A bioinspired doxorubicin-carried albumin Nanocage against aggressive Cancer via systemic targeting of tumor and lymph node metastasis.

Cancer metastasis and recurrence are obstacles to successful treatment of aggressive cancer. To address this challenge, chemotherapy is indispensable as an essential part of comprehensive cancer treatment, particularly for subsequent therapy after surgical resection. However, small-molecule drugs for chemotherapy always cause inadequate efficacy and severe side effects against cancer metastasis and recurrence caused by lymph node metastases. Here, we developed doxorubicin-carried albumin nanocages (Dox-AlbCages) with appropriate particle sizes and pH/enzyme-responsive drug release for tumor and lymph node dual-targeted therapy by exploiting the inborn transport properties of serum albumin. Inspired by the protein-templated biomineralization and remote loading of doxorubicin into liposomes, we demonstrated the controlled synthesis of Dox-AlbCages via the aggregation or crystallization of doxorubicin and ammonium sulfate within albumin nanocages using a biomineralization strategy. Dox-AlbCages allowed efficient encapsulation of Dox in the core protected by the albumin corona shell, exhibiting favorable properties for enhanced tumor and lymph node accumulation and preferable cellular uptake for tumor-specific chemotherapy. Intriguingly, Dox-AlbCages effectively inhibited tumor growth and metastasis in orthotopic 4 T1 breast tumors and prevented postsurgical tumor recurrence and lung metastasis. At the same time, Dox-AlbCages had fewer side effects than free Dox. This nanoplatform provides a facile strategy for designing tumor- and lymph node-targeted nanomedicines for suppressing cancer metastasis and recurrence.

Cold tolerance and metabolism of red-haired pine bark beetle Hylurgus ligniperda (Coleoptera: Curculionidae) during the overwintering period.

Hylurgus ligniperda invaded Shandong, China, through imported forest timber, posing a threat to China's forest health. Exotic insects with broad environmental tolerance, including low temperatures, may have a better chance of surviving the winters and becoming invasive. Understanding the cold-tolerance strategies of H. ligniperda may help to design sustainable pest management approaches. In this study, we aim to investigate the cold-tolerance ability and relevant physiological indicators in overwintering H. ligniperda adults to determine any possible overwintering strategies. Supercooling points (SCPs) for adults H. ligniperda differed significantly across months and reached the lowest level in the mid- and post-overwintering period, the minimum SCPs -6.45 ±â€…0.18 °C. As the cold exposure temperature decreased, the survival rate of adults gradually decreased, and no adult survived more than 1 day at -15 °C, and the LLT50 for 1 day was -7.1 °C. Since H. ligniperda adults can survive internal ice formation, they are freeze-tolerant insects. Throughout the overwintering period, the SCPs and the water, protein, sorbitol, and glycerol content in adults decreased initially and then increased. We reported significant correlations between total protein, sorbitol, trehalose, and glycerol content in the beetles and SCPs. Glycogen, lipid, protein, trehalose, and sorbitol content in adult beetles may directly affect their cold-tolerance capacity and survival during winter. This study provides a physiological and biochemical basis for further study of metabolism and cold-tolerance strategies in H. ligniperda adults, which may help predict population dynamics and distribution potential of pests.

Risk factors and prognostic analysis of right ventricular dysfunction after lung resection for NSCLC.

Objectives: Lung cancer is the leading cause of cancer death, and 80-85% of all lung cancer cases are non-small cell lung cancer (NSCLC). Surgical resection is the standard treatment for early-stage NSCLC. However, lung resection, a surgical procedure, can result in complications and increased mortality. Recent studies have shown a significant correlation between complications after lung resection and right ventricular dysfunction. Methods: Transthoracic echocardiography-derived right ventricular-pulmonary artery coupling (RV-PAC) was utilized to assess right ventricular function in these patients. Multivariate logistic regression analysis was also conducted to assess risk factors independently associated with RV-PA uncoupling. The 3- and 5-year cumulative survival rates were estimated with Kaplan-Meier curves, and differences between groups were analyzed using the Mantel-Cox log-rank test. Results: RV-PA uncoupling was defined as a TAPSE/PASP value < 0.67 mm/mm Hg according to spline analysis. The results of multivariable logistic regression analysis indicated that diabetes is an independent risk factor for right ventricular dysfunction after lung resection in patients with NSCLC. Kaplan-Meier analysis revealed a significant decrease in the survival rate of patients with RV-PA uncoupling at both the 3-year follow-up (73% vs 40%, p < 0.001) and 5-year follow-up (64% vs 37%, p < 0.001). Conclusions: After lung resection for NSCLC, the patient's right ventricular function predicts prognosis. Patients with right ventricular dysfunction, particularly those with diabetes mellitus, have a worse prognosis. It is crucial to actively prevent and correct risk factors to reduce the mortality rate in these patients.

Joint association of sedentary time and physical activity with abnormal heart rate recovery in young and middle-aged adults.

BACKGROUND: Abnormal heart rate recovery (HRR), representing cardiac autonomic dysfunction, is an important predictor of cardiovascular disease. Prolonged sedentary time (ST) is associated with a slower HRR. However, it is not clear how much moderate-to-vigorous physical activity (MVPA) is required to mitigate the adverse effects of sedentary behavior on HRR in young and middle-aged adults. This study aimed to examine the joint association of ST and MVPA with abnormal HRR in this population. METHODS: A cross-sectional analysis was conducted on 1253 participants (aged 20-50 years, 67.8% male) from an observational study assessing cardiopulmonary fitness in Fujian Province, China. HRR measured via cardiopulmonary exercise tests on a treadmill was calculated as the difference between heart rate at peak exercise and 2 min after exercise. When the HRR was ≤ 42 beats·minute-1 within this time, it was considered abnormal. ST and MVPA were assessed by the IPAQ-LF. Individuals were classified as having a low sedentary time (LST [< 6 h·day-1]) or high sedentary time (HST [≥ 6 h·day-1]) and according to their MVPA level (low MVPA [0-149 min·week-1], medium MVPA [150-299 min·week-1], high MVPA [≥ 300 min·week-1]). Finally, six ST-MVPA groups were derived. Associations between ST-MVPA groups with abnormal HRR incidence were examined using logistic regression models. RESULTS: 53.1% of the young and middle-aged adults had less than 300 min of MVPA per week. In model 2, adjusted for possible confounders (e.g. age, sex, current smoking status, current alcohol consumption, sleep status, body mass index), HST was associated with higher odds of an abnormal HRR compared to LST (odds ratio (OR) = 1.473, 95% confidence interval (CI) = 1.172-1.852). Compared with the reference group (HST and low MVPA), the HST and high MVPA groups have a lower chance of abnormal HRR (OR, 95% CI = 0.553, 0.385-0.795). Compared with individuals with HST and low MVPA, regardless of whether MVPA is low, medium, or high, the odds of abnormal HRR in individuals with LST is significantly reduced (OR, 95% CI = 0.515, 0.308-0.857 for LST and low MVPA; OR, 95% CI = 0.558, 0.345-0.902 for LST and medium MVPA; OR, 95% CI = 0.476, 0.326-0.668 for LST and high MVPA). CONCLUSION: Higher amounts of MVPA appears to mitigate the increased odds of an abnormal HRR associated with HST for healthy young and middle-aged adults.

Association between depression and infertility risk among American women aged 18-45 years: the mediating effect of the NHHR.

BACKGROUND/OBJECTIVE: Depression and infertility are major medical and social problems. The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) serves as an innovative and reliable lipid marker for cardiovascular disease risk assessment. Previous research has indicated a potential correlation among lipid metabolism, depression, and infertility. Nonetheless, the exact involvement of lipid metabolism in modulating the pathological mechanisms associated with depression-induced infertility remains to be fully elucidated. The aim of this study was to explore the connection between depression and infertility and to assess whether the NHHR mediates this association. METHODS: A cross-sectional analysis was performed utilizing data from there cycles (2013-2018) of the National Health and Nutrition Examination Survey (NHANES) database. Female infertility was assessed according to the responses to the RHQ074 question in the reproductive health questionnaire module. Depression states were evaluated using the Patient Health Questionnaire-9 and classified into three grades based on the total scores: no depression (0-4 points), minimal-to-mild depression (5-9 points) and moderate-to-severe depression (10 or more points). The NHHR was calculated from laboratory cholesterol test results. Baseline population characteristics were compared, and subgroup analyses were carried out based on the stratification of age and body mass index (BMI). Weighted multivariable logistic regression and linear regression models, with adjustments for various covariables, were employed to examine the associations among depression, infertility and the NHHR. Finally, mediation analysis was utilized to explore the NHHR's potential mediating role in depression states and female infertility. RESULTS: Within this cross-sectional study, 2,668 women aged 18 to 45 years residing in the United States were recruited, 305 (11.43%) of whom experienced infertility. The study revealed a markedly higher prevalence of depression (P = 0.040) and elevated NHHR (P < 0.001) among infertile women compared to the control cohort. Furthermore, moderate-to-severe depression states independently correlated with increased infertility risk, irrespective of adjustments for various covariables. Subgroup analysis indicated a positive association between depression and infertility risk within certain age categories, although no such relationship was observed within subgroups stratified by BMI. The findings from the weighted logistic regression analysis demonstrated that the elevated NHHR is positively associated with heightened infertility risk. Additionally, the weighted linear regression analysis indicated that moderate-to-severe depression is positively linked to the NHHR levels as well. Finally, the association between depression states and female infertility was partially mediated by the NHHR, with the mediation proportion estimated at 6.57%. CONCLUSION: In the United States, depression is strongly correlated with an increased likelihood of infertility among women of childbearing age, with evidence suggesting that this relationship is mediated by the NHHR. Subsequent research efforts should further explore the underlying mechanisms connecting depression and infertility.

Blocking Sigmar1 exacerbates methamphetamine-induced hypertension.

AIM: Methamphetamine (METH) chronic exposure is an important risk factor for hypertension development. However, the mechanisms behind METH-induced hypertension remain unclear. Therefore, we aimed to reveal the potential mechanisms underlying METH-induced hypertension. METHODS AND RESULTS: We structured the mouse hypertension model by METH, and observed that METH-treated mice have presented vascular remodeling (large-and small-size arteries) with collagen deposit around the vessel and increasing blood pressure (BP) and Sigma1 receptor (Sigmar1) in vascular tissue. We hypothesized that Sigmar1 is crucial in METH-induced hypertension and vascular remodeling. Sigmar1 knockout (KO) mice and antagonist (BD1047) pretreated mice exposed to METH for six-week showed higher BP and more collagen deposited around vessels than wild-type (WT) mice exposed to METH for six-week, in contrast, mice pretreated with Sigmar1 agonist (PRE-084) had unchanged BP and perivascular collagen despite the six-week METH exposure. Furthermore, we found that METH exposure induced vascular smooth muscle cells (VSMCs) and mesenchymal stem cells to differentiate into the myofibroblast-like cell and secrete collagen into surrounding vessels. Mechanically, Sigmar1 can suppress the COL1A1 expression by blocking the classical fibrotic TGF-ß/Smad2/3 signaling pathway in METH-exposed VSMCs and mesenchymal stem cells. CONCLUSION: Our results suggest that Sigmar1 is involved in METH-induced hypertension and vascular fibrosis by blocking the activation of the TGF-ß/Smad2/3 signaling pathway. Accordingly, Sigmar1 may be a novel therapeutic target for METH-induced hypertension and vascular fibrosis.

Comprehensive genetic analysis uncovers the mutational spectrum of MFRP and its genotype-phenotype correlation in a large cohort of Chinese microphthalmia patients.

PURPOSE: Microphthalmia is a severe congenital ocular disease featured by abnormal ocular development. The aim of this study was to detail the genetic and clinical characteristics of a large cohort of Chinese patients with microphthalmia related to MFRP variants, focusing on uncovering genotype-phenotype correlations. METHODS: Fifty microphthalmia patients from 44 unrelated Chinese families were recruited. Whole-exome sequencing (WES) was conducted to analyze the coding regions and adjacent intronic regions of MFRP. Axial lengths (AL) were measured for all probands and available family members. Protein structures of mutations with high frequency in our cohort were predicted. The genotype-phenotype correlations were explored by statistical analysis. RESULTS: Sixteen MFRP variants were detected in 17 families, accounting for 38.64 % of all microphthalmia families. There were 9 novel mutations (c.427+1G>C, c.428-2A>C, c.561_575del:p.A188_E192del, c.836G>A:p.C279Y, c.1010_1021del:p.H337_E340del:p.Y479*, c.1516_1517del:p.S506Pfs*66, c.1561T>G:p.C521G, c.1616G>A:p.R539H, and c.1735C>T:p.P579S) and six previously reported variants in MFRP, with p.E496K and p.H337_E340del being highly frequent, found in eight (47.06 %) and two families (11.76 %), respectively. Seven variants (43.75 %) were located in the C-terminal cysteine-rich frizzled-related domain (CRD) (7/16, 43.75 %). Protein prediction implicated p.E496K and p.H337_E340del mutations might lead to a destabilization of the MFRP protein. The average AL of all 42 eyes was 16.02 ± 1.05 mm, and 78.36 % of eyes with AL < 16 mm harbored p.E496K variant. Twenty-six eyes with variant variant had shorter AL than that of the other 16 eyes without this variant (p = 0.006), highlighting a novel genotype-phenotype correlation. CONCLUSIONS: In this largest cohort of Chinese patients with microphthalmia, the 9 novel variants, high frequency of p.E496W, and mutation hotspots in CRD reveals unique insights into the MFRP mutation spectrum among Chinese patients, indicating ethnic variability. A new genotype-phenotype correlation that p.E496K variant associated with a shorter AL is unveiled. Our findings enhance the current knowledge of MFRP-associated microphthalmia and provide valuable information for prenatal diagnosis as well as future therapy.

Electroacupuncture improves vascular cognitive impairment no dementia: A Randomized Clinical Trial.

BACKGROUND: Electroacupuncture (EA) could represent a clinically effective treatment strategy for patients with vascular cognitive impairment no dementia (VCIND). This randomized trial aims to explore the underlying mechanism of EA in VCIND patients through cognitive function assessment and neuroimaging assessment. METHODS: 140 eligible patients with VCIND were recruited and randomly divided into EA group (n = 70) and Control group (n = 70). The Montreal Cognitive Assessment (MoCA), and the Auditory Verbal Learning Test (AVLT), the Stroop color-naming task (STROOP), and the resting-state functional magnetic resonance imaging assessment. The EA group received treatment for 30 min/day, 5 times/week, for 8 weeks. RESULTS: EA intervention could increase the MoCA score and improve the neutral and consistency response of the STROOP test in VCIND patients (P < 0.05). fMRI functional connectivity analysis showed that, after EA, the default mode network (DMN) function of the posterior cingulate gyrus, left middle frontal gyrus, left anterior cingulate gyrus, left and right superior temporal gyrus, right insula, left precentral gyrus and other brain regions were significantly higher than that in the control group. The functional connectivity between the posterior cingulate gyrus-left middle frontal gyrus and the posterior cingulate gyrus-right superior temporal gyrus was positively correlated with cognitive function (P < 0.05). Gray Matter Volume increased in VCIND after EA(P < 0.05). CONCLUSIONS: EA can increase the functional connectivity between posterior cingulate gyrus-other gyri in VCIND patients. The functional connectivity is positively correlated with cognitive function.

Biomechanical analysis of trunk and lower limbs during stair activity in patients with scoliosis.

Staircases are a frequently encountered obstacle in daily life, requiring individuals to navigate ascending and descending movements that place additional demands on the trunk and lower limbs compared to walking on level surfaces. Therefore, it is crucial to examine the biomechanical characteristics of the trunk and lower limbs in individuals with scoliosis during stair activity. The aim of this study was to investigate the biomechanical differences in trunk and lower limbs during daily stair activities between patients with scoliosis and a healthy population. Additionally, the study aimed to explore the relationship between trunk abnormalities and lower limb biomechanics, providing a clinical and objective assessment basis for scoliosis. The Qualisys system, based in Gothenburg, Sweden, was employed for data collection in this study, with a sampling frequency of 150 Hz. It captured the kinematics of the trunk and lower limbs, as well as the kinetics of the lower limbs during stair ascent and descent for both the 28 individuals with scoliosis and the 28 control participants. The results indicate that scoliosis patients demonstrated significantly higher asymmetry compared to the control group in various measures during ascent and decent. These include different parts of kinematics and kinetics. Scoliosis patients demonstrate noticeable variations in their movement patterns compared to the healthy population when engaging in stair activities. Specifically, during stair ascent, scoliosis patients exhibit a seemingly more rigid movement pattern, whereas descent is characterized by an unstable pattern.

The maternal drug exposure birth cohort (DEBC) in China.

Drug exposure during pregnancy lacks global fetal safety data. The maternal drug exposure birth cohort (DEBC) study, a prospective longitudinal investigation, aims to explore the correlation of maternal drug exposure during pregnancy with pregnancy outcomes, and establish a human biospecimen biobank. Here we describe the process of establishing DEBC and show that the drug exposure rate in the first trimester of pregnant women in DEBC (n = 112,986) is 30.70%. Among the drugs used, dydrogesterone and progesterone have the highest exposure rates, which are 11.97% and 10.82%, respectively. The overall incidence of adverse pregnancy outcomes is 13.49%. Dydrogesterone exposure during the first trimester is correlated with higher incidences of stillbirth, preterm birth, low birth weight, and birth defects, along with a lower incidence of miscarriage/abortion. Due to the limitations of this cohort study, causative conclusions cannot be drawn. Further follow-up and in-depth data analysis are planned for future studies.

Tai Chi-Induced Exosomal LRP1 is Associated With Memory Function and Hippocampus Plasticity in aMCI Patients.

OBJECTIVES: The study was designed to identify the potential peripheral processes of circulating exosome in response to Tai Chi (TC) exercise and the possibility of its loaded cargos in mediating the effects of TC training on cognitive function among older adults with amnestic mild cognitive impairment (aMCI). DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter randomized controlled trial. One hundred community-dwelling old adults with aMCI were randomly assigned (1:1) to experimental (n = 50) and control groups (n = 50). INTERVENTION: The experimental group participated in TC exercise 5 times/week, with each session lasting 60 minutes for 12 weeks. Both experimental and control groups received health education every 4 weeks. MEASUREMENTS: The primary outcome was global cognitive function. Neurocognitive assessments, MRI examination, and large-scale proteomics analysis of peripheric exosome were conducted at baseline and after 12-week training. Outcome assessors and statisticians were blinded to group allocation. RESULTS: A total of 96 participants (96%) completed all outcome measurements. TC training improved global cognitive function (adjusted mean difference [MD] = 1.9, 95%CI 0.93-2.87, p <0.001) and memory (adjusted MD = 6.42, 95%CI 2.09-10.74, p = 0.004), increased right hippocampus volume (adjusted MD = 88.52, 95%CI 13.63-163.4, p = 0.021), and enhanced rest state functional connectivity (rsFC) between hippocampus and cuneus, which mediated the group effect on global cognitive function (bootstrapping CIs: [0.0208, 1.2826], [0.0689, 1.2211]) and verbal delay recall (bootstrapping CI: [0.0002, 0.6277]). Simultaneously, 24 differentially expressed exosomal proteins were detected in tandem mass tag-labelling proteomic analysis. Of which, the candidate protein low-density lipoprotein receptor-related protein 1 (LRP1) was further confirmed by parallel reaction monitoring and ELISA. Moreover, the up-regulated LRP1 was both positively associated with verbal delay recall and rsFC (left hippocampus-right cuneus). CONCLUSION: TC promotes LRP1 release via exosome, which was associated with enhanced memory function and hippocampus plasticity in aMCI patients. Our findings provided an insight into potential therapeutic neurobiological targets focusing on peripheric exosome in respond to TC exercise.

Therapeutic Effectiveness of Leukocyte- and Platelet-rich Fibrin for Diabetic Foot Ulcers: A Retrospective Study.

OBJECTIVE: Diabetic foot ulcer (DFU) is one of the most serious complications of diabetes. Leukocyte- and platelet-rich fibrin (L-PRF) is a second-generation autologous platelet-rich plasma. This study aims to investigate the clinical effects of L-PRF in patients with diabetes in real clinical practice. METHODS: Patients with DFU who received L-PRF treatment and standard of care (SOC) from 2018 to 2019 in Tongji Hospital were enrolled. The clinical information including patient characteristics, wound evaluation (area, severity, infection, blood supply), SOC of DFU, and images of ulcers was retrospectively extracted and analyzed. L-PRF treatment was performed every 7±2 days until the ulcer exhibited complete epithelialization or an overall percent volume reduction (PVR) greater than 80%. Therapeutic effectiveness, including overall PVR and the overall and weekly healing rates, was evaluated. RESULTS: Totally, 26 patients with DFU were enrolled, and they had an ulcer duration of 47.0 (35.0, 72.3) days. The severity and infection of ulcers varied, as indicated by the Site, Ischemia, Neuropathy, Bacterial Infection, and Depth (SINBAD) scores of 2-6, Wagner grades of 1-4, and the Perfusion, Extent, Depth, Infection and Sensation (PEDIS) scores of 2-4. The initial ulcer volume before L-PRF treatment was 4.94 (1.50, 13.83) cm3, and the final ulcer volume was 0.35 (0.03, 1.76) cm3. The median number of L-PRF doses was 3 (2, 5). A total of 11 patients achieved complete epithelialization after the fifth week of treatment, and 19 patients achieved at least an 80% volume reduction after the seventh week. The overall wound-healing rate was 1.47 (0.63, 3.29) cm3/week, and the healing rate was faster in the first 2 weeks than in the remaining weeks. Concurrent treatment did not change the percentage of complete epithelialization or healing rate. CONCLUSION: Adding L-PRF to SOC significantly improved wound healing in patients with DFU independent of the ankle brachial index, SINBAD score, or Wagner grade, indicating that this method is appropriate for DFU treatment under different clinical conditions.

An audio-semantic multimodal model for automatic obstructive sleep Apnea-Hypopnea Syndrome classification via multi-feature analysis of snoring sounds.

Introduction: Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a common sleep-related breathing disorder that significantly impacts the daily lives of patients. Currently, the diagnosis of OSAHS relies on various physiological signal monitoring devices, requiring a comprehensive Polysomnography (PSG). However, this invasive diagnostic method faces challenges such as data fluctuation and high costs. To address these challenges, we propose a novel data-driven Audio-Semantic Multi-Modal model for OSAHS severity classification (i.e., ASMM-OSA) based on patient snoring sound characteristics. Methods: In light of the correlation between the acoustic attributes of a patient's snoring patterns and their episodes of breathing disorders, we utilize the patient's sleep audio recordings as an initial screening modality. We analyze the audio features of snoring sounds during the night for subjects suspected of having OSAHS. Audio features were augmented via PubMedBERT to enrich their diversity and detail and subsequently classified for OSAHS severity using XGBoost based on the number of sleep apnea events. Results: Experimental results using the OSAHS dataset from a collaborative university hospital demonstrate that our ASMM-OSA audio-semantic multimodal model achieves a diagnostic level in automatically identifying sleep apnea events and classifying the four-class severity (normal, mild, moderate, and severe) of OSAHS. Discussion: Our proposed model promises new perspectives for non-invasive OSAHS diagnosis, potentially reducing costs and enhancing patient quality of life.

Effects of Recombinant Human Granulocyte/Macrophage Colony-Stimulating Factor on Diabetic Lower Extremity Ulcers: Case Series of Nine Patients.

Background: Diabetic lower extremity ulcer, including diabetic foot ulcer (DFU) and leg ulcer, is one of the refractory complications of diabetes, the treatment of which is challenging, expensive, and lengthy. Recombinant Human Granulocyte/Macrophage Colony-stimulating Factor (rhGM-CSF) is an immunomodulatory cytokine that has been mainly applied in the treatment of hematological diseases. Clinical evidence regarding GM-CSF in the treatment of diabetic lower extremity ulcers is limited. This study is the first case series that investigates the repurpose effects of rhGM-CSF on diabetic ulcer healing in real clinical practice. Methods: Nine patients diagnosed with diabetes and refractory lower extremity ulcer (ulcer duration ≥2 weeks) were included from September 2021 to February 2023 in the Division of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Patients with Wagner grade ≥4 and SINDAD ≥5 were excluded. The included subjects were treated with rhGM-CSF plus standard of care (SOC) including glycemic control, foot care education, debridement of necrotic tissues, topical wound dressings, offloading, and infection control when necessary. The observation endpoint was complete epithelialization. Their clinical manifestations, laboratory tests, and therapeutic effects were extracted and analyzed. Results: The case series included 9 cases aged from 29 to 80 years and all the patients were male. Seven of 9 patients presented neuropathic ulcer. Only one case showed non-infected ulcer from tissue samples and one case presented ankle brachial index (ABI) <0.9. It was observed that the ulcer areas among these 9 patients gradually declined throughout the whole treatment period with the average healing velocity 0.32 ± 013 cm2/day and the mean time to complete healing 16.0 ± 3.7 days. The relative area (percentage of initial ulcer area) decreased to 66.7 ± 13.0% on average after the first treatment. Ulcers in all the 9 patients achieved complete epithelialization after 4-8 times treatments. Conclusion: The case series suggests rhGM-CSF as a promising therapeutic strategy for the treatment of diabetic ulceration. More robust data from randomized controlled trials are required to further evaluate its clinical efficacy.

Electroacupuncture regulates Rab5a-mediating NGF transduction to improve learning and memory ability in the early stage of AD mice.

AIMS: Nerve growth factor (NGF) loss is a potential factor for the degeneration of basal forebrain cholinergic neurons (BFCNs) in Alzheimer's disease (AD), and Rab5a is a key regulatory molecule of NGF signaling transduction. Here, we investigated the changes of Rab5a in 5 × FAD mice and further explored the mechanism of Electroacupuncture (EA) treatment in improving cognition in the early stage of AD. METHODS: The total Rab5a and Rab5a-GTP in 5-month-old 5 × FAD mice and wild-type mice were detected using WB and IP technologies. 5 × FAD mice were treated with EA at the Bai hui (DU20) and Shen ting (DU24) acupoints for 4 weeks and CRE/LOXP technology was used to confirm the role of Rab5a in AD mediated by EA stimulation. The Novel Object Recognition and Morris water maze tests were used to evaluate the cognitive function of 5 × FAD mice. The Nissl, immunohistochemistry, and Thioflavin S staining were used to observe pathological morphological changes in the basal forebrain circuit. The Golgi staining was used to investigate the synaptic plasticity of the basal forebrain circuit and WB technology was used to detect the expression levels of cholinergic-related and NGF signal-related proteins. RESULTS: The total Rab5a was unaltered, but Rab5a-GTP increased and the rab5a-positive early endosomes appeared enlarged in the hippocampus of 5 × FAD mice. Notably, EA reduced Rab5a-GTP in the hippocampus in the early stage of 5 × FAD mice. EA could improve object recognition memory and spatial learning memory by reducing Rab5a activity in the early stage of 5 × FAD mice. Moreover, EA could reduce Rab5a activity to increase NGF transduction and increase the levels of phosphorylated TrkA, AKT, and ERK in the basal forebrain and hippocampus, and increase the expression of cholinergic-related proteins, such as ChAT, vAchT, ChT1, m1AchR, and m2AchR in the basal forebrain and ChAT, m1AchR, and m2AchR in the hippocampus, improving synaptic plasticity in the basal forebrain hippocampal circuit in the early stage of 5 × FAD mice. CONCLUSIONS: Rab5a hyperactivation is an early pathological manifestation of 5 × FAD mice. EA could suppress Rab5a-GTP to promote the transduction of NGF signaling, and enhance the synaptic plasticity of the basal forebrain hippocampal circuit improving cognitive impairment in the early stage of 5 × FAD mice.

The fate of plastic wraps in constructed wetland: Surface structure and microbial community.

The high use of plastic wraps leads to significant environmental pollution. In this study, the surface structure and microbial community evolution of commercially available plastic wraps [polyethylene (PE), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), and polylactic acid (PLA)] in constructed wetlands (CWs) were investigated. The results indicated that all plastic wraps gradually decreased in molecular weight, crystallinity, melting, and crystallization temperatures, whereas a gradual increase was observed in the surface roughness, polymer dispersity index (PDI), carbonyl index (CI) and Shannon index of microorganisms colonizing the CWs. The aging rate of the plastic wrap was in the order: PLA > PVC > PE > PVDC, at the same site in the CWs, and it was in the order: soil surface > plant roots > subsoil, for the same plastic wrap. The diversity of microorganisms colonizing the same plastic wrap was in the order: plant roots > subsoil > soil surface. The Shannon indices of microorganisms on plastic wraps were lower than those in the soil, indicating that the diversity of microorganisms colonizing plastic wraps is limited. Additionally, the microbial community structure on the plastic surface was co-differentiated by the plastic type, placement position in the CWs, and aging time. Significantly different microbial community structures were found on the PVC and PVDC wrap surfaces, revealing that the chlorine in plastics limits microbial diversity. Unclassified members of Rhizobiaceae and Pseudomonadaceae were the dominant genera on the surface of the plastic wraps, suggesting that they may be the microorganisms involved in plastic degradation processes. The study provides valuable perspectives to facilitate a comprehensive understanding of the migration, fate, and environmental risks associated with microplastics (MPs) in wetlands.

Gender differences in the association between physical activity and cognitive subdomains among elders with type 2 diabetes and mild cognitive impairment: a cross-sectional study.

OBJECTIVES: The objective of this study was to evaluate the gender differences in the correlation between physical activity (PA) and cognitive subdomains in elderly individuals with type 2 diabetes (T2D) and mild cognitive impairment (MCI). DESIGN: Cross-sectional study. SETTING: The research was carried out in communities located in Fuzhou, Fujian Province and Beijing Municipality. PARTICIPANTS: Community-dwelling elders with T2D and MCI aged 60 years or older were eligible for this study. PRIMARY OUTCOME MEASURES AND ANALYSES: The weekly PA score was assessed using the International Physical Activity Questionnaire (IPAQ). The cognitive subdomains were evaluated through a battery of cognitive assessments, including the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test Part B, Digit Symbol Substitution Test (DSST) and the Stroop Color-Word Test (SCWT). Multiple linear regression models were employed to examine the association between PA and cognitive subdomains in both male and female individuals. RESULTS: In older men, higher total IPAQ score was positively correlated with higher RAVLT (P=0.011) and SCWT (P=0.049). There was a significant interaction between the total PA score and gender in relation to RAVLT (P=0.008) and SCWT (P=0.027). Moreover, there was a positive correlation between moderate-vigorous PA level and RAVLT in older men (P=0.007). Additionally, a positive correlation was found between moderate-vigorous PA level and DSST in older women (P=0.038). CONCLUSION: In older individuals with T2D and MCI, the association between PA and cognitive subdomains differs between men and women. This discrepancy may impact the customisation of exercise recommendations.

Differential Gene Analysis of Langerhans Cell Histiocytosis and the Significance of MMP1-Targeted Drug Repositioning.

Langerhans cell histiocytosis (LCH) is a rare condition predominantly affecting young children. Activation of the MAPK pathway has offered key new insights into the pathogenesis of LCH; however, the precise mechanisms underlying its occurrence and development are still far from being completely elucidated. There is still a relapse/reactivation rate in patients with multisystem LCH. Therefore, this study aimed to investigate other potential LCH pathophysiologies and prospective therapeutic targets. The gene expression omnibus (GEO) database was used to retrieve gene expression profiles of LCH (GSE16395). Three distinct types of analyses were performed after identifying the common differentially expressed genes (DEGs) in LCH: hub gene identification, functional annotation, module construction, drug repositioning, and expression analysis via immunohistochemistry (IHC). We identified 417 common DEGs and 50 central hub genes. This functional study highlighted the significance of keratinization, skin development, and inflammation. In addition, we predicted new drug candidates (RS2 drugs targeting matrix metalloprotease1, MMP1) that could be used for LCH treatment. Finally, gene-miRNA and gene-TF networks and immune cell infiltration were analyzed for MMP1-related genes. MMP1 expression levels in LCH tissues were validated by IHC. Our study identified the central communal genes and novel drug candidates. These shared pathways and hub genes offer new perspectives on future mechanisms of action and therapeutic targets.

Landscape of transcriptome-wide m6A modification in diabetic liver reveals rewiring of PI3K-Akt signaling after physical exercise.

AIM: Type 2 diabetes mellitus (T2DM) is one of the most common diseases, and epigenetic modification N6-methyladenosine (m6A) is essential for transcriptional modulation involved in its development. However, the precise role and landscape of transcriptome-wide m6A alterations in molecular adaptations after physical exercise have yet to be fully elucidated. METHODS: Four-week-old male C57BL/6J mice received a high-fat diet (HFD) for 12 weeks to establish a diabetic state, and HFD mice were simultaneously subjected to physical exercise (HFD + EX). The hepatic RNA m6A methylome was examined, the conjoint MeRIP-seq and RNA-seq was performed, and the exercise-modulated genes were confirmed. RESULTS: Physical exercise significantly ameliorates liver metabolic disorder and triggers a dynamic change in hepatic RNA m6A. By analyzing the distribution of m6A in transcriptomes, an abundance of m6A throughout mRNA transcripts and a pattern of conserved m6A after physical exercise was identified. It is noteworthy that conjoint MeRIP-seq and RNA-seq data revealed that both differentially methylated genes and differentially expressed genes were enriched in all stages of the PI3K-Akt signaling pathway, in particular the upstream nodes of this pathway, which are considered a valuable therapeutic target for T2DM. Moreover, in vivo and in vitro analyses showed that exercise-mediated methyltransferase Rbm15 positively regulated the expression of two upstream genes (Itga3 and Fgf21) in an m6A-dependent manner. CONCLUSION: These findings highlight the pivotal role of the exercise-induced m6A epigenetic network and contribute insights into the intricate epigenetic mechanism underlying insulin signaling.