Changes in iron load in specific brain areas lead to neurodegenerative diseases of the central nervous system.

The causes of neurodegenerative diseases remain largely elusive, increasing their personal and societal impacts. To reveal the causal effects of iron load on Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis and multiple sclerosis, we used Mendelian randomisation and brain imaging data from a UK Biobank genome-wide association study of 39,691 brain imaging samples (predominantly of European origin). Using susceptibility-weighted images, which reflect iron load, we analysed genetically significant brain regions. Inverse variance weighting was used as the main estimate, while MR Egger and weighted median were used to detect heterogeneity and pleiotropy. Nine clear associations were obtained. For AD and PD, an increased iron load was causative: the right pallidum for AD and the right caudate, left caudate and right accumbens for PD. However, a reduced iron load was identified in the right and left caudate for multiple sclerosis, the bilateral hippocampus for mixed vascular dementia and the left thalamus and bilateral accumbens for subcortical vascular dementia. Thus, changes in iron load in different brain regions have causal effects on neurodegenerative diseases. Our results are crucial for understanding the pathogenesis and investigating the treatment of these diseases.

A Multicentre Randomized Controlled Clinical Study of Cross Electro-Nape-Acupuncture (CENA) for the Treatment of Pseudobulbar Palsy in Patients with Tracheotomy Intubation for Severe Cerebral Haemorrhage.

Objective: The objective is to evaluate the clinical efficacy of cross electro-nape-acupuncture (CENA) in the treatment of pseudobulbar palsy in patients with tracheotomy intubation for severe cerebral haemorrhage and to provide an innovative acupuncture method for the treatment of such patients. Methods: A total of 126 patients from six trial centres who met the inclusion criteria were randomly divided into three groups according to the random number table method in the ratio of 1 : 1 : 1, with 42 patients in each group, and the three groups were divided into CENA group, electro-acupuncture group, and acupuncture group. Each group's acupuncture treatment lasted for 30 minutes, and the needles were removed at the end of the treatment. Acupuncture was performed once a week on Sunday only and twice a day from Monday to Saturday, a total of 4 weeks of treatment. The SWT, FDA, ChSWAL-QOL, and TCRGS scores of the three groups of patients before and after treatment were compared to evaluate the effect of CENA on remodelling the function of swallowing reflex and cough reflex and promoting the recovery of dysarthria and swallowing quality of life in pseudobulbar palsy in patients with tracheotomy intubation for severe cerebral haemorrhage. Results: After treatment, the WST and TCRGS grade scores decreased and the FDA and ChSWAL-QOL scores increased significantly in all three groups compared with the pretreatment scores and were statistically significant. There was a significant difference between the three groups for these four indicators after treatment; the comparison between groups showed significant differences in the CENA group compared to the electro-acupuncture and acupuncture groups. The efficiency of the CENA group was significantly better than that of the electro-acupuncture and acupuncture groups. Conclusion: Compared with the acupuncture and electro-acupuncture groups, the CENA could better promote the remodelling of swallowing function and cough reflex function, promote the recovery of dysarthria, and better improve the quality of life of patients with pseudobulbar palsy from tracheotomy intubation in severe cerebral haemorrhage.

Prenatal exposure to bisphenol AF induced male offspring reproductive dysfunction by triggering testicular innate and adaptive immune responses.

As an emerging endocrine-disrupting component with a chemical structure related to Bisphenol A (BPA), Bisphenol AF (BPAF) has become widely distributed in the environment and human surroundings. Although numerous studies have focused on its reproductive toxicity, the impact of prenatal BPAF exposure on the reproductive system of adult male offspring, particularly testicular morphology and function, as well as the underlying mechanisms, remains largely understudied. This study found prenatal BPAF exposure at a dose of 300 µg/kg b.w. induced a 32% loss of seminal vesicle weight, a 12% reduction in the anogenital distance index (AGI), and impairments to testicular morphology, such as a reduced diameter of seminiferous tubules and thickness of the seminiferous epithelium, as well as a more than 2 - fold decrease in testosterone level, and 41% and 19% reduction of sperm count and vitality, respectively, in the 10 week-old male offsprings. Testicular RNA-Seq data showed that 334 differential expressed genes (DEGs) were primarily involved in several immunological processes, including host defense response, innate and adaptive immune response, cellular response to interferon (IFN)-ß and γ, antigen processing and presentation, regulation of T cell activation, etc. Importantly, our results revealed a pattern recognition receptor - absent in melanoma-2 (Aim2) was significantly increased in the testes of exposed males, thus triggering a testicular innate antiviral immunological response, leading to an increase of F4/80+ and CD11b+ macrophage. Subsequently, Aim2 activated the downstream signaling nuclear factor kappa-B (NF-κB), stimulated the transcription of IFN-ß and -γ, and then induced cytokine production while upregulating MHC class II molecules to activate CD4+ and CD8+ Tcells, suggesting that an adaptive immune response was also elicited. The results demonstrated that prenatal BPAF exposure could provoke innate and adaptive immunological responses in the testes of adult males through the Aim2-NF-κB-IFNs signaling pathway. Our work provided insights into understanding the reproductive toxicity caused by BPAF and clarified the possible mechanisms, which offered a potential therapeutic target and treatment strategy for BPAF exposure-induced reproductive dysfunction.

Quantifying human mobility resilience to the COVID-19 pandemic: A case study of Beijing, China.

Human mobility, as a fundamental requirement of everyday life, has been most directly impacted during the COVID-19 pandemic. Existing studies have revealed its ensuing changes. However, its resilience, which is defined as people's ability to resist such impact and maintain their normal mobility, still remains unclear. Such resilience reveals people's response capabilities to the pandemic and quantifying it can help us better understand the interplay between them. Herein, we introduced an integrated framework to quantify the resilience of human mobility to COVID-19 based on its change process. Taking Beijing as a case study, the resilience of different mobility characteristics among different population groups, and under different waves of COVID-19, were compared. Overall, the mobility range and diversity were found to be less resilient than decisions on whether to move. Females consistently exhibited lower resilience than males; middle-aged people exhibited the lowest resilience under the first wave of COVID-19 while older adult's resilience became the lowest during the COVID-19 rebound. With the refinement of pandemic-control measures, human mobility resilience was enhanced. These findings reveal heterogeneities and variations in people's response capabilities to the pandemic, which can help formulate targeted and flexible policies, and thereby promote sustainable and resilient urban management.

Clinical Efficacy of Auricular Acupressure plus Eye Exercises in the Treatment of Adolescent Pseudomyopia.

Objective: To assess the clinical efficacy of auricular acupressure plus eye exercises in the treatment of adolescent pseudomyopia, to discover an easier and safer way to treat pseudomyopia. Methods: Forty adolescent patients with pseudomyopia were randomly recruited and assigned (1 : 1) to receive either eye exercises (single group, including 11 males and 9 females) or auricular acupressure plus eye exercises (combined group, including 12 males and 8 females). The clinical endpoint was the clinical efficacy after 28 days of treatment. Results: The baseline characteristics of the combined group were comparable with those of the single group (P > 0.05). Auricular acupressure plus eye exercises was associated with a significantly higher clinical efficacy versus eye exercises alone (P < 0.05). Conclusion: Ear acupressure plus eye exercises features promising clinical efficacy in the treatment of adolescent pseudomyopia, effectively arresting the progression of pseudomyopia to true myopia.

Low-dose cadmium exposure promotes osteoclastogenesis by enhancing autophagy via inhibiting the mTOR/p70S6K1 signaling pathway.

Cadmium (Cd)-induced bone damage may be mediated through activating osteoclastogenesis. However, the underlying mechanism is unknown. The purpose of this study was to explore the effect and possible mechanism of CdCl2-induced osteoclastogenesis in RAW264.7 cells. We found that a low concentration of CdCl2 (0.025 and 0.050 µM) did not affect the viability of RAW264.7 cells, but promoted osteoclastogenesis. A low concentration of CdCl2 increased the mRNA and protein expression of osteoclastogenesis-related genes. TRAP staining and transmission electron microscopy (TEM) also demonstrated that CdCl2 promoted osteoclastogenesis. A low concentration of CdCl2 upregulated the levels of LC3-II and Beclin-1, and decreased p62 expression. TEM showed relatively abundant autophagic vacuoles (autophagosomes) after CdCl2 exposure. A low concentration of CdCl2 downregulated the expression levels of Mtor and p70S6K1, and the relative protein expression ratios of p-mTOR/mTOR and p-p70S6K1/p70S6K1. When cells were treated with the autophagy inhibitor chloroquine (CQ) or mTOR activator MHY1485 combined with CdCl2, the expressions of osteoclastogenesis related-genes were decreased and autophagy was attenuated compared with cells treated with CdCl2 alone. Deficiencies in autophagosomes and osteoclasts were also observed. Taken together, the results indicate that a low concentration of CdCl2 promotes osteoclastogenesis by enhancing autophagy via inhibiting the mTOR/p70S6K1 signaling pathway.

Effects of cross electro-nape-acupuncture (CENA) on recovery of consciousness and tracheotomy tube sealing in serious cerebral hemorrhage.

OBJECTIVE: This study was designed to explore the effects of cross electro-nape-acupuncture (CENA) treatment on the recovery of consciousness and tracheotomy tube sealing in patients with serious cerebral hemorrhage (SCH). METHODS: A total of 60 patients with SCH admitted to the Intensive Care Unit of the South Hospital of the Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine from November 2020 to June 2021 were selected and randomized into two groups: the CENA group and a control group, given no acupuncture. Both groups were given the same basic treatment and patients in the CENA group were additionally given CENA treatment. Glasgow coma scale (GCS) scores, mismatch negative wave (MMN) and the cough reflex grading score (TCRGS) were recorded and compared after treatment for four weeks. The time to tracheostomy tube sealing was also recorded. RESULTS: After treatment, the GCS scores and MMN latency values of the two groups were significantly improved, with significantly better GCS scores and MMN latency values in the CENA group than in the control group. After treatment, the two groups of TCRGS were reduced, with more significant decreases in the CENA group than in the control group. CONCLUSION: With CENA, it took less time to achieve recovery of consciousness, improve cough reflex score and shortened the time to tracheal tube cutting and sealing in patients with SCH.

Interleukin-1ß-Treated Mesenchymal Stem Cells Inhibit Inflammation in Hippocampal Astrocytes Through Exosome-Activated Nrf-2 Signaling.

BACKGROUND: Interleukin-1ß (IL-1)-treated mesenchymal stem cells (MSCs) and IL-1-MSCs-conditioned medium (CM) exert anti-inflammatory roles. Astrocytes are essential for the modulation of synaptic activity and neuronal homeostasis in the brain. Exosomes are the critical mediators in intercellular communication. However, the mechanism underlying the anti-inflammatory effect of IL-1-treated MSCs remains unknown. METHODS: In this study, exosomes (IL-1-Exo) were isolated from IL-1-treated MSCs. In addition, lipopolysaccharide (LPS)-treated hippocampal astrocytes and status epilepticus (SE) mice were treated with IL-1-Exo. Inflammatory activity, astrogliosis, and cognitive performance were measured to determine the effect of IL-1-Exo on inflammation. RESULTS: The results revealed that IL-1-Exo significantly inhibited LPS-induced astrogliosis and inflammatory responses of astrocytes. Also, IL-1-Exo reversed the LPS-induced effect on calcium signaling. The Nrf2 signaling pathway was associated with the effect of IL-1-Exo in LPS-treated astrocytes. Furthermore, IL-1-Exo reduced the inflammatory response and improved the cognitive performance of SE mice. CONCLUSION: The results suggest that IL-1-Exo inhibited LPS-induced inflammatory responses in astrocytes and SE mice and that the effect of IL-1-Exo was primarily mediated through the Nrf-2 signaling pathway. This study provides a new understanding of the molecular mechanism of inflammation-associated brain diseases and an avenue to develop nanotherapeutic agents for the treatment of inflammatory conditions in the brain.

Microglia exosomal miRNA-137 attenuates ischemic brain injury through targeting Notch1.

Microglia are the resident immune cells in the central nervous system and play an essential role in brain homeostasis and neuroprotection in brain diseases. Exosomes are crucial in intercellular communication by transporting bioactive miRNAs. Thus, this study aimed to investigate the function of microglial exosome in the presence of ischemic injury and related mechanism. Oxygen-glucose deprivation (OGD)-treated neurons and transient middle cerebral artery occlusion (TMCAO)-treated mice were applied in this study. Western blotting, RT-PCR, RNA-seq, luciferase reporter assay, transmission electron microscope, nanoparticle tracking analysis, immunohistochemistry, TUNEL and LDH assays, and behavioral assay were applied in mechanistic and functional studies. The results demonstrated that exosomes derived from microglia in M2 phenotype (BV2-Exo) were internalized by neurons and attenuated neuronal apoptosis in response to ischemic injury in vitro and in vivo. BV2-Exo also decreased infarct volume and behavioral deficits in ischemic mice. Exosomal miRNA-137 was upregulated in BV2-Exo and participated in the partial neuroprotective effect of BV2-Exo. Furthermore, Notch1 was a directly targeting gene of exosomal miRNA-137. In conclusion, these results suggest that BV2-Exo alleviates ischemia-reperfusion brain injury through transporting exosomal miRNA-137. This study provides novel insight into microglial exosomes-based therapies for the treatment of ischemic brain injury.

Mesenchymal stem cell-derived exosome miR-542-3p suppresses inflammation and prevents cerebral infarction.

BACKGROUND: Cerebral infarction ranks as the second leading cause of disability and death globally, and inflammatory response of glial cells is the main cause of brain damage during cerebral infarction. METHODS: Studies have shown that mesenchymal stem cells (MSCs) can secrete exosomes and contribute to cerebral disease. Here, we would explore the function of MSC-derived exosome in cerebral infarction. RESULTS: Microarray indicated a decrease of miR-542-3p and an increase of Toll-Like Receptor 4 (TLR4) in middle cerebral artery occlusion (MCAO) mice comparing with sham mice. And luciferase and RIP analysis indicated a binding of miR-542-3p and TLR4. Then, we injected AAV9-miR-542-3p into paracele of sham or MCAO mice. Functional analysis showed that AAV9-miR-542-3p inhibited infarction area and the number of degenerating neurons and suppressed inflammatory factors' expression and inflammatory cell infiltration. As well, transfection of miR-542-3p mimics into HA1800 cells underwent oxygen and glucose deprivation (OGD). Similarly, overexpression of miR-542-3p alleviated OGD induced cell apoptosis, ROS, and activation of inflammation response. Moreover, miR-542-3p could be packaged into MSCs and secreted into HA1800 cells. The extractive exosome-miR-21-3p treatment relieved MCAO- or OGD-induced cerebral injury and inflammation through targeting TLR4. CONCLUSION: These results confirmed that MSC-derived exosome miR-542-3p prevented ischemia-induced glial cell inflammatory response via inhibiting TLR4. These results suggest possible therapeutic strategies for using exosome delivery of miR-542-3p to cure cerebral ischemic injury.

How did human dwelling and working intensity change over different stages of COVID-19 in Beijing?

The COVID-19 pandemic has changed human daily activities significantly. Understanding the nature, causes, and extent of these changes is essential to evaluate the pandemic's influence on commerce, transportation, employment, and environment, among others. However, existing studies mainly focus on changes to general human mobility patterns; few have investigated changes in specific human daily activities. Based on one-year longitudinal mobile phone positioning data for more than 31 million users in Beijing, we tracked intensity changes in two basic human daily activities, dwelling and working, over the stages of COVID-19. The results show that during COVID-19 outbreak, human working intensity decreased about 60% citywide, while dwelling intensity decreased about 40% in some work and education areas. After COVID-19 was under control, intensity in most regions has recovered, but that in schools, hotels, entertainment venues, and tourism areas has not. These intensity changes at regional scale are due to behavior changes at individual scale: about 43% of residents left Beijing before COVID-19, while only 16% have returned back; all commuters decreased their commuting times during COVID-19, while only 75% have reverted to normal. The findings reveal variations in human activities caused by COVID-19 that can support targeted urban management in the post-epidemic era.

7­Difluoromethyl­5,4'­dimethoxygenistein exerts anti­angiogenic effects on acute promyelocytic leukemia HL­60 cells by inhibiting the TLR4/NF­κB signaling pathway.

Angiogenesis plays an important role in the development and metastasis of tumors, and anti-angiogenesis agents are used to treat tumors. For example, the acute promyelocytic leukemia (APL) may be treated with arsenic trioxide. Angiogenesis in APL is a multi­step dynamic equilibrium process coordinated by various angiogenic stimulators and inhibitors, which play key roles in the occurrence, progression and chemosensitivity of this disease. Our research group previously synthesized 7­difluoromethyl­5,4'­dimethoxygenistein (DFMG), and found that it inhibits angiogenesis during atherosclerotic plaque formation. In the present study, the effect and mechanism of DFMG in angiogenesis induced by APL HL­60 cells was investigated using a chick embryo chorioallantoic membrane model and Matrigel tubule formation assays. The results obtained revealed an anti­angiogenesis effect of DFMG towards HL­60 cells. When the Toll­like receptor 4/nuclear factor­κB (TLR4/NF­κB) signaling pathway was inhibited, the anti­angiogenic effect of DFMG was further enhanced. However, when the TLR4/NF­κB signaling pathway was activated, the anti­angiogenic effect of DFMG was attenuated. These results demonstrated that DFMG inhibits angiogenesis induced by APL HL­60 cells, and provides insights into the mechanism by which DFMG inhibits the TLR4/NF­κB signaling pathway. In conclusion, in the present study, the anti­angiogenesis effect of DFMG on APL has been reported, and the mechanism by which DFMG induced the anti­angiogenesis effect was explored. These findings have provided a potential new drug candidate for the treatment of patients with APL.

Education, Altitude, and Humidity Can Interactively Explain Spatial Discrepancy and Predict Short Stature in 213,795 Chinese School Children.

Backgrounds and Objectives: The north-south height distinctions in Chinese children suggest that some geographical-climatic factors could determine height variation of short stature. In a national health survey, we aimed to explore the spatial distribution of short stature on city scales, and detect its socio-economic and geographical-climatic factors. Methods: Data on the prevalence of short stature were obtained from a 2014 cross-sectional survey of China (CNSSCH). In total, 213,795 Han Chinese students aged 7-18 years, from 106 cities across 30 provinces, were included. Both China and World Health Organization (WHO) growth references were adopted to define short stature. Results: A spatial clustering was apparent in the distribution of short stature. After multivariable adjustment, altitude and humidity significantly increased the risk of high prevalence in short stature, according to the WHO (odds ratio [OR] = 1.61 and 1.26, 95% confidence interval [CI]: 1.20-2.17 and 1.03-1.54) and China (OR = 1.54 and 1.26; 95% CI: 1.15-2.05 and 1.02-1.55) growth references. Additionally, education significantly decreased the risk of high prevalence in short stature according to the WHO (OR = 0.40; 95% CI: 0.22-0.74) and China (OR = 0.42; 95% CI: 0.22-0.77) growth references. Combining both altitude >400 m and education <9 years, as well as education <9 years and humidity >70%, received the largest effect-size estimate, and significance retained after multivariable adjustment. Conclusions: Our findings indicate that high altitude and humidity increased the risk of high prevalence in short stature, high education was associated with low prevalence. Additionally, we observed possible interactions between education and altitude/humidity. They may interactively explain spatial discrepancy and predict short stature in Chinese school children. Further validations are necessary.

Spatial and demographic disparities in short stature among school children aged 7-18 years: a nation-wide survey in China, 2014.

OBJECTIVES: To identify spatial disparities and demographic characteristics of short stature, we analysed the prevalence of short stature collected in a nationwide health survey. SETTINGS: Data were obtained from the 2014 Chinese National Survey on Students Constitution and Health (a cross-sectional study of China). Participants came from 30 provinces, autonomous regions, and municipalities (except Tibet, Hong Kong, Macao, and Taiwan). PARTICIPANTS: There were 213 795 Han school children between 7 and 18 years old enrolled in our study. All participants were sampled by stratified cluster. PRIMARY AND SECONDARY OUTCOME MEASURES: Short stature; Chinese and WHO age-specific and gender-specific height growth references were used for short stature assessment. RESULTS: The age-standardised and age-gender-standardised prevalence of short stature nationwide was 3.70% and 2.69% according to Chinese and WHO growth references, respectively. The short stature prevalence differed significantly among age groups, urban and rural areas, and regions with different socioeconomic development levels (all p<0.0001). The prevalence was 2.23% in urban versus 5.12% in rural areas (p<0.001). The prevalence was 2.60% in developed, 3.72% in intermediately developed, and 4.69% in underdeveloped regions (p<0.0001). These values were all according to China's growth reference, but similar patterns were observed on prevalence based on the WHO reference. The spatial distribution of prevalence of short stature presented a clustered pattern. Moran's I value was 0.474 (p<0.001) and 0.478 (p<0.001) according to the Chinese and WHO growth references, respectively. The southwest part of China showed a higher prevalence of short stature, whereas lower prevalence of short stature was observed mainly in the northeast part of China. CONCLUSIONS: There is an appreciably high prevalence of short stature in rural, underdeveloped areas of China. There are high prevalence spatial clusters of short stature in southwestern China. This provides corroborating evidence for a tailored strategy on short stature prevention and reduction in special areas.