Rapidly progressive malignant glomus tumor of the breast: a case report and review of the literature.

The glomus tumor is a rare neoplasm that is typically found subungually in the extremities and functions as a specialized neurovascular organ. An extremely rare site for glomus tumors is the breast, with only a few reported cases. Breast glomus tumors present with three typical clinical signs: dull pain, focal tenderness, and cold sensitivity. Less than 10% of all glomus tumors are malignant. We herein present a case of a malignant glomus tumor originating in the breast. Distant metastasis was ruled out, and the tumor was completely resected. However, the patient unexpectedly developed rapid systemic metastasis, detected 5 weeks after tumor removal. Despite the administration of analgesics and targeted therapy, the patient died 1 month later. When treating patients with undiagnosed breast tumors, clinicians should pay attention to unexplained and repeatedly reported symptoms and consider the possibility of a rare disease. Our literature search revealed no cases of malignant glomus tumors originating in the breast, making this case the first of its kind.

Exosomal lncRNA TUG1 derived from BMSC ameliorate collagen-induced arthritis via BLIMP1-mediated Th17/Treg balance.

BACKGROUND: Aberrant differentiation of Th17 cells has been identified as a critical factor in the development of rheumatoid arthritis (RA). BLIMP1 plays a key role in regulating plasma cell differentiation, T helper cell differentiation and Treg cell differentiation. Treatment with exosome injection or bone marrow mesenchymal stem cell (BMSC) transplantation reduce joint damage in RA. But the precise regulatory mechanisms remain unclear. METHODS: We injected BMSC-derived exosomes into RA mice, and then performed histological analysis on mouse ankle joints. We cultured CD4+ T cells in vitro, then added exosomes with or without si-TUG1 and induced the differentiation of Th17 cells and Treg cells, and then we used flow cytometry to detect the ratio of Th17 cells and Treg cells. Furthermore, we injected exosomes into sh-NC or sh-BLIMP1-treated RA mice, and then performed histological analysis on the ankle joints. RESULT: The results of our study demonstrate that exosome treatment decreased the proportion of differentiated Th17 cells, while increasing the proportion of Treg cells. And we observed that the Exo si-TUG1 group had an increased proportion of Th17 cells and a decreased proportion of Treg cells. We observed an increase in BLIMP1 expression in both the peripheral blood of mice and in CD4+ T cells cultured in vitro in the Exo group. Conversely, the Exo si-TUG1 group showed a decrease in BLIMP1 expression. Notably, inhibiting BLIMP1 expression led to the reversal of the therapeutic effects of exosomes. CONCLUSION: Our findings suggest that BMSC-derived exosomes promote the expression of BLIMP1 through Lnc TUG1-carrying exosomes, which may modulate the balance between Th17 cells and Treg cells. This mechanism ultimately alleviates damage caused by RA, suggesting that BMSC-derived exosomes enriched in Lnc TUG1 hold promise as a potential therapeutic approach for treating RA.

Learning lifespan brain anatomical correspondence via cortical developmental continuity transfer.

Identifying anatomical correspondences in the human brain throughout the lifespan is an essential prerequisite for studying brain development and aging. But given the tremendous individual variability in cortical folding patterns, the heterogeneity of different neurodevelopmental stages, and the scarce of neuroimaging data, it is difficult to infer reliable lifespan anatomical correspondence at finer scales. To solve this problem, in this work, we take the advantage of the developmental continuity of the cerebral cortex and propose a novel transfer learning strategy: the model is trained from scratch using the age group with the largest sample size, and then is transferred and adapted to the other groups following the cortical developmental trajectory. A novel loss function is designed to ensure that during the transfer process the common patterns will be extracted and preserved, while the group-specific new patterns will be captured. The proposed framework was evaluated using multiple datasets covering four lifespan age groups with 1,000+ brains (from 34 gestational weeks to young adult). Our experimental results show that: 1) the proposed transfer strategy can dramatically improve the model performance on populations (e.g., early neurodevelopment) with very limited number of training samples; and 2) with the transfer learning we are able to robustly infer the complicated many-to-many anatomical correspondences among different brains at different neurodevelopmental stages. (Code will be released soon: https://github.com/qidianzl/CDC-transfer).

Disease burden of AIDS in last 30-year period and its predicted level in next 25-years based on the global burden disease 2019.

BACKGROUND: This study examines global trends in acquired immune deficiency syndrome (AIDS) incidence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2019, focusing on regional disparities in AIDS incidence, mortality, and DALYs across various levels of socio-demographic index (SDI). It also investigates variations in AIDS incidence, mortality, and DALYs across different age groups, and projects specific trends for the next 25 years. METHODS: Comprehensive data on AIDS from 1990 to 2019 in 204 countries and territories was obtained from a GBD study. This included information on AIDS incidence, mortality, DALYs, and age-standardized rates (ASRs). Projections for AIDS incidence and mortality over the next 25 years were generated using the Bayesian age-period-cohort model. RESULTS: From 1990 to 2019, the global incidence of HIV cases increased from 1,989,282 to 2,057,710, while the age-standardized incidence rate (ASIR) decreased from 37.59 to 25.24 with an estimated annual percentage change (EAPC) of -2.38. The ASIR exhibited an upward trend in high SDI and high-middle SDI regions, a stable trend in middle SDI regions, and a downward trend in low-middle SDI and low SDI regions. In regions with higher SDI, the ASIR was higher in males than in females, while the opposite was observed in lower SDI regions. Throughout 1990 to 2019, the age-standardized death rate (ASDR) and age-standardized DALY rate remained stable, with EAPCs of 0.24 and 0.08 respectively. Countries with the highest HIV burden affecting women and children under five years of age are primarily situated in lower SDI regions, particularly in sub-Saharan Africa. Projections indicate a significant continued decline in the age-standardized incidence and mortality rates of AIDS over the next 25 years, for both overall and by gender. CONCLUSIONS: The global ASIR decreased from 1990 to 2019. Higher incidence and death rates were observed in the lower SDI region, indicating a greater susceptibility to AIDS among women and < 15 years old. This underscores the urgent need for increased resources to combat AIDS in this region, with focused attention on protecting women and < 15 years old as priority groups. The AIDS epidemic remained severe in sub-Saharan Africa. Projections for the next 25 years indicate a substantial and ongoing decline in both age-standardized incidence and mortality rates.

Genetic analysis of QTLs for lysine content in four maize DH populations.

BACKGROUND: Low levels of the essential amino acid lysine in maize endosperm is considered to be a major problem regarding the nutritional quality of food and feed. Increasing the lysine content of maize is important to improve the quality of food and feed nutrition. Although the genetic basis of quality protein maize (QPM) has been studied, the further exploration of the quantitative trait loci (QTL) underlying lysine content variation still needs more attention. RESULTS: Eight maize inbred lines with increased lysine content were used to construct four double haploid (DH) populations for identification of QTLs related to lysine content. The lysine content in the four DH populations exhibited continuous and normal distribution. A total of 12 QTLs were identified in a range of 4.42-12.66% in term of individual phenotypic variation explained (PVE) which suggested the quantitative control of lysine content in maize. Five main genes involved in maize lysine biosynthesis pathways in the QTL regions were identified in this study. CONCLUSIONS: The information presented will allow the exploration of candidate genes regulating lysine biosynthesis pathways and be useful for marker-assisted selection and gene pyramiding in high-lysine maize breeding programs.

Strain evolution from the ferroelectric to the relaxor state in (0.67 - x)BiFeO3-0.33BaTiO3-xBi(Mg0.5Zr0.5)O3 lead-free ceramics.

The BiFeO3-BaTiO3 solid solution exhibits enhanced electric properties due to its modified phase structure with relaxor characteristics and reduced leakage current. Despite these advancements, the underlying mechanism behind the phase transition from a ferroelectric to a relaxor state in BF-BT ceramics remains largely unexplored. Here, the evolution of strain in (0.67 - x)BiFeO3-0.33BaTiO3-xBi(Mg0.5Zr0.5)O3 ceramics is investigated, with a focus on the strain transition from a ferroelectric to a relaxor phase. A strengthening of relaxor behavior is observed in the modified rhombohedral (R) and pseudocubic (PC) phase structure, resulting in optimal strain (Suni = 0.25%, Spos = 0.24%) at x = 0.04. The enhanced strain is attributed to the promotion of domain switching and the presence of strong random fields, with polar nanoregions integrating into a long-range ordered matrix. Furthermore, a gradual increase in strain with rising temperature is noted, driven by increased polarization and the expansion of ferroelectric domains. This study underscores the critical role of structural modifications in augmenting the electric response of BF-BT ceramics, thereby advancing the development of lead-free piezoelectric materials.

The deubiquitinase OTUD5 stabilizes SLC7A11 to promote progression and reduce paclitaxel sensitivity in triple-negative breast cancer.

Ferroptosis is a newly defined form of programmed cell death characterized by iron-dependent lipid peroxide accumulation and is associated with the progression of cancer. Solute carrier family 7 member 11 (SLC7A11), a key component of cystine/glutamate antiporter, has been characterized as a critical regulator of ferroptosis. Although many studies have established the transcriptional regulation of SLC7A11, it remains largely unknown how the stability of SLC7A11 is regulated in cancers, especially in triple-negative breast cancer (TNBC). Here we demonstrated that ovarian tumor domain-containing protein 5 (OTUD5), which deubiquitinated and stabilized SLC7A11, played a key role in TNBC progression and paclitaxel chemosensitivity through modulating ferroptosis. The clinical data analysis showed OTUD5 was higher expressed in TNBC, which positively correlated with SLC7A11 level. Mechanistically, OTUD5 interacted with SLC7A11 and cleaved K48-linked polyubiquitin chains from SLC7A11 to enhance the stability of SLC7A11. Taken together, these findings uncover a functional and mechanistic role of OTUD5 in TNBC progression and paclitaxel sensitivity, indicating OTUD5 could be a potential target for TNBC treatment.

Immune escape between endoplasmic reticulum stress-related cancer cells and exhausted CD8+T cells leads to neoadjuvant chemotherapy resistance in ovarian cancer.

Our study aims to explore the effects of neoadjuvant chemotherapy (NACT) on tumour cells and immune cells in the immune microenvironment of patients with high-grade serous ovarian cancer (HGSOC). Single-cell RNA sequencing data of paired ovarian cancer tissues were analysed before and after NACT in 11 patients with HGSOC. The effect of NACT on two major cell components of the tumour microenvironment, epithelial cells and CD8+T cells, was investigated. The mechanisms of epithelial cell evasion by NACT and immune killing were explored from the perspectives of gene expression, functional characteristics, transcriptional regulation, and cell communication. Key targets for reversing NACT resistance were identified and possible therapeutic strategies proposed. While NACT improved the de novo differentiation of anti-tumour CD8+T cells, enhancing their anti-tumour function, it increased the proportion of cancer cells with high HSP90B1 expression. Thus, the potential reasons for NACT resistance were identified as: 1) high levels of endoplasmic reticulum stress (ERS) characteristics, 2) high expression of the MDK-NCL ligand-receptor pair between them and exhausted CD8+T cells before NACT, and 3) high expression of the NECTIN2-TIGIT immune ligand-receptor pair between them and exhausted CD8+T cells after NACT. Thus, our study reveals the mechanisms underlying NACT resistance in patients with HGSOC from the perspective of the independent and interactive roles of cancer cells and CD8+T cells. We propose therapeutic strategies targeting the ERS marker HSP90B1 and the immune escape marker MDK before or during NACT, while targeting NECTIN2 blockade after NACT. This approach may offer new insights into combination treatments for patients with HGSOC displaying NACT resistance.

Exploring the Stepped Care Model in Delivering Primary Mental Health Services-A Scoping Review.

The stepped care model (SCM) is a patient-centred approach to mental health care, offering a range of services from least to most intensive, tailored to individual needs. This scoping review examines the adoption, effectiveness, challenges and implications associated with applying SCM within primary mental health service delivery. Evidence from global sources suggests the model is viable, effective and useful. This review explores the literature available, clarifies fundamental concepts and identifies existing knowledge gaps. The literature search included CINAHL, MEDLINE, PsycINFO, Scopus, the Federation University library, Google and Google Scholar databases. A systematic keyword-based search using terms like "stepped care model," "mental health," and "primary care"; and a combination of keywords and subject headings, were used. The search strategy was refined by considering factors such as relevance, publication date, objectives and outcomes. This strategy yielded 20 papers compiled in this review. They include randomised controlled trials and cross-sectional studies. The review supports SCM adoption in primary mental health care but acknowledges the need for further research. Key inclusions of the review include cost-effectiveness, diverse diagnoses, efficacy and the model's structural configuration. Clear treatment details, delivery methods, intervention durations and chronological sequences are essential. This systematic approach enhances generalisability across different SCM models and areas, strengthening reliable inferences. In summary, the SCM holds promise for enhancing mental health service delivery. However, there is a need to further examine the factors that determine its effectiveness and understand the different ways in which SCM is implemented. Such inquiry forms the foundation for implementing and advancing mental health care services in Australia and internationally.

The AP-2 Family of Transcription Factors-Still Undervalued Regulators in Gastroenterological Disorders.

Activating enhancer-binding protein 2 (AP-2) is a family of transcription factors (TFs) that play crucial roles in regulating embryonic and oncogenic development. In addition to splice isoforms, five major family members encoded by the TFAP2A/B/C/D/E genes have been identified in humans, i.e., AP-2α/ß/γ/δ/ε. In general, the first three TFs have been studied more thoroughly than AP-2δ or AP-2ε. Currently, there is a relatively limited body of literature focusing on the AP-2 family in the context of gastroenterological research, and a comprehensive overview of the existing knowledge and recommendations for further research directions is lacking. Herein, we have collected available gastroenterological data on AP-2 TFs, discussed the latest medical applications of each family member, and proposed potential future directions. Research on AP-2 in gastrointestinal tumors has predominantly been focused on the two best-described family members, AP-2α and AP-2γ. Surprisingly, research in the past decade has highlighted the importance of AP-2ε in the drug resistance of gastric cancer (GC) and colorectal cancer (CRC). While numerous questions about gastroenterological disorders await elucidation, the available data undoubtedly open avenues for anti-cancer targeted therapy and overcoming chemotherapy resistance. In addition to gastrointestinal cancers, AP-2 family members (primarily AP-2ß and marginally AP-2γ) have been associated with other health issues such as obesity, type 2 diabetes, liver dysfunction, and pseudo-obstruction. On the other hand, AP-2δ has been poorly investigated in gastroenterological disorders, necessitating further research to delineate its role. In conclusion, despite the limited attention given to AP-2 in gastroenterology research, pivotal functions of these transcription factors have started to emerge and warrant further exploration in the future.

The prognostic impact of malnutrition on the outcomes of patients with vertebrobasilar artery occlusion following endovascular treatment.

BACKGROUND AND PURPOSE: Malnutrition is associated with poor outcomes in different diseases. Our aim was to investigate whether measures of malnutrition could be used to predict 90-day outcomes in patients with vertebrobasilar artery occlusion (VBAO) undergoing endovascular treatment (EVT). METHODS: We retrospectively analyzed patients with VBAO who received EVT at three comprehensive stroke centers. Malnutrition was assessed using the controlling nutritional status (CONUT) score, geriatric nutritional risk index (GNRI), and prognostic nutritional index (PNI). Primary outcome was good functional outcome defined as modified Rankin Scale (mRS) 0-3 measured at 90 days. RESULTS: A total of 285 patients were enrolled, of which 260 (91.22%) met the requirements. According to the CONUT, GNRI, and PNI scores, the proportions of patients classified as moderately or severely malnourished were 7.3%, 3.08%, and 35%, respectively. In the multivariate regression model after adjusting for potential confounders, malnutrition (severe risk versus normal nutritional status) was significantly associated with an increased risk of poor prognosis for CONUT scores (adjusted odds ratio [OR]14.91, 95%CI, 1.69 - 131.71; P = 0.015), GNRI scores (adjusted [OR] 10.67, 1.17 - 96.93; P =0.036) and PNI scores (adjusted [OR] 4.61, 2.28 - 9.31; P< 0.001). Similar results were obtained when malnutrition scores were analyzed as continuous variables. Adding the 3 malnutrition measures to the risk reclassification that included traditional risk factors significantly improved the predictive value of 3-month poor prognosis. CONCLUSIONS: Our study showed that malnutrition may be associated with poor prognosis within 3 months of EVT in patients with VBAO.

Challenges and Needs in Digital Health Practice and Nursing Education Curricula: Gap Analysis Study.

Background: Australian nursing programs aim to introduce students to digital health requirements for practice. However, innovation in digital health is more dynamic than education providers' ability to respond. It is uncertain whether what is taught and demonstrated in nursing programs meets the needs and expectations of clinicians with regard to the capability of the nurse graduates. Objective: This study aims to identify gaps in the National Nursing and Midwifery Digital Health Capability Framework , based on the perspectives of clinical nurses, and in nurse educators' confidence and knowledge to teach. The findings will direct a future co-design process. Methods: This study triangulated the findings from 2 studies of the Digital Awareness in Simulated Health project and the National Nursing and Midwifery Digital Capability Framework. The first was a qualitative study that considered the experiences of nurses with digital health technologies during the COVID-19 pandemic, and the second was a survey of nurse educators who identified their confidence and knowledge to teach and demonstrate digital health concepts. Results: The results were categorized by and presented from the perspectives of nurse clinicians, nurse graduates, and nurse educators. Findings were listed against each of the framework capabilities, and omissions from the framework were identified. A series of statements and questions were formulated from the gap analysis to direct a future co-design process with nursing stakeholders to develop a digital health capability curriculum for nurse educators. Conclusions: Further work to evaluate nursing digital health opportunities for nurse educators is indicated by the gaps identified in this study.

Effect of plant species on wastewater treatment performance of a subsurface vertical-flow constructed wetland with step-feeding at low temperature.

To improve the treatment performance of constructed wetlands under low-temperature conditions, this study investigated the effects of plant species on wastewater treatment performance at low temperature and the associated microbiological characteristics in a subsurface vertical-flow constructed wetland (VFCW) with step-feeding. The results showed that the redox microenvironment in the VFCW filter with step-feeding could be restored and optimized by planting appropriate species that can tolerate low temperature, ensuring a high nitrification performance for the system. Correspondingly, the abundance and activity of three functional microbes (namely nitrifiers, denitrifiers, and anammox bacteria) increased to different degrees in the system, eventually ensuring ideal nitrogen removal by the VFCW. Compared with the VFCW planted with Phragmites australis and Acorus gramineus, the operation performance of the VFCW planted with Iris wilsonii could be recovered at low temperature, and its chemical oxygen demand, total phosphorus, total nitrogen, and ammonium nitrate removal rates could respectively reach 95.7%, 99.2%, 93.0%, and 94.4%, respectively. Moreover, nitrogen removal in the system relied on the nitrification/denitrification and partial denitrification - anaerobic ammonium oxidation processes. Nitrosomonas, Nitrospira, Thauera, and Candidatus Brocadia were the four dominant bacterial genera in the filter layer.

Perfusion deficit and vessel wall characteristics to predict recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion.

BACKGROUND: To investigate the association between perfusion deficit, vessel wall characteristics, and risk of recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion. METHODS: We retrospectively reviewed chronic symptomatic patients due to anterior circulation large vessel occlusion in our center. All patients received multiparametric magnetic resonance imaging (including perfusion-weighted imaging and high-resolution vessel wall imaging) within 4 weeks to 3 months after symptom onset. The association between baseline clinical or imaging variables and recurrent ischemic events was assessed in bivariate models and multivariable logistic regression to identify independent predictors of recurrence. RESULTS: Among 71 enrolled patients, 21.1% (15/71) patients had recurrent ischemic events (nine ischemic strokes and six transient ischemic attacks) during a 2-year follow-up. In bivariate models, hypertension, occlusion with hyperintense signals, the presence of intraluminal thrombus, Tmax >4 s volume, Tmax >6 s volume, Tmax >8 s volume, and Tmax >10 s volume were associated with recurrence (all p < 0.05). In multivariate analysis, hypertension (p = 0.039, OR 10.057 (95% CI, 1.123-90.048)), higher deficit volume of Tmax >4 s (p = 0.011, OR 1.012 (95% CI, 1.003-1.021)) and occlusion with hyperintense signal (p = 0.030, OR 6.732 (95% CI, 1.200-37.772)) were still independent predictors of recurrent ischemic events. CONCLUSIONS: Besides hypertension history, higher deficit volume of Tmax >4 s and occlusion with hyperintense signal determined using multiparametric MRI are strongly associated with risk for recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion. Future studies are needed to determine the utility of revascularization strategies in such high-risk patients.

Analysis of the correlation between cervical HPV infection, cervical lesions and vaginal microecology.

Background: Vaginal microbiota is involved in human papillomavirus (HPV) infection and cervical cancer (CC) progression, and the specific changes in vaginal microbial composition during this process remains uncertain. Objective: This study aimed to observe the changes in the specific composition of vaginal microorganisms in different cervical lesions and identify biomarkers at different stages of lesions. Methods: In this study we used the illumina high-throughput gene sequencing technology to determine the V4 region of 16SrRNA and observed the vaginal microbial composition in different cervical lesions. Results: The vaginal microbiota of patients with high-risk HPV infection and cervical lesions is significantly different from that of the normal population, but there is no significant difference in the richness of vaginal microbes. The diversity of vaginal species in CC patients is higher than that in high-risk HPV infection or CIN patients. The main manifestation is an increase in the diversity of vaginal microbes, a decrease in the relative abundance of cyanobacteria and Lactobacillus, and an increase in the relative abundance of dialister, peptonephila and other miscellaneous bacteria. There are characteristic vaginal biomarker in normal women, high risk HPV patients and CC patients. In detail, the biomarker in the normal group was varibaculum, the biomarker in the high-risk HPV group was saccharopolyspora, the biomarker of the CC group was the Proteobacteria, Corynebacterium, Coprococcus, Peptococcus and Ruminococcus. Conclusions: The study indicated that the compositions of vaginal microbes in different cervical lesions is different. The vaginal microbial composition has a certain diagnostic effect on healthy women, patients with high-risk HPV infection and cervical lesions. These microbes may serve as potential biomarkers for CC. It also provided an effective way for the treatment of HPV infections and cervical lesions.

Genomic characterization of an emerging Rickettsia barbariae isolated from tick eggs in northwestern China.

The continual emergence of tick-borne rickettsioses has garnered widespread global attention. Candidatus Rickettsia barbariae (Candidatus R. barbariae), which emerged in Italy in 2008, has been detected in humans from northwestern China. However, the lack of Candidatus R. barbariae genome and isolated strains limits the understanding of its biological characteristics and genomic features. Here, we isolated the Rickettsia for the first time from eggs of Rhipicephalus turanicus in northwestern China, and assembled its whole genome after next-generation sequencing, so we modified the proposed name to Rickettsia barbariae (R. barbariae) to conform to the International Code of Nomenclature of Prokaryotes. Phylogenetic analysis based on the whole genome revealed that it was most closely related to the pathogenic Rickettsia parkeri and Rickettsia africae. All virulence factors, present in the pathogenic spotted fever group rickettsiae, were identified in the R. barbariae isolate. These findings highlight the pathogenic potential of R. barbariae and the necessity for enhanced surveillance of the emerging Rickettsia in the human population.

BIN1 deficiency enhances ULK3-dependent autophagic flux and reduces dendritic size in mouse hippocampal neurons.

Genome-wide association studies identified variants around the BIN1 (bridging integrator 1) gene locus as prominent risk factors for late-onset Alzheimer disease. In the present study, we decreased the expression of BIN1 in mouse hippocampal neurons to investigate its neuronal function. Bin1 knockdown via RNAi reduced the dendritic arbor size in primary cultured hippocampal neurons as well as in mature Cornu Ammonis 1 excitatory neurons. The AAV-mediated Bin1 RNAi knockdown also generated a significant regional volume loss around the injection sites at the organ level, as revealed by 7-Tesla structural magnetic resonance imaging, and an impaired spatial reference memory performance in the Barnes maze test. Unexpectedly, Bin1 knockdown led to concurrent activation of both macroautophagy/autophagy and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1). Autophagy inhibition with the lysosome inhibitor chloroquine effectively mitigated the Bin1 knockdown-induced dendritic regression. The subsequent molecular studydemonstrated that increased expression of ULK3 (unc-51 like kinase 3), which is MTOR-insensitive, supported autophagosome formation in BIN1 deficiency. Reducing ULK3 activity with SU6668, a receptor tyrosine kinase inhibitor, or decreasing neuronal ULK3 expression through AAV-mediated RNAi, significantly attenuated Bin1 knockdown-induced hippocampal volume loss and spatial memory decline. In Alzheimer disease patients, the major neuronal isoform of BIN1 is specifically reduced. Our work suggests this reduction is probably an important molecular event that increases the autophagy level, which might subsequently promote brain atrophy and cognitive impairment through reducing dendritic structures, and ULK3 is a potential interventional target for relieving these detrimental effects.Abbreviations: AV: adeno-associated virus; Aß: amyloid-ß; ACTB: actin, beta; AD: Alzheimer disease; Aduk: Another Drosophila Unc-51-like kinase; AKT1: thymoma viral proto-oncogene 1; AMPK: AMP-activated protein kinase; AP: autophagosome; BafA1: bafilomycin A1; BDNF: brain derived neurotrophic factor; BIN1: bridging integrator 1; BIN1-iso1: BIN1, isoform 1; CA1: cornu Ammonis 1; CA3: cornu Ammonis 3; CLAP: clathrin and adapter binding; CQ: chloroquine; DMEM: Dulbecco's modified Eagle medium; EGFP: enhanced green fluorescent protein; GWAS: genome-wide association study; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MRI: magnetic resonance imaging; MTOR; mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; PET: positron emission tomography; qRT-PCR: real-time quantitative reverse transcription PCR; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; TFEB: transcription factor EB; ULK1: unc-51 like kinase 1; ULK3: unc-51 like kinase 3.

The nociceptive inputs of the paraventricular hypothalamic nucleus in formalin stimulated mice.

The paraventricular hypothalamic nucleus (PVH) is an important neuroendocrine center involved in pain regulation, but the nociceptive afferent routes for the nucleus are still unclear. We examined the profile of PVH receiving injurious information by a combination of retrograde tracing with Fluoro-Gold (FG) and FOS expression induced by formalin stimuli. The result showed that formalin injection induced significantly increased expression of FOS in the PVH, among which oxytocin containing neurons are one neuronal phenotype. Immunofluorescent staining of FG and FOS revealed that double labeled neurons were strikingly distributed in the area 2 of the cingulate cortex (Cg2), the lateral septal nucleus (LS), the periaqueductal gray (PAG), the posterior hypothalamic area (PH), and the lateral parabrachial nucleus (LPB). In the five regions, LPB had the biggest number and the highest ratio of FOS expression in FG labeled neurons, with main subnuclei distribution in the external, superior, dorsal, and central parts. Further immunofluorescent triple staining disclosed that about one third of FG and FOS double labeled neurons in the LPB were immunoreactive for calcitonin gene related peptide (CGRP). In conclusion, the present study demonstrates the nociceptive input profile of the PVH area under inflammatory pain and suggests that neurons in the LPB may play essential roles in transmitting noxious information to the PVH.

Comparison of sensitivity between blood parameters and a genotoxic biomarker at low blood Pb levels: A population-based study.

BACKGROUND: Previous studies reported that lead (Pb) exposure induced adverse health effects at high exposure concentrations, however, there have been limited data on sensitivity comparisons among different health outcomes at low blood Pb levels. OBJECTIVES: To compare sensitivity between blood parameters and a genotoxic biomarker among workers exposed to low blood Pb levels (< 20 µg/dl), and to estimate a benchmark dose (BMD). METHODS: Pb-exposed workers were recruited from a lead-acid storage battery plant. Their blood lead levels (BLLs) were measured. Blood parameters and micronuclei (MN) frequencies were determined. Multivariate linear or Poisson regression was used to analyze relationships between blood parameters or MN frequencies with BLLs. Two BMD software were used to calculate BMD and its 95 % lower confidence limit (BMDL) for BLLs. RESULTS: The median BLL for 611 workers was 10.44 µg/dl with the 25th and 75th percentile being 7.37 and 14.62 µg/dl among all participants. There were significantly negative correlations between blood parameters and BLLs. However, MN frequencies correlated positively with BLLs (all P<0.05). Results from the two BMD software revealed that the dichotomous model was superior to the continuous model, and the BMDL for BLL derived from red blood cell (RBC) was 15.11 µg/dl, from hemoglobin (HGB) was 8.50 µg/dl, from mean corpuscular hemoglobin (MCH) was 7.87 µg/dl, from mean corpuscular hemoglobin concentration (MCHC) was 3.98 µg/dl, from mean corpuscular volume (MCV) was 11.44 µg/dl, and from hematocrit (HCT) was 6.65 µg/dl. The conservative BMDL obtained from the MN data was 7.52 µg/dl. CONCLUSION: Our study shows that low dose Pb exposure caused decrease of blood parameters and increase of MN frequencies. The genotoxic biomarker was more sensitive than most blood parameters. BMDLs for BLL derived from MN frequencies and the red blood cell indicators should be considered as new occupational exposure limits. Our results suggest that MN assay can be considered as a part of occupational health examination items.

Adenosine protects cardiomyocytes against acrolein-induced cardiotoxicity by enhancing mitochondrial homeostasis, antioxidant defense, and autophagic flux via ERK-activated FoxO1 upregulation.

Acrolein is a ubiquitous gaseous air pollutant and endogenous toxicant, which poses strong risk for oxidative stress-related diseases such as cardiovascular disease. Adenosine has been identified as potential therapeutic agent for age-related cardiovascular disease, while the molecular mechanisms underlying its cardioprotection remain elusive. In the present study, we investigated the myocardial protective effects and the mechanism of adenosine on acrolein-induced toxicity in H9c2 cells and primary neonatal rat cardiomyocytes. We found that acrolein caused apoptosis of cardiomyocytes resulting from oxidative damage, autophagy defect, and mitochondrial dysfunction, as evidenced by loss of mitochondrial membrane potential, impairment of mitochondrial biogenesis, dynamics, and oxidative phosphorylation, decrease of mitochondrial deoxyribonucleic acid (mtDNA) copy number and adenosine 5'-triphosphate (ATP) production. Adenosine pretreatment protected against acrolein-induced cardiotoxicity by maintaining mitochondrial homeostasis, activating the phase II detoxifying enzyme system, promoting autophagic flux, and alleviating mitochondrial-dependent apoptosis. We further demonstrated that the up-regulation of forkhead box protein O1 (FoxO1) mediated by extracellular regulated protein kinases (ERK) activation contributes to the cardioprotection of adenosine. These results expand the application of adenosine in cardioprotection to preventing myocardial damages induced by environmental pollutant acrolein exposure, and uncover the adenosine-ERK-FoxO1 axis as the underlying mechanism mediating the protection of mitochondrial homeostasis, Nrf2-mediated antioxidant defense and autophagic flux, shedding light on the better understanding about the pathological mechanism of cardiovascular disease caused by environmental pollutants and applications of adenosine in cardioprotection.