Biology subjects

Martin, W. J.

Publications and source records attributed to Martin, W. J..

5 recordsLinked to original sources

bioRxiv2022

Renegade Bacterial Genetic Sequences in a Stealth Adapted Virus: Biological and Diagnostic Implications

There are major differences between viruses, bacteria, and eukaryotic cells in the structuring of their genomes, modes of replication, and capacity to horizontally transfer genetic sequences. DNA sequencing studies on a virus cultured from a patient with chronic fatigue syndrome (CFS) have confirmed a previously underappreciated capacity of certain viruses to capture and transfer bacterial and cellular genetic sequences between eukaryotic cells as part of the infectious process. The virus originated from an African green monkey simian cytomegalovirus (SCMV). It is termed a stealth adapted virus since infection is not accompanied by inflammation. The immune evasion is attributed to the loss and mutation of the genes coding for the relatively few components that are normally targeted by the cellular immune system. This article provides further elucidation of the origins of many of the bacterial-derived genetic sequences present in the virus. There are multiple clones with close but non-identical sequence alignments with different genomic regions of the Ochrobactrum quorumnocens A44 species of bacteria. Another set of clones matched most closely to diverse genomic regions of Mycoplasma fermentans bacteria. The sequences of several other clones could only be approximately aligned to those of different types of bacteria. The sequence of clone 3B513 is consistent with genetic contributions from the genomes of several types of bacteria. The term viteria refers to viruses with bacteria-derived genetic sequences. They are the likely primary cause of CFS and autism, and to act as major cofactors in many illnesses, including AIDS. As a more general phenomenon viteria with different types of renegade bacterial sequences can lead to the mistaken diagnoses of bacterial rather than viral diseases. It is important to genetically sequence additional stealth adapted viruses from patients with a wide range of illnesses, including those currently being attributed to Mycoplasma, Borrelia, or Streptococcal infections.

microbiology↗

bioRxiv2019

Differential modulation of ventral tegmental area circuits by the nociceptin/orphanin FQ system

The neuropeptide nociceptin/orphanin FQ (N/OFQ) can be released by stressors and is associated with disorders of emotion regulation and reward processing. N/OFQ and its receptor, NOP, are enriched in dopaminergic pathways, and intra-ventricular agonist delivery decreases dopamine levels in the dorsal striatum, nucleus accumbens (NAc), and ventral tegmental area (VTA). We used whole cell electrophysiology in acute rat midbrain slices to investigate synaptic actions of N/OFQ. N/OFQ was primarily inhibitory, causing outward currents in both immunocytochemically identified dopaminergic (tyrosine hydroxylase positive (TH(+)) and non-dopaminergic (TH(-)) VTA neurons (effect at 1 M: 20 {+/-} 4 pA). Surprisingly, this effect was mediated by augmentation of postsynaptic GABAAR currents, unlike the substantia nigra pars compacta (SNc), where the N/OFQ induced outward currents were K+ channel dependent. A smaller population, 19% of all VTA neurons, responded to low concentrations N/OFQ with inward currents (10 nM: -11 {+/-} 2 pA). Following 100 nM N/OFQ, the response to a second N/OFQ application was markedly diminished in VTA neurons (14 {+/-} 10% of first response), but not in SNc neurons (90 {+/-} 20% of first response). N/OFQ generated outward currents in medial prefrontal cortex (mPFC)-projecting VTA neurons, but inward currents in a subset of posterior anterior cingulate cortex-projecting VTA neurons. While N/OFQ inhibited NAc-projecting VTA cell bodies, it had little effect on electrically or optogenetically evoked terminal dopamine release in the NAc measured ex vivo with fast scan cyclic voltammetry. These results extend our understanding of the N/OFQ system in brainstem circuits implicated in many neurobehavioral disorders. Significance statementThe neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are engaged under conditions of stress and are associated with reward processing disorders. Both peptide and receptor are highly enriched in ventral tegmental area (VTA) pathways underlying motivation and reward. Using whole cell electrophysiology in rat midbrain slices we found: 1) NOPs are functional on both dopaminergic and non-dopaminergic VTA neurons; 2) N/OFQ differentially regulates VTA neurons based on neuroanatomical projection target; and 3) repeated application of N/OFQ produces evidence of receptor desensitization in the VTA but not the SNc. These results reveal candidate mechanisms by which the NOP system regulates motivation and emotion.

neuroscience↗

bioRxiv2018

Highly Predictive Transdiagnostic Features Shared across Schizophrenia, Bipolar Disorder, and ADHD Identified Using a Machine Learning Based Approach

The Diagnostic and Statistical Manual of Mental Disorders (DSM) is the standard for diagnosing psychiatric disorders in the United States. However, evidence has suggested that symptoms in psychiatric disorders are not restricted to the boundaries between DSM categories, implying an underlying latent transdiagnostic structure of psychopathology. Here, we applied an importance-guided machine learning technique for model selection to item-level data from self-reported instruments contained within the Consortium for Neuropsychiatric Phenomics dataset. From 578 questionnaire items, we identified a set of features which consisted of 85 items that were shared across diagnoses of schizophrenia (SCZ), bipolar disorder (BD), and attention deficit/hyperactivity disorder (ADHD). A classifier trained on the transdiagnostic features reliably distinguished the patient group as a whole from healthy controls (classification AUC = 0.95) and only 10 items were needed to attain the performance level of AUC being 0.90. A sum score created from the items produced high separability between patients and healthy controls (Cohens d = 2.85), and it outperformed predefined sum scores and sub-scores within the instruments (Cohens d ranging between 0.13 and 1.21). The transdiagnostic features comprised both symptom domains (e.g. dysregulated mood, attention deficit, and anhedonia) and personality traits (e.g. neuroticism, impulsivity, and extraversion). Moreover, by comparing the features that were common across the three patient groups with those that were most predictive of a single patient category, we can describe the unique features for each patient group superimposed on the transdiagnostic feature structure. Overall, our results reveal a latent transdiagnostic symptom/behavioral phenotypic structure shared across SCZ, BD, and ADHD and present a new perspective to understand insights offered by self-report psychiatric instruments.

pathology↗

bioRxiv2018

Machine learning models identify multimodal measurements highly predictive of transdiagnostic symptom severity for mood, anhedonia, and anxiety

Background: Insights from neuroimaging-based biomarker research have not yet translated into clinical practice. This translational gap could be because of a focus of psychiatric biomarker research on diagnostic classification, rather than on prediction of transdiagnostic psychiatric symptom severity. Currently, no transdiagnostic, multimodal predictive models of symptom severity that include neurobiological characteristics have been described. Methods: We built predictive models of three common symptoms in psychiatric disorders (dysregulated mood, anhedonia, and anxiety) from the Consortium for Neuropsychiatric Phenomics dataset (n=272) which contains clinical scale assessments, resting-state functional-MRI (rs-fMRI) and structural-MRI (sMRI) imaging measures from patients with schizophrenia, bipolar disorder, attention deficit and hyperactivity disorder, and healthy control subjects. We used an efficient, data-driven feature selection approach to identify the most predictive features from these high-dimensional data. Results: This approach optimized modeling and explained 65-90% of variance across the three symptom domains, compared to 22% without using the feature selection approach. The top performing multimodal models retained a high level of interpretability which enabled several clinical and scientific insights. First, to our surprise, structural features did not substantially contribute to the predictive strength of these models. Second, the Temperament and Character Inventory scale emerged as a highly important predictor of symptom variation across diagnoses. Third, predictive rs-fMRI connectivity features were widely distributed across many intrinsic resting-state networks (RSN). Conclusions: Combining rs-fMRI with select questions from clinical scales enabled high levels of prediction of symptom severity across diagnostically distinct patient groups and revealed that connectivity measures beyond a few intrinsic RSNs may carry relevant information for symptom severity.

neuroscience↗

bioRxiv2017

Hierarchy of transcriptomic specialization across human cortex captured by myelin map topography

Hierarchy provides a unifying principle for the macroscale organization of anatomical and functional properties across primate cortex, yet the microscale bases of specialization across human cortex are poorly understood. Cortical hierarchy is conventionally informed by invasive measurements of long-range projections, creating the need for a principled proxy measure of hierarchy in humans. Moreover, cortex exhibits marked interareal variation in patterns of gene expression, yet organizing principles of its transcriptional architecture remain unclear. We hypothesized that functional specialization of human cortical microcircuitry involves hierarchical gradients of gene expression. We found that a noninvasive neuroimaging measure, the MRI-derived myelin map, reliably indexes hierarchy and closely resembles the dominant pattern of transcriptomic variation across human cortex. We found strong hierarchical gradients in expression profiles of genes related to microcircuit function and neuropsychiatric disorders. Our findings suggest that hierarchy defines an axis shared by the transcriptomic and anatomical architectures of human cortex, and that hierarchical gradients of microscale properties contribute to macroscale specialization of cortical function.

neuroscience↗