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In this report, we systematically characterize 32 response regulators (RRs) from a metal tolerant groundwater isolate, Pseudomonas stutzeri RCH2 to assess the impact of host-derived post-translational phosphorylation. As observed by distinct shifted bands in a phos-tag gel, 12 of the 24 detected RRs show homogenous mixtures of phosphorylated proteins or heterogenous mixtures of unphosphorylated and phosphorylated proteins. By evaluating the phosphorylation state of CzcR and CopR II under varying assay parameters, we found that changes to pH and exogenous addition of phospho-donors (e.g. acetyl phosphate) have little to no effect on phosphorylation state. By applying protein production conditions that decrease the pool of intracellular acetyl-phosphate in E. coli , we found a reduction in the phosphorylated population of CopR II when magnesium was added to the medium, but observed no change in phosphorylated population when CopR II is expressed in E. coli BL21 (DE3) ∆pta , a mutant with a metabolic disruption to the acetyl-phosphate pathway. Therefore, the specific mechanism of post-translational phosphorylation of RRs in E. coli remains obscure. These findings show the importance of characterizing the phosphorylation state of proteins when heterologously expressed, since their biochemical and physiological properties can be dependent on post-translational modification.

Neurodegenerative diseases are etiologically and clinically heterogeneous conditions, often reflecting a spectrum of disease rather than well-defined disorders. The underlying molecular complexity of these diseases has made the discovery and validation of useful biomarkers challenging. The search of characteristic genetic and transcriptomic indicators for preclinical disease diagnosis, prognosis, or subtyping is an area of ongoing effort and interest. The next generation of biomarker studies holds promise by implementing meaningful longitudinal and multi-modal approaches in large scale biobank and healthcare system scale datasets. This work will only be possible in an open science framework. This review summarizes the current state of genetic and transcriptomic biomarkers in Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, providing a comprehensive landscape of recent literature and future directions.

The effects of one genetic factor upon Parkinson’s disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the ‘missing heritability’ of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson’s Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p -value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65–1.95, p  = 2.7 × 10 −43 ). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2 , its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.

OBJECTIVES To assess relations between the adiposity of children and their parents and to establish whether tracking of adiposity from childhood to adulthood varies according to the parental body mass index (BMI). METHODS Longitudinal data from the 1958 British birth cohort study were used (6540 men and 6207 women). The height and weight of the study subjects were measured at 7, 11, 16, 23 (self reported), and 33 years. Parental height and weight were self reported when their children were 11 years old. The children were classified into six parental BMI (weight/height2) groups. RESULTS At each age of follow up the mean BMI of the children increased as the parental BMI increased. Higher risks of adult (33 year) obesity were evident among children with overweight or obese parents: the odds for sons and daughters with two obese parents (compared with those with both parents of normal BMI) were 8.4 and 6.8, respectively. The children of two obese parents also showed the strongest child to adult tracking of BMI as indicated by the correlation between ages 7 and 33 (r = 0.46, 0.54, sons and daughters, respectively). CONCLUSIONS The children of obese and overweight parents have an increased risk of obesity. Subjects with two obese parents are fatter in childhood and also show a stronger pattern of tracking from childhood to adulthood. As the prevalence of parental obesity increases in the general population the extent of child to adult tracking of BMI is likely to strengthen.

Genome-wide association studies (GWAS) of Alzheimer’s disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer’s disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer’s disease and related dementias.

The under‐representation of non‐European cohorts in neurodegenerative disease genome‐wide association studies (GWAS) hampers precision medicine efforts. Despite the inherent genetic and phenotypic diversity in these diseases, GWAS research consistently exhibits a disproportionate emphasis on participants of European ancestry. This study reviews GWAS up to 2022, focusing on non‐European or multi‐ancestry neurodegeneration studies. We conducted a systematic review of GWAS results and publications up to 2022, focusing on non‐European or multi‐ancestry neurodegeneration studies. Rigorous article inclusion and quality assessment methods were employed. Of 123 neurodegenerative disease (NDD) GWAS reviewed, 82% predominantly featured European ancestry participants. A single European study identified over 90 risk loci, compared to a total of 50 novel loci in identified in all non‐European or multi‐ancestry studies. Notably, only six of the loci have been replicated. The significant under‐representation of non‐European ancestries in NDD GWAS hinders comprehensive genetic understanding. Prioritizing genomic diversity in future research is crucial for advancing NDD therapies and understanding. Highlights Eighty‐two percent of neurodegenerative genome‐wide association studies (GWAS) focus on Europeans. Only 6 of 50 novel neurodegenerative disease (NDD) genetic loci have been replicated. Lack of diversity significantly hampers understanding of NDDs. Increasing diversity in NDD genetic research is urgently required. New initiatives are aiming to enhance diversity in NDD research.

Open science and collaboration are necessary to facilitate the advancement of Parkinson’s disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities, thus we coordinated a virtual 3-day hackathon event, during which 49 early-career scientists from 12 countries built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. Each team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. Hackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early-career researchers. The resources generated can be used to accelerate research on the genetics of PD.

Second language acquisition (SLA) and psycholinguistic researchers are interested in how inferences are processed in first language (L1) and second language (L2) reading to better understand how learners negotiate for meaning within a text. Preliminary evidence from brain-based studies suggests that bridging inferences (i.e., connecting pronouns and referents) may rely more heavily on short-term memory (STM) (Burkhardt, 2006) while predictive inferences (i.e., forecasting upcoming events from textual information) may rely more heavily on cognitive control (CC) (Jin et al., 2009). However, despite these advances, it is still not clear whether or not L2 readers have access to the necessary linguistic structures (Horiba, 1996) or, instead, if proficiency level is a confounding variable (Cohen, 1998; Guerrero, 2005; Leontiev, 1981). To address these gaps, an L1 English reading study and an L2 English reading study were carried out to explore whether or not inferences are processed differently than non-inferences, whether or not bridging and predictive inferences are processed differently from one another, and which cognitive resources are recruited during the processing of bridging and predictive inferences. The L1 and L2 data were compared to see if inference processing differs based on language background. L1 English speakers (n = 50) and L2 English-L1 Spanish speakers (n = 23) completed a cumulative self-paced reading task in a distraction paradigm; participants read scenarios that required them to make a bridging inference, a predictive inference or no inference with interference (while completing a secondary task that taxed STM or CC) or without interference. Independent measures of STM and CC were also collected to see whether these scores were associated with reading performance. The results indicated that L1 and proficient L2 readers process inferences similarly. Participants relied on CC for bridging and predictive inferences, supporting a multi-component framework of attentional control capacity (Barnes & Jones, 2000). These results are consistent with research on individual difference in SLA (e.g., Dornyei & Skehan, 2003), in that they suggest that CC may influence L2 classroom learning and account for the variation in L2 reading acquisition. Additionally, the findings have implications for L2 testing, as they pose a threat to the internal validity of standardized reading tests and ultimately the grade-level placement of L2 readers.

In this report, we systematically characterize 32 response regulators (RRs) from a metal tolerant groundwater isolate, Pseudomonas stutzeri RCH2 to assess the impact of host-derived post-translational phosphorylation. As observed by distinct shifted bands in a phos-tag gel, 12 of the 24 detected RRs show homogenous mixtures of phosphorylated proteins or heterogenous mixtures of unphosphorylated and phosphorylated proteins. By evaluating the phosphorylation state of CzcR and CopR II under varying assay parameters, we found that changes to pH and exogenous addition of phospho-donors (e.g. acetyl phosphate) have little to no effect on phosphorylation state. By applying protein production conditions that decrease the pool of intracellular acetyl-phosphate in E. coli, we found a reduction in the phosphorylated population of CopR II when magnesium was added to the media, but observed no change in phosphorylated population when CopR II is expressed in E. coli BL21 (DE3) ∆pta, a mutant with a metabolic disruption to the acetyl-phosphate pathway. Therefore, the specific mechanism of post-translational phosphorylation of RRs in E. coli remains obscure. These findings show the importance of characterizing the phosphorylations state of proteins when heterologously expressed, since their biochemical and physiological properties are dependent on post-translational modification. Competing Interest Statement The authors have declared no competing interest.