clarify the role of miR-548aa in tumorigenesis, gene targeting, predictive value and its expression levels in tumoral versus adjacent marginal tissues in CRC patients. This study included 35 CRC patients who underwent surgery to remove their tumor tissue. Tumor samples and adjacent marginal tissue were collected and gene expression was analyzed through real-time PCR. The correlation between miR-548aa expression levels and clinical parameters were investigated. Our findings showed a significant increase in the expression of miR-548aa in tumoral tissues compared to marginal tissues (p < 0.05). The upregulation of miR-548aa was significantly detected in CRC samples, showing an area under the curve of 0.89 (p = 0.002), indicating strong sensitivity and specificity for CRC diagnosis. To prediction of miRNA target genes and construction of regulatory networks of miR-548aa, we used bioinformatics tools including TargetScan and miRDB. Protein-protein interaction (PPI) network was constructed through STRING database and visualized using Cytoscape software. Dysregulation of miR-548aa is closely related to tumorigenesis in colorectal tissues, which affects disease progression and clinical outcomes. The miR-548aa can be introduced as a proposed biomolecule involved in mechanism of tumorigenesis, gene targeting and predictive value for CRC diagnosis and a target for therapeutic intervention.

How spinal GABAergic circuits modulate cerebral processing of postsurgical pain.

Post-surgical pain affects millions each year, hindering recovery and quality of life. Surgical procedures cause tissue damage and inflammation, leading to peripheral and central sensitization, resulting in pain at rest or hyperalgesia to mechanical stimuli, among others. In a rat model for post-surgical pain, spinal GABAergic transmission via GABAA receptors reduces mechanical hypersensitivity but has no effect on pain at rest. While fMRI studies show consistent brain activity changes during mechanical stimulation in post-surgical pain, central processing of pain at rest and the role of spinal GABAergic circuits on surgical pain processing is currently unclear. The aim of this study was to evaluate the influence of an acute surgical incision, a proxy for post-surgical pain, on the cerebral processing of pain at rest and mechanical hypersensitivity, and to assess the influence of spinal GABAA-circuits on this processing. In rats, a unilateral incision injury affected sensorimotor and thalamo-limbic subnetworks at rest and following mechanical stimulation, indicating changes in neural processing relevant to pain at rest and mechanical hypersensitivity in post-surgical pain. Enhancing spinal GABAergic tone increased functional connectivity (FC) in parts of these subnetworks during mechanical stimulation, but not at rest, highlighting spino-cerebral interactions in post-surgical pain regulation relevant for mechanical hypersensitivity and potentially the development of chronic pain after surgery but likely not for pain at rest. These findings underscore the complex and interconnected nature of brain networks in post-surgical pain processing, and provide insights into potential spinal targets for pharmacological intervention to alleviate post-surgical pain and prevent it's chronification.

Drinking intention-behavior links vary by affect among heavy-drinking young adults: An ecological momentary assessment and transdermal sensor study.

Drinking intention is a predictor of heavy-drinking episodes and could serve as a real-time target for preventive interventions. However, the association is inconsistent and relatively weak. Considering the affective context when intentions are formed might improve results by revealing conditions in which intention-behavior links are strongest and the predictive power of intentions is greatest. We investigated the links between drinking intentions reported in the morning and same-day drinking behavior, moderated by positive and negative affect (PA, NA) in a sample of heavy-drinking young adults. Participants wore the SCRAM continuous alcohol monitor transdermal alcohol sensor anklet for 6 consecutive days in their natural environments and responded to daily ecological momentary assessments that included morning intentions to drink and PA/NA items. Drinking events and patterns were measured using morning-report counts and features from the sensor. Bayesian gamma-hurdle and Poisson multilevel models with noninformative priors tested day-level associations. We hypothesized that drinking intention-behavior associations would be strongest on days with high levels of PA, but we did not hypothesize directionality for the NA effect given the conflicting results in previous literature. Day-level drinking intention-behavior associations were stronger on days with higher versus lower PA according to sensors features. Associations were also stronger on days with lower versus higher NA. The strength of intention-behavior links may partly depend on the affective contexts in which intentions are formed. Results could fine-tune intervention approaches by elucidating the affective contexts in which intentions may more clearly link to drinking behavior to reduce the intensity of an episode-better anticipating problematic drinking among young adults. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Staphylococcus aureus Proteins Implicated in the Reduced Virulence of sarA and sarA/agr Mutants in Osteomyelitis.

Using a murine osteomyelitis model, we recently demonstrated that Staphylococcus aureus sarA and sarA/agr mutants generated in the USA300 strain LAC are attenuated to a greater extent than an isogenic agr mutant and that this can be attributed to a significant extent to the increased production of extracellular proteases in both mutants. Based on this, we used a mass-based proteomics approach to compare the proteomes of LAC, its isogenic agr, sarA, and sarA/agr mutants, and isogenic derivatives of all four of these strains unable to produce the extracellular proteases aureolysin, SspA, SspB, ScpA, or SplA-F. This allowed us to identify proteins that were present in reduced amounts in sarA, and sarA/agr mutants owing to the increased production of extracellular proteases. A total of 1039 proteins were detected in conditioned media (CM) from overnight cultures of LAC, and protease-mediated degradation was shown to contribute to the reduced abundance of 224 of these (21.6%) in CM from the sarA and sarA/agr mutants. Among these were specific proteins previously implicated in the pathogenesis and therapeutic recalcitrance of S. aureus osteomyelitis. This demonstrates that the ability of sarA to limit protease production plays a key role in post-translational remodeling of the S. aureus proteome to a degree that can be correlated with reduced virulence in our osteomyelitis model, and that it does so irrespective of the functional status of agr. This also suggests that at least some of these 224 proteins may be viable targets for prophylactic or therapeutic intervention.

Genetic analyses identify brain functional networks associated with the risk of Parkinson's disease and drug-induced parkinsonism.

Brain functional networks are associated with parkinsonism in observational studies. However, the causal effects between brain functional networks and parkinsonism remain unclear. We aimed to assess the potential bidirectional causal associations between 191 brain resting-state functional magnetic resonance imaging (rsfMRI) phenotypes and parkinsonism including Parkinson's disease (PD) and drug-induced parkinsonism (DIP). We used Mendelian randomization (MR) to assess the bidirectional associations between brain rsfMRI phenotypes and parkinsonism, followed by several sensitivity analyses for robustness validation. In the forward MR analyses, we found that three rsfMRI phenotypes genetically determined the risk of parkinsonism. The connectivity in the visual network decreased the risk of PD (OR = 0.391, 95% CI = 0.235 ~ 0.649, P= 2.83 × 10-4, P_FDR= 0.039). The connectivity of salience and motor networks increased the risk of DIP (OR = 4.102, 95% CI = 1.903 ~ 8.845, P= 3.17 × 10-4, P_FDR= 0.044). The connectivity of limbic and default mode networks increased the risk of DIP (OR = 14.526, 95% CI = 3.130 ~ 67.408, P= 6.32 × 10-4, P_FDR= 0.0437). The reverse MR analysis indicated that PD and DIP had no effect on brain rsfMRI phenotypes. Our findings reveal causal relationships between brain functional networks and parkinsonism, providing important interventional and therapeutic targets for different parkinsonism.

High Plasma Polyamine Levels Are Associated With an Increased Risk of Poststroke Cognitive Impairment: A Multicenter Prospective Study From CATIS.

Polyamines have been suggested to play pivotal roles in ischemic stroke and neurodegenerative disorders, but the associations of plasma polyamines with poststroke cognitive impairment (PSCI) remain unclear. We aimed to prospectively investigate the associations of plasma putrescine, spermidine, and spermine with PSCI among patients with ischemic stroke in a multicenter cohort study. We measured plasma polyamine levels at baseline among 619 patients with ischemic stroke from a preplanned ancillary study of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). We used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke, and PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. According to the Mini-Mental State Examination score, plasma polyamines were positively associated with PSCI. The adjusted odds ratios of PSCI for the highest versus lowest quartile of putrescine, spermidine, and spermine were 1.81 (95% CI, 1.09-3.00), 1.81 (95% CI, 1.09-3.01), and 1.92 (95% CI, 1.15-3.20), respectively. In addition, plasma putrescine (net reclassification improvement, 32.08%; P<0.001; integrated discrimination improvement, 1.62%; P=0.002), spermidine (net reclassification improvement, 25.29%; P=0.002; integrated discrimination improvement, 1.22%; P=0.006), and spermine (net reclassification improvement, 16.54%; P=0.045; integrated discrimination improvement, 1.36%; P=0.004) could significantly improve the risk reclassification of PSCI beyond established risk factors. There were similar significant relationships when PSCI was defined by Montreal Cognitive Assessment score. Higher plasma polyamine levels were associated with increased risk of PSCI among patients with ischemic stroke. Our findings suggest that plasma polyamines should be implicated in the pathophysiologic processes of PSCI and may be the potential intervention targets for PSCI. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

BMP6, a potential biomarker of inflammatory fibrosis and promising protective factor for dilated cardiomyopathy

BackgroundDilated cardiomyopathy (DCM) stands as one of the most prevalent and severe causes of heart failure. Inflammation plays a pivotal role throughout the progression of DCM to heart failure, while age acts as a natural predisposing factor for all cardiovascular diseases. These two factors often interact, contributing to cardiac fibrosis, which is both a common manifestation and a pathogenic driver of adverse remodeling in DCM-induced heart failure.MethodBulk RNA-seq, single-cell RNA-seq, Mendelian randomization analysis, animal model construction, and BMP6 knockdown were utilized to identify and validate potential specific markers and targets for intervention in DCM heart failure.ResultsWe found that DCM hearts exhibit pronounced inflammatory cell infiltration and fibrosis. Both bulk RNA-seq and single-cell RNA-seq analyses revealed aberrant BMP6 expression specifically in fibroblasts. The ROC curve underscores the high specificity of BMP6 in relation to DCM, while Mendelian randomization analysis further confirms BMP6 as a protective factor against DCM. Notably, BMP6 knockdown led to a decrease in SMAD6 expression and a marked elevation in COL1A1 expression levels, indicating its antifibrotic role.ConclusionBMP6 emerges as a promising biomarker for DCM, and its functional role in exerting an antifibrotic effect underscores its potential as a therapeutic target.

Association between autoimmune gastritis and gastric polyps: Clinical characteristics and risk factors.

The relationship between autoimmune gastritis (AIG) and gastric polyps (GPs) is not well understood. To explore the clinical characteristics and risk factors of AIG with GPs in patients. This double center retrospective study included 530 patients diagnosed with AIG from July 2019 to July 2023. We collected clinical, biochemical, serological, and demographic data were of each patient. Logistic regression analyses, both multivariate and univariate, were conducted to pinpoint independent risk factors for GPs in patients with AIG patients. Receiver operating characteristic curves were utilized to establish the optimal cutoff values, sensitivity, and specificity of these risk factors for predicting GPs in patients with AIG. Patients with GPs had a higher median age than those without GPs [61 (52.25-69) years vs 58 (47-66) years, P = 0.006]. The gastrin-17 levels were significantly elevated in patients with GPs compared with those without GPs [91.9 (34.2-138.9) pmol/mL vs 60.9 (12.6-98.4) pmol/mL, P < 0.001]. Additionally, the positive rate of parietal cell antibody (PCA) antibody was higher in these patients than in those without GPs (88.6% vs 73.6%, P < 0.001). Multivariate and univariate analyses revealed that PCA positivity [odds ratio (OR) = 2.003, P = 0.017], pepsinogen II (OR = 1.053, P = 0.015), and enterochromaffin like cells hyperplasia (OR = 3.116, P < 0.001) were significant risk factors for GPs, while pepsinogen I was identified as a protective factor. PCA positivity and enterochromaffin like cells hyperplasia are significant risk factor for the development of GPs in patients with AIG. Elevated gastrin-17 levels may also play a role in this process. These findings suggest potential targets for further research and therapeutic intervention in managing GPs in patients with AIG.