The Roles of PI3K/AKT/mTOR and MAPK/ERK Signaling Pathways in Human Pheochromocytomas

Objectives. The roles of PI3K/AKT/mTOR and MAPK/ERK pathways involved in the pathogenesis of pheochromocytoma and paraganglioma (PPGL) were demonstrated mostly by in vitro studies with rat or mouse cells and were mainly studied at transcriptional level. This study aimed to investigate the effect of these pathways on the proliferation of human PPGL cells and the activation of these pathways in PPGLs. Methods. Human PPGL cells were treated with sunitinib and inhibitors of PI3K (LY294002), MEK1/2 (U0126), and mTORC1/2 (AZD8055). Cell proliferation was detected by MTT assay. Protein phosphorylation was detected by Western blotting. Results. In most PPGLs, AKT, ERK1/2, and mTOR were activated. LY294002 (10 μM), U0126 (10 μM), AZD8055 (1 μM), and sunitinib (1 μM) inhibited PPGL cell proliferation in ten primary cultures of tissues, including four from patients with gene mutations. MEK1/2 inhibitor decreased mTOR phosphorylation. Inhibition of mTOR reduced phosphorylation of AKT and ERK1/2. Sunitinib inhibited phospho-ERK1/2 and phospho-mTOR. Conclusion. Our study suggested that PI3K/AKT/mTOR and MAPK/ERK signaling pathways play vital roles in human PPGL and are activated in most PPGLs. Inhibiting multiple pathways might be a novel therapeutic approach for PPGLs

The Roles of PI3K/AKT/mTOR and MAPK/ERK Signaling Pathways in Human Pheochromocytomas

Objectives. The roles of PI3K/AKT/mTOR and MAPK/ERK pathways involved in the pathogenesis of pheochromocytoma and paraganglioma (PPGL) were demonstrated mostly by in vitro studies with rat or mouse cells and were mainly studied at transcriptional level. This study aimed to investigate the effect of these pathways on the proliferation of human PPGL cells and the activation of these pathways in PPGLs. Methods. Human PPGL cells were treated with sunitinib and inhibitors of PI3K (LY294002), MEK1/2 (U0126), and mTORC1/2 (AZD8055). Cell proliferation was detected by MTT assay. Protein phosphorylation was detected by Western blotting. Results. In most PPGLs, AKT, ERK1/2, and mTOR were activated. LY294002 (10 M), U0126 (10 M), AZD8055 (1 M), and sunitinib (1 M) inhibited PPGL cell proliferation in ten primary cultures of tissues, including four from patients with gene mutations. MEK1/2 inhibitor decreased mTOR phosphorylation. Inhibition of mTOR reduced phosphorylation of AKT and ERK1/2. Sunitinib inhibited phospho-ERK1/2 and phospho-mTOR. Conclusion. Our study suggested that PI3K/AKT/mTOR and MAPK/ERK signaling pathways play vital roles in human PPGL and are activated in most PPGLs. Inhibiting multiple pathways might be a novel therapeutic approach for PPGLs

Identification of two rare NPRL3 variants in two Chinese families with familial focal epilepsy with variable foci 3: NGS analysis with literature review

Background: The GAP Activity Towards Rags 1 (GATOR1) complex, which includes DEPDC5, NPRL2, and NPRL3, plays a key role in epilepsy. It has been reported that focal epilepsy is associated with mutations in the NPRL3 gene in some cases. We report two rare mutations in the NPRL3 gene in two unrelated Chinese families with focal epilepsy in this study.Methods: The proband and her brother in family E1 first experienced seizures at 1.5 and 6 years of age, respectively. Despite resection of epileptogenic foci, she still suffered recurrent seizures. The first seizure of a 20-year-old male proband in family E2 occurred when he was 2 years old. To identify pathogenic variants in these families, whole-exome sequencing (WES) was performed on genomic DNA from peripheral blood.Results: In family E1, the trio-WES analysis of the proband and her brother without apparent structural brain abnormalities identified a heterozygous variant in the NPRL3 gene (c.954C>A, p.Y318*, NM_001077350.3). In family E2, the proband carried a heterozygous NPRL3 mutation (c.1545-1G>C, NM_001077350.3). Surprisingly, the mothers of the two probands each carried the variants, but neither had an attack. Bioinformatics analysis predicted that the mutation (c.954C>A) was in the highly conserved amino acid residues of NPRL3, which affected the α-helix of NPRL3 protein, leading to a truncated protein. The splice variant (c.1545-1G>C) resulted in the loss of the last exon of the NPRL3 gene.Conclusion: The results of this study provide a foundation for diagnosing NPRL3-related epilepsy by enriching their genotypes and phenotypes and help us identify the genetic etiologies of epilepsy in these two families

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Strong Convergence Theorems for Generalized Split Feasibility Problems in Banach Spaces

In this paper, we establish new strong convergence theorems of proposed algorithms under suitable new conditions for the generalized split feasibility problem in Banach spaces. As applications, new strong convergence theorems for equilibrium problems, fixed point problems and split common fixed point problems are also studied. Our new results are distinct from recent results on the topic in the literature

Sign Changing Solutions with Clustered Layers Near the Origin for Singularly Perturbed Semilinear Elliptic Problems On a Ball

We study sign changing solutions to equations of the form -∊²∆u+u=f(u) in B, ∂v u=0 on ∂B, where B is the unit ball in ℝ^N (N≥2), ∊ is a positive constant and f(u) behaves like |u|^p-1 u (but not necessarily odd) with

Reservoir-Induced Hydrological Alterations Using Ecologically Related Hydrologic Metrics: Case Study in the Beijiang River, China

Anthropogenic activities have a tremendous impact on water ecosystems worldwide, especially in China. To quantitatively evaluate the hydrological alteration connected with aquatic lives and river ecological risks, we took the Beijiang River located in South China as the case study and used ecosurplus (defined as ecological carrying capacity exceeding ecological consumption)/ecodeficit (defined as ecological consumption exceeding carrying capacity) and Indicators of Hydrological Alterations to evaluate hydrological changes. The Ecologically Relevant Hydrologic Indicators were employed to select the key indices of Indicators of Hydrological Alterations, and the eco-environmental water demand calculation provide an effective way for the reservoir operation. Results showed that: (1) High flows contributed more to the ecodeficit, while low flows contributed more to the ecosurplus; (2) the ecodeficit in some parts of the river basin might exceed the ecosurplus after reservoir construction, especially along the main stream; and (3) the determination of eco-environmental water demand is a feasible way for improving the environment by controlling reservoirs. The current study can help guide the optimization of hydrological operation in the basin toward making the ecosystem healthier and has potential to further provide a reference for other basins in terms of hydrological alterations driven by anthropogenic activities

Synthesis and Characterization of Single-Phase α-Cordierite Glass-Ceramics for LTCC Substrates from Tuff

Single-phase α-cordierite glass-ceramics for a low-temperature co-fired ceramic (LTCC) substrate were fabricated from tuff as the main raw material, using the non-stoichiometric formula of α-cordierite with excess MgO without adding any sintering additives. The sintering/crystallization behavior and the various performances of dielectric properties, thermal expansion, and flexural strength of the glass-ceramics were detected. The results indicated that only single-phase α-cordierite crystal was precipitated from the basic glass sintered at the range 875–950 °C, and μ-cordierite crystal was not observed during the whole sintering-crystallization process. The properties of glass-ceramics were first improved and then deteriorated with the increase in tuff content and sintering temperature. Fortunately, the glass-ceramics sintered at 900 °C with 45 wt.% tuff content possessed excellent properties: high densify (2.62 g∙cm−3), applicable flexural strength (136 MPa), low dielectric loss (0.010, at 10 MHz), low dielectric constant (5.12, at 10 MHz, close to α-cordierite), and suitable coefficients of thermal expansion (CTE, 3.89 × 10−6 K−1)

Multiple Metabolites Derived from Mushrooms and Their Beneficial Effect on Alzheimer’s Diseases

Mushrooms with edible and medicinal potential have received widespread attention because of their diverse biological functions, nutritional value, and delicious taste, which are closely related to their rich active components. To date, many bioactive substances have been identified and purified from mushrooms, including proteins, carbohydrates, phenols, and vitamins. More importantly, molecules derived from mushrooms show great potential to alleviate the pathological manifestations of Alzheimer’s disease (AD), which seriously affects the health of elderly people. Compared with current therapeutic strategies aimed at symptomatic improvement, it is particularly important to identify natural products from resource-rich mushrooms that can modify the progression of AD. This review summarizes recent investigations of multiple constituents (carbohydrates, peptides, phenols, etc.) isolated from mushrooms to combat AD. In addition, the underlying molecular mechanisms of mushroom metabolites against AD are discussed. The various mechanisms involved in the antiAD activities of mushroom metabolites include antioxidant and anti-neuroinflammatory effects, apoptosis inhibition, and stimulation of neurite outgrowth, etc. This information will facilitate the application of mushroom-derived products in the treatment of AD. However, isolation of new metabolites from multiple types of mushrooms and further in vivo exploration of the molecular mechanisms underlying their antiAD effect are still required

Image1_Identification of two rare NPRL3 variants in two Chinese families with familial focal epilepsy with variable foci 3: NGS analysis with literature review.TIF

Background: The GAP Activity Towards Rags 1 (GATOR1) complex, which includes DEPDC5, NPRL2, and NPRL3, plays a key role in epilepsy. It has been reported that focal epilepsy is associated with mutations in the NPRL3 gene in some cases. We report two rare mutations in the NPRL3 gene in two unrelated Chinese families with focal epilepsy in this study.Methods: The proband and her brother in family E1 first experienced seizures at 1.5 and 6 years of age, respectively. Despite resection of epileptogenic foci, she still suffered recurrent seizures. The first seizure of a 20-year-old male proband in family E2 occurred when he was 2 years old. To identify pathogenic variants in these families, whole-exome sequencing (WES) was performed on genomic DNA from peripheral blood.Results: In family E1, the trio-WES analysis of the proband and her brother without apparent structural brain abnormalities identified a heterozygous variant in the NPRL3 gene (c.954C>A, p.Y318*, NM_001077350.3). In family E2, the proband carried a heterozygous NPRL3 mutation (c.1545-1G>C, NM_001077350.3). Surprisingly, the mothers of the two probands each carried the variants, but neither had an attack. Bioinformatics analysis predicted that the mutation (c.954C>A) was in the highly conserved amino acid residues of NPRL3, which affected the α-helix of NPRL3 protein, leading to a truncated protein. The splice variant (c.1545-1G>C) resulted in the loss of the last exon of the NPRL3 gene.Conclusion: The results of this study provide a foundation for diagnosing NPRL3-related epilepsy by enriching their genotypes and phenotypes and help us identify the genetic etiologies of epilepsy in these two families.</p