Abstract
Recognizing the importance of timely guidance regarding the rapidly evolving field of hepatitis C management, the American Association for the Study of Liver Diseases (AASLD) and the ...Infectious Diseases Society of America (IDSA) developed a web-based process for the expeditious formulation and dissemination of evidence-based recommendations. Launched in 2014, the hepatitis C virus (HCV) guidance website undergoes periodic updates as necessitated by availability of new therapeutic agents and/or research data. A major update was released electronically in September 2017, prompted primarily by approval of new direct-acting antiviral agents and expansion of the guidance's scope. This update summarizes the latest release of the HCV guidance and focuses on new or amended recommendations since the previous September 2015 print publication. The recommendations herein were developed by volunteer hepatology and infectious disease experts representing AASLD and IDSA and have been peer reviewed and approved by each society's governing board.
Abstract
Inferring phenotypic outcomes from genomic features is both a promise and challenge for systems biology. Using gene expression data to predict phenotypic outcomes, and functionally ...validating the genes with predictive powers are two challenges we address in this study. We applied an evolutionarily informed machine learning approach to predict phenotypes based on transcriptome responses shared both within and across species. Specifically, we exploited the phenotypic diversity in nitrogen use efficiency and evolutionarily conserved transcriptome responses to nitrogen treatments across Arabidopsis accessions and maize varieties. We demonstrate that using evolutionarily conserved nitrogen responsive genes is a biologically principled approach to reduce the feature dimensionality in machine learning that ultimately improved the predictive power of our gene-to-trait models. Further, we functionally validated seven candidate transcription factors with predictive power for NUE outcomes in Arabidopsis and one in maize. Moreover, application of our evolutionarily informed pipeline to other species including rice and mice models underscores its potential to uncover genes affecting any physiological or clinical traits of interest across biology, agriculture, or medicine.
The anterior cingulate cortex (ACC) is critical for the perception and unpleasantness of pain.1,2,3,4,5,6 It receives nociceptive information from regions such as the thalamus and amygdala and ...projects to several cortical and subcortical regions of the pain neuromatrix.7,8 ACC hyperexcitability is one of many functional changes associated with chronic pain, and experimental activation of ACC pyramidal cells produces hypersensitivity to innocuous stimuli (i.e., allodynia).9,10,11,12,13,14 A less-well-studied projection to the ACC arises from a small forebrain region, the claustrum.15,16,17,18,19,20 Stimulation of excitatory claustrum projection neurons preferentially activates GABAergic interneurons, generating feed-forward inhibition onto excitatory cortical networks.21,22,23,24 Previous work has shown that claustrocingulate projections display altered activity in prolonged pain25,26,27; however, it remains unclear whether and how the claustrum participates in nociceptive processing and high-order pain behaviors. Inhibition of ACC activity reverses mechanical allodynia in animal models of persistent and neuropathic pain,1,9,28 suggesting claustrum inputs may function to attenuate pain processing. In this study, we sought to define claustrum function in acute and chronic pain. We found enhanced claustrum activity after a painful stimulus that was attenuated in chronic inflammatory pain. Selective inhibition of claustrocingulate projection neurons enhanced acute nociception but blocked pain learning. Inversely, chemogenetic activation of claustrocingulate neurons had no effect on basal nociception but rescued inflammation-induced mechanical allodynia. Together, these results suggest that claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.
•Nociceptive stimuli engage the claustrum in a temporally specific manner•Chronic pain leads to a loss of function of the claustrocingulate pathway•Inhibition of this circuit lowers pain thresholds but interferes with pain learning•Activation of this pathway in chronic pain reverses pain hypersensitivity
Faig et al. show that pain activates the claustrum in a temporally specific manner. Chronic pain leads to loss of function of claustrocingulate projection neurons, and activation of this pathway reverses pain hypersensitivity. This study shows that the claustrum is an important node in pain processing and identifies a novel mechanism for chronic pain.
This systematic review assessed the effectiveness of capacity building interventions relevant to public health practice. The aim is to inform and improve capacity building interventions.
Four ...strategies were used: 1) electronic database searching; 2) reference lists of included papers; 3) key informant consultation; and 4) grey literature searching. Inclusion (e.g., published in English) and exclusion criteria (e.g., non-English language papers published earlier than 2005) are outlined with included papers focusing on capacity building, learning plans, or professional development plans within public health and related settings, such as non-governmental organizations, government, or community-based organizations relating to public health or healthcare. Outcomes of interest included changes in knowledge, skill or confidence (self-efficacy), changes in practice (application or intent), and perceived support or supportive environments, with outcomes reported at the individual, organizational or systems level(s). Quality assessment of all included papers was completed.
Fourteen papers were included in this review. These papers reported on six intervention types: 1) internet-based instruction, 2) training and workshops, 3) technical assistance, 4) education using self-directed learning, 5) communities of practice, and 6) multi-strategy interventions. The available literature showed improvements in one or more capacity-building outcomes of interest, mainly in terms of individual-level outcomes. The available literature was moderate in quality and showed a range of methodological issues.
There is evidence to inform capacity building programming and how interventions can be selected to optimize impact. Organizations should carefully consider methods for analysis of capacity building interventions offered; specifically, through which mechanisms, to whom, and for which purpose. Capacity-building interventions can enhance knowledge, skill, self-efficacy (including confidence), changes in practice or policies, behaviour change, application, and system-level capacity. However in applying available evidence, organizations should consider the outcomes of highest priority, selecting intervention(s) effective for the outcome(s) of interest. Examples are given for selecting intervention(s) to match priorities and context, knowing effectiveness evidence is only one consideration in decision making. Future evaluations should: extend beyond the individual level, assess outcomes at organizational and systems levels, include objective measures of effect, assess baseline conditions, and evaluate features most critical to the success of interventions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recently, the ionic liquid (IL) choline dihydrogen phosphate was demonstrated to improve the thermostability and shelf life of several model proteins, thus exhibiting potential as a stabilizing ...excipient or solvent for protein therapeutics. Before novel ILs can be used for biomedical applications, comprehensive data is required to establish biocompatibility, including cytotoxicity effects and solution behavior. In this study five phosphate-based anion moieties were analyzed: H2PO4- (DHP), dibutyl phosphate (DBP), bis(2-ethylhexyl) phosphate (BEH), bis(2,4,4-trimethylpentyl) phosphinate (TMP), and O,Oprime or minute-diethyl dithiophosphate (DEP), all paired with the cation choline (C). Toxicity levels for these ILs, and a common sugar and salts, were established using a J774 murine macrophage cell line. The sugar trehalose, and the simple salts sodium chloride and choline chloride yielded EC50 values of 100, 63 and 34 mM, respectively. The EC50 values (mM) of CDHP (20), CDBP (9.1), and CDEP (8.2) were lower than, but within the range of simple salts NaCl (62.8) and choline Cl (33.7). The EC50 values of CTMP and CBEH were considerably lower, 0.25 and 0.30 mM, respectively. CDHP and CBEH displayed a hormetic response. Osmolality measurements indicated that CDHP, CDBP, and CDEP exhibit nearly complete dissociation in aqueous solution, with osmotic coefficients of 1.0, 0.9, and 0.8, whereas CTMP and CBEH have coefficients of 0.5 and 0.3, and are more molecular in character. A high correlation between the EC50 value and the anion mass fraction indicated that anion size and the presence of moderately long and/or branched alkyl chains may affect viability.
Targeted selection-based genome-editing approaches have enabled many fundamental discoveries and are used routinely with high precision. We found, however, that replacement of
with a common selection ...cassette in budding yeast led to reduced expression and function for the adjacent gene,
, despite all
coding and regulatory sequences remaining intact. Cassette-induced repression of MRP51 drove all mutant phenotypes detected in cells deleted for
. This behavior resembled the 'neighboring gene effect' (NGE), a phenomenon of unknown mechanism whereby cassette insertion at one locus reduces the expression of a neighboring gene. Here, we leveraged strong off-target mutant phenotypes resulting from cassette replacement of
to provide mechanistic insight into the NGE. We found that the inherent bidirectionality of promoters, including those in expression cassettes, drives a divergent transcript that represses
through combined transcriptional interference and translational repression mediated by production of a long undecoded transcript isoform (LUTI). Divergent transcript production driving this off-target effect is general to yeast expression cassettes and occurs ubiquitously with insertion. Despite this, off-target effects are often naturally prevented by local sequence features, such as those that terminate divergent transcripts between the site of cassette insertion and the neighboring gene. Thus, cassette-induced off-target effects can be eliminated by the insertion of transcription terminator sequences into the cassette, flanking the promoter. Because the driving features of this off-target effect are broadly conserved, our study suggests it should be considered in the design and interpretation of experiments using integrated expression cassettes in other eukaryotic systems, including human cells.
Interindividual gene copy-number variation (CNV) of complement component
C4 and its associated polymorphisms in gene size (long and short) and protein isotypes (C4A and C4B) probably lead to ...different susceptibilities to autoimmune disease. We investigated the
C4 gene CNV in 1,241 European Americans, including patients with systemic lupus erythematosus (SLE), their first-degree relatives, and unrelated healthy subjects, by definitive genotyping and phenotyping techniques. The gene copy number (GCN) varied from 2 to 6 for total
C4, from 0 to 5 for
C4A, and from 0 to 4 for
C4B. Four copies of total
C4, two copies of
C4A, and two copies of
C4B were the most common GCN counts, but each constituted only between one-half and three-quarters of the study populations. Long
C4 genes were strongly correlated with
C4A (
R=0.695;
P<.0001). Short
C4 genes were correlated with
C4B (
R=0.437;
P<.0001). In comparison with healthy subjects, patients with SLE clearly had the GCN of total
C4 and
C4A shifting to the lower side. The risk of SLE disease susceptibility significantly increased among subjects with only two copies of total
C4 (patients 9.3%; unrelated controls 1.5%; odds ratio OR = 6.514;
P=.00002) but decreased in those with ≥5 copies of
C4 (patients 5.79%; controls 12%; OR=0.466;
P=.016). Both zero copies (OR=5.267;
P=.001) and one copy (OR=1.613;
P=.022) of
C4A were risk factors for SLE, whereas ≥3 copies of
C4A appeared to be protective (OR=0.574;
P=.012). Family-based association tests suggested that a specific haplotype with a single short
C4B in tight linkage disequilibrium with the −308A allele of
TNFA was more likely to be transmitted to patients with SLE. This work demonstrates how gene CNV and its related polymorphisms are associated with the susceptibility to a human complex disease.
The activating natural killer (NK)-cell receptor KIR3DS1 has been linked to the outcome of various human diseases, including delayed progression of disease caused by human immunodeficiency virus type ...1 (HIV-1), yet a ligand that would account for its biological effects has remained unknown. We screened 100 HLA class I proteins and found that KIR3DS1 bound to HLA-F, a result we confirmed biochemically and functionally. Primary human KIR3DS1(+) NK cells degranulated and produced antiviral cytokines after encountering HLA-F and inhibited HIV-1 replication in vitro. Activation of CD4(+) T cells triggered the transcription and surface expression of HLA-F mRNA and HLA-F protein, respectively, and induced binding of KIR3DS1. HIV-1 infection further increased the transcription of HLA-F mRNA but decreased the binding of KIR3DS1, indicative of a mechanism for evading recognition by KIR3DS1(+) NK cells. Thus, we have established HLA-F as a ligand of KIR3DS1 and have demonstrated cell-context-dependent expression of HLA-F that might explain the widespread influence of KIR3DS1 in human disease.
Extracellular vesicles (EVs), once considered a pathway for cells to remove waste, have now emerged as an important mechanism for intercellular communication. EVs are particularly appealing in ...understanding the central nervous system (CNS) communication, given that there are very diverse cell types in the CNS and constant communications among various cells to respond to the frequently changing environment. While they are heterogeneous and new vesicles are continuously to be discovered, EVs are primarily classified as plasma membrane-derived microvesicles (MVs) and endosome-derived exosomes. Secretion of EVs has been shown from all CNS cell types in vitro and intercellular EV signaling has been implicated in neural development, axon integrity, neuron to glia communication, and propagation of protein aggregates formed by disease pathogenic proteins. However, significant hurdles remain to be tackled in understanding their physiological and pathological roles as well as how they can be developed as biomarkers or new therapeutics. Here we provide our summary on the known cell biology of EVs and discuss opportunities and challenges in understanding EV biology in the CNS and particularly their involvement in ALS pathogenesis.
Re-directing T cells via chimeric antigen receptors (CARs) was first tested in HIV-infected individuals with limited success, but these pioneering studies laid the groundwork for the clinically ...successful CD19 CARs that were recently FDA approved. Now there is great interest in revisiting the concept of using CAR-expressing T cells as part of a strategy to cure HIV. Many lessons have been learned on how to best engineer T cells to cure cancer, but not all of these lessons apply when developing CARs to treat and cure HIV. This mini review will focus on how early CAR T cell studies in HIV paved the way for cancer CAR T cell therapy and how progress in cancer CAR therapy has and will continue to be instructive for the development of HIV CAR T cell therapy. Additionally, the unique challenges that must be overcome to develop a successful HIV CAR T cell therapy will be highlighted.
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