bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants in the Ig Variable Domain of Human HAVCR1 (TIM-1) Are Required To Enhance Hepatitis C Virus Entry
Authors: Kachko Alla , Costafreda Maria Isabel , Zubkova Iryna , Jacques Jerome , Takeda Kazuyo , Wells Frances , Kaplan Gerardo , Major Marian E. 
Published: January 2018

ABSTRACT
Hepatitis C virus (HCV) is the leading cause of chronic hepatitis in humans. Several host molecules participate in HCV cell entry, but this process remains unclear. The complete unraveling of the HCV entry process is important to further understand viral pathogenesis and develop therapeutics. Human hepatitis A virus (HAV) cellular receptor 1 (HAVCR1), CD365, also known as TIM-1, functions as a phospholipid receptor involved in cell entry of several enveloped viruses. Here, we studied the role of HAVCR1 in HCV infection. HAVCR1 antibody inhibited entry in a dose-dependent manner. HAVCR1 soluble constructs neutralized HCV, which did not require the HAVCR1 mucinlike region and was abrogated by a mutation of N to A at position 94 (N94A) in the Ig variable (IgV) domain phospholipid-binding pocket, indicating a direct interaction of the HAVCR1 IgV domain with HCV virions. However, knockout of HAVCR1 in Huh7 cells reduced but did not prevent HCV growth. Interestingly, the mouse HAVCR1 ortholog, also a phospholipid receptor, did not enhance infection and a soluble form failed to neutralize HCV, although replacement of the mouse IgV domain with the human HAVCR1 IgV domain restored the enhancement of HCV infection. Mutations in the cytoplasmic tail revealed that direct HAVCR1 signaling is not required to enhance HCV infection. Our data show that the phospholipid-binding function and other determinant(s) in the IgV domain of human HAVCR1 enhance HCV infection. Although the exact mechanism is not known, it is possible that HAVCR1 facilitates entry by stabilizing or enhancing attachment, leading to direct interactions with specific receptors, such as CD81.

IMPORTANCE
Hepatitis C virus (HCV) enters cells through a multifaceted process. We identified the human hepatitis A virus cellular receptor 1 (HAVCR1), CD365, also known as TIM-1, as a facilitator of HCV entry. Antibody blocking and silencing or knockout of HAVCR1 in hepatoma cells reduced HCV entry. Our findings that the interaction of HAVCR1 with HCV early during infection enhances entry but is not required for infection support the hypothesis that HAVCR1 facilitates entry by stabilizing or enhancing virus binding to the cell surface membrane and allowing the correct virus-receptor positioning for interaction with the main HCV receptors. Furthermore, our data show that in addition to the phospholipid-binding function of HAVCR1, the enhancement of HCV infection involves other determinants in the IgV domain of HAVCR1. These findings expand the repertoire of molecules that HCV uses for cell entry, adding to the already complex mechanism of HCV infection and pathogenesis.
Paramyxovirus V Proteins Interact with the RIG-I/TRIM25 Regulatory Complex and Inhibit RIG-I Signaling
Authors: Sánchez-Aparicio Maria T. , Feinman Leighland J. , García-Sastre Adolfo , Shaw Megan L. 
Published: January 2018

ABSTRACT
Paramyxovirus V proteins are known antagonists of the RIG-I-like receptor (RLR)-mediated interferon induction pathway, interacting with and inhibiting the RLR MDA5. We report interactions between the Nipah virus V protein and both RIG-I regulatory protein TRIM25 and RIG-I. We also observed interactions between these host proteins and the V proteins of measles virus, Sendai virus, and parainfluenza virus. These interactions are mediated by the conserved C-terminal domain of the V protein, which binds to the tandem caspase activation and recruitment domains (CARDs) of RIG-I (the region of TRIM25 ubiquitination) and to the SPRY domain of TRIM25, which mediates TRIM25 interaction with the RIG-I CARDs. Furthermore, we show that V interaction with TRIM25 and RIG-I prevents TRIM25-mediated ubiquitination of RIG-I and disrupts downstream RIG-I signaling to the mitochondrial antiviral signaling protein. This is a novel mechanism for innate immune inhibition by paramyxovirus V proteins, distinct from other known V protein functions such as MDA5 and STAT1 antagonism.

IMPORTANCE
The host RIG-I signaling pathway is a key early obstacle to paramyxovirus infection, as it results in rapid induction of an antiviral response. This study shows that paramyxovirus V proteins interact with and inhibit the activation of RIG-I, thereby interrupting the antiviral signaling pathway and facilitating virus replication.
Exploration of the Germline Genome of the Ciliate
Chilodonella uncinata
through Single-Cell Omics (Transcriptomics and Genomics)
Authors: Maurer-Alcalá Xyrus X. , Knight Rob , Katz Laura A. 
Published: January 2018

ABSTRACT

Separate germline and somatic genomes are found in numerous lineages across the eukaryotic tree of life, often separated into distinct tissues (e.g., in plants, animals, and fungi) or distinct nuclei sharing a common cytoplasm (e.g., in ciliates and some foraminifera). In ciliates, germline-limited (i.e., micronuclear-specific) DNA is eliminated during the development of a new somatic (i.e., macronuclear) genome in a process that is tightly linked to large-scale genome rearrangements, such as deletions and reordering of protein-coding sequences. Most studies of germline genome architecture in ciliates have focused on the model ciliates
Oxytricha trifallax
,
Paramecium tetraurelia
, and
Tetrahymena thermophila
, for which the complete germline genome sequences are known. Outside of these model taxa, only a few dozen germline loci have been characterized from a limited number of cultivable species, which is likely due to difficulties in obtaining sufficient quantities of “purified” germline DNA in these taxa. Combining single-cell transcriptomics and genomics, we have overcome these limitations and provide the first insights into the structure of the germline genome of the ciliate
Chilodonella uncinata
, a member of the understudied class
Phyllopharyngea
. Our analyses reveal the following: (i) large gene families contain a disproportionate number of genes from scrambled germline loci; (ii) germline-soma boundaries in the germline genome are demarcated by substantial shifts in GC content; (iii) single-cell omics techniques provide large-scale quality germline genome data with limited effort, at least for ciliates with extensively fragmented somatic genomes. Our approach provides an efficient means to understand better the evolution of genome rearrangements between germline and soma in ciliates.

IMPORTANCE
Our understanding of the distinctions between germline and somatic genomes in ciliates has largely relied on studies of a few model genera (e.g.,
Oxytricha
,
Paramecium
,
Tetrahymena
). We have used single-cell omics to explore germline-soma distinctions in the ciliate
Chilodonella uncinata
, which likely diverged from the better-studied ciliates ~700 million years ago. The analyses presented here indicate that developmentally regulated genome rearrangements between germline and soma are demarcated by rapid transitions in local GC composition and lead to diversification of protein families. The approaches used here provide the basis for future work aimed at discerning the evolutionary impacts of germline-soma distinctions among diverse ciliates.
ATG8 Is Essential Specifically for an Autophagy-Independent Function in Apicoplast Biogenesis in Blood-Stage Malaria Parasites
Authors: Walczak Marta , Ganesan Suresh M. , Niles Jacquin C. , Yeh Ellen 
Published: January 2018

ABSTRACT

Plasmodium
parasites and related pathogens contain an essential nonphotosynthetic plastid organelle, the apicoplast, derived from secondary endosymbiosis. Intriguingly, a highly conserved eukaryotic protein, autophagy-related protein 8 (ATG8), has an autophagy-independent function in the apicoplast. Little is known about the novel apicoplast function of ATG8 and its importance in blood-stage
Plasmodium falciparum
. Using a
P. falciparum
strain in which ATG8 expression was conditionally regulated, we showed that
P. falciparum
ATG8 (
Pf
ATG8) is essential for parasite replication. Significantly, growth inhibition caused by the loss of
Pf
ATG8 was reversed by addition of isopentenyl pyrophosphate (IPP), which was previously shown to rescue apicoplast defects in
P. falciparum
. Parasites deficient in
Pf
ATG8, but whose growth was rescued by IPP, had lost their apicoplast. We designed a suite of functional assays, including a new fluorescence
in situ
hybridization (FISH) method for detection of the low-copy-number apicoplast genome, to interrogate specific steps in apicoplast biogenesis and detect apicoplast defects which preceded the block in parasite replication. Though protein import and membrane expansion of the apicoplast were unaffected, the apicoplast was not inherited by daughter parasites. Our findings demonstrate that, though multiple autophagy-dependent and independent functions have been proposed for
Pf
ATG8, only its role in apicoplast biogenesis is essential in blood-stage parasites. We propose that
Pf
ATG8 is required for fission or segregation of the apicoplast during parasite replication.

IMPORTANCE
Plasmodium
parasites, which cause malaria, and related apicomplexan parasites are important human and veterinary pathogens. They are evolutionarily distant from traditional model organisms and possess a unique plastid organelle, the apicoplast, acquired by an unusual eukaryote-eukaryote endosymbiosis which established novel protein/lipid import and organelle inheritance pathways in the parasite cell. Though the apicoplast is essential for parasite survival in all stages of its life cycle, little is known about these novel biogenesis pathways. We show that malaria parasites have adapted a highly conserved protein required for macroautophagy in yeast and mammals to function specifically in apicoplast inheritance. Our finding elucidates a novel mechanism of organelle biogenesis, essential for pathogenesis, in this divergent branch of pathogenic eukaryotes.
Acute small intestinal inflammation results in persistent lymphatic alterations
Authors: Rehal Sonia , Stephens Matthew , Roizes Simon , Liao Shan , von der Weid Pierre-Yves 
Published: January 2018

Inflammatory bowel disease (IBD) has a complex pathophysiology with limited treatments. Structural and functional changes in the intestinal lymphatic system have been associated with the disease, with increased risk of IBD occurrence linked to a history of acute intestinal injury. To examine the potential role of the lymphatic system in inflammation recurrence, we evaluated morphological and functional changes in mouse mucosal and mesenteric lymphatic vessels, and within the mesenteric lymph nodes during acute ileitis caused by a 7-day treatment with dextran sodium sulfate (DSS). We monitored whether the changes persisted during a 14-day recovery period and determined their potential consequences on dendritic cell (DC) trafficking between the mucosa and lymphoid tissues. DSS administration was associated with marked lymphatic abnormalities and dysfunctions exemplified by lymphangiectasia and lymphangiogenesis in the ileal mucosa and mesentery, increased mesenteric lymphatic vessel leakage, and lymphadenopathy. Lymphangiogenesis and lymphadenopathy were still evident after recovery from intestinal inflammation and correlated with higher numbers of DCs in mucosal and lymphatic tissues. Specifically, a deficit in CD103+ DCs observed during acute DSS in the lamina propria was reversed and further enhanced during recovery. We concluded that an acute intestinal insult caused alterations of the mesenteric lymphatic system, including lymphangiogenesis, which persisted after resolution of inflammation. These morphological and functional changes could compromise DC function and movement, increasing susceptibility to further gastrointestinal disease. Elucidation of the changes in mesenteric and intestinal lymphatic function should offer key insights for new therapeutic strategies in gastrointestinal disorders such as IBD. NEW & NOTEWORTHY Lymphatic integrity plays a critical role in small intestinal homeostasis. Acute intestinal insult in a mouse model of acute ileitis causes morphological and functional changes in mesenteric and intestinal lymphatic vessels. While some of the changes significantly regressed during inflammation resolution, others persisted, including lymphangiogenesis and altered dendritic cell function and movement, potentially increasing susceptibility to the recurrence of gastrointestinal inflammation.
GBT1118, a compound that increases the oxygen affinity of hemoglobin, improves survival in murine hypoxic acute lung injury
Authors: Putz Nathan D. , Shaver Ciara M. , Dufu Kobina , Li Chien-Ming , Xu Qing , Hutchaleelaha Athiwat , Lehrer-Graiwer Josh , Majka Susan M. , Ware Lorraine B. , Bastarache Julie A. 
Published: January 2018

Acute respiratory distress syndrome (ARDS) is characterized by lung inflammation and pulmonary edema, leading to arterial hypoxemia and death if the hypoxemia is severe. Strategies to correct hypoxemia have the potential to improve clinical outcomes in ARDS. The goal of this study was to evaluate the potential of hemoglobin modification as a novel therapy for ARDS-induced hypoxemia. The therapeutic effect of two different doses of GBT1118, a compound that increases the oxygen affinity of hemoglobin, was evaluated in a murine model of acute lung injury induced by intratracheal LPS instillation 24 h before exposure to 5% or 10% hypoxia ( n = 8–15 per group). As expected, administration of GBT1118 to mice significantly increased the oxygen affinity of hemoglobin. Compared with mice receiving vehicle control, mice treated with GBT1118 had significantly lower mortality after LPS + 5% hypoxia (47% with vehicle vs. 22% with low-dose GBT1118, 13% with high-dose GBT1118, P = 0.032 by log rank) and had reduced severity of illness. Mice treated with GBT1118 showed a sustained significant increase in SpO2 over 4 h of hypoxia exposure. Treatment with GBT1118 did not alter alveolar-capillary permeability, bronchoalveolar lavage (BAL) inflammatory cell counts, or BAL concentrations of IL-1β, TNF-α, or macrophage inflammatory protein-1α. High-dose GBT1118 did not affect histological lung injury but did decrease tissue hypoxia as measured intensity of pimonidazole (Hypoxyprobe) staining in liver ( P = 0.043) and kidney ( P = 0.043). We concluded that increasing the oxygen affinity of hemoglobin using GBT1118 may be a novel therapy for treating hypoxemia associated with acute lung injury. NEW & NOTEWORTHY In this study, we show that GBT1118, a compound that increases hemoglobin affinity for oxygen, improves survival and oxygen saturation in a two-hit lung injury model of intratracheal LPS without causing tissue hypoxia. Modulation of hemoglobin oxygen affinity represents a novel therapeutic approach to treatment of acute lung injury and acute respiratory distress syndrome, conditions characterized by hypoxemia.
Motor unit territories in human genioglossus estimated with multichannel intramuscular electrodes
Authors: Luu Billy L. , Muceli Silvia , Saboisky Julian P. , Farina Dario , Héroux Martin E. , Bilston Lynne E. , Gandevia Simon C. , Butler Jane E. 
Published: January 2018

The discharge patterns of genioglossus motor units during breathing have been well-characterized in previous studies, but their localization and territories are not known. In this study, we used two newly developed intramuscular multichannel electrodes to estimate the territories of genioglossus motor units in the anterior and posterior regions of the muscle. Seven healthy men participated. Each electrode contained fifteen bipolar channels, separated by 1 mm, and was inserted percutaneously below the chin, perpendicular to the skin, to a depth of 36 mm. Single motor unit activity was recorded with subjects awake, supine, and breathing quietly through a nasal mask for 180 s. Motor unit territories were estimated from the spike-triggered averages of the electromyographic signal from each channel. A total of 30 motor units were identified: 22 expiratory tonic, 1 expiratory phasic, 2 tonic, 3 inspiratory tonic, and 2 inspiratory phasic. Motor units appeared to be clustered based on unit type, with peak activities for expiratory units predominantly located in the anterior and superficial fibers of genioglossus and inspiratory units in the posterior region. Of these motor unit types, expiratory tonic units had the largest estimated territory, a mean 11.3 mm (SD 1.9). Estimated territories of inspiratory motor units ranged from 3 to 6 mm. In accordance with the distribution of motor unit types, the estimated territory of genioglossus motor units varied along the sagittal plane, decreasing from anterior to posterior. Our findings suggest that genioglossus motor units have large territories relative to the cross-sectional size of the muscle. NEW & NOTEWORTHY In this study, we used a new multichannel intramuscular electrode to address a fundamental property of human genioglossus motor units. We describe the territory of genioglossus motor units in the anterior and posterior regions of the muscle and show a decrease in territory size from anterior to posterior and that expiratory-related motor units have larger estimated territories than inspiratory-related motor units.
Unilateral strength training leads to muscle-specific sparing effects during opposite homologous limb immobilization
Authors: Andrushko Justin W. , Lanovaz Joel L. , Björkman Kelsey M. , Kontulainen Saija A. , Farthing Jonathan P. 
Published: January 2018

Cross education (CE) occurs after unilateral training whereby performance of the untrained contralateral limb is enhanced. A few studies have shown that CE can preserve or “spare” strength and size of an opposite immobilized limb, but the specificity (i.e., trained homologous muscle and contraction type) of these effects is unknown. The purpose was to investigate specificity of CE “sparing” effects with immobilization. The nondominant forearm of 16 participants was immobilized with a cast, and participants were randomly assigned to a resistance training (eccentric wrist flexion, 3 times/week) or control group for 4 weeks. Pre- and posttesting involved wrist flexors and extensors eccentric, concentric and isometric maximal voluntary contractions (via dynamometer), muscle thickness (via ultrasound), and forearm muscle cross-sectional area (MCSA; via peripheral quantitative computed tomography). Only the training group showed strength preservation across all contractions in the wrist flexors of the immobilized limb (training: −2.4% vs. control: −21.6%; P = 0.04), and increased wrist flexors strength of the nonimmobilized limb (training: 30.8% vs. control: −7.4%; P = 0.04). Immobilized arm MCSA was preserved for the training group only (training: 1.3% vs. control: −2.3%; P = 0.01). Muscle thickness differed between groups for the immobilized (training: 2.8% vs. control: −3.2%; P = 0.01) and nonimmobilized wrist flexors (training: 7.1% vs. control: −3.7%; P = 0.02). Strength preservation was nonspecific to contraction type ( P = 0.69, [Formula: see text] = 0.03) yet specific to the trained flexors muscle. These findings suggest that eccentric training of the nonimmobilized limb can preserve size of the immobilized contralateral homologous muscle and strength across multiple contraction types.NEW & NOTEWORTHY Unilateral strength training preserves strength, muscle thickness, and muscle cross-sectional area in an opposite immobilized limb. The preservation of size and strength was confined to the trained homologous muscle group. However, strength was preserved across multiple contraction types.
Bayesian quantification of sensory reweighting in a familial bilateral vestibular disorder (DFNA9)
Authors: Alberts Bart B. G. T. , Selen Luc P. J. , Verhagen Wim I. M. , Pennings Ronald J. E. , Medendorp W. Pieter 
Published: January 2018

DFNA9 is a rare progressive autosomal dominantly inherited vestibulo-cochlear disorder, resulting in a homogeneous group of patients with hearing impairment and bilateral vestibular function loss. These patients suffer from a deteriorated sense of spatial orientation, leading to balance problems in darkness, especially on irregular surfaces. Both behavioral and functional imaging studies suggest that the remaining sensory cues could compensate for the loss of vestibular information. A thorough model-based quantification of this reweighting in individual patients is, however, missing. Here we psychometrically examined the individual patient’s sensory reweighting of these cues after complete vestibular loss. We asked a group of DFNA9 patients and healthy control subjects to judge the orientation (clockwise or counterclockwise relative to gravity) of a rod presented within an oriented square frame (rod-in-frame task) in three different head-on-body tilt conditions. Our results show a cyclical frame-induced bias in perceived gravity direction across a 90° range of frame orientations. The magnitude of this bias was significantly increased in the patients compared with the healthy control subjects. Response variability, which increased with head-on-body tilt, was also larger for the patients. Reverse engineering of the underlying signal properties, using Bayesian inference principles, suggests a reweighting of sensory signals, with an increase in visual weight of 20–40% in the patients. Our approach of combining psychophysics and Bayesian reverse engineering is the first to quantify the weights associated with the different sensory modalities at an individual patient level, which could make it possible to develop personal rehabilitation programs based on the patient’s sensory weight distribution.NEW & NOTEWORTHY It has been suggested that patients with vestibular deficits can compensate for this loss by increasing reliance on other sensory cues, although an actual quantification of this reweighting is lacking. We combine experimental psychophysics with a reverse engineering approach based on Bayesian inference principles to quantify sensory reweighting in individual vestibular patients. We discuss the suitability of this approach for developing personal rehabilitation programs based on the patient’s sensory weight distribution.