Positive association between insulin resistance and fatty liver disease in psoriasis: evidence from a cross-sectional study.

Background: Fatty liver disease (FLD) is a common comorbidity of psoriasis and is often referred to as non-alcoholic fatty liver disease (NAFLD). However, the role of inflammation or insulin resistance (IR) in FLD is inconclusive. The study aims to explore whether FLD in psoriasis patients is more related to insulin resistance or systemic inflammation level. Methods: Data for this study were collected from the Shanghai Psoriasis Effectiveness Evaluation Cohort, a prospective cohort that examines psoriasis characteristics in the Chinese population. IR was assessed using the triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) indicators. Systemic non-specific inflammation was assessed using the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), and systemic immune inflammation index (SII). Results: The analysis included a total of 647 patients. Subsequent logistic regression analysis revealed that NLR, dNLR, and SII were not significantly associated with FLD in psoriasis patients, while TyG and TyG-BMI showed significant associations with FLD. Subgroup analysis indicated that in the majority of subgroups, TyG and TyG-BMI were significantly associated with FLD, particularly TyG-BMI. Excluding individuals with methotrexate and acitretin resulted in consistent findings with the main analysis. Further analysis revealed a significantly higher diagnosis rate of metabolic-associated fatty liver disease (MAFLD) compared to NAFLD. Conclusions: Metabolic factors play a crucial role in FLD in patients with psoriasis, and TyG and TyG-BMI are potential predictors of FLD. Therefore, MAFLD can be recommend as a term to describe FLD in psoriasis patients. Trial registration: https://www.chictr.org.cn/showproj.html?proj=58256, identifier ChiCTR2000036186. A multi-center clinical study of systemic treatment strategies for psoriasis in Chinese population. Registered 31 August 2020.

Insulin Resistance Impairs Biological Agents Response in Moderate-to-Severe Plaque Psoriasis: Insights from a Prospective Cohort Study in China.

BACKGROUND: Psoriasis and insulin resistance (IR) are closely related, but it remains unclear whether IR affects the treatment of patients with psoriasis. OBJECTIVE: The objective of this study was to investigate whether IR impairs the treatment response to biologic agents in patients with moderate-to-severe plaque psoriasis. METHODS: This project was based on a prospective cohort study design. Data for this study were collected from the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH), which is a prospective cohort exploring treatment strategies for psoriasis in China. IR was assessed using the triglyceride glucose-body mass index (TyG-BMI). Psoriasis severity was assessed using the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). Multiple logistic regression was used to explore the differences between patients with high and low levels of IR. Subgroup and sensitivity analyses were performed to examine the robustness of the study results. RESULTS: A total of 290 patients were included in the analysis. Based on the median TyG-BMI, the patients were divided into two groups: High and Low. The High group exhibited a higher prevalence of diabetes, higher BMI, fasting blood glucose, and triglyceride compared with the Low group. Further analysis of the treatment efficacy revealed that the High group had lower response rates for PASI 75, PASI 90, and PGA 0/1 after 12 weeks of treatment. In the Low group, 81.94% of patients achieved PASI 75, 58.33% achieved PASI 90, and 75.69% achieved PGA 0/1. However, the proportion of responses at each endpoint was significantly lower in the High group. The impairment in response to PGA 0/1 was more significant in the High group, indicated by lower odd ratios. Subsequent subgroup analysis and sensitivity analysis produced consistent results. CONCLUSION: IR is associated with lower effectiveness of biologics in patients with psoriasis. CLINICAL TRIAL REGISTRATION: [www.chictr.org.cn], identifier [ChiCTR2000036186].

Better efficacy, lower recurrence rate and decreased CD8+TRM with guselkumab treatment for generalized pustular psoriasis: A prospective cohort study from China.

Generalized pustular psoriasis (GPP) is a severe and uncommon form of psoriasis, for which treatment options are limited. There is an urgent need to expand the treatment options for GPP. Currently, adalimumab, secukinumab, and guselkumab are considered effective for GPP, but there is a lack of prospective direct comparative studies on their efficacy for GPP. We conducted a prospective, single-center, observational study on 50 GPP patients to compare the efficacy, safety, and recurrence rates of these three biologics. Adalimumab, secukinumab, and guselkumab resulted in varying degrees of improvement in patients with GPP, but guselkumab exhibited superior efficacy and a lower recurrence rate than the other two drugs. This enhanced response may be attributed to the significant reduction in CD8+ tissue-resident memory T cells within GPP lesions caused by guselkumab.

A novel online calculator based on clinical features and hematological parameters to predict total skin clearance in patients with moderate to severe psoriasis.

BACKGROUND: Treatment responses to biologic agents vary between patients with moderate to severe psoriasis; while some patients achieve total skin clearance (TSC), a proportion of patients may only experience partial improvement. OBJECTIVE: This study was designed to identify potential predictors for achieving TSC in psoriasis patients treated with IL-17 inhibitors. It also aimed to develop an easy-to-use calculator incorporating these factors by the nomogram to predict TSC response. METHODS: A total of 381 patients with psoriasis receiving ixekizumab were included in the development cohort and 229 psoriasis patients who initiated secukinumab treatment were included in the validation cohort. The study endpoint was achieving TSC after 12 weeks of IL-17 inhibitors treatment, defined as the 100% improvement in Psoriasis Area and Severity Index (PASI 100). Multivariate Cox regression analyses and LASSO analysis were performed to identify clinical predictors and blood predictors respectively. RESULTS: The following parameters were identified as predictive factors associated with TSC: previous biologic treatment, joint involvement, genital area affected, early response (PASI 60 at week 4), neutrophil counts and uric acid levels. The nomogram model incorporating these factors achieved good discrimination in the development cohort (AUC, 0.721; 95% CI 0.670-0.773) and validation cohort (AUC, 0.715; 95% CI 0.665-0.760). The calibration curves exhibited a satisfactory fit, indicating the accuracy of the model. Furthermore, the decision curve analysis confirmed the clinical utility of the nomogram, highlighting its favorable value for practical application. Web-based online calculator has been developed to enhance the efficiency of clinical applications. CONCLUSIONS: This study developed a practical and clinically applicable nomogram model for the prediction of TSC in patients with moderate to severe psoriasis. The nomogram model demonstrated robust predictive performance and exhibited significant clinical utility. Trial registration A multi-center clinical study of systemic treatment strategies for psoriasis in Chinese population;ChiCTR2000036186; Registered 31 August 2020; https://www.chictr.org.cn/showproj.html?proj=58256 .

Quality of Life Benefit and Clinical Predictors of Complete Skin Clearance in Psoriasis: A Multicenter, Prospective, Real-World Study.

BACKGROUND: Newer biologics, such as interleukin (IL)-17 inhibitors, make it possible to achieve complete skin clearance (CSC) in patients with moderate-to-severe psoriasis. However, the clinical meaningfulness and predictive factors of CSC in daily practice have not yet been fully investigated. OBJECTIVE: The study was conducted to, first, assess the impact of CSC on quality of life (QoL) improvements compared with treatment responses without clearance and, second, identify clinical parameters as predictors of CSC response in psoriasis patients treated with ixekizumab. METHODS: Patients attending 26 dermatology centers across China were recruited into this real-world setting between August 2020 and May 2022. Prospective cohort study in which response to ixekizumab was assessed using the Psoriasis Area and Severity Index (PASI) and Dermatology Quality of Life Index (DLQI). The absolute DLQI score and DLQI (0) response at week 12 were compared between groups achieving various levels of skin clearance. A stepwise logistic regression analysis was applied to identify which baseline clinical characteristics were predictive factors for CSC. RESULTS: After 12 weeks of treatment, 226 of 511 (44.2%) patients achieved CSC, defined as 100% improvement in PASI score (PASI-100). A significantly higher proportion of patients with CSC versus almost clear skin (PASI 90-99) achieved DLQI score of 0, corresponding to the experience of no impairment on QoL (54.4% vs. 37.7%, p = 0.001). Females patients were more likely than males to achieve CSC response (odds ratio [OR] = 1.83; 95% confidence interval [CI]: 1.24-2.70), while previous biologic treatment (OR = 0.43; 95% CI: 0.24-0.81) and joint affected (OR = 0.61; 95% CI: 0.42-0.89) were significantly associated with less CSC response. CONCLUSIONS: This study highlights the fact that clinical parameters are important in determining CSC response in psoriasis. In daily practice, achieving CSC represents a clinically meaningful treatment goal, especially from the patient perspective.

TLR7-MyD88-DC-CXCL16 axis results neutrophil activation to elicit inflammatory response in pustular psoriasis.

Pustular psoriasis (PP) is a chronic inflammatory disease associated with multiple complications, often with hyperthermia and hypoproteinemia, and its continued progression can be life-threatening. Toll-like receptor 7 (TLR7) induces dendritic cell (DC) production of inflammatory factors that exacerbate the inflammatory response in PP. A membrane-bound chemokine expressed on DCs, CXC motif chemokine ligand 16 (CXCL16) is overexpressed in PP lesions, and neutrophils express its receptor CXC chemokine receptor 6 (CXCR6). There are few studies on the PP immune microenvironment and it is unclear whether TLR7 and CXCL16 can be used as targets in PP therapy. Skin tissue (n = 5) and blood (n = 20) samples were collected from PP and healthy normal controls. The skin tissue transcriptome was analyzed to obtain the differentially expressed genes, and the immune microenvironment was deciphered using pathway enrichment. Tissue sequencing analysis indicated that TLR7, CXCL16, DCs, and neutrophils were involved in the PP process. The enzyme-linked immunosorbent assay, reverse transcription-PCR, and scoring table results demonstrated that TLR7 induced DC secretion of CXCL16, which enabled neutrophil activation of the secretion of the inflammatory factors interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α). The co-culture of neutrophils with DCs treated with TLR7 inhibitor or TLR7 agonist demonstrated that TLR7 regulated neutrophil activation, migration, and apoptosis. We constructed imiquimod-induced psoriasis-like skin lesions in wild-type, Cd11c-Cre Myd88f/f, and Mrp8-Cre Cxcr6f/f mice. The mouse models suggested that TLR7 might influence DC release of CXCL16 and neutrophil proinflammatory effects by interfering with the myeloid differentiation primary response gene 88 (MyD88) signaling pathway. In conclusion, the TLR7-MyD88-DC-CXCL16 axis is an important mechanism that promotes neutrophil migration to PP skin lesions and stimulates the inflammatory response.

Skin sympathetic nerve activity as a biomarker for outcomes in spontaneous intracerebral hemorrhage.

OBJECTIVE: A rapid and accurate forecast for the early prognosis of ICH patients is challenging. This study investigated whether heart rate variability (HRV) and skin sympathetic nerve activity (SKNA) could prognosticate poor neurological outcomes in ICH patients. METHODS: Between November 2020 and November 2021, we studied 92 spontaneous ICH patients in the First Affiliated Hospital of Nanjing Medical University. Glasgow Outcome Scale (GOS) score at 2 weeks after the ICH was used to categorize patients into good and poor outcome groups. The modified Rankin Scale (mRS) assessed patients' ability to live independently for 1 year. We utilized a portable high-frequency electrocardiogram (ECG) recording system to record the HRV and SKNA information in ICH patients and control participants. RESULTS: 77 patients were eligible for the prediction of neurological outcome and were allocated into the good (n = 22) or poor (n = 55) outcome groups based on the GOS grade. In univariate logistic regression analysis, significant variables that could differentiate the outcomes were age, hypertension, tracheal intubation, Glasgow Coma Scale (GCS) score, existing intraventricular hemorrhage, white blood cells, neutrophil, lnVLF, lnTP, and aSKNA. Variables in the best fit multivariable logistic regression model were age, hypertension, GCS score, neutrophils, and aSKNA. The GCS score was the only independent risk factor for poor outcomes. At 30 days and 1 year of follow-up, patients with lower aSKNA had poor outcomes. INTERPRETATION: ICH patients had reduced aSKNA, which could be a prognostic indicator. A lower aSKNA suggested a worse prognosis. The present data indicate that ECG signals could be helpful for prognosticating ICH patients.

Positive association between different triglyceride glucose index-related indicators and psoriasis: evidence from NHANES.

Background: Psoriasis is a chronic inflammatory skin disease with effects that extend beyond the skin. Insulin resistance (IR) has been associated with psoriasis, but it remains unclear how indicators related to the triglyceride glucose (TyG) index, which were associate with IR, are associated with the condition. Objective: The purpose of this study was to investigate the association between psoriasis and three TyG-related indicators: triglyceride glucose-body mass index (TyG-BMI), triglyceride glucose-waist to height ratio (TyG-WHtR), and triglyceride glucose-waist circumference (TyG-WC). Methods: Data from adults aged 20 to 80 years in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2006 and 2009 to 2014 were utilized. Institutional Review Board approval and documented written consent was obtained from participants by NHANES (Protocol #2005-06). The patients were divided into three groups based on TyG-BMI, TyG-WC, and TyG-WHtR: Q1 (1st quintile), Q2 (2nd-3rd quintiles), and Q3 (4th-5th quintiles). Differences between the groups were further explored. Multivariate logistic regressions were used to investigate the correlation between these three indicators and psoriasis, with results expressed as odds ratios (OR) and 95% confidence intervals (CI). Subgroup analysis and supplementary analysis was further conducted to explore potential influencing factors. Results: The study included 9,291 participants, of which 260 had psoriasis. Compared Q2 and Q3 of TyG-BMI, TyG-WC, and TyG-WHtR to Q1, there were significantly associate with psoriasis. Among the three indicators, TyG-WC consistently had the highest OR values in Models 1 and 2 (Model 1: Q3 OR (95% CI) = 2.155 (1.442-3.220); Model 2: Q3 OR (95% CI) = 2.029 (1.341-3.069)). While in Model 3, the TyG-BMI shows more significant relationship with psoriasis (Model 3 of TyG-BMI: Q3 OR (95% CI) = 1.948 (1.300-3.000)). Similar results were observed in the majority of subgroups and in supplementary analysis. Conclusion: This study identified a stable and strong positive association between TyG-related indicators (TyG-BMI, TyG-WC, and TyG-WHtR) and psoriasis. This association persisted even after adjusting for multiple factors. It is suggested that high IR is significantly associated with psoriasis.

Drug Survival Outcomes Associated with the Real-World Use of Ixekizumab, Secukinumab, Guselkumab, and Adalimumab for the Treatment of Plaque Psoriasis in China: A 52-Week Single-Center Retrospective Study.

Background: Data pertaining to biologic agents used for treating psoriasis in real-world settings are lacking at present. To compare drug survival at 52 weeks for a range of biologics used to treat psoriasis under real-world conditions. Methods: This was a retrospective, single-center, observational study of a cohort of patients diagnosed with plaque psoriasis treated using ixekizumab, secukinumab, guselkumab, or adalimumab between January 2020 and December 2021. Baseline demographic characteristics, duration of psoriasis, and prior biological treatments for all patients were recorded. Drug survival rates were analyzed in different patient groups using Kaplan-Meier curves and Log rank tests. Results: In total, this study included 386 plaque psoriasis patients, of whom 70, 175, 36, and 105 were, respectively, treated using ixekizumab, secukinumab, guselkumab, and adalimumab. Over a 52-week period, the overall cumulative drug survival rates for ixekizumab, secukinumab, guselkumab, and adalimumab were 67.1%, 63.0%, 72.2%, and 37.1%, respectively. Lack of efficacy was the primary cause of discontinuation for these biologic therapies, followed by economic burden and adverse event incidence. Conclusion: These results suggest that guselkumab exhibited superior drug survival, drug survival outcomes for ixekizumab and secukinumab were comparable, and significantly better than those of adalimumab in China. Preventing a loss of drug efficacy represents a primary approach to improving biologic drug survival in psoriasis patients.

Changes in chemical composition and starch structure in rice noodle cultivar influence Rapid Visco analysis and texture analysis profiles under shading.

GuichaoII, a rice variety with high amylose content widely used to make rice noodles, exhibits high hardness (631.07-729.43), gel consistency (8.47-9.47 mm), and hold viscosity/peak viscosity (HPV/PKV) (0.85-0.88); however, it has a low protein content (5.74-6.96%) and swelling factor (5.49-9.77). Herein, GuichaoII was subjected to low-light stress (53% reduction) during the grain filling stage. The amylose content and crystallinity of GuichaoII and the control variety Shuhui 498 decreased while the protein content, short-chain branch ratio, and degree of branching increased, which affected the ability of the rice flour to absorb water and expand during the gelatinization process. The PKV, HPV, breakdown viscosity, and final viscosity were significantly reduced, while the hardness was significantly increased, and the gel consistency and the gelatinization quality of the rice were reduced, severely limiting the processing and production of rice noodles.

Based on Gene Expression Analysis: Low-Density Neutrophil Expression Is a Characteristic of the Fast Responders Treated With Guselkumab for Psoriasis.

Psoriasis is a worldwide chronic inflammatory skin disease. The treatment of disease is usually designed according to its severity. In this research, RNA-seq was performed on 37 patients with psoriasis treated with guselkumab before and after treatment, and the patients were divided into fast responder and slow responder according to PASI score to analyze the differentially expressed genes (DEGs) between them. Moreover, The biological mechanism of psoriasis was explored by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Gene Ontology (GO) analysis, and Gene Set Enrichment Analysis (GSEA) analysis. And then, this protein-protein interaction network was constructed and 17 DEGs including IL-1ß, CXCL8, S100A12 and MMP9 were analyzed by GSVA. DEGs were detected by GO and KEGG analysis of target genes, which were primarily associated with immune response, neutrophil activation, neutrophil degranulation. GSEA reminded that fast responders were mainly involved in low-density neutrophils and abundant NK cells. And the GSVA showed that the DEGs were down-regulated after the early stage of the fast responder and the reverse in the slow responder by GSVA analysis. On the whole, these results indicated that these DEGs may serve as a psoriasis potential diagnostic and predictive biomarkers after been treated by guselkumab.

Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, ß (females) = 0.08, P (females) = 5.76 × 10-09, ß (males) = -0.01, P(males) = 0.70, ß (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.

PUMAS: fine-tuning polygenic risk scores with GWAS summary statistics.

Polygenic risk scores (PRSs) have wide applications in human genetics research, but often include tuning parameters which are difficult to optimize in practice due to limited access to individual-level data. Here, we introduce PUMAS, a novel method to fine-tune PRS models using summary statistics from genome-wide association studies (GWASs). Through extensive simulations, external validations, and analysis of 65 traits, we demonstrate that PUMAS can perform various model-tuning procedures using GWAS summary statistics and effectively benchmark and optimize PRS models under diverse genetic architecture. Furthermore, we show that fine-tuned PRSs will significantly improve statistical power in downstream association analysis.

SUPERGNOVA: local genetic correlation analysis reveals heterogeneous etiologic sharing of complex traits.

Local genetic correlation quantifies the genetic similarity of complex traits in specific genomic regions. However, accurate estimation of local genetic correlation remains challenging, due to linkage disequilibrium in local genomic regions and sample overlap across studies. We introduce SUPERGNOVA, a statistical framework to estimate local genetic correlations using summary statistics from genome-wide association studies. We demonstrate that SUPERGNOVA outperforms existing methods through simulations and analyses of 30 complex traits. In particular, we show that the positive yet paradoxical genetic correlation between autism spectrum disorder and cognitive performance could be explained by two etiologically distinct genetic signatures with bidirectional local genetic correlations.

Estimating genetic nurture with summary statistics of multigenerational genome-wide association studies.

Marginal effect estimates in genome-wide association studies (GWAS) are mixtures of direct and indirect genetic effects. Existing methods to dissect these effects require family-based, individual-level genetic, and phenotypic data with large samples, which is difficult to obtain in practice. Here, we propose a statistical framework to estimate direct and indirect genetic effects using summary statistics from GWAS conducted on own and offspring phenotypes. Applied to birth weight, our method showed nearly identical results with those obtained using individual-level data. We also decomposed direct and indirect genetic effects of educational attainment (EA), which showed distinct patterns of genetic correlations with 45 complex traits. The known genetic correlations between EA and higher height, lower body mass index, less-active smoking behavior, and better health outcomes were mostly explained by the indirect genetic component of EA. In contrast, the consistently identified genetic correlation of autism spectrum disorder (ASD) with higher EA resides in the direct genetic component. A polygenic transmission disequilibrium test showed a significant overtransmission of the direct component of EA from healthy parents to ASD probands. Taken together, we demonstrate that traditional GWAS approaches, in conjunction with offspring phenotypic data collection in existing cohorts, could greatly benefit studies on genetic nurture and shed important light on the interpretation of genetic associations for human complex traits.

Cerebrospinal fluid metabolomics identifies 19 brain-related phenotype associations.

The study of metabolomics and disease has enabled the discovery of new risk factors, diagnostic markers, and drug targets. For neurological and psychiatric phenotypes, the cerebrospinal fluid (CSF) is of particular importance. However, the CSF metabolome is difficult to study on a large scale due to the relative complexity of the procedure needed to collect the fluid. Here, we present a metabolome-wide association study (MWAS), which uses genetic and metabolomic data to impute metabolites into large samples with genome-wide association summary statistics. We conduct a metabolome-wide, genome-wide association analysis with 338 CSF metabolites, identifying 16 genotype-metabolite associations (metabolite quantitative trait loci, or mQTLs). We then build prediction models for all available CSF metabolites and test for associations with 27 neurological and psychiatric phenotypes, identifying 19 significant CSF metabolite-phenotype associations. Our results demonstrate the feasibility of MWAS to study omic data in scarce sample types.

Relationship between chalkiness and the structural and thermal properties of rice starch after shading during grain-filling stage.

Chalkiness is a major concern in rice production and its acceptance and is increased by shade stress. However, the relationship between rice chalkiness and the structural and thermal properties of starch is unclear. Here, we investigated the effect of shade stress on rice starch properties. The chalky grain rate and chalkiness degree significantly decreased with the amylose content, Mn, and ΔH and increased with surface area- and volume-weighted mean diameters, branching degree, ratio of 1022/995 cm-1, and molecular weight polydispersity. Shade stress significantly increased the volume- and surface area-weighted mean diameters and Mw and decreased the amylose content, A chain proportion of amylopectin, Mn, and regularity of starch. These effects led to an increase in the molecular weight polydispersity and branching degree and a decrease in the crystallinity degree and 1045/1022 cm-1 ratio, thereby reducing starch ΔH and uniformity. These factors contributed to increased chalkiness of rice under shade stress.

Genetic variants and functional pathways associated with resilience to Alzheimer's disease.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.