bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of a Community Care Station Program With Structured Exercise Intervention on Physical Performance and Balance in Community-Dwelling Older Adults: A Prospective 2-Year Observational Study
Authors: Liang Chung-Chao , Change Qi-Xing , Hung Yu-Chou , Chen Chizan-Chung , Lin Chun-Hsiang , Wei Yu-Chun , Chen Jia-Ching 
Published: March 2017

The Taiwanese government has developed community care stations (CCSs) for community-based older adult care. We investigated the effects of a structured exercise intervention, applied at CCS for 6 months, on physical performance and balance in community-dwelling older adults, including a 2-year reassessment. Fifty-eight participants (aged 76.9 ± 6.3 years) participated in the study. The Elderly Mobility Scale, Short Physical Performance Battery (SPPB), Timed Up and Go (TUG), gait speed, functional reach, one-leg-stance (OLS), and flexibility were evaluated at baseline, 6 months, and 2 years. Compared with baseline, the participants improved significantly in the SPPB (0.93 points), TUG (1.94 s), gait speed (0.13 m/s), and right and left OLS (2.56 and 3.12 s) at 6 months. Furthermore, these significant effects, except for OLS, were maintained at the 2-year reassessment according to repeated-measures ANOVA (p < .01). Our preliminary data suggest that adding a structured exercise program can benefit older adults participating in Taiwanese CCSs.
Gender Differences in the Domain-Specific Contributions to Moderate-to-Vigorous Physical Activity, Accessed by GPS
Authors: Pizarro Andreia Nogueira , Schipperijn Jasper , Ribeiro José Carlos , Figueiredo António , Mota Jorge , Santos Maria Paula 
Published: March 2017

Background:Identifying where children spend their activity-time may help define relevant domains for effective PA promotion and better understand the relation between PA and environment. Our study aimed to identify how boys and girls allocate their active time in the different domains.Methods:374 children (201 girls; mean age = 11.7 years) wore an accelerometer and a GPS for 7 days. PALMS software combined data, categorized nonsedentary time and bouts of moderate-to-vigorous physical activity (MVPA). Geographical information system allocated activity into 4 domains: school, leisure, transport and home.Results:Overall, a higher proportion of time in MVPA was found in the transport domain (45.5%), school (30.5%), leisure (21.3%), and home (2.7%). Gender differences were found for the proportion of time spent across domains. Girls (54.5%) had more MVPA than boys (35.2%) in the transport domain, whereas boys spent more MVPA time in school (37.0%) and leisure (24.9%) than girls (24.7% and 18.1, respectively).Conclusions:Interventions to increase transport behavior may be relevant for children’s MVPA. School is an important domain for boys PA, while for girls increasing the supportiveness of the school environment for PA should be a priority. Strategies should consider gender differences when targeting each domain.
Precipitation drives global variation in natural selection
Authors: Siepielski Adam M. , Morrissey Michael B. , Buoro Mathieu , Carlson Stephanie M. , Caruso Christina M. , Clegg Sonya M. , Coulson Tim , DiBattista Joseph , Gotanda Kiyoko M. , Francis Clinton D. , Hereford Joe , Kingsolver Joel G. , Augustine Kate E. , Kruuk Loeske E. B. , Martin Ryan A. , Sheldon Ben C. , Sletvold Nina , Svensson Erik I. , Wade Michael J. , MacColl Andrew D. C. 
Published: March 2017

Climate-driven selectionClimate change will fundamentally alter many aspects of the natural world. To understand how species may adapt to this change, we must understand which aspects of the changing climate exert the most powerful selective forces. Siepielskiet al.looked at studies of selection across species and regions and found that, across biomes, the strongest sources of selection were precipitation and transpiration changes. Importantly, local and regional climate change explained patterns of selection much more than did global change.Science, this issue p.959
The atom, the molecule, and the covalent organic framework
Authors: Diercks Christian S. , Yaghi Omar M. 
Published: March 2017

A framework for molecular assembly
Covalent molecular frameworks are crystalline microporous materials assembled from organic molecules through strong covalent bonds in a process termed reticular synthesis. Diercks and Yaghi review developments in this area, noting the parallels between framework assembly and the covalent assembly of atoms into molecules, as described just over a century ago by Lewis. Emerging challenges include functionalization of existing frameworks and the creation of flexible materials through the design of woven structures.

Science
, this issue p.
eaal1585
Utility of Second-Generation Line Probe Assay (Hain MTBDR
plus
) Directly on 2-Month Sputum Specimens for Monitoring Tuberculosis Treatment Response
Authors: Rockwood Neesha , Wojno Justyna , Ghebrekristos Yonas , Nicol Mark P. , Meintjes Graeme , Wilkinson Robert J. 
Published: March 2017

ABSTRACT

The utility of a line probe assay (Genotype MTBDR
plus
) performed directly on 2-month sputa to monitor tuberculosis treatment response is unknown. We assessed if direct testing of 2-month sputa with MTBDR
plus
can predict 2-month culture conversion and long-term treatment outcome. Xpert MTB/RIF-confirmed rifampin-susceptible tuberculosis cases were recruited at tuberculosis diagnosis and followed up at 2 and 5 to 6 months. MTBDR
plus
was performed directly on 2-month sputa and on all positive cultured isolates at 2 and 5 to 6 months. We also investigated the association of a positive direct MTBDR
plus
at 2 months with subsequent unsuccessful tuberculosis treatment outcome (failure/death during treatment or subsequent disease recurrence). A total of 279 patients (62% of whom were HIV-1 coinfected) were recruited. Direct MTBDR
plus
at 2 months had a sensitivity of 78% (95% confidence interval [CI], 65 to 87) and specificity of 80% (95% CI, 74 to 84) to predict culture positivity at 2 months with a high negative predictive value of 93% (95% CI, 89 to 96). Inconclusive genotypic susceptibility results for both rifampin and isoniazid were seen in 26% of MTBDR
plus
tests performed directly on sputum. Compared to a reference of MTBDR
plus
performed on positive cultures, the false-positive resistance rate for direct testing of MTBDR
plus
on sputa was 4% for rifampin and 2% for isoniazid. While a positive 2-month smear was not significantly associated with an unsuccessful treatment outcome (adjusted odds ratio [aOR], 2.69; 95% CI, 0.88 to 8.21), a positive direct MTBDR
plus
at 2 months was associated with an unsuccessful outcome (aOR 2.87; 95% CI, 1.11 to 7.42). There is moderate utility of direct 2-month MTBDR
plus
to predict culture conversion at 2 months and also to predict an unfavorable outcome.
Evaluating Novel Diagnostics in an Outbreak Setting: Lessons Learned from Ebola
Authors: Pollock Nira R. , Wonderly Betsy 
Published: March 2017

ABSTRACT
Inadequate access to rapid testing for Ebola virus disease during the 2014-to-2016 outbreak led to an explosion in the development of diagnostics that could be performed at or near the point of care and by less-experienced operators, leading in turn to an acute need for novel test evaluation. Here, we present the challenges to development and evaluation of novel diagnostics in an emergency setting and suggestions for potential new “global emergency standards” to address them.
A Strategy for Cultivation of Retargeted Oncolytic Herpes Simplex Viruses in Non-cancer Cells
Authors: Leoni Valerio , Gatta Valentina , Casiraghi Costanza , Nicosia Alfredo , Petrovic Biljana , Campadelli-Fiume Gabriella 
Published: March 2017

ABSTRACT

The oncolytic herpes simplex virus (HSV) that has been approved for clinical practice and those HSVs in clinical trials are attenuated viruses, often with the neurovirulence gene γ
1
34.5 and additional genes deleted. One strategy to engineer nonattenuated oncolytic HSVs consists of retargeting the viral tropism to a cancer-specific receptor of choice, exemplified by HER2 (human epidermal growth factor receptor 2), which is present in breast, ovary, and other cancers, and in detargeting from the natural receptors. Because the HER2-retargeted HSVs strictly depend on this receptor for infection, the viruses employed in preclinical studies were cultivated in HER2-positive cancer cells. The production of clinical-grade viruses destined for humans should avoid the use of cancer cells. Here, we engineered the R-213 recombinant, by insertion of a 20-amino-acid (aa) short peptide (named GCN4) in the gH of R-LM113; this recombinant was retargeted to HER2 through insertion in gD of a single-chain antibody (scFv) to HER2. Next, we generated a Vero cell line expressing an artificial receptor (GCN4R) whose N terminus consists of an scFv to GCN4 and therefore is capable of interacting with GCN4 present in gH of R-213. R-213 replicated as well as R-LM113 in SK-OV-3 cells, implying that addition of the GCN4 peptide was not detrimental to gH. R-213 grew to relatively high titers in Vero-GCN4R cells, efficiently spread from cell to cell, and killed both Vero-GCN4R and SK-OV-3 cells, as expected for an oncolytic virus. Altogether, Vero-GCN4R cells represent an efficient system for cultivation of retargeted oncolytic HSVs in non-cancer cells.

IMPORTANCE
There is growing interest in viruses as oncolytic agents, which can be administered in combination with immunotherapeutic compounds, including immune checkpoint inhibitors. The oncolytic HSV approved for clinical practice and those in clinical trials are attenuated viruses. An alternative to attenuation is a cancer specificity achieved by tropism retargeting to selected cancer receptors. However, the retargeted oncolytic HSVs strictly depend on cancer receptors for infection. Here, we devised a strategy for
in vitro
cultivation of retargeted HSVs in non-cancer cells. The strategy envisions a double-retargeting approach: one retargeting is via gD to the cancer receptor, and the second retargeting is via gH to an artificial receptor expressed in Vero cells. The double-retargeted HSV uses alternatively the two receptors to infect cancer cells or producer cells. A universal non-cancer cell line for growth of clinical-grade retargeted HSVs represents a step forward in the translational phase.
Pathways of Prion Spread during Early Chronic Wasting Disease in Deer
Authors: Hoover Clare E. , Davenport Kristen A. , Henderson Davin M. , Denkers Nathaniel D. , Mathiason Candace K. , Soto Claudio , Zabel Mark D. , Hoover Edward A. 
Published: March 2017

ABSTRACT

Among prion infections, two scenarios of prion spread are generally observed: (i) early lymphoid tissue replication or (ii) direct neuroinvasion without substantial antecedent lymphoid amplification. In nature, cervids are infected with chronic wasting disease (CWD) prions by oral and nasal mucosal exposure, and studies of early CWD pathogenesis have implicated pharyngeal lymphoid tissue as the earliest sites of prion accumulation. However, knowledge of chronological events in prion spread during early infection remains incomplete. To investigate this knowledge gap in early CWD pathogenesis, we exposed white-tailed deer to CWD prions by mucosal routes and performed serial necropsies to assess PrP
CWD
tissue distribution by real-time quaking-induced conversion (RT-QuIC) and tyramide signal amplification immunohistochemistry (TSA-IHC). Although PrP
CWD
was not detected by either method in the initial days (1 and 3) postexposure, we observed PrP
CWD
seeding activity and follicular immunoreactivity in oropharyngeal lymphoid tissues at 1 and 2 months postexposure (MPE). At 3 MPE, PrP
CWD
replication had expanded to all systemic lymphoid tissues. By 4 MPE, the PrP
CWD
burden in all lymphoid tissues had increased and approached levels observed in terminal disease, yet there was no evidence of nervous system invasion. These results indicate the first site of CWD prion entry is in the oropharynx, and the initial phase of prion amplification occurs in the oropharyngeal lymphoid tissues followed by rapid dissemination to systemic lymphoid tissues. This lymphoid replication phase appears to precede neuroinvasion.

IMPORTANCE
Chronic wasting disease (CWD) is a universally fatal transmissible spongiform encephalopathy affecting cervids, and natural infection occurs through oral and nasal mucosal exposure to infectious prions. Terminal disease is characterized by PrP
CWD
accumulation in the brain and lymphoid tissues of affected animals. However, the initial sites of prion accumulation and pathways of prion spread during early CWD infection remain unknown. To investigate the chronological events of early prion pathogenesis, we exposed deer to CWD prions and monitored the tissue distribution of PrP
CWD
over the first 4 months of infection. We show CWD uptake occurs in the oropharynx with initial prion replication in the draining oropharyngeal lymphoid tissues, rapidly followed by dissemination to systemic lymphoid tissues without evidence of neuroinvasion. These data highlight the two phases of CWD infection: a robust prion amplification in systemic lymphoid tissues prior to neuroinvasion and establishment of a carrier state.
C-Terminal HIV-1 Transframe p6* Tetrapeptide Blocks Enhanced Gag Cleavage Incurred by Leucine Zipper Replacement of a Deleted p6* Domain
Authors: Yu Fu-Hsien , Huang Kuo-Jung , Wang Chin-Tien 
Published: March 2017

ABSTRACT
HIV-1 protease (PR) functions as a homodimer mediating virus maturation following virus budding. Gag-Pol dimerization is believed to trigger embedded PR activation by promoting PR dimer formation. Early PR activation can lead to markedly reduced virus yields due to premature Gag cleavage. The p6* peptide, located between Gag and PR, is believed to ensure virus production by preventing early PR maturation. Studies aimed at finding supporting evidence for this proposal are limited due to a reading frame overlap between p6* and the p6gag budding domain. To determine if p6* affects virus production via the modulation of PR activation, we engineered multiple constructs derived from Dp6*PR (an assembly- and processing-competent construct with Pol fused at the inactivated PR C terminus). The data indicated that a p6* deletion adjacent to active PR significantly impaired virus processing. We also observed that the insertion of a leucine zipper (LZ) dimerization motif in the deleted region eliminated virus production in a PR activity-dependent manner, suggesting that the LZ insertion triggered premature PR activation by facilitating PR dimer formation. As few as four C-terminal p6* residues remaining at the p6*/PR junction were sufficient to restore virus yields, with a Gag processing profile similar to that of the wild type. Our study provides supporting evidence in a virus assembly context that the C-terminal p6* tetrapeptide plays a role in preventing premature PR maturation.

IMPORTANCE
Supporting evidence for the assumption that p6* retards PR maturation in the context of virus assembly is lacking. We found that replacing p6* with a leucine zipper peptide abolished virus assembly due to the significant enhancement of Gag cleavage. However, as few as four C-terminal p6* residues remaining in the deleted region were sufficient for significant PR release, as well as for counteracting leucine zipper-incurred premature Gag cleavage. Our data provide evidence that (i) p6* ensures virus assembly by preventing early PR activation and (ii) four C-terminal p6* residues are critical for modulating PR activation. Current PR inhibitor development efforts are aimed largely at mature PR, but there is a tendency for HIV-1 variants that are resistant to multiple protease inhibitors to emerge. Our data support the idea of modulating PR activation by targeting PR precursors as an alternative approach to controlling HIV-1/AIDS.
Interferon Gamma Prevents Infectious Entry of Human Papillomavirus 16 via an L2-Dependent Mechanism
Authors: Day Patricia M. , Thompson Cynthia D. , Lowy Douglas R. , Schiller John T. 
Published: March 2017

ABSTRACTIn this study, we report that gamma interferon (IFN-γ) treatment, but not IFN-α, -β, or -λ treatment, dramatically decreased infection of human papillomavirus 16 (HPV16) pseudovirus (PsV). In a survey of 20 additional HPV and animal papillomavirus types, we found that many, but not all, PsV types were also inhibited by IFN-γ. Microscopic and biochemical analyses of HPV16 PsV determined that the antiviral effect was exerted at the level of endosomal processing of the incoming capsid and depended on the JAK2/STAT1 pathway. In contrast to infection in the absence of IFN-γ, where L1 proteolytic products are produced during endosomal capsid processing and L2/DNA complexes segregate from L1 in the late endosome and travel to the nucleus, IFN-γ treatment led to decreased L1 proteolysis and retention of L2 and the viral genome in the late endosome/lysosome. PsV sensitivity or resistance to IFN-γ treatment was mapped to the L2 protein, as determined with infectious hybrid PsV, in which the L1 protein was derived from an IFN-γ-sensitive HPV type and the L2 protein from an IFN-γ-insensitive type or vice versa.IMPORTANCEA subset of HPV are the causative agents of many human cancers, most notably cervical cancer. This work describes the inhibition of infection of multiple HPV types, including oncogenic types, by treatment with IFN-γ, an antiviral cytokine that is released from stimulated immune cells. Exposure of cells to IFN-γ has been shown to trigger the expression of proteins with broad antiviral effector functions, most of which act to prevent viral transcription or translation. Interestingly, in this study, we show that infection is blocked at the early step of virus entry into the host cell by retention of the minor capsid protein, L2, and the viral genome instead of trafficking into the nucleus. Thus, a novel antiviral mechanism for IFN-γ has been revealed.
Influenza A Virus Virulence Depends on Two Amino Acids in the N-Terminal Domain of Its NS1 Protein To Facilitate Inhibition of the RNA-Dependent Protein Kinase PKR
Authors: Schierhorn Kristina L. , Jolmes Fabian , Bespalowa Julia , Saenger Sandra , Peteranderl Christin , Dzieciolowski Julia , Mielke Maja , Budt Matthias , Pleschka Stephan , Herrmann Andreas , Herold Susanne , Wolff Thorsten 
Published: March 2017

ABSTRACT

The RNA-dependent protein kinase (PKR) has broad antiviral activity inducing translational shutdown of viral and cellular genes and is therefore targeted by various viral proteins to facilitate pathogen propagation. The pleiotropic NS1 protein of influenza A virus acts as silencer of PKR activation and ensures high-level viral replication and virulence. However, the exact manner of this inhibition remains controversial. To elucidate the structural requirements within the NS1 protein for PKR inhibition, we generated a set of mutant viruses, identifying highly conserved arginine residues 35 and 46 within the NS1 N terminus as being most critical not only for binding to and blocking activation of PKR but also for efficient virus propagation. Biochemical and Förster resonance energy transfer (FRET)-based interaction studies showed that mutation of R35 or R46 allowed formation of NS1 dimers but eliminated any detectable binding to PKR as well as to double-stranded RNA (dsRNA). Using
in vitro
and
in vivo
approaches to phenotypic restoration, we demonstrated the essential role of the NS1 N terminus for blocking PKR. The strong attenuation conferred by NS1 mutation R35A or R46A was substantially alleviated by stable knockdown of PKR in human cells. Intriguingly, both NS1 mutant viruses did not trigger any signs of disease in PKR
+/+
mice, but replicated to high titers in lungs of PKR
−/−
mice and caused lethal infections. These data not only establish the NS1 N terminus as highly critical for neutralization of PKR's antiviral activity but also identify this blockade as an indispensable contribution of NS1 to the viral life cycle.

IMPORTANCE
Influenza A virus inhibits activation of the RNA-dependent protein kinase (PKR) by means of its nonstructural NS1 protein, but the underlying mode of inhibition is debated. Using mutational analysis, we identified arginine residues 35 and 46 within the N-terminal NS1 domain as highly critical for binding to and functional silencing of PKR. In addition, our data show that this is a main activity of amino acids 35 and 46, as the strong attenuation of corresponding mutant viruses in human cells was rescued to a large extent by lowering of PKR expression levels. Significantly, this corresponded with restoration of viral virulence for NS1 R35A and R46A mutant viruses in PKR
−/−
mice. Therefore, our data establish a model in which the NS1 N-terminal domain engages in a binding interaction to inhibit activation of PKR and ensure efficient viral propagation and virulence.
MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection
Authors: Huang Jun , Zhu Lingyan , Qiu Chao , Xu Xuan , Zhang Linxia , Ding Xiangqing , Liao Qibin , Xu Jianqing , Zhang Xiaoyan 
Published: March 2017

ABSTRACT
Persistent immune activation during chronic human immunodeficiency virus type 1 (HIV-1) infection facilitates immune dysfunction and thereby fuels disease progression. The translocation of bacterial derivatives into blood and the hyperinflammatory responsiveness of monocytes have been considered important causative factors for persistent immune activation. Whether microRNAs (miRNAs) are involved in regulating monocyte-mediated inflammatory responses during chronic HIV-1 infection remains elusive. In this study, we show that miR-126-5p functions as a positive regulator of monocyte-mediated inflammatory responses. Significantly increased miRNA miR-126-5p and decreased cylindromatosis (CYLD) were observed in primary monocytes from chronic HIV-1 patients. Inhibition of miR-126-5p in monocytes from chronic HIV-1 patients attenuated the responsiveness of these cells to lipopolysaccharide (LPS) stimulation. Gain-of-function assays confirmed that miR-126-5p could downregulate CYLD, which in turn caused an upregulation of phosphorylation of JNK protein (pJNK) and enhanced inflammatory responses of monocytes to LPS stimulation. Overall, miR-126-5p upregulates the responsiveness of monocytes to LPS stimulation in chronic HIV-1 infection, and the suppression of miR-126-5p and the promotion of CYLD expression in primary monocytes may represent a practical immune intervention strategy to contain persistent inflammation in chronic HIV-1 infection.

IMPORTANCE
Monocyte-mediated hyperinflammatory responses during chronic HIV-1 infection are important causative factors driving AIDS progression; however, the underlying mechanism has not been fully addressed. We demonstrated that miR-126-5p, one of the most upregulated miRNAs during chronic HIV-1 infection, could enhance the inflammatory responses of monocytes to LPS by suppressing the inhibitory protein CYLD and thereby unleashing the expression of pJNK in the LPS/Toll-like receptor 4/mitogen-activated protein kinase pathway. This observation reveals a new mechanism for HIV-1 pathogenesis, which could be targeted by immune intervention.