Prevention of ribosome collision-induced neuromuscular degeneration by SARS CoV-2-encoded Nsp1.

An overarching goal of aging and age-related neurodegenerative disease research is to discover effective therapeutic strategies applicable to a broad spectrum of neurodegenerative diseases. Little is known about the extent to which targetable pathogenic mechanisms are shared among these seemingly diverse diseases. Translational control is critical for maintaining proteostasis during aging. Gaining control of the translation machinery is also crucial in the battle between viruses and their hosts. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing COVID-19 pandemic. Here, we show that overexpression of SARS-CoV-2-encoded nonstructural protein 1 (Nsp1) robustly rescued neuromuscular degeneration and behavioral phenotypes in Drosophila models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These diseases share a common mechanism: the accumulation of aberrant protein species due to the stalling and collision of translating ribosomes, leading to proteostasis failure. Our genetic and biochemical analyses revealed that Nsp1 acted in a multipronged manner to resolve collided ribosomes, abort stalled translation, and remove faulty translation products causative of disease in these models, at least in part through the ribosome recycling factor ABCE1, ribosome-associated quality-control factors, autophagy, and AKT signaling. Nsp1 exhibited exquisite specificity in its action, as it did not modify other neurodegenerative conditions not known to be associated with ribosome stalling. These findings uncover a previously unrecognized mechanism of Nsp1 in manipulating host translation, which can be leveraged for combating age-related neurodegenerative diseases that are affecting millions of people worldwide and currently without effective treatment.

The mTORC2/AKT/VCP axis is associated with quality control of the stalled translation of poly(GR) dipeptide repeats in C9-ALS/FTD.

Expansion of G4C2 hexanucleotide repeats in the chromosome 9 ORF 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (C9-ALS/FTD). Dipeptide repeats generated by unconventional translation, especially the R-containing poly(GR), have been implicated in C9-ALS/FTD pathogenesis. Mutations in other genes, including TAR DNA-binding protein 43 KD (TDP-43), fused in sarcoma (FUS), and valosin-containing protein, have also been linked to ALS/FTD, and upregulation of amyloid precursor protein (APP) is observed at the early stage of ALS and FTD. Fundamental questions remain as to the relationships between these ALS/FTD genes and whether they converge on similar cellular pathways. Here, using biochemical, cell biological, and genetic analyses in Drosophila disease models, patient-derived fibroblasts, and mammalian cell culture, we show that mechanistic target of rapamycin complex 2 (mTORC2)/AKT signaling is activated by APP, TDP-43, and FUS and that mTORC2/AKT and its downstream target valosin-containing protein mediate the effect of APP, TDP-43, and FUS on the quality control of C9-ALS/FTD-associated poly(GR) translation. We also find that poly(GR) expression results in reduction of global translation and that the coexpression of APP, TDP-43, and FUS results in further reduction of global translation, presumably through the GCN2/eIF2α-integrated stress response pathway. Together, our results implicate mTORC2/AKT signaling and GCN2/eIF2α-integrated stress response as common signaling pathways underlying ALS/FTD pathogenesis.

Aberrant functional connectivity in insular subregions in somatic depression: a resting-state fMRI study.

BACKGROUND: Somatic depression (SD) is different from non-somatic depression (NSD), and insular subregions have been associated with somatic symptoms. However, the pattern of damage in the insular subregions in SD remains unclear. The aim of this study was to use functional connectivity (FC) analyses to explore the bilateral ventral anterior insula (vAI), bilateral dorsal anterior insula (dAI), and bilateral posterior insula (PI) brain circuits in SD patients. METHODS: The study included 28 SD patients, 30 NSD patients, and 30 matched healthy control (HC) subjects. All participants underwent 3.0 T resting state functional magnetic resonance imaging. FC analyses were used to explore synchronization between insular subregions and the whole brain in the context of depression with somatic symptoms. Pearson correlation analyses were performed to assess relationships between FC values in brain regions showing significant differences and the total and factor scores on the 17-item Hamilton Rating Scale for Depression (HAMD17). RESULTS: Compared with the NSD group, the SD group showed significantly decreased FC between the left vAI and the right rectus gyrus, right fusiform gyrus, and right angular gyrus; between the right vAI and the right middle cingulate cortex, right precuneus, and right superior frontal gyrus; between the left dAI and the left fusiform gyrus; and between the right dAI and the left postcentral gyrus. Relative to the NSD group, the SD group exhibited increased FC between the left dAI and the left fusiform gyrus. There were no differences in FC between bilateral PI and any brain regions among the SD, NSD, and HC groups. Within the SD group, FC values between the left vAI and right rectus gyrus were positively correlated with cognitive impairment scores on the HAMD17; FC values between the right vAI and right superior frontal gyrus were positively related to the total scores and cognitive impairment scores on the HAMD17 (p < 0.05, uncorrected). CONCLUSIONS: Aberrant FC between the anterior insula and the frontal and limbic cortices may be one possible mechanism underlying SD.

TIGAR regulates mitochondrial functions through SIRT1-PGC1α pathway and translocation of TIGAR into mitochondria in skeletal muscle.

TP53-induced glycolysis and apoptosis regulator (TIGAR), a glycolytic inhibitor, plays vital roles in regulating cellular metabolism and oxidative stress. However, the role of highly expressed TIGAR in skeletal muscle remains unexplored. In the present study, TIGAR levels varied in different skeletal muscles and fibers. An exhaustive swimming test with a load corresponding to 5% of body weight was utilized in mice to assess the effects of TIGAR on exercise-induced fatigue and muscle damage. The running time and metabolic indicators were significantly greater in wild-type (WT) mice compared with TIGAR knockout (KO) mice. Poor exercise capacity was accompanied by decreased type IIA fibers in TIGAR KO mice. Decreased mitochondrial number and mitochondrial oxidative phosphorylation were observed more in TIGAR KO mice than in WT mice, which were involved in sirtuin 1 (SIRT1)-mediated deacetylation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and resveratrol treatment in TIGAR KO mice can increase mitochondrial content and exercise time. Much more TIGAR was also detected in mitochondria during exhaustive exercise. In addition, TIGAR, rather than mitochondria-targeted TIGAR achieved by in vitro plasmid transfection, promoted SIRT1-PGC1α pathway. Glutathione S-transferase-TIGAR pull-down assay followed by liquid chromatography mass spectrometry found that TIGAR interacted with ATP synthase F1 subunit α (ATP5A1), and its binding to ATP5A1 increased during exhaustive exercise. Overexpression of mitochondrial-TIGAR enhanced ATP generation, maintained mitochondrial membrane potential and reduced mitochondrial oxidative stress under hypoxia condition. Taken together, our results uncovered a novel role for TIGAR in mitochondrial regulation in fast-twitch oxidative skeletal muscle through SIRT1-PGC1α and translocation into mitochondria, which contribute to the increase in exercise endurance of mice.-Geng, J., Wei, M., Yuan, X., Liu, Z., Wang, X., Zhang, D., Luo, L., Wu, J., Guo, W., Qin, Z.-H. TIGAR regulates mitochondrial functions through SIRT1-PGC1α pathway and translocation of TIGAR into mitochondria in skeletal muscle.

Andrographolide triggers autophagy-mediated inflammation inhibition and attenuates chronic unpredictable mild stress (CUMS)-induced depressive-like behavior in mice.

Depression is one of the most common psychiatric disorders in the world. Andrographolide is a natural product that displays evident anti-inflammatory activities. The purpose of the present study was to explore the antidepressant potential of andrographolide in chronic unpredictable mild stress (CUMS)-induced depressive-like behavior in mice. Performance in behavioral tests such as the forced swim test, sucrose preference test, tail suspension test and Y-maze was improved following andrographolide administration. The pro-inflammatory mediator NO and cytokines IL-1ß, IL-6 as well as TNF-α were measured in the prefrontal cortex using a reagent kit, ELISA and real-time PCR. NF-κB signaling, NLRP3 inflammasome assembly and autophagy process were examined in the prefrontal cortex using western blotting. It was observed that 5 mg/kg andrographolide treatment obviously improved depressive-like behavior. In addition, 5 mg/kg andrographolide treatment also decreased the expression of pro-inflammatory mediators and cytokines (NO, COX-2, iNOS, IL-1ß, IL-6 and TNF-α), NF-κB signaling (p-p65, p-IκBα) and NLRP3 inflammasome assembly (NLRP3, ASC and caspase-1) in the prefrontal cortex. Moreover, autophagy levels increased after andrographolide treatment. Finally, the antidepressant and anti-inflammatory effects of andrographolide were compromised by the application of chloroquine (CQ), which suggested that andrographolide-induced autophagy was mainly affected by the initiation rather than the blocking of autophagic flux. In conclusion, these results suggest that andrographolide produces antidepressant-like and anti-inflammatory effects in CUMS-induced mice which maybe mediated by the upregulation of autophagy.

MicroRNA-related single-nucleotide polymorphism of XPO5 is strongly correlated with the prognosis and chemotherapy response in advanced non-small-cell lung cancer patients.

This study was performed to investigate if the microRNA-related single-nucleotide polymorphisms (miR-SNPs) of XPO5 gene predicted the prognosis and pathological features of advanced non-small-cell lung cancer patients receiving chemotherapy. A total of 131 advanced non-small-cell lung cancer (NSCLC) patients were recruited. MicroRNA (miRNA) binding site prediction software was adopted for the prediction and screening of SNPs in XPO5 and miRNA binding regions. Polymerase chain reaction (PCR) amplification was further performed. Time-dependent survival-free curves were constructed using the Kaplan-Meier technique. Univariate and the multivariate survival analyses were conducted for confirmation of prognostic factor for advanced NSCLC patients receiving chemotherapy. There were no significant differences of SNP distribution frequencies between groups, without statistical significance (P > 0.05). Included clinical pathological features and chemotherapy regimens showed no apparent statistical significance in influencing the curative effect of chemotherapy in advanced NSCLC patients (all P > 0.05). While the objective response rate (ORR) in patients who carried AA and AC genotype was 35.48 and 51.22 %, respectively, with statistically significant difference (P < 0.05). Univariate survival analysis indicated that patients who carried AA genotype showed a significantly lower 5-year survival rate to those who carried AC genotype (P < 0.05). And, considering pathological features, statistical significance was found in patients with different pathological types, lymph node metastasis, differentiation degree, T staging, and pathological staging (all P < 0.05). Multivariate analysis results indicated that the SNP sites of rs11077 might be an independent prognostic factor of advanced NSCLC patients receiving chemotherapy (risk ratio [RR] = 0.346; 95 % confidence interval [95 % CI] = 0.174-0.685, P = 0.002). Other clinical features were all considered to have no apparent effect in influencing the prognostic outcomes of advanced NSCLC patients receiving chemotherapy except lymph node metastasis (P < 0.05). miR-SNP rs11077 of XPO5 may be independently connected with the prognosis and chemotherapy response of advanced NSCLC patients, and patients with AC genotype have relatively improved prognostic outcomes and better curative effect of chemotherapy than those with AA allele of XPO5. Further, lymph node metastasis may be also involved in influencing the prognosis of advanced NSCLC patients.

Nonadiabatic Electron Dynamics in Orthogonal Two-Color Laser Fields with Comparable Intensities.

We theoretically investigate the nonadiabatic subcycle electron dynamics in orthogonally polarized two-color laser fields with comparable intensities. The photoelectron dynamics is simulated by exact solution to the 3D time-dependent Schrödinger equation, and also by two other semiclassical methods, i.e., the quantum trajectory Monte Carlo simulation and the Coulomb-corrected strong field approximation. Through these methods, we identify the underlying mechanisms of the subcycle electron dynamics and find that both the nonadiabatic effects and the Coulomb potential play very important roles. The contribution of the nonadiabatic effects manifest in two aspects, i.e., the nonadiabatic ionization rate and the nonzero initial velocities at the tunneling exit. The Coulomb potential has a different impact on the electrons' trajectories for different relative phases between the two pulses.

Mechanisms of below-threshold harmonic generation in atoms.

Most previous studies have focused on high-order harmonic generation beyond the ionization threshold; mechanisms of below-threshold harmonics are less understood. We schematically study the harmonic emission process in this region by numerically solving the time-dependent Schrödinger equation of an atom in laser fields. We show that, besides the quantum path interference mechanism recently identified, the effects induced by the Coulomb potential also have a critical impact on these harmonics. These mechanisms can be distinguished in the structure of harmonic spectra by changing the laser wavelength and peak intensity. We find that the long quantum orbits can influence lower-order harmonics at a higher laser intensity. In addition, we show that the intensity-dependent steps of harmonic yield can disappear for certain harmonic orders, due to the trapping in the Rydberg states before recombination, which can explain recent experimental observations.

Classical-quantum correspondence for above-threshold ionization.

We measure high resolution photoelectron angular distributions (PADs) for above-threshold ionization of xenon atoms in infrared laser fields. Based on the Ammosov-Delone-Krainov theory, we develop an intuitive quantum-trajectory Monte Carlo model encoded with Feynman's path-integral approach, in which the Coulomb effect on electron trajectories and interference patterns are fully considered. We achieve a good agreement with the measured PADs of atoms for above-threshold ionization. The quantum-trajectory Monte Carlo theory sheds light on the role of ionic potential on PADs along the longitudinal and transverse direction with respect to the laser polarization, allowing us to unravel the classical coordinates (i.e., tunneling phase and initial momentum) at the tunnel exit for all of the photoelectrons of the PADs. We study the classical-quantum correspondence and build a bridge between the above-threshold ionization and the tunneling theory.

Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis.

Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. Here we show that ZNF598 undergoes regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stresses in mammalian cells and Drosophila. ZNF598 promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborts stalled translation of mitochondrial outer membrane-associated mRNAs, removes faulty translation products causal of disease, and improves mitochondrial and tissue health. These results shed lights on the regulation of ZNF598 and its functional role in mitochondrial and tissue homeostasis.

[Changes in Th17 and CD4+CD25+ Treg cells and their significance among children with hand, foot and mouth disease].

OBJECTIVE: To investigate the changes in peripheral blood Th17 and CD4(+)CD25(+) regulatory T (Treg) cells and their significance among children with hand, foot and mouth disease (HFMD). METHODS: Eighty-nine children with HFMD, including 55 cases of common HFMD and 34 cases of severe HFMD, were included in the study; and 30 healthy children were selected as the control group. The percentages of Th17 and CD4(+)CD25(+) Treg cells in CD4(+) T cells in peripheral blood were determined by flow cytometry. The expression levels of interleukin (IL)-10, transforming growth factor-ß (TGF-ß), and IL-17 were measured by enzyme-linked immunosorbent assay. RESULTS: Compared with the control group, the cases of common HFMD and severe HFMD had significantly increased levels of Th17 cells and IL-17 (P<0.05) but significantly decreased levels of CD4(+)CD25(+) Treg cells, IL-10, and TGF-ß (P<0.05). The severity of the HFMD was positively correlated with the levels of Th17 cells and IL-17 in peripheral blood but negatively correlated with the levels of CD4(+)CD25(+) Treg cells, IL-10, and TGF-ß. CONCLUSIONS: Children with HFMD have increased response of Th17 cells but decreased response of CD4(+)CD25(+) Treg cells in peripheral blood. Th17/CD4(+)CD25(+) Treg cell imbalance may play an important role in the pathogenesis of HFMD.

[Application of Demirjian and Chaillet method in age estimation of Uyghur and Han children and adolescents in Urumqi].

PURPOSE: To evaluate the applicability and accuracy of Demirjian and Chaillet method in estimating the actual age of Uygur and Han children and adolescents in Urumqi. METHODS: A total of 1144 orthopantomograms were included in the study, and the seven permanent teeth in the left jaw were divided into different stages according to two dental age estimation methods, and the dental age was converted to tooth age after checking the table and assigning points, and the dental age and its chronological age were compared with t test or rank sum test using SPSS 21.0 software package, and the accuracy of the two methods was evaluated by comparing the mean absolute error of the two methods. RESULTS: Demirjian method was overestimated by an average of 0.46 years (0.47 years for males and 0.43 years for women) in the Han population, 0.36 years for men and 0.26 years for women in Uyghur population, the difference was significant between Uyghur and Han boys (P＜0.05). Chaillet method yielded an average underestimate of 0.01 years (0.04 years for men and -0.08 years for women) in the Han population, and 0.08 years(0.02 years for men and -0.21 years for women) in the Uyghur population, there was no significant difference between Uyghur and Han boys and girls(P＞0.05). CONCLUSIONS: When assessing the age of Uyghurhan children and adolescents in Urumqi, Chaillet method is more accurate than the Demirjian method. When applying dental age estimation method in different regions, it is necessary to evaluate the accuracy of the estimation method and revise it if necessary to improve the accuracy.

RLSegNet: An Medical Image Segmentation Network Based on Reinforcement Learning.

In the area of medical image segmentation, the spatial information can be further used to enhance the image segmentation performance. And the 3D convolution is mainly used to better utilize the spatial information. However, how to better utilize the spatial information in the 2D convolution is still a challenging task. In this paper, we propose an image segmentation network based on reinforcement learning (RLSegNet), which can translate the image segmentation process into a serial of decision-making problem. The proposed RLSegNet is a U-shaped network, which is composed of three components: the feature extraction network, the Mask Prediction Network (MPNet), and the up-sampling network with the cascade attention module. The deep semantic feature in the image is first extracted by adopting the feature extraction network. Then, the Mask Prediction Network (MPNet) is proposed to generate the prediction mask for the current frame based on the prior knowledge (segmentation result). And the proposed cascade attention module is mainly used to generate the weighted feature mask so that the up-sampling network pays more attention to the interesting region. Specifically, the state, action and reward used in the reinforcement learning are redesigned in the proposed RLSegNet to translate the segmentation process as the decision-making process, which performs as the reinforcement learning to realize the brain tumor segmentation. Extensive experiments are conducted on the BRATS 2015 dataset to evaluate the proposed RLSegNet. The experimental results demonstrate that the proposed method can achieve a better segmentation performance, in comparison with other state-of-the-art methods.

Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome.

Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), the most prevalent form of inherited intellectual disability. Here, we show that FMRP interacts with the voltage-dependent anion channel (VDAC) to regulate the formation and function of endoplasmic reticulum (ER)-mitochondria contact sites (ERMCSs), structures that are critical for mitochondrial calcium (mito-Ca2+) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca2+ transfer. Genetic and pharmacological inhibition of VDAC or other ERMCS components restored synaptic structure, function, and plasticity and rescued locomotion and cognitive deficits of the Drosophila dFmr1 mutant. Expressing FMRP C-terminal domain (FMRP-C), which confers FMRP-VDAC interaction, rescued the ERMCS formation and mito-Ca2+ homeostasis defects in FXS patient iPSC-derived neurons and locomotion and cognitive deficits in Fmr1 knockout mice. These results identify altered ERMCS formation and mito-Ca2+ homeostasis as contributors to FXS and offer potential therapeutic targets.

MVFusFra: A Multi-View Dynamic Fusion Framework for Multimodal Brain Tumor Segmentation.

Medical practitioners generally rely on multimodal brain images, for example based on the information from the axial, coronal, and sagittal views, to inform brain tumor diagnosis. Hence, to further utilize the 3D information embedded in such datasets, this paper proposes a multi-view dynamic fusion framework (hereafter, referred to as MVFusFra) to improve the performance of brain tumor segmentation. The proposed framework consists of three key building blocks. First, a multi-view deep neural network architecture, which represents multi learning networks for segmenting the brain tumor from different views and each deep neural network corresponds to multi-modal brain images from one single view. Second, the dynamic decision fusion method, which is mainly used to fuse segmentation results from multi-views into an integrated method. Then, two different fusion methods (i.e., voting and weighted averaging) are used to evaluate the fusing process. Third, the multi-view fusion loss (comprising segmentation loss, transition loss, and decision loss) is proposed to facilitate the training process of multi-view learning networks, so as to ensure consistency in appearance and space, for both fusing segmentation results and the training of the learning network. We evaluate the performance of MVFusFra on the BRATS 2015 and BRATS 2018 datasets. Findings from the evaluations suggest that fusion results from multi-views achieve better performance than segmentation results from the single view, and also implying effectiveness of the proposed multi-view fusion loss. A comparative summary also shows that MVFusFra achieves better segmentation performance, in terms of efficiency, in comparison to other competing approaches.

Role of potential bioactive metabolites from traditional Chinese medicine for type 2 diabetes mellitus: An overview.

Type 2 diabetes mellitus (T2DM) is a metabolic disease with persistent hyperglycemia primarily caused by insulin resistance (IR). The number of diabetic patients globally has been rising over the past decades. Although significant progress has been made in treating diabetes mellitus (DM), existing clinical drugs for diabetes can no longer fully meet patients when they face complex and huge clinical treatment needs. As a traditional and effective medical system, traditional Chinese medicine (TCM) has a unique understanding of diabetes treatment and has developed many classic and practical prescriptions targeting DM. With modern medicine and pharmacy advancements, researchers have discovered that various bioactive metabolites isolated from TCM show therapeutic on DM. Compared with existing clinical drugs, these bioactive metabolites demonstrate promising prospects for treating DM due to their excellent biocompatibility and fewer adverse reactions. Accordingly, these valuable metabolites have attracted the interest of researchers worldwide. Despite the abundance of research works and specialized-topic reviews published over the past years, there is a lack of updated and systematic reviews concerning this fast-growing field. Therefore, in this review, we summarized the bioactive metabolites derived from TCM with the potential treatment of T2DM by searching several authoritative databases such as PubMed, Web of Science, Wiley Online Library, and Springer Link. For the convenience of readers, the content is divided into four parts according to the structural characteristics of these valuable compounds (flavonoids, terpenoids, alkaloids, and others). Meanwhile, the detailed mechanism and future directions of these promising compounds curing DM are also summarized in the related sections. We hope this review inspires increasingly valuable and significant research focusing on potential bioactive metabolites from TCM to treat DM in the future.

Inefficient quality control of ribosome stalling during APP synthesis generates CAT-tailed species that precipitate hallmarks of Alzheimer's disease.

Amyloid precursor protein (APP) metabolism is central to Alzheimer's disease (AD) pathogenesis, but the key etiological driver remains elusive. Recent failures of clinical trials targeting amyloid-ß (Aß) peptides, the proteolytic fragments of amyloid precursor protein (APP) that are the main component of amyloid plaques, suggest that the proteostasis-disrupting, key pathogenic species remain to be identified. Previous studies suggest that APP C-terminal fragment (APP.C99) can cause disease in an Aß-independent manner. The mechanism of APP.C99 pathogenesis is incompletely understood. We used Drosophila models expressing APP.C99 with the native ER-targeting signal of human APP, expressing full-length human APP only, or co-expressing full-length human APP and ß-secretase (BACE), to investigate mechanisms of APP.C99 pathogenesis. Key findings are validated in mammalian cell culture models, mouse 5xFAD model, and postmortem AD patient brain materials. We find that ribosomes stall at the ER membrane during co-translational translocation of APP.C99, activating ribosome-associated quality control (RQC) to resolve ribosome collision and stalled translation. Stalled APP.C99 species with C-terminal extensions (CAT-tails) resulting from inadequate RQC are prone to aggregation, causing endolysosomal and autophagy defects and seeding the aggregation of amyloid ß peptides, the main component of amyloid plaques. Genetically removing stalled and CAT-tailed APP.C99 rescued proteostasis failure, endolysosomal/autophagy dysfunction, neuromuscular degeneration, and cognitive deficits in AD models. Our finding of RQC factor deposition at the core of amyloid plaques from AD brains further supports the central role of defective RQC of ribosome collision and stalled translation in AD pathogenesis. These findings demonstrate that amyloid plaque formation is the consequence and manifestation of a deeper level proteostasis failure caused by inadequate RQC of translational stalling and the resultant aberrantly modified APP.C99 species, previously unrecognized etiological drivers of AD and newly discovered therapeutic targets.

A Mobile-Based Intervention for Dietary Behavior and Physical Activity Change in Individuals at High Risk for Type 2 Diabetes Mellitus: Randomized Controlled Trial.

BACKGROUND: Intensive lifestyle modifications have proved effective in preventing type 2 diabetes mellitus (T2DM), yet the efficiency and effectiveness of these modifications need to be improved. Emerging social media interventions are considered useful in promoting these lifestyles; nevertheless, few studies have investigated the effectiveness of combining them with behavior theory. OBJECTIVE: This study aims to examine the effectiveness of a 6-month mobile-based intervention (DHealthBar, a WeChat applet) combined with behavioral theory compared with a printed intervention in improving dietary behaviors, physical activity, and intention to change these behaviors among populations at high risk for T2DM. METHODS: Participants aged 23 to 67 years were recruited offline in Beijing, China, and were randomized into the intervention group or the control group, which received educational content via DHealthBar or a printed handbook, respectively. Educational materials were culturally tailored recommendations on improving dietary behaviors, physical activity, and intention to change based on the transtheoretical model. Participants in the intervention arm received push notifications twice per week on WeChat and had access to the educational content for the 6-month study period. Participants in the control arm received the same intervention content through printed materials. The outcomes of participants' behavior change, intention to change behavior, and anthropometric characteristics were collected via online measuring tools at baseline, 3 months, and 6 months. RESULTS: In this study, 79 enrolled individuals completed baseline information collection (control: n=38 vs intervention: n=41), and 96% (76/79) completed the 6-month follow-up visit. Attrition rates did not differ significantly between the 2 groups (χ21=0.0, P=.61). Baseline equivalence was found. Participants in both groups reported a statistically significant decrease in energy intake at the 2 follow-up assessments compared with baseline (3 months, control: exp[ß]=0.83, 95% CI 0.74-0.92 vs intervention: exp[ß]=0.76, 95% CI 0.68-0.85; 6 months, control: exp[ß]=0.87, 95% CI 0.78-0.96 vs intervention: exp[ß]=0.57, 95% CI 0.51-0.64). At 6 months, a significantly larger decrease was observed in the intervention group in energy, fat, and carbohydrate intake, accompanied with a significantly larger increase in moderate-intensity physical activity compared with the control group (energy: exp[ß]=0.66, 95% CI 0.56-0.77; fat: exp[ß]=0.71, 95% CI 0.54-0.95; carbohydrates: exp[ß]=0.83, 95% CI 0.66-1.03; moderate-intensity physical activity: exp[ß]=2.05, 95% CI 1.23-3.44). After 6 months of the intervention, participants in the intervention group were more likely to be at higher stages of dietary behaviors (exp[ß]=26.80, 95% CI 3.51-204.91) and physical activity (exp[ß]=15.60, 95% CI 2.67-91.04) than the control group. CONCLUSIONS: DHealthBar was initially effective in improving dietary behavior, physical activity, and intention to change these behaviors among populations who were at high risk of developing T2DM, with significant differences in the changes of outcomes over the 6-month intervention period. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000032323; https://tinyurl.com/y4h8q4uf.

DRAM1 plays a tumor suppressor role in NSCLC cells by promoting lysosomal degradation of EGFR.

Lung cancer is the leading cause of cancer-associated mortality worldwide. DNA damage-regulated autophagy modulator 1 (DRAM1) plays an important roles in autophagy and tumor progression. However, the mechanisms by which DRAM1 inhibits tumor growth are not fully understood. Here, we report that DRAM1 was decreased in nonsmall-cell lung carcinoma (NSCLC) and was associated with poor prognosis. We confirmed that DRAM1 inhibited the growth, migration, and invasion of NSCLC cells in vitro. Furthermore, overexpression of DRAM1 suppressed xenografted NSCLC tumors in vivo. DRAM1 increased EGFR endocytosis and lysosomal degradation, downregulating EGFR signaling pathway. On one side, DRAM1 interacted with EPS15 to promote EGFR endocytosis, as evidence by the results of proximity labeling followed by proteomics; on the other, DRAM1 recruited V-ATP6V1 subunit to lysosomes, thereby increasing the assemble of the V-ATPase complex, resulting in decreased lysosomal pH and increased activation of lysosomal proteases. These two actions of DRAM1 results in acceleration of EGFR degradation. In summary, these in vitro and in vivo studies uncover a novel mechanism through which DRAM1 suppresses oncogenic properties of NSCLC by regulating EGFR trafficking and degradation and highlights the potential value of DRAM1 as a prognostic biomarker in lung cancers.

Traditional Chinese medicine (Liang-Xue-Di-Huang Decoction) for hemorrhoid hemorrhage: Study Protocol Clinical Trial (SPIRIT Compliant).

BACKGROUND: Hemorrhoidal disease (HD) is one of the commonest proctologic condition in the general population. Medical therapy for HD has not been formally confirmed due to the inconsistent of results. Liang-Xue-Di-Huang Decoction, a kind of ancient Chinese classical prescription, has been used to treat HD from the 19th century in China. However, clinical research of Liang-Xue-Di-Huang Decoction in the treatment of HD was lack. We designed this study to evaluate the efficacy and safety of Liang-Xue-Di-Huang Decoction in the treatment of HD. METHODS/DESIGN: A randomized, controlled, double blind, double-mimetic agent, and multicenter trial to evaluate the efficacy and safety of Liang-Xue-Di-Huang Decoction is proposed. HD patients (stage I, II, III) will be randomly assigned into experimental group or control group. HD patients will receive a 7-day treatments and a 7-day follow-up. The primary outcome measure is the Hemorrhoid Bleeding Score in 7 and 14 days. The Secondary outcome measures are Goligher prolapse score and quality-of-life score in 7 and 14 days. DISCUSSION: This study will provide objective evidences to evaluate the efficacy and safety of Liang-Xue-Di-Huang Decoction in treatment of HD.