Biology subjects

Johnson, K. W.

Publications and source records attributed to Johnson, K. W..

9 recordsLinked to original sources

bioRxiv2026

Ocean acidification alters hypoxia sensitivity and oxyregulation in reef-building corals

Coastal marine ecosystems are increasingly threatened by multiple stressors such as ocean acidification and deoxygenation, but how these co-occurring stressors interact is often poorly understood. This is especially true for tropical coral reefs where deoxygenation is an emerging yet understudied threat. Using hypoxia response curves combined with rigorous pH control, we show that acidification alters hypoxia sensitivity and oxyregulation of reef-building corals in a species-specific manner: three species exhibited increased sensitivity to various degrees, while the fourth showed enhanced tolerance. Consequently, acidification pushes critical hypoxia thresholds into oxygen regimes already prevalent on reefs today, potentially driving shifts in community composition and accelerating risks to reef resilience as these stressors intensify in the future. Our findings challenge assumptions of uniform coral vulnerability under multi-faceted climate change, emphasizing the need for trait-based approaches and to account for stressor interactions in predictive models to better anticipate coral reef futures under rapid climate change.

ecology↗

bioRxiv2026

Presynaptic NMDA receptors on mouse mossy fiber terminals mediate rapid BDNF release by ketamine and hydroxynorketamine

Major depressive disorder is associated with deficits in hippocampal synaptic plasticity that depend on brain-derived neurotrophic factor (BDNF) release from both axonal and dendritic compartments. Antidepressant efficacy requires enhanced BDNF signaling, thought to be mediated by drug-induced BDNF release from postsynaptic dendritic spines. Here, we show that fast-acting antidepressants rapidly trigger BDNF secretion from presynaptic terminals in hippocampal area CA3. At antidepressant-relevant concentrations, ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) induced BDNF release within minutes from mossy fiber terminals of dentate granule neurons in rat hippocampal cultures, with no detectable secretion from dendritic spines. This antidepressant-evoked BDNF release required presynaptic NMDA receptors (preNMDARs). Conditional genetic deletion of preNMDARs from granule neurons abolished ketamine- and HNK-induced BDNF exocytosis in acute mouse hippocampal slices, establishing a presynaptic receptor mechanism for antidepressant-induced neurotrophin release. In CA3 pyramidal neurons that receive mossy fiber input, both compounds induced rapid remodeling of dendritic spines, resulting in increased spine density. Together, these findings identify presynaptic terminals as a previously unrecognized source of antidepressant-evoked BDNF release and establish a new cellular mechanism for the rapid synaptic effects of fast-acting antidepressants.

neuroscience↗

bioRxiv2025

Compound hypoxia with heat or acidification stress induces synergistic and additive effects on coral physiology

As climate change accelerates, coastal marine ecosystems are increasingly exposed to co-occurring stressors whose combined effects are nonlinear and difficult to predict. Deoxygenation is a rapidly intensifying yet underrecognized threat to coral reefs that interacts with heat and acidification to alter coral physiology and stress resilience. However, the effects of hypoxia-related compound events on corals are largely unknown, underscoring the need for multi-stressor studies. Here, we conducted two extended-exposure experiments (12-17 days) across the coral species Porites furcata, Porites astreoides and Siderastrea siderea, to disentangle the individual and combined effects of low dissolved oxygen (hypoxia) with either heat or acidification. We measured eight phenotypic traits related to growth, metabolism, and symbiosis health to test whether hypoxia imposes energetic constraints or other physiological stress that amplify the effects of heat or acidification. Standardized effect size analysis across 24 stressor-trait combinations revealed 13 additive, 10 synergistic, and only one antagonistic response. Hypoxia consistently suppressed dark respiration by 37-49% across species and altered photophysiology in the two Porites species, whereas acidification alone had minimal effects, particularly in S. siderea. Heat stress caused the most pronounced declines across nearly all traits, and when combined with hypoxia, it produced the highest number of synergistic interactions. In contrast, the combination of hypoxia and acidification largely resulted in additive responses, suggesting that independent physiological mechanisms underlie these effects. All corals showed strong metabolic depression under hypoxia which is likely beneficial as a short-term adaptive response but may impose energetic constraints in the long-term. These findings highlight deoxygenation as critical yet often overlooked drivers of coral reef vulnerability. More multi-stressor experiments across a range of species are urgently needed to improve predictions of reef resilience under future ocean conditions, where compound stress events are expected to become more frequent and severe.

ecology↗

bioRxiv2025

Physiological mechanisms underlying coral acclimatization capacity to novel, multi-stressor conditions

Reef-building corals are under pressure to acclimatize and/or adapt to multiple co-occurring stressors, including climate change and declines in water quality. However, their capacity to do so is largely unknown. Yet, some corals naturally persist in habitats with multi-stressor conditions which can provide crucial insight into coral adaptive capacity under future ocean conditions. To assess the role of phenotypic plasticity and local adaptation in coral acclimatory responses to novel conditions, we reciprocally transplanted two coral species (Siderastrea siderea, branching Porites) between a multi-stressor, highly variable inland bay and a more stable fringing reef, and measured key phenotypic traits after 0, 4, and 12 months. Reef-origin corals demonstrated high plasticity when transplanted to the bay, as both species maintained high survival and calcification, and matched bay natives phenotypic traits. Yet, both species had reduced photosynthesis-to-respiration ratios, highlighting the risk of metabolic tradeoffs unless compensated for through increased heterotrophy. Conversely, bay-origin corals had enhanced photosynthetic performance but lower calcification on the reef. Reaction norms provided stronger evidence for environmental specialization in bay-origin than reef-origin corals, which could limit their use as stress-tolerant source corals for reef restoration. Overall, our findings suggest multi-stressor variability may promote specialized genotypes, rather than increased phenotypic plasticity.

ecology↗

bioRxiv2022

A common human brain-derived neurotrophic factor polymorphism leads to sustained depression of excitatory synaptic transmission by isoflurane in hippocampus

Multiple presynaptic and postsynaptic targets have been identified for the reversible neurophysiological effects of general anesthetics on synaptic transmission and neuronal excitability. However, the synaptic mechanisms involved in persistent depression of synaptic transmission resulting in more prolonged neurological dysfunction following anesthesia are less clear. Here, we show that brain-derived neurotrophic factor (BDNF), a growth factor implicated in synaptic plasticity and dysfunction, enhances glutamate synaptic vesicle exocytosis, and that attenuation of vesicular BDNF release by isoflurane contributes to transient depression of excitatory synaptic transmission in mice. This reduction in synaptic vesicle exocytosis was irreversible in neurons that release less endogenous BDNF due to a polymorphism (BDNF Val66Met) compared to wild-type mouse hippocampal neurons following isoflurane exposure. These effects were prevented by exogenous application of BDNF. Our findings identify a role for a common human BDNF single nucleotide polymorphism (Val66Met; rs6265) in persistent changes of synaptic function following isoflurane exposure. These persistent alterations in excitatory synaptic transmission have important implications for the role of genotype in anesthetic effects on synaptic plasticity and neurocognitive function.

neuroscience↗

bioRxiv2021

Pleiotropic Variability Score: A Genome Interpretation Metric to Quantify Phenomic Associations of Genomic Variants

A more complete understanding of phenomic space is critical for elucidating genome-phenome relationships and for assessing disease risk from genome sequencing. To incorporate knowledge of how related a variants associations are, we developed a new genome interpretation metric called Pleiotropic Variability Score (PVS). PVS uses semantic reasoning to score the relatedness of a genetic variants associated phenotypes based on those phenotypes relationships in the human phenotype ontology (HPO) and disease ontology (DO). We tested 78 unique semantic similarity methods and integrated six robust metrics to define the pleiotropy score of SNPs. We computed PVS for 12,541 SNPs which were mapped to 382 HPO and 317 DO unique phenotype terms in a genotype-phenotype catalog (10,021 SNPs mapped to DO phenotypes and 8,569 SNPs mapped to HPO phenotypes). We validated the utility of PVS by computing pleiotropy using an electronic health record linked genomic database (BioME, n=11,210). Further we demonstrate the application of PVS in personalized medicine using "personalized pleiotropy score" reports for individuals with genomic data that could potentially aid in variant interpretation. We further developed a software framework to incorporate PVS into VCF files and to consolidate pleiotropy assessment as part of genome interpretation pipelines. As the genome-phenome catalogs are growing, PVS will be a useful metric to assess genetic variation to find SNPs with highly pleiotropic effects. Additionally, variants with varying degree of pleiotropy can be prioritized for explorative studies to understand specific roles of SNPs and pleiotropic hubs in mediating novel phenotypes and drug development.

bioinformatics↗

bioRxiv2019

fragilityindex: An R Package for Statistical Fragility Estimates in Biomedicine

Poor reproducibility is a growing crisis in biomedical research. The fragility index was introduced as a convenient measure to estimate how fragile statistical results in clinical trials are to small perturbations in event outcome counts. There is currently no freely available R package to produce this calculation. Furthermore, the original definition of the method is applicable only to 2x2 contingency tables. As such, we developed an R package to calculate fragility index. We have also extended the concept of a statistical fragility index to two of the most commonly used methods in clinical research, survival analysis via weighted log-rank tests and logistic regression, and implemented these technique sin this R package. We describe example applications of these methods to existing publically available datasets. This R package is freely available under the AGPL license on CRAN (https://cran.r-project.org/web/packages/fragilityindex/index.html). The most recent versions may be downloaded and installed via Github (https://github.com/kippjohnson/fragilityindex).

bioinformatics↗

bioRxiv2018

Predictive modeling of susceptibility to substance abuse, mortality and drug-drug interactions in opioid patients

Opioid addiction causes high degree of morbidity and mortality. Preemptive identification of patients at risk of opioid dependence and developing intelligent clinical decisions to deprescribe opioids to the vulnerable patient population may help in reducing the burden. Identifying patients susceptible to mortality due to opioid-induced side effects and understanding the landscape of drug-drug interaction pairs aggravating opioid usage are significant, yet, unexplored research questions. In this study, we present a collection of predictive models to identify patients at risk of opioid abuse, mortality and drug-drug interactions in the context of opioid usage. Using publicly available dataset from MIMIC-III, we developed predictive models (opioid abuse models a=Logistic Regression; b=Extreme Gradient Boosting and mortality model= Extreme Gradient Boosting) and identified potential drug-drug interaction patterns. To enable the translational value of our work, the predictive model and all associated software code is provided. This repository could be used to build clinical decision aids and thus improve the optimization of prescription rates for vulnerable population.

epidemiology↗

bioRxiv2018

Rapid Therapeutic Recommendations in the Context of a Global Public Health Crisis using Translational Bioinformatics Approaches: A proof-of-concept study using Nipah Virus Infection

We live in a world of emerging new diseases and old diseases resurging in more aggressive forms. Drug development by pharmaceutical companies is a market-driven and costly endeavor, and thus it is often a challenge when drugs are needed for diseases endemic only to certain regions or which affect only a few patients. However, biomedical open data is accessible and reusable for reanalysis and generation of a new hypotheses and discovery. In this study, we leverage biomedical data and tools to analyze available data on Nipah Virus (NiV) infection. NiV infection is an emerging zoonosis that is transmissible to humans and is associated with high mortality rates. In this study, explored the application of computational drug repositioning and chemogenomic enrichment analyses using host transcriptome data to match drugs that could reverse the virus-induced gene signature. We performed analyses using two gene signatures: i) A previously published gene signature (n=34), and ii) a gene signature generated using the characteristic direction method (n= 5,533). Our predictive framework suggests that several drugs including FDA approved therapies like beclometasone, trihexyphenidyl, S-propranolol etc. could modulate the NiV infection induced gene signatures in endothelial cells. A target specific analysis of CXCL10 also suggests the potential application of Eldelumab, an investigative therapy for Crohns disease and ulcerative colitis, as a putative candidate for drug repositioning. To conclude, we also discuss challenges and opportunities in clinical trials (n-of-1 and adaptive trials) for repositioned drugs. Further follow-up studies including biochemical assays and clinical trials are required to identify effective therapies for clinical use. Our proof-of-concept study highlights that translational bioinformatics methods including gene expression analyses and computational drug repositioning could augment epidemiological investigations in the context of an emerging disease with no effective treatment.

microbiology↗