Reoperative extended arch repair for acute type a aortic dissection after previous cardiac surgery: insights from a relatively young redo series.

OBJECTIVES: To evaluate the impact of previous cardiac surgery (PCS) on clinical outcomes after reoperative extended arch repair for acute type A aortic dissection (ATAAD). METHODS: This study included 37 ATAAD patients with PCS (PCS group) and 992 without PCS (no-PCS group). Propensity score-matching yielded a subgroup of 36 pairs (1:1). In-hospital outcomes and mid-term survival were compared between the two groups. RESULTS: The PCS group was older (56.7 ± 14.2 vs 52.2 ± 12.6 years, p = 0.036) and underwent a longer cardiopulmonary bypass (median, 212 vs 183 min, p < 0.001) compared with the no-PCS group. Operative death occurred in 88 (8.6%) patients, exhibiting no significant difference between groups (13.5% vs 8.4%, p = 0.237). Major postoperative morbidity was observed in 431 (41.9%) patients, also showing no difference between groups (45.9% vs 41.7%, p = 0.615). Moreover, the multivariable logistic regression analysis revealed that PCS was not significantly associated with operative mortality (adjusted odds ratio [OR] 2.58, 95% confidence interval [CI] 0.91-7.29, p = 0.075) or major morbidity (adjusted OR 1.92, 95% CI 0.88-4.18, p = 0.101). The 3-year cumulative survival rates were 71.1% for the PCS group and 83.9% for the no-PCS group (log-rank p = 0.071). Additionally, Cox regression indicated that PCS was not significantly associated with midterm mortality (adjusted hazard ratio 1.40, 95% CI 0.44-4.41, p = 0.566). After matching, no significant differences were found between groups in terms of operative mortality (p > 0.999), major morbidity (p > 0.999), and midterm survival (p = 0.564). CONCLUSIONS: No significant differences were found between ATAAD patients with PCS and those without PCS regarding in-hospital outcomes and midterm survival after extended arch repair.

Genome-wide identification of the Q-type C2H2 zinc finger protein gene family and expression analysis under abiotic stress in lotus (Nelumbo nucifera G.).

BACKGROUND: Lotus (Nelumbo nucifera G.) is an important aquatic plant with high ornamental, economic, cultural and ecological values, but abiotic stresses seriously affect its growth and distribution. Q-type C2H2 zinc finger proteins (ZFPs) play an important role in plant growth development and environmental stress responses. Although the Q-type C2H2 gene family has been identified in some plants, limited reports has been carried out it in lotus. RESULTS: In this study, we identified 45 Q-type NnZFP members in lotus. Based on the phylogenetic tree, these Q-type NnZFP gene family members were divided into 4 groups, including C1-1i, C1-2i, C1-3i and C1-4i. Promoter cis-acting elements analysis indicated that most Q-type NnZFP gene family members in lotus were associated with response to abiotic stresses. Through collinearity analyses, no tandem duplication gene pairs and 14 segmental duplication gene pairs were identified, which showed that duplication events might play a key role in the expansion of the Q-type NnZFP gene family. The synteny results suggested that 54 and 28 Q-type NnZFP genes were orthologous to Arabidopsis and rice, respectively. The expression patterns of these Q-type NnZFP genes revealed that 30 Q-type NnZFP genes were expressed in at least one lotus tissue. Nn5g30550 showed relatively higher expression levels in all tested tissues. 12 genes were randomly selected with at least one gene from each phylogenetic clade, and the expression of these selected genes were confirmed by qRT-PCR (quantitative real-time polymerase chain reaction). The results indicated that Q-type NnZFP genes were extensively involved in cadmium, drought, salt and cold stresses responses. Among them, 11 genes responded to at least three different stress treatments, especially Nn2g12894, which induced by all four treatments. CONCLUSIONS: These results could increase our understanding of the characterization of the Q-type NnZFP gene family and provide relevant information for further functional analysis of Q-type NnZFP genes in plant development, and abiotic stress tolerance in lotus.

Mid-life plasma proteins associated with late-life prefrailty and frailty: a proteomic analysis.

Physical frailty is a syndrome that typically manifests in later life, although the pathogenic process causing physical frailty likely begins decades earlier. To date, few studies have examined the biological signatures in mid-life associated with physical frailty later in life. Among 4,189 middle-aged participants (57.8 ± 5.0 years, 55.8% women) from the Atherosclerosis Risk in Community (ARIC) study, we evaluated the associations of 4,955 plasma proteins (log 2-transformed and standardized) measured using the SomaScan platform with their frailty status approximately 20 years later. Using multinomial logistic regression models adjusting for demographics, health behaviors, kidney function, total cholesterol, and comorbidities, 12 and 221 proteins were associated with prefrailty and frailty in later life, respectively (FDR p < 0.05). Top frailty-associated proteins included neurocan core protein (NCAN, OR = 0.66), fatty acid-binding protein heart (FABP3, OR = 1.62) and adipocyte (FABP4, OR = 1.65), as well proteins involved in the contactin-1 (CNTN1), toll-like receptor 5 (TLR5), and neurogenic locus notch homolog protein 1 (NOTCH1) signaling pathway relevant to skeletal muscle regeneration, myelination, and inflammation. Pathway analyses suggest midlife dysregulation of inflammation, metabolism, extracellular matrix, angiogenesis, and lysosomal autophagy among those at risk for late-life frailty. After further adjusting for midlife body mass index (BMI) - an established frailty risk factor - only CNTN1 (OR = 0.75) remained significantly associated with frailty. Post-hoc analyses demonstrated that the top 41 midlife frailty-associated proteins mediate 32% of the association between mid-life BMI and late-life frailty. Our findings provide new insights into frailty etiology earlier in the life course, enhancing the potential for prevention.

Structure-based discovery of CFTR potentiators and inhibitors.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, whereas its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here, we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify CFTR modulators. We docked ∼155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered mid-nanomolar potentiators, as well as inhibitors, that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.

Chitosan-based GOx@Co-MOF composite hydrogel: A promising strategy for enhanced antibacterial and wound healing effects.

A novel composite hydrogel was synthesized via Schiff base reaction between chitosan and di-functional poly(ethylene glycol) (DF-PEG), incorporating glucose oxidase (GOx) and cobalt metal-organic frameworks (Co-MOF). The resulting CS/PEG/GOx@Co-MOF composite hydrogel was characterized using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), and energy-dispersive X-ray spectroscopy (EDS). The results confirmed successful integration and uniform distribution of Co-MOF within the hydrogel matrix. Functionally, the hydrogel exploits the catalytic decomposition of glucose by GOx to generate gluconic acid and hydrogen peroxide (H2O2), while Co-MOF gradually releases metal ions and protects GOx. This synergy enhanced the antibacterial activity of the composite hydrogel against both Gram-positive (S. aureus) and Gram-negative bacteria (E. coli), outperforming conventional chitosan-based hydrogels. The potential of the composite hydrogel in treating wound infections was evaluated through antibacterial and wound healing experiments. Overall, CS/PEG/GOx@Co-MOF hydrogel holds great promise for the treatment of wound infections, paving the way for further research and potential clinical applications.

Relationship between skeletal mitochondrial function and digital markers of free-living physical activity in older adults.

This study examined the association between in vivo skeletal mitochondrial function and digital free-living physical activity patterns-a measure that summarizes biological, phenotypic, functional, and environmental effects on mobility. Among 459 participants (mean age 68 years; 55% women) in the Baltimore Longitudinal Study of Aging, mitochondrial function was quantified as skeletal muscle oxidative capacity via post-exercise phosphocreatine recovery rate (τPCr) in the vastus lateralis muscle of the left thigh, using 31P magnetic resonance spectroscopy. Accelerometry was collected using a 7-day, 24-h wrist-worn protocol and summarized into activity amount, intensity, endurance, and accumulation patterning metrics. Linear regression, two-part linear and logistic (bout analyses), and linear mixed effects models (time-of-day analyses) were used to estimate associations between τPCr and each physical activity metric. Interactions by age, sex, and gait speed were tested. After covariate adjustment, higher τPCr (or poorer mitochondrial function) was associated with lower activity counts/day (ß = - 6593.7, SE = 2406.0; p = 0.006) and activity intensity (- 81.5 counts, SE = 12.9; p < 0.001). For activity intensity, the magnitude of association was greater for men and those with slower gait speed (interaction p < 0.02 for both). Conversely, τPCr was not associated with daily active minutes/day (p = 0.15), activity fragmentation (p = 0.13), or endurance at any bout length (p > 0.05 for all). Time-of-day analyses show participants with high τPCr were less active from 6:00 a.m. to 12:00 a.m. than those with low τPCr. Results indicate that poorer skeletal mitochondrial function is primarily associated with lower engagement in high intensity activities. Our findings help define the connection between laboratory-measured mitochondrial function and real-world physical activity behavior.

HAMMF: Hierarchical attention-based multi-task and multi-modal fusion model for computer-aided diagnosis of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative condition, and early intervention can help slow its progression. However, integrating multi-dimensional information and deep convolutional networks increases the model parameters, affecting diagnosis accuracy and efficiency and hindering clinical diagnostic model deployment. Multi-modal neuroimaging can offer more precise diagnostic results, while multi-task modeling of classification and regression tasks can enhance the performance and stability of AD diagnosis. This study proposes a Hierarchical Attention-based Multi-task Multi-modal Fusion model (HAMMF) that leverages multi-modal neuroimaging data to concurrently learn AD classification tasks, cognitive score regression, and age regression tasks using attention-based techniques. Firstly, we preprocess MRI and PET image data to obtain two modal data, each containing distinct information. Next, we incorporate a novel Contextual Hierarchical Attention Module (CHAM) to aggregate multi-modal features. This module employs channel and spatial attention to extract fine-grained pathological features from unimodal image data across various dimensions. Using these attention mechanisms, the Transformer can effectively capture correlated features of multi-modal inputs. Lastly, we adopt multi-task learning in our model to investigate the influence of different variables on diagnosis, with a primary classification task and a secondary regression task for optimal multi-task prediction performance. Our experiments utilized MRI and PET images from 720 subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. The results show that our proposed model achieves an overall accuracy of 93.15% for AD/NC recognition, and the visualization results demonstrate its strong pathological feature recognition performance.

High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life.

Importance: Heart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions. Objective: To identify shared pathways between incident HF and frailty in late life using large-scale proteomics. Design, Setting, and Participants: In this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10 638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants in the Cardiovascular Health Study (CHS). Data analysis was conducted from February 2022 to June 2023. Exposures: Protein aptamers, measured at study V3 and V5. Main Outcomes and Measures: Outcomes assessed included incident HF hospitalization after V3 and after V5, prevalent frailty at V5, and incident frailty between V5 and visit 6 (V6; 2016-2017; n = 4131). Frailty was assessed using the Fried criteria. Analyses were adjusted for age, gender, race, field center, hypertension, diabetes, smoking status, body mass index, estimated glomerular filtration rate, prevalent coronary heart disease, prevalent atrial fibrillation, and history of myocardial infarction. Mendelian randomization (MR) analysis was performed to assess potential causal effects of candidate proteins on HF and frailty. Results: A total of 4877 protein aptamers were measured among 10 638 participants at V3 (mean [SD] age, 60 [6] years; 4886 [46%] men). Overall, 286 proteins were associated with incident HF after V3 (822 events; P < 1.0 × 10-5), 83 of which were also associated with incident after V5 (336 events; P < 1.7 × 10-4). Among HF-free participants at V5 (n = 3908; mean [SD] age, 75 [5] years; 1861 [42%] men), 48 of 83 HF-associated proteins were associated with prevalent frailty (223 cases; P < 6.0 × 10-4), 18 of which were also associated with incident frailty at V6 (152 cases; P < 1.0 × 10-3). These proteins enriched fibrosis and inflammation pathways and demonstrated stronger associations with incident HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction. All 18 proteins were associated with both prevalent frailty and incident HF in CHS. MR identified potential causal effects of several proteins on frailty and HF. Conclusions and Relevance: In this study, the proteins associated with risk of HF and frailty enrich for pathways related to inflammation and fibrosis as well as risk of HFpEF. Several of these proteins could potentially contribute to the shared pathophysiology of frailty and HF.

Quantitative imaging for predicting hematoma expansion in intracerebral hemorrhage: A multimodel comparison.

BACKGROUND: Several studies report that radiomics provides additional information for predicting hematoma expansion in intracerebral hemorrhage (ICH). However, the comparison of diagnostic performance of radiomics for predicting revised hematoma expansion (RHE) remains unclear. METHODS: The cohort comprised 312 consecutive patients with ICH. A total of 1106 radiomics features from seven categories were extracted using Python software. Support vector machines achieved the best performance in both the training and validation datasets. Clinical factors models were constructed to predict RHE. Receiver operating characteristic curve analysis was used to assess the abilities of non-contrast computed tomography (NCCT) signs, radiomics features, and combined models to predict RHE. RESULTS: We finally selected the top 21 features for predicting RHE. After univariate analysis, 4 clinical factors and 5 NCCT signs were selected for inclusion in the prediction models. In the training and validation dataset, radiomics features had a higher predictive value for RHE (AUC = 0.83) than a single NCCT sign and expansion-prone hematoma. The combined prediction model including radiomics features, clinical factors, and NCCT signs achieved higher predictive performances for RHE (AUC = 0.88) than other combined models. CONCLUSIONS: NCCT radiomics features have a good degree of discrimination for predicting RHE in ICH patients. Combined prediction models that include quantitative imaging significantly improve the prediction of RHE, which may assist in the risk stratification of ICH patients for anti-expansion treatments.

Age-related changes after intracerebral hemorrhage: a comparative proteomics analysis of perihematomal tissue.

The risk factors and causes of intracerebral hemorrhage (ICH) and the degree of functional recovery after ICH are distinct between young and elderly patients. The increasing incidence of ICH in young adults has become a concern; however, research on the molecules and pathways involved ICH in subjects of different ages is lacking. In this study, tandem mass tag (TMT)-based proteomics was utilized to examine the protein expression profiles of perihematomal tissue from young and aged mice 24 h after collagenase-induced ICH. Among the 5,129 quantified proteins, ICH induced 108 and 143 differentially expressed proteins (DEPs) in young and aged mice, respectively; specifically, there were 54 common DEPs, 54 unique DEPs in young mice and 89 unique DEPs in aged mice. In contrast, aging altered the expression of 58 proteins in the brain, resulting in 39 upregulated DEPs and 19 downregulated DEPs. Bioinformatics analysis indicated that ICH activated different proteins in complement pathways, coagulation cascades, the acute phase response, and the iron homeostasis signaling pathway in mice of both age groups. Protein-protein interaction (PPI) analysis and ingenuity pathway analysis (IPA) demonstrated that the unique DEPs in the young and aged mice were related to lipid metabolism and carbohydrate metabolism, respectively. Deeper paired-comparison analysis demonstrated that apolipoprotein M exhibited the most significant change in expression as a result of both aging and ICH. These results help illustrate age-related protein expression changes in the acute phase of ICH.

Comprehensive analysis of the prognostic value and immunological role of IDO1 gene in pan-cancer.

OBJECTIVE: It has been demonstrated that IDO1, a target of immune checkpoint inhibition, functions as an oncogene in the majority of human malignancies. IDO1's function in human pan-cancers hasn't been thoroughly studied, though. MATERIALS AND METHODS: The Kaplan-Meier (K-M) and COX analyses were applied to the survival analysis. Furthermore, we used Spearman's correlation analysis to examine the associations between IDO1 and microsatellite instability (MSI), DNA methyltransferases (DNMTs), tumor mutational burden (TMB), the associated genes of mismatch repair (MMR), and immune checkpoint biomarkers. Moreover, immunohistochemical analysis and qRT-PCR were used to evaluate IDO1's expression in pan-cancer cells. RESULTS: The findings of this study reveal that IDO1 has abnormal expression in a number of malignancies and is related to the prognosis for UVM, LGG, KIRP, GBM, LAML, OV, READ, MESO, SARC, SKCM, and HNSC. Furthermore, the aberrant IDO1 expression was connected to the TMB, MSI, MMR, drug sensitivity, immune cells infiltrating, and tumor immune microenvironment across a variety of cancer types. The PCR results showed that in contrast to normal cells, IDO1 was found to be significantly highly expressed in breast cancer cells and hepatocellular carcinoma cells, and significantly lowly expressed in gastric cancer cells. CONCLUSION: The clinical treatment of IDO1 is now better supported by a theoretical basis and guidelines provided by our study.

Evaluating a novel 24-hour rest/activity rhythm marker of preclinical ß-amyloid deposition.

STUDY OBJECTIVES: To compare sleep and 24-hour rest/activity rhythms (RARs) between cognitively normal older adults who are ß-amyloid-positive (Aß+) or Aß- and replicate a novel time-of-day-specific difference between these groups identified in a previous exploratory study. METHODS: We studied 82 cognitively normal participants from the Baltimore Longitudinal Study of Aging (aged 75.7 ±â€…8.5 years, 55% female, 76% white) with wrist actigraphy data and Aß+ versus Aß- status measured by [11C] Pittsburgh compound B positron emission tomography. RARs were calculated using epoch-level activity count data from actigraphy. We used novel, data-driven function-on-scalar regression analyses and standard RAR metrics to cross-sectionally compare RARs between 25 Aß+ and 57 Aß- participants. RESULTS: Compared to Aß- participants, Aß+ participants had higher mean activity from 1:00 p.m. to 3:30 p.m. when using less conservative pointwise confidence intervals (CIs) and from 1:30 p.m. to 2:30 p.m. using more conservative, simultaneous CIs. Furthermore, Aß+ participants had higher day-to-day variability in activity from 9:00 a.m. to 11:30 a.m. and lower variability from 1:30 p.m. to 4:00 p.m. and 7:30 p.m. to 10:30 p.m. according to pointwise CIs, and lower variability from 8:30 p.m. to 10:00 p.m. using simultaneous CIs. There were no Aß-related differences in standard sleep or RAR metrics. CONCLUSIONS: Findings suggest Aß+ older adults have higher, more stable day-to-day afternoon/evening activity than Aß- older adults, potentially reflecting circadian dysfunction. Studies are needed to replicate our findings and determine whether these or other time-of-day-specific RAR features have utility as markers of preclinical Aß deposition and if they predict clinical dementia and agitation in the afternoon/evening (i.e. "sundowning").

Large library docking for cannabinoid-1 receptor agonists with reduced side effects.

Large library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones for de novo synthesis and testing. Nine were active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki = 0.7 uM) led to '4042, a 1.9 nM ligand and a full CB1R agonist. A cryo-EM structure of the purified enantiomer of '4042 ('1350) in complex with CB1R-Gi1 confirmed its docked pose. The new agonist was strongly analgesic, with generally a 5-10-fold therapeutic window over sedation and catalepsy and no observable conditioned place preference. These findings suggest that new cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from their analgesia, supporting the further development of cannabinoids as pain therapeutics.

Musculoskeletal Pain Characteristics and Objectively Measured Physical Activity in Older Adults.

BACKGROUND: Pain is associated with reports of restricted physical activity (PA), yet the association between musculoskeletal pain characteristics and objectively measured PA quantities and patterns in late life is not well understood. METHODS: A total of 553 adults (mean age 75.8 ±â€…8.4 years, 54.4% women) in the Baltimore Longitudinal Study of Aging (BLSA) completed a health interview and subsequent 7-day wrist-worn ActiGraph assessment in the free-living environment between 2015 and 2020. Pain characteristics, including pain presence in 6x sites (ie, shoulders, hands/wrists, low back, hip, knees, and feet), pain laterality in each site, and pain distribution were assessed. PA metrics were summarized into total daily activity counts (TAC), activity fragmentation, active minutes/day, and diurnal patterns of activity. Linear regression models and mixed-effects models examined the association between pain characteristics and PA outcomes, adjusted for demographics and comorbidities. RESULTS: Unilateral knee pain was associated with 184 070 fewer TAC (p = .039) and 36.2 fewer active minutes/day (p = .032) compared to those without knee pain. Older adults with shoulder pain or hand/wrist pain had more active minutes compared to those without pain (p < .05 for all). For diurnal patterns of activity, participants with knee pain had fewer activity counts during the afternoon (12:00 pm to 5:59 pm). Analyses stratified by sex showed that these associations were only significant among women. CONCLUSIONS: Our study highlights the importance of assessing pain laterality in addition to pain presence and suggests that pain interferes with multiple aspects of daily activity. Longitudinal studies are needed to assess the temporality of these findings.

A Comprehensive Pan-cancer Analysis of the Biological Immunomodulatory Function and Clinical Value of CD27.

Background: CD27 is an immunological checkpoint gene, plays a critical function inInhibition or activation of cancer immunity. The CD27/CD27L axis is its pathway of action. Therefore, our goal was to examine the predictive role of CD27 in the clinical prognosis of 33 cancer types and its functions in cancer progression, as well as explore the link between pan-cancer CD27 gene expression and immune infiltration. Methods: By comprehensive use of datasets and methods from TCGA, cBioPortal, GTEx, HPA, KM-plotter, Spearman, CellMinerTM, R packages and RT-qPCR, we delved deeper into the potential impact of the CD27 on cancer development. These include expression differences, immune infiltration, matrix infiltration, gene mutations, DNA methylation, signaling pathways, TMB, MSI, and prognosis. Also, we explored CD27 interactions with different drugs. Results: The results showed that, mutated CD27 was highly expressed in most cancers. The CD27 showed strong diagnostic value in 4 cancers and marked a positive prognosis for CESC, intracervical adenocarcinoma, HNSC, and endometrial cancer, and a poor prognosis for UVM. In addition, CD27 affects multiple immune and inflammatory signaling pathways and is positively correlated with immune cell infiltration, T cell differentiation, macrophage M1 polarization, stromal infiltration, and drug sensitivity. DNA methylation is involved in CD27 expression in cancer. Conclusion: CD27, which is mutated in cancers and appears widely highly expressed and altered tumor immune invasion and stromal invasion by affecting multiple immune-related and inflammation signaling pathways, plays a significant role in CESC, HNSC, UCEC and UVM, and may be used as a therapeutic target for related cancers.

Prognostic value and immunological role of PD-L1 gene in pan-cancer.

OBJECTIVE: PD-L1, a target of immune checkpoint blockade, has been proven to take the role of an oncogene in most human tumors. However, the role of PD-L1 in human pan-cancers has not yet been fully investigated. MATERIALS AND METHODS: Pan-cancer analysis was conducted to analyze expression, genetic alterations, prognosis analysis, and immunological characteristics of PD-L1. Estimating the correlation between PD-L1 expression and survival involved using pooled odds ratios and hazard ratios with 95% CI. The Kaplan-Meier (K-M) technique, COX analysis, and receiver operating characteristic (ROC) curves were applied to the survival analysis. Additionally, we investigated the relationships between PD-L1 and microsatellite instability (MSI), tumor mutational burden (TMB), DNA methyltransferases (DNMTs), the associated genes of mismatch repair (MMR), and immune checkpoint biomarkers using Spearman's correlation analysis. Also, immunohistochemical analysis and qRT-PCR were employed in evaluating PD-L1's protein and mRNA expression in pan-caner. RESULTS: PD-L1 showed abnormal mRNA and protein expression in a variety of cancers and predicted prognosis in cancer patients. Furthermore, across a variety of cancer types, the aberrant PD-L1 expression was connected to the MSI, MMR, TMB, drug sensitivity, and tumor immune microenvironment (TIME). Moreover, PD-L1 was significantly correlated with infiltrating levels of immune cells (T cell CD8 + , neutrophil, and so on). CONCLUSION: Our study provides a better theoretical basis and guidance for the clinical treatment of PD-L1.

Small vs. Large Library Docking for Positive Allosteric Modulators of the Calcium Sensing Receptor.

Drugs acting as positive allosteric modulators (PAMs) to enhance the activation of the calcium sensing receptor (CaSR) and to suppress parathyroid hormone (PTH) secretion can treat hyperparathyroidism but suffer from side effects including hypocalcemia and arrhythmias. Seeking new CaSR modulators, we docked libraries of 2.7 million and 1.2 billion molecules against transforming pockets in the active-state receptor dimer structure. Consistent with simulations suggesting that docking improves with library size, billion-molecule docking found new PAMs with a hit rate that was 2.7-fold higher than the million-molecule library and with hits up to 37-fold more potent. Structure-based optimization of ligands from both campaigns led to nanomolar leads, one of which was advanced to animal testing. This PAM displays 100-fold the potency of the standard of care, cinacalcet, in ex vivo organ assays, and reduces serum PTH levels in mice by up to 80% without the hypocalcemia typical of CaSR drugs. Cryo-EM structures with the new PAMs show that they induce residue rearrangements in the binding pockets and promote CaSR dimer conformations that are closer to the G-protein coupled state compared to established drugs. These findings highlight the promise of large library docking for therapeutic leads, especially when combined with experimental structure determination and mechanism.

Comparison of sleep parameters from wrist-worn ActiGraph and Actiwatch devices.

Sleep and physical activity, two important health behaviors, are often studied independently using different accelerometer types and body locations. Understanding whether accelerometers designed for monitoring each behavior can provide similar sleep parameter estimates may help determine whether one device can be used to measure both behaviors. Three hundred and thirty one adults (70.7 ±â€…13.7 years) from the Baltimore Longitudinal Study of Aging wore the ActiGraph GT9X Link and the Actiwatch 2 simultaneously on the non-dominant wrist for 7.0 ±â€…1.6 nights. Total sleep time (TST), wake after sleep onset (WASO), sleep efficiency, number of wake bouts, mean wake bout length, and sleep fragmentation index (SFI) were extracted from ActiGraph using the Cole-Kripke algorithm and from Actiwatch using the software default algorithm. These parameters were compared using paired t-tests, Bland-Altman plots, and Deming regression models. Stratified analyses were performed by age, sex, and body mass index (BMI). Compared to the Actiwatch, the ActiGraph estimated comparable TST and sleep efficiency, but fewer wake bouts, longer WASO, longer wake bout length, and higher SFI (all p < .001). Both devices estimated similar 1-min and 1% differences between participants for TST and SFI (ß = 0.99, 95% CI: 0.95, 1.03, and 0.91, 1.13, respectively), but not for other parameters. These differences varied by age, sex, and/or BMI. The ActiGraph and the Actiwatch provide comparable absolute and relative estimates of TST, but not other parameters. The discrepancies could result from device differences in movement collection and/or sleep scoring algorithms. Further comparison and calibration is required before these devices can be used interchangeably.

Structure-based discovery of CFTR potentiators and inhibitors.

The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel whose loss of function leads to cystic fibrosis, while its hyperactivation leads to secretory diarrhea. Small molecules that improve CFTR folding (correctors) or function (potentiators) are clinically available. However, the only potentiator, ivacaftor, has suboptimal pharmacokinetics and inhibitors have yet to be clinically developed. Here we combine molecular docking, electrophysiology, cryo-EM, and medicinal chemistry to identify novel CFTR modulators. We docked ~155 million molecules into the potentiator site on CFTR, synthesized 53 test ligands, and used structure-based optimization to identify candidate modulators. This approach uncovered novel mid-nanomolar potentiators as well as inhibitors that bind to the same allosteric site. These molecules represent potential leads for the development of more effective drugs for cystic fibrosis and secretory diarrhea, demonstrating the feasibility of large-scale docking for ion channel drug discovery.

Involvement of CD44 and MAPK14-mediated ferroptosis in hemorrhagic shock.

To elucidate the induction of ferroptotic pathways and the transcriptional modulation of pivotal genes in the context of hemorrhagic shock. The R software was used to analyze the GSE64711 dataset, isolating genes relevant to ferroptosis. Enrichment analyses and protein interaction networks were assembled. Using WGCNA hub genes were identified and intersected with ferroptosis-related genes, highlighting hub genes CD44 and MAPK14. In a rat hemorrhagic shock model, cardiac ROS, Fe2+, MDA, and GSH levels were assessed. Key ferroptotic proteins (SLC7A11/GPX4) in myocardial tissues were examined via western blot. Hub genes, CD44 and MAPK14, expressions were confirmed through immunohistochemistry. Analyzing the GSE64711 dataset revealed 337 differentially expressed genes, including 12 linked to ferroptosis. Enrichment analysis highlighted pathways closely related to ferroptosis. Using Genemania, we found these genes mainly affect ROS metabolism and oxidative stress response. WGCNA identified CD44 and MAPK14 as hub genes. Rat myocardial tissue validation showed significant cardiac damage and elevated ROS and MDA levels, and decreased GSH levels in the hemorrhagic shock model. The ferroptotic pathway SLC7A11/GPX4 was activated, and immunohistochemistry showed a significant increase in the expression levels of CD44 and MAPK14 in the hemorrhagic shock rat model. We demonstrated the presence of tissue ferroptosis in hemorrhagic shock by combining bioinformatics analysis with in vivo experimentation. Specifically, we observed the activation of the SLC7A11/GPX4 ferroptotic pathway. Further, CD44 and MAPK14 were identified as hub genes in hemorrhagic shock.