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Viruses Feb 2022Virus-like particles resemble infectious virus particles in size, shape, and molecular composition; however, they fail to productively infect host cells. Historically,... (Review)
Review
Virus-like particles resemble infectious virus particles in size, shape, and molecular composition; however, they fail to productively infect host cells. Historically, the presence of virus-like particles has been inferred from total particle counts by microscopy, and infectious particle counts or plaque-forming-units (PFUs) by plaque assay; the resulting ratio of particles-to-PFUs is often greater than one, easily 10 or 100, indicating that most particles are non-infectious. Despite their inability to hijack cells for their reproduction, virus-like particles and the defective genomes they carry can exhibit a broad range of behaviors: interference with normal virus growth during co-infections, cell killing, and activation or inhibition of innate immune signaling. In addition, some virus-like particles become productive as their multiplicities of infection increase, a sign of cooperation between particles. Here, we review established and emerging methods to count virus-like particles and characterize their biological functions. We take a critical look at evidence for defective interfering virus genomes in natural and clinical isolates, and we review their potential as antiviral therapeutics. In short, we highlight an urgent need to better understand how virus-like genomes and particles interact with intact functional viruses during co-infection of their hosts, and their impacts on the transmission, severity, and persistence of virus-associated diseases.
Topics: Animals; Colony-Forming Units Assay; Defective Viruses; Genome, Viral; Humans; Microscopy, Electron, Transmission; Viral Plaque Assay; Virion; Virus Diseases; Virus Replication
PubMed: 35215979
DOI: 10.3390/v14020383 -
Bacteriophage Jan 2011In this commentary I consider use of the term "lysis from without" (LO) along with the phenomenon's biological relevance. LO originally described an early bacterial...
In this commentary I consider use of the term "lysis from without" (LO) along with the phenomenon's biological relevance. LO originally described an early bacterial lysis induced by high-multiplicity virion adsorption and that occurs without phage production (here indicated as LO(V)). Notably, this is more than just high phage multiplicities of adsorption leading to bacterial killing. The action on bacteria of exogenously supplied phage lysin, too, has been described as a form of LO (here, LO(L)). LO(V) has been somewhat worked out mechanistically for T4 phages, has been used to elucidate various phage-associated phenomena including discovery of the phage eclipse, may be relevant to phage ecology, and, with resistance to LO (LO(R)), is blocked by certain phage gene products. Speculation as to the impact of LO(V) on phage therapy also is fairly common. Since LO(V) assays are relatively easily performed and not all phages are able to induce LO(V), a phage's potential to lyse bacteria without first infecting should be subject to at least in vitro experimental confirmation before the LO(V) label is applied. The term "abortive infection" may be used more generally to describe non-productive phage infections that kill bacteria.
PubMed: 21687534
DOI: 10.4161/bact.1.1.13980 -
Journal of Neurochemistry May 2020Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes... (Review)
Review
Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019: Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.
Topics: Animals; Biomarkers; Congresses as Topic; Humans; Inclusion Bodies; Mutation; Portugal; Synucleinopathies; alpha-Synuclein
PubMed: 31957016
DOI: 10.1111/jnc.14965 -
Journal of Child & Adolescent Trauma Jun 2022Multiplicity, the experience of more than one self in the body, is an under-researched area of young people's mental health. The aim of this study was to explore the...
Multiplicity, the experience of more than one self in the body, is an under-researched area of young people's mental health. The aim of this study was to explore the perspectives of experts-by-experience within a community sample regarding two specific resources: a co-produced self-help guide about multiplicity for adolescents, and a set of guidelines for supporting someone who identifies as 'multiple'. 34 participants (M= 22.06, 2.26 SD; 15F, 1M, 18NBG) completed an online survey consisting of open-ended and Likert scale questions to assess the language, utility, transferability and therapeutic impact of the materials. Descriptive statistics and a Foucauldian-informed Narrative Analysis were employed to analyse responses, producing a summary of utility and two narrative chapters. The emergent chapters, 'Breaking the Stigma' and 'Recognising the Many', highlight the need for greater understanding and awareness of multiplicity, with psychoeducation materials viewed as helpful. Inclusive language can reduce stigma and normalise multiplicity as a response to trauma. With greater understanding, practitioners and researchers can collaborate with young people through trauma wise care, providing multiplicity sensitive language and support. Overall, the term 'parts' was viewed as problematic by the participants as it could imply the plural system is not coexisting as a whole. Additionally, opinions varied as to how much diagnostic language could and should be used to describe multiplicity; linguistically and conceptually. Importantly, compassion was seen as particularly essential for younger selves within the system; older in their years and presence, but often more vulnerable within the societies in which the system resides.
PubMed: 35600531
DOI: 10.1007/s40653-021-00377-7 -
Frontiers in Psychiatry 2021Adverse childhood experiences (ACEs) might be related to cognitive impairments observed in schizophrenia spectrum disorders (SSD). However, it remains unknown what...
Adverse childhood experiences (ACEs) might be related to cognitive impairments observed in schizophrenia spectrum disorders (SSD). However, it remains unknown what aspects of ACEs are associated with cognitive impairments in SSD. Therefore, we aimed to investigate the association between various characteristics of ACEs (age at first exposure, severity, and multiplicity) and cognition in SSD and healthy controls (HCs). We enrolled 127 individuals with SSD and 56 HCs. Cognitive performance was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The Childhood Experience of Care and Abuse Questionnaire was administered to record a history of ACEs. The following characteristics of ACEs were analyzed: multiplicity, severity, and age at first exposure. Individuals with SSD had significantly lower scores on all RBANS domains. Multiplicity and severity of ACEs were significantly higher in patients with SSD compared to HCs. In both groups, greater multiplicity of ACEs was associated with lower scores of global cognition and delayed memory. Additionally, in subjects with SSD, greater multiplicity and younger age at first exposure were associated with lower scores of attention. The present findings indicate that greater multiplicity and younger age at first exposure are the most important aspects of ACEs contributing to cognitive impairments observed in SSD. Moreover, ACEs might exert differential impact on cognition in SSD and HCs.
PubMed: 34305680
DOI: 10.3389/fpsyt.2021.684099 -
Light, Science & Applications Feb 2022Matrix computation, as a fundamental building block of information processing in science and technology, contributes most of the computational overheads in modern signal... (Review)
Review
Matrix computation, as a fundamental building block of information processing in science and technology, contributes most of the computational overheads in modern signal processing and artificial intelligence algorithms. Photonic accelerators are designed to accelerate specific categories of computing in the optical domain, especially matrix multiplication, to address the growing demand for computing resources and capacity. Photonic matrix multiplication has much potential to expand the domain of telecommunication, and artificial intelligence benefiting from its superior performance. Recent research in photonic matrix multiplication has flourished and may provide opportunities to develop applications that are unachievable at present by conventional electronic processors. In this review, we first introduce the methods of photonic matrix multiplication, mainly including the plane light conversion method, Mach-Zehnder interferometer method and wavelength division multiplexing method. We also summarize the developmental milestones of photonic matrix multiplication and the related applications. Then, we review their detailed advances in applications to optical signal processing and artificial neural networks in recent years. Finally, we comment on the challenges and perspectives of photonic matrix multiplication and photonic acceleration.
PubMed: 35115497
DOI: 10.1038/s41377-022-00717-8 -
Scientific Reports May 2022A machine learning technique is used to fit multiplicity distributions in high energy proton-proton collisions and applied to make predictions for collisions at higher...
A machine learning technique is used to fit multiplicity distributions in high energy proton-proton collisions and applied to make predictions for collisions at higher energies. The method is tested with Monte Carlo event generators. Charged-particle multiplicity and transverse-momentum distributions within different pseudorapidity intervals in proton-proton collisions were simulated using the PYTHIA event generator for center of mass energies [Formula: see text]= 0.9, 2.36, 2.76, 5, 7, 8, 13 TeV for model training and validation and at 10, 20, 27, 50, 100 and 150 TeV for model predictions. Comparisons are made in order to ensure the model reproduces the relation between input variables and output distributions for the charged particle multiplicity and transverse-momentum. The multiplicity and transverse-momentum distributions are described and predicted very well, not only in the case of the trained but also in the case of untrained energy values. The study proposes a way to predict multiplicity distributions at a new energy by extrapolating the information inherent in the lower energy data. Using real data instead of Monte Carlo, as measured at the LHC, the technique has the potential to project the multiplicity distributions for different intervals at very high collision energies, e.g. 27 TeV or 100 TeV for the upgraded HE-LHC and FCC-hh respectively, using only data collected at the LHC, i.e. at center of mass energies from 0.9 up to 13 TeV.
PubMed: 35589722
DOI: 10.1038/s41598-022-11618-6 -
Cell Death & Disease Oct 2022Triplication of the SNCA gene, encoding the protein alpha-Synuclein (αSyn), is a rare cause of aggressive and early-onset parkinsonism. Herein, we generated iPSCs from...
Modeling native and seeded Synuclein aggregation and related cellular dysfunctions in dopaminergic neurons derived by a new set of isogenic iPSC lines with SNCA multiplications.
Triplication of the SNCA gene, encoding the protein alpha-Synuclein (αSyn), is a rare cause of aggressive and early-onset parkinsonism. Herein, we generated iPSCs from two siblings with a recently described compact SNCA gene triplication and suffering from severe motor impairments, psychiatric symptoms, and cognitive deterioration. Using CRISPR/Cas9 gene editing, each SNCA copy was inactivated by targeted indel mutations generating a panel of isogenic iPSCs with a decremental number from 4 down to none of functional SNCA gene alleles. We differentiated these iPSC lines in midbrain dopaminergic (DA) neuronal cultures to characterize αSyn aggregation in native and seeded conditions and evaluate its associated cellular dysfunctions. Utilizing a new nanobody-based biosensor combined with super-resolved imaging, we were able to visualize and measure αSyn aggregates in early DA neurons in unstimulated conditions. Calcium dysregulation and mitochondrial alterations were the first pathological signs detectable in early differentiated DA neuronal cultures. Accelerated αSyn aggregation was induced by exposing neurons to structurally well-characterized synthetic αSyn fibrils. 4xSNCA DA neurons showed the highest vulnerability, which was associated with high levels of oxidized DA and amplified by TAX1BP1 gene disruption. Seeded DA neurons developed large αSyn deposits whose morphology and internal constituents resembled Lewy bodies commonly observed in Parkinson's disease (PD) patient brain tissues. These findings provide strong evidence that this isogenic panel of iPSCs with SNCA multiplications offers a remarkable cellular platform to investigate mechanisms of PD and validate candidate inhibitors of native and seeded αSyn aggregation.
Topics: Humans; alpha-Synuclein; Dopaminergic Neurons; Induced Pluripotent Stem Cells; Calcium; Parkinson Disease
PubMed: 36261424
DOI: 10.1038/s41419-022-05330-6 -
Exploratory Research in Clinical and... Mar 2022Public health-sectors of most low- and middle-income countries (LMICs) run a central medical stores (CMS) model that is monopolistic in character. Concerns raised about...
Public health-sectors of most low- and middle-income countries (LMICs) run a central medical stores (CMS) model that is monopolistic in character. Concerns raised about monopolistic CMS arrangements stress the need to encourage cost-reducing efforts and improve service levels (outputs) by having multiple competing logistics institutions. This paper examines the desirability of consolidation or multiplicity in supply logistics by focusing on the task of inventory management (that is, distribution, storage and warehousing). The paper uses theory and historical evidence to describe and suggest a desired form of multiplicity in LMICs. Consolidation shouldn't progress to the point of monopoly and multiplicity doesn't mean having an infinite number of logistics institutions. A limited number (2-10) of logistics institutions, that are full-line and national in their scope and scale of operations, should be enough to provide choice, support competition and minimize the risk of supply disruptions. Health policy and planning in LMICs should explore ways of turning existing logistics institutions in the public, private and non-governmental sectors into a multiplicity of types that are capable of assuring uninterrupted supplies of health commodities.
PubMed: 35478501
DOI: 10.1016/j.rcsop.2022.100105 -
BMC Medical Research Methodology Feb 2022Opinions and practices vary around the issue of performing multiple statistical tests in randomised controlled trials (RCTs). We carried out a study to collate... (Review)
Review
BACKGROUND
Opinions and practices vary around the issue of performing multiple statistical tests in randomised controlled trials (RCTs). We carried out a study to collate information about opinions and practices using a methodological rapid review and a survey, specifically of publicly funded pragmatic RCTs that are not seeking marketing authorisation. The aim was to identify the circumstances under which researchers would make a statistical adjustment for multiplicity.
METHODS
A review was performed extracting information from articles reporting primary analyses of pragmatic RCTs in one of seven high quality medical journals, in January to June (inclusive) 2018. A survey (Survey Monkey) eliciting opinions and practices around multiplicity was distributed to the 47 registered clinical trials units (CTUs) in the UK.
RESULTS
One hundred and thirty-eight RCTs were included in the review, and survey responses were received from 27/47 (57%) CTUs. Both the review and survey indicated that adjusting for multiplicity was considered most important for multiple treatment comparisons; adjustment was performed for 11/23 (48%) published trials, and 24/27 (89%) CTU statisticians reported they would consider adjustment. Opinions and practices varied around adjustment for multiplicity arising from multiple primary outcomes and interim analyses. Adjustment was considered less important for multiplicity due to multiple secondary outcomes (adjustment performed for 17/136 [13%] published trials and 3/27 [11%] CTU statisticians would consider adjustment) and subgroup analyses (8/85 [9%] published trials adjusted and 6/27 CTU [22%] statisticians would consider adjustment).
CONCLUSIONS
There is variation in opinions about adjustment for multiplicity among both statisticians reporting RCTs and applied statisticians working in CTUs. Further guidance is needed on the circumstances in which adjustment should be considered in relation to primary trial hypotheses, and if there are any situations in which adjustment would be recommended in the context of secondary analyses.
Topics: Humans; Publications; Randomized Controlled Trials as Topic; Research Personnel; Surveys and Questionnaires
PubMed: 35125091
DOI: 10.1186/s12874-022-01525-9