MGST3 regulates BACE1 protein translation and amyloidogenesis by controlling the RGS4-mediated AKT signaling pathway.

Microsomal glutathione transferase 3 (MGST3) regulates eicosanoid and glutathione metabolism. These processes are associated with oxidative stress and apoptosis, suggesting that MGST3 might play a role in the pathophysiology of Alzheimer's disease. Here, we report that knockdown (KD) of MGST3 in cell lines reduced the protein level of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the resulting amyloidogenesis. Interestingly, MGST3 KD did not alter intracellular reactive oxygen species level but selectively reduced the expression of apoptosis indicators which could be associated with the receptor of cysteinyl leukotrienes, the downstream metabolites of MGST3 in arachidonic acid pathway. We then showed that the effect of MGST3 on BACE1 was independent of cysteinyl leukotrienes but involved a translational mechanism. Further RNA-seq analysis identified that regulator of G-protein signaling 4 (RGS4) was a target gene of MGST3. Silencing of RGS4 inhibited BACE1 translation and prevented MGST3 KD-mediated reduction of BACE1. The potential mechanism was related to AKT activity, as the protein level of phosphorylated AKT was significantly reduced by silencing of MGST3 and RGS4, and the AKT inhibitor abolished the effect of MGST3/RGS4 on phosphorylated AKT and BACE1. Together, MGST3 regulated amyloidogenesis by controlling BACE1 protein expression, which was mediated by RGS4 and downstream AKT signaling pathway.

Arabidopsis synaptotagmin 1 mediates lipid transport in a lipid composition-dependent manner.

The endoplasmic reticulum (ER)-plasma membrane (PM) contact sites (EPCSs) are structurally conserved in eukaryotes. The Arabidopsis ER-anchored synaptotagmin 1 (SYT1), enriched in EPCSs, plays a critical role in plant abiotic stress tolerance. It has become clear that SYT1 interacts with PM to mediate ER-PM connectivity. However, whether SYT1 performs additional functions at EPCSs remains unknown. Here, we report that SYT1 efficiently transfers phospholipids between membranes. The lipid transfer activity of SYT1 is highly dependent on phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2 ], a signal lipid accumulated at the PM under abiotic stress. Mechanically, while SYT1 transfers lipids fundamentally through the synaptotagmin-like mitochondrial-lipid-binding protein (SMP) domain, the efficient lipid transport requires the C2A domain-mediated membrane tethering. Interestingly, we observed that Ca2+ could stimulate SYT1-mediated lipid transport. In addition to PI(4,5)P2 , the Ca2+ activation requires the phosphatidylserine, another negatively charged lipid on the opposed membrane. Together, our studies identified Arabidopsis SYT1 as a lipid transfer protein at EPCSs and demonstrated that it takes conserved as well as divergent mechanisms with other extend-synaptotagmins. The critical role of lipid composition and Ca2+ reveals that SYT1-mediated lipid transport is highly regulated by signals in response to abiotic stresses.

Enhanced silicate weathering accelerates forest carbon sequestration by stimulating the soil mineral carbon pump.

Enhanced silicate rock weathering (ERW) is an emerging strategy for carbon dioxide removal (CDR) from the atmosphere to mitigate anthropogenic climate change. ERW aims at promoting soil inorganic carbon sequestration by accelerating geochemical weathering processes. Theoretically, ERW may also impact soil organic carbon (SOC), the largest carbon pool in terrestrial ecosystems, but experimental evidence for this is largely lacking. Here, we conducted a 2-year field experiment in tropical rubber plantations in the southeast of China to evaluate the effects of wollastonite powder additions (0, 0.25, and 0.5 kg m-2) on both soil organic and inorganic carbon at 0-10 cm depth. We found that ERW significantly increased the concentration of SOC and HCO3 -, but the increases in SOC were four and eight times higher than that of HCO3 - with low- and high-level wollastonite applications. ERW had positive effects on the accrual of organic carbon in mineral-associated organic matter (MAOM) and macroaggregate fractions, but not on particulate organic matter. Path analysis suggested that ERW increased MAOM mainly by increasing the release of Ca, Si, and Fe, and to a lesser extent by stimulating root growth and microbial-derived carbon inputs. Our study indicates that ERW with wollastonite can promote SOC sequestration in stable MOAM in surface soils through both the soil mineral carbon pump and microbial carbon pump. These effects may have been larger than the inorganic CDR during our experiment. We argue it is essential to account for the responses of SOC in the assessments of CDR by ERW.

Enhanced rock weathering increased soil phosphorus availability and altered root phosphorus-acquisition strategies.

Enhanced rock weathering (ERW) has been proposed as a measure to enhance the carbon (C)-sequestration potential and fertility of soils. The effects of this practice on the soil phosphorus (P) pools and the general mechanisms affecting microbial P cycling, as well as plant P uptake are not well understood. Here, the impact of ERW on soil P availability and microbial P cycling functional groups and root P-acquisition traits were explored through a 2-year wollastonite field addition experiment in a tropical rubber plantation. The results show that ERW significantly increased soil microbial carbon-use efficiency and total P concentrations and indirectly increased soil P availability by enhancing organic P mobilization and mineralization of rhizosheath carboxylates and phosphatase, respectively. Also, ERW stimulated the activities of P-solubilizing (gcd, ppa and ppx) and mineralizing enzymes (phoADN and phnAPHLFXIM), thus contributing to the inorganic P solubilization and organic P mineralization. Accompanying the increase in soil P availability, the P-acquisition strategy of the rubber fine roots changed from do-it-yourself acquisition by roots to dependence on mycorrhizal collaboration and the release of root exudates. In addition, the direct effects of ERW on root P-acquisition traits (such as root diameter, specific root length, and mycorrhizal colonization rate) may also be related to changes in the pattern of belowground carbon investments in plants. Our study provides a new insight that ERW increases carbon-sequestration potential and P availability in tropical forests and profoundly affects belowground plant resource-use strategies.

Short-term regulation of TSFM level does not alter amyloidogenesis and mitochondrial function in type-specific cells.

BACKGROUND: Mitochondrial Ts translation elongation factor (TSFM) is an enzyme that catalyzes exchange of guanine nucleotides. By forming a complex with mitochondrial Tu translation elongation factor (TUFM), TSFM participates in mitochondrial protein translation. We have previously reported that TUFM regulates translation of beta-site APP cleaving enzyme 1 (BACE1) via ROS (reactive oxygen species)-dependent mechanism, suggesting a potential role in amyloid precursor protein (APP) processing associated with Alzheimer's disease (AD), which led to the speculation that TSFM may regulate APP processing in a similar way to TUFM. METHODS AND RESULTS: Here, we report that in cultured cells, knockdown or overexpression TSFM did not change protein levels in BACE1 and APP. Besides, the levels of cytoplasmic ROS and mitochondrial superoxide, in addition to ATP level, cell viability and mitochondrial membrane potential were not significantly altered by TSFM knockdown in the short term. Further transcriptome analysis revealed that expression of majority of mitochondrial genes were not remarkably changed by TSFM silencing. The possibility of TSFM involved in cardiomyopathy and cancer development was uncovered using bioinformatics analysis. CONCLUSIONS: Collectively, short-term regulation of TSFM level in cultured cells does not cause a significant change in proteins involved in APP processing, levels in ROS and ATP associated with mitochondrial function. Whereas our study could contribute to comprehend certain clinical features of TSFM mutations, the roles of TSFM in cardiomyopathy and cancer development might deserve further investigation.

Preparation, characterisation, and pharmacodynamic study of myricetin pH-sensitive liposomes.

AIMS: Myricetin (MYR) was incorporated into pH-sensitive liposomes in order to improve its bioavailability and anti-hyperuricemic activity. METHODS: The MYR pH-sensitive liposomes (MYR liposomes) were prepared using thin film dispersion method, and assessed by particle size (PS), polydispersed index (PDI), zeta potential (ZP), encapsulation efficiency, drug loading, and in vitro release rate. Pharmacokinetics and anti-hyperuricemic activities were also evaluated. RESULTS: The PS, PDI, ZP, encapsulation efficiency, and drug loading of MYR liposomes were 184.34 ± 1.05 nm, 0.215 ± 0.005, -38.46 ± 0.30 mV, 83.42 ± 1.07%w/w, and 6.20 ± 0.31%w/w, respectively. The release rate of MYR liposomes was higher than free MYR, wherein the cumulative value responded to pH. Besides, the Cmax of MYR liposomes was 4.92 ± 0.20 µg/mL. The level of uric acid in the M-L-H group (200 mg/kg) was reduced by 54.74%w/v in comparison with the model group. CONCLUSION: MYR liposomes exhibited pH sensitivity and could potentially enhance the oral bioavailability and anti-hyperuricemic efficacy of MYR.

The Surfactant Role on a Droplet Passing through a Constricted Microchannel in a Pressure-Driven Flow: A Lattice Boltzmann Study.

The role of surfactants in the flow of a droplet driven by a pressure gradient through a constricted microchannel is simulated by using our recently developed lattice Boltzmann method. We first study the surfactant role on a droplet flowing through a microchannel with a shrunken square section under different surfactant concentrations and capillary numbers (i.e., imposed pressure gradients). As the surfactant concentration increases, the droplet flow regime first changes from the flow regime I of the droplet getting stuck at the entrance of the constricted channel to the flow regime II of the droplet flowing through the constricted channel with breakup, and then to the flow regime III of the droplet flowing through the constricted channel without breakup. As the capillary number increases, the surfactant role on the number of mother droplets breaking up and the time of mother droplets completely flowing through the constricted section tend to decrease, suggesting that the surfactant effects are gradually weakened. Then, a phase diagram describing how the surfactant concentration and capillary number affect the droplet flow regime is presented. As the surfactant concentration increases, the critical capillary number that distinguishes droplet flow regimes I from II gradually decreases, while the critical capillary number that distinguishes droplet flow regimes II from III first increases and then decreases.

A case report of a brain abscess due to prevotella oris and a review of the literature.

BACKGROUND: Brain abscesses caused by Prevotella oris are rarely reported. Here, we described a case of a brain infection caused by Prevotella oris that was detected by metagenomic next-generation sequencing (mNGS). CASE PRESENTATION: A 63-year-old man with no medical history reported headache in the right frontotemporal region, fever, and intermittent diplopia. Magnetic resonance imaging (MRI) revealed abnormal signals and enhancement changes in the superior sellar region. mNGS testing showed that cerebrospinal fluid collected from the spine was positive for Prevotella oris. After receiving a combined treatment of antibiotic therapy, the patient recovered well. CONCLUSION: We reviewed the relevant literature and summarized the characteristics and prognosis of this type of bacterial infection to provide ideas for clinicians to diagnose and treat this disease.

Low-cost and flexible paper-based plasmonic nanostructure for a highly sensitive SERS substrate.

The application of a noble-metal-based plasmon-enhanced substrate to detect low-concentration analytes has attracted extensive attention. Most of the substrates used in recently reported researches are based on two-dimensional structures. Hence, we prepared a higher efficiency Raman activity substrate with a filter paper structure, which not only provides more plasmonic "hot spots," but also facilitates analyte extraction and detection due to the flexibility of the paper. The preparation of the plasmonic paper substrate adopted centrifugation to deposit the alloy nanoparticles onto the paper base. The optimal particle deposition condition was found by adjusting the centrifugal force and centrifugation time. Then, the surface-enhanced Raman spectroscopy (SERS) performance of the substrate was enhanced by altering the plasmon resonance peak on the surface of the nanoparticles. The enhancement factor of this paper-based substrate was 1.55×107, with high detection uniformity (10-6 M, rhodamine 6G) and a low detection limit (10-11 M, rhodamine 6G). Then, we applied the SERS substrate to pesticide detection; the detection limit of the thiram reached 10-6 M. As a result, the simple and cost-effective paper-based SERS substrate obtained in this way has high detection performance for pesticides and can be used for rapid detection in the field, which is beneficial to food safety and environmental safety.

Temperature Monitoring During Microwave Hyperthermia Based on BP-Nakagami Distribution.

OBJECTIVE: The purpose of this study is to accurately monitor temperature during microwave hyperthermia. We propose a temperature estimation model BP-Nakagami based on neural network for Nakagami distribution. METHODS: In this work, we designed the microwave hyperthermia experiment of fresh ex vivo pork tissue and phantom, collected ultrasonic backscatter data at different temperatures, modeled these data using Nakagami distribution, and calculated Nakagami distribution parameter m. A neural network model was built to train the relationship between Nakagami distribution parameter m and temperature, and a BP-Nakagami temperature model with good fitting was obtained. The temperature model is used to draw the two-dimensional temperature distribution map of biological tissues in microwave hyperthermia. Finally, the temperature estimated by the model is compared with the temperature measured by thermocouples. RESULTS: The error between the temperature estimated by the temperature model and the temperature measured by the thermocouple is within 1°C in the range of 25°C-50°C for ex vivo pork tissue, and the error between the temperature estimated by the temperature model and the temperature measured by the thermocouple is within 0.5°C in the range of 25°C-50°C for phantom. CONCLUSIONS: The results show that the temperature estimation model proposed by us is an effective model for monitoring the internal temperature change of biological tissues.

Analysis of VOC emissions and O3 control strategies in the Fenhe Plain cities, China.

Long-term continuous hourly measurements of ambient volatile organic compounds (VOCs) are scarce at the regional scale. In this study, a one-year hourly measurement campaign of VOCs was performed in Lvliang, Linfen, and Yuncheng in the heavily polluted Fenhe Plain region in China. The VOC average (±standard deviation, std) concentrations in Lvliang, Linfen, and Yuncheng were 44.4 ± 24.9, 45.7 ± 24.9, and 37.5 ± 25.0 ppbv, respectively. Compared to published data from the past two decades in China, the observed VOCs were at high concentration levels. VOCs in the Fenhe Plain cities were significantly impacted by industrial sources according to calculated emission ratios but were less affected by liquefied petroleum gas and natural gas (LPG/NG) and traffic emissions than those in megacities abroad. The emission inventories and observation data were combined for verification and identification of the key VOC species and sources controlling ozone (O3). Industrial emissions were the largest source of VOCs, accounting for 65%-79% of the total VOC emissions, while the coking industry accounted for 45.2%-66.0%. The emission inventories significantly underestimated oxygenated VOC (OVOC) emissions through the verification of VOC emission ratios. O3 control scenarios were analyzed by changing VOC/NOX reduction ratios through a photochemical box model. O3 control strategies were formulated considering local pollution control plans, emission inventories, and O3 formation regimes. The O3 reduction of reactivity-control measures was comparable with emission-control measures, ranging from 16% to 41%, which was contrary to the general perception that ozone formation potential (OFP)-based measures were more efficient for O3 reduction. Sources with high VOC emissions are accompanied by high OFP on the Fenhe Plain, indicating that the control of high-emission sources can effectively mitigate O3 pollution on this region.

Characteristics and source apportionment of PM2.5 under the dual influence of the Spring Festival and the COVID-19 pandemic in Yuncheng city.

Based on the online and membrane sampling data of Yuncheng from January 1st to February 12th, 2020, the formation mechanism of haze under the dual influence of Spring Festival and COVID-19 (Corona Virus Disease) was analyzed. Atmospheric capacity, chemical composition, secondary transformation, source apportionment, backward trajectory, pollution space and enterprise distribution were studied. Low wind speed, high humidity and small atmospheric capacity inhibited the diffusion of air pollutants. Four severe pollution processes occurred during the period, and the pollution degree was the highest around the Spring Festival. In light, medium and heavy pollution periods, the proportion of SNA (SO42-, NO3- and NH4+) was 59.6%, 56.0% and 54.9%, respectively, which was the largest components of PM2.5; the [NO3-]/[SO42-] ratio was 2.1, 1.5 and 1.7, respectively, indicating that coal source had a great influence; the changes of NOR (nitrogen oxidation ratio, 0.44, 0.45, 0.61) and SOR (sulphur oxidation ratio, 0.40, 0.49, 0.65) indicated the accumulation of secondary aerosols with increasing pollution. The coal combustion, motor vehicle, secondary inorganic sources and industrial sources contributed 36.8%, 26.59%, 11.84% and 8.02% to PM2.5 masses, respectively. Backward trajectory showed that the influence from the east was greater during the Spring Festival, and the pollutants from the eastern air mass were higher, which would aggravate the pollution. Meteorological and Spring Festival had a great impact on heavy pollution weather. Although some work could not operate due to the impact of the COVID-19 epidemic, the emission of pollutants did not reduce much.

Environment and COVID-19 incidence: A critical review.

The coronavirus disease 2019 (COVID-19) pandemic is an unprecedented worldwide health crisis. Many previous research studies have found and investigated its links with one or some natural or human environmental factors. However, a review on the relationship between COVID-19 incidence and both the natural and human environment is still lacking. This review summarizes the inter-correlation between COVID-19 incidence and environmental factors. Based on keyword searching, we reviewed 100 relevant peer-reviewed articles and other research literature published since January 2020. This review is focused on three main findings. One, we found that individual environmental factors have impacts on COVID-19 incidence, but with spatial heterogeneity and uncertainty. Two, environmental factors exert interactive effects on COVID-19 incidence. In particular, the interactions of natural factors can affect COVID-19 transmission in micro- and macro- ways by impacting SARS-CoV-2 survival, as well as human mobility and behaviors. Three, the impact of COVID-19 incidence on the environment lies in the fact that COVID-19-induced lockdowns caused air quality improvement, wildlife shifts and socio-economic depression. The additional value of this review is that we recommend future research perspectives and adaptation strategies regarding the interactions of the environment and COVID-19. Future research should be extended to cover both the effects of the environment on the COVID-19 pandemic and COVID-19-induced impacts on the environment. Future adaptation strategies should focus on sustainable environmental and public policy responses.

Enhanced secondary organic aerosol formation during dust episodes by photochemical reactions in the winter in Wuhan.

To investigate the effect of frequently occurring mineral dust on the formation of secondary organic aerosol (SOA), 106 volatile organic compounds (VOCs), trace gas pollutants and chemical components of PM2.5 were measured continuously in January 2021 in Wuhan, Central China. The observation period was divided into two stages that included a haze period and a following dust period, based on the ratio of PM2.5 and PM10 concentrations. The average ratio of secondary organic carbon (SOC) to elemental carbon (EC) was 1.98 during the dust period, which was higher than that during the haze period (0.69). The contribution of SOA to PM2.5 also increased from 2.75% to 8.64%. The analysis of the relationships between the SOA and relative humidity (RH) and the odd oxygen (e.g., OX = O3 + NO2) levels suggested that photochemical reactions played a more important role in the enhancement of SOA production during the dust period than the aqueous-phase reactions. The heterogeneous photochemical production of OH radicals in the presence of metal oxides during the dust period was believed to be enhanced. Meanwhile, the ratios of trans-2-butene to cis-2-butene and m-/p-xylene to ethylbenzene (X/E) dropped significantly, confirming that stronger photochemical reactions occurred and SOA precursors formed efficiently. These results verified the laboratory findings that metal oxides in mineral dust could catalyse the oxidation of VOCs and induce higher SOA production.

Calcium-dependent and -independent lipid transfer mediated by tricalbins in yeast.

Membrane contact sites (MCSs) formed between the endoplasmic reticulum (ER) and the plasma membrane (PM) provide a platform for nonvesicular lipid exchange. The ER-anchored tricalbins (Tcb1, Tcb2, and Tcb3) are critical tethering factors at ER-PM MCSs in yeast. Tricalbins possess a synaptotagmin-like mitochondrial-lipid-binding protein (SMP) domain and multiple Ca2+-binding C2 domains. Although tricalbins have been suggested to be involved in lipid exchange at the ER-PM MCSs, it remains unclear whether they directly mediate lipid transport. Here, using in vitro lipid transfer assays, we discovered that tricalbins are capable of transferring phospholipids between membranes. Unexpectedly, while its lipid transfer activity was markedly elevated by Ca2+, Tcb3 constitutively transferred lipids even in the absence of Ca2+. The stimulatory activity of Ca2+ on Tcb3 required intact Ca2+-binding sites on both the C2C and C2D domains of Tcb3, while Ca2+-independent lipid transport was mediated by the SMP domain that transferred lipids via direct interactions with phosphatidylserine and other negatively charged lipid molecules. These findings establish tricalbins as lipid transfer proteins, and reveal Ca2+-dependent and -independent lipid transfer activities mediated by these tricalbins, providing new insights into their mechanism in maintaining PM integrity at ER-PM MCSs.

Low-cost micro-spectrometer based on a nano-imprint and spectral-feature reconstruction algorithm.

Reconstructive micro-spectrometers have shown great potential in many fields such as medicine, agriculture, and astronomy. However, the performance of these spectrometers is seriously limited by the spectral varieties of response pixels and anti-noise ability of reconstruction algorithms. In this work, we propose a spectral reconstruction (SR) algorithm, whose anti-noise ability is at least four times better than the current algorithms. A micro-spectrometer is realized by fabricating a large number of Fabry-Perot (FP) micro-filters onto a cheap complementary metal-oxide semiconductor (CMOS) chip for demonstration by using a very high-efficiency technology of nano-imprinting. Nano-imprint technology can complete hundreds of spectral pixels with rich spectral features at one time and with low cost. In cooperation with the SR algorithm, such a micro-spectrometer can have a spectral resolution as high as 3 nm with much lower angular sensitivity than a photonic crystal-based micro-spectrometer. It can obtain the target's spectrum from only a single shot, which has wide applications in spectral analysis etc.

Depression and memory function - evidence from cross-lagged panel models with unit fixed effects in ELSA and HRS.

BACKGROUND: Individuals with depression are often found to perform worse on cognitive tests and to have an increased risk of dementia. The causes and the direction of these associations are however not well understood. We looked at two specific hypotheses, the aetiological risk factor hypothesis and the reverse causality hypothesis. METHOD: We analysed observational data from two cohorts, English Longitudinal Study of Ageing (ELSA) and Health and Retirement Study (HRS), using cross-lagged panel models with unit fixed effects. Each model was run once with depression and repeated with cognition as the dependent variable and the other variable as the main explanatory variable. All models were estimated separately for contemporaneous effects and lagged effects up to 8 years in the past. We contrasted the results with models making the random effects assumption. RESULTS: Evidence from the fixed effects models is mixed. We find no evidence for the reverse causality hypothesis in ELSA and HRS. While there is no evidence for the aetiological risk factors hypothesis in ELSA, results from HRS indicate some effects. CONCLUSION: Our findings suggest that current levels of cognitive function do not influence future levels of depression. Results in HRS provide some evidence that current levels of depressive symptoms influence future cognition.

Alcohol affordability: implications for alcohol price policies. A cross-sectional analysis in middle and older adults from UK Biobank.

BACKGROUND: Increasing the price of alcohol reduces alcohol consumption and harm. The role of food complementarity, transaction costs and inflation on alcohol demand are determined and discussed in relation to alcohol price policies. METHODS: UK Biobank (N = 502,628) was linked by region to retail price quotes for the years 2007 to 2010. The log residual food and alcohol prices, and alcohol availability were regressed onto log daily alcohol consumption. Model standard errors were adjusted for clustering by region. RESULTS: Associations with alcohol consumption were found for alcohol price (ß = -0.56, 95% CI, -0.92 to -0.20) and availability (ß = 0.06, 95% CI, 0.04 to 0.07). Introducing, food price reduced the alcohol price consumption association (ß = -0.26, 95% CI, -0.50 to -0.03). Alcohol (B = 0.001, 95% CI, 0.0004 to 0.001) and food (B = 0.001, 95% CI, 0.0005 to 0.0006) price increased with time and were associated (ρ = 0.57, P < 0.001). CONCLUSION: Alcohol and food are complements, and the price elasticity of alcohol reduces when the effect of food price is accounted for. Transaction costs did not affect the alcohol price consumption relationship. Fixed alcohol price policies are susceptible to inflation.

Associations of perceived adverse lifetime experiences with brain structure in UK Biobank participants.

BACKGROUND: Adversity experiences (AEs) are major risk factors for psychiatric illness, and ample evidence suggests that adversity-related changes in brain structure enhance this vulnerability. To achieve greater understanding of the underlying biological pathways, increased convergence among findings is needed. Suggested future directions may benefit from the use of large population samples which may contribute to achieving this goal. We addressed mechanistic pathways by investigating the associations between multiple brain phenotypes and retrospectively reported AEs in early life (child adversity) and adulthood (partner abuse) in a large population sample, using a cross-sectional approach. METHODS: The UK Biobank resource was used to access imaging-derived phenotypes (IDPs) from 6,751 participants (aged: M = 62.1, SD = 7.2, range = 45-80), together with selected reports of childhood AEs and adult partner abuse. Principal component analysis was used to reduce the dimensionality of the data prior to multivariate tests. RESULTS: The data showed that participants who reported experiences of childhood emotional abuse ('felt hated by family member as a child') had smaller cerebellar and ventral striatum volumes. This result was also depicted in a random subset of participants; however, we note small effect sizes ( ηp2  < .01), suggestive of modest biological changes. CONCLUSIONS: Using a large population cohort, this study demonstrates the value of big datasets in the study of adversity and using automatically preprocessed neuroimaging phenotypes. While retrospective and cross-sectional characteristics limit interpretation, this study demonstrates that self-perceived adversity reports, however nonspecific, may still expose neural consequences, identifiable with increased statistical power.

Prognostic characterization of immune molecular subtypes in non-small cell lung cancer to immunotherapy.

BACKGROUND: Non-small cell lung cancer (NSCLC) was usually associated with poor prognosis and invalid therapeutical response to immunotherapy due to biological heterogeneity. It is urgent to screen reliable biomarkers, especially immunotherapy-associated biomarkers, that can predict outcomes of these patients. METHODS: Gene expression profiles of 1026 NSCLC patients were collected from The Cancer Genome Atlas (TCGA) datasets with their corresponding clinical and somatic mutation data. Based on immune infiltration scores, molecular clustering classification was performed to identify immune subtypes in NSCLC. After the functional enrichment analysis of subtypes, hub genes were further screened using univariate Cox, Lasso, and multivariate Cox regression analysis, and the risk score was defined to construct the prognostic model. Other microarray data and corresponding clinical information of 603 NSCLC patients from the GEO datasets were applied to conduct random forest models for the prognosis of NSCLC with 100 runs of cross-validation. Finally, external datasets with immunotherapy and chemotherapy were further applied to explore the significance of risk-scores in clinical immunotherapy response for NSCLC patients. RESULTS: Compared with Subtype-B, the Subtype-A, associated with better outcomes, was characterized by significantly higher stromal and immune scores, T lymphocytes infiltration scores and up-regulation of immunotherapy markers. In addition, we found and validated an eleven -gene signatures for better application of distinguishing high- and low-risk NSCLC patients and predict patients' prognosis and therapeutical response to immunotherapy. Furthermore, combined with other clinical characteristics based on multivariate Cox regression analysis, we successfully constructed and validated a nomogram to effectively predict the survival rate of NSCLC patients. External immunotherapy and chemotherapy cohorts validated the patients with higher risk-scores exhibited significant therapeutic response and clinical benefits. CONCLUSION: These results demonstrated the immunological and prognostic heterogeneity within NSCLC and provided a new clinical application in predicting the prognosis and benefits of immunotherapy for the disease.