Motor neuron disease in Hong Kong Chinese: Epidemiology and clinical picture

This study documents the clinical features, incidence and prevalence of motor neuron disease (MND) in Hong Kong Chinese. Patients with MND who were alive between 1989 and 1992 were recruited by retrieval of medical records from the four major hospitals in Hong Kong, and by referral of neurologists, neurosurgeons and medical consultants. Mortality statistics was provided by the Census and Statistics Department. A total of 84 cases were identified with a male preponderance of 1.98:1. The average annual period incidence was 0.31/100,000 and the point prevalence on December 31, 1992, was 0.95/100,000. The mean age at onset was 55.5 years (range 19-81) with a peak observed from 55 to 65 years. The clinical features are similar to other reported series of MND. The incidence and mortality of MND in Hong Kong are therefore lower than the worldwide figures of 2.0/100,000 and 1.5/100,000, respectively.published_or_final_versio

Phage Displayed Peptides to Avian H5N1 Virus Distinguished the Virus from Other Viruses

The purpose of the current study was to identify potential ligands and develop a novel diagnostic test to highly pathogenic avian influenza A virus (HPAI), subtype H5N1 viruses using phage display technology. The H5N1 viruses were used as an immobilized target in a biopanning process using a 12-mer phage display random peptide library. After five rounds of panning, three phages expressing peptides HAWDPIPARDPF, AAWHLIVALAPN or ATSHLHVRLPSK had a specific binding activity to H5N1 viruses were isolated. Putative binding motifs to H5N1 viruses were identified by DNA sequencing. In terms of the minimum quantity of viruses, the phage-based ELISA was better than antiserum-based ELISA and a manual, semi-quantitative endpoint RT-PCR for detecting H5N1 viruses. More importantly, the selected phages bearing the specific peptides to H5N1 viruses were capable of differentiating this virus from other avian viruses in enzyme-linked immunosorbent assays

Quetiapine in the treatment of schizophrenia and related disorders

Quetiapine was developed in 1985 by scientists at AstraZeneca (formerly Zeneca) Pharmaceuticals. It received official US Food and Drug Administration approval in September 1997 and approval in Germany in 2000. Since then, quetiapine has been used in the treatment of severe mental illness in approximately 70 countries including Canada, most Western European countries, and Japan. Quetiapine is a dibenzothiazepine derivative with a relatively broad receptor binding profile. It has major affinity to cerebral serotonergic (5HT2A), histaminergic (H1), and dopaminergic D1 and D2 receptors, moderate affinity to α1- und α2-adrenergic receptors, and minor affinity to muscarinergic M1 receptors; it demonstrates a substantial selectivity for the limbic system. This receptor occupancy profile with relatively higher affinity for the 5HT2A receptor compared with the D2 receptor is in part responsible for the antipsychotic characteristics and low incidence of extrapyramidal side-effects of quetiapine. The efficacy of quetiapine in reducing positive and negative symptoms of schizophrenia has been proven in several clinical trials with placebo-controlled comparators. Quetiapine has also demonstrated robust efficacy for treatment of cognitive, anxious-depressive, and aggressive symptoms in schizophrenia. Long-term trials show sustained tolerability for a broad spectrum of symptoms. Quetiapine has also proven efficacy and tolerability in the treatment of moderate to severe manic episodes, and in the treatment of juveniles with oppositional-defiant or conduct disorders, and in the geriatric dementia population. Recent data indicate that quetiapine may also be effective in the treatment of bipolar depressive symptoms without increasing the risk of triggering manic episodes, and in borderline personality disorder. In comparison with other antipsychotics, quetiapine has a favorable side-effect profile. In clinical trials only small insignificant prolongations of the QT interval were observed. Weight-gain liabilities and new-onset metabolic side-effects occupy a middle-ground among newer antipsychotics. As a result of its good efficacy and tolerability profile quetiapine has become well established in the treatment of schizophrenia and manic episodes

Niche stiffness underlies the ageing of central nervous system progenitor cells.

Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations1. One example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs)2. A relatively overlooked potential source of this loss of function is the stem cell 'niche'-a set of cell-extrinsic cues that include chemical and mechanical signals3,4. Here we show that the OPC microenvironment stiffens with age, and that this mechanical change is sufficient to cause age-related loss of function of OPCs. Using biological and synthetic scaffolds to mimic the stiffness of young brains, we find that isolated aged OPCs cultured on these scaffolds are molecularly and functionally rejuvenated. When we disrupt mechanical signalling, the proliferation and differentiation rates of OPCs are increased. We identify the mechanoresponsive ion channel PIEZO1 as a key mediator of OPC mechanical signalling. Inhibiting PIEZO1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the ageing CNS. We also show that PIEZO1 is important in regulating cell number during CNS development. Thus we show that tissue stiffness is a crucial regulator of ageing in OPCs, and provide insights into how the function of adult stem and progenitor cells changes with age. Our findings could be important not only for the development of regenerative therapies, but also for understanding the ageing process itself.The work was supported by European Research Council (ERC) grant 772798 (to K.J.C.) and 772426 (to K.F.); the UK Multiple Sclerosis Society (to R.J.M.F.); Biotechnology and Biological Sciences Research Council (BBSRC) grant BB/M008827/1 (to K.J.C and R.J.M.F.) and BB/N006402/1 (to K.F.); the Adelson Medical Research Foundation (R.J.M.F. and D.H.R.); an EMBO Long-Term Fellowship ALTF 1263-2015 and European Commission FP7 actions LTFCOFUND2013, GA-2013-609409 (to I.P.W.); and a core support grant from the Wellcome Trust and Medical Research Council (MRC) to the Wellcome Trust–MRC Cambridge Stem Cell Institute

Influenza Polymerase Activity Correlates with the Strength of Interaction between Nucleoprotein and PB2 through the Host-Specific Residue K/E627

The ribonucleoprotein (RNP) complex is the essential transcription-replication machinery of the influenza virus. It is composed of the trimeric polymerase (PA, PB1 and PB2), nucleoprotein (NP) and RNA. Elucidating the molecular mechanisms of RNP assembly is central to our understanding of the control of viral transcription and replication and the dependence of these processes on the host cell. In this report, we show, by RNP reconstitution assays and co-immunoprecipitation, that the interaction between NP and polymerase is crucial for the function of the RNP. The functional association of NP and polymerase involves the C-terminal ‘627’ domain of PB2 and it requires NP arginine-150 and either lysine-627 or arginine-630 of PB2. Using surface plasmon resonance, we demonstrate that the interaction between NP and PB2 takes place without the involvement of RNA. At 33, 37 and 41°C in mammalian cells, more positive charges at aa. 627 and 630 of PB2 lead to stronger NP-polymerase interaction, which directly correlates with the higher RNP activity. In conclusion, our study provides new information on the NP-PB2 interaction and shows that the strength of NP-polymerase interaction and the resulting RNP activity are promoted by the positive charges at aa. 627 and 630 of PB2

Modulation of porosity in a solid material enabled by bulk photoisomerization of an overcrowded alkene

FWN – Publicaties zonder aanstelling Universiteit Leide

Exclusive J/ψ detection and physics with ECCE

The file available on this institutional repository is an arXiv preprint which may not have been certified by peer review. The definitive version of record published by Elsevier is available at https://doi.org/10.48550/arXiv.2207.10356.Copyright © The Authors 2023. The EIC Comprehensive Chromodynamics Experiment (ECCE) detector has been recommended as a reference design for the proposed Electron-Ion Collider (EIC) program. This paper presents simulation studies of exclusive J/ψ detection and selected physics impact results in EIC using the projected ECCE detector concept. Exclusive quarkonium photoproduction is one of the most popular processes in EIC, which has a large cross section and a simple final state. Due to the gluonic nature of the exchange Pomeron, this process can be related to the gluon distributions in the nucleus. Preliminary results estimate the excellent statistics benefited from the large cross section of J/ψ photoproduction and superior performance of ECCE detector concept. The precise measurement of exclusive J/ψ photoproduction at EIC will help us to more deeply understand nuclear gluon distributions, near threshold production mechanism and nucleon mass structure.X. Li and W. Zha are supported by the National Natural Science Foundation of China (12005220, 12175223) and MOST (2018YFE0104900). The authors would like to thank the ECCE Consortium for performing a full simulation of their detector design, for providing up-to-date information on EIC run conditions, and for suggestions and comments on the manuscript. X. Li and W. Zha would like to thank Y. Zhou for useful suggestions and discussions related to this analysis. W. Zha is supported by Anhui Provincial Natural Science Foundation No. 2208085J23 and Youth Innovation Promotion Association of Chinese Academy of Sciences. AANL group are supported by the Science Committee of RA , in the frames of the research project 21AG-1C028

Mechanism of eIF6 release from the nascent 60S ribosomal subunit.

SBDS protein (deficient in the inherited leukemia-predisposition disorder Shwachman-Diamond syndrome) and the GTPase EFL1 (an EF-G homolog) activate nascent 60S ribosomal subunits for translation by catalyzing eviction of the antiassociation factor eIF6 from nascent 60S ribosomal subunits. However, the mechanism is completely unknown. Here, we present cryo-EM structures of human SBDS and SBDS-EFL1 bound to Dictyostelium discoideum 60S ribosomal subunits with and without endogenous eIF6. SBDS assesses the integrity of the peptidyl (P) site, bridging uL16 (mutated in T-cell acute lymphoblastic leukemia) with uL11 at the P-stalk base and the sarcin-ricin loop. Upon EFL1 binding, SBDS is repositioned around helix 69, thus facilitating a conformational switch in EFL1 that displaces eIF6 by competing for an overlapping binding site on the 60S ribosomal subunit. Our data reveal the conserved mechanism of eIF6 release, which is corrupted in both inherited and sporadic leukemias.Supported by a Federation of European Biochemical Societies Long term Fellowship (to FW), Specialist Programme from Bloodwise [12048] (AJW), the Medical Research Council [MC_U105161083] (AJW) and [U105115237] (RRK), Wellcome Trust strategic award to the Cambridge Institute for Medal Research [100140], Tesni Parry Trust (AJW), Ted’s Gang (AJW) and the Cambridge NIHR Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nsmb.311

Copper-Triggered Aggregation of Ubiquitin

Neurodegenerative disorders share common features comprising aggregation of misfolded proteins, failure of the ubiquitin-proteasome system, and increased levels of metal ions in the brain. Protein aggregates within affected cells often contain ubiquitin, however no report has focused on the aggregation propensity of this protein. Recently it was shown that copper, differently from zinc, nickel, aluminum, or cadmium, compromises ubiquitin stability and binds to the N-terminus with 0.1 micromolar affinity. This paper addresses the role of copper upon ubiquitin aggregation. In water, incubation with Cu(II) leads to formation of spherical particles that can progress from dimers to larger conglomerates. These spherical oligomers are SDS-resistant and are destroyed upon Cu(II) chelation or reduction to Cu(I). In water/trifluoroethanol (80∶20, v/v), a mimic of the local decrease in dielectric constant experienced in proximity to a membrane surface, ubiquitin incubation with Cu(II) causes time-dependent changes in circular dichroism and Fourier-transform infrared spectra, indicative of increasing β-sheet content. Analysis by atomic force and transmission electron microscopy reveals, in the given order, formation of spherical particles consistent with the size of early oligomers detected by gel electrophoresis, clustering of these particles in straight and curved chains, formation of ring structures, growth of trigonal branches from the rings, coalescence of the trigonal branched structures in a network. Notably, none of these ubiquitin aggregates was positive to tests for amyloid and Cu(II) chelation or reduction produced aggregate disassembly. The early formed Cu(II)-stabilized spherical oligomers, when reconstituted in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomes and in POPC planar bilayers, form annular and pore-like structures, respectively, which are common to several neurodegenerative disorders including Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and prion diseases, and have been proposed to be the primary toxic species. Susceptibility to aggregation of ubiquitin, as it emerges from the present study, may represent a potential risk factor for disease onset or progression while cells attempt to tag and process toxic substrates

Functional Effects of Parasites on Food Web Properties during the Spring Diatom Bloom in Lake Pavin: A Linear Inverse Modeling Analysis

This study is the first assessment of the quantitative impact of parasitic chytrids on a planktonic food web. We used a carbon-based food web model of Lake Pavin (Massif Central, France) to investigate the effects of chytrids during the spring diatom bloom by developing models with and without chytrids. Linear inverse modelling procedures were employed to estimate undetermined flows in the lake. The Monte Carlo Markov chain linear inverse modelling procedure provided estimates of the ranges of model-derived fluxes. Model results support recent theories on the probable impact of parasites on food web function. In the lake, during spring, when ‘inedible’ algae (unexploited by planktonic herbivores) were the dominant primary producers, the epidemic growth of chytrids significantly reduced the sedimentation loss of algal carbon to the detritus pool through the production of grazer-exploitable zoospores. We also review some theories about the potential influence of parasites on ecological network properties and argue that parasitism contributes to longer carbon path lengths, higher levels of activity and specialization, and lower recycling. Considering the “structural asymmetry” hypothesis as a stabilizing pattern, chytrids should contribute to the stability of aquatic food webs