bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insights into the Mechanism of Inhibition of CXCR4: Identification of Piperidinylethanamine Analogs as Anti-HIV-1 Inhibitors
Authors: Das Debananda , Maeda Kenji , Hayashi Yasuhiro , Gavande Navnath , Desai Darshan V. , Chang Simon B. , Ghosh Arun K. , Mitsuya Hiroaki 
Published: March 2015

ABSTRACT

The cellular entry of HIV-1 into CD4
+
T cells requires ordered interactions of HIV-1 envelope glycoprotein with C-X-C chemokine receptor type 4 (CXCR4) receptors. However, such interactions, which should be critical for rational structure-based discovery of new CXCR4 inhibitors, remain poorly understood. Here we first determined the effects of amino acid substitutions in CXCR4 on HIV-1
NL
4
-
3
glycoprotein-elicited fusion events using site-directed mutagenesis-based fusion assays and identified 11 potentially key amino acid substitutions, including D97A and E288A, which caused >30% reductions in fusion. We subsequently carried out a computational search of a screening library containing ∼604,000 compounds, in order to identify potential CXCR4 inhibitors. The computational search used the shape of IT1t, a known CXCR4 inhibitor, as a reference and employed various algorithms, including shape similarity, isomer generation, and docking against a CXCR4 crystal structure. Sixteen small molecules were identified for biological assays based on their high shape similarity to IT1t, and their putative binding modes formed hydrogen bond interactions with the amino acids identified above. Three compounds with piperidinylethanamine cores showed activity and were resynthesized. One molecule, designated CX6, was shown to significantly inhibit fusion elicited by X4 HIV-1
NL
4
-
3
glycoprotein (50% inhibitory concentration [IC
50
], 1.9 μM), to inhibit Ca
2+
flux elicited by stromal cell-derived factor 1α (SDF-1α) (IC
50
, 92 nM), and to exert anti-HIV-1 activity (IC
50
, 1.5 μM). Structural modeling demonstrated that CX6 bound to CXCR4 through hydrogen bond interactions with Asp97 and Glu288. Our study suggests that targeting CXCR4 residues important for fusion elicited by HIV-1 envelope glycoprotein should be a useful and feasible approach to identifying novel CXCR4 inhibitors, and it provides important insights into the mechanism by which small-molecule CXCR4 inhibitors exert their anti-HIV-1 activities.
Origin, Evolution, and Virulence of Porcine Deltacoronaviruses in the United States
Authors: Ma Yuanmei , Zhang Yu , Liang Xueya , Lou Fangfei , Oglesbee Michael , Krakowka Steven , Li Jianrong 
Published: March 2015

ABSTRACT
A novel porcine deltacoronavirus (PdCV) was first discovered in Ohio and Indiana in February 2014, rapidly spread to other states in the United States and Canada, and caused significant economic loss in the swine industry. The origin and virulence of this novel porcine coronavirus are not known. Here, we characterized U.S. PdCV isolates and determined their virulence in gnotobiotic and conventional piglets. Genome analyses revealed that U.S. PdCV isolates possess unique genetic characteristics and share a close relationship with Hong Kong and South Korean PdCV strains and coronaviruses (CoVs) of Asian leopard cats and Chinese ferret-badgers. The PdCV-positive intestinal content (Ohio CVM1) and the cell culture-adapted PdCV Michigan (MI) strain were orally inoculated into gnotobiotic and/or conventional piglets. Within 1 to 3 days postinfection, profuse watery diarrhea, vomiting, and dehydration were observed. Clinical signs were associated with epithelial necrosis in the gastric pits and small intestine, the latter resulting in severe villous atrophy. Mild interstitial pneumonia was identified in the lungs of PdCV-infected piglets. High levels of viral RNA (8 to 11 log RNA copies/g) were detected in intestinal tissues/luminal contents and feces of infected piglets, whereas moderate RNA levels (2 to 5 log RNA copies/g) were detected in blood, lung, liver, and kidney, indicating multisystemic dissemination of the virus. Polyclonal immune serum against PdCV but not immune serum against porcine epidemic diarrhea virus (PEDV) reacted with PdCV-infected small-intestinal epithelial cells, indicating that PdCV is antigenically distinct from PEDV. Collectively, we demonstrate for the first time that PdCV caused severe gastrointestinal diseases in swine.

IMPORTANCE
Porcine coronaviruses (CoVs) are major viral infectious diseases of swine. Examples of porcine CoVs include porcine transmissible gastroenteritis coronavirus (TGEV), porcine epidemic diarrhea virus (PEDV), and porcine respiratory coronavirus (PRCV). In February 2014, another porcine CoV, porcine deltacoronavirus (PdCV), emerged in Ohio and Indiana and subsequently spread rapidly across the United States and Canada
,
causing significant economic losses. Here, we report the detailed genetic characterization, phylogeny, and virulence of emergent PdCV strains in the United States. We found that PdCV caused severe diarrhea, vomiting, and dehydration in gnotobiotic and conventional piglets, signs that were clinically indistinguishable from those caused by PEDV and TGEV. In addition to extensive intestinal lesions, PdCV caused significant lesions in the stomach and mild pulmonary lesions that have not been reported for TGEV and PEDV. The finding that PdCV is a significant enteric disease of swine highlights the need to develop effective measures to control this disease.
Identification of a Gamma Interferon-Activated Inhibitor of Translation-Like RNA Motif at the 3′ End of the Transmissible Gastroenteritis Coronavirus Genome Modulating Innate Immune Response
Authors: Marquez-Jurado Silvia , Nogales Aitor , Zuñiga Sonia , Enjuanes Luis , Almazán Fernando 
Published: March 2015

ABSTRACT

A 32-nucleotide (nt) RNA motif located at the 3′ end of the transmissible gastroenteritis coronavirus (TGEV) genome was found to specifically interact with the host proteins glutamyl-prolyl-tRNA synthetase (EPRS) and arginyl-tRNA synthetase (RRS). This RNA motif has high homology in sequence and secondary structure with the gamma interferon-activated inhibitor of translation (GAIT) element, which is located at the 3′ end of several mRNAs encoding proinflammatory proteins. The GAIT element is involved in the translation silencing of these mRNAs through its interaction with the GAIT complex (EPRS, heterogeneous nuclear ribonucleoprotein Q, ribosomal protein L13a, and glyceraldehyde 3-phosphate dehydrogenase) to favor the resolution of inflammation. Interestingly, we showed that the viral RNA motif bound the GAIT complex and inhibited the
in vitro
translation of a chimeric mRNA containing this RNA motif. To our knowledge, this is the first GAIT-like motif described in a positive RNA virus. To test the functional role of the GAIT-like RNA motif during TGEV infection, a recombinant coronavirus harboring mutations in this motif was engineered and characterized. Mutations of the GAIT-like RNA motif did not affect virus growth in cell cultures. However, an exacerbated innate immune response, mediated by the melanoma differentiation-associated gene 5 (MDA5) pathway, was observed in cells infected with the mutant virus compared with the response observed in cells infected with the parental virus. Furthermore, the mutant virus was more sensitive to beta interferon than the parental virus. All together, these data strongly suggested that the viral GAIT-like RNA motif modulates the host innate immune response.

IMPORTANCE
The innate immune response is the first line of antiviral defense that culminates with the synthesis of interferon and proinflammatory cytokines to limit virus replication. Coronaviruses encode several proteins that interfere with the innate immune response at different levels, but to date, no viral RNA counteracting antiviral response has been described. In this work, we have characterized a 32-nt RNA motif located at the 3′ end of the TGEV genome that specifically interacted with EPRS and RRS. This RNA motif presented high homology with the GAIT element, involved in the modulation of the inflammatory response. Moreover, the disruption of the viral GAIT-like RNA motif led to an exacerbated innate immune response triggered by MDA5, indicating that the GAIT-like RNA motif counteracts the host innate immune response. These novel findings may be of relevance for other coronaviruses and could serve as the basis for the development of novel antiviral strategies.
A Group A Streptococcus ADP-Ribosyltransferase Toxin Stimulates a Protective Interleukin 1β-Dependent Macrophage Immune Response
Authors: Lin Ann E. , Beasley Federico C. , Keller Nadia , Hollands Andrew , Urbano Rodolfo , Troemel Emily R. , Hoffman Hal M. , Nizet Victor 
Published: March 2015

ABSTRACT

The M1T1 clone of group A Streptococcus (GAS) is associated with severe invasive infections, including necrotizing fasciitis and septicemia. During invasive M1T1 GAS disease, mutations in the
covRS
regulatory system led to upregulation of an ADP-ribosyltransferase, SpyA. Surprisingly, a GAS Δ
spyA
mutant was resistant to killing by macrophages and caused higher mortality with impaired bacterial clearance in a mouse intravenous challenge model. GAS expression of SpyA triggered macrophage cell death in association with caspase-1-dependent interleukin 1β (IL-1β) production, and differences between wild-type (WT) and Δ
spyA
GAS macrophage survival levels were lost in cells lacking caspase-1, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), or pro-IL-1β. Similar
in vitro
findings were identified in macrophage studies performed with pseudomonal exotoxin A, another ADP-ribosylating toxin. Thus, SpyA triggers caspase-1-dependent inflammatory cell death in macrophages, revealing a toxin-triggered IL-1β-dependent innate immune response pathway critical in defense against invasive bacterial infection.

IMPORTANCE
Group A Streptococcus (GAS) is a leading human pathogen capable of producing invasive infections even in healthy individuals. GAS bacteria produce a toxin called SpyA that modifies host proteins through a process called ADP ribosylation. We describe how macrophages, frontline defenders of the host innate immune system, respond to SpyA by undergoing a specialized form of cell death in which they are activated to release the proinflammatory cytokine molecule interleukin 1β (IL-1β). Release of IL-1β activates host immune cell clearance of GAS, as we demonstrated in tissue culture models of macrophage bacterial killing and
in vivo
mouse infectious-challenge experiments. Similar macrophage responses to a related toxin of
Pseudomonas
bacteria were also shown. Thus, macrophages recognize certain bacterial toxins to activate a protective immune response in the host.
Heparan Sulfate-Dependent Enhancement of Henipavirus Infection
Authors: Mathieu Cyrille , Dhondt Kévin P. , Châlons Marie , Mély Stéphane , Raoul Hervé , Negre Didier , Cosset François-Loïc , Gerlier Denis , Vivès Romain R. , Horvat Branka 
Published: March 2015

ABSTRACT

Nipah virus and Hendra virus are emerging, highly pathogenic, zoonotic paramyxoviruses that belong to the genus
Henipavirus
. They infect humans as well as numerous mammalian species. Both viruses use ephrin-B2 and -B3 as cell entry receptors, and following initial entry into an organism, they are capable of rapid spread throughout the host. We have previously reported that Nipah virus can use another attachment receptor, different from its entry receptors, to bind to nonpermissive circulating leukocytes, thereby promoting viral dissemination within the host. Here, this attachment molecule was identified as heparan sulfate for both Nipah virus and Hendra virus. Cells devoid of heparan sulfate were not able to mediate henipavirus
trans
-infection and showed reduced permissivity to infection. Virus pseudotyped with Nipah virus glycoproteins bound heparan sulfate and heparin but no other glycosaminoglycans in a surface plasmon resonance assay. Furthermore, heparin was able to inhibit the interaction of the viruses with the heparan sulfate and to block cell-mediated
trans
-infection of henipaviruses. Moreover, heparin was shown to bind to ephrin-B3 and to restrain infection of permissive cells
in vitro
. Consequently, treatment with heparin devoid of anticoagulant activity improved the survival of Nipah virus-infected hamsters. Altogether, these results reveal heparan sulfate as a new attachment receptor for henipaviruses and as a potential therapeutic target for the development of novel approaches against these highly lethal infections.

IMPORTANCE
The
Henipavirus
genus includes two closely related, highly pathogenic paramyxoviruses, Nipah virus and Hendra virus, which cause elevated morbidity and mortality in animals and humans. Pathogenesis of both Nipah virus and Hendra virus infection is poorly understood, and efficient antiviral treatment is still missing. Here, we identified heparan sulfate as a novel attachment receptor used by both viruses to bind host cells. We demonstrate that heparin was able to inhibit the interaction of the viruses with heparan sulfate and to block cell-mediated
trans
-infection of henipaviruses. Moreover, heparin also bound to the viral entry receptor and thereby restricted infection of permissive cells
in vitro
. Consequently, heparin treatment improved survival of Nipah virus-infected hamsters. These results uncover an important role of heparan sulfate in henipavirus infection and open novel perspectives for the development of heparan sulfate-targeting therapeutic approaches for these emerging infections.
Impact of increased visceral adiposity with normal weight on the progression of arterial stiffness in Japanese patients with type 2 diabetes
Authors: Bouchi Ryotaro , Minami Isao , Ohara Norihiko , Nakano Yujiro , Nishitani Rie , Murakami Masanori , Takeuchi Takato , Akihisa Momoko , Fukuda Tatsuya , Fujita Masamichi , Yoshimoto Takanobu , Ogawa Yoshihiro 
Published: March 2015

ObjectiveNormal-weight abdominal obesity has been reported to be associated with poor mortality. We aimed to investigate the impact of increased visceral adiposity with normal weight (OB(−)VA(+)) on the progression of arterial stiffness in patients with type 2 diabetes.MethodsThis was a cross-sectional study of 414 patients with type 2 diabetes (mean age 64±12 years; 40.3% female). Visceral fat area (VFA, cm2) was measured by a dual bioelectrical impedance analyzer. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV, cm/s). Patients were divided into four groups by VFA and body mass index (BMI, kg/m2) as the following: BMI<25 kg/m2and VFA<100 cm2(obesity (OB)(−)visceral adiposity (VA)(−)), BMI≥25 kg/m2and VFA<100 cm2(OB(+)VA(−)), BMI<25 kg/m2and VFA≥100 cm2(OB(−)VA(+)), and BMI≥25 kg/m2and VFA≥100 cm2(OB(+)VA(+)). Multivariate linear regression analysis was done to determine the impact of OB(−)VA(+) on arterial stiffness.ResultsAmong the patients, 7.2% were OB(−)VA(+) with higher baPWV levels (1956±444 cm/s) than those with OB(+)VA(−) (1671±416 cm/s, p=0.014), those with OB(+)VA(+) (1744±317 cm/s, p=0.048), and those with OB(−)VA(−) (1620±397 cm/s, p=0.024). In multivariate linear regression analysis, OB(−)VA(+) remained independently associated with baPWV (standardized β 0.184, p=0.001).ConclusionsThis study provides evidence for the burden of arterial stiffness in OB(−)VA(+) patients with type 2 diabetes; therefore, evaluation of visceral adiposity is of clinical relevance for the better management of non-obese individuals as well as obese populations.
Effectiveness of school-based smoking prevention curricula: systematic review and meta-analysis
Authors: Thomas Roger E , McLellan Julie , Perera Rafael 
Published: March 2015

ObjectiveTo assess effectiveness of school-based smoking prevention curricula keeping children never-smokers.DesignSystematic review, meta-analysis. Data: MEDLINE (1966+), EMBASE (1974+), Cinahl, PsycINFO (1967+), ERIC (1982+), Cochrane CENTRAL, Health Star, Dissertation Abstracts, conference proceedings. Data synthesis: pooled analyses, fixed-effects models, adjusted ORs. Risk of bias assessed with Cochrane Risk of Bias tool.Setting50 randomised controlled trials (RCTs) of school-based smoking curricula.ParticipantsNever-smokers age 5–18 (n=143 495); follow-up ≥6 months; all countries; no date/language limitations.InterventionsInformation, social influences, social competence, combined social influences/competence and multimodal curricula.Outcome measureRemaining a never-smoker at follow-up.ResultsPooling all curricula, trials with follow-up ≤1 year showed no statistically significant differences compared with controls (OR 0.91 (0.82 to 1.01)), though trials of combined social competence/social influences curricula had a significant effect on smoking prevention (7 trials, OR 0.59 (95% CI 0.41 to 0.85)). Pooling all trials with longest follow-up showed an overall significant effect in favour of the interventions (OR 0.88 (0.82 to 0.95)), as did the social competence (OR 0.65 (0.43 to 0.96)) and combined social competence/social influences curricula (OR 0.60 (0.43 to 0.83)). No effect for information, social influences or multimodal curricula. Principal findings were not sensitive to inclusion of booster sessions in curricula or to whether they were peer-led or adult-led. Differentiation into tobacco-only or multifocal curricula had a similar effect on the primary findings. Few trials assessed outcomes by gender: there were significant effects for females at both follow-up periods, but not for males.ConclusionsRCTs of baseline never-smokers at longest follow-up found an overall significant effect with average 12% reduction in starting smoking compared with controls, but no effect for all trials pooled at ≤1 year. However, combined social competence/social influences curricula showed a significant effect at both follow-up periods.Systematic review registrationCochrane Tobacco Review Group CD001293.
Cost-effectiveness of interventions to control cardiovascular diseases and type 2 diabetes mellitus in South Asia: protocol for a systematic review
Authors: Singh Kavita , Chandra Sekaran Ambalam M , Bhaumik Soumyadeep , Aisola Malini , Chattopadhyay Kaushik , Gamage Anuji U , de Silva Padmal , Selvaraj Sakthivel , Roy Ambuj , Prabhakaran Dorairaj , Tandon Nikhil 
Published: March 2015

IntroductionWhile a number of strategies are being implemented to control cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM), the cost-effectiveness of these in the South Asian context has not been systematically evaluated. We aim to systematically review the economic (cost-effectiveness) evidence available on the individual-, group- and population-level interventions for control of CVD and T2DM in South Asia.Methods and analysisThis review will consider all relevant economic evaluations, either conducted alongside randomised controlled trials or based on decision modelling estimates. These studies must include participants at risk of developing CVD/T2DM or with established disease in one or more of the South Asian countries (India, Bangladesh, Pakistan, Sri Lanka, Nepal, Maldives, Bhutan and Afghanistan). We will identify relevant papers by systematically searching all major databases and registries. Selected articles will be screened by two independent researchers. Methodological quality of the studies will be assessed using a modified Drummond and a Phillips checklist. Cochrane guidelines will be followed for bias assessment in the effectiveness studies.ResultsResults will be presented in line with the PRISMA (Preferred Reporting Items for Systematic review and Meta-analysis) checklist, and overall quality of evidence will be presented as per the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach.Ethics and disseminationThe study has received ethics approval from the All India Institute of Medical Sciences, New Delhi, India. The results of this review will provide policy-relevant recommendations for the uptake of cost-effectiveness evidence in prioritising decisions on essential chronic disease care packages for South Asia.Study registration numberPROSPERO CRD42013006479.
A cross-sectional study of shift work, sleep quality and cardiometabolic risk in female hospital employees
Authors: Lajoie P , Aronson K J , Day A , Tranmer J 
Published: March 2015

ObjectivesInvestigating the potential pathways linking shift work and cardiovascular diseases (CVD), this study aimed to identify whether sleep disturbances mediate the relationship between shift work and the metabolic syndrome, a cluster of CVD risk factors.DesignCross-sectional study.SettingA tertiary-level, acute care teaching hospital in Southeastern Ontario, Canada.ParticipantsFemale hospital employees working a shift schedule of two 12 h days, two 12 h nights, followed by 5 days off (n=121) were compared with female day-only workers (n=150).Primary and secondary outcome measuresEach of the seven components of the Pittsburgh Sleep Quality Index (PSQI) was measured. Of these, PSQI global score, sleep latency and sleep efficiency were examined as potential mediators in the relationship between shift work and the metabolic syndrome.ResultsShift work status was associated with poor (>5) PSQI global score (OR=2.10, 95% CI 1.20 to 3.65), poor (≥2) sleep latency (OR=2.18, 95% CI 1.23 to 3.87) and poor (≥2) sleep efficiency (OR=2.11, 95% CI 1.16 to 3.84). Although shift work was associated with the metabolic syndrome (OR=2.29, 95% CI 1.12 to 4.70), the measured components of sleep quality did not mediate the relationship between shift work and the metabolic syndrome.ConclusionsWomen working in a rapid forward rotating shift pattern have poorer sleep quality according to self-reported indicators of the validated PSQI and they have a higher prevalence of the metabolic syndrome compared with women who work during the day only. However, sleep quality did not mediate the relationship between shift work and the metabolic syndrome, suggesting that there are other psychophysiological pathways linking shift work to increased risk for CVD.
Does transcutaneous electrical nerve stimulation (TENS) alleviate the pain experienced during bone marrow sampling in addition to standard techniques? A randomised, double-blinded, controlled trial
Authors: Tucker David L , Rockett Mark , Hasan Mehedi , Poplar Sarah , Rule Simon A 
Published: March 2015

AimsBone marrow aspiration and trephine (BMAT) biopsies remain important tests in haematology. However, the procedures can be moderately to severely painful despite standard methods of pain relief. To test the efficacy of transcutaneous electrical nerve stimulation (TENS) in alleviating the pain from BMAT in addition to standard analgesia using a numerical pain rating scale (NRS).Methods70 patients requiring BMAT were randomised (1:1) in a double-blind, placebo-controlled trial. –35 patients received TENS impulses at a strong but comfortable amplitude (intervention group) and 35 patients received TENS impulses just above the sensory threshold (control group) (median pulse amplitude 20 and 7 mA, respectively). Patients and operators were blinded to group allocation. Pain assessments were made using a numerical pain scale completed after the procedure.ResultsNo significant difference in NRS pain recalled after the procedure was detected (median pain score 5.7 (95% CI 4.8 to 6.6) in control vs 5.6 (95% CI 4.8 to 6.4) in the intervention group). However, 100% of patients who had previous experience of BMAT and >94% of participants overall felt they benefited from using TENS and would recommend it to others for this procedure. There were no side effects from the TENS device, and it was well tolerated.ConclusionsTENS is a safe, non-invasive adjunct to analgesia for reducing pain during bone marrow biopsy and provides a subjective benefit to most users; however, no objective difference in pain scores was detected when using TENS in this randomised controlled study.Clinical registration numberNCT02005354.