Biology subjects

Baker, J.

Publications and source records attributed to Baker, J..

4 recordsLinked to original sources

bioRxiv2018

Spatial and Temporal Analysis of the Stomach and Small Intestinal Microbiota in Fasted Healthy Humans

Although the microbiota in the proximal gastrointestinal (GI) tract has been implicated in health and disease, much of these microbes remains understudied compared to the distal GI tract. This study characterized the microbiota across multiple proximal GI sites over time in healthy individuals.\n\nAs part of a study of the pharmacokinetics of oral mesalamine administration, healthy, fasted volunteers (N=8; 10 observation periods total) were orally intubated with a four-lumen catheter with multiple aspiration ports. Samples were taken from stomach, duodenal, and multiple jejunal sites, sampling hourly ([≤]7 hours) to measure mesalamine (administered at t=0), pH, and 16S rRNA gene-based composition.\n\nWe observed a predominance of Firmicutes across proximal GI sites, with significant variation compared to stool. The microbiota was more similar within individuals over time than between subjects, with the fecal microbiota being unique from that of the small intestine. The stomach and duodenal microbiota displayed highest intra-individual variability compared to jejunal sites, which were more stable across time. We observed significant correlations in the duodenal microbial composition with changes in pH; linear mixed models identified positive correlations with multiple Streptococcus operational taxonomic units (OTU) and negative correlations with multiple Prevotella and Pasteurellaceae OTUs. Few OTUs correlated with mesalamine concentration.\n\nThe stomach and duodenal microbiota exhibited greater compositional dynamics compared to the jejunum. Short-term fluctuations in the duodenal microbiota was correlated with pH. Given the unique characteristics and dynamics of the proximal GI tract microbiota, it is important to consider these local environments in health and disease states.

microbiology↗

bioRxiv2018

ATRAID, a genetic factor that regulates the clinical action of nitrogen-containing bisphosphonates on bone.

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFFs) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase (FDPS), resulting in defects in protein prenylation. Yet it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID. Loss of ATRAID function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Lastly, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare non-synonymous coding variants in patients with ONJ or AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people. One Sentence SummaryATRAID is essential for responses to the commonly prescribed osteoporosis drugs nitrogen-containing bisphosphonates. OverlineBONE

genomics↗

bioRxiv2017

150 million years of sustained increase in pterosaur flight efficiency

The long-term accumulation of biodiversity has been punctuated by remarkable evolutionary transitions that allowed organisms to exploit new ecological opportunities, and often resulted in large radiations of species. The Mesozoic flying reptiles - pterosaurs - which dominated the skies for over 150 million years (Myr), were the product of such a transition. The ancestors of pterosaurs were small and likely bipedal early archosaurs, which were certainly well adapted to terrestrial locomotion. More than 220 Myr ago, at some point in the Triassic, pterosaurs took flight and subsequently appear to have become capable and efficient flyers. However, the evolutionary processes that led to this efficiency remain enigmatic. Given the lack of proto-pterosaurs it is difficult to study how flight first evolved in this group, but we can test hypotheses about evolutionary changes to the energetics of locomotion following the transition to flight. Early pterosaurs were challenged by the c ...

evolutionary biology↗

bioRxiv2016

Genome-Wide Association Study Reveals First Locus for Anorexia Nervosa and Metabolic Correlations

Anorexia nervosa (AN) is a serious eating disorder characterized by restriction of energy intake relative to requirements, resulting in abnormally low body weight. It has a lifetime prevalence of approximately 1%, disproportionately affects females1,2, and has no well replicated evidence of effective pharmacological or psychological treatments despite high morbidity and mortality2. Twin studies support a genetic basis for the observed aggregation of AN in families3, with heritability estimates of 48%-74%4. Although initial genome-wide association studies (GWASs) were underpowered5,6, evidence suggested that signals for AN would be detected with increased power5. We present a GWAS of 3,495 AN cases and 10,982 controls with one genome-wide significant locus (index variant rs4622308, p=4.3x10-9) in a region (chr12:56,372,585-56,482,185) which includes six genes. The SNP-chip heritability [Formula] of AN from these data is 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability stems from common genetic variation. Using these GWAS results, we also find significant positive genetic correlations with schizophrenia, neuroticism, educational attainment, and HDL cholesterol, and significant negative genetic correlations with body mass, insulin, glucose, and lipid phenotypes. Our results support the reconceptualization of AN as a disorder with both psychiatric and metabolic components.

genomics↗