Biology subjects

Fox, V.

Publications and source records attributed to Fox, V..

4 recordsLinked to original sources

bioRxiv2025

Subtyping psychotic disorders using a data-driven approach reveals divergent cortical and cellular signatures

Structural brain abnormalities in psychosis are well-replicated but heterogenous posing a barrier to uncovering the pathophysiology, etiology, and treatment of psychosis. To parse neurostructural heterogeneity and assess for the presence of anatomically-derived subtypes, we applied a data-driven method, similarity network fusion (SNF), to structural neuroimaging data in a broad cohort of individuals with psychosis (schizophrenia spectrum disorders (SSD) n=280; bipolar disorder with psychotic features (BD) n=101). SNF identified two transdiagnostic subtypes in psychosis (subtype 1: n=158 SSD, n=75 BD; subtype 2: n=122 SSD, n=26 BD) that exhibited divergent patterns of abnormal cortical surface area and subcortical volumes. Compared to controls (n=243), subtype 1 showed moderate enlargement of surface area in frontal and parietal areas and larger dorsal striatal volumes, whereas subtype 2 demonstrated markedly smaller surface areas in frontal and temporal areas and subcortical volumes, including hippocampus, amygdala, thalamus and ventral striatum. When comparing subtypes on clinical characteristics, subtype 2 had more severe negative symptoms, greater neuropsychological impairment, and lower estimated premorbid intellectual functioning compared to subtype 1. Integrating cell-type data imputed from gene expression in the Allen Human Brain Atlas revealed an association between interregional reductions in surface area and layer 5 glutamatergic neuron abundance, critical for corticostriatal network connectivity and cognitive function, whereas reductions in cortical thickness spatially coupled with glia cell and interneuron abundance, in subtype 2. These outcomes indicate that regional variations in surface area, linked to different cell-types than cortical thickness, may be an important biomarker for understanding the pathophysiological trajectories of psychotic disorders.

neuroscience↗

bioRxiv2025

The cerebrospinal fluid virome in people with HIV: links to neuroinflammation and cognition

Despite effective HIV suppression, neuroinflammation and neurocognitive issues are prevalent in people with HIV (PWH) yet poorly understood. HIV infection alters the human virome, and virome perturbations have been linked to neurocognitive issues in people without HIV. Once thought to be sterile, the cerebrospinal fluid (CSF) hosts a recently discovered virome, presenting an unexplored avenue for understanding brain and mental health in PWH. This cross-sectional study analyzed 85 CSF samples (74 from PWH on suppressive antiretroviral therapy, and 11 from controls without HIV, CWH) through shotgun metagenomics for DNA/RNA viruses. Taxonomic composition (reads and contigs), and {beta} diversity, and relative abundance (RA) of prokaryotic (PV), human eukaryotic (hEV), and non-human eukaryotic viruses (nhEV) were evaluated in relation to HIV infection, markers of neuroinflammation and neurodegeneration, cognitive functions, and depressive symptoms. Sensitivity analyses and post-hoc cluster analysis on the RA of viral groups and blood-brain barrier permeability were also performed. Of 46 read-positive CSF samples, 93.5% contained PV sequences, 47.8% hEV, and 45.6% nhEV. Alpha diversity was lower in PWH versus CWH, although p>0.05. At {beta} diversity analysis, HIV status explained 3.3% of the variation in viral composition (p=0.016). Contigs retained 13 samples positive for 8 hEV, 2 nhEV, and 6 PV. Higher RA of PV was correlated with higher CSF S100{beta} (p=0.002) and {beta}-Amyloid 1-42 fragment ({beta}A-42, p=0.026), while higher RA of nhEV with poorer cognitive performance (p=0.022). Conversely, higher RA of hEV correlated with better cognition (p=0.003) and lower {beta}A-42 (p=0.012). Sensitivity analyses in virome-positive samples only confirmed these findings. Three CSF clusters were identified and showed differences in astrocytosis, {beta}A-42, tau protein, and cognitive functions. Participants with hEV-enriched CSF showed better cognitive performance compared to those with virus-devoid and nhEV-enriched CSF (modelsp<0.05). This study provides the first comprehensive description of the CSF virome in PWH, revealing associations with neuroinflammation and cognition. These findings highlight the potential involvement of the CSF virome in brain health and inform about its composition, origin, and potential clinical implications in people with and without HIV. Author SummaryHIV can affect brain health and mental well-being, even in people on successful antiretroviral therapy. The reasons behind this are still unclear. HIV also influences the communities of microbes and viruses living in the human body, and recent research suggests that the human virome, the collection of all viruses within the body, may play a role in cognitive functions, mood, and brain health. For a long time, scientists believed that the cerebrospinal fluid (CSF), which surrounds the brain, was sterile, while robust evidence has shown that the CSF hosts its own unique virome. Via advanced genetic sequencing (shotgun metagenomics), we analyzed the CSF virome in people with and without HIV looking for possible links to neuroinflammation, cognitive performance, and depression. We found that while HIV infection does affect the composition of CSF viral communities, there were no remarkable differences in the CSF virome of individuals with and without HIV. Most viral sequences appeared to come outside the brain. A higher abundance of non-human viral sequences, such as viruses of bacteria, plants, fungi, and animals, was associated with neuroinflammation and poorer cognitive performance. On the other hand, a higher abundance of human viruses correlated with better cognitive function and healthier signature of neuromarkers. These findings provide new insights into the presence and characteristics of the human CSF virome and how it might influence brain health. They also suggest new potential mechanisms of HIV-associated neuropathology.

microbiology↗

bioRxiv2025

Characterizing massa intermedia morphology in schizophrenia: associations with aging, neuropsychological functioning, and atypical hippocampal development

The massa intermedia (MI) is a midline structure connecting the left and right thalamus that typically develops during the 2nd trimester of pregnancy. Missing and smaller MI has been linked to neurodevelopmental disorders, including schizophrenia (SZ), and subtle deficits in cognition. However, findings are inconsistent and the association between MI and other anatomical variants linked to atypical brain development in SZ, including incomplete hippocampal inversion (IHI), is unclear. Presence/absence and morphology of the MI were ascertained on structural T1-weighted MRI images obtained at 3T in SZ (n = 223) and healthy individuals (n = 194) and compared between groups. Associations between MI morphology, cognitive function, and incomplete hippocampal inversion (IHI) were assessed. Prevalence of missing MI was 1.7% and did not differ between groups. MI was significantly smaller in SZ (p <.001). However, follow-up analyses revealed that smaller MI size in SZ was due to a significant Diagnosis x Age interaction characterized by a stronger negative age effect in SZ. IHI was significantly more common in individuals with missing MI. Neurocognition was not correlated with MI size when controlling for age and diagnosis. Stronger effects of age on MI size in SZ suggests that abnormal MI size measured in adulthood may not be a reliable static indicator of atypical neurodevelopment, but may reflect disease progression or accelerated aging. Missing MI was rare in our sample. Conversely, missing MI is associated with IHI suggesting a shared neurodevelopmental disruption in the 2nd trimester.

neuroscience↗

bioRxiv2022

Streptococcus pyogenes Φ1207.3 is a temperate bacteriophage carrying the macrolide efflux gene pair mef(A)-msr(D) and capable to lysogenise different Streptococci

Streptococcus pyogenes prophage {phi}1207.3 (formerly Tn1207.3) carries the mef(A)-msr(D) efflux resistance genes, responsible for type M macrolide resistance. To investigate if {phi}1207.3 is a functional bacteriophage, we transferred the element from the original S. pyogenes host in a prophage-free and competence-deficient S. pneumoniae strain. Pneumococcal cultures of the {phi}1207.3-carrying lysogen were treated with mitomycin C to assess if {phi}1207.3 enters the lytic cycle. Mitomycin C induced a limited phage burst and a growth impairment resulting in early entrance in the stationary phase. To determine if {phi}1207.3 is able to produce mature phage particles we prepared concentrated supernatants recovered from a mitomycin C induced pneumococcal culture by sequential centrifugation and ultracentrifugation steps. Negative staining Transmission Electron Microscopy (TEM) of supernatants revealed the presence of phage particles with an icosahedral, electron dense capsid and a long, non-contractile tail, typical of a siphovirus. Quantification of {phi}1207.3 was performed by qPCR and semi-quantitatively by TEM. PCR quantified 3.34 x 104 and 6.06 x 104 excised forms of phage genome per ml of supernatant obtained from the untreated and mitomycin C treated cultures, respectively. By TEM, we estimated 3.02 x 103 and 7.68 x 103 phage particles per ml of supernatant. The phage preparations of {phi}1207.3 infected and lysogenised pneumococcal recipient strains at a frequency of 7.5 x 10-6 lysogens/recipient, but did not show sufficient lytic activity to form plaques. Phage lysogenisation efficiently occurred after 30 minutes of contact of the phages with the recipient cells and required a minimum of 103 phage particles. ImportanceBacteriophages play an important role in bacterial physiology and genome evolution. The widespread use of genome sequencing revealed that bacterial genomes can contain several different integrated temperate bacteriophages, which can constitute up to 20% of the genome. Most of these bacteriophages are only predicted in silico and never shown to be functional. In fact, it is often difficult to induce the lytic cycle of temperate bacteriophages. In this work, we show that {phi}1207.3, a peculiar bacteriophage originally from Streptococcus pyogenes, which can lysogenise different Streptococci and carries the macrolide resistance mef(A)-msr(D) gene pair, is capable of producing mature virions, but only at a low level, while not being able to produce plaques. This temperate phage is probably a partially functional phage, which seems to have lost lytic characteristics to specialize into lysogenisation. While we are not used to conceive phages separately from lysis, this behavior could actually be more frequent than expected.

microbiology↗