bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors
Authors: Mann Axel , Friedrich Nikolas , Krarup Anders , Weber Jacqueline , Stiegeler Emanuel , Dreier Birgit , Pugach Pavel , Robbiani Melissa , Riedel Tina , Moehle Kerstin , Robinson John A. , Rusert Peter , Plückthun Andreas , Trkola Alexandra 
Published: March 2013

ABSTRACT
Here, we applied the designed ankyrin repeat protein (DARPin) technology to develop novel gp120-directed binding molecules with HIV entry-inhibiting capacity. DARPins are interesting molecules for HIV envelope inhibitor design, as their high-affinity binding differs from that of antibodies. DARPins in general prefer epitopes with a defined folded structure. We probed whether this capacity favors the selection of novel gp120-reactive molecules with specificities in epitope recognition and inhibitory activity that differ from those found among neutralizing antibodies. The preference of DARPins for defined structures was notable in our selections, since of the four gp120 modifications probed as selection targets, gp120 arrested by CD4 ligation proved the most successful. Of note, all the gp120-specific DARPin clones with HIV-neutralizing activity isolated recognized their target domains in a conformation-dependent manner. This was particularly pronounced for the V3 loop-specific DARPin 5m3_D12. In stark contrast to V3-specific antibodies, 5m3_D12 preferentially recognized the V3 loop in a specific conformation, as probed by structurally arrested V3 mimetic peptides, but bound linear V3 peptides only very weakly. Most notably, this conformation-dependent V3 recognition allowed 5m3_D12 to bypass the V1V2 shielding of several tier 2 HIV isolates and to neutralize these viruses. These data provide a proof of concept that the DARPin technology holds promise for the development of HIV entry inhibitors with a unique mechanism of action.
Binding of Transmembrane Mucins to Galectin-3 Limits Herpesvirus 1 Infection of Human Corneal Keratinocytes
Authors: Woodward A. M. , Mauris J. , Argüeso P. 
Published: March 2013

ABSTRACT
Epithelial cells lining mucosal surfaces impose multiple barriers to viral infection. At the ocular surface, the carbohydrate-binding protein galectin-3 maintains barrier function by cross-linking transmembrane mucins on the apical glycocalyx. Despite these defense mechanisms, many viruses have evolved to exploit fundamental cellular processes on host cells. Here, we use affinity assays to show that herpes simplex virus type 1 (HSV-1), but not HSV-2, binds human galectin-3. Knockdown of galectin-3 in human corneal keratinocytes by small interfering RNA significantly impaired HSV-1 infection, but not expression of nectin-1, indicating that galectin-3 is a herpesvirus entry mediator. Interestingly, exposure of epithelial cell cultures to transmembrane mucin isolates decreased viral infectivity. Moreover, HSV-1 failed to elute the biological counterreceptor MUC16 from galectin-3 affinity columns, suggesting that association of transmembrane mucins to galectin-3 provides protection against viral infection. Together, these results indicate that HSV-1 exploits galectin-3 to enhance virus attachment to host cells and support a protective role for transmembrane mucins under physiological conditions by masking viral entry mediators on the epithelial glycocalyx.
Systematic Analysis of Enhancer and Critical
cis
-Acting RNA Elements in the Protein-Encoding Region of the Hepatitis C Virus Genome
Authors: Chu Derrick , Ren Songyang , Hu Stacy , Wang Wei Gang , Subramanian Aparna , Contreras Deisy , Kanagavel Vidhya , Chung Eric , Ko Justine , Amirtham Jacob Appadorai Ranjit Singh , Sinha Sanjeev , Jalali Ziba , Hardy David W. , French Samuel W. , Arumugaswami Vaithilingaraja 
Published: March 2013

ABSTRACT

Hepatitis C virus (HCV) causes chronic hepatitis, cirrhosis, and liver cancer.
cis
-acting RNA elements of the HCV genome are critical for translation initiation and replication of the viral genome. We hypothesized that the coding regions of nonstructural proteins harbor enhancer and essential
cis
-acting replication elements (CRE). In order to experimentally identify new
cis
RNA elements, we utilized an unbiased approach to introduce synonymous substitutions. The HCV genome coding for nonstructural proteins (nucleotide positions 3872 to 9097) was divided into 17 contiguous segments. The wobble nucleotide positions of each codon were replaced, resulting in 33% to 41% nucleotide changes. The HCV genome containing one of each of 17 mutant segments (S1 to S17) was tested for genome replication and infectivity. We observed that silent mutations in segment 13 (S13) (nucleotides [nt] 7457 to 7786), S14 (nt 7787 to 8113), S15 (nt 8114 to 8440), S16 (nt 8441 to 8767), and S17 (nt 8768 to 9097) resulted in impaired genome replication, suggesting CRE structures are enriched in the NS5B region. Subsequent high-resolution mutational analysis of NS5B (nt 7787 to 9289) using approximately 51-nucleotide contiguous subsegment mutant viruses having synonymous mutations revealed that subsegments SS8195-8245, SS8654-8704, and SS9011-9061 were required for efficient viral growth, suggesting that these regions act as enhancer elements. Covariant nucleotide substitution analysis of a stem-loop, JFH-SL9098, revealed the formation of an extended stem structure, which we designated JFH-SL9074. We have identified new enhancer RNA elements and an extended stem-loop in the NS5B coding region. Genetic modification of enhancer RNA elements can be utilized for designing attenuated HCV vaccine candidates.
Serum- and Glucocorticoid-Regulated Kinase 1 Is Required for Nuclear Export of the Ribonucleoprotein of Influenza A Virus
Authors: Alamares-Sapuay Judith G. , Martinez-Gil Luis , Stertz Silke , Miller Matthew S. , Shaw Megan L. , Palese Peter 
Published: March 2013

ABSTRACT
We previously performed a small interfering RNA (siRNA) screen and identified serum- and glucocorticoid-regulated kinase 1 (SGK1) as a host factor required for influenza A virus replication. However, the role of SGK1 in the influenza viral life cycle has never been examined. In this study, we demonstrate that SGK1 is required for optimal replication of influenza virus, using the SGK1 inhibitor GSK 650394 and SGK1-specific siRNAs. We also demonstrate that SGK1 is required for viral ribonucleoprotein nuclear export.
Mucosal Priming with a Replicating-Vaccinia Virus-Based Vaccine Elicits Protective Immunity to Simian Immunodeficiency Virus Challenge in Rhesus Monkeys
Authors: Sun Caijun , Chen Zhiwei , Tang Xian , Zhang Yinfeng , Feng Liqiang , Du Yanhua , Xiao Lijun , Liu Li , Zhu Weijun , Chen Ling , Zhang Linqi 
Published: March 2013

ABSTRACT

Mucosal surfaces are not targeted by most human immunodeficiency virus type 1 (HIV-1) vaccines, despite being major routes for HIV-1 transmission. Here we report a novel vaccination regimen consisting of a mucosal prime with a modified replicating vaccinia virus Tiantan strain (MVTT
SIVgpe
) and an intramuscular boost with a nonreplicating adenovirus strain (Ad5
SIVgpe
). This regimen elicited robust cellular immune responses with enhanced magnitudes, sustainability, and polyfunctionality, as well as higher titers of neutralizing antibodies against the simian immunodeficiency virus SIV
mac1A11
in rhesus monkeys. The reductions in peak and set-point viral loads were significant in most animals, with one other animal being protected fully from high-dose intrarectal inoculation of SIV
mac239
. Furthermore, the animals vaccinated with this regimen were healthy, while ∼75% of control animals developed simian AIDS. The protective effects correlated with the vaccine-elicited SIV-specific CD8
+
T cell responses against Gag and Pol. Our study provides a novel strategy for developing an HIV-1 vaccine by using the combination of a replicating vector and mucosal priming.
A Literature Review of de qi in clinical studies
Authors: Park Ji-Eun , Ryu Yeon-Hee , Liu Yan , Jung Hee-Jung , Kim Ae-Ran , Jung So-Young , Choi Sun-Mi 
Published: March 2013

Objectives De qi is a sensation experienced by a patient or an acupuncturist during acupuncture treatment. Although de qi is considered to be important in acupuncture treatment, there are not many studies about de qi and its character. The purpose of this study is to review de qi questionnaires and evaluate the relationship between de qi and acupuncture points, stimulation and treatment effects. Methods A search was conducted using three English-language databases (PubMed, Cochrane and ScienceDirect) and seven Korean databases with the keywords ‘ de qi’ and ‘needle sensation’. The included studies were then categorised as following: (1) de qi measurement tools, (2) the relationship between de qi and acupuncture points, (3) the relationship between de qi and stimulation, (4) the relationship between de qi and treatment effects and (5) attitudes and opinions toward de qi. Results Several questionnaires have been developed to evaluate de qi, and the most frequent sensation in those questionnaires was ‘heavy’ and ‘numb’. Although a few studies showed specificity to acupuncture points, information is still lacking to be able to draw a clear conclusion about the relationship between de qi and acupuncture points. Also, greater de qi was elicited in real acupuncture than placebo acupuncture in many studies. The relationship between de qi and treatment effects was controversial. Conclusions It seems that real acupuncture induced greater de qi than sham acupuncture, and the relationship between de qi, acupuncture points and treatment effects was controversial. However, the current literature evaluating de qi is not sufficient to derive clear conclusions. Further studies with more objective indices and rigorous methodologies are needed.
Development and validation of a brief screening instrument for psychosocial risk associated with genetic testing: a pan-Canadian cohort study
Authors: Esplen Mary Jane , Cappelli Mario , Wong Jiahui , Bottorff Joan L , Hunter Jon , Carroll June , Dorval Michel , Wilson Brenda , Allanson Judith , Semotiuk Kara , Aronson Melyssa , Bordeleau Louise , Charlemagne Nicole , Meschino Wendy 
Published: March 2013

ObjectivesTo develop a brief, reliable and valid instrument to screen psychosocial risk among those who are undergoing genetic testing for Adult-Onset Hereditary Disease (AOHD).DesignA prospective two-phase cohort study.Setting5 genetic testing centres for AOHD, such as cancer, Huntington's disease or haemochromatosis, in ambulatory clinics of tertiary hospitals across Canada.Participants141 individuals undergoing genetic testing were approached and consented to the instrument development phase of the study (Phase I). The Genetic Psychosocial Risk Instrument (GPRI) developed in Phase I was tested in Phase II for item refinement and validation. A separate cohort of 722 individuals consented to the study, 712 completed the baseline package and 463 completed all follow-up assessments. Most participants were female, at the mid-life stage. Individuals in advanced stages of the illness or with cognitive impairment or a language barrier were excluded.InterventionsPhase I: GPRI items were generated from (1) a review of the literature, (2) input from genetic counsellors and (3) phase I participants. Phase II: further item refinement and validation were conducted with a second cohort of participants who completed the GPRI at baseline and were followed for psychological distress 1-month postgenetic testing results.Primary and secondary outcome measuresGPRI, Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Brief Symptom Inventory (BSI) and Impact of Event Scale (IES).ResultsThe final 20-item GPRI had a high reliability—Cronbach's α at 0.81. The construct validity was supported by high correlations between GPRI and BSI and IES. The predictive value was demonstrated by a receiver operating characteristic curve of 0.78 plotting GPRI against follow-up assessments using HAM-D and HAM-A.ConclusionsWith a cut-off score of 50, GPRI identified 84% of participants who displayed distress postgenetic testing results, supporting its potential usefulness in a clinical setting.
e-Health preparedness assessment in the context of an influenza pandemic: a qualitative study in China
Authors: Li Junhua , Seale Holly , Ray Pradeep , Wang Quanyi , Yang Peng , Li Shuang , Zhang Yi , MacIntyre C Raina 
Published: March 2013

ObjectiveTo assess the preparedness status of a hospital in Beijing, China for implementation of an e-Health system in the context of a pandemic response.DesignThis research project used qualitative methods and involved two phases: (1) group interviews were conducted with key stakeholders to examine how the surveillance system worked with information and communication technology (ICT) support in Beijing, the results of which provided background information for a case study at the second phase and (2) individual interviews were conducted in order to gather a rich data set in relation to e-Health preparedness at the selected hospital.SettingIn phase 1, group interviews were conducted at Centres for Disease Prevention and Control (CDC) in Beijing. In phase 2, individual interviews were performed at a secondary hospital selected for the case study.ParticipantsIn phase 1, three group interviews were undertaken with 12 key stakeholders (public health/medical practitioners from the Beijing city CDC, two district CDCs and a tertiary hospital) who were involved in the 2009 influenza A (H1N1) pandemic response in Beijing. In phase 2, individual interviews were conducted with 23 participants (including physicians across medical departments, an IT manager and a general administrative officer).Primary and secondary measuresFor the case study, five areas were examined to assess the hospital's preparedness for implementation of an e-Health system in the context of a pandemic response: (1) motivational forces for change; (2) healthcare providers’ exposure to e-Health; (3) technological preparedness; (4) organisational non-technical ability to support a clinical ICT innovation and (5) sociocultural issues at the organisation in association with e-Health implementation and a pandemic response.ResultsThis article reports a small subset of the case study results from which major issues were identified under three main themes in relation to the hospital's preparedness. These issues include a poor sharing of patient health records, prescription errors, unavailability of software tools to assist physicians in answering patient questions, physicians’ concerns about the reliability of ICT and the high monetary cost of e-health implementation and uncertainty over return on investment, and their dissatisfaction with the software in use.ConclusionsPrior to the implementation of e-Health, planning must be undertaken to ensure the smooth introduction of the system. The assessment of organisational preparedness is an important step in this planning process. On the basis of a case study, deficient areas of organisational preparedness were identified for the prospective implementation of electronic health records. Accordingly, we suggested possible solutions for the areas in need of improvement to facilitate e-Health implementation's success.
Predicting palliative care needs and mortality in end stage renal disease: use of an at-risk register
Authors: Feyi Kennedy , Klinger Sarah , Pharro Georgina , Mcnally Liz , James Ajith , Gretton Kate , Almond Michael K 
Published: March 2013

IntroductionThe Gold Standard Frameworks (GSF) Committee devised Prognostic Indicator Guidance in November 2007 to ‘aid identification of adult patients with advanced disease, in the last months or year of life, who are in need of supportive or palliative care’.MethodsThis research used the GSF `surprise question' to formulate a list of patients predicted to die within 1 year with end stage renal failure and to establish the specificity and sensitivity of this register.Results58 patients were added to the list during the follow-up period of which 28 (48.3%) died during the same period giving an annual mortality of 32.2%. In comparison with the patients who died during the follow-up period but were not added to the at-risk register, those on the register had a much higher mortality rate (32.2% vs 7.8%). Identification of patients with chronic kidney disease and reduced life expectancy by this method appears to have a high sensitivity (66.7%) and specificity (77.9%). In particular, the negative predictive value for mortality for those on the at-risk register appears to be very high (88.3%), indicating the very low mortality among those not on the register.ConclusionsPatients with chronic kidney disease and a reduced life expectancy can be accurately identified by a multi-disciplinary team using the surprise trigger question with a relatively high sensitivity and specificity. The accurate identification of patients with reduced life expectancy allows appropriate end of life care planning to begin in keeping with patients' wishes and within published guidelines.
The Vulnerable Elders Survey and its prognostic relationship to survival in an older community-based palliative population
Authors: Chapman Michael David , Le Brian H C , Gorelik Alexandra 
Published: March 2013

ObjectivesFrailty denotes a vulnerability to poor outcomes and is a common risk factor for mortality in older persons. The Vulnerable Elders Survey (VES) is an easy to administer validated screening tool to detect a frail population. Assessment of frailty has the potential to aid in prognostication for the older community dwelling palliative population. This study seeks to evaluate the relationship of the VES to prognosis in this population.MethodsProspective cohort study of patients over 65 years old admitted to a community palliative care service. The VES was performed in addition to the usual assessments of physical function. Comorbidity was assessed using the Charlson Comorbidity Index (CCI). Physical function and CCI were assessed to determine whether they improved the prognostic power of the VES. Patients were followed-up for 8 months with the primary endpoint of survival.Results197 patients completed the study with a high proportion of malignant diagnoses (87.5%); 98% of patients died during the study with a median survival of 61 days; 93.4% of patients were vulnerable on the VES and high risk scores predicted death within 100 days.ConclusionsIn this study the VES demonstrated high rates of vulnerability and has the potential to improve the accuracy of prognosis in older palliative community dwelling patients. Improving prognostication has potential clinical benefits, including aiding clinical communication and determining the best use of community services. The limitations of this study and the evolving understanding of frailty suggest that further work in this area is required.
Does hormone replacement therapy (HRT) cause breast cancer? An application of causal principles to three studies
Authors: Shapiro Samuel , Farmer Richard D T , Stevenson John C , Burger Henry G , Mueck Alfred O , Gompel Anne 
Published: March 2013

BackgroundBased principally on findings in three studies, the Collaborative Reanalysis (CR), the Women's Health Initiative (WHI), and the Million Women Study, it is claimed that hormone replacement therapy (HRT) is an established cause of breast cancer. The authors have previously reviewed those studies (Parts 1–4). The WHI findings were first published in 2002, following which the use of HRT rapidly declined. A correspondingly rapid decline in the incidence of breast cancer has been reported, and attributed to the drop in the use of HRT. The evidence, however, is conflicting.MethodsUsing generally accepted causal criteria, in this article (Part 5) the authors evaluate reported trends in the incidence of breast cancer.ResultsThe evidence to suggest a correlated decline in the incidence of breast cancer following a decline in the use of HRT has not adequately satisfied the criteria of time order, detection bias, confounding, statistical stability and strength of association, internal consistency, and external consistency; biological plausibility is difficult to assess.ConclusionsBased on the observed trends in the incidence of breast cancer following the decline in HRT use, the ecological evidence is too limited either to support or refute the possibility that HRT causes breast cancer.
The effect of lactic acidosis on the generation and compensation of mixed respiratory‐metabolic acidosis in neonatal calves
Authors: Bleul U. , Götz E. 
Published: March 2013

Postnatal mixed respiratory‐metabolic acidosis is common in calves, and depending on its severity can impair vitality or even cause death. Carbon dioxide accounts for the respiratory component and L‐lactate for the metabolic component of the mixed acidosis, but it remains unclear which component determines the severity and duration of the acidosis. In a first attempt to clarify, this was investigated retrospectively in 31 calves during the first two hours of life, and in 13 calves during the first three days of life. Venous blood was collected for blood gas analysis and measurement of acid‐base variables and L‐lactate concentration. pH Was more strongly correlated with L‐lactate concentration (r2 =0.808) than with partial pressure of CO2 (pCO2, r2 =0.418). Duration of parturition had a distinct effect on pH and L‐lactate concentration but not on pCO2 ; calves born within six hours of rupture of the allantoic sac had a higher pH and lower L‐lactate concentration than calves born after a longer duration of parturition (both P<0.01). Normalisation of pCO2 took four hours and normalisation of L‐lactate took 48 hours. It was concluded that L‐lactate is a more important factor in the pathogenesis of acidosis than pCO2, and that the duration of metabolic acidosis exceeds that of respiratory acidosis in perinatal asphyxia of calves.
CATEGORICAL TINKERTOYS FOR ${\mathcal N} = 2$ GAUGE THEORIES
Authors: CECOTTI SERGIO 
Published: March 2013

In view of classification of the quiver 4d [Formula: see text] supersymmetric gauge theories, we discuss the characterization of the quivers with superpotential [Formula: see text] associated to a [Formula: see text] QFT which, in some corner of its parameter space, looks like a gauge theory with gauge group G. The basic idea is that the Abelian category [Formula: see text] of (finite-dimensional) representations of the Jacobian algebra [Formula: see text] should enjoy what we call the Ringel property of type G; in particular, [Formula: see text] should contain a universal "generic" subcategory, which depends only on the gauge group G, capturing the universality of the gauge sector. More precisely, there is a family of "light" subcategories [Formula: see text], indexed by points λ ∈ N, where N is a projective variety whose irreducible components are copies of ℙ1in one-to-one correspondence with the simple factors of G. If λ is the generic point of the ith irreducible component, [Formula: see text] is the universal subcategory corresponding to the ith simple factor of G. Matter, on the contrary, is encoded in the subcategories [Formula: see text] where {λa} is a finite set of closed points in N.In particular, for a Gaiotto theory there is one such family of subcategories, [Formula: see text], for each maximal degeneration of the corresponding surface Σ, and the index variety N may be identified with the degenerate Gaiotto surface itself: generic light subcategories correspond to cylinders, while closed-point subcategories to "fixtures" (spheres with three punctures of various kinds) and higher-order generalizations. The rules for "gluing" categories are more general than the geometric gluing of surfaces, allowing for a few additional exceptional [Formula: see text] theories which are not of the Gaiotto class. We include several examples and some amusing consequence, as the characterization in terms of quiver combinatorics of asymptotically free theories.