Biology subjects

Baker, J.

Publications and source records attributed to Baker, J..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

Loss of FOXP3 function causes expansion of two pools of autoreactive T cells in patients with IPEX syndrome.

The monogenic autoimmune disease Immunedysregulation polyendocrynopathy entheropathy X-linked syndrome (IPEX) has elucidated the essential function of the transcription factor FOXP3 and of thymic-derived regulatory T (Treg) cells in controlling autoimmunity. However, the presence of autoreactive T cells in IPEX remains undetermined, thus representing a crucial gap in understanding the origin of autoimmunity in a FOXP3 deficient immune system. Combining epigenetic analysis as a lineage marker of Treg identity and TCR sequencing to assess the self-reactive clones, we showed that IPEX patients have two pools of expanded autoreactive T cells. The first originates from the expansion of autoreactive effector T cells (Teff), likely due to loss of Treg suppressive function since it is absent in carrier mothers, in whom Treg cells are functional. The second pool originates, unexpectedly, from Treg cells which lose their phenotypic markers, including CD25 and FOXP3. We call these loss of identity Treg cells and show that they are i) suppressed by healthy donor Treg in a patient post hematopoietic transplantation despite low donor chimerism, and ii) not detectable in patients with Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED), a monogenic autoimmune disease of thymic origin. Moreover, we demonstrate that FOXP3 knock-out in Treg cells leads to increased Treg expansion and production of Th17 and Th2 cytokines, known to be increased in IPEX patients. These results suggest that the loss of identity Treg cells could directly contribute to immune dysregulation in IPEX. Collectively, we provide a better understanding of autoimmunity and novel ways to monitor the effects of Treg cell therapies in IPEX disease or other autoimmune diseases. One Sentence SummaryMutations of FOXP3 gene in humans cause expansion of autoreactive T cells originating from both effector T cells and regulatory T cells which gain effector function.

immunology↗

bioRxiv2021

Antibodies to ILT3 abrogate myeloid immunosuppression and enable tumor killing

Tumor myeloid suppressor cells impede response to T cell checkpoint immunotherapy. Immunoglobulin-like transcript 3 (ILT3, gene name, LILRB4) expressed on dendritic cells (DCs) promotes antigen-specific tolerance. Circulating monocytic MDSCs that express ILT3 have been linked to clinical outcomes and a soluble form of ILT3 is elevated in certain cancers. We find that LILRB4 expression is correlated with Gene Expression Profile of T-cell inflamed tumor microenvironment shown to be significantly associated with response to the anti-PD1 antibody pembrolizumab across several tumor types. A potent and selective anti-ILT3 mAb effectively antagonized IL-10 polarization of DCs and enabled T cell priming. In an MLR assay anti-ILT3 combined with pembrolizumab afforded greater CD8+ T cell activation compared to either agent alone. Anti-ILT3 antibodies impaired the acquisition of a suppressive phenotype of monocytes co-cultured with SK-MEL-5 cancer cells, accompanied by a reduction in surface detection of peptidase inhibitor 16, a cis interaction candidate for ILT3. Growth of myeloid cell-abundant SK-MEL-5 tumors was abrogated by ILT3 blockade and remodeling of the immune tumor microenvironment was evident by CyTOF. These data support the testing of anti-ILT3 antibodies for the treatment of a wide range of solid tumors replete with myeloid cells.

cancer biology↗

bioRxiv2021

Nanopore adaptive sampling for mitogenome sequencing and bloodmeal identification in hematophagous insects

Blood-feeding insects are important vectors for an array of zoonotic pathogens. Despite significant research focused on well-documented insect vectors of One Health importance, resources for molecular species identification of a large number of hematophagous arthropods are limited. Advancements in next-generation sequencing technologies provide opportunities for targeting mitochondrial genomes of blood-feeding insects, as well as their bloodmeal hosts. This dual approach holds great promise for elucidating complex disease transmission pathways and enhancing the molecular resources for the identification of cryptic insect species. To this end, we leveraged the newly developed Oxford Nanopore Adaptive Sampling (NAS) pipeline to dually sequence the mitogenomes of hematophagous insects and their bloodmeals. Using NAS, we sequenced the entire mitogenomes of Aedes vexans, Culex restuans, Culex territans, and Chrysops niger and successfully identified bloodmeal hosts of Chrysops niger, Culex restuans, and Aedes trivittatus. We show that NAS has the utility to simultaneously molecularly identify blood-feeding insects and characterize disease transmission pathways through bloodmeal host identification. Moreover, our data indicate NAS can facilitate a wide array of molecular systematic studies through novel phylogenetic capture methods. We conclude the NAS approach has great potential for informing global One Health initiatives centered on the mitigation of vector-borne disease through dual vector and bloodmeal identification.

genomics↗

bioRxiv2021

Multi-parameter optical imaging of immune cell activity in chimeric antigen receptor T-cell and checkpoint blockade therapies

Longitudinal multimodal imaging presents unique opportunities for noninvasive surveillance and prediction of treatment response to cancer immunotherapy. In this work we first designed a novel granzyme B activated self-assembly small molecule, G-SNAT, for quantitative assessment of cytotoxic T lymphocyte mediated cancer cell killing in vivo. In lymphoma tumor bearing mice, the retention of cyanine 5 labeled G-SNAT-Cy5 was shown to be highly correlated to CAR T-cell mediated granzyme B release and tumor eradication. In colorectal tumor-bearing transgenic mice, expressing firefly luciferase in hematopoietic cells, and which received combination treatment of anti-PD-1 and anti-CTLA-4, longitudinal bioluminescence and fluorescence imaging revealed the dynamics of immune cell expansion, trafficking, tumor infiltration, and cytotoxic activity which predicted therapeutic outcome before tumor shrinkage was evident. These results support further development of G-SNAT for imaging early immune response to checkpoint blockade and CAR T-cell therapy in patients and highlight the utility of multimodality imaging for improved mechanistic insights into cancer immunotherapy.

immunology↗

bioRxiv2021

Mobile Footprinting: Linking Individual Distinctiveness in Mobility Patterns to Mood, Sleep, and Brain Functional Connectivity

Mapping individual differences in behavior is fundamental to personalized neuroscience. Here, we establish that statistical patterns of smartphone-based mobility features represent unique "footprints" that allow individual identification. Critically, mobility footprints exhibit varying levels of person-specific distinctiveness and are associated with individual differences in affective instability, circadian irregularity, and brain functional connectivity. Together, this work suggests that real-world mobility patterns may provide an individual-specific signature linking brain, behavior, and mood.

neuroscience↗

bioRxiv2021

Allogeneic CAR-invariant Natural Killer T Cells Exert Potent Antitumor Effects Through Host CD8 T cell Cross-Priming

The development of allogeneic chimeric antigen receptor (CAR) T cell therapies for off-the-shelf use is a major goal yet faces two main immunological challenges, namely the risk of graft-versus-host-disease (GvHD) induction by the transferred cells and the rejection by the host immune system limiting their persistence. We demonstrate that allogeneic CAR-engineered invariant natural killer T (iNKT) cells, a cell population without GvHD-induction potential that displays immunomodulatory properties, exerted potent direct and indirect antitumor activity in murine models of B-cell lymphoma when administered across major MHC-barriers. In addition to their known direct cytotoxic effect, allogeneic CAR iNKT cells induced tumor-specific antitumor immunity through host CD8 T cell cross-priming, resulting in a potent antitumor effect lasting longer than the physical persistence of the allogeneic cells. The utilization of off-the-shelf allogeneic CAR iNKT cells could meet significant unmet needs in the clinic.

immunology↗

bioRxiv2021

A Large-Scale Brain Network Mechanism for Increased Seizure Propensity in Alzheimer's Disease

People with Alzheimers disease (AD) are 6-10 times more likely to develop seizures than the healthy aging population. Leading hypotheses largely consider increased excitability of local cortical tissue as primarily responsible for increased seizure prevalence in AD. However, both local dynamics and large-scale brain network structure are believed to be crucial for determining seizure likelihood and phenotype. In this study, we combine computational modelling with electrophysiological data to demonstrate a potential large-scale brain network mechanism for increased seizure propensity in people with AD. EEG was recorded from 21 people with probable AD and 26 healthy controls. At the time of EEG acquisition, all participants were free from seizures. Whole brain functional connectivity derived from source-reconstructed EEG recordings was used to build subject-specific brain network models of seizure transitions using an approach previously validated on participants with epilepsy vs controls. As cortical tissue excitability was increased in the simulations, network models of AD simulations were more likely to transition into seizures than simulations from healthy controls. Our results suggest an increased group-level probability of developing seizures at a future time for AD participants. We subsequently used the model to assess seizure propensity of different regions across the cortex. We found the most important regions for seizure generation were those typically burdened by amyloid-beta at the early stages of AD, as previously reported by in-vivo and post-mortem staging of amyloid plaques. These included cingulate, medial temporal, and orbital regions. Analysis of these spatial distributions also give potential insight into mechanisms of increased susceptibility to generalized (as opposed to focal) seizures in AD vs controls. This research suggests avenues for future studies testing patients with seizures, e.g. co-morbid AD/epilepsy patients, and comparisons with PET and MRI scans to relate regional seizure propensity with amyloid/tau pathology and cortical atrophy. Author summaryPeople with Alzheimers disease (AD) are more likely to develop seizures than cognitively healthy people. In this study, we aimed to understand whether whole-brain network structure is related to this increased seizure likelihood. We used electroencephalography (EEG) to estimate brain networks from people with AD and healthy controls. We subsequently inserted these networks into a model brain and simulated disease progression by increasing the excitability of brain tissue. We found the simulated AD brains were more likely to develop seizures than the simulated control brains. No participants had seizures when we collected data, so our results suggest an increased probability of developing seizures at a future time for AD participants. Therefore functional brain network structure may play a role in increased seizure likelihood in AD. We also used the model to examine which brain regions were most important for generating seizures, and found that the seizure-generating regions corresponded to those typically affected in early AD. Our results also provide a potential explanation for why people with AD are more likely to have generalized seizures (i.e. seizures involving the whole brain, as opposed to focal seizures which only involve certain areas) than the general population with epilepsy.

neuroscience↗

bioRxiv2020

Genome wide identification of QTL associated with yield and yield components in two popular wheat cultivars TAM 111 and TAM 112

Two drought-tolerant wheat cultivars, TAM 111 and TAM 112, have been widely grown in the Southern Great Plains of the U.S. and used as parents in many wheat breeding programs worldwide. This study aimed to reveal genetic control of yield and yield components in the two cultivars under both dryland and irrigated conditions. A mapping population containing 124 F5:7 recombinant inbred lines (RILs) was developed from the cross of TAM 112/TAM 111. A set of 5,948 SNPs from the wheat 90K iSelect array and double digest restriction-site associated DNA sequencing was used to construct high-density genetic maps. Data for yield and yield components were obtained from 11 environments. QTL analyses were performed based on 11 individual environments, across all environments, within and across mega-environments. Thirty-six unique consistent QTL regions were distributed on 13 chromosomes including 1A, 1B, 1D, 2A, 2D, 3D, 4B, 4D, 6A, 6B, 6D, 7B, and 7D. Ten unique QTL with pleiotropic effects were identified on four chromosomes and eight were in common with the consistent QTL. These QTL increased dry biomass grain yield by 16.3 g m-2, plot yield by 28.1 g m-2, kernels spike-1 by 0.7, spikes m-2 by 14.8, thousand kernel weight by 0.9 g with favorable alleles from either parent. TAM 112 alleles mainly increased spikes m-2 and thousand kernel weight while TMA 111 alleles increased kernels spike-1, harvest index and grain yield. The saturated genetic map and markers linked to significant QTL from this study will be very useful in developing high throughput genotyping markers for tracking the desirable haplotypes of these important yield-related traits in popular parental cultivars.

genetics↗

bioRxiv2019

The Min system disassembles FtsZ foci and inhibits polar peptidoglycan remodeling in Bacillus subtilis

A microfluidic system coupled with fluorescence microscopy is a powerful approach for quantitative analysis of bacterial growth. Here, we measure parameters of growth and dynamic localization of the cell division initiation protein FtsZ in Bacillus subtilis. Consistent with previous reports, we find that after division FtsZ rings remain at the cell pole, and FtsZ ring disassembly coincides with rapid Z-ring accumulation at the midcell. In cells mutated for minD, however, the polar FtsZ rings persist indefinitely, suggesting that the primary function of the Min system is in Z-ring disassembly. The inability to recycle FtsZ monomers in the minD mutant results in maintenance of multiple Z-rings simultaneously, that are restricted by competition for newly synthesized FtsZ. Whereas the parameters of FtsZ dynamics change in the minD mutant, the overall cell cycle remains the same, albeit with elongated cells necessary to accumulate a threshold concentration of FtsZ for promoting medial division. Finally, the minD mutant characteristically produces minicells composed of polar peptidoglycan shown to be inert for remodeling in the wild type. Polar peptidoglycan, however, loses its inert character in the minD mutant suggesting that not only is the Min system important for recycling FtsZ but also may have a secondary role in the regulation of peptidoglycan remodeling. IMPORTANCEMany bacteria grow and divide by binary fission in which a mothercell divides into two identical daughter cells. To produce two equally sized daughters, the division machinery, guided by FtsZ, must dynamically localize to the midcell each cell cycle. Here, we quantitatively analyze FtsZ dynamics during growth and find that the Min system of Bacillus subtilis is essential to disassemble FtsZ rings after division. Moreover, a failure to efficiently recycle FtsZ results in an increase in cell size. Finally, we show that the Min system has an additional role in inhibiting cell wall turnover and contributes to the "inert" property of cell walls at the poles.

microbiology↗

bioRxiv2019

Estimating northern fur seal pup production: A case study of batch mark abundance estimation

We describe a hierarchical N-mixture model for estimating northern fur seal pup production from batch mark-resight data. Our goal was to improve upon a traditional design-based estimation method used for over 50 years. To this end, we propose a hierarchical N-mixture model to account for differences in animal availability for resighting and observer detection probabilities. A Bayesian approach is used for inference with three separate methods proposed for necessary computations. First a straightforward posterior sample is drawn using MCMC. This was considered the gold standard for this analysis. However, we also consider an approximate model-based on Gaussian approximation of the Poisson and binomial distributions used in the exact hierarchical model. By using the Gaussian approximations, analytic integration can be used to marginalize over latent components. Inference can then be made by maximizing the posterior to find the mode. Following this we investigate both delta-method and parametric bootstrap approaches for calculating abundance and the associated standard errors with batch sampling data collected on northern fur seals in 2016. Each of the three newly proposed methods produced virtually identical estimates and standard errors. In addition, the parametric bootstrap approximation to a posterior sample was also virtually the same as the MCMC derived sample. There were a handful of small differences in the point estimates of abundance but these were not large enough to be especially notable. There were some noticeable differences in uncertainty estimates. The production estimate coefficients of variation ranged from 2.5-9.5% for the model-based estimates, but 0.0-12.5% for the design-based estimates. The design-based estimates of uncertainty were more volatile using the design-based method with some standard error estimates unreasonably small. Through a case study we have provided support for using Gaussian approximation in N-mixture type models when abundance is relatively large. These situations are typically challenging for fitting models using any sort of marginalization because there is no analytic solution for the exact models. However, when abundances are large using a Gaussian approximated model allows for analytic integration over latent abundance states which can greatly facilitate methodology such as maximum likelihood or posterior inference.

ecology↗

bioRxiv2019

Cariogenic Streptococcus mutans produces strain-specific antibiotics that impair commensal colonization

Streptococcus mutans is a common constituent of dental plaque and an etiologic agent of dental caries (tooth decay). Here we elucidate a biosynthetic pathway, encoded by globally distributed strains of S. mutans, which produces a series of bioactive small molecules including reutericyclin and two N-acyl tetramic acid analogues active against oral commensal bacteria. This pathway may provide S. mutans with a competitive advantage, promoting dysbiosis and caries pathogenesis.

microbiology↗

bioRxiv2019

Shared Genetic Risk between Eating Disorder- and Substance-Use-Related Phenotypes: Evidence from Genome-Wide Association Studies

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa (BN) and problem alcohol use (genetic correlation [rg], twin-based=0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge-eating, AN without binge-eating, and a BN factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder (MDD). Total sample sizes per phenotype ranged from ~2,400 to ~537,000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (rg=0.18; false discovery rate q=0.0006), cannabis initiation and AN (rg=0.23; q<0.0001), and cannabis initiation and AN with binge-eating (rg=0.27; q=0.0016). Conversely, significant negative genetic correlations were observed between three non-diagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge-eating (rgs=-0.19 to -0.23; qs<0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for MDD loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships between these behaviors.

genetics↗

bioRxiv2019

Daytime Color Preference in Drosophila Depends on the Circadian Clock and TRP Channels

By guiding animals towards food and shelter and repelling them from potentially harmful situations, light discrimination according to colour can confer survival advantages1,2. Such colour-dependent behaviour may be experiential or innate. Data on innate colour preference remain controversial in mammals3 and limited in simpler organisms4-7. Here we show that when given a choice among blue, green and dim light, fruit flies exhibit an unexpectedly complex pattern of colour preference that changes with the time of day. Flies show a strong preference for green in the early morning and late afternoon, a reduced green preference at midday and a robust avoidance of blue throughout the day. Genetic manipulations reveal that the peaks in green preference require rhodopsin-based photoreceptors, and are controlled by the circadian clock. The midday reduction in green preference in favour of dim light depends on the Transient Receptor Potential (TRP) channels dTRPA1 and Pyrexia (Pyx), and is also timed by the clock. In contrast, blue avoidance is primarily mediated by class IV multidendritic neurons, requires the TRP channel Painless (Pain) and is independent of the clock. With unexpected roles for several TRP channels in Drosophila colour-specific phototransduction, our results reveal distinct pathways of innate colour preference that coordinate the flys behavioural dynamics in ambient light.

neuroscience↗

bioRxiv2019

The effect of light vs dark coat color on thermal status in Labrador Retriever dogs.

Although dark coat color in dogs has been theorized as a risk factor for thermal stress, there is little evidence in the scientific literature to support that position. We utilized 16 non-conditioned Labradors (8 black and 8 yellow) in a three-phase test to examine effects of coat color on thermal status of the dog. Rectal, gastrointestinal (GI), surface temperature, and respiration rate measured in breaths per minute (bpm), were collected prior to (Baseline -- phase 1) and immediately after a controlled 30-minute walk in an open-air environment on a sunny day (Sunlight -- phase 2). Follow up measurements were taken 15 minutes after walking (Cool down - phase 3) to determine post-exposure return to baseline. No effect of coat color was measured for rectal, gastrointestinal or surface temperature, or respiration (P > 0.05) in dogs following their 30-minute walk. Temperatures increased similarly across both coat colors (rectal 1.88 {degrees}C and 1.83 {degrees}C; GI 1.89 {degrees}C and 1.94 {degrees}C; eye 1.89 {degrees}C and 1.94 {degrees}C; abdominal 2.93 {degrees}C and 2.35 {degrees}C) for black and yellow dogs respectively during the sunlight phase (P > 0.05). All temperatures and respiration rates decreased similarly across coat colors for rectal (0.9{degrees}C and 1.0{degrees}C) and GI (1.5 {degrees}C and 1.3{degrees}C) for black and yellow dogs respectively (P > 0.05). Similarly, sex did not impact thermal status across rectal, gastrointestinal or surface temperature or respiration rates measured (P > 0.05). These data contradict the commonly held theory that dogs with darker coat color may experience a greater thermal change when exposed to direct sunlight compared to dogs with a lighter coat color.

systems biology↗

bioRxiv2019

The Work Performed By Biological Motors

Molecular motors are enzymes that perform work (F {middle dot} x) when they move along a track a distance x against a constant force F. This work is performed through intermediate chemical steps in a motors ATPase reaction cycle, each step having a free energy change associated with it that is a sum of chemical, {Delta}{micro}chem, and mechanical, {Delta}{micro}ext, potentials. Defining {Delta}{micro}ext is fundamental to our understanding of how molecular motors work, yet after decades of study the definition of {Delta}{micro}ext remains disputed. Some postulate that {Delta}{micro}ext is a function of both F and x, while others assume that {Delta}{micro}ext is a function of neither F nor x, and still others argue that {Delta}{micro}ext is a function of F but not x. Here we evaluate these models and conclude that only the latter - a mechanochemical model proposed by A.V. Hill in the 1930s - describes molecular motor mechanochemistry.

biophysics↗

bioRxiv2018

Visual field advantage: Redefined by training?

In 1990, Fred Previc postulated that most peri-personal space interactions occurred in the lower visual field (LVF), leading to an advantage when compared to the upper visual field (UVF). It is not clear if extensive practice can affect the difference between interactions in the LVF/UVF. We tested male and female basketball varsity athletes and non-athletes on a DynaVision D2 visuomotor reaction task. We recruited basketball players because in their training they spend significant amount of time processing upper visual field information. We found a lower visual field advantage in all participants, but this advantage was significantly reduced in the athletes. The results suggest that training can be a powerful modulator of visuomotor function.

neuroscience↗

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↗