Pan-cancer evaluation of clinical value of mitotic network activity index (MNAI) and its predictive value for immunotherapy

Increased mitotic activity is associated with the genesis and aggressiveness of many cancers. To assess the clinical value of mitotic activity as prognostic biomarker, we performed a pan-cancer study on the mitotic network activity index (MNAI) constructed based on 54-gene mitotic apparatus network. Our pan-cancer assessment on TCGA (33 tumor types, 10,061 patients) and validation on other publicly available cohorts (23 tumor types, 9,209 patients) confirmed the significant association of MNAI with overall survival, progression-free survival, and other prognostic endpoints in multiple cancer types, including lower-grade gliomas (LGG), breast invasive carcinoma (BRCA), as well as many others. We also showed significant association between MNAI and genetic instability, which provides a biological explanation of its prognostic impact at pan-cancer landscape. Our association analysis revealed that patients with high MNAI benefitted more from anti-PD-1 and Anti-CTLA-4 treatment. In addition, we demonstrated that multimodal integration of MNAI and the AI-empowered Cellular Morphometric Subtypes (CMS) significantly improved the predictive power of prognosis compared to using MNAI and CMS alone. Our results suggest that MNAI can be used as a potential prognostic biomarker for different tumor types toward different clinical endpoints, and multimodal integration of MNAI and CMS exceeds individual biomarker for precision prognosis

Effects of a genetic variant rs13266634 in the zinc transporter 8 gene (SLC30A8) on insulin and lipid levels before and after a high-fat mixed macronutrient tolerance test in U.S. adults

BackgroundThe common C-allele of rs13266634 (c.973C>T or p.Arg325Trp) in SLC30A8 (ZNT8) is associated with increased risk of type 2 diabetes. While previous studies have examined the correlation of the variant with insulin and glucose metabolism, the effects of this variant on insulin and lipid responses after a lipid challenge in humans remain elusive. The goal of this study was to determine whether the C-allele had an impact on an individual's risk to metabolic syndromes in U.S. adults.MethodWe studied the genotypes of rs13266634 in 349 individuals aged between 18 and 65 y with BMI ranging from 18.5 to 45 kg/m2. The subjects were evaluated for insulin, glucose, HbA1c, ghrelin, and lipid profiles before and after a high-fat mixed macronutrient tolerance test (MMTT).ResultsWe found that the effects of variants rs13266634 on glucose and lipid metabolism were sex-dimorphic, greater impact on males than on females. Insulin incremental area under the curve (AUC) after MMTT was significantly decreased in men with the CC genotype (p < 0.05). Men with the CC genotype also had the lowest fasting non-esterified fatty acid (NEFA) concentrations. On the other hand, the TT genotype was associated with a slower triglyceride removal from the circulation in men after MMTT. The reduced triglyceride removal was also observed in subjects with BMI ≥ 30 carrying either the heterozygous or homozygous T-allele. Nevertheless, the SNP had little effect on fasting or postprandial blood glucose and cholesterol concentrations.ConclusionWe conclude that the CC genotype negatively affects insulin response after MMTT while the T-allele may negatively influence lipolysis during fasting and postprandial blood triglyceride removal in men and obese subjects, a novel finding in this study

The western extension of Xiahe fault in West Qinling：Discussion on seismogenic structure of Qinghai Zeku MS4.9 earthquake in 2017

The epicenter of the 2017 Qinghai Zeku MS4.9 earthquake was located near the SN-striking Riyueshan fault, while the focal mechanism solutions and the dominant arrangement of seismic sequence are inconsistent with the Riyueshan fault. In this paper, we have discovered EW- and NW-trending faults near the epicenter, by methods of remote sensing interpretation and field investigation. These faults are western terminal structures of Xiahe fault, in which the EW-trending faults are north-dipping and associated with kinematics including both left-lateral and vertical slip. Meanwhile, we use double differential positioning to relocate seismic sequences of Zeku MS4.9 earthquake. Results show that seismic arrangements consist of two segments striking NW and EW. The seismic profile crossing EW-striking segment indicates a north-dipping fault plane. Well consistence is found between Xiahe fault and seismic arrangements of Zeku MS4.9 earthquake, which leads us to the speculation that the seismogenic fault of Zeku earthquake is Xiahe fault. From a regional perspective, the Xiahe fault might be one strand of dissipating faults in the western end of the West Qinling fault, and the Zeku MS4.9 earthquake represents tectonic activity of the western end of the West Qinling fault. Besides，the northwestward turn of fault striking and reverse slipping of Xiahe fault might also be attributed to the right-lateral shearing effects of Riyueshan fault. Results of this paper highlight the significance of improving active fault traces, especially for the secondary or pre-existing faults in a tectonic active area

The temporal trend of disease burden attributable to metabolic risk factors in China, 1990–2019 : An analysis of the Global Burden of Disease study

Background and aims: The disease burden attributable to metabolic risk factors is rapidly increasing in China, especially in older people. The objective of this study was to (i) estimate the pattern and trend of six metabolic risk factors and attributable causes in China from 1990 to 2019, (ii) ascertain its association with societal development, and (iii) compare the disease burden among the Group of 20 (G20) countries. Methods: The main outcome measures were disability-adjusted life-years (DALYs) and mortality (deaths) attributable to high fasting plasma glucose (HFPG), high systolic blood pressure (HSBP), high low-density lipoprotein (HLDL) cholesterol, high body-mass index (HBMI), kidney dysfunction (KDF), and low bone mineral density (LBMD). The average annual percent change (AAPC) between 1990 and 2019 was analyzed using Joinpoint regression. Results: For all six metabolic risk factors, the rate of DALYs and death increased with age, accelerating for individuals older than 60 and 70 for DALYs and death, respectively. The AAPC value in rate of DALYs and death were higher in male patients than in female patients across 20 age groups. A double-peak pattern was observed for AAPC in the rate of DALYs and death, peaking at age 20–49 and at age 70–95 plus. The age-standardized rate of DALYs increased for HBMI and LBMD, decreased for HFPG, HSBP, KDF, and remained stable for HLDL from 1990 to 2019. In terms of age-standardized rate of DALYs, there was an increasing trend of neoplasms and neurological disorders attributable to HFPG; diabetes and kidney diseases, neurological disorders, sense organ diseases, musculoskeletal disorders, neoplasms, cardiovascular diseases, digestive diseases to HBMI; unintentional injuries to LBMD; and musculoskeletal disorders to KDF. Among 19 countries of Group 20, in 2019, the age-standardized rate of DALYs and death were ranked fourth to sixth for HFPG, HSBP, and HLDL, but ranked 10th to 15th for LBMD, KDF, and HBMI, despite the number of DALYs and death ranked first to second for six metabolic risk factors. Conclusions: Population aging continuously accelerates the metabolic risk factor driven disease burden in China. Comprehensive and tight control of metabolic risk factors before 20 and 70 may help to mitigate the increasing disease burden and achieve healthy aging, respectively

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

BACKGROUND: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. METHODS: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. FINDINGS: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. INTERPRETATION: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic. FUNDING: Bill & Melinda Gates Foundation

Allelic Insufficiency of Zinc Transporter 8 (Znt8) In Mice and Its Effect on T2D Prevention

Zinc transporter 8 (ZNT8) transports zinc from the cytoplasm into the secretory vesicle for insulin crystallization and storage in pancreatic beta-cells. Individuals with ZNT8 allelic insufficiency have reduced risk of type 2 diabetes. However, the underlying mechanism of this protective effect is not well understood. ZNT1-10 in pancreatic islets and in β-cell lines derived from human and mice were examined using immunohistochemistry and immunofluorescence microscopic analysis. The data suggests that there are functional conservations of the ZNT proteins between humans and mice and mouse models of zinc transporters can be used for studying mechanisms of zinc-associated risks of T2D in humans. When fed a high-fat diet (45% kcal fat) for 17 weeks, male Znt8+/- mice had an improved glucose tolerance compared to the wild type mice during glucose challenge. Importantly, the total glucagon secretion assessed by the area under the curve during glucose challenge was significantly lower (~40%) in male Znt8+/- mice than the control mice. Furthermore, quantitative RT-PCR results suggested that Znt8 mRNA expression was strongly and positively correlated with the expression of glucagon (R2=0.75, p=2.43*10-4) and Sst (R2=0.8788, p=6.78*10-6) in pancreatic islets. Most importantly, ZNT8 was found to colocalize with somatostatin in the mouse pylorus mucosa, but not with ghrelin, GIP, GLP1, and CCK. Znt8 heterozygotes may be protected from high-fat-induced glucose intolerance or type 2 diabetes due to enhanced suppression of glucagon levels leading to better glycemic control. Colocalized expression of ZNT8 and somatostatin suggest a role of ZNT8 in regulating SST production and secretion, which may have an indirect impact on the rate of digestion and absorption of foods in the gut as well as the secretions of pancreatic hormones after meals. These findings would provide new research targets to uncover the role of ZNT8 in T2D development

Allelic Insufficiency of Zinc Transporter 8 (Znt8) In Mice and Its Effect on T2D Prevention

Zinc transporter 8 (ZNT8) transports zinc from the cytoplasm into the secretory vesicle for insulin crystallization and storage in pancreatic beta-cells. Individuals with ZNT8 allelic insufficiency have reduced risk of type 2 diabetes. However, the underlying mechanism of this protective effect is not well understood. ZNT1-10 in pancreatic islets and in β-cell lines derived from human and mice were examined using immunohistochemistry and immunofluorescence microscopic analysis. The data suggests that there are functional conservations of the ZNT proteins between humans and mice and mouse models of zinc transporters can be used for studying mechanisms of zinc-associated risks of T2D in humans. When fed a high-fat diet (45% kcal fat) for 17 weeks, male Znt8+/- mice had an improved glucose tolerance compared to the wild type mice during glucose challenge. Importantly, the total glucagon secretion assessed by the area under the curve during glucose challenge was significantly lower (~40%) in male Znt8+/- mice than the control mice. Furthermore, quantitative RT-PCR results suggested that Znt8 mRNA expression was strongly and positively correlated with the expression of glucagon (R2=0.75, p=2.43*10-4) and Sst (R2=0.8788, p=6.78*10-6) in pancreatic islets. Most importantly, ZNT8 was found to colocalize with somatostatin in the mouse pylorus mucosa, but not with ghrelin, GIP, GLP1, and CCK. Znt8 heterozygotes may be protected from high-fat-induced glucose intolerance or type 2 diabetes due to enhanced suppression of glucagon levels leading to better glycemic control. Colocalized expression of ZNT8 and somatostatin suggest a role of ZNT8 in regulating SST production and secretion, which may have an indirect impact on the rate of digestion and absorption of foods in the gut as well as the secretions of pancreatic hormones after meals. These findings would provide new research targets to uncover the role of ZNT8 in T2D development

A Neurophysiological Study of Musical Pitch Identification in Mandarin-Speaking Cochlear Implant Users

Music perception in cochlear implant (CI) users is far from satisfactory, not only because of the technological limitations of current CI devices but also due to the neurophysiological alterations that generally accompany deafness. Early behavioral studies revealed that similar mechanisms underlie musical and lexical pitch perception in CI-based electric hearing. Although neurophysiological studies of the musical pitch perception of English-speaking CI users are actively ongoing, little such research has been conducted with Mandarin-speaking CI users; as Mandarin is a tonal language, these individuals require pitch information to understand speech. The aim of this work was to study the neurophysiological mechanisms accounting for the musical pitch identification abilities of Mandarin-speaking CI users and normal-hearing (NH) listeners. Behavioral and mismatch negativity (MMN) data were analyzed to examine musical pitch processing performance. Moreover, neurophysiological results from CI users with good and bad pitch discrimination performance (according to the just-noticeable differences (JND) and pitch-direction discrimination (PDD) tasks) were compared to identify cortical responses associated with musical pitch perception differences. The MMN experiment was conducted using a passive oddball paradigm, with musical tone C4 (262 Hz) presented as the standard and tones D4 (294 Hz), E4 (330 Hz), G#4 (415 Hz), and C5 (523 Hz) presented as deviants. CI users demonstrated worse musical pitch discrimination ability than did NH listeners, as reflected by larger JND and PDD thresholds for pitch identification, and significantly increased latencies and reduced amplitudes in MMN responses. Good CI performers had better MMN results than did bad performers. Consistent with findings for English-speaking CI users, the results of this work suggest that MMN is a viable marker of cortical pitch perception in Mandarin-speaking CI users

ZNT7 binds to CD40 and influences CD154‐triggered p38 MAPK activity in B lymphocytes—a possible regulatory mechanism for zinc in immune function

Zinc deficiency impairs the immune system leading to frequent infections. Although zinc is known to play critical roles in maintaining healthy immune function, the underlying molecular targets are largely unknown. In this study, we demonstrate that zinc is important for the CD154-CD40-mediated activation of downstream signaling pathways in human B lymphocytes. CD40 is a receptor localized on the cell surface of many immune cells, including B lymphocytes. It binds to CD154, a membrane protein expressed on antigen-activated T helper (Th) lymphocytes. This CD154-CD40 interaction leads to B-cell activation. We showed that cellular zinc deficiency impaired the CD154-CD40-mediated p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation. We also showed that zinc supplemental treatment of B lymphocytes had limited effect on this CD40-mediated p38 MAPK signaling. Most importantly, we demonstrated that the zinc transporter protein zinc transporter 7 (ZNT7) interacted with CD40 using immunoprecipitation analyses. ZNT7 knockdown in B lymphocytes had a negative effect on the cell surface expression of CD40. Consequently, the CD40-mediated p38 MAPK signaling transduction was down-regulated in ZNT7 KD B lymphocytes. Conversely, this p38 MAPK signaling activity was up-regulated by overexpression (OE) of ZNT7 in B lymphocytes. Moreover, we found that ZNT7 knockdown in B lymphocytes constitutively up- and down-regulated the inhibitor of i kappa B kinase and AKT serine/threonine kinase phosphorylation, respectively, which implies the activation of survival signaling in ZNT7 KD B cells. We conclude that CD40 is the target molecule for ZNT7 in regulation of immune function of B lymphocytes