The enhancing effects of selenomethionine on harmine in attenuating pathological cardiac hypertrophy via glycolysis metabolism.

Pathological cardiac hypertrophy, a common feature in various cardiovascular diseases, can be more effectively managed through combination therapies using natural compounds. Harmine, a ß-carboline alkaloid found in plants, possesses numerous pharmacological functions, including alleviating cardiac hypertrophy. Similarly, Selenomethionine (SE), a primary organic selenium source, has been shown to mitigate cardiac autophagy and alleviate injury. To explores the therapeutic potential of combining Harmine with SE to treat cardiac hypertrophy. The synergistic effects of SE and harmine against cardiac hypertrophy were assessed in vitro with angiotensin II (AngII)-induced hypertrophy and in vivo using a Myh6R404Q mouse model. Co-administration of SE and harmine significantly reduced hypertrophy-related markers, outperforming monotherapies. Transcriptomic and metabolic profiling revealed substantial alterations in key metabolic and signalling pathways, particularly those involved in energy metabolism. Notably, the combination therapy led to a marked reduction in the activity of key glycolytic enzymes. Importantly, the addition of the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) did not further potentiate these effects, suggesting that the antihypertrophic action is predominantly mediated through glycolytic inhibition. These findings highlight the potential of SE and harmine as a promising combination therapy for the treatment of cardiac hypertrophy.

Aquibaculum sediminis sp. nov., a halotolerant bacteria isolated from salt lake sediment.

An aerobic, Gram-stain negative bacterium was isolated from sediment samples of Barkol salt lake in Hami City, Xinjiang Uygur Autonomous Region, China, with the number EGI_FJ10229T. The strain is ellipse-shaped, oxidase-negative, catalase-positive, and has white, round, smooth, opaque colonies on marine 2216 E agar plate. Growth occurs at 4.0-37.0 â„ƒ (optimal:30.0 â„ƒ), pH 7.0-9.0 (optimal: pH 8.0) and NaCl concentration of 0-8.0% (optimal: 3.0%). Phylogenetic analysis based on 16S rRNA gene and genome sequences indicated that the isolated strain should be assigned to the genus Aquibaculum and was most closely related to Aquibaculum arenosum CAU 1616 T. Average nucleotide identity (ANI) and Average amino-acid identity (AAI) values between the type species of the genus Aquibaculum and other related type species were lower than the threshold values recommended for bacterial species. The genomic DNA G + C content of EGI_FJ10229T was 65.41%. The major polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylcholine, phosphatidylethanolamine and unidentified phospholipid. The major fatty acids (> 5%) were C19:0 cyclo ω8c (42.0%) and C18:1 ω7c (33.78%). The respiratory quinone identified was Q-10. Differential phenotypic and genotypic characteristics of this strain and species of genus Aquibaculum showed that the strain should be classified as representing a new species belonging to this genus, for which the name Aquibaculum sediminis sp. nov. is proposed. The type strain of the proposed novel species is EGI_FJ10229T (= KCTC 8570 T = GDMCC 1.4598 T).

Catalytic Enantioselective Synthesis of Planar Chiral Pillar[5]arenes via Asymmetric Sonogashira Coupling.

As a novel type of macrocycles with attractive planar chirality, pillar[5]arenes have gained increasing research interest over the past decades, enabling their widespread applications in diverse fields such as porous materials, molecular machines, and chiral luminescence materials. However, the catalytic methodology towards the enantioselective synthesis of planar chiral pillar[5]arenes remains elusive. Here we report a novel method for the enantioselective synthesis of planar chiral pillar[5]arenes via asymmetric Sonogashira coupling, giving access to a wide range of highly functionalized planar chiral pillar[5]arenes, including both homo- and hetero-rimmed ones, with excellent enantioselectivities. Attractively, the resultant planar chiral pillar[5]arenes show great potential for widespread use in many areas such as chiral luminescent materials. This work not only enables the successful synthesis of planar chiral pillar[5]arenes with abundant structural and functional diversity as key building blocks for practical applications but also enriches the asymmetric cross-coupling methodologies in organic synthetic chemistry.

Therapeutic potential of xtr-miR-22-3p from Plastrum testudinis in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is marked by a block at the promyelocyte stage. Treatments like ATRA and ATO face resistance and relapse issues. Plastrum testudinis, a traditional Chinese medicine, may offer therapeutic potential. This study investigated xtr-miR-22-3p from P. testudinis for treating APL. High expression of xtr-miR-22-3p was confirmed, with target prediction indicating interactions with key genes, including PML. xtr-miR-22-3p reduced HL-60 leukemia cell growth, altered the cell cycle, and selectively inhibited HL-60 proliferation while promoting BMSC growth, suggesting its potential as a targeted APL therapy.

Spatial Transcriptomics Reveals the Transcriptomic Signatures in a Mouse Model of Pediatric Metabolic Dysfunction-Associated Steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is considered the progressive form of metabolic dysfunction-associated steatotic liver disease, which is the leading cause of chronic liver disease in children. However, the pathogenesis of pediatric MASH remains poorly understood because of the lack of animal models. In this study, we developed a mouse model of pediatric MASH and characterized the hepatic transcriptomic profile using spatial transcriptomics technology. C57BL/6J mice were fed a Western diet (WD) along with weekly injections of carbon tetrachloride (CCl4) from the age of 3 to 8 weeks. After 5 weeks of feeding, WD + CCl4-treated mice showed significant liver injury without the development of insulin resistance. Histologically, WD + CCl4 induced key features of type 2 MASH, the most common type observed in children, characterized by liver steatosis, portal inflammation, and portal fibrosis. Through spatial transcriptomics analysis of liver tissues, we identified that cluster 0 in the mouse from the WD + CCl4 group was enriched in pathways associated with lipid metabolism. Further investigation revealed that cytochrome p450 2E1 was the top marker gene of cluster 0, and its expression was increased in the periportal area of mice from the WD + CCl4 group. These findings suggest that our mouse model of pediatric MASH mirrors the histologic features of human MASH, and the up-regulation of cytochrome p450 2E1 may be linked to the disease pathogenesis.

Catalytic Edges in One-Dimensional Covalent Organic Frameworks for the Oxygen Reduction Reaction.

Metal-free covalent organic frameworks (COFs) are employed in oxygen reduction reactions (ORR) because of their diverse structural units and controllable catalytic sites, and the edge sites have high catalytic activity than the basal sites. However, it is still challenge to modulate the edge sites in COFs, because the extended frameworks in two- or three-dimensional topologies resulted in limited edge parts. In this study, we have demonstrated the edge site modulation engineering based on one dimensional (1D) COFs to catalyze the ORR, which featured distinct edge groups-carbonyl, diaminopyrazine, phenylimidazole, and benzaldehyde imidazole units. The synthesized COFs had same ordered frameworks, similar pore structure, but had different electronic states of the carbons along the edge sites, which results in tailored catalytic properties. Notably, the COF functionalized with a phenylimidazole edge group exhibited superior catalytic performance compared to the other synthesized COFs. And the theoretical calculation further revealed the different edge sites have tunable binding ability of the intermediates OOH*, which contributed modulated activity. Our findings introduce a novel way for designing COFs optimized for ORR applications through molecular level control of edge sites.

The irregular developmental duration mainly caused by the broad-complex in Chilo suppressalis.

Chilo suppressalis, a critical rice stem borer pest, poses significant challenges to rice production due to its overlapping generations and irregular developmental duration. These characteristics complicate pest management strategies. According to the dynamic analysis of the overwintering adults of C. suppressalis in fields, it indicates that the phenomenon of irregular development of C. suppressalis exists widely and continuously. This study delves into the potential role of the Broad-Complex (Br-C) gene in the developmental duration of C. suppressalis. Four isoforms of Br-C, named CsBr-C Z1, CsBr-C Z2, CsBr-C Z4, and CsBr-C Z7, were identified. After CsBr-Cs RNAi, the duration of larva development spans extended obviously. And, the average developmental duration of dsCsBr-Cs feeding individuals increased obviously. Meanwhile, the average developmental duration of the dsCsBr-C Z2 feeding group was the longest among all the RNAi groups. After dsCsBr-Cs feeding continuously, individuals pupated at different instars changed obviously: the proportion of individuals pupated at the 5th instar decreased and pupated at the 7th instar or higher increased significantly. Moreover, the pupation rate of dsCsBr-Cs (except dsCsBr-C Z7) were significantly lower than that of dsGFP. The same results were obtained from the mutagenesis in CsBr-C genes mediated by CRISPR/Cas9. The average developmental duration of CsBr-Cs knockout individuals was significantly prolonged. And, the instar of pupation in knockout individuals was also delayed significantly. In conclusion, this work showed that CsBr-Cs played a crucial role in pupal commitment and affected the developmental duration of C. suppressalis significantly.

Highly sensitive detection platform-based diagnosis of oesophageal squamous cell carcinoma in China: a multicentre, case-control, diagnostic study.

BACKGROUND: Early detection and screening of oesophageal squamous cell carcinoma rely on upper gastrointestinal endoscopy, which is not feasible for population-wide implementation. Tumour marker-based blood tests offer a potential alternative. However, the sensitivity of current clinical protein detection technologies is inadequate for identifying low-abundance circulating tumour biomarkers, leading to poor discrimination between individuals with and without cancer. We aimed to develop a highly sensitive blood test tool to improve detection of oesophageal squamous cell carcinoma. METHODS: We designed a detection platform named SENSORS and validated its effectiveness by comparing its performance in detecting the selected serological biomarkers MMP13 and SCC against ELISA and electrochemiluminescence immunoassay (ECLIA). We then developed a SENSORS-based oesophageal squamous cell carcinoma adjunct diagnostic system (with potential applications in screening and triage under clinical supervision) to classify individuals with oesophageal squamous cell carcinoma and healthy controls in a retrospective study including participants (cohort I) from Sun Yat-sen University Cancer Center (SYSUCC; Guangzhou, China), Henan Cancer Hospital (HNCH; Zhengzhou, China), and Cancer Hospital of Shantou University Medical College (CHSUMC; Shantou, China). The inclusion criteria were age 18 years or older, pathologically confirmed primary oesophageal squamous cell carcinoma, and no cancer treatments before serum sample collection. Participants without oesophageal-related diseases were recruited from the health examination department as the control group. The SENSORS-based diagnostic system is based on a multivariable logistic regression model that uses the detection values of SENSORS as the input and outputs a risk score for the predicted likelihood of oesophageal squamous cell carcinoma. We further evaluated the clinical utility of the system in an independent prospective multicentre study with different participants selected from the same three institutions. Patients with newly diagnosed oesophageal-related diseases without previous cancer treatment were enrolled. The inclusion criteria for healthy controls were no obvious abnormalities in routine blood and tumour marker tests, no oesophageal-associated diseases, and no history of cancer. Finally, we assessed whether classification could be improved by integrating machine-learning algorithms with the system, which combined baseline clinical characteristics, epidemiological risk factors, and serological tumour marker concentrations. Retrospective SYSUCC cohort I (randomly assigned [7:3] to a training set and an internal validation set) and three prospective validation sets (SYSUCC cohort II [internal validation], HNCH cohort II [external validation], and CHSUMC cohort II [external validation]) were used in this step. Six machine-learning algorithms were compared (the least absolute shrinkage and selector operator regression, ridge regression, random forest, logistic regression, support vector machine, and neural network), and the best-performing algorithm was chosen as the final prediction model. Performance of SENSORS and the SENSORS-based diagnostic system was primarily assessed using accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). FINDINGS: Between Oct 1, 2017, and April 30, 2020, 1051 participants were included in the retrospective study. In the prospective diagnostic study, 924 participants were included from April 2, 2022, to Feb 2, 2023. Compared with ELISA (108·90 pg/mL) and ECLIA (41·79 pg/mL), SENSORS (243·03 fg/mL) showed 448 times and 172 times improvements, respectively. In the three retrospective validation sets, the SENSORS-based diagnostic system achieved AUCs of 0·95 (95% CI 0·90-0·99) in the SYSUCC internal validation set, 0·93 (0·89-0·97) in the HNCH external validation set, and 0·98 (0·97-1·00) in the CHSUMC external validation set, sensitivities of 87·1% (79·3-92·3), 98·6% (94·4-99·8), and 93·5% (88·1-96·7), and specificities of 88·9% (75·2-95·8), 74·6% (61·3-84·6), and 92·1% (81·7-97·0), respectively, successfully distinguishing between patients with oesophageal squamous cell carcinoma and healthy controls. Additionally, in three prospective validation cohorts, it yielded sensitivities of 90·9% (95% CI 86·1-94·2) for SYSUCC, 84·8% (76·1-90·8) for HNCH, and 95·2% (85·6-98·7) for CHSUMC. Of the six machine-learning algorithms compared, the random forest model showed the best performance. A feature selection step identified five features to have the highest performance to predictions (SCC, age, MMP13, CEA, and NSE) and a simplified random forest model using these five features further improved classification, achieving sensitivities of 98·2% (95% CI 93·2-99·7) in the internal validation set from retrospective SYSUCC cohort I, 94·1% (89·9-96·7) in SYSUCC prospective cohort II, 88·6% (80·5-93·7) in HNCH prospective cohort II, and 98·4% (90·2-99·9) in CHSUMC prospective cohort II. INTERPRETATION: The SENSORS system facilitates highly sensitive detection of oesophageal squamous cell carcinoma tumour biomarkers, overcoming the limitations of detecting low-abundance circulating proteins, and could substantially improve oesophageal squamous cell carcinoma diagnostics. This method could act as a minimally invasive screening tool, potentially reducing the need for unnecessary endoscopies. FUNDING: The National Key R&D Program of China, the National Natural Science Foundation of China, and the Enterprises Joint Fund-Key Program of Guangdong Province. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A New Strategy to Inhibit Scar Formation by Accelerating Normal Healing Using Silicate Bioactive Materials.

Inspired by the scar-free wound healing in infants, an anti-scar strategy is proposed by accelerating wound healing using silicate bioactive materials. Bioglass/alginate composite hydrogels are applied, which significantly inhibit scar formation in rabbit ear scar models. The underlining mechanisms include stimulation of Integrin Subunit Alpha 2 expression in dermal fibroblasts to accelerate wound healing, and induction of apoptosis of hypertrophic scar fibroblasts by directly stimulating the N-Acylsphingosine Amidohydrolase 2 expression in hypertrophic scar fibroblasts, and indirectly upregulating the secretion of Cathepsin K in dermal fibroblasts. Considering specific functions of the bioactive silicate materials, two scar treatment regimes are tested. For severe scars, a regenerative intervention is applied by surgical removal of the scar followed by the treatment with bioactive hydrogels to reduce the formation of scars by activating dermal fibroblasts. For mild scars, the bioactive dressing is applied on the formed scar and reduces scar by inducing scar fibroblasts apoptosis.

Effect of per- and polyfluoroalkyl substances on neurodevelopment: Evidence-based risk assessment in the TRAEC strategy context.

Although emerging evidence on the association between per- and polyfluoroalkyl substances (PFASs) and neurodevelopment have been investigated, there is no consensus on the effect of maternal PFASs on neurodevelopment in offspring. Here, we assessed the risk of maternal PFASs exposure on the neurodevelopment of offspring using a novel Targeted Risk Assessment of Environmental Chemicals (TRAEC) strategy based on multiple evidence. The evidence from five online databases were analyzed the effect of PFASs on neurodevelopment. The potential neurodevelopment risk of PFASs was evaluated by the TRAEC strategy, which was conducted on a comprehensive scoring system with reliability, correlation, outcome fitness and integrity. The studies from five databases and additional researchers' experiments were included the present study to proceed following risk assessment. Based on the framework with TRAEC strategy, the comprehensive evaluation of health risks was classified as low (absolute value 0-4), medium (absolute value 4-8), high (absolute value 8-10). In the present study, the effect of PFASs exposure on neurodevelopment was a medium-risk level with 5.61 overall risk-score. The population-attributable risk (PAR) was 8.26 % for maternal PFASs exposure. The study identified a low-risk effect of prenatal PFASs exposure on ASD and behavioral disabilities. The chain length, type of PFASs and neurodevelopmental trajectories contributed to the risk of maternal PFASs on the neurodevelopment of offspring. Consistent with results of four criteria-based tools (ToxRTool, SciRAP, OHAT and IRIS), health risk assessment based on the TRAEC strategy demonstrated robustness and reliability in the present study. These results illustrated a medium-risk effect of maternal PFASs exposure on neurodevelopmental disorders of offspring. In addition, the TRAEC strategy provided a scientific and structured method for effect evaluation between prenatal PFASs and neurodevelopmental disorders, promoting the consistency and validation in risk assessment.

A conserved cell-type gradient across the human mediodorsal and paraventricular thalamus.

The mediodorsal thalamus (MD) and adjacent midline nuclei are important for cognition and mental illness, but their cellular composition is not well defined. Using single-nucleus and spatial transcriptomics, we identified a conserved excitatory neuron gradient, with distinct spatial mapping of individual clusters. One end of the gradient was expanded in human MD compared to mice, which may be related to the expansion of granular prefrontal cortex in hominids. Moreover, neurons preferentially mapping onto the parvocellular division MD were associated with genetic risk for schizophrenia and bipolar disorder. Midbrain-derived inhibitory interneurons were enriched in human MD and implicated in genetic risk for major depressive disorder.

Development and application of a nomogram model for predicting the risk of central precocious puberty in obese girls.

Objective: The purpose of this study is to develop and assess a nomogram risk prediction model for central precocious puberty (CPP) in obese girls. Methods: We selected 154 cases of obese girls and 765 cases of non-obese girls with precocious puberty (PP) who underwent the gonadotropin-releasing hormone stimulation test at the Jiangxi Provincial Children's Hospital. Univariate analysis and multivariate analysis were conducted to identify predictors of progression to CPP in girls with PP. A predictive model was developed and its predictive ability was preliminarily evaluated. The nomogram was used to represent the risk prediction model for CPP in girls with obesity. The model was validated internally using the Bootstrap method, and its efficacy was assessed using calibration curves and clinical decision analysis curves. Results: In obese girls with PP, basal luteinizing hormone (LH) and follicular stimulating hormone (FSH) levels, as well as uterine volume, were identified as independent risk factors for progression to CPP. In non-obese girls, the basal LH level, bone age, and uterine volume were identified as independent risk factors for progression to CPP. With an AUC of 0.896, the risk prediction model for obese girls, was found to be superior to that for non-obese girls, which had an AUC of 0.810. The model displayed strong predictive accuracy. Additionally, a nomogram was used to illustrate the CPP risk prediction model for obese girls. This model performs well in internal validation and is well calibrated, providing a substantial net benefit for clinical use. Conclusion: A medical nomogram model of CPP risk in obese girls comprised of basal LH value, basal FSH value, and uterine volume, which can be used to identify those at high risk for progression of CPP in obese girls and develop individualized prevention programs.

Inverted U-Shaped relationship Between Systemic Immune-Inflammation Index and Pulmonary Function: A Large Population-Based Study in US Adults.

Background: Systemic immune-inflammation index (SII) is a novel comprehensive inflammatory marker. Inflammation is associated with impaired lung function. We aimed to explore the possible relationship between SII and lung function to examine the potential of SII in predicting lung function decline. Methods: A cross-sectional survey was conducted using the data of the NHANES from 2007 to 2012. Multiple linear regression models were used to analyze the linear relationship between SII and pulmonary functions. Sensitivity analyses, subgroup analyses, and interaction tests were used to examine the robustness of this relationship across populations. Fitted smooth curves and threshold effect analysis were used to describe the nonlinear relationships. Results: A total of 10,125 patients were included in this study. After adjusting for all covariates, multiple linear regression model analysis showed that high Log2-SII level was significantly associated with decreased FVC(ß, -23.4061; 95% CI, -42.2805- -4.5317), FEV1(ß, -46.7730; 95% CI, -63.3371- -30.2089), FEV1%(ß, -0.7923; 95% CI, -1.1635- -0.4211), FEV1/FVC(ß, -0.6366; 95% CI, -0.8328- -0.4404) and PEF(ß, -121.4468; 95% CI,-164.1939- -78.6998). The negative correlation between Log2-SII and pulmonary function indexes remained stable in trend test and stratified analysis. Inverted U-shaped relationships between Log2-SII and FVC, FEV1, FEV1%, and PEF were observed, while a negative linear correlation existed between FEV1/FVC and Log2-SII. The cutoff values of the nonlinear relationship between Log2-SII and FVC, FEV1, FEV1%, PEF were 8.3736, 8.0688, 8.3745, and 8.5255, respectively. When SII exceeded the critical value, the lung function decreased significantly. Conclusion: This study found a close correlation between SII and pulmonary function indicators. This study investigated the SII threshold when lung functions began to decline in the overall population. SII may become a promising serological indicator for predicting lung function decline. However, prospective studies were needed further to establish the causal relationship between these two factors.

Schizophrenia risk-associated SNPs affect expression of microRNA 137 host gene: a postmortem study.

Common variants in the MicroRNA 137 host gene MIR137HG and its adjacent gene DPYD have been associated with schizophrenia risk and the latest Psychiatric Genomics Consortium (PGC). Genome-Wide Association Study on schizophrenia has confirmed and extended these findings. To elucidate the association of schizophrenia risk-associated SNPs in this genomic region, we examined the expression of both mature and immature transcripts of the miR-137 host gene (MIR137HG) in the dorsolateral prefrontal cortex (DLPFC) and subgenual anterior cingulate cortex (sgACC) of postmortem brain samples of donors with schizophrenia and psychiatrically-unaffected controls using qPCR and RNA-Seq approaches. No differential expression of miR-137, MIR137HG, or its transcripts was observed. Two schizophrenia risk-associated SNPs identified in the PGC study, rs11165917 (DLPFC: P = 2.0e-16; sgACC: P = 6.4e-10) and rs4274102 (DLPFC: P = 0.036; sgACC: P = 0.002), were associated with expression of the MIR137HG long non-coding RNA transcript MIR137HG-203 (ENST00000602672.2) in individuals of European ancestry. Carriers of the minor (risk) allele of rs11165917 had significantly lower expression of MIR137HG-203 compared with those carrying the major allele. However, we were unable to validate this result by short-read sequencing of RNA extracted from DLPFC or sgACC tissue. This finding suggests that immature transcripts of MIR137HG may contribute to genetic risk for schizophrenia.

Efficiency evaluation of dual-energy CT to predict the postoperative early recurrence of pancreatic ductal adenocarcinoma.

OBJECTIVES: To evaluate the efficacy of quantitative parameters from dual-energy CT (DECT) and basic CT features in predicting the postoperative early recurrence (ER) of pancreatic ductal adenocarcinoma (PDAC). METHODS: In this study, patients with PDAC who underwent radical resection and DECT from 2018 to 2022 were enrolled and categorised into ER and non-ER groups. The clinical data, basic CT features and DECT parameters of all patients were analyzed. Independent predictors of ER were identified with Logistic regression analyses. Three models (model A: basic CT features; model B: DECT parameters; model C: basic CT features + DECT parameters) were established. Receiver operating characteristic curve analysis was utilized to evaluate predictive performance. RESULTS: A total of 150 patients were enrolled (ER group: n = 63; non-ER group: n = 87). Rim enhancement (odds ratio [OR], 3.32), peripancreatic strands appearance (OR, 2.68), electron density in the pancreatic parenchymal phase (P-Rho; OR, 0.90), arterial enhancement fraction (AEF; OR, 0.05) and pancreatic parenchyma fat fraction in the delayed phase (OR, 1.25) were identified as independent predictors of ER. Model C showed the highest area under the curve of 0.898. In addition, the corresponding ER risk factors were identified separately for resectable and borderline resectable PDAC subgroups. CONCLUSIONS: DECT quantitative parameters allow for the noninvasive prediction of postoperative ER in patients with PDAC, and the combination of DECT parameters and basic CT features shows a high prediction efficiency. Our model can help to identify patients with high-risk factors to guide preoperative decision making.

Altered dynamic functional connectivity of nucleus accumbens subregions in major depressive disorder: the interactive effect of childhood trauma and diagnosis.

Major depressive disorder (MDD) with childhood trauma represents a heterogeneous clinical subtype of depression. Previous research has observed alterations in the reward circuitry centered around the nucleus accumbens (NAc) in MDD patients. However, limited investigations have focused on aberrant functional connectivity (FC) within NAc subregions among MDD with childhood trauma. Thus, this study adopts analyses of both static FC (sFC) and dynamic FC (dFC) to examine neurobiological changes in MDD with childhood trauma. The bilateral nucleus accumbens shell (NAc-shell) and nucleus accumbens core (NAc-core) were selected as the seeds. Four participant groups were included: MDD with childhood trauma (n = 48), MDD without childhood trauma (n = 30), healthy controls (HCs) with childhood trauma (n = 57), and HCs without childhood trauma (n = 46). Our findings revealed both abnormal sFC and dFC between NAc-shell and NAc-core and regions including the middle occipital gyrus (MOG), anterior cingulate cortex, and inferior frontal gyrus in MDD with childhood trauma. Furthermore, a significant correlation was identified between the dFC of the left NAc-shell and the right MOG in relation to childhood trauma. Additionally, abnormal dFC moderated the link between childhood abuse and depression severity. These outcomes shed light on the neurobiological underpinnings of MDD with childhood trauma.

The impact of a lung-protective ventilation mode using transpulmonary driving pressure titrated positive end-expiratory pressure on the prognosis of patients with acute respiratory distress syndrome.

OBJECTIVE: This study aimed to assess the impact of a lung-protective ventilation strategy utilizing transpulmonary driving pressure titrated positive end-expiratory pressure (PEEP) on the prognosis [mechanical ventilation duration, hospital stay, 28-day mortality rate and incidence of ventilator-associated pneumonia (VAP), survival outcome] of patients with Acute Respiratory Distress Syndrome (ARDS). METHODS: A total of 105 ARDS patients were randomly assigned to either the control group (n = 51) or the study group (n = 53). The control group received PEEP titration based on tidal volume [A tidal volume of 6 mL/kg, flow rate of 30-60 L/min, frequency of 16-20 breaths/min, constant flow rate, inspiratory-to-expiratory ratio of 1:1 to 1:1.5, and a plateau pressure ≤ 30-35 cmH2O. PEEP was adjusted to maintain oxygen saturation (SaO2) at or above 90%, taking into account blood pressure], while the study group received PEEP titration based on transpulmonary driving pressure (Esophageal pressure was measured as a surrogate for pleural pressure using an esophageal pressure measurement catheter connected to the ventilator. Tidal volume and PEEP were adjusted based on the observed end-inspiratory and end-expiratory transpulmonary pressures, aiming to maintain a transpulmonary driving pressure below 15 cmH2O during mechanical ventilation. Adjustments were made 2-4 times per day). Statistical analysis and comparison were conducted on lung function indicators [oxygenation index (OI), arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2)] as well as other measures such as heart rate, mean arterial pressure, and central venous pressure in two groups of patients after 48 h of mechanical ventilation. The 28-day mortality rate, duration of mechanical ventilation, length of hospital stay, and ventilator-associated pneumonia (VAP) incidence were compared between the two groups. A 60-day follow-up was performed to record the survival status of the patients. RESULTS: In the control group, the mean age was (55.55 ± 10.51) years, with 33 females and 18 males. The pre-ICU hospital stay was (32.56 ± 9.89) hours. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was (19.08 ± 4.67), and the mean Murray Acute Lung Injury score was (4.31 ± 0.94). In the study group, the mean age was (57.33 ± 12.21) years, with 29 females and 25 males. The pre-ICU hospital stay was (33.42 ± 10.75) hours. The mean APACHE II score was (20.23 ± 5.00), and the mean Murray Acute Lung Injury score was (4.45 ± 0.88). They presented a homogeneous profile (all P > 0.05). Following intervention, significant improvements were observed in PaO2 and OI compared to pre-intervention values. The study group exhibited significantly higher PaO2 and OI compared to the control group, with statistically significant differences (all P < 0.05). After intervention, the study group exhibited a significant increase in PaCO2 (43.69 ± 6.71 mmHg) compared to pre-intervention levels (34.19 ± 5.39 mmHg). The study group's PaCO2 was higher than the control group (42.15 ± 7.25 mmHg), but the difference was not statistically significant (P > 0.05). There were no significant differences in hemodynamic indicators between the two groups post-intervention (all P > 0.05). The study group demonstrated significantly shorter mechanical ventilation duration and hospital stay, while 28-day mortality rate and incidence of ventilator-associated pneumonia (VAP) showed no significant differences. Kaplan-Meier survival analysis revealed a significantly better survival outcome in the study group at the 60-day follow-up (HR = 0.565, 95% CI: 0.320-0.999). CONCLUSION: Lung-protective mechanical ventilation using transpulmonary driving pressure titrated PEEP effectively improves lung function, reduces mechanical ventilation duration and hospital stay, and enhances survival outcomes in patients with ARDS. However, further study is needed to facilitate the wider adoption of this approach.

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes.

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate fine neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the cortical interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic neurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto- or chemo-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.

Pyramidal neurons proportionately alter the identity and survival of specific cortical interneuron subtypes.

The mammalian cerebral cortex comprises a complex neuronal network that maintains a delicate balance between excitatory neurons and inhibitory interneurons. Previous studies, including our own research, have shown that specific interneuron subtypes are closely associated with particular pyramidal neuron types, forming stereotyped local inhibitory microcircuits. However, the developmental processes that establish these precise networks are not well understood. Here we show that pyramidal neuron types are instrumental in driving the terminal differentiation and maintaining the survival of specific associated interneuron subtypes. In a wild-type cortex, the relative abundance of different interneuron subtypes aligns precisely with the pyramidal neuron types to which they synaptically target. In Fezf2 mutant cortex, characterized by the absence of layer 5 pyramidal tract neurons and an expansion of layer 6 intratelencephalic neurons, we observed a corresponding decrease in associated layer 5b interneurons and an increase in layer 6 subtypes. Interestingly, these shifts in composition are achieved through mechanisms specific to different interneuron types. While SST interneurons adjust their abundance to the change in pyramidal neuron prevalence through the regulation of programmed cell death, parvalbumin interneurons alter their identity. These findings illustrate two key strategies by which the dynamic interplay between pyramidal neurons and interneurons allows local microcircuits to be sculpted precisely. These insights underscore the precise roles of extrinsic signals from pyramidal cells in the establishment of interneuron diversity and their subsequent integration into local cortical microcircuits.