Autophagy-mediated degradation of NOTCH1 intracellular domain controls the epithelial to mesenchymal transition and cancer metastasis

Backgound Autophagy controls levels of cellular components during normal and stress conditions; thus, it is a pivotal process for the maintenance of cell homeostasis. In cancer, autophagy protects cells from cancerous transformations that can result from genomic instability induced by reactive oxygen species or other damaged components, but it can also promote cancer survival by providing essential nutrients during the metabolic stress condition of cancer progression. However, the molecular mechanism underlying autophagy-dependent regulation of the epithelial to mesenchymal transition (EMT) and metastasis is still elusive. Methods The intracellular level of NOTCH1 intracellular domain (NICD) in several cancer cells was studied under starvation, treatment with chloroquine or ATG7-knockdown. The autophagy activity in these cells was assessed by immunocytochemistry and molecular analyses. Cancer cell migration and invasion under modulation of autophagy were determined by in vitro scratch and Matrigel assays. Results In the study, autophagy activation stimulated degradation of NICD, a key transcriptional regulator of the EMT and cancer metastasis. We also found that NICD binds directly to LC3 and that the NICD/LC3 complex associates with SNAI1 and sequestosome 1 (SQSTM1)/p62 proteins. Furthermore, the ATG7 knockdown significantly inhibited degradation of NICD under starvation independent of SQSTM1-associated proteasomal degradation. In addition, NICD degradation by autophagy associated with the cellular level of SNAI1. Indeed, autophagy inhibited nuclear translocation of NICD protein and consequently decreased the transcriptional activity of its target genes. Autophagy activation substantially suppressed in vitro cancer cell migration and invasion. We also observed that NICD and SNAI1 levels in tissues from human cervical and lung cancer patients correlated inversely with expression of autophagy-related proteins. Conclusions These findings suggest that the cellular level of NICD is regulated by autophagy during cancer progression and that targeting autophagy-dependent NICD/SNAI1 degradation could be a strategy for the development of cancer therapeutics

HEALTHY Intervention: Fitness, Physical Activity, and Metabolic Syndrome Results

This study aimed to assess the effect of the HEALTHY intervention on the metabolic syndrome (Met-S), fitness, and physical activity levels of US middle-school students

Molecular Engineering Using an Anthanthrone Dye for Low-Cost Hole Transport Materials: A Strategy for Dopant-Free, High-Efficiency, and Stable Perovskite Solar Cells

In this report, highly efficient and humidity-resistant perovskite solar cells (PSCs) using two new small molecule hole transporting materials (HTM) made from a cost-effective precursor anthanthrone (ANT) dye, namely, 4,10-bis(1,2-dihydroacenaphthylen-5-yl)-6,12-bis(octyloxy)-6,12-dihydronaphtho[7,8,1,2,3-nopqr]tetraphene (ACE-ANT-ACE) and 4,4′-(6,12-bis(octyloxy)-6,12-dihydronaphtho[7,8,1,2,3-nopqr]tetraphene-4,10-diyl)bis(N,N-bis(4-methoxyphenyl)aniline) (TPA-ANT-TPA) are presented. The newly developed HTMs are systematically compared with the conventional 2,2′,7,7′-tetrakis(N,N′-di-p-methoxyphenylamino)-9,9′-spirbiuorene (Spiro-OMeTAD). ACE-ANT-ACE and TPA-ANT-TPA are used as a dopant-free HTM in mesoscopic TiO2/CH3NH3PbI3/HTM solid-state PSCs, and the performance as well as stability are compared with Spiro-OMeTAD-based PSCs. After extensive optimization of the metal oxide scaffold and device processing conditions, dopant-free novel TPA-ANT-TPA HTM-based PSC devices achieve a maximum power conversion efficiency (PCE) of 17.5% with negligible hysteresis. An impressive current of 21 mA cm−2 is also confirmed from photocurrent density with a higher fill factor of 0.79. The obtained PCE of 17.5% utilizing TPA-ANT-TPA is higher performance than the devices prepared using doped Spiro-OMeTAD (16.8%) as hole transport layer at 1 sun condition. It is found that doping of LiTFSI salt increases hygroscopic characteristics in Spiro-OMeTAD; this leads to the fast degradation of solar cells. While, solar cells prepared using undoped TPA-ANT-TPA show dewetting and improved stability. Additionally, the new HTMs form a fully homogeneous and completely covering thin film on the surface of the active light absorbing perovskite layers that acts as a protective coating for underlying perovskite films. This breakthrough paves the way for development of new inexpensive, more stable, and highly efficient ANT core based lower cost HTMs for cost-effective, conventional, and printable PSCs

What can we learn from COVID-19?: examining the resilience of primary care teams

IntroductionThe COVID-19 pandemic continues to place an unprecedented strain on the US healthcare system, and primary care is no exception. Primary care services have shifted toward a team-based approach for delivering care in the last decade. COVID-19 placed extraordinary stress on primary care teams at the forefront of the pandemic response efforts. The current work applies the science of effective teams to examine the impact of COVID-19—a crisis or adverse event—on primary care team resilience.MethodsLittle empirical research has been done testing the theory of team resilience during an extremely adverse crisis event in an applied team setting. Therefore, we conducted an archival study by using large-scale national data from the Veterans Health Administration to understand the characteristics and performance of 7,023 Patient Aligned Care Teams (PACTs) during COVID-19.ResultsOur study found that primary care teams maintained performance in the presence of adversity, indicating possible team resilience. Further, team coordination positively predicted team performance (B = 0.53) regardless of the level of adversity a team was experiencing.DiscussionThese findings in turn attest to the need to preserve team coordination in the presence of adversity. Results carry implications for creating opportunities for teams to learn and adjust to an adverse event to maintain performance and optimize team-member well-being. Teamwork can act as a protective factor against high levels of workload, burnout, and turnover, and should be studied further for its role in promoting team resilience

Retardation of arsenic transport through a Pleistocene aquifer

Groundwater drawn daily from shallow alluvial sands by millions of wells over large areas of south and southeast Asia exposes an estimated population of over a hundred million people to toxic levels of arsenic1. Holocene aquifers are the source of widespread arsenic poisoning across the region2, 3. In contrast, Pleistocene sands deposited in this region more than 12,000 years ago mostly do not host groundwater with high levels of arsenic. Pleistocene aquifers are increasingly used as a safe source of drinking water4 and it is therefore important to understand under what conditions low levels of arsenic can be maintained. Here we reconstruct the initial phase of contamination of a Pleistocene aquifer near Hanoi, Vietnam. We demonstrate that changes in groundwater flow conditions and the redox state of the aquifer sands induced by groundwater pumping caused the lateral intrusion of arsenic contamination more than 120 metres from a Holocene aquifer into a previously uncontaminated Pleistocene aquifer. We also find that arsenic adsorbs onto the aquifer sands and that there is a 16–20-fold retardation in the extent of the contamination relative to the reconstructed lateral movement of groundwater over the same period. Our findings suggest that arsenic contamination of Pleistocene aquifers in south and southeast Asia as a consequence of increasing levels of groundwater pumping may have been delayed by the retardation of arsenic transport.National Science Foundation (U.S.) (NSF grant EAR09-11557)Swiss Agency for Development and Cooperation (Grant NAFOSTED 105-09-59-09 to CETASD, the Centre for Environmental Technology and Sustainable Development (Vietnam))National Institute of Environmental Health Sciences (NIEHS grant P42 ES010349)National Institute of Environmental Health Sciences (NIEHS grant P42 ES016454

Surveillance and treatment of primary hepatocellular carcinoma (aka. STOP HCC): protocol for a prospective cohort study of high-risk patients for HCC using GALAD-score.

Vietnam and Saudi Arabia have high disease burden of primary hepatocellular carcinoma (HCC). Early detection in asymptomatic patients at risk for HCC is a strategy to improve survival outcomes in HCC management. GALAD score, a serum-based panel, has demonstrated promising clinical utility in HCC management. However, in order to ascertain its potential role in the surveillance of the early detection of HCC, GALAD needs to be validated prospectively for clinical surveillance of HCC (i.e., phase IV biomarker validation study). Thus, we propose to conduct a phase IV biomarker validation study to prospectively survey a cohort of patients with advanced fibrosis or compensated cirrhosis, irrespective of etiologies, using semi-annual abdominal ultrasound and GALAD score for five years. We plan to recruit a cohort of 1,600 patients, male or female, with advanced fibrosis or cirrhosis (i.e., F3 or F4) and MELD ≤ 15, in Vietnam and Saudi Arabia (n = 800 each). Individuals with a liver mass ≥ 1 cm in diameter, elevated alpha-fetoprotein (AFP) (≥ 9 ng/mL), and/or elevated GALAD score (≥ -0.63) will be scanned with dynamic contrast-enhanced magnetic resonance imaging (MRI), and a diagnosis of HCC will be made by Liver Imaging Reporting and Data System (LiRADS) assessment (LiRADS-5). Additionally, those who do not exhibit abnormal imaging findings, elevated AFP titer, and/or elevated GALAD score will obtain a dynamic contrast-enhanced MRI annually for five years to assess for HCC. Only MRI nearest to the time of GALAD score measurement, ultrasound and/or AFP evaluation will be included in the diagnostic validation analysis. MRI will be replaced with an abdominal computed tomography scan when MRI results are poor due to patient conditions such as movement etc. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced MRI will not be carried out in study sites in both countries. Bootstrap resampling technique will be used to account for repeated measures to estimate standard errors and confidence intervals. Additionally, we will use the Cox proportional hazards regression model with covariates tailored to the hypothesis under investigation for time-to-HCC data as predicted by time-varying biomarker data. The present work will evaluate the performance of GALAD score in early detection of liver cancer. Furthermore, by leveraging the prospective cohort, we will establish a biorepository of longitudinally collected biospecimens from patients with advanced fibrosis or cirrhosis to be used as a reference set for future research in early detection of HCC in the two countries. Name of the registry: ClinicalTrials.gov Registration date: 22 April 2022 Trial registration number: NCT05342350 URL of trial registry record

Pro-Survival Role for Parkinson's Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons

A mouse genetic study reveals a novel cell-survival role for the Parkinson's disease-associated gene DJ-1 in dopaminergic neurons that have reduced support from endogenous survival factors

"New" Veneziano amplitudes from "old" Fermat (hyper) surfaces

The history of discovery of bosonic string theory is well documented. This theory evolved as an attempt to find a multidimensional analogue of Euler's beta function. Such an analogue had in fact been known in mathematics literature at least in 1922 and was studied subsequently by mathematicians such as Selberg, Weil and Deligne among others. The mathematical interpretation of this multidimensional beta function is markedly different from that described in physics literature. This paper aims to bridge the gap between the existing treatments. Preserving all results of conformal field theories intact, developed formalism employing topological, algebro-geometric, number-theoretic and combinatorial metods is aimed to provide better understanding of the Veneziano amplitudes and, thus, of string theories.Comment: 92 pages LaTex, some typos removed, discussion section is added along with several additional latest reference