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Objective To examine the associations of LRRK2 p.G2019S, GBA1 p.N409S, polygenic risk scores (PRS), and APOE E4 on PD penetrance, risk, and symptoms. Methods We conducted a US‐based observational case–control study using data from the 23andMe Inc. and Fox Insight Genetic Substudy (FIGS) databases. The total cohort included 7,586,842 participants (n = 35,163 PD); 8791 LRRK2 p.G2019S carriers (565 with PD), 37,427 GBA1 p.N409S carriers (524 with PD), 244 dual LRRK2/GBA1 carriers (37 with PD), and 7.5 million noncarriers (34,037 with PD). PRS was calculated from the most recently published European genome‐wide association study. Survival models estimated the cumulative incidence of PD. Logistic regressions estimated the relative odds of reporting motor and non‐motor symptoms according to genetic exposure. Results By the age of 80 years, the cumulative incidence of PD was 30% for dual carriers, 24% for LRRK2 p.G2019S carriers, 4% for GBA1 p.N409S carriers, and 2% for noncarriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. GBA1 p.N409S PD was associated with the highest burden of non‐motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, and LRRK2 p.G2019S with the lowest. APOE E4 dosage was associated with greater odds of reporting hallucinations and cognitive impairment in addition to carrier status. Interpretation Our findings support the use of genetic screening to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetics.

Variants that alter the DNA-binding specificity of transcription factors could affect the specificity for and expression of potentially many target genes, as has been observed in several tumor-derived mutations. Here we examined if such trans expression quantitative trait loci (trans-eQTLs) could similarly result from common genetic variants. We chose to focus on the Cys2-His2 class of zinc finger transcription factors because they are the most abundant superfamily of transcription factors in human and have well-characterized DNA binding interactions. We identified 430 SNPs that cause missense substitutions in the DNA-contacting residues. Fewer common missense SNPs were found at DNA-contacting residues compared with non-DNA-contacting residues (P = 0.00006), consistent with possible functional selection against SNPs at DNA-contacting positions. Functional predictions based on zinc finger transcription factor (ZNF) DNA binding preferences also suggested that many common substitutions could potentially alter binding specificity. However, Hardy-Weinberg Equilibrium analysis and examination of seven orthologs within the primate lineage failed to find evidence of trans-eQTLs associated with the DNA-contacting positions or evidence of a different selection pressure on a contemporary and evolutionary timescales. The overall conclusion was that common SNPs that alter the DNA-contacting residues of these factors are unlikely to produce strong trans-eQTLs, consistent with the observations by others that trans-eQTLs in humans tend to be few and weak. Some rare SNPs might alter specificity and remained rare due to purifying selection. The study also underscores the need for large-scale eQTLs mapping efforts that might provide experimental evidence for SNPs that alter the choice of transcription factor binding sites.

Defects in a plethora of cellular processes can lead to genomic instability in the cells, corresponding to activation of the DNA damage response (DDR). The scope of the diversity of these cellular processes is only beginning to be understood. We found that down-regulation of IK, inhibitor of K562, leads to activation of the DNA damage response and defects in gene expression. Previous works in B cells showed that the overexpression of IK abrogates the gamma-interferon induction of major histocompatibility (MHC) class II expression, suggesting that IK is a negative regulatior of MHC class II expression. Additionally, several large-scale mass spectrometry studies identified IK in pre-mRNA processing complexes along with other transcription cofactors. Through coimmunoprecipitation and mass-spectrometry, we identified two other interactors of IK that when down-regulated also lead to activation of the DNA damage response and defects in expression of many genes. Here we characterized this novel IK complex and its role in the DNA damage response. Components of the complex colocalize with RNA polymerase II foci, in agreement with a role of the complex in regulating gene expression. Interestingly, one of the components is phosphorylated by the central regulators of the DNA damage response, ATM/ATR, in response to a wide variety of DNA damaging agents, suggesting that the function of the complex is regulated by the DNA damage response and that this complex may play an important role in the DNA damage response. Altogether, the results presented highlight the integral relationship between processes involved in gene expression and genomic stability. These processes, such as transcription and pre-mRNA metabolism, occur on chromatin and pose a threat to genomic stability. However, they are necessary for life and for the expression of the gatekeepers of the genome. Hence, these processes must be tightly regulated to preserve genome integrity while at the same time allow gene expression to occur. Future studies will provide mechanistic details of the interface between these processes and genomic stability. An understanding of this interface may help elucidate potential mechanisms employed by precancerous lesions to become overt malignant tumors and perhaps lead to identification of novel therapeutic targets for blocking tumorigenesis.

Human genetic variants causing loss of function (LoF) of protein-coding genes provide natural in vivo models of gene inactivation, which are powerful indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes. Gain of kinase function variants in LRRK2 are known to significantly increase the risk of Parkinsons disease suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. Whilst preclinical studies in model organisms have raised some on-target toxicity concerns, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here we systematically analyse LoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD) and over 4 million participants in the 23andMe genotyped dataset, to assess their impact at a molecular and phenotypic level. After thorough variant curation, we identify 1,358 individuals with high-confidence predicted LoF variants in LRRK2, several with experimental validation. We show that heterozygous LoF of LRRK2 reduces LRRK2 protein level by ~50% but is not associated with reduced life expectancy, or with any specific phenotype or disease state. These data suggest that therapeutics that downregulate LRRK2 levels or kinase activity by up to 50% are unlikely to have major on-target safety liabilities. Our results demonstrate the value of large scale genomic databases and phenotyping of human LoF carriers for target validation in drug discovery.

Tracking SARS-CoV-2 genetic diversity is strongly indicated because diversifying selection may lead to the emergence of novel variants resistant to naturally acquired or vaccine-induced immunity. To monitor New York City (NYC) for the presence of novel variants, we deep sequence most of the receptor binding domain coding sequence of the S protein of SARS-CoV-2 isolated from the New York City wastewater. Here we report detecting increasing frequencies of novel cryptic SARS-CoV-2 lineages not recognized in GISAID’s EpiCoV database. These lineages contain mutations that had been rarely observed in clinical samples, including Q493K, Q498Y, E484A, and T572N and share many mutations with the Omicron variant of concern. Some of these mutations expand the tropism of SARS-CoV-2 pseudoviruses by allowing infection of cells expressing the human, mouse, or rat ACE2 receptor. Finally, pseudoviruses containing the spike amino acid sequence of these lineages were resistant to different classes of receptor binding domain neutralizing monoclonal antibodies. We offer several hypotheses for the anomalous presence of these lineages, including the possibility that these lineages are derived from unsampled human COVID-19 infections or that they indicate the presence of a non-human animal reservoir. To monitor the presence of novel SARS-CoV-2 variants in New York City, Smyth et al. perform deep-sequencing of the receptor binding domain of S protein in wastewater samples and find novel cryptic lineages containing mutations affecting ACE2-tropism and showing decreased neutralization by antibodies.

Background Foxtail millet ( Setaria italica L. P. Beauv ) has been considered as a tractable model crop in recent years due to its short growing cycle, lower amount of repetitive DNA, inbreeding nature, small diploid genome, and outstanding abiotic stress-tolerance characteristics. With modern agriculture facing various adversities, it’s urgent to dissect the mechanisms of how foxtail millet responds and adapts to drought and stress on the proteomic-level. Results In this research, a total of 2474 differentially expressed proteins were identified by quantitative proteomic analysis after subjecting foxtail millet seedlings to drought conditions. 321 of these 2474 proteins exhibited significant expression changes, including 252 up-regulated proteins and 69 down-regulated proteins. The resulting proteins could then be divided into different categories, such as stress and defense responses, photosynthesis, carbon metabolism, ROS scavenging, protein synthesis, etc., according to Gene Ontology annotation. Proteins implicated in fatty acid and amino acid metabolism, polyamine biosynthesis, hormone metabolism, and cell wall modifications were also identified. These obtained differential proteins and their possible biological functions under drought stress all suggested that various physiological and metabolic processes might function cooperatively to configure a new dynamic homeostasis in organisms. The expression patterns of five drought-responsive proteins were further validated using western blot analysis. The qRT-PCR was also carried out to analyze the transcription levels of 21 differentially expressed proteins. The results showed large inconsistency in the variation between proteins and the corresponding mRNAs, which showed once again that post-transcriptional modification performs crucial roles in regulating gene expression. Conclusion The results offered a valuable inventory of proteins that may be involved in drought response and adaption, and provided a regulatory network of different metabolic pathways under stress stimulation. This study will illuminate the stress tolerance mechanisms of foxtail millet, and shed some light on crop germplasm breeding and innovation.

Sun-induced fluorescence (SIF) in the far-red region provides a new noninvasive measurement approach that has the potential to quantify dynamic changes in light-use efficiency and gross primary production (GPP). However, the mechanistic link between GPP and SIF is not completely understood. We analyzed the structural and functional factors controlling the emission of SIF at 760 nm (F760) in a Mediterranean grassland manipulated with nutrient addition of nitrogen (N), phosphorous (P) or nitrogen–phosphorous (NP). Using the soil–canopy observation of photosynthesis and energy (SCOPE) model, we investigated how nutrient-induced changes in canopy structure (i.e. changes in plant forms abundance that influence leaf inclination distribution function, LIDF) and functional traits (e.g. N content in dry mass of leaves, N%, Chlorophyll a+b concentration (Cab) and maximum carboxylation capacity (V cmax)) affected the observed linear relationship between F760 and GPP. We conclude that the addition of nutrients imposed a change in the abundance of different plant forms and biochemistry of the canopy that controls F760. Changes in canopy structure mainly control the GPP–F760 relationship, with a secondary effect of Cab and V cmax. In order to exploit F760 data to model GPP at the global/regional scale, canopy structural variability, biodiversity and functional traits are important factors that have to be considered.

Expression of a barley transcription factor SUSIBA2 in rice generates a plant with high-starch content and low-methane emissions by conferring a shift in the carbon flux that favours the allocation of photosynthates to aboveground biomass rather than to the roots. A rice cultivar for a warming world Rice paddies produce 7–17% of global emissions of the potent greenhouse gas methane, a figure likely to increase as rice cultivation expands to meet growing demand. This paper reports the development of a rice that produces seeds and stems with increased biomass and starch content, combined with reduced methane emission and rhizospheric methanogen levels. This new rice strain was created by the addition of a single gene, encoding the barley transcription factor SUSIBA2 to a conventional rice cultivar. SUSIBA2 confers a shift of carbon flux that favours the allocation of the products of photosynthesis to aboveground biomass over their allocation to roots. In a warming climate, 'high-starch low-methane' rice could offer a sustainable means for providing high-quality biomass while reducing the negative effect of rice agriculture on atmospheric greenhouse gas emissions. Atmospheric methane is the second most important greenhouse gas after carbon dioxide, and is responsible for about 20% of the global warming effect since pre-industrial times 1 , 2 . Rice paddies are the largest anthropogenic methane source and produce 7–17% of atmospheric methane 2 , 3 . Warm waterlogged soil and exuded nutrients from rice roots provide ideal conditions for methanogenesis in paddies with annual methane emissions of 25–100-million tonnes 3 , 4 . This scenario will be exacerbated by an expansion in rice cultivation needed to meet the escalating demand for food in the coming decades 4 . There is an urgent need to establish sustainable technologies for increasing rice production while reducing methane fluxes from rice paddies. However, ongoing efforts for methane mitigation in rice paddies are mainly based on farming practices and measures that are difficult to implement 5 . Despite proposed strategies to increase rice productivity and reduce methane emissions 4 , 6 , no high-starch low-methane-emission rice has been developed. Here we show that the addition of a single transcription factor gene, barley SUSIBA2 (refs 7 , 8 ), conferred a shift of carbon flux to SUSIBA2 rice, favouring the allocation of photosynthates to aboveground biomass over allocation to roots. The altered allocation resulted in an increased biomass and starch content in the seeds and stems, and suppressed methanogenesis, possibly through a reduction in root exudates. Three-year field trials in China demonstrated that the cultivation of SUSIBA2 rice was associated with a significant reduction in methane emissions and a decrease in rhizospheric methanogen levels. SUSIBA2 rice offers a sustainable means of providing increased starch content for food production while reducing greenhouse gas emissions from rice cultivation. Approaches to increase rice productivity and reduce methane emissions as seen in SUSIBA2 rice may be particularly beneficial in a future climate with rising temperatures resulting in increased methane emissions from paddies 9 , 10 .

Photocatalyst overall water splitting is usually restricted by low carrier separation efficiency and a slow surface reaction rate. Cocatalysts provide a satisfactory solution to significantly improve photocatalytic performance. In this review, some recent advances in cocatalysts for photocatalytic overall water splitting are gathered and divided into groups. Firstly, the loading method of the cocatalyst is introduced. Then, the role of the cocatalyst applied for the photocatalytic overall water splitting process is further discussed. Finally, the key challenges and possible research directions of photocatalytic overall water splitting are proposed. This review is expected to promote research on the design of efficient cocatalysts in photocatalytic systems for overall water splitting.

The Atmospheric River Tracking Method Intercomparison Project (ARTMIP) is an international collaborative effort to understand and quantify the uncertainties in atmospheric river (AR) science based on detection algorithm alone. Currently, there are many AR identification and tracking algorithms in the literature with a wide range of techniques and conclusions. ARTMIP strives to provide the community with information on different methodologies and provide guidance on the most appropriate algorithm for a given science question or region of interest. All ARTMIP participants will implement their detection algorithms on a specified common dataset for a defined period of time. The project is divided into two phases: Tier 1 will utilize the Modern-Era Retrospective analysis for Research and Applications, version 2 (MERRA-2) reanalysis from January 1980 to June 2017 and will be used as a baseline for all subsequent comparisons. Participation in Tier 1 is required. Tier 2 will be optional and include sensitivity studies designed around specific science questions, such as reanalysis uncertainty and climate change. High-resolution reanalysis and/or model output will be used wherever possible. Proposed metrics include AR frequency, duration, intensity, and precipitation attributable to ARs. Here, we present the ARTMIP experimental design, timeline, project requirements, and a brief description of the variety of methodologies in the current literature. We also present results from our 1-month “proof-of-concept” trial run designed to illustrate the utility and feasibility of the ARTMIP project.