Anti-diabetic effect of anthocyanin cyanidin-3-O-glucoside: data from insulin resistant hepatocyte and diabetic mouse.

BACKGROUND: Anthocyanins are a group of natural products widely found in plants. They have been found to alleviate the disorders of glucose metabolism in type 2 diabetes mellitus (T2DM), while the underlying mechanisms remain unclear. METHODS: HepG2 and L02 cells were incubated with 0.2 mM PA and 30 mM glucose for 24 h to induce IR, and cells treated with 5 mM glucose were used as the control. C57BL/6 J male mice and db/db male mice were fed with a chow diet and gavaged with pure water or cyanidin-3-O-glucoside (C3G) solution (150 mg/kg/day) for 6 weeks. RESULTS: In this study, the anthocyanin C3G, extracted from red bayberry, was found to alleviate disorders of glucose metabolism, which resulted in increased insulin sensitivity in hepatocytes, and achieved by enhancing the glucose consumption as well as glycogen synthesis in insulin resistance (IR) hepatpcytes. Subsequently, the expression of key proteins involved in IR was detected by western blotting analysis. Protein tyrosine phosphatase-1B (PTP1B), a negative regulator of insulin signaling, could reduce cellular sensitivity to insulin by inhibiting the phosphorylation of insulin receptor substrate-2 (IRS-2). Results of this study showed that C3G inhibited the increase in PTP1B after high glucose and palmitic acid treatment. And this inhibition was accompanied by increased phosphorylation of IRS proteins. Furthermore, the effect of C3G on improving IR in vivo was validated by using a diabetic db/db mouse model. CONCLUSION: These findings demonstrated that C3G could alleviate IR in vitro and in vivo to increase insulin sensitivity, which may offer a new insight for regulating glucose metabolism during T2DM by using the natural dietary bioactive components. C3G promotes the phosphorylation of IRS-2 proteins by suppressing the expression of PTP1B, and then enhances the sensitivity of hepatocyte to insulin.

Exploring the Effects of Cyanidin-3-O-Glucoside on Type 2 Diabetes Mellitus: Insights into Gut Microbiome Modulation and Potential Antidiabetic Benefits.

Berries and their functional components have been put forward as an alternative to pharmacological treatments of type 2 diabetes mellitus (T2DM), and more attention has been paid to the gut microbiome in the pathophysiology of T2DM. Thus, we tried to examine the metabolic impact of red bayberry-derived cyanidin-3-O-glucoside (C3G) and investigate whether the antidiabetic effects of C3G were associated with the gut microbiome. As a result, C3G administration was found to reduce blood glucose levels of diabetic db/db mice, accompanied by increased levels of glucagon-like peptide (GLP-1) and insulin. Moreover, 16S rRNA analysis showed that the dominant microbiota modulated by C3G were pivotal in the glucose metabolism. Furthermore, the modulation of C3G on metabolic activities of gut bacteria leads to an increase in intestinal levels of key metabolites, particularly short-chain fatty acids. This contribution helps in promoting the secretion of GLP-1, which in turn increases insulin release with the purpose of reducing blood glucose levels. Overall, these findings may offer new thoughts concerning C3G against metabolic disorders in T2DM.

The burden of fracture in China from 1990 to 2019.

PURPOSE: Osteoporosis is one of the most common clinical problems among the elderly population. China is one of the countries most threatened by osteoporosis and fragility fracture, because of its large population and aging population trends during recent decades. We aimed to estimate the disease burden of fracture from 1990 to 2019 in China. METHODS: We performed a secondary analysis of fractures using detailed information for China from the Global Burden of Disease Study 2019. Fracture incidence and prevalence, rate of years lost to disability from fractures, and term secular trends in China from 1990 to 2019 were compared by sex, age, cause, and nature of fracture. RESULTS: The numbers for incidence and prevalence of fracture and years lived with disability (YLDs) from fractures in China increased from 12.54 million, 28.35 million, and 1.71 million in 1990 to 21.27 million, 67.85 million, and 3.79 million in 2019, respectively, increases of 70%, 139%, and 122%, respectively. In 2019, falls was the leading cause of fractures, with an age-standardized incidence rate (ASIR) of 762 per 100 000 (95% uncertainty interval [UI] 629-906), an age-standardized prevalence rate (ASPR) of 1863 per 100 000 (95% UI 1663-2094), and an age-standardized YLD rate (ASYR) of 103 per 100 000 (95% UI 69-147). Fall-associated deaths and disability-adjusted life-years (DALYs) from low bone mineral density increased greatly during the most recent three decades. Fracture of patella, tibia or fibula, and ankle were the most frequent fracture types, with an ASYR of 116 per 100 000 (95% UI 75-169). Hip fracture had more incident cases in adults ≥ 60 years old, and was more frequent for females. CONCLUSIONS: The burden from fractures has increased significantly since 1990 in China. Falls and road injuries are the main causes of the increase. The fall-associated health burden from osteoporosis needs to be prioritized, with longer-term commitment to its reduction required.

Population serum proteomics uncovers a prognostic protein classifier for metabolic syndrome.

Metabolic syndrome (MetS) is a complex metabolic disorder with a global prevalence of 20%-25%. Early identification and intervention would help minimize the global burden on healthcare systems. Here, we measured over 400 proteins from ∼20,000 proteomes using data-independent acquisition mass spectrometry for 7,890 serum samples from a longitudinal cohort of 3,840 participants with two follow-up time points over 10 years. We then built a machine-learning model for predicting the risk of developing MetS within 10 years. Our model, composed of 11 proteins and the age of the individuals, achieved an area under the curve of 0.774 in the validation cohort (n = 242). Using linear mixed models, we found that apolipoproteins, immune-related proteins, and coagulation-related proteins best correlated with MetS development. This population-scale proteomics study broadens our understanding of MetS and may guide the development of prevention and targeted therapies for MetS.

Global, regional and national burden of endocrine, metabolic, blood and immune disorders 1990-2019: a systematic analysis of the Global Burden of Disease study 2019.

Background: Endocrine, metabolic, blood and immune disorders (EMBID) is a vital public health problem globally, but the study on its burden and global trends was scarce. We aimed to evaluate the global burden of disease and trends in EMBID from 1990 to 2019. Methods: We extracted the data of EMBID-related on death cases, Age-standardized death rates (ASDRs), disability-adjusted life-years (DALYs), Age-standardized DALY rates, years of life lost (YLLs), Age-standardized YLL rates, years lived with disability (YLDs) and Age-standardized YLD rates between 1990 and 2019 from the Global Burden of Disease 2019, by sex, age, and year at the global and geographical region levels. The Annual rate of change was directly extracted from Global Health Data Exchange (GHDx) and we also calculated the age-related age-standardized rate (ASR) to quantify trends in EMBID-related deaths, DALYs, YLLs and YLDs. Result: Globally, the EMBID-related ASDRs showed an increasing trend, whereas the DALYs ASR, YLLs ASR and YLDs ASR were decreased between 1990 to 2019. Furthermore, High-income North America and Southern Sub-Saharan Africa had the highest both ASDRs and DALYs ASR, and Southern Sub-Saharan Africa and Caribbean had the highest both YLDs ASR and YLLs ASR in 2019. Males had a higher EMBID-related ASDRs than females, but the DALYs ASR in females were higher than males. The burden of EMBID was higher in older-aged compared to other age groups, especially in developed regions. Conclusion: Although EMBID-related ASRs for DALYs-, YLLs- and YLDs declined at the global level from 1990 to 2019, but the ASDRs was increasing. This implied high healthcare costs and more burden of ASDRs due to EMBID in the future. Therefore, there was an urgent need to adopt geographic targets, age-specific targets, prevention strategies and treatments for EMBID to reduce negative health outcomes globally.

The Burden of Diabetes-Related Chronic Kidney Disease in China From 1990 to 2019.

Objective: To analyze the trends in disease burden of diabetes-related chronic kidney disease (CKD) by year, age, gender and types of diabetes in China from 1990 to 2019. Methods: Data on prevalence, deaths and disability-adjusted life years (DALYs) for diabetes-related CKD were extracted from the Global Burden of Disease (GBD) 2019 study. Analyses were performed by year, age, gender and types of diabetes. Results: In China, the numbers of deaths and DALYs of diabetes-related CKD continuously increased but the age-standardized rates (per 100,000 population) decreased over 30 years, in which the numbers of deaths and DALYs attributable to type 1 diabetes mellitus (T1DM)-related CKD barely changed and the age-standardized rates decreased over the years; and the number of deaths and DALYs attributable to type 2 diabetes mellitus (T2DM)-related CKD continuously increased, but the age-standardized rates also decreased. In 2019, 76.03 (58.24-95.61) thousand deaths and 2.13 (1.65-2.67) million DALYs were attributable to diabetes-related CKD, of which, T2DM accounted for 83.32% and 77.0% respectively, and T1DM accounted for the rest. Increasing gender disparity was seen, with males being more heavily impacted. The burden of diabetes-related CKD varied among different age groups, with the numbers of deaths and DALYs attributable to T1DM-related CKD peaking between 45 and 54 years of age and T2DM-related CKD peaking between 75 and 79 years of age; and the crude rates of deaths and DALYs attributable to T1DM-related CKD peaking between 70 and 79 years of age and 40 to 54 years of age, respectively, and T2DM-related CKD peaking over 90 years of age. Among neighboring and G20 countries, the burden of diabetes-related CKD in China was relatively controlled reflected by the ranking of adjusted death and DALYs rates. Conclusions: The burden of diabetes-related CKD in China worsens and shows gender disparities and different age distribution. Greater efforts are needed to improve the health outcomes of these patients, especially among males.

Experimental study of unconventional modified filling energy absorption and control mechanism in high energy storage rock masses.

Aiming at the problems that it is difficult to predict rock burst accurately in engineering practice and the implementation parameters of rock burst prevention measures depend on some empirical formulas, in order to study the advantages and disadvantages of different in-situ modification mechanisms deeply, determine the applicable conditions of unusual in-situ modification measures, and provide a theoretical basis for forming adaptive in-situ modification control schemes. Two kinds of modified control methods using the same foundation involve engineering scale and indoor scale. With the help of scale transformation, the whole failure process analysis test of bearing rock samples was carried out. The results show that various modification measures can effectively control the properties, and realize "hard-rock softening or soft-rock hardening" by changing the physical and mechanical parameters of the target rock sample. Compared with the control group, the automatic parameters of rocks deteriorated significantly under different modification measures. The evolution law of carrying energy is similar. However, there are obvious diversity between various modification measures in plastic stage and post-peaking phase stage, which provides favorable conditions for rock burst prevention. Based on this, an adaptive modification control system was constructed. At the same time, filling materials is considered to increase the energy of post-peaking phase (non newtonian fluid: energy-absorbing materials), and further slow down the intensity of released energy within post-peaking phase stage. Because rock burst is characterized by rapid release of energy, non newtonian fluid has a good absorption effect on high-speed impact force. Therefore, in the design test, the effect of non newtonian fluid is realized by applying a high loading rate, and the evaluation of energy absorption effect of bearing rock samples filled with non newtonian fluid in borehole is considered.

A Novel Predictive Model for Adrenocortical Carcinoma Based on Hypoxia- and Ferroptosis-Related Gene Expression.

Background: The impact of hypoxia on ferroptosis is important in cancer proliferation, but no predictive model combining hypoxia and ferroptosis for adrenocortical carcinoma (ACC) has been reported. The purpose of this study was to construct a predictive model based on hypoxia- and ferroptosis-related gene expression in ACC. Methods: We assessed hypoxia- and ferroptosis-related gene expression using data from 79 patients with ACC in The Cancer Genome Atlas (TCGA). Then, a predictive model was constructed to stratify patient survival using least absolute contraction and selection operation regression. Gene expression profiles of patients with ACC in the Gene Expression Omnibus (GEO) database were used to verify the predictive model. Results: Based on hypoxia-related gene expression, 79 patients with ACC in the TCGA database were divided into three molecular subtypes (C1, C2, and C3) with different clinical outcomes. Patients with the C3 subtype had the shortest survival. Ferroptosis-related genes exhibited distinct expression patterns in the three subtypes. A predictive model combining hypoxia- and ferroptosis-related gene expression was constructed. A nomogram was constructed using age, sex, tumor stage, and the predictive gene model. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that the gene signature was mainly related to the cell cycle and organelle fission. Conclusion: This hypoxia-and ferroptosis-related gene signature displayed excellent predictive performance for ACC and could serve as an emerging source of novel therapeutic targets in ACC.

The Global Burden of Osteoporosis, Low Bone Mass, and Its Related Fracture in 204 Countries and Territories, 1990-2019.

Background: Low bone mineral density (LBMD), including osteoporosis and low bone mass, has becoming a serious public health concern. We aimed to estimate the disease burden of LBMD and its related fractures in 204 countries and territories over the past 30 years. Methods: We collected detailed information and performed a secondary analysis for LBMD and its related fractures from the Global Burden of Disease Study 2019. Numbers and age-standardized rates related to LBMD of disability-adjusted life-years (DALYs) and deaths in 204 countries and territories were compared by age, gender, socio-demographic index (SDI), and location. Results: Global deaths and DALYs number attributable to LBMD increased from 207 367 and 8 588 936 in 1990 to 437 884 and 16 647 466 in 2019, with a raise of 111.16% and 93.82%, respectively. DALYs and deaths number of LBMD-related fractures increased 121.07% and 148.65% from 4 436 789 and 121248 in 1990 to 9 808 464 and 301 482 in 2019. In 2019, the five countries with the highest disease burden of DALYs number in LBMD-related fractures were India (2 510 288), China (1 839 375), United States of America (819 445), Japan (323 094), and Germany (297 944), accounting for 25.59%, 18.75%, 8.35%, 3.29%, and 3.04%. There was a quadratic correlation between socio-demographic index (SDI) and burden of LBMD-related fractures: DALYs rate was 179.985-420.435SDI+417.936SDI2(R2 = 0.188, p<0.001); Deaths rate was 7.879-13.416SDI+8.839 SDI2(R2 = 0.101, p<0.001). Conclusions: The global burden of DALYs and deaths associated with LBMD and its related fractures has increased significantly since 1990. There were differences in disease burden between regions and countries. These estimations could be useful in priority setting, policy-making, and resource allocation in osteoporosis prevention and treatment.

Global burden of non-communicable diseases attributable to dietary risks in 1990-2019.

BACKGROUND: Dietary risks have raised attention worldwide during recent decades. The present burden-of-disease study aimed to evaluate the global dietary risks for non-communicable diseases (NCDs) from 1990 to 2019 and quantify their impact on mortality and disability-adjusted life-years (DALYs). Data from the 2019 Global Burden of Disease Study on deaths and DALYs from NCDs attributable to worldwide dietary risks were obtained and underwent deep analysis by year, age, gender, location, leading risks and leading causes, and their associations were examined. The socio-demographic index (SDI) was used as an indicator of national socio-economic status, as well as the relationships between age-standardised rates of deaths or DALYs and socio-economic status. RESULTS: In 2019, 7.9 million deaths and 187.7 million DALYs were attributable to dietary risk factors. High intake of sodium and low intake of whole grains and fruits were leading dietary risks for deaths and DALYs worldwide. However, both indices showed a decreasing trend by year, an increase by age and a higher disease burden in males. The main distribution of dietary-related NCDs was located in highly populated countries. A negative association between the SDI and disease burden and a positive association between the SDI and male preponderance were found. CONCLUSIONS: Dietary risk factors for NCDs increased significantly and varied across regions during 1990-2019. Therefore, greater efforts are needed to raise public awareness of interventions and improve dietary practices aiming to reduce the disease burden caused by suboptimal dietary intake, especially in developing countries and among males.

Age, Gender and Geographic Differences in Global Health Burden of Cirrhosis and Liver Cancer due to Nonalcoholic Steatohepatitis.

Objective: Recently, Nonalcoholic Steatohepatitis (NASH) has become a major contributor to cirrhosis and liver cancer. Therefore, the Global Burden of Disease (GBD) 2017 was used to comprehensively analyze the global, regional, and national burden of cirrhosis and liver cancer due to NASH between 1990 and 2017. Methods: Data for cirrhosis and liver cancer due to NASH were extracted from the GBD study 2017. Socio-demographic Index (SDI) in 2017 was cited as indicators of socioeconomic status. ARIMA model was established to forecast the future health burden. Kruskal-Wallis test and Pearson linear correlation were adopted to evaluate the gender disparity and association with socioeconomic level. Results: From 1990-2017, the global disability-adjusted life years (DALYs) numbers of liver cancer due to NASH increased from 0.71 million to 1.46 million. The age-standardized DALYs rates of liver cancer due to NASH were negatively associated with SDI levels (r=0.-409, p<0.001). Geographically, Australasia experienced the largest increase in the burden of liver cancer due to NASH, with the age-standardized DALYs rate increasing by 143.54%. The global prevalence number of liver cancer due to NASH peaked at 60-64 years in males and at 65-69 years in females. Globally, the burden was heavier in males compared with females. Male-female-ratio of age-standardized DALYs rates in liver cancer due to NASH were positively related to SDI (r=0.303, P=0.011). Conclusion: The global burden of NASH-associated liver cancer has increased significantly since 1990, with age, gender and geographic disparity. Public awareness of liver diseases due to NASH should be emphasized.

Population genomic, climatic and anthropogenic evidence suggest the role of human forces in endangerment of green peafowl (Pavo muticus).

Both anthropogenic impacts and historical climate change could contribute to population decline and species extinction, but their relative importance is still unclear. Emerging approaches based on genomic, climatic and anthropogenic data provide a promising analytical framework to address this question. This study applied such an integrative approach to examine potential drivers for the endangerment of the green peafowl (Pavo muticus). Several demographic reconstructions based on population genomes congruently retrieved a drastic population declination since the mid-Holocene. Furthermore, a comparison between historical and modern genomes suggested genetic diversity decrease during the last 50 years. However, climate-based ecological niche models predicted stationary general range during these periods and imply the little impact of climate change. Further analyses suggested that human disturbance intensities were negatively correlated with the green peafowl's effective population sizes and significantly associated with its survival status (extirpation or persistence). Archaeological and historical records corroborate the critical role of humans, leaving the footprint of low genomic diversity and high inbreeding in the survival populations. This study sheds light on the potential deep-time effects of human disturbance on species endangerment and offers a multi-evidential approach in examining underlying forces for population declines.

Global burden and gender disparity of vision loss associated with diabetes retinopathy.

PURPOSE: To assess the trend patterns and gender disparity in global burden of vision loss due to diabetic retinopathy (DR) by year, age, region and socioeconomic status using prevalence and years lived with disability (YLDs) from Global Burden of Disease (GBD) study 2017. METHODS: Prevalence and YLDs data of vision loss attributable to DR were extracted from GBD Study 2017 in 195 countries and territories. Socio-demographic Index (SDI) in 2017 was cited as indicators of socioeconomic status. Kruskal-Wallis test, Dunn's multiple comparisons and Pearson linear correlation were adopted to evaluate the gender disparity and association with socioeconomic levels. RESULTS: Globally, total age-standardized prevalence and YLDs rates of vision loss due to DR peaked around 2005, with prevalence rate of 58.98 [95% uncertainty interval (UI) 50.95-68.56] and YLDs rate of 5.00 (95% UI 3.51-6.84) per 100 000 population, respectively. The burden were expected to increase to 65.74 (95% UI 60.14-70.86) and 5.68 (95% UI 4.07-7.22) by 2050. The burden would increase according to our projection based on current epidemiological situation. However, gender disparity has existed since 1990 and been enlarging in recent years, with female being more heavily impacted. This pattern remained with ageing among different stages of vision impairments and varied through GBD super regions. Gender difference (females minus males) of age-standardized prevalence rates was positively related to SDI (r = 0.1661, p = 0.0203). Diabetes has become a more important risk over the past 3 decades among the leading causes of vision loss. CONCLUSIONS: The DR-related vision loss burden tended to increase under ageing population according to our projection with significant gender disparity. Public awareness of DR and gender sensitive health policy should be emphasized.

Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025.

Diabetes mellitus is a leading cause of mortality and reduced life expectancy. We aim to estimate the burden of diabetes by type, year, regions, and socioeconomic status in 195 countries and territories over the past 28 years, which provide information to achieve the goal of World Health Organization Global Action Plan for the Prevention and Control of Noncommunicable Diseases in 2025. Data were obtained from the Global Burden of Disease Study 2017. Overall, the global burden of diabetes had increased significantly since 1990. Both the trend and magnitude of diabetes related diseases burden varied substantially across regions and countries. In 2017, global incidence, prevalence, death, and disability-adjusted life-years (DALYs) associated with diabetes were 22.9 million, 476.0 million, 1.37 million, and 67.9 million, with a projection to 26.6 million, 570.9 million, 1.59 million, and 79.3 million in 2025, respectively. The trend of global type 2 diabetes burden was similar to that of total diabetes (including type 1 diabetes and type 2 diabetes), while global age-standardized rate of mortality and DALYs for type 1 diabetes declined. Globally, metabolic risks (high BMI) and behavioral factors (inappropriate diet, smoking, and low physical activity) contributed the most attributable death and DALYs of diabetes. These estimations could be useful in policy-making, priority setting, and resource allocation in diabetes prevention and treatment.

Global burden of noncommunicable disease attributable to high body mass index in 195 countries and territories, 1990-2017.

PURPOSE: The increasing burden of noncommunicable diseases (NCDs) attributable to high body mass index (BMI) represents both a threat and an opportunity for intervention. Estimates of the global latest trend of high BMI-related NCDs and its association with socioeconomic status can facilitate strategic intervention and inform further research. METHODS: This global burden of disease study extracted global, regional, and national data on death and disability-adjusted life years (DALYs) attributable to high BMI-related NCDs from the GBD Study 2017. Secondary analyses were performed by year, age, sex, and specific causes of death and DALYs. The 2017 Socio-demographic Index (SDI) was used as an indicator of national socioeconomic status. The association between age-standardized death or DALYs rate and socioeconomic status were analyzed. RESULTS: Worldwide, 4.7 million deaths and 147.7 million DALYs of NCDs were related to high BMI in 2017, with a projection to 5.5 million deaths and 176.9 million DALYs in 2025. Globally, high BMI-related burden showed an increasing trend with males being more heavily impacted overall. The trend and magnitude of high BMI-related disease burden varied substantially in different geographical and socioeconomic regions. Specifically, the low-middle, middle, and high-middle SDI countries were associated with a higher burden. The leading three causes of DALYs attributable to high BMI in 2017 were ischemic heart diseases, stroke, and diabetes mellitus. CONCLUSIONS: High BMI-related burden of NCDs is worsening, particularly in developing countries. Our findings may enhance public awareness of interventions to reduce the diseases burden caused by high BMI.

Biallelic loss-of-function mutations in JAM2 cause primary familial brain calcification.

Primary familial brain calcification is a monogenic disease characterized by bilateral calcifications in the basal ganglia and other brain regions, and commonly presents motor, psychiatric, and cognitive symptoms. Currently, four autosomal dominant (SLC20A2, PDGFRB, PDGFB, XPR1) and one autosomal recessive (MYORG) causative genes have been identified. Compared with patients with autosomal dominant primary familial brain calcification, patients with the recessive form of the disease present with more severe clinical and imaging phenotypes, and deserve more clinical and research attention. Biallelic mutations in MYORG cannot explain all autosomal recessive primary familial brain calcification cases, indicating the existence of novel autosomal recessive genes. Using homozygosity mapping and whole genome sequencing, we detected a homozygous frameshift mutation (c.140delT, p.L48*) in the JAM2 gene in a consanguineous family with two affected siblings diagnosed with primary familial brain calcification. Further genetic screening in a cohort of 398 probands detected a homozygous start codon mutation (c.1A>G, p.M1?) and compound heterozygous mutations [c.504G>C, p.W168C and c.(67+1_68-1)_(394+1_395-1), p.Y23_V131delinsL], respectively, in two unrelated families. The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages. All patients presented with severe calcifications in the cortex in addition to extensive calcifications in multiple brain areas (lenticular nuclei, caudate nuclei, thalamus, cerebellar hemispheres, ± brainstem; total calcification scores: 43-77). JAM2 encodes junctional adhesion molecule 2, which is highly expressed in neurovascular unit-related cell types (endothelial cells and astrocytes) and is predominantly localized on the plasma membrane. It may be important in cell-cell adhesion and maintaining homeostasis in the CNS. In Chinese hamster ovary cells, truncated His-tagged JAM2 proteins were detected by western blot following transfection of p.Y23_V131delinsL mutant plasmid, while no protein was detected following transfection of p.L48* or p.1M? mutant plasmids. In immunofluorescence experiments, the p.W168C mutant JAM2 protein failed to translocate to the plasma membrane. We speculated that mutant JAM2 protein resulted in impaired cell-cell adhesion functions and reduced integrity of the neurovascular unit. This is similar to the mechanisms of other causative genes for primary familial brain calcification or brain calcification syndromes (e.g. PDGFRB, PDGFB, MYORG, JAM3, and OCLN), all of which are highly expressed and functionally important in the neurovascular unit. Our study identifies a novel causative gene for primary familial brain calcification, whose vital function and high expression in the neurovascular unit further supports impairment of the neurovascular unit as the root of primary familial brain calcification pathogenesis.

Ongoing green peafowl protection in China.

The green peafowl (Pavo muticus) is one of the most threatened pheasants in the world. In China, it is widely appreciated for its beauty as well as historical and cultural value, but current populations number less than 500 individuals. Recently, Tang and colleagues reported in Science that the green peafowl is likely to become extinct due to the construction of the Jiasajiang Level 1 Hydropower Station within the Red River Upstream District (RRUD) and thus called for a stop to this project (Tang et al., 2019). According to our recent surveys, however, this species is still extant in 22 counties of Yunnan Province, China, among which, only two within the RRUD have been predicted to be affected by floods from the hydropower station. Therefore, the conclusion that the species will likely go extinct in China upon completion of the dam is unwarranted. In fact, construction of the Jiasajiang Level 1 Hydropower Station was stopped in August 2017. The main challenge for green peafowl conservation is that over 65% of the population occurs outside of protected reserves in China. Fortunately, the Chinese government has adopted an Ecological Redline (ERL) strategy to achieve ecological civilization plans, thus bringing new hope to the conservation of green peafowls both inside and outside of protected reserves. As a top conservation priority for China, the government is fully committed to conserving this peafowl.

Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists.

RATIONALE: Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. To date no treatment strategies have been developed to regulate clinical VC. OBJECTIVE: The objective of this study was to investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model. METHODS AND RESULTS: Young adult osteoprotegerin-deficient mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409-treated mice were paralleled by markedly lower alkaline phosphatase activity and a dramatic reduction in the expression of transcription factors, including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH-A was dissected in smooth muscle cells isolated from human and mouse aortas. Calcification of smooth muscle cells induced by osteogenic medium was inhibited in the presence of GHRH or MR409, as evidenced by reduced alkaline phosphatase activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor-selective small interfering RNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A which in turn blocked nicotinamide adenine dinucleotide phosphate oxidase activity and reduced production of reactive oxygen species, thus blocking the phosphorylation of nuclear factor κB (p65), a key intermediate in the ligand of receptor activator for nuclear factor-κ B-Runx2/alkaline phosphatase osteogenesis program. A protein kinase A-selective small interfering RNA or the chemical inhibitor H89 abolished these beneficial effects of MR409. CONCLUSIONS: GHRH-A controls osteogenesis in smooth muscle cells by targeting cross talk between protein kinase A and nuclear factor κB (p65) and through the suppression of reactive oxygen species production that induces the Runx2 gene and alkaline phosphatase. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC.