👤 John D Tompkins

CNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered into 15 broad categories by International Classification of Diseases-10 (ICD-10) coding. These donors were collected by six repositories comprising the National Institutes of Health NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants were detected in whole-genome sequencing (WGS), normalized and annotated to describe their functional impact, resulting in 171,121,209 unique variants and 1,078,774 non-silent variants. These raw and normalized data have been made available as a neurogenomics resource in the National Institute of Mental Health Data Archive (NIMH NDA) (nda.nih.gov), combined with donor-matched deep demographic and phenotypic data from the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate applications, we replicated the strong association observed in previous studies between pathogenic CAG nucleotide repeat expansions in the HTT gene with the clinical diagnosis of Huntington's disease, as well as associations of the APOE gene with Alzheimer's disease, and examined the association of polygenic risk scores with the three most common disease diagnoses in the cohort. Show less

Both sexually selected traits and mate preferences for these traits can be context dependent, yet how variation in preferred traits could select for context dependent preferences has rarely been examined. The signal reliability hypothesis predicts that mate preferences vary across contexts (e.g., environments) in relation to the reliability of the information preferred traits provide in those contexts. Extensive variation in copy number of mc4r B alleles on the Y-chromosome that associates with male size in Xiphophorus multilineatus allowed us to use a split-sibling design to determine if male size is more likely to provide information about male genotype (i.e., dam) when males were reared in a warm as compared to a cold environment. We then examined strength of preference for male size by females reared in the same two environments. We found that males were larger in the cold environment, but male size was more variable across dams in the warm environment, and therefore male size would be a more reliable indicator of dam (i.e., genetics) in the warm environment. Females reared in the warm environment had stronger mate preferences based on male size than cold reared females, with a significant influence of dam on strength of preference. Therefore, strength of female preference for male size was influenced by the temperature in which they were reared, with the direction of the difference across treatments supporting the signal reliability hypothesis. Understanding how the reliability of male traits can select for contextual variation in the strength of the female mate preferences will further our discovery of adaptive mate preferences. For example, a relationship between the strength of a female's mate preference and their growth rates was detected in the context where females had a preference based on male size, supporting a hypothesis from previous work with this species of disassortative mating in relation to growth rates to mitigate a documented growth-mortality tradeoff. Show less

Introduction: Despite significant advances in pediatric burn care, bloodstream infections (BSIs) remain a compelling challenge during recovery. A personalized medicine approach for accurate prediction of BSIs before they occur would contribute to prevention efforts and improve patient outcomes. Methods: We analyzed the blood transcriptome of severely burned (total burn surface area [TBSA] ≥20%) patients in the multicenter Inflammation and Host Response to Injury ("Glue Grant") cohort. Our study included 82 pediatric (aged <16 years) patients, with blood samples at least 3 days before the observed BSI episode. We applied the least absolute shrinkage and selection operator (LASSO) machine-learning algorithm to select a panel of biomarkers predictive of BSI outcome. Results: We developed a panel of 10 probe sets corresponding to six annotated genes ( ARG2 [ arginase 2 ], CPT1A [ carnitine palmitoyltransferase 1A ], FYB [ FYN binding protein ], ITCH [ itchy E3 ubiquitin protein ligase ], MACF1 [ microtubule actin crosslinking factor 1 ], and SSH2 [ slingshot protein phosphatase 2 ]), two uncharacterized ( LOC101928635 , LOC101929599 ), and two unannotated regions. Our multibiomarker panel model yielded highly accurate prediction (area under the receiver operating characteristic curve, 0.938; 95% confidence interval [CI], 0.881-0.981) compared with models with TBSA (0.708; 95% CI, 0.588-0.824) or TBSA and inhalation injury status (0.792; 95% CI, 0.676-0.892). A model combining the multibiomarker panel with TBSA and inhalation injury status further improved prediction (0.978; 95% CI, 0.941-1.000). Conclusions: The multibiomarker panel model yielded a highly accurate prediction of BSIs before their onset. Knowing patients' risk profile early will guide clinicians to take rapid preventive measures for limiting infections, promote antibiotic stewardship that may aid in alleviating the current antibiotic resistance crisis, shorten hospital length of stay and burden on health care resources, reduce health care costs, and significantly improve patients' outcomes. In addition, the biomarkers' identity and molecular functions may contribute to developing novel preventive interventions. Show less

G-quadruplexes (G4s) are nucleic acid structures found enriched within gene regulatory sequences. G4s control fundamental cellular processes, including replication, transcription, and translation. Proto-oncogenes are enriched with G4 sequences, while tumor-suppressor genes are depleted, suggesting roles for G4s in cell survival and proliferation. Specialized helicases participate in G4-mediated gene regulation via enzymatic unwinding activity. One such enzyme, DHX36/G4R1, is the major G4-helicase and is a master regulator of G4-DNAs and mRNAs. G4-resolution promotes the expression of proproliferative genes; as such, DHX36/G4R1 promotes cell proliferation. Little is known about how DHX36/G4R1 itself is regulated in nondividing cells. We hypothesized that DHX36/G4R1 protein binding partners are altered when a cell transitions from a dividing to a quiescent state. We found that DHX36/G4R1 co-purifies with a distinct set of proteins under quiescent conditions, which may represent a novel complex that regulates DHX36/G4R1 during cell cycle transitions and have implications for development and cancer. Show less

Quantitative real-time PCR was used to test whether cavernous nerve injury leads to a decrease in major pelvic ganglia (MPG) neuronal nicotinic ACh receptor (nAChR) subunit and postsynaptic density (PSD)-93 transcript levels. Subunits α3, β4, and α7, commonly expressed in the MPG, were selected for analysis. After 72 h in explant culture, MPG transcript levels for α3, β4, α7, and PSD-93 were significantly depressed. Three days after cavernous nerve axotomy or crush in vivo, transcript levels for α3, β4, and PSD-93, but not for α7, were significantly depressed. Three days after dissection of the cavernous nerve free of underlying tissue and application of a 5-mm lateral stretch (manipulation), transcript levels for α3 and PSD-93 were also significantly decreased. Seven days after all three surgical procedures, α3 transcript levels remained depressed, but PSD-93 transcript levels were still decreased only after axotomy or nerve crush. At 30 days postsurgery, transcript levels for the nAChR subunits and PSD-93 had recovered. ACh-induced currents were significantly smaller in MPG neurons dissociated from 3-day explant cultured ganglia than from those recorded in neurons dissociated from acutely isolated ganglia; this observation provides direct evidence showing that a decrease in nAChR function was coincident with a decrease in nAChR subunit transcript levels. We conclude that a downregulation of nAChR subunit and PSD-93 expression after cavernous nerve injury, or even manipulation, could interrupt synaptic transmission within the MPG and thus contribute to the loss of neural control of urogenital organs after pelvic surgeries. Show less