Miracle-dz/UniFAR-FTUs huggingface dataset:
Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

Glutamine plus glutamate (Glx), as well as N-acetylaspartate compounds (NAAc, N-acetylaspartate plus N-acetyl-aspartyl-glutamate), a marker of neuronal viability, can be quantified with proton magnetic resonance spectroscopy (1H-MRS). We used 1H-MRS imaging to assess Glx and NAAc, as well as total-choline (glycerophospho-choline plus phospho-choline), myo-inositol and total-creatine (creatine plus phosphocreatine) from an axial supraventricular slab of gray matter (GM, medial-frontal and medial-parietal) and white matter (WM, bilateral-frontal and bilateral-parietal) voxels. Schizophrenia subjects (N = 104) and healthy controls (N = 97) with a broad age range (16 to 65) were studied. In schizophrenia, Glx was increased in GM (P < .001) and WM (P = .01), regardless of age. However, with greater age, NAAc increased in GM (P < .001) but decreased in WM (P < .001) in schizophrenia. In patients, total creatine decreased with age in WM (P < .001). Finally, overall cognitive score correlated positively with WM neurometabolites in controls but negatively in the schizophrenia group (NAAc, P < .001; and creatine [only younger], P < .001). We speculate the results support an ongoing process of increased glutamate metabolism in schizophrenia. Later in the illness, disease progression is suggested by increased cortical compaction without neuronal loss (elevated NAAc) and reduced axonal integrity (lower NAAc). Furthermore, this process is associated with fundamentally altered relationships between neurometabolite concentrations and cognitive function in schizophrenia.
High Affinity Peptide Inhibitors of the Hepatitis C Virus NS3-4A Protease Refractory to Common Resistant Mutants

Background: NS3-4A is a validated target for antiviral therapeutics whereby HCV rapidly develops resistant mutants. Results: Peptides coordinating with a unique NS3-4A site and strongly inhibiting common resistance mutants were developed. Conclusion: A unique “finger” structure extends binding of the inhibitory peptides to a novel druggable site. Significance: Novel leads are of interest for the design of inhibitors refractory to known resistance mutants. Hepatitis C virus (HCV) NS3-4A protease is essential for viral replication. All current small molecular weight drugs against NS3-4A are substrate peptidomimetics that have a similar binding and resistance profile. We developed inhibitory peptides (IPs) capping the active site and binding via a novel “tyrosine” finger at an alternative NS3-4A site that is of particular interest for further HCV drug development. The peptides are not cleaved due to a combination of geometrical constraints and impairment of the oxyanion hole function. Selection and optimization through combinatorial phagemid display, protein crystallography, and further modifications resulted in a 32-amino acid peptide with a Ki of 0.53 nm. Inhibition of viral replication in cell culture was demonstrated by fusion to a cell-penetrating peptide. Negligible susceptibility to known (A156V and R155K) resistance mutations of the NS3-4A protease was observed. This work shows for the first time that antiviral peptides can target an intracellular site and reveals a novel druggable site on the HCV protease.
Biological Mechanisms Whereby Social Exclusion May Contribute to the Etiology of Psychosis: A Narrative Review

The purpose of this review is to examine whether a contribution of social exclusion to the pathogenesis of psychosis is compatible with the dopamine hypothesis and/or the neurodevelopmental hypothesis. Humans experience social exclusion as defeating. An animal model for defeat is the resident-intruder paradigm. The defeated animal shows evidence of an increased sensitivity to amphetamine, increased dopamine release in the nucleus accumbens and prefrontal cortex, and increased firing of dopaminergic neurons in the ventral tegmental area. As for humans, one study showed that amphetamine-induced striatal dopamine release was significantly greater among nonpsychotic young adults with severe hearing impairment than among normal hearing controls. Two other studies reported an association between childhood trauma and increased dopamine function in striatal subregions. Several studies have suggested that the perigenual anterior cingulate cortex (pgACC) may play a role in the processing of social stress. Importantly, the pgACC regulates the activity of the ventral striatum through bidirectional interconnections. We are not aware of studies in humans that examined whether (proxies for) social exclusion contributes to the structural brain changes present at psychosis onset. Animal studies, however, reported that long-term isolation may lead to reductions in volume of the total brain, hippocampus, or medial prefrontal cortex. Other animal studies reported that social defeat can reduce neurogenesis. In conclusion, the answer to the question as to whether there are plausible mechanisms whereby social exclusion can contribute to the pathogenesis of psychosis is cautiously affirmative.
Genetic influences on the broad spectrum of autism: Study of proband‐ascertained twins

An investigation of genetic structures underlying autistic traits was performed with samples from twins for which at least one proband had been ascertained as having autism spectrum disorders (ASDs) in our catchment area. In order to adjust for recent concepts of autism, we employed criteria for the broad spectrum of disease and the childhood autism rating scale (CARS) for quantitative assessment. The CARS test was performed on 45 twin pairs (19 monozygotic, 26 dizygotic) detected with a regional routine screening system. The obtained CARS scores were subjected to structural equation modeling (SEM), incorporating sex differences for each causal influence ascertainment correction, using the Mx software. A best fitting model of causal influences on autistic traits measured continuously, incorporating additive genetic (A) and non‐shared environmental influences (E), was generated. With this AE model, the estimated heritability was 0.73 for males and 0.87 for females, based on the continuous CARS scores. There was no evidence for the existence of sex‐specific genetic influences. Autistic traits were highly heritable in twins with even broad spectrum of autism, corresponding to the results of early studies based on classical autism. Additive genetic factors were more influential in females than males. © 2008 Wiley‐Liss, Inc.
Association analysis of dynamin‐binding protein (DNMBP) on chromosome 10q with late onset Alzheimer's disease in a large caucasian UK sample

A recent scan of single nucleotide polymorphisms (SNPs) in the region 40–107 Mb on chromosome 10q in a large Japanese case–control cohort identified six SNPs in or near the dynamin‐binding protein gene (DNMBP) that were associated with late onset Alzheimer's disease (LOAD) in individuals lacking the APOE ε4 allele [Kuwano et al. (2006); Hum Mol Genet 15:2170–2182]. We genotyped these six SNPs in 1,212 unrelated Caucasian patients of UK origin with LOAD and 1,389 ethnically, gender and age matched control subjects. We did not observe a statistically significant association with the risk of LOAD for any of the six SNPs in the sample as a whole. When stratifying the sample by APOE one SNP (intergenic SNP rs11190302) was associated with LOAD in individuals lacking the ε4 allele (genotypic P = 0.027, allelic P = 0.066). However this association was in the opposite direction to that detected in the Japanese population. It remains to be determined whether DNMBP is associated with LOAD. © 2008 Wiley‐Liss, Inc.
A Small Novel A-Kinase Anchoring Protein (AKAP) That Localizes Specifically Protein Kinase A-Regulatory Subunit I (PKA-RI) to the Plasma Membrane*

Background: AKAPs tethering the type I regulatory subunit of cAMP-dependent kinase (PKA-RI) have only been marginally described. Results: Here a novel small AKAP (smAKAP) is identified and characterized as a PKA-RI-specific AKAP. Conclusion: smAKAP is a novel AKAP that localizes PKA-RI specifically to the plasma membrane. Significance: PKA-RI is specifically localized through a novel AKAP. Protein kinase A-anchoring proteins (AKAPs) provide spatio-temporal specificity for the omnipotent cAMP-dependent protein kinase (PKA) via high affinity interactions with PKA regulatory subunits (PKA-RI, RII). Many PKA-RII-AKAP complexes are heavily tethered to cellular substructures, whereas PKA-RI-AKAP complexes have remained largely undiscovered. Here, using a cAMP affinity-based chemical proteomics strategy in human heart and platelets, we uncovered a novel, ubiquitously expressed AKAP, termed small membrane (sm)AKAP due to its specific localization at the plasma membrane via potential myristoylation/palmitoylation anchors. In vitro binding studies revealed specificity of smAKAP for PKA-RI (Kd = 7 nm) over PKA-RII (Kd = 53 nm) subunits, co-expression of smAKAP with the four PKA R subunits revealed an even more exclusive specificity of smAKAP for PKA-RIα/β in the cellular context. Applying the singlet oxygen-generating electron microscopy probe miniSOG indicated that smAKAP is tethered to the plasma membrane and is particularly dense at cell-cell junctions and within filopodia. Our preliminary functional characterization of smAKAP provides evidence that, like PKA-RII, PKA-RI can be tightly tethered by a novel repertoire of AKAPs, providing a new perspective on spatio-temporal control of cAMP signaling.
Distinct Roles of the C-terminal 11th Transmembrane Helix and Luminal Extension in the Partial Reactions Determining the High Ca2+ Affinity of Sarco(endo)plasmic Reticulum Ca2+-ATPase Isoform 2b (SERCA2b)*

Background: Little is known about the mechanism by which the luminal extension (LE) and 11th transmembrane helix (TM11) of SERCA2b regulate function. Results: Mutant and chimeric SERCA constructs were analyzed kinetically. Conclusion: The LE affects Ca2+ interaction in E1 and E1P, whereas TM11 affects Ca2+-free E2/E2P states. Significance: Distinct roles of LE and TM11 in controlling the enzyme cycle are revealed. The molecular mechanism underlying the characteristic high apparent Ca2+ affinity of SERCA2b relative to SERCA1a and SERCA2a isoforms was studied. The C-terminal tail of SERCA2b consists of an 11th transmembrane helix (TM11) with an associated 11-amino acid luminal extension (LE). The effects of each of these parts and their interactions with the SERCA environment were examined by transient kinetic analysis of the partial reaction steps in the Ca2+ transport cycle in mutant and chimeric Ca2+-ATPase constructs. Manipulations to the LE of SERCA2b markedly increased the rate of Ca2+ dissociation from Ca2E1. Addition of the SERCA2b tail to SERCA1a slowed Ca2+ dissociation, but only when the luminal L7/8 loop of SERCA1 was simultaneously replaced with that of SERCA2, thus suggesting that the LE interacts with L7/8 in Ca2E1. The interaction of LE with L7/8 is also important for the low rate of the Ca2E1P → E2P conformational transition. These findings can be rationalized in terms of stabilization of the Ca2E1 and Ca2E1P forms by docking of the LE near L7/8. By contrast, low rates of E2P dephosphorylation and E2 → E1 transition in SERCA2b depend critically on TM11, particularly in a SERCA2 environment, but do not at all depend on the LE or L7/8. This indicates that interaction of TM11 with SERCA2-specific sequence element(s) elsewhere in the structure is critical in the Ca2+-free E2/E2P states. Collectively these properties ensure a higher Ca2+ affinity of SERCA2b relative to other SERCA isoforms, not only on the cytosolic side, but also on the luminal side.
Polycomb Repressive Complex 1 (PRC1) Disassembles RNA Polymerase II Preinitiation Complexes*♦

Background: PRC1 silences transcription by an unknown mechanism. Results: PRC1 can both block and dissociate PICs in general with the exception of TFIID. Conclusion: PRC1 gene silencing may involve the ability of TFIID to remain bound to gene promoters, leaving them in a poised state. Significance: Understanding how PRC1 regulates transcription deepens our basic understanding of key developmental processes. Despite the important role of Polycomb in genome-wide silencing, little is known of the specific biochemical mechanism by which it inactivates transcription. Here we address how recombinant Polycomb repressive complex 1 (PRC1) inhibits activated RNA polymerase II preinitiation complex (PIC) assembly using immobilized H3K27-methylated chromatin templates in vitro. Recombinant PRC1 inhibited transcription, but had little effect on binding of the activator as reported previously. In contrast, Mediator and the general transcription factors were blocked during assembly or dissociated from preassembled PICs. Importantly, among the PIC components, Tata Binding Protein (TBP) was the most resistant to eviction by PRC1. Immobilized template experiments using purified PRC1, transcription factor II D (TFIID), and Mediator indicate that PRC1 blocks the recruitment of Mediator, but not TFIID. We conclude that PRC1 functions to block or dissociate PICs by interfering with Mediator, but leaves TBP and perhaps TFIID intact, highlighting a specific mechanism for PRC1 transcriptional silencing. Analysis of published genome-wide datasets from mouse embryonic stem cells revealed that the Ring1b subunit of PRC1 and TBP co-enrich at developmental genes. Further, genes enriched for Ring1b and TBP are expressed at significantly lower levels than those enriched for Mediator, TBP, and Ring1b. Collectively, the data are consistent with a model in which PRC1 and TFIID could co-occupy genes poised for activation during development.
Genome‐wide linkage of cotinine pharmacokinetics suggests candidate regions on chromosomes 9 and 11

Characterizing cotinine pharmacokinetics is a useful way to study nicotine metabolism because the same liver enzyme is primarily responsible for the metabolism of both, and the clearances of nicotine and cotinine are highly correlated. We conducted a whole‐genome linkage analysis to search for candidate regions influencing quantitative variation in cotinine pharmacokinetics in a large‐scale pharmacokinetic study with 61 families containing 224 healthy adult participants. The strongest linkage signal was identified at 135 cM of chromosome 9 with LOD = 2.81 and P = 0.0002; two other suggestive linkage peaks appear at 31.4 and 73.5 cM of chromosome 11 with LOD = 1.96 (P = 0.0013) and 1.94 (P = 0.0014). The confidence level of the linkage between the three genome regions and cotinine pharmacokinetics is statistically significant with a genome‐wide empirical probability of P = 0.029. © 2008 Wiley‐Liss, Inc.
Impact of antiretroviral therapy on HIV-1 transmission dynamics

Background: There has been increasing concern about a resurgent epidemic of HIV-1 amongst men having sex with men in the Netherlands, which has parallels with similar epidemics now occurring in many other countries. methods: A transmission model applicable to HIV-1 epidemics, including the use of antiretroviral therapy, is presented in a set of ordinary differential equations. The model is fitted by maximum likelihood to national HIV-1 and AIDS diagnosis data from 1980-2006, estimating parameters on average changes in unsafe sex and time to diagnosis. Robustness is studied with a detailed univariate sensitivity analysis, and a range of hypothetical scenarios are explored for the past and next decade. results: With a reproduction number around the epidemic threshold one, the HIV-1 epidemic among amongst men having sex with men in the Netherlands is still not under control. Scenario analysis showed that in the absence of limiting infectiousness in treated patients, the epidemic could have been more than double its current size. Ninety percent of new HIV transmissions is estimated to take place before diagnosis. Decreasing time from infection to diagnosis, which was 2.5 years on average in 2006, can prevent many future infections. conclusions: Sexual risk-behaviour of men having sex with men who are not aware of their infection is the most likely factor driving this epidemic. 1HIV Monitoring Foundation, Amsterdam, the Netherlands; 2Department of Infectious Disease Epidemiology, and 4Medical Research Council Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College London, UK; 3Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, the Netherlands; Impact of antIretrovIral therapy on hIv-1 transmIssIon dynamIcs
Glycosylation Is Dispensable for Sorting of Synaptotagmin 1 but Is Critical for Targeting of SV2 and Synaptophysin to Recycling Synaptic Vesicles*

Background: Whether glycosylation is essential for targeting of synaptic vesicle proteins is unclear. Results: Glycosylation-deficient synaptotagmin 1 is correctly targeted and functions normally whereas trafficking of SV2 and synaptophysin is severely affected by the loss of glycosylation. Conclusion: Glycosylation is of differential importance for different synaptic vesicle proteins. Significance: This represents the first quantitative comparison of the trafficking of wild-type and mutant synaptic vesicle glycoproteins. Glycosylation is a major form of post-translational modification of synaptic vesicle membrane proteins. For example, the three major synaptic vesicle glycoproteins, synaptotagmin 1, synaptophysin, and SV2, represent ∼30% of the total copy number of vesicle proteins. Previous studies suggested that glycosylation is required for the vesicular targeting of synaptotagmin 1, but the role of glycosylation of synaptophysin and SV2 has not been explored in detail. In this study, we analyzed all glycosylation sites on synaptotagmin 1, synaptophysin, and SV2A via mutagenesis and optical imaging of pHluorin-tagged proteins in cultured neurons from knock-out mice lacking each protein. Surprisingly, these experiments revealed that glycosylation is completely dispensable for the sorting of synaptotagmin 1 to SVs whereas the N-glycans on SV2A are only partially dispensable. In contrast, N-glycan addition is essential for the synaptic localization and function of synaptophysin. Thus, glycosylation plays distinct roles in the trafficking of each of the three major synaptic vesicle glycoproteins.
LRRK2 G2385R modulates age at onset in Parkinson's disease: A multi‐center pooled analysis

LRRK2 G2385R Modulates Age at Onset in Parkinson’s Disease: A Multi-Center Pooled Analysis E.K. Tan, R. Peng, Y.R. Wu, R.M. Wu, Y.H. Wu-Chou, L.C. Tan, X.K. An, C.M. Chen, S. Fook-Chong, and C.S. Lu* Departments of Neurology and Clinical Research, Singapore General Hospital, National Neuroscience Institute, Singapore, Singapore Duke-NUS Graduate Medical School, Singapore, Singapore Department of Neurology, West China Hospital, Sichuan University, Chengdu, China Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, Taiwan Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan Human Molecular Genetics Laboratory, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, Taiwan
‘Teleswallowing’: a case study of remote swallowing assessment

Purpose – Telemedicine has enabled speech and language therapists (SLTs) to remotely assess swallowing difficulties (dysphagia) experienced by nursing home residents. The new technique, “teleswallowing”, was designed by the Speech and Language Therapy Service at Blackpool Teaching Hospitals NHS Foundation Trust. It allows prompt assessment, avoiding potential risks of aspiration pneumonia, malnutrition, poor rehabilitation, increased hospital stays and reduced quality of life (Hinchey et al., 2005; Langmore et al., 1998). The purpose of this paper is to report on a second pilot of teleswallowing and the concomitant adoption study. Design/methodology/approach – The adoption study employed qualitative methods, including consultations with senior managers, semi-structured interviews with nursing home matrons/managers and nurses, two focus groups and semi-structured interviews with SLTs. The project clinical lead kept an activity log, which was used to estimate resource savings. Findings – Over a three-month .
Distinct Roles of Ser-764 and Lys-773 at the N Terminus of von Willebrand Factor in Complex Assembly with Coagulation Factor VIII*

Background: von Willebrand factor (VWF) protects factor VIII (FVIII) from rapid clearance and degradation. Results: Mass spectrometric footprinting revealed that FVIII protects Lys-773 and the N-terminal Ser-764 of VWF from chemical modification. VWF(S764A) showed increased and VWF(K773A) showed decreased FVIII binding. Conclusion: The N terminus of VWF is critical for FVIII binding. Significance: This study sheds new light on the mechanism of FVIII-VWF complex assembly. Complex formation between coagulation factor VIII (FVIII) and von Willebrand factor (VWF) is of critical importance to protect FVIII from rapid in vivo clearance and degradation. We have now employed a chemical footprinting approach to identify regions on VWF involved in FVIII binding. To this end, lysine amino acid residues of VWF were chemically modified in the presence of FVIII or activated FVIII, which does not bind VWF. Nano-LC-MS analysis showed that the lysine residues of almost all identified VWF peptides were not differentially modified upon incubation of VWF with FVIII or activated FVIII. However, Lys-773 of peptide Ser-766–Leu-774 was protected from chemical modification in the presence of FVIII. In addition, peptide Ser-764–Arg-782, which comprises the first 19 amino acid residues of mature VWF, showed a differential modification of both Lys-773 and the α-amino group of Ser-764. To verify the role of Lys-773 and the N-terminal Ser-764 in FVIII binding, we employed VWF variants in which either Lys-773 or Ser-764 was replaced with Ala. Surface plasmon resonance analysis and competition studies revealed that VWF(K773A) exhibited reduced binding to FVIII and the FVIII light chain, which harbors the VWF-binding site. In contrast, VWF(S764A) revealed more effective binding to FVIII and the FVIII light chain compared with WT VWF. The results of our study show that the N terminus of VWF is critical for the interaction with FVIII and that Ser-764 and Lys-773 have opposite roles in the binding mechanism.
A protocol format for the preparation, registration and publication of systematic reviews of animal intervention studies

Systematicreviews areanimportantmethodtosupportevidencebaseddecisions inhealthcare(research). Although notyet as common as clinical systematic reviews, the number of systematic reviews of animal studies has been increasing steadily in recent years. An important method to promote high-quality systematic reviews is to pre-specify the review methodology in a protocol, before the conduct of the systematic review itself. In contrast to clinicalsystematicreviews, astandardprotocolformatforsystematicreviewsofanimalstudiesisnotyetavailable.Here,wepresenta protocol format tailored to the preparation, registration and publication of systematic reviews of animal intervention studies (i.e. systematic reviews of animal experiments studying the efficacy and/or safety of interventions intended for use in human patients). In analogy to the Cochrane review protocol, the format helps authors predefine the methodological approach of their systematic review, from research question to data synthesis. We recommend that authors prospectively complete and agree on the protocol, and register and/or publish it to allow feedback on the proposed methodology and to avoid the introduction of bias during the review process. Opportunities for obtaining feedback, and for registration and publication of review protocols are also discussed.