Functional Variation Research Articles

Association of Chromosome 17 Aneuploidy, TP53 Deletion, Expression and Its rs1042522 Variant with Multiple Myeloma Risk and Response to Thalidomide/Bortezomib Treatment.

Multiple myeloma (MM) is a multifactorial genetic disorder caused by interactive effects of environmental and genetic factors. The proper locus of the TP53 gene (17p13.1) and its protein is essential in genomic stability. The most common variant of the TP53 gene-p.P72R (rs1042522)-shows functional variation. The aim of our study was a complex analysis of the TP53 p.P72R variant and TP53 gene expression in relation to chromosomal changes of the TP53 gene locus, as well as MM risk and outcome. Genomic DNA from 129 newly diagnosed MM patients was analyzed by methods of automated DNA sequencing (for TP53 variant analysis) and cIg-FISH (for chromosomal aberrations analysis). RNA was used in real-time PCR to determine the TP53 expression. In MM patients, the TP53 variant was not in Hardy-Weinberg equilibrium. The RR genotype was associated with lower MM risk (OR = 0.44, p = 0.004). A higher number of plasma cells was found in patients with RR genotype in comparison to those with PP + PR genotypes (36.74% vs. 28.30%, p = 0.02). A higher expression of the TP53 gene was observed in PP + PR genotypes vs. RR homozygote (p < 0.001), in smokers vs. non-smokers (p = 0.02). A positive Pearson's correlation was found between the TP53 expression level and the number of plasma cells (r = 0.26, p = 0.04). The presence of chromosome 17 aberrations with or without TP53 locus did not affect the MM risk and outcome. Similar results were observed in the case of TP53 gene expression and the p.P72R variant.

PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants

Pathogenic variants of phospholipase C gamma 2 (PLCG2) cause 2 related forms of autosomal-dominant immune dysregulation (ID), PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammatory PLAID (APLAID). Since describing these conditions, many PLCG2 variants of uncertain significance have been identified by clinical sequencing of patients with diverse features of ID. We sought to functionally classify PLCG2 variants and explore known and novel genotype-function-phenotype relationships. Clinical data from patients with PLCG2 variants were obtained via standardized questionnaire. PLCG2 variants were generated by mutagenesis of enhanced green fluorescent protein (EGFP)-PLCG2 plasmid, which was overexpressed in Plcg2-deficient DT-40 B cells. B-cell receptor-induced calcium flux and extracellular signal-regulated kinase phosphorylation were assayed by flow cytometry. In some cases, stimulation-induced calcium flux was also measured in primary patient cells. Three-fourths of PLCG2 variants produced functional alteration of B-cell activation, invitro. Thirteen variants led to gain of function (GOF); however, most functional variants defined a new class of PLCG2 mutation, monoallelic loss of function (LOF). Susceptibility to infection and autoinflammation were common with both GOF and LOF variants, whereas a new phenotypic cluster consisting of humoral immune deficiency, autoinflammation, susceptibility to herpesvirus infection, and natural killer cell dysfunction was observed in association with multiple heterozygous LOF variants detected in both familial and sporadic cases. In some cases, PLCG2 variants produced greater effects in natural killer cells than in B cells. This work expands the genotypic and phenotypic associations with functional variation in PLCG2, including a novel form of ID in carriers of heterozygous loss of PLCG2 function. It also demonstrates the need for more diverse assays for assessing the impact of PLCG2 variants on human disease.

A comparative study on digestion and SEM based topological behaviour of six native starches hydrolysed using porcine pancreatic enzymes

The variation in structure and function of any biomolecule plays a vital role as far as the digestibility, absorption and other metabolic regulations are concerned. The amorphous to crystalline arrangement of any starchy granule reflects the polymorphic type and so-forth determines the digestion pattern as rapid, slow or resistant. The granule morphology in its native form and its ultrastructural arrangement are also crucial factors in determining the digestion behaviour of any native starch granule. The present study depicted that the digestion profile of any starchy granule is not only dictated by the compositional variation of amylose to amylopectin ratio but also the thickness of the granule layer. Although the native starch of banana and potato resisted digestion by porcine pancreatic enzymes due to the presence of thick granule layer, but the thin granule layer of taro, cassava, rice and maize starch were not able to resist the action of hydrolytic enzymes.

Global well-posedness of the 1d compressible Navier–Stokes system with rough data

In this paper, we study the global well-posedness problem for the 1d compressible Navier–Stokes systems (cNSE) in gas dynamics with rough initial data. First, Liu and Yu (2022) [30] established the global well-posedness theory for the 1d isentropic cNSE with initial velocity data in BV space. Then, it was extended to the 1d full cNSE with initial velocity and temperature data in BV space by Wang et al. (2022) [31]. We improve the global well-posedness result of Liu and Yu with initial velocity data in W2γ,1 space; and of Wang–Yu–Zhang with initial velocity data in L2∩W2γ,1 space and initial data of temperature in W˙−23,65∩W˙2γ−1,1 for any γ>0arbitrarily small. Our essential ideas are based on establishing various “end-point” smoothing estimates for the 1d parabolic equation.

Functional Variation in the FAAH Gene Is Directly Associated with Subjective Well-Being and Indirectly Associated with Problematic Alcohol Use.

Fatty acid amide hydrolase (FAAH) is an enzyme that degrades anandamide, an endocannabinoid that modulates mesolimbic dopamine release and, consequently, influences states of well-being. Despite these known interactions, the specific role of FAAH in subjective well-being remains underexplored. Since well-being is a dynamic trait that can fluctuate over time, we hypothesized that we could provide deeper insights into the link between FAAH and well-being using longitudinal data. To this end, we analyzed well-being data collected three years apart using the WHO (Ten) Well-Being Index and genotyped a functional polymorphism in the FAAH gene (rs324420, Pro129Thr) in a sample of 2822 individuals. We found that the A-allele of rs324420, which results in reduced FAAH activity and elevated anandamide levels, was associated with lower well-being scores at both time points (Wave I, B: -0.52, p = 0.007; Wave II, B: -0.41, p = 0.03, adjusted for age and sex). A subsequent phenome-wide association study (PheWAS) affirmed our well-being findings in the UK Biobank (N = 126,132, alternative C-allele associated with elevated happiness, p = 0.008) and revealed an additional association with alcohol dependence. In our cohort, using lagged longitudinal mediation analyses, we uncovered evidence of an indirect association between rs324420 and problematic alcohol use (AUDIT-P) through the pathway of lower well-being (indirect effect Boot: 0.015, 95% CI [0.003, 0.030], adjusted for AUDIT in Wave I). We propose that chronically elevated anandamide levels might influence disruptions in the endocannabinoid system-a biological contributor to well-being-which could, in turn, contribute to increased alcohol intake, though multiple factors may be at play. Further genetic studies and mediation analyses are needed to validate and extend these findings.

Gender and cytoarchitecture differences: Functional connectivity of the hippocampal sub-regions

IntroductionThe hippocampus plays a significant role in learning, memory encoding, and spatial navigation. Typically, the hippocampus is investigated as a whole region of interest. However, recent work has developed fully detailed atlases based on cytoarchitecture properties of brain regions, and the hippocampus has been sub-divided into seven sub-areas that have structural differences in terms of distinct numbers of cells, neurons, and other structural and chemical properties. Moreover, gender differences are of increasing concern in neuroscience research. Several neuroscience studies have found structural and functional variations between the brain regions of females and males, and the hippocampus is one of these regions. AimThe aim of this study to explore whether the cytoarchitecturally distinct sub-regions of the hippocampus have varying patterns of functional connectivity with different networks of the brain and how these functional connections differ in terms of gender differences. MethodThis study investigated 200 healthy participants using seed-based resting-state functional magnetic resonance imaging (rsfMRI). The primary aim of this study was to explore the resting connectivity and gender distinctions associated with specific sub-regions of the hippocampus and their relationship with major functional brain networks. ResultsThe findings revealed that the majority of the seven hippocampal sub-regions displayed functional connections with key brain networks, and distinct patterns of functional connectivity were observed between the hippocampal sub-regions and various functional networks within the brain. Notably, the default and visual networks exhibited the most consistent functional connections. Additionally, gender-based analysis highlighted evident functional resemblances and disparities, particularly concerning the anterior section of the hippocampus. ConclusionThis study highlighted the functional connectivity patterns and involvement of the hippocampal sub-regions in major brain functional networks, indicating that the hippocampus should be investigated as a region of multiple distinct functions and should always be examined as sub-regions of interest. The results also revealed clear gender differences in functional connectivity.

Variation in executive function relates to BMI increases in youth who were initially of a healthy weight in the ABCD Study.

The study aim was to determine whether (A) differences in executive function (EF) and cognition precede weight gain or (B) weight gain causes changes to EF and cognition. Data were gathered from the Adolescent Brain Cognitive Development (ABCD) Study (release 4.0; ages 9-12 years old [N = 2794]; 100% had healthy weight at baseline [i.e., 9/10 years old], 12.4% had unhealthy weight by ages 11/12 years). EF and cognition were assessed across several domains (e.g., impulsivity, inhibitory control, processing speed, memory); BMI was calculated from height and weight. Nested random-effects mixed models examined (A) BMI ~ EF × Time (i.e., variation in EF/cognition precedes weight gain) and (B) EF ~ BMI × Time (weight gain causes changes to EF/cognition) and controlled for sex, puberty, and caregiver education; random effects were site and subject. Variation in impulsivity, memory, learning, and processing speed was associated with greater increases in BMI trajectories from 9 to 12 years old. Weight gain was associated with a decrease in inhibitory control, but no other associations were observed. Underlying variation in EF and cognition may be important for weight gain, but 2 years of weight gain may not be enough to have clinical implications for EF and cognition beyond inhibitory control. These findings suggest that more attention should be paid to the inclusion of EF programs in obesity prevention efforts.

Within-individual leaf trait variation increases with phenotypic integration in a subtropical tree diversity experiment.

Covariation of plant functional traits, that is, phenotypic integration, might constrain their variability. This was observed for inter- and intraspecific variation, but there is no evidence of a relationship between phenotypic integration and the functional variation within single plants (within-individual trait variation; WTV), which could be key to understand the extent of WTV in contexts like plant-plant interactions. We studied the relationship between WTV and phenotypic integration in c. 500 trees of 21 species in planted forest patches varying in species richness in subtropical China. Using visible and near-infrared spectroscopy (Vis-NIRS), we measured nine leaf morphological and chemical traits. For each tree, we assessed metrics of single and multitrait variation to assess WTV, and we used plant trait network properties based on trait correlations to quantify phenotypic integration. Against expectations, strong phenotypic integration within a tree led to greater variation across leaves. Not only this was true for single traits, but also the dispersion in a tree's multitrait hypervolume was positively associated with tree's phenotypic integration. Surprisingly, we only detected weak influence of the surrounding tree-species diversity on these relationships. Our study suggests that integrated phenotypes allow the variability of leaf phenotypes within the organism and supports that phenotypic integration prevents maladaptive variation.

Bidirectional genetic overlap between autism spectrum disorder and cognitive traits

Autism spectrum disorder (ASD) is a highly heritable condition with a large variation in cognitive function. Here we investigated the shared genetic architecture between cognitive traits (intelligence (INT) and educational attainment (EDU)), and risk loci jointly associated with ASD and the cognitive traits. We analyzed data from genome-wide association studies (GWAS) of INT (n = 269,867), EDU (n = 766,345) and ASD (cases n = 18,381, controls n = 27,969). We used the bivariate causal mixture model (MiXeR) to estimate the total number of shared genetic variants, local analysis of co-variant annotation (LAVA) to estimate local genetic correlations, conditional false discovery rate (cond/conjFDR) to identify specific overlapping loci. The MiXeR analyses showed that 12.7k genetic variants are associated with ASD, of which 12.0k variants are shared with EDU, and 11.1k are shared with INT with both positive and negative relationships within overlapping variants. The majority (59–68%) of estimated shared loci have concordant effect directions, with a positive, albeit modest, genetic correlation between ASD and EDU (rg = 0.21, p = 2e−13) and INT (rg = 0.22, p = 4e−12). We discovered 43 loci jointly associated with ASD and cognitive traits (conjFDR<0.05), of which 27 were novel for ASD. Functional analysis revealed significant differential expression of candidate genes in the cerebellum and frontal cortex. To conclude, we quantified the genetic architecture shared between ASD and cognitive traits, demonstrated mixed effect directions, and identified the associated genetic loci and molecular pathways. The findings suggest that common genetic risk factors for ASD can underlie both better and worse cognitive functioning across the ASD spectrum, with different underlying biology.

Factors Affecting Young Customer Choice of Mobile Phones: Based on a Questionnaire Survey

The sales of mobile phones have increased dramatically since 2010, and over one billion mobile phones have been sold per year since 2014. The competition in the mobile phone market is ever-growing, leading to greater variation in design characteristics, prices, and functions of mobile phones. As younger generations are overrepresented in the purchasing of mobile phones, their product expectations are a significant factor in the market behavior. This paper conducts a questionnaire survey on the ways that young people receive information on mobile phones and the factors that influence their purchasing decisions, and it further discusses the factors that are crucial for attracting consumers, and suggestions will be provided for manufactures about which functions and characteristics that they should develop further to fill consumer needs. The survey indicates that the young generation mostly get information of mobile phones from advertising, accept much higher prices than general population, attach great importance to the brand, pixel and build-in speaker of mobile phones.

Suppression of Secondary Electron Emission from Nickel Surface by Graphene Composites Based on First-Principles Method.

Secondary electron emission (SEE) is a fundamental phenomenon of particle/surface interaction, and the multipactor effect induced by SEE can result in disastrous impacts on the performance of microwave devices. To suppress the SEE-induced multipactor, an Ni (111) surface covered with a monolayer of graphene was proposed and studied theoretically via the density functional theory (DFT) method. The calculation results indicated that redistribution of the electron density at the graphene/Ni (111) interface led to variations in the work function and the probability of SEE. To validate the theoretical results, experiments were performed to analyze secondary electron yield (SEY). The measurements showed a significant decrease in the SEY on an Ni (111) surface covered with a monolayer of graphene, accompanied by a decrease in the work function, which is consistent with the statistical evidence of a strong correlation between the work function and SEY of metals. A discussion was given on explaining the experimental phenomenon using theoretical calculation results, where the empty orbitals lead to an electron trapping effect, thereby reducing SEY.

EUPHEMISMS IN PHILIPINE CULTURE POTRAYED IN FILIPINO MOVIES

This study explores the euphemisms in Philippine culture portrayed in Filipino movies. This study attempts to answer the research questions: (1) What euphemisms are used in the movies (a) Remington and the Curse of Zombadings and (b) Die Beautiful along with metaphor, idioms, and hyperbole? and (2) What are the functions of the euphemisms used in the two movies? The researchers analyzed the data using the lens of latent content analysis and qualitative analysis to unpack the meanings and relationships. The data were taken from the script supported by the transcription method. The method of data analysis is described in great detail–Transcribing, Data Reduction, and Data Selection. Study found various euphemisms under metaphor (ng ganun, confimed, Diana Rose, in fairness, magbooking, kaligayahan, and usapan ng mga tao ‘to); Idioms (malakandila ang mga daliri, natuluan ng kandila); Hyperbole (dynamite, mitsa, busy po masyado, hindi kailangan ng utak dito) in the movie Remington and the Curse of Zombadings. In the movie Die Beautiful, numerous euphemisms were also categorized on its types: Metaphor (pambabae, pag inampon mo yang batang yan magiging babae ka na, bantot, lason, mani, wala naman sa kalingkingan, hindi ka pa nagpapabreastfeeding, magkapechay, number 2; Idioms (pakainin kita ng sangkatutak na star margarine, nanginginig yung matres, naputikan ka na); Hyperbole (kahit anino, wala, anak lang ng anak hindi naman nanay, anglalaking wawasak sa’aking puri, 3 inches lang yung ano). Therewere variations of functions seen according to the speaker euphemisms' contexts and purpose, made to inform (conveys new information), evaluate (conveys opinions and attitude), modalize (conveys attitude towards truth and utterance), convince(persuade), criticize (for giving criticisms), order (giving instructions), and refuse (to deny or reject).

Information theory and thermodynamic properties of diatomic molecules using molecular potential.

Owing to the devise applications of molecules in industries, the bound state solution of the non-relativistic wave equation with a molecular potential function has been obtained in a closed-form using the Nikiforov-Uvarov method. The solutions of the bound state are then applied to study the information-theoretic measures such as the one-dimensional Shannon and Renyi entropic densities. The expectation values for the position and momentum spaces were obtained to verify the Heisenberg's uncertainty principle. Utilizing the energy spectrum equation, the thermodynamic vibrational partition function is obtained via the Poisson summation. Other thermodynamic function variations with absolute temperature have been obtained numerically for four diatomic molecules (H2, N2, O2, and HF) using Maple 18 software. The Shannon global entropic sum inequality has also been verified. The Renyi sum for constrained index parameters satisfies the global entropic inequality. The thermodynamic properties of the four molecules are similar and conform to works reported in the existing literature. The obtained vibrational energies are in fair agreement with the ones obtained using other forms of potential energy. The result further indicates that the lowest bounds for the Shannon, Renyi, and Heisenberg inequalities are ground states phenomena.

Mother-child correlation of kidney function: data from the Yamanashi Adjunct Study of Japan Environment and Children's Study(JECS).

Individual variation in kidney function can be affected by both congenital and acquired factors, and kidney function in children is possibly correlated with that in their mothers. However, the mother-child correlation in kidney function remains directly unconfirmed. We conducted a cross-sectional study of 655 healthy pairs of 7- or 8-year-old children and their mothers as an adjunct study of a nationwide epidemiological study (Japan Environment and Children's Study). Both serum creatinine level (all children, r = 0.324, p < 0.001; girls, r = 0.365, p < 0.001; boys, r = 0.278, p < 0.001) and estimated glomerular filtration rate (eGFR) (r = 0.274, p < 0.001; r = 0.352, p < 0.001; r = 0.195, p < 0.001, respectively) in children were weakly associated with their maternal values. In the single linear regression analyses, maternal values of serum creatinine and eGFR were significantly associated with the children's values. Moreover, several body composition values in children, such as weight-SDS, fat (%), and predicted muscle weight, were also significantly associated with kidney function values in children. In the multiple linear regression analysis for serum creatinine levels in children, in which weight-SDS and predicted muscle weight in children were selected as adjustment factors, maternal serum creatinine level showed a significant positive association (B = 0.214, p < 0.001 in the adjusted model). Moreover, in the multiple linear regression analysis for eGFR value in children, in which fat (%) and predicted muscle weight in children were selected as adjustment factors, maternal eGFR values showed a significant positive association (B = 0.319, p < 0.001). We directly confirmed mother-child correlations in both serum creatinine levels and eGFR values, particularly in girls. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information.

Investigation of machine learning algorithms for taxonomic classification of marine metagenomes.

Taxonomic profiling of microbial communities is essential to model microbial interactions and inform habitat conservation. This work develops approaches in constructing training/testing data sets from publicly available marine metagenomes and evaluates the performance of machine learning (ML) approaches in read-based taxonomic classification of marine metagenomes. Predictions from two models are used to test accuracy in metagenomic classification and to guide improvements in ML approaches. Our study provides insights on the methods, results, and challenges of deep learning on marine microbial metagenomic data sets. Future machine learning approaches can be improved by rectifying genome coverage and class imbalance in the training data sets, developing alternative models, and increasing the accessibility of computational resources for model training and refinement.

Factors Associated With Sports Function and Psychological Readiness to Return to Sports at 12 Months After Anterior Cruciate Ligament Reconstruction: A Cross-sectional Study

Background: Sports function and psychological readiness to return to sports (RTS) are important outcomes when evaluating rehabilitation after anterior cruciate ligament reconstruction (ACLR). It is, however, unclear which specific factors contribute most to these outcomes. Purpose: To determine associations between demographic characteristics, objective measurements of physical function, patient-reported outcome measure scores, sports-related function assessed with the Knee injury and Osteoarthritis Outcome Score (KOOS) Sport and Recreation subscale, and psychological readiness to RTS assessed with the Anterior Cruciate Ligament–Return to Sport after Injury (ACL-RSI) scale at 1 year after ACLR. Study Design: Cross-sectional study; Level of evidence, 3. Methods: At a mean of 12.5 ± 2.0 months after ACLR, 143 participants (50.3% female), with a mean age of 25.0 ± 5.7 years, were assessed for demographic characteristics, physical factors (hop performance, muscle strength, ankle and hip range of motion), and psychological factors (KOOS Pain and Symptoms subscales, Perceived Stress Scale, fear of reinjury) as well as the KOOS Sport and Recreation subscale and ACL-RSI scale. Backward linear regression models were used to evaluate factors associated with sports function and psychological readiness to RTS. Results: Lower isokinetic knee extension peak torque (limb symmetry index) (B = 18.38 [95% CI, 3.01-33.75]), lower preinjury activity level (B = 2.00 [95% CI, 0.87-3.14]), greater knee pain (B = 0.90 [95% CI, 0.70-1.10]), shorter time between injury and reconstruction (B = 0.16 [95% CI, 0.05-0.26]), and greater fear of reinjury (B = 0.11 [95% CI, 0.01-0.20]) were associated with a worse KOOS Sport and Recreation subscore (R2 = 0.683). A shorter hop distance (B = 0.15 [95% CI, 0.00-0.29]) was associated with a lower ACL-RSI score (R2 = 0.245). Conclusion: A combination of knee muscle strength, activity level, knee pain, timing of surgery, and fear of reinjury accounted for approximately 70% of the variation in sports function at 1 year after ACLR. In contrast, there was only 1 weak association between physical function and psychological readiness to RTS at this time point. Thus, factors associated with current sports function are much better known than features related to psychological readiness to RTS.

JS03.5.A CLINICALLY COLLECTED VARIABLES FAIL TO RELIABLY PREDICT COGNITIVE FUNCTIONING IN UNTREATED GLIOMA PATIENTS

Abstract BACKGROUND Previous research has identified several clinically collected variables (e.g., age and WHO grade) that are significantly related to impairments in cognitive functions before surgery in patients with a glioma. The degree to which clinically collected variables can collectively explain differences in cognitive functioning between patients, however, remains unclear, as most studies did not evaluate the total amount of variability between patients explained by a set of predictors. Furthermore, only linear or rank-based methods with a small number of variables have been used. In this study, we used various machine learning models to quantify the amount of variability in cognitive functioning we can explain using a comprehensive set of variables as identified from the literature that were collected as part of clinical care. The extent to which cognitive functioning can be reliably predicted reveals the degree to which these variables can explain individual differences between patients. MATERIAL AND METHODS We trained 11 machine learning models to predict pre-surgical cognitive function in patients with a glioma (n=354) across eight cognitive tests. Included variables comprised sociodemographics, tumor characteristics, medication, presenting symptoms, ASA score, comorbidities, and anxiety and depression scores. Model performance was evaluated on four objectives 1) predicting impairment on at least one cognitive test, 2) predicting the number of tests on which a patient is impaired, 3) predicting impairment for each test separately, and 4) predicting cognitive function for each test separately. Model performance, hyperparameter selection, and feature importance were analyzed and clinical implications were discussed. RESULTS Best-performing models demonstrated above-random performance for most objectives. Performance, however, was unreliable with poor predictions for a substantial number of patients on most objectives. Best-performing models were relatively simple and used most variables for prediction while not relying strongly on any specific variable. CONCLUSION Our results show that the clinically collected variables included in this study fail to reliably predict cognitive functioning. This indicates that these variables are unable to explain a considerable amount of variability between patients, despite many of these variables being significantly related to cognitive function in previous studies. Our results suggest that a multi-parametric (i.e., more holistic) view of an individual patient may be necessary to explain differences in cognitive functioning, ideally considering imaging markers, biological markers, sociodemographics, and clinical characteristics. Finally, our results stress the need to collect larger cross-center and multimodal datasets to better explain and predict individual differences in cognitive function.

A genetic variant in the immune-related gene ERAP1 affects colorectal cancer prognosis.

Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism. We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments. The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 ( ERAP1 ) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1 . The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes. The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1 . No. NCT00454519 ( https://clinicaltrials.gov/ ).

Surface evolution of AlGaN nanowire decorated by cesium atoms: A first principle study

Surface decoration with cesium on the photocathode is an effective method to reduce surface barriers and promote electron emission. In this study, we investigated the changes in surface properties of AlGaN nanowire coated with Cs atoms using first-principle calculations. The N bridge site is the most stable site for a single atom deposition. As more Cs atoms are deposited on the surface, the average adsorption energy increases along with the weakened ionization of Cs adatoms. The Bader charge of surface Al and Ga atoms undertake significant changes in comparison with tiny alteration of N atoms, especially for Al atom with a decrease of 0.41 |e|/atom. The variation in surface work function reaches a maximum of 2.3 ∼ 2.5 eV at Cs coverage of 0.5 ∼ 0.75 ML, which can be attributed to the synergistic effect of dipole length and charge redistribution. The donor states underneath CBM induced by the orbital overlap of Al-p, Ga-p and Cs-d electrons accompanied by the downward band bending in the band structures. This work provides theoretical insight into the surface evolution of Cs-decorated AlGaN nanowires and offers guidance for the development of state-of-the-art nanostructured vacuum devices.

The functional impact of rare variation across the regulatory cascade

Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease.