The cAMP receptor protein from Gardnerella vaginalis is not regulated by ligands.

Overgrowth of Gardnerella vaginalis causes an imbalance in vaginal microecology. The pathogenicity of G. vaginalis is directly regulated by the cAMP receptor protein (CRP). In this study, we resolve the crystal structure of CRPGv at a resolution of 2.22 Å and find some significant differences from homologous proteins. The first 23 amino acids of CRPGv are inserted into the ligand binding pocket, creating a strong steric barrier to ligand entry that has not been seen previously in its homologues. In the absence of ligands, the two α helices used by CRPGv to bind oligonucleotide chains are exposed and can specifically bind TGTGA-N6-TCACA sequences. cAMP and other ligands of CRP homologs are not cofactors of CRPGv. There is no coding gene of the adenylate cyclase, and cAMP could not be identified in G. vaginalis by liquid chromatography tandem mass spectrometry. We speculate that CRPGv may achieve fine regulation through a conformational transformation different from that of its homologous proteins, and this conformational transformation is no longer dependent on small molecules, but may be aided by accessory proteins. CRPGv is the first discovered CRP that is not ligand-regulated, and its active conformation provides a structural basis for drug screening.

EmbB and EmbC regulate the sensitivity of Mycobacterium abscessus to echinomycin.

Treatment of Mycobacterium abscessus (Mab) infections is very challenging due to its intrinsic resistance to most available drugs. Therefore, it is crucial to discover novel anti-Mab drugs. In this study, we explored an intrinsic resistance mechanism through which Mab resists echinomycin (ECH). ECH showed activity against Mab at a minimum inhibitory concentration (MIC) of 2 µg/ml. A ΔembC strain in which the embC gene was knocked out showed hypersensitivity to ECH (MIC: 0.0078-0.0156 µg/ml). The MICs of ECH-resistant strains screened with reference to ΔembC ranged from 0.25 to 1 µg/ml. Mutations in EmbB, including D306A, D306N, R350G, V555I, and G581S, increased the Mab's resistance to ECH when overexpressed in ΔembC individually (MIC: 0.25-0.5 µg/ml). These EmbB mutants, edited using the CRISPR/Cpf1 system, showed heightened resistance to ECH (MIC: 0.25-0.5 µg/ml). The permeability of these Mab strains with edited genes and overexpression was reduced, as evidenced by an ethidium bromide accumulation assay, but it remained significantly higher than that of the parent Mab. In summary, our study demonstrates that ECH exerts potent anti-Mab activity and confirms that EmbB and EmbC are implicated in Mab's sensitivity to ECH. Mutation in EmbB may partially compensate for a loss of EmbC function.

Distinct Olfactory Bulb-Cortex Neural Circuits Coordinate Cognitive Function in Parkinson's Disease.

Cognitive dysfunction stands as a prevalent and consequential non-motor manifestation in Parkinson's disease (PD). Although dysfunction of the olfactory system has been recognized as an important predictor of cognitive decline, the exact mechanism by which aberrant olfactory circuits contribute to cognitive dysfunction in PD is unclear. Here, we provide the first evidence for abnormal functional connectivity across olfactory bulb (OB) and piriform cortex (PC) or entorhinal cortex (EC) by clinical fMRI, and dysfunction of neural coherence in the olfactory system in PD mice. Moreover, we discovered that 2 subpopulations of mitral/tufted (M/T) cells in OB projecting to anterior PC (aPC) and EC precisely mediated the process of cognitive memory respectively by neural coherence at specific frequencies in mice. In addition, the transcriptomic profiling analysis and functional genetic regulation analysis further revealed that biorientation defective 1 (Bod1) may play a pivotal role in encoding OBM/T-mediated cognitive function. We also verified that a new deep brain stimulation protocol in OB ameliorated the cognitive function of Bod1-deficient mice and PD mice. Together, aberrant coherent activity in the olfactory system can serve as a biomarker for assessing cognitive function and provide a candidate therapeutic target for the treatment of PD.

Causal Effects of Gut Microbiota and Metabolites on Chronic Obstructive Pulmonary Disease: A Bidirectional Two Sample Mendelian Randomization Study.

Background: Recent evidence suggests that the gut microbiome and metabolites are intricately involved in Chronic Obstructive Pulmonary Disease (COPD) pathogenesis, yet the precise causal relationships remain unclear due to confounding factors and reverse causation. This study employs bidirectional two-sample Mendelian Randomization (MR) to clarify these connections. Methods: Summary data from publicly available Genome-Wide Association Studies (GWAS) concerning the gut microbiome, metabolites, and COPD were compiled. The selection of genetic instrumental variables (Single Nucleotide Polymorphisms, or SNPs) for MR analysis was conducted meticulously, primarily utilizing the Inverse Variance Weighting (IVW) method, supplemented by MR-Egger regression and the Weighted Median (WM) approach. The evaluation of heterogeneity and horizontal pleiotropy was performed using Cochran's Q test, the MR-Egger intercept test, and the MR-PRESSO global test. Sensitivity analyses, including leave-one-out tests, were conducted to verify the robustness of our results. And the mediation effect of gut microbiota-mediated changes in metabolites on the causal relationship with COPD was analyzed. Results: Our study identified nine significant gut microbiota taxa and thirteen known metabolites implicated in COPD pathogenesis. Moreover, associations between the onset of COPD and the abundance of five bacterial taxa, as well as the concentration of three known metabolites, were established. These findings consistently withstood sensitivity analyses, reinforcing their credibility. Additionally, our results revealed that gut microbiota contribute to the development of COPD by mediating changes in metabolites. Conclusion: Our bidirectional Two-Sample Mendelian Randomization analysis has revealed reciprocal causal relationships between the abundance of gut microbiota and metabolite concentrations in the context of COPD. This research holds promise for identifying biomarkers for early COPD diagnosis and monitoring disease progression, thereby opening new pathways for prevention and treatment. Further investigation into the underlying mechanisms is essential to improve our understanding of COPD onset.

Chinese expert consensus on blood lipid management in patients with diabetes (2024 edition).

Diabetes is a significant independent risk factor for atherosclerotic cardiovascular disease (ASCVD), with dyslipidemia playing a critical role in the initiation and progression of ASCVD in diabetic patients. In China, the current prevalence of dyslipidemia in diabetes is high, but the control rate remains low. Therefore, to enhance lipid management in patients with diabetes, the Endocrinology and Metabolism Physician Branch of the Chinese Medical Doctor Association, in collaboration with the Experts' Committee of the National Society of Cardiometabolic Medicine, has convened experts to develop a consensus on the management of dyslipidemia in patients with type 1 or type 2 diabetes. The development of this consensus is informed by existing practices in lipid management among Chinese diabetic patients, incorporating contemporary evidence-based findings and guidelines from national and international sources. The consensus encompasses lipid profile characteristics, the current epidemiological status of dyslipidemia, ASCVD risk stratification, and lipid management procedures in diabetic patients. For the first time, both low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol have been recommended as primary targets for lipid intervention in diabetic patients. The consensus also includes a summary and recommendations for lipid management strategies in special diabetic populations, including children and adolescents, individuals aged 75 years and older, patients with chronic kidney disease, metabolic-associated fatty liver disease, and those who are pregnant. This comprehensive consensus aims to improve cardiovascular outcomes in diabetic patients by contributing to the dissemination of key clinical advancements and guiding clinical practice.

The Causal Effects between Mood Swings and Gastrointestinal Diseases: A Mendelian Randomization Study.

Background: Numerous studies have examined the links between mental disorders such as depression and bipolar disorder, and gastrointestinal (GI) diseases. However, few studies have investigated the link between mood swings and GI diseases. Given the impact of mood swings on various conditions and the growing comprehension of the gut-brain axis, this study aims to explore their causal relationship using Mendelian randomization (MR) methods. Methods: Single-nucleotide polymorphisms (SNPs) associated with mood swings were obtained from a recent study. SNPs associated with GI diseases were identified from the FinnGen project. We conducted two-sample bidirectional MR analyses using three methods, primarily the inverse variance weighting (IVW) method. Furthermore, we performed sensitivity analyses and false discovery rate (FDR) analysis to validate the accuracy and robustness of the results. Results: Bidirectional MR analysis revealed significant causal effects between mood swings and GI diseases according to the IVW method (odds ratio (OR): 1.213; 95% confidence interval (CI): 1.118-1.316; P = 3.490e-6; P FDR = 8.730e-5). Mood swings were linked to an increased risk for 11 of 24 diseases, including five upper GI diseases (gastroesophageal reflux disease (GERD), acute gastritis, gastroduodenal ulcer, duodenal ulcer, and functional dyspepsia), two lower GI diseases (diverticular disease of the intestine and irritable bowel syndrome (IBS)) and four hepatobiliary and pancreatic diseases (nonalcoholic fatty liver disease (NAFLD), chronic pancreatitis, acute pancreatitis, and pancreatic cancer). Inverse MR analysis showed no causal relationship between 24 GI diseases and mood swings. Conclusions: This comprehensive MR analysis suggests that genetically predicted mood swings may be a risk factor in the development of GI diseases. Interventions for mood swings may help to treat GI diseases.

Stimuli-responsive prodrugs with self-immolative linker for improved cancer therapy.

Self-immolative prodrugs have gained significant attention as an innovative approach for targeted cancer therapy. These prodrugs are engineered to release the active anticancer agents in response to specific triggers within the tumor microenvironment, thereby improving therapeutic precision while reducing systemic toxicity. This review focuses on the molecular architecture and design principles of self-immolative prodrugs, emphasizing the role of stimuli-responsive linkers and activation mechanisms that enable controlled drug release. Recent advancements in this field include the development of prodrugs that incorporate targeting moieties for enhanced site-specificity. Moreover, the review discusses the incorporation of targeting moieties to achieve site-specific drug delivery, thereby improving the selectivity of treatment. By summarizing key research from the past five years, this review highlights the potential of self-immolative prodrugs to revolutionize cancer treatment strategies and pave the way for their integration into clinical practice.

Impact of chemical aging on pyrogenic carbon colloid facilitated transport and transformation of Cr (VI) in anoxic environments.

Frequent wildfires have accumulated the pyrogenic carbon (PyC) colloids in the environment, where they undergo environmental aging processes. The altered properties of aged PyC colloids may affect their ability to facilitate transformation and transport of contaminants in post-fire environments, posing unknown threats to ecological security. This study investigated the effect of chemical aging on the PyC colloid-facilitated transformation and transport of chromium (Cr) using batch experiments, column experiments, and transport model simulations. Results showed that aged PyC colloids exhibited weaker electron-donating capacity, and the reduction of Cr (VI) to Cr (III) decreased from 37.6 % to 13.5 % with the increasing aging time. Although PyC colloid transport increased with aging time, the PyC colloid-facilitated Cr (III) transport decreased because of the weakened reduction of Cr (VI). The transport of PyC colloid-facilitated Cr (III) was weaker at low pH. The reactive solute transport model well simulated the aged PyC colloid-facilitated transformation and transport of Cr (VI). Our findings highlight the significance of aging processes and environmentally relevant conditions in influencing the PyC colloid-facilitated transformation and transport of Cr, which is crucial for assessing risks of wildfire-driven Cr pollution and the potential of PyC for in-situ pollution control.

Assessment of diagnostic value of unilateral systematic biopsy combined with targeted biopsy in detecting clinically significant prostate cancer.

Objectives: This retrospective study assessed the diagnostic accuracy of targeted biopsy (TB) and unilateral systematic biopsy in detecting clinically significant prostate cancer (csPCa) in 222 men with single magnetic resonance imaging (MRI) lesions (Prostate Imaging Reporting and Data System [PI-RADS] ≥ 3). Methods: Patients underwent multiparametric MRI and MRI/ultrasound fusion TB and 12-needle standard biopsy (SB) from September 2016 to June 2021. The study compared the diagnostic performance of TB + iSB (ipsilateral), TB + contralateral system biopsy (cSB) (contralateral), and TB alone for csPCa using the χ 2 test and analysis of variance. Results: Among 126 patients with csPCa (ISUP ≥ 2), detection rates for TB + iSB, TB + cSB, and TB were 100, 98.90, and 100% for lesions, respectively. TB + iSB showed the highest sensitivity and negative predictive value. No significant differences in accuracy were found between TB + iSB and the gold standard for type 3 lesions (P = 1). For types 4-5, detection accuracy was comparable across methods (P = 0.314, P = 0.314, P = 0.153). TB had the highest positive needle count rate, with TB + iSB being second for type 3 lesions (4.08% vs 6.57%, P = 0.127). Conclusion: TB + iSB improved csPCa detection rates and reduced biopsy numbers, making it a viable alternative to TB + SB for single MRI lesions.

Palladium-Catalyzed Cyclization and Direct Arylation of 1-[2-(2,2-Dibromoethenyl)phenyl]-1H-pyrrole with Allenes.

A novel and efficient palladium-catalyzed highly regioselective reaction of 1-[2-(2,2-dibromoethenyl)phenyl]-1H-pyrrole with allenes was realized to synthesize pyrrolo[1,2-a]quinolones. The tandem process involves intermolecular cyclization and intramolecular direct arylation, leading to the formation three new C-C bonds and two new rings. Notably, this transformation exhibits broad substrate scope and high functional group tolerance.

Synergistic Coordination Effect and Metal-Support Interaction Engineering of Single-Atom Mn-N2 Sites for Boosting Sensitive and Selective Dopamine Biosensing in Human Serum.

Coordination environment of metal atoms is core for designing high-performance single-atom catalysts (SACs), while metal-support interaction also has an important effect on structure-function relationship. Nevertheless, the interaction effect of metal-support is mostly ignored. Through synergistic regulation of coordination environment and metal-support interaction, Mn SAC with atom-dispersed Mn-N2 sites on dopamine (DA) support is synthesized for sensitive and selective DA oxidation based on theoretical calculations and experimental explorations. MnN2 presents the more optimal catalytic site for DA oxidation than other coordination conditions, enhancing sensitivity including a wide range, a low limit of detection, and particularly a very low catalytic potential. The construction of Mn-N2 active sites on DA carbon promotes the coupling between Mn metal atoms and DA support, decreasing work function, facilitating electron exchange, shortening response time, and boosting selectivity. Both the catalytic mechanism of Mn SAC toward DA and the relation construction of catalyst's structure and catalytic function are established.

Fragment Addition-Based Design of Heteroaromatic-Biphenyl-DAPYs as Potent and Orally Available Non-nucleoside Reverse Transcriptase Inhibitors Featuring Significantly Enhanced Safety.

Our previously disclosed biphenyl-DAPY 3 emerged as a potent inhibitor against WT HIV-1 and various mutant strains. Yet, its journey toward clinical application was thwarted by pronounced cytotoxicity and low selectivity (CC50 = 6 µM, SI = 3515). The safety improvement approach we employed in this work entailed the incorporation of diverse heteroaromatic substituents at the C5 position to exploit the tolerant regions of the NNRTIs' binding pocket through fragment addition-based drug design strategy, ultimately leading to the identification of a series of novel heteroaromatic-biphenyl-DAPYs. The exemplary compound 10d revealed a striking reduction in cytotoxicity (CC50 > 272.81 µM), nearly 45.5 times lower than 3, while showcasing 15-fold increase in selectivity (SI > 52632). This analog sustained exceptional anti-HIV-1 activity against both WT HIV-1 (EC50 = 5 nM) and various mutant strains. Compared to 3, a markedly slower rate of metabolism in human liver microsomes of 10d was observed. Its pharmacokinetic profile was equally captivating, featuring excellent oral bioavailability (F = 57.4%). Moreover, 10d exhibited a delicate sensitivity toward CYP, minimal inhibition of hERG, and no detectable acute toxicity in vivo. These enchanting findings illuminated the potential of 10d as a promising candidate for HIV-1 therapy.

Flexible Graphene Field-Effect Transistors and Their Application in Flexible Biomedical Sensing.

Flexible electronics are transforming our lives by making daily activities more convenient. Central to this innovation are field-effect transistors (FETs), valued for their efficient signal processing, nanoscale fabrication, low-power consumption, fast response times, and versatility. Graphene, known for its exceptional mechanical properties, high electron mobility, and biocompatibility, is an ideal material for FET channels and sensors. The combination of graphene and FETs has given rise to flexible graphene field-effect transistors (FGFETs), driving significant advances in flexible electronics and sparked a strong interest in flexible biomedical sensors. Here, we first provide a brief overview of the basic structure, operating mechanism, and evaluation parameters of FGFETs, and delve into their material selection and patterning techniques. The ability of FGFETs to sense strains and biomolecular charges opens up diverse application possibilities. We specifically analyze the latest strategies for integrating FGFETs into wearable and implantable flexible biomedical sensors, focusing on the key aspects of constructing high-quality flexible biomedical sensors. Finally, we discuss the current challenges and prospects of FGFETs and their applications in biomedical sensors. This review will provide valuable insights and inspiration for ongoing research to improve the quality of FGFETs and broaden their application prospects in flexible biomedical sensing.

Deep learning models for the prediction of acute postoperative pain in PACU for video-assisted thoracoscopic surgery.

BACKGROUND: Postoperative pain is a prevalent symptom experienced by patients undergoing surgical procedures. This study aims to develop deep learning algorithms for predicting acute postoperative pain using both essential patient details and real-time vital sign data during surgery. METHODS: Through a retrospective observational approach, we utilized Graph Attention Networks (GAT) and graph Transformer Networks (GTN) deep learning algorithms to construct the DoseFormer model while incorporating an attention mechanism. This model employed patient information and intraoperative vital signs obtained during Video-assisted thoracoscopic surgery (VATS) surgery to anticipate postoperative pain. By categorizing the static and dynamic data, the DoseFormer model performed binary classification to predict the likelihood of postoperative acute pain. RESULTS: A total of 1758 patients were initially included, with 1552 patients after data cleaning. These patients were then divided into training set (n = 931) and testing set (n = 621). In the testing set, the DoseFormer model exhibited significantly higher AUROC (0.98) compared to classical machine learning algorithms. Furthermore, the DoseFormer model displayed a significantly higher F1 value (0.85) in comparison to other classical machine learning algorithms. Notably, the attending anesthesiologists' F1 values (attending: 0.49, fellow: 0.43, Resident: 0.16) were significantly lower than those of the DoseFormer model in predicting acute postoperative pain. CONCLUSIONS: Deep learning model can predict postoperative acute pain events based on patients' basic information and intraoperative vital signs.

Control Patterning of Cyanobiphenyl Liquid Crystals for Electricity Applications.

Controlling molecular self-assembly from organic solution evaporation is an important strategy for developing many functional materials and systems. In this work, it is demonstrated that 4-octyloxy-4'-cyanobiphenyl (8OCB) liquid crystals can be patterned into well-oriented stripes with very high micrometer-scale precision using a sandwich system through a dewetting method. The preparation temperature, concentration, and surface energy are combined to control the morphology and orientation of 8OCB microstripe arrays assisted by silicon micropillars. Microstripes prepared below the isotropic temperature were uniform, well-ordered, and showed high electricity. In addition, 8OCB molecules have a strong tendency toward antiparallel alignment, nearly standing up on the substrate with long axes parallel to the microstripe. Also, we point out the mechanism for the self-assembly process of 8OCB on the air-liquid and liquid-solid surface.

Multi-contrast image super-resolution with deformable attention and neighborhood-based feature aggregation (DANCE): Applications in anatomic and metabolic MRI.

Multi-contrast magnetic resonance imaging (MRI) reflects information about human tissues from different perspectives and has wide clinical applications. By utilizing the auxiliary information from reference images (Refs) in the easy-to-obtain modality, multi-contrast MRI super-resolution (SR) methods can synthesize high-resolution (HR) images from their low-resolution (LR) counterparts in the hard-to-obtain modality. In this study, we systematically discussed the potential impacts caused by cross-modal misalignments between LRs and Refs and, based on this discussion, proposed a novel deep-learning-based method with Deformable Attention and Neighborhood-based feature aggregation to be Computationally Efficient (DANCE) and insensitive to misalignments. Our method has been evaluated in two public MRI datasets, i.e., IXI and FastMRI, and an in-house MR metabolic imaging dataset with amide proton transfer weighted (APTW) images. Experimental results reveal that our method consistently outperforms baselines in various scenarios, with significant superiority observed in the misaligned group of IXI dataset and the prospective study of the clinical dataset. The robustness study proves that our method is insensitive to misalignments, maintaining an average PSNR of 30.67 dB when faced with a maximum range of ±9°and ±9 pixels of rotation and translation on Refs. Given our method's desirable comprehensive performance, good robustness, and moderate computational complexity, it possesses substantial potential for clinical applications.

Methamphetamine-induced impairment of memory and fleeting neuroinflammation: Profiling mRNA changes in mouse hippocampus following short-term and long-term exposure.

Methamphetamine (METH) has been implicated in inducing memory impairment, but the precise mechanisms underlying this effect remain unclear. Current research often limits itself to singular models or focuses on individual gene or protein functions, which hampers a comprehensive understanding of the underlying mechanisms. In this study, we established three METH mouse exposure models, extracted hippocampal nuclei, and utilized RNA sequencing to analyze changes in mRNA expression profiles. Our results indicate that METH significantly impairs the learning and memory capabilities of mice. Additionally, we observed that METH-induced inflammatory responses occur in the early phase and do not further exacerbate with repeated injections. However, RNA sequencing revealed the persistent enrichment of inflammatory pathway molecules, which correlated with worsened behaviors. This suggests that although METH-induced neuroinflammation plays a critical role in learning and memory impairment, the continued enrichment of inflammatory pathway molecules is associated with behavioral outcomes. These findings provide crucial evidence for the potential application of immune intervention in METH-related disorders.

FGF21 modulates immunometabolic homeostasis via the ALOX15/15-HETE axis in early liver graft injury.

Fibroblast growth factor 21 (FGF21) is essential for modulating hepatic homeostasis, but the impact of FGF21 on liver graft injury remains uncertain. Here, we show that high FGF21 levels in liver graft and serum are associated with improved graft function and survival in liver transplantation (LT) recipients. FGF21 deficiency aggravates early graft injury and activates arachidonic acid metabolism and regional inflammation in male mouse models of hepatic ischemia/reperfusion (I/R) injury and orthotopic LT. Mechanistically, FGF21 deficiency results in abnormal activation of the arachidonate 15-lipoxygenase (ALOX15)/15-hydroxy eicosatetraenoic acid (15-HETE) pathway, which triggers a cascade of innate immunity-dominated pro-inflammatory responses in grafts. Notably, the modulating role of FGF21/ALOX15/15-HETE pathway is more significant in steatotic livers. In contrast, pharmacological administration of recombinant FGF21 effectively protects against hepatic I/R injury. Overall, our study reveals the regulatory mechanism of FGF21 and offers insights into its potential clinical application in early liver graft injury after LT.

Highly efficient CO2 mineralization: Mechanisms and feasibility of utilizing electrolytic manganese residue as a feedstock and implementing ammonia recycling.

Electrolytic manganese residue (EMR) and CO2 emissions from the electrolytic manganese metal (EMM) production process present significant challenges to achieving cleaner production within the industry. Given the high capacity for CO2 sequestration and the stability of the sequestered forms, CO2 mineralization methods utilizing minerals or industrial residues have garnered considerable research interest. The efficacy of such methods is fundamentally dependent on the properties of the materials employed. EMR, due to its calcium sulfate dihydrate (CaSO4·2H2O) content, possesses an intrinsic potential for CO2 solidification. In this study, we propose a novel method for CO2 mineralization utilizing EMR, coupled with NH3·H2O recycling. Experimental results indicated that under conditions of a reaction temperature of 55 °C and a pH of approximately 8, each ton of EMR can sequester 0.16 t of CO2, with equilibrium achieved within 10 min. The mineralization mechanism was elucidated using SEM, TG curves, and XRD analyses, which revealed that Ca2+ ions are initially leached from CaSO4·2H2O in the EMR, subsequently precipitating with CO32- ions to form CaCO3. This CaCO3 layer effectively covers the surface of CaSO4·2H2O, inhibiting further Ca2+ release and stabilizing the reaction equilibrium. Furthermore, the ammonia in the solution is regenerated into NH3·H2O, facilitating its reuse and preventing secondary pollution. The utilization of EMR for CO2 mineralization not only mitigates carbon emissions in the EMM production process but also promotes environmentally sustainable practices in the industry. This study highlights a promising pathway towards achieving carbon neutrality and cleaner production in electrolytic manganese production.