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.
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, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (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.
Psoriasis and insulin resistance (IR) are closely related, but it remains unclear whether IR affects the treatment of patients with psoriasis.
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.
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.
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.
IR is associated with lower effectiveness of biologics in patients with psoriasis.
www.chictr.org.cn, identifier ChiCTR2000036186.
Lodging is a leading cause of yield loss in rice (Oryza sativa L.). To elucidate the effect of field configuration on lodging‐related traits at the single‐stem and whole hill levels, indica hybrid ...rice cultivars, Yixiangyou2115 and Shuyou217, were grown under traditional dense planting (30 × 12 cm row‐hill spacing) and under fewer hills with more seedlings (30 × 23 cm row‐hill spacing) in 2019 and 2020. The results show that there was no significant difference in single‐stem lodging index between fewer hills with more seedlings and traditional dense planting, as shown by the similarity in plant height, relative gravity center height, culm wall thickness, culm diameter, and breaking strength. However, compared with traditional dense planting, fewer hills with more seedlings significantly increased the anti‐thrust of whole plant and the ventilation rate between whole hills by 45.02%–117.36% and 58.18%–117.39%, respectively. This contributed to the marked improvement in the lodging resistance of whole rice hills, where plant inclination angle and apparent lodging rate were reduced by 41.75%–75.46% and 53.49%–63.33%, respectively. Furthermore, there was no significant difference in grain yield between the two configurations. These results indicate that the field configuration of fewer hills with more seedlings can improve the lodging resistance of whole hills while maintaining the grain yield of machine‐transplanted rice.
Core Ideas
Fewer hills with more seedlings (FHS) led to similar single‐stem lodging resistance as traditional dense planting.
FHS increased the anti‐thrust of whole plant and decreased the plant inclination angle of the whole hill.
FHS led to higher ventilation rate and lower apparent lodging rate of the rice population.
FHS can maintain stable yields for machine‐transplanted rice.
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.
Low light levels during rice (Oryza sativa L.) growing seasons may lead to significant reductions in grain yield and quality. The effect of shading stress on remobilization of nonstructural ...carbohydrates (NSC) from the stem plus sheath (SPS) to the grain, a process crucial to rice grain formation, was investigated. Field shading experiments were conducted in Hanyuan and Wenjiang, China, using two rice varieties (Huanghuazhan and Guichao II) subjected to shading stress after heading. StoredNSC of 60.00-159.15 gm.sup.-2 were remobilized from SPS after heading, contributing 9.63%-23.63% to grain dry weight at maturity. Shading stress resulted in the 23.99%-50.30% and 31.65%-61.33% reduction in NSC content of SPS at 20 d after heading (DAH20) and maturity stages, respectively. This contributed to the 13.80%-89.00% increase in the remobilization of stored NSC from SPS to the grain (RASN) and 15.86%-73.30% increase in remobilization percentage of removed NSC from SPS to the grain (RPRN). The effect of shading stress on remobilization differed between sites and varieties. Owing to a greater sink capacity, shading stress led to a higher RASN and RPRN from heading to DAH20 for 'Huanghuazhan' in Hanyuan. To compensate for photosynthate deficiency under shading stress, rice is adapted to remobilize stored NSC during early grain filling stages. Consequently, grain yield loss caused by shading could be reduced by increasing the SPS remobilization ability (especially in low light areas). Increasing NSC accumulation in SPS before heading for later remobilization may be a feasible way to alleviate rice yield loss under adverse light conditions. Key words: Nonstructural carbohydrates, Oryza sativa, remobilization characteristics, shading stress, yield.
A plethora of studies on self-organization has been carried out in broad areas including chemistry, biology, astronomy, medical science, telecommunications, etc., in both academia and industry. ...Following the studies on swarm intelligence observed in social species, the artificial self-organized systems are expected to exhibit some intelligent features （e.g., flexibility, robustness, decentralized control, self-evolution, etc.） that may have made social species so successful in the biosphere. In this paper, the application of swarm intelligence in communications networks will be studied, and we survey different aspects of bio-inspired mechanisms and examine various algorithms that have been proposed to improve the performance of artificial systems. Some fundamental self-organized networking （SON） mechanisms, designing principles and optimization approaches for artificial systems will then be investigated, followed by some well-known bio-inspired algorithms （e.g., coop- eration, division of labor, distributed network synchronization, load balancing, etc.） as well as their applications to the maintenance/operation/optimization of artificial systems being analyzed. Besides, some new emerging technologies, such as the Self-X capabilities and cognitive machine-to-machine （M2M） optimization for the 3rd Generation Partnership Project （3GPP） Long Term Evolution （LTE）/LTE-Advanced systems, are also surveyed. Finally, the remaining challenges to be faced in designing the future heterogeneous systems will be discussed.
Background
Approximately 30% of older adults are cognitively normal at death despite presence of Alzheimer’s disease (AD) neuropathology at autopsy. Studying these “resilient” individuals may lead to ...the discovery of novel therapeutic targets. In addition, growing evidence suggests sex differences in downstream neurodegenerative consequences of AD neuropathology, with recent studies highlighting notable sex‐specific genetic drivers of AD pathogenesis. We sought to extend this work by elucidating sex‐specific genetic factors underlying resilience to AD.
Method
We used our published genetic resilience pipeline to assess sex‐specific genetic predictors (Dumitrescu et al., 2020). Briefly, we used modern psychometric approaches to harmonize cognitive measures across four cohorts of cognitive aging (N=5054), in‐vivo amyloid PET across two studies, and leveraged autopsy measures of amyloidosis (CERAD staging) across two studies. A continuous measure of resilience was quantified using a latent variable framework whereby higher scores reflected better‐than‐predicted cognitive performance given amyloidosis level and lower scores reflected worse‐than‐predicted performance. We then performed sex‐stratified GWASs and sex‐interaction GWASs, covarying for age and the first three principal components and meta‐analyzed across cohorts. Finally, we performed sex‐stratified genetic correlation analyses (GNOVA) between our meta‐analysis results and summary statistics from 63 complex traits.
Result
Among individuals with normal cognition, we identified a female‐specific locus on chromosome 10 (rs827389, p(females)=7.4E‐09, p(males)=0.64, p(interaction)=8.3E‐05, MAF=0.46). This variant is a modest eQTL for KIN (p=0.003), a gene encoding a DNA/RNA binding protein (http://www.braineac.org). In our genetic correlation analyses, we observed male‐specific correlations between resilience and two heart rate‐related traits, whereby higher resilience was associated with lower genetic risk for poor heart health. We also observed opposing genetic correlations between resilience and multiple sclerosis such that females with higher resilience scores had lower susceptibility for multiple sclerosis (p.FDR=0.009), whereas males with higher resilience had higher susceptibility (p.FDR=0.001).
Conclusion
Our results highlight sex‐specific genes and pathways that may drive resilience in a biological sex‐dependent manner, although independent replication is needed. The best target to enhance resilience to AD neuropathology may depend on sex and genetic context of an individual. Future work should continue to evaluate sex differences in the genetic architecture of the AD neuropathological cascade.
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