The SORL1 gene and convergent neural risk for Alzheimer\u27s disease across the human lifespan

Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer\u27s disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer\u27s risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer\u27s phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: (1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n = 118, age 18-86; n = 68, age 8-40); (2) gene expression using the Braincloud postmortem healthy control sample (n = 269, age 0-92) and (3) Alzheimer\u27s neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI) and Alzheimer\u27s individuals (n = 710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner in fronto-temporal white matter tracts in both samples at 5% family-wise error-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan

Amygdala Nuclei Volumes Are Selectively Associated With Social Network Size in Homeless and Precariously Housed Persons

Objective: The amygdala is a brain region comprised of a group of functionally distinct nuclei that play a central role in social behavior. In homeless and precariously housed individuals, high rates of multimorbidity, and structural aspects of the environment may dysregulate social functioning. This study examined the neurobiological substrates of social connection in homeless and precariously housed persons by examining associations between amygdala nuclei volumes and social network size. Methods: Sixty participants (mean age 43.6 years; 73.3% male) were enrolled from an ongoing study of homeless and precariously housed adults in Vancouver, Canada. Social network size was assessed using the Arizona Social Support Interview Schedule. Amygdala nuclei volumes were extracted from anatomic T1-weighted MRI data. The central and basolateral amygdala nuclei were selected as they are implicated in anxiety-related and social behaviors. The hippocampus was included as a control brain region. Multivariable regression analysis investigated the relationship between amygdala nuclei volumes and social network size. Results: After controlling for age, sex, and total brain volume, individuals with the larger amygdala and central nucleus volumes had a larger network size. This association was not observed for the basolateral amygdala complex, though subsequent analysis found the basal and accessory basal nuclei of the basolateral amygdala were significantly associated with social network size. No association was found for the lateral amygdala nucleus or hippocampus. Conclusions: These findings suggest that select amygdala nuclei may be differentially involved in the social connections of persons with multimorbid illness and social marginalization

Maintenance treatment with quetiapine versus discontinuation after one year of treatment in patients with remitted first episode psychosis: randomised controlled trial

Objective To study rates of relapse in remitted patients with first episode psychosis who either continued or discontinued antipsychotic drugs after at least one year of maintenance treatment

The impacts of yoga and aerobic exercise on neuro-cognition and brain structure in early psychosis: a preliminary analysis of the randomized controlled clinical trial

This journal suppl. entitled: Abstracts of the 3rd Biennial Schizophrenia International Research ConferenceCognitive impairment was detectable in early psychosis together with a decreased hippocampal volume (Wright et al., 2000). These cognitive deficits of attention and memory often result in severe and longstanding functional impairment. Reducing cognitive impairment with pharmacological intervention has not been universally successful (Addington, 2007). The current study aims to explore the effects of aerobic exercise and mind-body exercise (yoga) on cognitive functioning and brain structure for female patients in the early phase of psychosis. We further propose to investigate potential differential effects of these two forms of exercise. 61 female early psychosis patients were recruited from two hospital/clinic sites and randomized into aerobic ...postprin

Spaceflight Alters Bacterial Gene Expression and Virulence and Reveals Role for Global Regulator Hfq

A comprehensive analysis of both the molecular genetic and phenotypic responses of any organism to the spaceflight environment has never been accomplished due to significant technological and logistical hurdles. Moreover, the effects of spaceflight on microbial pathogenicity and associated infectious disease risks have not been studied. The bacterial pathogen Salmonella typhimurium was grown aboard Space Shuttle mission STS-115 and compared to identical ground control cultures. Global microarray and proteomic analyses revealed 167 transcripts and 73 proteins changed expression with the conserved RNA-binding protein Hfq identified as a likely global regulator involved in the response to this environment. Hfq involvement was confirmed with a ground based microgravity culture model. Spaceflight samples exhibited enhanced virulence in a murine infection model and extracellular matrix accumulation consistent with a biofilm. Strategies to target Hfq and related regulators could potentially decrease infectious disease risks during spaceflight missions and provide novel therapeutic options on Earth

Effectiveness of pharmacological treatments for severe agitation in real-world emergency settings: protocol of individual-participant-data network meta-analysis.

BACKGROUND Severe psychomotor agitation and aggression often require immediate pharmacological intervention, but clear evidence-based recommendations for choosing among the multiple options are lacking. To address this gap, we plan a systematic review and individual-participant-data network meta-analysis to investigate their comparative effectiveness in real-world emergency settings with increased precision. METHODS We will include randomized controlled trials investigating intramuscular or intravenous pharmacological interventions, as monotherapy or in combination, in adults with severe psychomotor agitation irrespective of the underlying diagnosis and requiring rapid tranquilization in general or psychiatric emergency settings. We will exclude studies before 2002, those focusing on specific reasons for agitation and placebo-controlled trials to avoid concerns related to the transitivity assumption and potential selection biases. We will search for eligible studies in BIOSIS, CENTRAL, CINAHL Plus, Embase, LILACS, MEDLINE via Ovid, PubMed, ProQuest, PsycINFO, ClinicalTrials.gov, and WHO-ICTRP. Individual-participant data will be requested from the study authors and harmonized into a uniform format, and aggregated data will also be extracted from the studies. At least two independent reviewers will conduct the study selection, data extraction, risk-of-bias assessment using RoB 2, and applicability evaluation using the RITES tool. The primary outcome will be the number of patients achieving adequate sedation within 30 min after treatment, with secondary outcomes including the need for additional interventions and adverse events, using odds ratios as the effect size. If enough individual-participant data will be collected, we will synthesize them in a network meta-regression model within a Bayesian framework, incorporating study- and participant-level characteristics to explore potential sources of heterogeneity. In cases where individual-participant data are unavailable, potential data availability bias will be explored, and models allowing for the inclusion of studies reporting only aggregated data will be considered. We will assess the confidence in the evidence using the Confidence in Network Meta-Analysis (CINeMA) approach. DISCUSSION This individual-participant-data network meta-analysis aims to provide a fine-tuned synthesis of the evidence on the comparative effectiveness of pharmacological interventions for severe psychomotor agitation in real-world emergency settings. The findings from this study can greatly be provided clearer evidence-based guidance on the most effective treatments. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42023402365

Component Processes of Decision Making in a Community Sample of Precariously Housed Persons: Associations With Learning and Memory, and Health-Risk Behaviors

The Iowa Gambling Task (IGT) is a widely used measure of decision making, but its value in signifying behaviors associated with adverse, “real-world” consequences has not been consistently demonstrated in persons who are precariously housed or homeless. Studies evaluating the ecological validity of the IGT have primarily relied on traditional IGT scores. However, computational modeling derives underlying component processes of the IGT, which capture specific facets of decision making that may be more closely related to engagement in behaviors associated with negative consequences. This study employed the Prospect Valence Learning (PVL) model to decompose IGT performance into component processes in 294 precariously housed community residents with substance use disorders. Results revealed a predominant focus on gains and a lack of sensitivity to losses in these vulnerable community residents. Hypothesized associations were not detected between component processes and self-reported health-risk behaviors. These findings provide insight into the processes underlying decision making in a vulnerable substance-using population and highlight the challenge of linking specific decision making processes to “real-world” behaviors

Prokayrotic Ubiquitin-Like Protein (Pup) Proteome of Mycobacterium tuberculosis

Prokaryotic ubiquitin-like protein (Pup) in Mycobacterium tuberculosis (Mtb) is the first known post-translational small protein modifier in prokaryotes, and targets several proteins for degradation by a bacterial proteasome in a manner akin to ubiquitin (Ub) mediated proteolysis in eukaryotes. To determine the extent of pupylation in Mtb, we used tandem affinity purification to identify its “pupylome”. Mass spectrometry identified 55 out of 604 purified proteins with confirmed pupylation sites. Forty-four proteins, including those with and without identified pupylation sites, were tested as substrates of proteolysis in Mtb. Under steady state conditions, the majority of the test proteins did not accumulate in degradation mutants, suggesting not all targets of pupylation are necessarily substrates of the proteasome under steady state conditions. Four proteins implicated in Mtb pathogenesis, Icl (isocitrate lyase), Ino1 (inositol-1-phosphate synthase), MtrA (Mtb response regulator A) and PhoP (phosphate response regulator P), showed altered levels in degradation defective Mtb. Icl, Ino1 and MtrA accumulated in Mtb degradation mutants, suggesting these proteins are targeted to the proteasome. Unexpectedly, PhoP was present in wild type Mtb but undetectable in the degradation mutants. Taken together, these data demonstrate that pupylation regulates numerous proteins in Mtb and may not always lead to degradation

Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia

<p>Abstract</p> <p>Background</p> <p>We have previously reported that the expression of the messenger ribonucleic acid (mRNA) for the NR2A subunit of the N-methyl-D-aspartate (NMDA) class of glutamate receptor was decreased in a subset of inhibitory interneurons in the cerebral cortex in schizophrenia. In this study, we sought to determine whether a deficit in the expression of NR2A mRNA was present in the subset of interneurons that contain the calcium buffer parvalbumin (PV) and whether this deficit was associated with a reduction in glutamatergic inputs in the prefrontal cortex (PFC) in schizophrenia.</p> <p>Methods</p> <p>We examined the expression of NR2A mRNA, labeled with a ³⁵S-tagged riboprobe, in neurons that expressed PV mRNA, visualized with a digoxigenin-labeled riboprobe via an immunoperoxidase reaction, in twenty schizophrenia and twenty matched normal control subjects. We also immunohistochemically labeled the glutamatergic axon terminals with an antibody against vGluT1.</p> <p>Results</p> <p>The density of the PV neurons that expressed NR2A mRNA was significantly decreased by 48-50% in layers 3 and 4 in the subjects with schizophrenia, but the cellular expression of NR2A mRNA in the PV neurons that exhibited a detectable level of this transcript was unchanged. In addition, the density of vGluT1-immunoreactive boutons was significantly decreased by 79% in layer 3, but was unchanged in layer 5 of the PFC in schizophrenia.</p> <p>Conclusion</p> <p>These findings suggest that glutamatergic neurotransmission via NR2A-containing NMDA receptors on PV neurons in the PFC may be deficient in schizophrenia. This may disinhibit the postsynaptic excitatory circuits, contributing to neuronal injury, aberrant information flow and PFC functional deficits in schizophrenia.</p