Publications by authors named "Colin Smith"

347 Publications

Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis.

Front Neurosci 2021 1;15:705306. Epub 2021 Sep 1.

Euan MacDonald Centre for MND Research, The University of Edinburgh, Edinburgh, United Kingdom.

Pathological hallmarks of amyotrophic lateral sclerosis (ALS), including protein misfolding, are well established in oligodendrocytes. More recently, an RNA trafficking deficit of key myelin proteins has been suggested in oligodendrocytes in ALS but the extent to which this affects myelination and the relative contribution of this to disease pathogenesis is unclear. ALS autopsy research findings showing demyelination contrasts with the routine clinical-pathological workup of ALS cases where it is rare to see white matter abnormalities other than simple Wallerian degeneration secondary to widespread neuronal loss. To begin to address this apparent variance, we undertook a comprehensive evaluation of myelination at an RNA, protein and structural level using human pathological material from sporadic ALS patients, genetic ALS patients (harboring mutation) and age- and sex-matched non-neurological controls. We performed (i) quantitative spatial profiling of the mRNA transcript encoding myelin basic protein (), (ii) quantification of MBP protein and (iii) the first quantitative structural assessment of myelination in ALS post-mortem specimens by electron microscopy. We show no differences in MBP protein levels or ultrastructural myelination, despite a significant dysregulation in the subcellular trafficking of mRNA in ALS patients compared to controls. We therefore confirm that whilst there are cell autonomous mRNA trafficking deficits affecting oligodendrocytes in ALS, this has no effect on myelin structure.
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http://dx.doi.org/10.3389/fnins.2021.705306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440970PMC
September 2021

MYD88 L265P mutation in primary central nervous system lymphoma is associated with better survival: A single-center experience.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab090. Epub 2021 Jul 7.

Department of Pathology, Western General Hospital, Edinburgh EH4 2XU, UK.

Background: The () mutation in primary central nervous system lymphomas (PCNSL) may be associated with unfavorable prognosis; however, current evidence remains limited. We aimed to characterize PCNSLs by integration of clinicopathological, molecular, treatment, and survival data.

Methods: We retrospectively identified and validated 57 consecutive patients with PCNSLs according to the 2017 WHO classification of lymphoid neoplasms over 13 years. Formalin-fixed paraffin-embedded tumor samples underwent polymerase chain reaction assay to detect mutation. We used Cox regression for survival analysis, including age, treatment, and as covariates. We searched the literature for studies reporting demographics, treatment, , and survival of PCNSL patients and incorporated individual patient data into our analyses.

Results: The median age was 66 years and 56% were women. All 57 patients had PCNSL of non-germinal center cell subtype and the majority (81%) received either single or combined therapies. There were 46 deaths observed over the median follow-up of 10 months. mutation status was available in 41 patients of which 36 (88%) were mutated. There was an association between mutation and better survival in the multivariable model (hazard ratio [HR] 0.277; 95% confidence interval [CI]: 0.09-0.83; = .023) but not in a univariable model. After incorporating additional 18 patients from the literature, this association was reproducible (HR 0.245; 95% CI: 0.09-0.64; = .004).

Conclusions: Adjusting for confounders, -mutant PCNSL appears to show improved survival. While further validation is warranted, detection of mutation will aid the identification of patients who may benefit from novel targeted therapies.
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http://dx.doi.org/10.1093/noajnl/vdab090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349182PMC
July 2021

"Let's Talk About Your Note": Using Open Notes as an Acceptance and Commitment Therapy Based Intervention in Mental Health Care.

Front Psychiatry 2021 19;12:704415. Epub 2021 Jul 19.

Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, United States.

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http://dx.doi.org/10.3389/fpsyt.2021.704415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328223PMC
July 2021

Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease.

Eur J Neurol 2021 Jul 31. Epub 2021 Jul 31.

University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, Edinburgh, UK.

Background And Purpose: Synapse degeneration in Alzheimer's disease (AD) correlates strongly with cognitive decline. There is well-established excitatory synapse loss in AD with known contributions of pathological amyloid beta (Aβ) to excitatory synapse dysfunction and loss. Despite clear changes in circuit excitability in AD and model systems, relatively little is known about pathology in inhibitory synapses.

Methods: Here human postmortem brain samples (n = 5 control, 10 AD cases) from temporal and occipital cortices were examined to investigate whether inhibitory synapses and neurons are lost in AD and whether Aβ may contribute to inhibitory synapse degeneration. Inhibitory neurons were counted in all six cortical layers using stereology software, and array tomography was used to examine synapse density and the accumulation of Aβ in synaptic terminals.

Results: Differing inhibitory neuron densities were observed in the different cortical layers. The highest inhibitory neuron density was observed in layer 4 in both brain regions and the visual cortex had a higher inhibitory neuron density than the temporal cortex. There was significantly lower inhibitory neuron density in AD than in control cases in all six cortical layers. High-resolution array tomography imaging revealed plaque-associated loss of inhibitory synapses and accumulation of Aβ in a small subset of inhibitory presynaptic terminals with the most accumulation near amyloid plaques.

Conclusions: Inhibitory neuron and synapse loss in AD may contribute to disrupted excitatory/inhibitory balance and cognitive decline. Future work is warranted to determine whether targeting inhibitory synapse loss could be a useful therapeutic strategy.
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http://dx.doi.org/10.1111/ene.15043DOI Listing
July 2021

Schizotypal personality disorder disguised as dissociative identity disorder.

BMJ Case Rep 2021 Jul 20;14(7). Epub 2021 Jul 20.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA

A 20-year-old man was admitted to an inpatient psychiatric unit for self-professed dissociative identity disorder. His presentation of multiple personalities without amnesia, dissociation or depersonalisation led to further examination of personality and cultural factors that may contribute to this uncommon presentation. Careful clinical investigation supported a diagnosis of schizotypal personality disorder with elements of fantastical thinking influenced by media presentations of dissociative identity disorder.
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http://dx.doi.org/10.1136/bcr-2021-243454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292736PMC
July 2021

Mental health interventions for persons living with HIV in low- and middle-income countries: a systematic review.

J Int AIDS Soc 2021 06;24 Suppl 2:e25722

HIV Mental Health Research Unit, Department of Psychiatry, Neuroscience Institute, University of Cape Town, Cape Town, South Africa.

Introduction: Addressing the intersection between mental health and HIV is critical for the wellbeing of persons living with HIV (PLWH). This systematic review synthesized the literature on mental health interventions for PLWH in low- and middle-income countries (LMICs) to determine intervention components and explore their relationship with intervention effectiveness.

Methods: We included only controlled clinical trials of interventions aiming to improve the mental health of PLWH. We conducted a search in the following databases: PubMed, CINAHL, PsycINFO and EMBASE for eligible studies describing the evaluation of interventions for mental health problems among PLWH in LMICs published through August 2020. Two reviewers independently screened references in two successive stages of title/abstract screening and then full-text screening for references meeting title/abstract criteria.

Results: We identified a total of 30 eligible articles representing 6477 PLWH who were assigned to either the intervention arm (n = 3182) or control arm (n = 3346). The mental health interventions evaluated were psychological (n = 17, 56.67%), pharmacological (n = 6, 20.00%), combined psychological and pharmacological (n = 1, 3.33%) and complementary/alternative treatments (n = 6, 20.00%). The mental health problems targeted were depression (n = 22, 73.33 %), multiple psychological symptoms (n = 1, 3.33%), alcohol and substance use problems (n = 4, 13.33%), post-traumatic stress disorder (n = 1, 3.33%) and HIV-related neuro-cognitive impairment (n = 2, 6.67%). Studies of interventions with significant effects had significantly a higher number of active ingredients than those without significant effects [3.41 (2.24) vs. 1.84 (1.46) Mean (SD)] [Mean difference = -1.56, 95% CI = -3.03 to -0.09, p = 0.037].

Conclusions: There continue to be advances in mental health interventions for PLWH with mental illness in LMICs. However, more research is needed to elucidate how intervention components lead to intervention effectiveness. We recommend scale up of culturally appropriate interventions that have been successfully evaluated in low- and middle-income countries.
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http://dx.doi.org/10.1002/jia2.25722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222847PMC
June 2021

Blinded review of hippocampal neuropathology in sudden unexplained death in childhood reveals inconsistent observations and similarities to explained paediatric deaths.

Neuropathol Appl Neurobiol 2021 Jun 23. Epub 2021 Jun 23.

Comprehensive Epilepsy Center, NYU Langone Health and School of Medicine, New York, New York, USA.

Aims: Hippocampal findings are implicated in the pathogenesis of sudden unexplained death in childhood (SUDC), although some studies have identified similar findings in sudden explained death in childhood (SEDC) cases. We blindly reviewed hippocampal histology in SUDC and SEDC controls.

Methods: Hippocampal haematoxylin and eosin (H&E) slides (n = 67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by nine blinded reviewers: three board-certified forensic pathologists, three neuropathologists and three dual-certified neuropathologists/forensic pathologists.

Results: Among nine reviewers, about 50% of hippocampal sections were rated as abnormal (52.5% SUDC, 53.0% controls), with no difference by cause of death (COD) (p = 0.16) or febrile seizure history (p = 0.90). There was little agreement among nine reviewers on whether a slide was within normal range (Fleiss' κ = 0.014, p = 0.47). Within reviewer groups, there were no findings more frequent in SUDC compared with controls, with variability in pyramidal neuron and dentate gyrus findings. Across reviewer groups, there was concordance for bilamination and granule cell loss. Neither SUDC (51.2%) nor control (55.9%) slides were considered contributory to determining COD (p = 0.41).

Conclusions: The lack of an association of hippocampal findings in SUDC and controls, as well as inconsistency of observations by multiple blinded reviewers, indicates discrepancy with previous studies and an inability to reliably identify hippocampal maldevelopment associated with sudden death (HMASD). These findings underscore a need for larger studies to standardise evaluation of hippocampal findings, identifying the range of normal variation and changes unrelated to SUDC or febrile seizures. Molecular studies may help identify novel immunohistological markers that inform on COD.
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http://dx.doi.org/10.1111/nan.12746DOI Listing
June 2021

Fatal insomnia: the elusive prion disease.

BMJ Case Rep 2021 Jun 22;14(6). Epub 2021 Jun 22.

College of Medicine and Health, University of Exeter, Exeter, UK.

A previously well 54- year-old woman presented with a short history of diplopia, cognitive decline, hallucinations and hypersomnolence. The patient had progressive deterioration in short-term memory, ocular convergence spasm, tremor, myoclonus, gait apraxia, central fever, dream enactment and seizures. Results of investigations were normal including MRI brain, electroencephalogram, cerebrospinal fluid (CSF, including CSF prion protein markers) and brain biopsy. The patient died from pneumonia and pulmonary embolus. Brain postmortem analysis revealed neuropathological changes in keeping with Fatal familial insomnia (FFI); the diagnosis was confirmed on genetic testing. FFI is caused by an autosomal dominant and highly penetrant pathogenic Prion Protein gene Although usually familial, fatal insomnia (FI) also occurs in a rare sporadic form. FI is a rare human prion disease with prominent sleep disturbance, autonomic, motor, cognitive and behavioural involvement. Patient management is with best supportive care and early suspected diagnosis allows for timely palliation.
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http://dx.doi.org/10.1136/bcr-2020-241289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220472PMC
June 2021

Free energy calculations of ALS-causing SOD1 mutants reveal common perturbations to stability and dynamics along the maturation pathway.

Protein Sci 2021 Sep 22;30(9):1804-1817. Epub 2021 Jun 22.

Department of Chemistry, Wesleyan University, Middletown, Connecticut, USA.

With over 150 heritable mutations identified as disease-causative, superoxide dismutase 1 (SOD1) has been a main target of amyotrophic lateral sclerosis (ALS) research and therapeutic efforts. However, recent evidence has suggested that neither loss of function nor protein aggregation is responsible for promoting neurotoxicity. Furthermore, there is no clear pattern to the nature or the location of these mutations that could suggest a molecular mechanism behind SOD1-linked ALS. Here, we utilize reliable and accurate computational techniques to predict the perturbations of 10 such mutations to the free energy changes of SOD1 as it matures from apo monomer to metallated dimer. We find that the free energy perturbations caused by these mutations strongly depend on maturational progress, indicating the need for state-specific therapeutic targeting. We also find that many mutations exhibit similar patterns of perturbation to native and non-native maturation, indicating strong thermodynamic coupling between the dynamics at various sites of maturation within SOD1. These results suggest the presence of an allosteric network in SOD1 which is vulnerable to disruption by these mutations. Analysis of these perturbations may contribute to uncovering a unifying molecular mechanism which explains SOD1-linked ALS and help to guide future therapeutic efforts.
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http://dx.doi.org/10.1002/pro.4132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376412PMC
September 2021

Epigenetic predictors of lifestyle traits applied to the blood and brain.

Brain Commun 2021 19;3(2):fcab082. Epub 2021 Apr 19.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh 2XU, UK.

Modifiable lifestyle factors influence the risk of developing many neurological diseases. These factors have been extensively linked with blood-based genome-wide DNA methylation, but it is unclear if the signatures from blood translate to the target tissue of interest-the brain. To investigate this, we apply blood-derived epigenetic predictors of four lifestyle traits to genome-wide DNA methylation from five post-mortem brain regions and the last blood sample prior to death in 14 individuals in the Lothian Birth Cohort 1936. Using these matched samples, we found that correlations between blood and brain DNA methylation scores for smoking, high-density lipoprotein cholesterol, alcohol and body mass index were highly variable across brain regions. Smoking scores in the dorsolateral prefrontal cortex had the strongest correlations with smoking scores in blood (=0.5,  = 14, =0.07) and smoking behaviour (=0.56,  = 9, =0.12). This was also the brain region which exhibited the largest correlations for DNA methylation at site cg05575921 - the single strongest correlate of smoking in blood-in relation to blood (=0.61,  = 14, =0.02) and smoking behaviour ( = -0.65,  = 9, =0.06). This suggested a particular vulnerability to smoking-related differential methylation in this region. Our work contributes to understanding how lifestyle factors affect the brain and suggest that lifestyle-related DNA methylation is likely to be both brain region dependent and in many cases poorly proxied for by blood. Though these pilot data provide a rarely-available opportunity for the comparison of methylation patterns across multiple brain regions and the blood, due to the limited sample size available our results must be considered as preliminary and should therefore be used as a basis for further investigation.
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http://dx.doi.org/10.1093/braincomms/fcab082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134833PMC
April 2021

Correlations in post-mortem imaging-histopathology studies of sporadic human cerebral small vessel disease: A systematic review.

Neuropathol Appl Neurobiol 2021 May 26. Epub 2021 May 26.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Aims: Sporadic human cerebral small vessel disease (SVD) commonly causes stroke and dementia but its pathogenesis is poorly understood. There are recognised neuroimaging and histopathological features. However, relatively few studies have examined the relationship between the radiological and pathological correlates of SVD; better correlation would promote greater insight into the underlying biological changes.

Methods: We performed a systematic review to collate and appraise the information derived from studies that correlated histological with neuroimaging-defined SVD lesions. We searched for studies describing post-mortem imaging and histological tissue examination in adults, extracted data from published studies, categorised the information and compiled this narrative.

Results: We identified 38 relevant studies, including at least 1146 subjects, 342 of these with SVD: 29 studies focussed on neuroradiological white matter lesions (WML), six on microinfarcts and three on dilated perivascular spaces (PVS) and lacunes. The histopathology terminology was diverse with few robust definitions. Reporting and methodology varied widely between studies, precluding formal meta-analysis. PVS and 'oedema' were frequent findings in WML, being described in at least 94 and 18 radiological WML, respectively, in addition to myelin pallor. Histopathological changes extended beyond the radiological lesion margins in at least 33 radiological WML. At least 43 radiological lesions not seen pathologically and at least 178 histological lesions were not identified on imaging.

Conclusions: Histopathological assessment of human SVD is hindered by inconsistent methodological approaches and unstandardised definitions. The data from this systematic review will help to develop standardised definitions to promote consistency in human SVD research.
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http://dx.doi.org/10.1111/nan.12737DOI Listing
May 2021

Got 2 Good Eyes But You Still Can't See: An Atypical Case of Wernicke's Encephalopathy.

Prim Care Companion CNS Disord 2021 May 13;23(3). Epub 2021 May 13.

Department of Medicine, Duke University Medical Center, Durham, North Carolina.

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http://dx.doi.org/10.4088/PCC.20l02780DOI Listing
May 2021

Recreational Nitrous Oxide and Pernicious Anemia-Associated Vitamin B Deficiency in a Patient Presenting With Sensorimotor Polyneuropathy.

Prim Care Companion CNS Disord 2021 Mar 11;23(2). Epub 2021 Mar 11.

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.

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http://dx.doi.org/10.4088/PCC.20l02751DOI Listing
March 2021

SARS-CoV-2-related vascular injury: mechanisms, imaging and models.

Microphysiol Syst 2021 Jan 26;5. Epub 2021 Jan 26.

Department of Biomedical Engineering, Duke University, Durham, NC, USA.

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http://dx.doi.org/10.21037/mps-20-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112618PMC
January 2021

The importance of ongoing international surveillance for Creutzfeldt-Jakob disease.

Nat Rev Neurol 2021 Jun 10;17(6):362-379. Epub 2021 May 10.

National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal and transmissible neurodegenerative disease associated with the accumulation of misfolded prion protein in the CNS. International CJD surveillance programmes have been active since the emergence, in the mid-1990s, of variant CJD (vCJD), a disease linked to bovine spongiform encephalopathy. Control measures have now successfully contained bovine spongiform encephalopathy and the incidence of vCJD has declined, leading to questions about the requirement for ongoing surveillance. However, several lines of evidence have raised concerns that further cases of vCJD could emerge as a result of prolonged incubation and/or secondary transmission. Emerging evidence from peripheral tissue distribution studies employing high-sensitivity assays suggests that all forms of human prion disease carry a theoretical risk of iatrogenic transmission. Finally, emerging diseases, such as chronic wasting disease and camel prion disease, pose further risks to public health. In this Review, we provide an up-to-date overview of the transmission of prion diseases in human populations and argue that CJD surveillance remains vital both from a public health perspective and to support essential research into disease pathophysiology, enhanced diagnostic tests and much-needed treatments.
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http://dx.doi.org/10.1038/s41582-021-00488-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109225PMC
June 2021

Non-white cases of sporadic Creutzfeldt-Jakob disease: A 28 year review of United Kingdom National Surveillance Data.

J Neurol Sci 2021 May 24;424:117416. Epub 2021 Mar 24.

National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK. Electronic address:

Aims: Descriptions of sporadic Creutzfeldt-Jakob disease (sCJD) in non-White populations are limited. Improved understanding may aid diagnoses and case ascertainment within surveillance programmes. We aimed to: 1) Ascertain the proportion of sCJD cases with non-White ethnicity in the United Kingdom (UK); 2) Compare clinical and investigation findings between non-White and White cases.

Methods: We analysed records of probable and definite sCJD cases assessed by the UK National CJD Research and Surveillance Unit over 28 years (1990-2017). Cases were stratified into White and non-White groups. Demographics, clinical features, investigation findings, and post-mortem numbers were compared.

Results: 1697 sCJD cases were included: 1642 (97%) White, 55 (3%) non-White (Asian/Asian British, Black/African/Caribbean). The proportion of non-Whites among sCJD cases is 7% lower than the proportion the non-White population make up in the UK (p < 0.001). This was not statistically significant when age-matched by ≥60 years (p = 0.071). Age at symptom onset was 4 years lower in the non-White population (p = 0.007). Clinical and investigation characteristics were otherwise similar between ethnic groupings. The proportion of non-Whites undergoing autopsy and classification as definite was 30% and 24% lower (p < 0.001) respectively in comparison to those for White cases.

Conclusions: Approximately 3% of sCJD cases in the UK are non-White, despite non-Whites representing approximately 10% of the UK population. This difference was not statistically significant when age-matched at ≥60 years. Non-White cases tend to be younger and likelihood of autopsy is lower; relevant considerations for surveillance programmes. Reasons for these differences in non-White populations are unclear and merit further evaluation.
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http://dx.doi.org/10.1016/j.jns.2021.117416DOI Listing
May 2021

Global proteomic analysis of extracellular matrix in mouse and human brain highlights relevance to cerebrovascular disease.

J Cereb Blood Flow Metab 2021 Sep 17;41(9):2423-2438. Epub 2021 Mar 17.

Translational Molecular Neuroscience Group, Weatherall Institute of Molecular Medicine, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

The extracellular matrix (ECM) is a key interface between the cerebrovasculature and adjacent brain tissues. Deregulation of the ECM contributes to a broad range of neurological disorders. However, despite this importance, our understanding of the ECM composition remains very limited mainly due to difficulties in its isolation. To address this, we developed an approach to extract the cerebrovascular ECM from mouse and human post-mortem normal brain tissues. We then used mass spectrometry with off-line high-pH reversed-phase fractionation to increase the protein detection. This identified more than 1000 proteins in the ECM-enriched fraction, with > 66% of the proteins being common between the species. We report 147 core ECM proteins of the human brain vascular matrisome, including collagens, laminins, fibronectin and nidogens. We next used network analysis to identify the connection between the brain ECM proteins and cerebrovascular diseases. We found that genes related to cerebrovascular diseases, such as , , and were significantly enriched in the cerebrovascular ECM network. This provides unique mechanistic insight into cerebrovascular disease and potential drug targets. Overall, we provide a powerful resource to study the functions of brain ECM and highlight a specific role for brain vascular ECM in cerebral vascular disease.
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http://dx.doi.org/10.1177/0271678X211004307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392779PMC
September 2021

Chemotranscriptomic Profiling Defines Drug-Specific Signatures of the Glycopeptide Antibiotics Dalbavancin, Vancomycin and Chlorobiphenyl-Vancomycin in a VanB-Type-Resistant Streptomycete.

Front Microbiol 2021 25;12:641756. Epub 2021 Feb 25.

Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, United Kingdom.

Dalbavancin, vancomycin and chlorobiphenyl-vancomycin share a high degree of structural similarity and the same primary mode of drug action. All inhibit bacterial cell wall biosynthesis through complexation with intermediates in peptidoglycan biosynthesis mediated via interaction with peptidyl-d-alanyl-d-alanine (d-Ala-d-Ala) residues present at the termini of the intermediates. VanB-type glycopeptide resistance in bacteria encodes an inducible reprogramming of bacterial cell wall biosynthesis that generates precursors terminating with d-alanyl-d-lactate (d-Ala-d-Lac). This system in confers protection against the natural product vancomycin but not dalbavancin or chlorobiphenyl-vancomycin, which are semi-synthetic derivatives and fail to sufficiently activate the inducible VanB-type sensory response. We used transcriptome profiling by RNAseq to identify the gene expression signatures elucidated in in response to the three different glycopeptide compounds. An integrated comparison of the results defines both the contribution of the VanB resistance system to the control of changes in gene transcription and the impact at the transcriptional level of the structural diversity present in the glycopeptide antibiotics used. Dalbavancin induces markedly more extensive changes in the expression of genes required for transport processes, RNA methylation, haem biosynthesis and the biosynthesis of the amino acids arginine and glutamine. Chlorobiphenyl-vancomycin exhibits specific effects on tryptophan and calcium-dependent antibiotic biosynthesis and has a stronger repressive effect on translation. Vancomycin predictably has a uniquely strong effect on the genes controlled by the VanB resistance system and also impacts metal ion homeostasis and leucine biosynthesis. Leaderless gene transcription is disfavoured in the core transcriptional up- and down-regulation taking place in response to all the glycopeptide antibiotics, while HrdB-dependent transcripts are favoured in the down-regulated group. This study illustrates the biological impact of peripheral changes to glycopeptide antibiotic structure and could inform the design of future semi-synthetic glycopeptide derivatives.
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http://dx.doi.org/10.3389/fmicb.2021.641756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947799PMC
February 2021

Rainfall as a trigger of ecological cascade effects in an Australian groundwater ecosystem.

Sci Rep 2021 Feb 12;11(1):3694. Epub 2021 Feb 12.

WA-Organic Isotope Geochemistry Centre, The Institute for Geoscience Research, School of Earth and Planetary Sciences, Curtin University, Perth, WA, 6102, Australia.

Groundwaters host vital resources playing a key role in the near future. Subterranean fauna and microbes are crucial in regulating organic cycles in environments characterized by low energy and scarce carbon availability. However, our knowledge about the functioning of groundwater ecosystems is limited, despite being increasingly exposed to anthropic impacts and climate change-related processes. In this work we apply novel biochemical and genetic techniques to investigate the ecological dynamics of an Australian calcrete under two contrasting rainfall periods (LR-low rainfall and HR-high rainfall). Our results indicate that the microbial gut community of copepods and amphipods experienced a shift in taxonomic diversity and predicted organic functional metabolic pathways during HR. The HR regime triggered a cascade effect driven by microbes (OM processors) and exploited by copepods and amphipods (primary and secondary consumers), which was finally transferred to the aquatic beetles (top predators). Our findings highlight that rainfall triggers ecological shifts towards more deterministic dynamics, revealing a complex web of interactions in seemingly simple environmental settings. Here we show how a combined isotopic-molecular approach can untangle the mechanisms shaping a calcrete community. This design will help manage and preserve one of the most vital but underrated ecosystems worldwide.
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http://dx.doi.org/10.1038/s41598-021-83286-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881013PMC
February 2021

Microglial inflammasome activation drives developmental white matter injury.

Glia 2021 May 8;69(5):1268-1280. Epub 2021 Jan 8.

Medical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.

Injury to the developing brain during the perinatal period often causes hypomyelination, leading to clinical deficits for which there is an unmet therapeutic need. Dysregulation of inflammation and microglia have been implicated, yet the molecular mechanisms linking these to hypomyelination are unclear. Using human infant cerebrospinal fluid (CSF) and postmortem tissue, we found that microglial activation of the pro-inflammatory molecular complex the NLRP3 inflammasome is associated with pathology. By developing a novel mouse brain explant model of microglial inflammasome activation, we demonstrate that blocking the inflammasome rescues myelination. In human and mouse, we discovered a link between the inflammasome product IL1β and increased levels of follistatin, an endogenous inhibitor of activin-A. Follistatin treatment was sufficient to reduce myelination, whereas myelination was rescued in injured explants upon follistatin neutralization or supplementation with exogenous activin-A. Our data reveal that inflammasome activation in microglia drives hypomyelination and identifies novel therapeutic strategies to reinstate myelination following developmental injury.
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http://dx.doi.org/10.1002/glia.23963DOI Listing
May 2021

Case 26-2020: A Woman with Altered Mental Status and Left-Sided Weakness.

N Engl J Med 2021 01;384(1):92

Duke University Medical Center, Durham, NC

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http://dx.doi.org/10.1056/NEJMc2030849DOI Listing
January 2021

Pre-clinical atherosclerosis is found at post-mortem, in the brains of men with HIV.

J Neurovirol 2021 02 6;27(1):80-85. Epub 2021 Jan 6.

Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, L69 7BE, UK.

The aim of this study is to ascertain the burden of pre-clinical atherosclerotic changes in the brains of young adult males with HIV and explore the impact of anti-retroviral therapy (ART). The study design is case-control, cross-sectional. Histological sections from HIV-positive post-mortem brain samples, with no associated opportunistic infection, from the MRC Edinburgh brain bank were evaluated. These were age and sex matched with HIV-negative controls. Immunohistochemical stains were performed to evaluate characteristics of atherosclerosis. The pathological changes were graded blinded to the HIV status and a second histopathologist reassessed 15%. Univariable models were used for statistical analyses; p ≤ 0.05 was considered significant. Nineteen HIV-positive post-mortem cases fulfilled our inclusion criteria. Nineteen HIV-negative controls were selected. We assessed mostly small-medium-sized vessels. For inflammation (CD45), 7 (36%) of the HIV+ had moderate/severe changes compared with none for the HIV- group (p < 0.001). Moderate/severe increase in smooth muscle remodeling (SMA) was found in 8 (42%) HIV+ and 0 HIV- brains (p < 0.001). Moderate/severe lipoprotein deposition (LOX-1) was found in 3 (15%) and 0 HIV-brains (p < 0.001). ART was associated with less inflammation [5 (63%) no ART versus 2 (18%) on ART (p = 0.028)] but was not associated with reduced lipid deposition or smooth muscle damage. In HIV infection, there are pre-clinical small- to medium-sized vessel atherosclerotic changes and ART may have limited impact on these changes. This could have implications on the increasing burden of cerebrovascular disease in HIV populations and warrants further investigation.
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http://dx.doi.org/10.1007/s13365-020-00917-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921050PMC
February 2021

Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study.

Acta Neuropathol 2021 02 5;141(2):159-172. Epub 2021 Jan 5.

Translational and Clinical Research Institute, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., "absent" vs. "present") and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff's α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff's α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.
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http://dx.doi.org/10.1007/s00401-020-02255-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847437PMC
February 2021

Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis.

Acta Neuropathol 2021 02 4;141(2):257-279. Epub 2021 Jan 4.

UK Dementia Research Institute at University of Edinburgh, University of Edinburgh, Edinburgh bioQuarter, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.

Axonal dysfunction is a common phenotype in neurodegenerative disorders, including in amyotrophic lateral sclerosis (ALS), where the key pathological cell-type, the motor neuron (MN), has an axon extending up to a metre long. The maintenance of axonal function is a highly energy-demanding process, raising the question of whether MN cellular energetics is perturbed in ALS, and whether its recovery promotes axonal rescue. To address this, we undertook cellular and molecular interrogation of multiple patient-derived induced pluripotent stem cell lines and patient autopsy samples harbouring the most common ALS causing mutation, C9orf72. Using paired mutant and isogenic expansion-corrected controls, we show that C9orf72 MNs have shorter axons, impaired fast axonal transport of mitochondrial cargo, and altered mitochondrial bioenergetic function. RNAseq revealed reduced gene expression of mitochondrially encoded electron transport chain transcripts, with neuropathological analysis of C9orf72-ALS post-mortem tissue importantly confirming selective dysregulation of the mitochondrially encoded transcripts in ventral horn spinal MNs, but not in corresponding dorsal horn sensory neurons, with findings reflected at the protein level. Mitochondrial DNA copy number was unaltered, both in vitro and in human post-mortem tissue. Genetic manipulation of mitochondrial biogenesis in C9orf72 MNs corrected the bioenergetic deficit and also rescued the axonal length and transport phenotypes. Collectively, our data show that loss of mitochondrial function is a key mediator of axonal dysfunction in C9orf72-ALS, and that boosting MN bioenergetics is sufficient to restore axonal homeostasis, opening new potential therapeutic strategies for ALS that target mitochondrial function.
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http://dx.doi.org/10.1007/s00401-020-02252-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847443PMC
February 2021

The Emerging Chronic Sequelae of COVID-19 and Implications for North Carolina.

N C Med J 2021 Jan-Feb;82(1):75-78

associate professor of medicine, Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina.

The acute morbidity and mortality of COVID-19 have been well described. Evidence is emerging that COVID-19 may also result in negative long-term medical and psychiatric outcomes. A broad response from the public health community in North Carolina that includes robust surveillance and catch-up care is needed to reduce the long-term sequelae of COVID-19.
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http://dx.doi.org/10.18043/ncm.82.1.75DOI Listing
January 2021

Psychiatric Care in a Novel Federal COVID-19 Treatment Center: Development of a Consultation-Liaison Psychiatry Service at the Javits New York Medical Station.

Mil Med 2021 05;186(5-6):129-131

Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA.

At the outset of the 2019 coronavirus disease (COVID-19) pandemic, New York City faced the highest burden of COVID-19 cases in the United States. In response, the U.S. Federal Government deployed medical providers from various uniformed services to treat patients with COVID-19 at the Jacob Javits Convention Center in New York City. There quickly arose a need for psychiatric services for patients with COVID-19 and psychological support for medical staff. Psychiatrists were tasked with establishing a consult-liaison psychiatry service in this unique environment. The authors detail the establishment of a novel consultation-liaison psychiatry service in a large convention center and explore lessons learned from this experience with the aim to empower uniformed psychiatrists to prepare for and deliver patient-focused care in pandemic settings.
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http://dx.doi.org/10.1093/milmed/usaa557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798787PMC
May 2021

Regional Differences in Neuroinflammation-Associated Gene Expression in the Brain of Sporadic Creutzfeldt-Jakob Disease Patients.

Int J Mol Sci 2020 Dec 25;22(1). Epub 2020 Dec 25.

Department of Pathology, Danish Reference Center for Prion Diseases, Copenhagen University Hospital, 2100 Copenhagen, Denmark.

Neuroinflammation is an essential part of neurodegeneration. Yet, the current understanding of neuroinflammation-associated molecular events in distinct brain regions of prion disease patients is insufficient to lay the ground for effective treatment strategies targeting this complex neuropathological process. To address this problem, we analyzed the expression of 800 neuroinflammation-associated genes to create a profile of biological processes taking place in the frontal cortex and cerebellum of patients who suffered from sporadic Creutzfeldt-Jakob disease. The analysis was performed using NanoString nCounter technology with human neuroinflammation panel+. The observed gene expression patterns were regionally and sub-regionally distinct, suggesting a variable neuroinflammatory response. Interestingly, the observed differences could not be explained by the molecular subtypes of sporadic Creutzfeldt-Jakob disease. Furthermore, analyses of canonical pathways and upstream regulators based on differentially expressed genes indicated an overlap between biological processes taking place in different brain regions. This suggests that even smaller-scale spatial data reflecting subtle changes in brain cells' functional heterogeneity and their immediate pathologic microenvironments are needed to explain the observed differential gene expression in a greater detail.
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http://dx.doi.org/10.3390/ijms22010140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795938PMC
December 2020

Incidental Attitude Formation via the Surveillance Task: A Preregistered Replication of the Olson and Fazio (2001) Study.

Psychol Sci 2021 01 10;32(1):120-131. Epub 2020 Dec 10.

Department of Experimental Clinical and Health Psychology, Ghent University.

Evaluative conditioning is one of the most widely studied procedures for establishing and changing attitudes. The surveillance task is a highly cited evaluative-conditioning paradigm and one that is claimed to generate attitudes without awareness. The potential for evaluative-conditioning effects to occur without awareness continues to fuel conceptual, theoretical, and applied developments. Yet few published studies have used this task, and most are characterized by small samples and small effect sizes. We conducted a high-powered ( = 1,478 adult participants), preregistered close replication of the original surveillance-task study (Olson & Fazio, 2001). We obtained evidence for a small evaluative-conditioning effect when "aware" participants were excluded using the original criterion-therefore replicating the original effect. However, no such effect emerged when three other awareness criteria were used. We suggest that there is a need for caution when using evidence from the surveillance-task effect to make theoretical and practical claims about "unaware" evaluative-conditioning effects.
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http://dx.doi.org/10.1177/0956797620968526DOI Listing
January 2021

Politics, Personality, and Impulsivity Can Color People's Perceptions of-and Responses to-Hurricane Threats of Varying Severity.

Pers Soc Psychol Bull 2021 Oct 7;47(10):1435-1451. Epub 2020 Dec 7.

University of Florida, Gainesville, USA.

Theory and research suggest that objective features of a threatening situation and individual differences influence threat responses. We examine three ways individual traits may relate to a threat response: (a) directly and independent of objective threat features, (b) indirectly through relationships with threat perception, or (c) as moderators of the relationship between objective threat features and responses. Using integrative data analysis (IDA), we aggregated data across three studies examining hurricane preparation intentions. Analysis supported two of the potential pathways. Supporting the first path, both openness and extraversion had direct, positive relationships with preparation likelihood. Supporting the second path, agreeableness, conscientiousness, and social conservatism positively related to preparation likelihood through a positive relationship with threat perception, whereas impulsivity and sensation-seeking negatively related to preparation likelihood through a negative relationship with threat perception. This work shows the pivotal role individual differences play regarding responses to uncertain threats.
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http://dx.doi.org/10.1177/0146167220969021DOI Listing
October 2021
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