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Wen-Jia Li,1,* Chen Yao,2,* Lu Han,1 Ji-Hong Zhou,1 Rui-Ming Pang2 1Department of Pulmonary and Critical Care Medicine, Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen City, People’s Republic of China; 2Department of Orthopedics and Traumatology, Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen City, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ji-Hong Zhou, Department of Pulmonary and Critical Care Medicine, Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen City, People’s Republic of China, Email zjh14569@163.com Rui-Ming Pang, Department of Orthopedics and Traumatology, Shenzhen Bao’an Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen City, People’s Republic of China, Email prm1757607@163.comBackground: The associations between gut microbiota and chronic obstructive pulmonary disease (COPD) have gained increasing attention and research interest among scholars. However, it remains unclear whether gut microbiota serves as a causal factor for COPD or if it is a consequence of the disease. Therefore, we investigated the causal relationship between COPD and gut microbiota, with intention of providing novel insights and references for clinical diagnosis and treatment.Methods: Based on the genome-wide association study (GWAS) data, we employed MR-Egger regression, random-effects inverse variance-weighted (IVW) method, and weighted median method for bidirectional Mendelian randomization (MR) analysis. We conducted Cochran’s Q test for heterogeneity assessment and performed multivariable analysis, sensitivity analysis, and heterogeneity testing to validate the reliability and stability of results.Results: Utilizing MR analysis, mainly employing the IVW method, we detected a collective of 11 gut microbiota species that exhibited associations with COPD. Among them, Bacteroidia, family XIII, Clostridium innocuum group, Barnesiella, Collinsella, Lachnospiraceae NK4A136 group, Lachnospiraceae UCG004, Lachnospiraceae UCG010, and Bacteroidales were found to be protective factors for COPD. On the other hand, Holdemanella and Marvinbryantia were identified as risk factors for COPD. Individuals with elevated levels of Holdemanella exhibited a 1.141-fold higher risk of developing COPD compared to their healthy counterparts, and those with increased levels of Marvinbryantia had a 1.154-fold higher risk. Reverse MR analysis yielded no evidence indicating a causal relationship between gut microbiota and COPD occurrence.Conclusion: Our study established a causal link between 11 specific gut microbiota species and COPD, offering novel insights and valuable references for targeted therapies in the clinical management of COPD. However, our results were mainly based on the analysis of database, and further clinical studies are needed to clarify the effects of gut microbiota on COPD and its specific protective mechanism.Keywords: gut microbiota, COPD, bidirectional MR, causal, association

Hui Wang,1,2 Shan Hai,1 Yixin Liu,1 Li Cao,1 Ying Liu,1 Ping Liu,2 Jianghua Zhou,3 Ying Yang,3 Birong Dong1,2 1Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, People’s Republic of China; 2National Clinical Research Center for Geriatrics, West China Hospital, Chengdu 610041, People’s Republic of China; 3Chengdu Fifth People’s Hospital, Chengdu 611130, People’s Republic of China Purpose: The aim of this study was to assess the prevalence of sarcopenia and depressive symptoms and estimate the association between them in elderly Chinese community-dwelling individuals.Patients and methods: A total of 948 elderly Chinese community-dwelling individuals were recruited through leaflets and posters from three communities in Chengdu, and 865 participants were analyzed in this cross-sectional study. Muscle mass was measured using the bioimpedance analysis, handgrip strength was measured with a handheld dynamometer, and physical performance was assessed via usual gait speed on a 6 m course. Sarcopenia was defined according to the recommended diagnostic algorithm of the Asia Working Group for Sarcopenia (AWGS). Depressive symptoms were assessed using the Chinese version of 15-item Geriatric Depression Scale (GDS-15) with a score of ≥5 indicative of the presence of depressive symptoms.Results: A total of 865 participants were included in the analysis. The participants had a mean age of 68.68±6.46 years. Sixty-one (7.1%) participants and 71 (8.2%) participants were identified as having sarcopenia and depressive symptoms, respectively. After adjusting for age, sex, and other potential confounders, sarcopenia was found to be significantly associated with depressive symptoms (odds ratio [OR]: 2.23, 95% CI 1.06–4.92).Conclusion: The prevalence rates of sarcopenia and depressive symptoms were 7.1 and 8.2%, respectively, in elderly Chinese community-dwelling individuals, and sarcopenia was significantly associated with depressive symptoms. Keywords: community-dwelling, depressive symptoms, elderly, Geriatric Depression Scale, sarcopenia

Objective: To validate the hypothesis that there exists an optimal axial compression stress range to enhance tibial fracture healing.Methods: Rabbits with a surgically induced V-shaped tibial fracture were separated into 2 main groups: the control group (C Group, n equal to 6) without application of any axial compression stress stimulation postoperatively and the stimulation group (S Group, n equal to 90). The S Group was further divided into 20 subgroups (S11 to S54) in terms of 5 axial compression stress stimulation levels (112.8 kPa, 289.8 kPa, 396.5 kPa, 472.7 kPa, and 602.3 kPa) and 4 experimental endpoints (1, 3, 5 and 8 weeks after operation). A custom made circular external fixator was used to provide the axial compression stress of the fracture sites. Based on X-ray observation, a fracture healing scoring system was created to evaluate the fracture healing process.Results: At 8 weeks after operation, there existed a "arch shape" relationship between healing score and axial compression stress stimulation level of fracture site. The optimal axial compression stress stimulation ranged from 289.8 kPa to 472.7 kPa, accompanying the best fracture healing, i.e. the fracture line became indistinct or almost disappeared, and a lot of callus jointed the two fracture ends. Meanwhile, at 5 weeks after operation, corresponding to the relatively low healing scores, there was a fracture healing performance similar to that at 8 weeks. Besides, at 1 or 3 weeks after operation, for all the axial compression stress levels (0-602.3 kPa), no obvious healing effect was found.Conclusions: It is implied from the stated X-ray observation results in this study that the potential optimal axial compression stress stimulation and optimal fracture healing time are available. The axial compression stress level of 289.8-472.7 kPa and fracture healing time of more than 8 weeks jointly comprise the optimal axial compression stress stimulation conditions to enhance tibial fracture healing. [ABSTRACT FROM AUTHOR]

Objective: A catastrophic earthquake struck Wenchuan region of West China on May 12, 2008 and caused more than 69 225 deaths. This study was to analyze injury characteristics and treatment of the seismic patients based on Chinese Trauma Databank, which will be helpful for improvement of future medical rescue in potential disasters.Methods: Based on inpatients'medical records of seismic patients admitted into 11 hospitals, data were registered with Trauma Database System Version 3.0. Patients'general information, causes, clinical characteristics and treatment of injuries were studied.Results: Main causes for seismic injuries were blunt strike (68.2%), crush/burying (18.7%) and slip/falling (11.5%). Slip/falling was the main cause for spinal injuries and accounted for 19.1%, which was higher than the percentage for other body part. Extremity injuries accounted for 54.8% of all injuries. Fractures accounted for 53.1%. Lower extremity fracture accounted for 70.1% of lower extremity injury and spinal fracture accounted for 85.9% of spinal injury. The proportion of spinal injuries with AIS larger than or equal to 4 was higher than that of other injured locations except for the abdomen. Debridement and suturation for single injury and multiple injury patients accounted for 64.7% and 42.9% of their operations respectively.Conclusions: Blunt strike, crush/burying and slip/falling are the main causes for seismic injuries. The most frequently injured site is extremity. The main injury type is fracture, especially for the lower extremities and the spine. Multiple injury patients were mainly treated by operation, including debridement and suturation, closed reduction and external fixation, etc. [ABSTRACT FROM AUTHOR]

Objective: To analyze characteristics and causes of road crash and injuries in China from 2003 to 2005.Methods: The data of road crash in 2003-2005 were collected to study the characteristics including total vehicle number, occurrence rates of traffic accidents and serious traffic accidents so as to discuss the causes and characteristics of road crash in China.Results: From 2003 to 2005, the numbers of traffic accidents, injuries and deaths as well as the mortality rates per 100,000 persons and per 10,000 vehicles declined in China. Until 2005, the total number of traffic accidents decreased to 450,000 and deaths to 99,000, with the mortality rate per 10,000 vehicles being 7.6 persons. While the drivers and passengers accounted for 33.2% and 26.6% of death casualties respectively in 2005. Most traffic accidents were caused by drivers, especially those with driving experience less than 3 years. Traffic accidents occurred on suburban roads accounted for 60%. The mortality rate of the traffic accidents per 100 km on the first grade road ranked the highest. The mortality rate of the traffic accidents on expressways ranked the highest, with continual increase of death and injury.Conclusions: At present, the increase trend of traffic accidents and casualties in China has been slowed down to some extent and shows a declining tendency, but the situation is far away from being optimistic. In order to cut down the number of traffic accidents and casualties, we should pay more attention to training and managing drivers with less than three driving years and those driving buses. Strict prevention measures should be laid on traffic accidents on first grade roads, expressways and suburban roads as well as the enhancement on improving first-aid system. [ABSTRACT FROM AUTHOR]

Objective: To study the influence of distal tibiofibular synostosis on ankle function.Methods: From October 1998 to October 2004, a total of 281 consecutive patients underwent operations because of ankle fractures or distal fractures of the tibia and fibula. Distal tibiofibular synostosis occurred after operation in 8 patients. The duration of follow-up averaged 20.6 months (14-44 months). The ankle function was assessed on the basis of functional rating system described by Mazur.(1)Results: According to Mazur's ankle evaluation system, 4 patients achieved an excellent result, 2 a good result and 2 a fair result. The dorsiflexion of the synostosis ankle reduced by 8.26 degrees as compared with that of the contralateral ankle, and there was little influence on the plantar flexion. All the patients had a normal gait.Conclusion: The distal tibiofibular synostosis after the operation of ankle fractures or distal fractures of the tibia and fibula usually gives rise to few symptoms and needs no specific treatment. [ABSTRACT FROM AUTHOR]

Purpose: To develop and validate a preoperative prediction model based on multimodal ultrasound and biochemical indicator for identifying microvascular invasion (MVI) in patients with a single hepatocellular carcinoma (HCC) ≤ 5 cm., Methods: From May 2022 to November 2023, a total of 318 patients with pathologically confirmed single HCC ≤ 5 cm from three institutions were enrolled. All of them underwent preoperative biochemical, conventional ultrasound (US), and contrast-enhanced ultrasound (CEUS) (Sonazoid, 0.6 mL, bolus injection) examinations. Univariate and multivariate logistic regression analyses on clinical information, biochemical indicator, and US imaging features were performed in the training set to seek independent predictors for MVI-positive. The models were constructed and evaluated using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis in both validation and test sets. Subgroup analyses in patients with different liver background and tumor sizes were conducted to further investigate the model's performance., Results: Logistic regression analyses showed that obscure tumor boundary in B-mode US, intra-tumoral artery in pulsed-wave Doppler US, complete Kupffer-phase agent clearance in Sonazoid-CEUS, and biomedical indicator PIVKA-II were independently correlated with MVI-positive. The combined model comprising all predictors showed the highest AUC, which were 0.937 and 0.893 in the validation and test sets. Good calibration and prominent net benefit were achieved in both sets. No significant difference was found in subgroup analyses., Conclusions: The combination of biochemical indicator, conventional US, and Sonazoid-CEUS features could help preoperative MVI prediction in patients with a single HCC ≤ 5 cm., Critical Relevance Statement: Investigation of imaging features in conventional US, Sonazoid-CEUS, and biochemical indicators showed a significant relation with MVI-positivity in patients with a single HCC ≤ 5 cm, allowing the construction of a model for preoperative prediction of MVI status to help treatment decision making., Key Points: MVI status is important for patients with a single HCC ≤ 5 cm. The model based on conventional US, Sonazoid-CEUS and PIVKA-II performs best for MVI prediction. The combined model has potential for preoperative prediction of MVI status., (© 2024. The Author(s).)

Objective: Offspring of mothers with depression are at increased risk for executive function (EF) deficits and later depressive symptoms, but limited studies examined EF as an intermediary pathway. This study examined the role of EF in mediating the association between maternal and child depressive symptoms., Method: Data were from a longitudinal birth cohort consisting of 739 participants followed from the antenatal period for 12 years. Mothers completed the Edinburgh Perinatal Depression Scale at 26-28 weeks' gestation, at 3 months, and 24 months postpartum. At 8.5-10 years, children self-reported the Children's Depression Inventory-2. Task-based and parent-reported EF measures were collected at four timepoints between 3.5 and 8.5 years. Latent growth curve models examined antenatal depressive symptoms and its trajectory in contributing to cold (i.e., cognitive) and hot (i.e., affective) EF. We then assessed the extent to which EF mediated this association., Results: Maternal depressive symptoms did not directly predict depressive symptoms in late childhood. Antenatal depressive symptoms predicted lower cold (ß = -0.13, 95% CI= -0.25, -0.004) and hot EF (ß = -0.26, 95% CI= -0.38, -0.15). Deficits in cold EF (ß = -0.26, 95% CI = -0.41, -0.11) acted as an intermediary path to depressive symptoms, while hot EF mediated the association between maternal and child depressive symptoms, forming an indirect path that accounted for 37.5% of the association., Conclusion: Deficits in hot EF may be a pathway in explaining the intergenerational transmission of depression. The finding suggests fostering EF skills as a potential strategy for at-risk children., (Copyright © 2024. Published by Elsevier Inc.)

We aimed to implement a fully automatic computed tomography (CT) image-detection programming algorithm as a pectus excavatum (PE) diagnostic tool, facilitating comprehensive chest wall deformity evaluation. We developed our algorithm using MATLAB, leveraging the Hounsfield unit threshold and region growing methods. The MATLAB graphical user interface enables the direct use of our program. We validated the model using CT images of anthropomorphic phantoms and one normal individual. The measurement values obtained by our algorithm demonstrated very small differences compared to the known anthropomorphic phantom model data and manual measurement. For algorithm testing, 17,214 chest CT scans obtained from 57 PE patients were processed by the algorithm and independently reviewed by a radiologist and a thoracic surgeon. The measurements of transverse, anteroposterior, and sternum-to-vertebral distance of the thoracic cavity, along with the calculated data of four indices, exhibited high positive correlations (0.94-0.99). The asymmetry index and maximum anteroposterior hemithorax distance exhibited moderate correlation (0.40-0.83). Our automatic PE diagnostic tool demonstrated high accuracy; four chest wall deformity indices were obtained simultaneously without any initial manual marking, correlating well with manual measurements., (© 2024. The Author(s).)

China is the largest mariculture country, and shellfish and algae output ranks first, showing high carbon sink capacity. In recent years, the single cultivation of macroalgae (Pyropia yezoensis) has been changed to macroalgae-shellfish mariculture in Haizhou Bay to increase the yield of P. yezoensis and improve the water environment quality. In this study, four surveys were carried out in July 2022 during the monoculture period of oyster (Magallana gigas), as well as at different stages of P. yezoensis culture (head-crop period, November 2022, peak growing season, January 2023, and end of harvesting, March 2023) in the mariculture and the surrounding waters of Haizhou Bay. The effects of different stages of culture on the seawater environment and seasonal and spatial variations in the carbonate system were analyzed, and the carbon sink capacity was preliminarily estimated. The results showed that in summer, the calcification of M. gigas and the primary production process of phytoplankton effectively reduced the dissolved inorganic carbon (DIC) level in the culture area. The culture area acts as a CO 2 sink, with an average air-sea CO 2 flux of -4.5 mmol m -2 d -1 . During the polyculture period, the P. yezoensis culture activities maintained the stability of the seawater carbonate system, and the culture area shows strong CO 2 sinks, with the average air-sea CO 2 flux of -24.10 mmol m -2 d -1 , -37.68 mmol m -2 d -1 , and -38.99 mmol m -2 d -1 , respectively. The absorption of CO 2 by large-scale cultured P. yezoensis through the "biological pump" effect is the main factor affecting the CO 2 exchange process at the air-sea interface, and the absorption rate of CO 2 by P. yezoensis at the mature stage is higher than that at the growth stage before harvesting. The study revealed that macroalgae-shellfish mariculture could promote mutual growth, alleviate environmental pressure, and enhance the carbon sink of the culture area. The relationship between mariculture and the carbon cycle of a mariculture ecosystem is very complicated, and its biochemical process should be given great attention for further study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The relationship between the dynamic changes in insulin resistance (IR) and the prognosis of septic patients remains unclear. This study aims to investigate the correlation between the clinical subphenotype of IR represented by the triglyceride-glucose (TyG) index trajectory and the mortality rate among patients with sepsis., Methods: In this retrospective cohort study, we utilized data from septic patients within the Medical Information Mart for Intensive Care (MIMIC)-IV database version 2.0 to construct trajectories of the TyG index over 72 h. Subsequently, we computed the similarity among various TyG index trajectories with the dynamic time warping (DTW) algorithm and utilized the hierarchical clustering (HC) algorithm to demarcate distinct cluster and identified subphenotypes according to the trajectory trend. Subsequently, we assessed the mortality risk between different subphenotypes using analyses such as survival analysis and validated the robustness of the results through propensity score matching (PSM) and various models., Results: A total of 2350 patients were included in the study. Two trajectory trends: TyG index decreasing (n = 926) and TyG index increasing (n = 1424) were identified, which indicated corresponding to the clinical subphenotype of increased and alleviative IR respectively. The 28-day and in-hospital mortality for the increased IR group was 28.51% and 25.49% respectively. In comparison, patients in the alleviative IR group with a 28-day mortality of 23.54% and an in-hospital mortality of 21.60%. These subphenotypes exhibited distinct prognosis, time dependent Cox model showed the increased IR group with a higher 28-day mortality [hazard ratio (HR): 1.07, 95% confidence interval (CI): 1.02-1.12, P = 0.01] and in-hospital mortality [HR: 1.05, 95% CI: 1.00-1.11, P = 0.045] compared to the alleviative IR group. Sensitivity analyses with various models further validated the robustness of our findings., Conclusion: Dynamic increase in the TyG index trajectory is associated with elevated mortality risk among patients with sepsis, which suggests that dynamic increased IR exacerbates the risk of poor outcomes in patients., (© 2024. The Author(s).)

Background: Heart rate is crucial for patients with septic shock, but there are few studies on the scope of heart rate. Therefore, we studied the relationship between different heart rates and mortality of critically ill patients with septic shock, and explored the optimal heart rate range, in order to provide new insights for clinical treatment of septic shock., Methods: This retrospective study utilized time-series heart rate data from the Medical Information Mart for Intensive Care (MIMIC) IV database. Patients with septic shock were identified as the Sepsis 3.0 criteria and received vasopressor therapy in the first 24 h since ICU admission. We calculated the time-weighted average heart rate (TWA-HR) based on the time-series data. The restricted cubic spline (RCS) analysis was employed to investigate the nonlinear relationship between heart rate and 28-day mortality, aiming to explore the optimal heart rate control target for septic patients and using this target as the exposure factor. The primary outcome was 28-day mortality, and the secondary outcome were ICU and in-hospital mortality. For the original cohort, we applied the log-rank test to infer the relationship between heart rate and mortality. To control for bias introduced by confounders, we utilized propensity score matching (PSM) to reduce imbalances between normal TWA-HR and high TWA-HR groups, and we established a series of models [the multivariable Cox model, matching weight (MW)-adjusted Cox model, multivariable logistic regression, MW-adjusted logistic regression, and doubly robust model] as sensitivity analyses and subgroup analyses to demonstrate the robustness of our findings., Results: A total of 13492 patients were included in our study. The RCS analysis based on Cox and logistic regression showed increased risk of mortality (P < 0.001, non-linear P < 0.001) when TWA-HR > 85 beats per minute (bpm). The log-rank test revealed in terms of the 28-day mortality, the hazard ratio (HR) (95% confidence interval [CI]) was 1.92 (1.78-2.06, P < 0.001) for patients with high TWA-HR compared to normal TWA-HR group. Similarly, for the ICU mortality, the HR (95% CI) was 1.64 (1.52-1.78, P < 0.001), and for the in-hospital mortality, the HR (95% CI) was 1.61 (1.48-1.76, P < 0.001). Collectively, the sensitivity analysis consistently demonstrated higher 28-day mortality, ICU mortality, and in-hospital mortality in patients with TWA-HR > 85 bpm., Conclusion: Patients with septic shock whose heart rate was controlled no more than 85 bpm during ICU stay received survival benefit in terms of 28-day, ICU and in-hospital mortality. ., (© 2024. The Author(s).)

Aims: This study endeavors to explore the ramifications of early dynamic blood glucose (BG) trajectories within the initial 48 h of intensive care unit (ICU) admission on mortality among critically ill heart failure (HF) patients., Methods: The study employed a retrospective observational design, analyzing dynamic BG data of HF patients from the Medical Information Mart for Intensive Care IV database. The BG trajectory subphenotypes were identified using the hierarchical clustering based on the dynamic time-warping algorithm. The primary outcome of the study was 28-day mortality, with secondary outcomes including 180-day and 1-year mortality., Results: We screened a total of 21,098 HF patients and finally 15,092 patients were included in the study. Our results identified three distinct BG trajectory subphenotypes: increasing (n = 3503), stabilizing (n = 6250), and decreasing (n = 5339). The increasing subphenotype was associated with the highest mortality risk at 28 days, 180 days, and 1 year. The stabilizing and decreasing subphenotypes showed significantly lower mortality risks across all time points, with hazard ratios ranging from 0.85 to 0.88 (P<0.05 for all). Sensitivity analyses confirmed the robustness of these findings after adjusting for various covariates., Conclusions: Increasing BG trajectory within 48 h of admission is significantly associated with higher mortality in patients with HF. It is necessary to devote greater attention to the early BG dynamic changes in HF patients to optimize clinical BG management and enhance patient prognosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Purpose: Dual-task walking is challenging for people with Parkinson disease (PD). Gait performance worsens while executing dual tasks, possibly due to a decline in executive function (EF). This study aimed to investigate the effects of dual-task training on EF and dual-task cost (DTC) in people with PD and to explore whether training-induced changes in EF were associated with changes in DTC., Methods: This study was a randomized controlled trial. A total of 28 people with PD participated. Participants were randomly assigned to the experimental group (dual-task training) and the control group (treadmill training). Both groups received a total of 16 training sessions during the 8 weeks. Assessments were conducted at baseline and postintervention. Primary outcomes included EF and dual-task cost., Results: Significant time-by-group interactions were found in executive function and DTC. The experimental group showed significant improvement in frontal assessment battery (FAB), trail-making test (TMT) part A, Stroop color and word test (SCWT), and DTC on speed in cognitive dual-task walking. There was a moderate to high correlation between the change values of the FAB, TMT part A, SCWT, and the change values of DTC in cognitive dual-task walking., Discussion and Conclusions: Compared to treadmill training, dual-task training resulted in greater improvements in EF and DTC. Training-induced changes in EF were linked to changes in DTC when walking while performing a cognitive task but not when walking while performing a motor task., Video Abstract: For more insights from the authors Supplemental Digital Content available at http://links.lww.com/JNPT/A485., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Academy of Neurologic Physical Therapy, APTA.)

Objective: Maternal stress influences in utero brain development and is a modifiable risk factor for offspring psychopathologies. Reward circuitry dysfunction underlies various internalizing and externalizing psychopathologies. This study examined (1) the association between maternal stress and microstructural characteristics of the neonatal nucleus accumbens (NAcc), a major node of the reward circuitry, and (2) whether neonatal NAcc microstructure modulates individual susceptibility to maternal stress in relation to childhood behavioral problems., Method: K-means longitudinal cluster analysis was performed to determine trajectories of maternal stress measures (Perceived Stress Scale [PSS], hair cortisol) from preconception to the third trimester. Neonatal NAcc microstructural measures (orientation density index [ODI] and intracellular volume fraction [ICVF]) were compared across trajectories. We then examined the interaction between maternal stress and neonatal NAcc microstructure on child internalizing and externalizing behaviors, assessed between ages 3 and 4 years., Results: Two trajectories of maternal stress magnitude ("low"/"high") were identified for both PSS (n = 287) and hair cortisol (n = 336). Right neonatal NAcc ODI (rNAcc-ODI) was significantly lower in "low" relative to "high" PSS trajectories (n = 77, p = .04). PSS at preconception had the strongest association with rNAcc-ODI (r = 0.293, p = .029). No differences in NAcc microstructure were found between hair cortisol trajectories. A significant interaction between preconception PSS and rNAcc-ODI on externalizing behavior was observed (n = 47, p = .047)., Conclusion: Our study showed that the preconception period contributes to in utero NAcc development, and that NAcc microstructure modulates individual susceptibility to preconception maternal stress in relation to externalizing problems., Plain Language Summary: In the S-PRESTO population-based cohort study conducted in Singapore with 351 women and their children, higher levels of maternal perceived stress within the year before pregnancy were associated with increased dendritic complexity within offsprings' nucleus accumbens, indicative of a more advanced developmental profile. Variations in right nucleus accumbens microstructure significantly modulated the association between maternal perceived stress at preconception and externalizing behaviors in early childhood. Study findings suggest that maternal stress in the preconception period accelerates in-utero nucleus accumbens development, leading to differential risk to externalizing problems in later childhood., (Copyright © 2024 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Oncogenic growth places great strain and dependence on the proteostasis network. This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and autophagy, two key stem cell proteostasis pathways, to prevent unfolded protein accumulation. Inactivation of HSF1 sensitized human AML cells to proteasome inhibition, marked by unfolded protein accumulation, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival, and significant slowing of disease progression and extension of survival in vivo . Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed AML cells, and significantly reduced AML burden and extended survival in vivo . Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, without severely affecting normal hematopoietic stem/progenitor cells. Combined autophagy and proteasome inhibition also activated the integrated stress response, but surprisingly this occurred in a PKR-dependent manner. These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.

A pervasive dilemma in neuroimaging is whether to prioritize sample size or scan time given fixed resources. Here, we systematically investigate this trade-off in the context of brain-wide association studies (BWAS) using functional magnetic resonance imaging (fMRI). We find that total scan duration (sample size × scan time per participant) robustly explains individual-level phenotypic prediction accuracy via a logarithmic model, suggesting that sample size and scan time are broadly interchangeable up to 20-30 min of data. However, the returns of scan time diminish relative to sample size, which we explain with principled theoretical derivations. When accounting for fixed overhead costs associated with each participant (e.g., recruitment, non-imaging measures), prediction accuracy in many small-scale and some large-scale BWAS might benefit from longer scan time than typically assumed. These results generalize across phenotypic domains, scanners, acquisition protocols, racial groups, mental disorders, age groups, as well as resting-state and task-state functional connectivity. Overall, our study emphasizes the importance of scan time, which is ignored in standard power calculations. Standard power calculations maximize sample size, at the expense of scan time, which can result in sub-optimal prediction accuracies and inefficient use of resources. Our empirically informed reference is available for future study design: WEB&#95;APPLICATION&#95;LINK., Competing Interests: Conflict of interest DB is shareholder and advisory board member of MindState Design Labs, USA.

Pooling MRI data from multiple datasets requires harmonization to reduce undesired inter-site variabilities, while preserving effects of biological variables (or covariates). The popular harmonization approach ComBat uses a mixed effect regression framework that explicitly accounts for covariate distribution differences across datasets. There is also significant interest in developing harmonization approaches based on deep neural networks (DNNs), such as conditional variational autoencoder (cVAE). However, current DNN approaches do not explicitly account for covariate distribution differences across datasets. Here, we provide mathematical results, suggesting that not accounting for covariates can lead to suboptimal harmonization. We propose two DNN-based covariate-aware harmonization approaches: covariate VAE (coVAE) and DeepResBat. The coVAE approach is a natural extension of cVAE by concatenating covariates and site information with site- and covariate-invariant latent representations. DeepResBat adopts a residual framework inspired by ComBat. DeepResBat first removes the effects of covariates with nonlinear regression trees, followed by eliminating site differences with cVAE. Finally, covariate effects are added back to the harmonized residuals. Using three datasets from three continents with a total of 2787 participants and 10,085 anatomical T1 scans, we find that DeepResBat and coVAE outperformed ComBat, CovBat and cVAE in terms of removing dataset differences, while enhancing biological effects of interest. However, coVAE hallucinates spurious associations between anatomical MRI and covariates even when no association exists. Future studies proposing DNN-based harmonization approaches should be aware of this false positive pitfall. Overall, our results suggest that DeepResBat is an effective deep learning alternative to ComBat. Code for DeepResBat can be found here: https://github.com/ThomasYeoLab/CBIG/tree/master/stable&#95;projects/harmonization/An2024&#95;DeepResBat., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The mitochondria‑associated endoplasmic reticulum (ER) membrane (MAM), serving as a vital link between the mitochondria and ER, holds a pivotal role in maintaining the physiological function of these two organelles. Its specific functions encompass the participation in the biosynthesis and functional regulation of the mitochondria, calcium ion transport, lipid metabolism, oxidative stress and autophagy among numerous other facets. Scientific exploration has revealed that MAMs hold potential as effective therapeutic targets influencing the mitochondria and ER within the context of cancer therapy. The present review focused on elucidating the related pathways of mitochondrial autophagy and ER stress and their practical application in ovarian cancer, aiming to identify commonalities existing between MAMs and these pathways, thereby extending to related applications of MAMs in ovarian cancer treatment. This endeavor aimed at exploring new potential for MAMs in clinically managing ovarian cancer.

The exploration of a facile approach to create structurally versatile substances carrying air-stable radicals is highly desired, but still a huge challenge in chemistry and materials science. Herein, a non-contact method to generate air-stable radicals by exposing pyridine/imidazole ring-bearing substances to volatile cyanuric chloride vapor, harnessed as a chemical fuel is reported. This remarkable feat is accomplished through a nucleophilic substitution reaction, wherein an intrinsic electron transfer event transpires spontaneously, originating from the chloride anion (Cl - ) to the cationic nitrogen (N + ) atom, ultimately giving rise to pyridinium/imidazolium radicals. Impressively, the generated radicals exhibit noteworthy stability in the air over one month owing to the delocalization of the unpaired electron through the extended and highly fused π-conjugated pyridinium/imidazolium-triazine unit. Such an approach is universal to diverse substances, including organic molecules, metal-organic complexes, hydrogels, polymers, and organic cage materials. Capitalizing on this versatile technique, surface radical functionalization can be readily achieved across diverse substrates. Moreover, the generated radical species showcase a myriad of high-performance applications, including mimicking natural peroxidase to accelerate oxidation reactions and achieving high-efficiency near-infrared photothermal conversion and photothermal bacterial inhibition., (© 2024 Wiley‐VCH GmbH.)

Perceived stress is an acknowledged risk factor for subthreshold depression (StD), and fluctuations in perceived stress are thought to disrupt the harmony of brain networks essential for emotional and cognitive functioning. This study aimed to elucidate the relationship between eye-open (EO) and eye-closed (EC) states, perceived stress, and StD. We recruited 27 individuals with StD and 33 healthy controls, collecting resting state fMRI data under both EC and EO conditions. We combined intrinsic connectivity and seed-based functional connectivity analyses to construct the functional network and explore differences between EC and EO conditions. Graph theory analysis revealed weakened connectivity strength in the right superior frontal gyrus (SFG) and right median cingulate and paracingulate gyrus (MCC) among participants with StD, suggesting an important role for these regions in the stress-related emotions dysregulation. Notably, altered SFG connectivity was observed to significantly relate to perceived stress levels in StD, and the SFG connection emerges as a neural mediator potentially influencing the relationship between perceived stress and StD. These findings highlight the role of SFG and MCC in perceived stress and suggest that understanding EC and EO states in relation to these regions is important in the neurobiological framework of StD. This may offer valuable perspectives for early prevention and intervention strategies in mental health disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Serum response factor (SRF) controls gene transcription in vascular smooth muscle cells (VSMCs) and regulates VSMC phenotypic switch from a contractile to a synthetic state, which plays a key role in the pathogenesis of cardiovascular diseases (CVD). It is not known how post-translational SUMOylation regulates the SRF activity in CVD. Here we show that Senp1 deficiency in VSMCs increased SUMOylated SRF and the SRF-ELK complex, leading to augmented vascular remodeling and neointimal formation in mice. Mechanistically, SENP1 deficiency in VSMCs increases SRF SUMOylation at lysine 143, reducing SRF lysosomal localization concomitant with increased nuclear accumulation and switching a contractile phenotype-responsive SRF-myocardin complex to a synthetic phenotype-responsive SRF-ELK1 complex. SUMOylated SRF and phospho-ELK1 are increased in VSMCs from coronary arteries of CVD patients. Importantly, ELK inhibitor AZD6244 prevents the shift from SRF-myocardin to SRF-ELK complex, attenuating VSMC synthetic phenotypes and neointimal formation in Senp1-deficient mice. Therefore, targeting the SRF complex may have a therapeutic potential for the treatment of CVD., (© 2024. The Author(s).)

Background: Cerebral vascular malformations (CCMs) are primarily found within the brain, where they result in increased risk for stroke, seizures, and focal neurological deficits. The unique feature of the brain vasculature is the blood-brain barrier formed by the brain neurovascular unit. Recent studies suggest that loss of CCM genes causes disruptions of blood-brain barrier integrity as the inciting events for CCM development. CCM lesions are proposed to be initially derived from a single clonal expansion of a subset of angiogenic venous capillary endothelial cells (ECs) and respective resident endothelial progenitor cells (EPCs). However, the critical signaling events in the subclass of brain ECs/EPCs for CCM lesion initiation and progression are unclear., Methods: Brain EC-specific CCM3-deficient ( Pdcd10 BECKO ) mice were generated by crossing Pdcd10 fl/fl mice with Mfsd2a -CreER T2 mice. Single-cell RNA-sequencing analyses were performed by the chromium single-cell platform (10× genomics). Cell clusters were annotated into EC subtypes based on visual inspection and GO analyses. Cerebral vessels were visualized by 2-photon in vivo imaging and tissue immunofluorescence analyses. Regulation of mTOR (mechanistic target of rapamycin) signaling by CCM3 and Cav1 (caveolin-1) was performed by cell biology and biochemical approaches., Results: Single-cell RNA-sequencing analyses from P10 Pdcd1 0 BECKO mice harboring visible CCM lesions identified upregulated CCM lesion signature and mitotic EC clusters but decreased blood-brain barrier-associated EC clusters. However, a unique EPC cluster with high expression levels of stem cell markers enriched with mTOR signaling was identified from early stages of the P6 Pdcd1 0 BECKO brain. Indeed, mTOR signaling was upregulated in both mouse and human CCM lesions. Genetic deficiency of Raptor (regulatory-associated protein of mTOR), but not of Rictor (rapamycin-insensitive companion of mTOR), prevented CCM lesion formation in the Pdcd10 BECKO model. Importantly, the mTORC1 (mTOR complex 1) pharmacological inhibitor rapamycin suppressed EPC proliferation and ameliorated CCM pathogenesis in Pdcd10 BECKO mice. Mechanistic studies suggested that Cav1/caveolae increased in CCM3-depleted EPC-mediated intracellular trafficking and complex formation of the mTORC1 signaling proteins., Conclusions: CCM3 is critical for maintaining blood-brain barrier integrity and CCM3 loss-induced mTORC1 signaling in brain EPCs initiates and facilitates CCM pathogenesis., Competing Interests: None.

The unstable quality of Polyporus umbellatus sclerotia during cultivation is the key factor affecting the quality and yield of P. umbellatus sclerotia. In order to provide technical support for obtaining superior P. umbellatus by molecular breeding, the genetic transformation system mediated by Agrobacterium tumefaciens was studied in this paper. A. tumefaciens-mediated method was used to investigate the effects of antibiotic concentration, strain type, A. tumefaciens concentration, receptor material, infection time, co-culture time, and screening conditions on the genetic transformation efficiency of P. umbellatus. The transformants were screened and detected by hygromycin resistance marker genes, polymerase chain reaction(PCR) of specific primers, and fluorescence detection methods. The results showed that the A. tumefaciens GV3101 strain could genetically transfer P. umbellatus mycelium cells, and the optimal conditions for infection were as follows: the A. tumefaciens concentration A&#95;(600 nm)= 0.6, P. umbellatus mycelium cells as receptor material, infection time of 30 min, and co-culture time of 3 days. The two-step screening method involving hygromycin of 9 and 13 μg·mL~(-1 )was the best screening condition. The results of hygromycin resistance screening, PCR detection of specific primers, and fluorescence detection showed that the exogenous gene eGFP had been transferred into the P. umbellatus mycelium cells, integrated into the genome, and successfully expressed. Under optimal conditions, the conversion efficiency could be increased to 2.3%, and the genetic transformation period was shortened from more than 90 days to less than 60 days. This study established and optimized the genetic transformation system of P. umbellatus mycelium cells mediated by A. tumefaciens, laying a foundation for the analysis of the molecular mechanism of P. umbellatus during growth and molecular breeding.