bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss-of-Function Mutations in HspR Rescue the Growth Defect of a Mycobacterium tuberculosis Proteasome Accessory Factor E (
pafE
) Mutant
Authors: Jastrab Jordan B. , Samanovic Marie I. , Copin Richard , Shopsin Bo , Darwin K. Heran 
Published: January 2017

ABSTRACT

Mycobacterium tuberculosis
uses a proteasome to degrade proteins by both ATP-dependent and -independent pathways. While much has been learned about ATP-dependent degradation, relatively little is understood about the ATP-independent pathway, which is controlled by
Mycobacterium tuberculosis
p
roteasome
a
ccessory
f
actor
E
(PafE). Recently, we found that a
Mycobacterium tuberculosis
pafE
mutant has slowed growth
in vitro
and is sensitive to killing by heat stress. However, we did not know if these phenotypes were caused by an inability to degrade the PafE-proteasome substrate HspR (
h
eat
s
hock
p
rotein
r
epressor), an inability to degrade any damaged or misfolded proteins, or a defect in another protein quality control pathway. To address this question, we characterized
pafE
suppressor mutants that grew similarly to
pafE
+
bacteria under normal culture conditions. All but one suppressor mutant analyzed contained mutations that inactivated HspR function, demonstrating that the slowed growth and heat shock sensitivity of a
pafE
mutant were caused primarily by the inability of the proteasome to degrade HspR.

IMPORTANCE
Mycobacterium tuberculosis
encodes a proteasome that is highly similar to eukaryotic proteasomes and is required for virulence. We recently discovered a proteasome cofactor, PafE, which is required for the normal growth, heat shock resistance, and full virulence of
M. tuberculosis
. In this study, we demonstrate that PafE influences this phenotype primarily by promoting the expression of protein chaperone genes that are necessary for surviving proteotoxic stress.
Murine Cytomegalovirus Deubiquitinase Regulates Viral Chemokine Levels To Control Inflammation and Pathogenesis
Authors: Hilterbrand Adam T. , Boutz Daniel R. , Marcotte Edward M. , Upton Jason W. 
Published: January 2017

ABSTRACT

Maintaining control over inflammatory processes represents a paradox for viral pathogens. Although many viruses induce host inflammatory responses to facilitate infection, control is necessary to avoid overactivation. One way is through the manipulation of proinflammatory chemokine levels, both host and viral. Murine cytomegalovirus (MCMV), a model betaherpesvirus, encodes a viral C-C chemokine, MCK2, which promotes host inflammatory responses and incorporates into virions to facilitate viral dissemination. Here, we show that the activity of M48, the conserved MCMV deubiquitinating enzyme (DUB), regulates MCK2 levels during infection. Inactivation of M48 DUB activity results in viral attenuation and exacerbates virally induced, MCK2-dependent inflammatory responses. M48 DUB activity also influences MCK2 incorporation into virions. Importantly, attenuation of DUB-mutant virus acute replication
in vitro
and
in vivo
is largely ameliorated by targeted deletion of MCK2. Thus, uncontrolled MCK2 levels appear to mediate DUB-mutant virus attenuation in specific tissues or cell types. This demonstrates that MCMV M48 DUB activity plays a previously unappreciated role in controlling MCK2 levels, thereby managing MCK2-dependent processes. These findings reveal a novel intrinsic control mechanism of virally induced inflammation and support the identification of betaherpesvirus DUBs as possible new targets for antiviral therapies.

IMPORTANCE
Human cytomegalovirus infections represent a tremendous burden not only to those afflicted but also to health care systems worldwide. As cytomegalovirus infections are a leading cause of nongenetic sensory loss and neurodevelopmental delay, it is imperative that valuable model systems exist in order that we might understand what viral factors contribute to replication and pathogenesis. Currently, the only approved drug treatments against CMV infection are nucleoside analogues, to which some strains have become resistant. Understanding unique viral enzymatic contributions to infections will allow the development of novel pharmacological therapies. Here, we show that M48, the conserved MCMV deubiquitinase, is critical for MCMV replication in mice and demonstrate that attenuation is due to deregulated production of a viral proinflammatory chemokine. The deubiquitinases of both human and murine CMV represent structurally unique DUBs and are therefore attractive targets for pharmacological intervention. Continued research into the substrates of these DUBs will lend additional insight into their potential as targets.
A
Clostridium difficile
-Specific, Gel-Forming Protein Required for Optimal Spore Germination
Authors: Donnelly M. Lauren , Li William , Li Yong-qing , Hinkel Lauren , Setlow Peter , Shen Aimee 
Published: January 2017

ABSTRACT

Clostridium difficile
is a Gram-positive spore-forming obligate anaerobe that is a leading cause of antibiotic-associated diarrhea worldwide. In order for
C. difficile
to initiate infection, its aerotolerant spore form must germinate in the gut of mammalian hosts. While almost all spore-forming organisms use transmembrane germinant receptors to trigger germination,
C. difficile
uses the pseudoprotease CspC to sense bile salt germinants. CspC activates the related subtilisin-like protease CspB, which then proteolytically activates the cortex hydrolase SleC. Activated SleC degrades the protective spore cortex layer, a step that is essential for germination to proceed. Since CspC incorporation into spores also depends on CspA, a related pseudoprotease domain, Csp family proteins play a critical role in germination. However, how Csps are incorporated into spores remains unknown. In this study, we demonstrate that incorporation of the CspC, CspB, and CspA germination regulators into spores depends on CD0311 (renamed GerG), a previously uncharacterized hypothetical protein. The reduced levels of Csps in
gerG
spores correlate with reduced responsiveness to bile salt germinants and increased germination heterogeneity in single-spore germination assays. Interestingly, asparagine-rich repeat sequences in GerG’s central region facilitate spontaneous gel formation
in vitro
even though they are dispensable for GerG-mediated control of germination. Since GerG is found exclusively in
C. difficile
, our results suggest that exploiting GerG function could represent a promising avenue for developing
C. difficile
-specific anti-infective therapies.

IMPORTANCE
The spore-forming bacterium
Clostridium difficile
is a leading cause of health care-associated infections. While a subset of antibiotics can treat
C. difficile
infections (CDIs), the primary determinant of CDI disease susceptibility is prior antibiotic exposure, since it reduces the colonization resistance conferred by a diverse microflora. Thus, therapies that minimize perturbations to the gut microbiome should be more effective at reducing CDIs and their recurrence, the main source of disease complications. Given that spore germination is essential for
C. difficile
to initiate infection and that
C. difficile
uses a unique pathway to initiate germination, methods that inhibit distinct elements of germination could selectively prevent
C. difficile
disease recurrence. Here, we identify GerG as a
C. difficile
-specific protein that controls the incorporation of germinant signaling proteins into spores. Since
gerG
mutant spores exhibit germination defects and are less responsive to germinant, GerG may represent a promising target for developing therapeutics against CDI.
Expressing the
Geobacter metallireducens
PilA in
Geobacter sulfurreducens
Yields Pili with Exceptional Conductivity
Authors: Tan Yang , Adhikari Ramesh Y. , Malvankar Nikhil S. , Ward Joy E. , Woodard Trevor L. , Nevin Kelly P. , Lovley Derek R. 
Published: January 2017

ABSTRACT

The electrically conductive pili (e-pili) of
Geobacter sulfurreducens
serve as a model for a novel strategy for long-range extracellular electron transfer. e-pili are also a new class of bioelectronic materials. However, the only other
Geobacter
pili previously studied, which were from
G. uraniireducens
, were poorly conductive. In order to obtain more information on the range of pili conductivities in
Geobacter
species, the pili of
G. metallireducens
were investigated. Heterologously expressing the PilA gene of
G. metallireducens
in
G. sulfurreducens
yielded a
G. sulfurreducens
strain, designated strain MP, that produced abundant pili. Strain MP exhibited phenotypes consistent with the presence of e-pili, such as high rates of Fe(III) oxide reduction and high current densities on graphite anodes. Individual pili prepared at physiologically relevant pH 7 had conductivities of 277 ± 18.9 S/cm (mean ± standard deviation), which is 5,000-fold higher than the conductivity of
G. sulfurreducens
pili at pH 7 and nearly 1 million-fold higher than the conductivity of
G. uraniireducens
pili at the same pH. A potential explanation for the higher conductivity of the
G. metallireducens
pili is their greater density of aromatic amino acids, which are known to be important components in electron transport along the length of the pilus. The
G. metallireducens
pili represent the most highly conductive pili found to date and suggest strategies for designing synthetic pili with even higher conductivities.

IMPORTANCE
e-pili are a remarkable electrically conductive material that can be sustainably produced without harsh chemical processes from renewable feedstocks and that contain no toxic components in the final product. Thus, e-pili offer an unprecedented potential for developing novel materials, electronic devices, and sensors for diverse applications with a new “green” technology. Increasing e-pili conductivity will even further expand their potential applications. A proven strategy is to design synthetic e-pili that contain tryptophan, an aromatic amino acid not found in previously studied e-pili. The studies reported here demonstrate that a productive alternative approach is to search more broadly in the microbial world. Surprisingly, even though
G. metallireducens
and
G. sulfurreducens
are closely related, the conductivities of their e-pili differ by more than 3 orders of magnitude. The ability to produce e-pili with high conductivity without generating a genetically modified product enhances the attractiveness of this novel electronic material.
The value of paediatric assessment in historic child sexual abuse
Authors: Al-Jilaihawi Sarah , Borg Kevin , Maguire Sabine , Hodes Deborah 
Published: January 2017

IntroductionA perception exists that there are few benefits of a paediatric assessment in historic child sexual abuse (CSA), as the likelihood of finding forensic evidence is low.AimTo determine the value of a comprehensive paediatric assessment in a dedicated clinic for children and young people who present following suspicion or allegation of historic CSA.MethodAll children with suspected or alleged historic CSA, defined as >7 days after the last episode of sexual assault in pubertal girls, or >3 days for prepubertal girls and all boys, were assessed in a specialised paediatric clinic. Clinic data were collected prospectively between October 2009 and November 2014 and through retrospective case note review.ResultsAmong the 249 children who presented with possible historic CSA, ages ranged from 0 to 17 years (median 7, SD 4.3). Of these children, 141 (57%) had a medical concern(s) related to the referral reason, 78 (31%) had an unrelated medical concern(s) and 55 (22%) had emotional or behavioural concerns requiring onward referral, while 18 (7%) children had physical signs supportive of CSA. Findings referable to social care were identified in 26 cases (10%), the police in 6 cases and 15 (6%) parents required professional help for anxiety symptoms.ConclusionsThis study highlights the value of a comprehensive paediatric assessment in a dedicated clinic for cases of suspected or alleged historic CSA, by identifying a broad variety of unmet health needs in this group. The findings have important implications for the child, their families and the multiagency team.
Resource use associated with type 2 diabetes in Africa, the Middle East, South Asia, Eurasia and Turkey: results from the International Diabetes Management Practice Study (IDMPS)
Authors: Gagliardino Juan J , Atanasov Petar K , Chan Juliana C N , Mbanya Jean C , Shestakova Marina V , Leguet-Dinville Prisca , Annemans Lieven 
Published: January 2017

ObjectiveType 2 diabetes (T2D) and its complications form a global healthcare burden but the exact impact in some geographical regions is still not well documented. We describe the healthcare resource usage (HRU) associated with T2D in Africa, the Middle East, South Asia, Eurasia and Turkey.Research design and methodsIn the fifth wave of the International Diabetes Management Practices Study (IDMPS; 2011–2012), we collected self-reported and physician-reported cross-sectional data from 8156 patients from 18 countries across 5 regions, including different types of HRU in the previous 3–6 months. Negative binomial regression was used to identify parameters associated with HRU, using incidence rate ratios (IRRs) to express associations.ResultsPatients in Africa (n=2220), the Middle East (n=2065), Eurasia (n=1843), South Asia (n=1195) and Turkey (n=842) experienced an annual hospitalization rate (mean±SD) of 0.6±1.9, 0.3±1.2, 1.7±4.1, 0.4±1.5 and 1.3±2.7, respectively. The annual number of diabetes-related inpatient days (mean±SD) was 4.7±22.7, 1.1±6.1, 16.0±30.0, 1.5±6.8 and 10.8±34.3, respectively. Despite some inter-regional heterogeneity, macrovascular complications (IRRs varying between 1.4 and 8.9), microvascular complications (IRRs varying between 3.4 and 4.3) and, to a large extent, inadequate glycemic control (IRRs varying between 1.89 and 10.1), were independent parameters associated with hospitalization in these respective regions.ConclusionsIn non-Western countries, macrovascular/microvascular complications and inadequate glycemic control were common and important parameters associated with increased HRU.
Healthcare resource consumption for intermittent urinary catheterisation: cost-effectiveness of hydrophilic catheters and budget impact analyses
Authors: Rognoni Carla , Tarricone Rosanna 
Published: January 2017

ObjectivesThis study presents a cost-effectiveness analysis comparing hydrophilic coated to uncoated catheters for patients performing urinary intermittent catheterisation. A national budget impact analysis is also included to evaluate the impact of intermittent catheterisation for management of bladder dysfunctions over a period of 5 years.DesignA Markov model (lifetime horizon, 1 year cycle length) was developed to project health outcomes (life years and quality-adjusted life years) and economic consequences related to patients using hydrophilic coated or uncoated catheters. The model was populated with catheter-related clinical efficacy data retrieved from randomised controlled trials and quality-of-life data (utility weights) from the literature. Cost data (EUR, 2015) were estimated on the basis of healthcare resource consumption derived from an e-survey addressed to key opinion leaders in the field.SettingItalian Healthcare Service perspective.PopulationPatients with spinal cord injury performing intermittent urinary catheterisation in the home setting.Main outcome measuresIncremental cost-effectiveness and cost-utility ratios (ICER and ICUR) of hydrophilic coated versus uncoated catheters and associated healthcare budget impact.ResultsThe base-case ICER and ICUR associated with hydrophilic coated catheters were €20 761 and €24 405, respectively. This implies that hydrophilic coated catheters are likely to be cost-effective in comparison to uncoated ones, as proposed Italian threshold values range between €25 000 and €66 400. Considering a market share at year 5 of 89% hydrophilic catheters and 11% uncoated catheters, the additional cost for Italy is approximately €12 million in the next 5 years (current market share scenario for year 0: 80% hydrophilic catheters and 20% uncoated catheters).ConclusionsConsidered over a lifetime, hydrophilic coated catheters are potentially a cost-effective choice in comparison to uncoated ones. These findings can assist policymakers in evaluating intermittent catheterisation in patients with spinal cord injury.
SheppHeartCABG trial—comprehensive early rehabilitation after coronary artery bypass grafting: a protocol for a randomised clinical trial
Authors: Højskov Ida Elisabeth , Moons Philip , Hansen Niels Viggo , La Cour Søren , Olsen Peter Skov , Gluud Christian , Winkel Per , Lindschou Jane , Thygesen Lau Caspar , Egerod Ingrid , Berg Selina Kikkenborg 
Published: January 2017

IntroductionPatients undergoing coronary artery bypass graft surgery often experience a range of symptoms. Studies indicate that non-pharmacological interventions such as exercise training and psychoeducation have a positive physiological and psychological effect in early outpatient rehabilitation. The SheppHeartCABG trial will investigate the effect of early comprehensive rehabilitation in early phase rehabilitation versus usual care. The aim of this paper is to present the protocol for the SheppHeartCABG trial.Methods/analysisSheppHeartCABG is an investigator-initiated randomised clinical superiority trial with blinded outcome assessment, employing 1:1 central randomisation to rehabilitation plus usual care versus usual care alone. On the basis of a sample size calculation, 326 patients undergoing coronary artery bypass grafting will be included from two clinical sites. All patients receive usual care and patients allocated to the experimental intervention follow 4 weeks rehabilitation consisting of an exercise programme, psycho-educative consultations and a compact mindfulness programme. The primary outcome is physical function measured by the 6-min walk test. The secondary outcomes are mental health and physical activity measured by the Medical Outcome Study Short Form (SF-12), anxiety and depression measured by the Hospital Anxiety and Depression Scale questionnaire, physical, emotional and global scores by the HeartQoL questionnaire, sleep measured by the Pittsburgh Sleep Quality Index, pain measured by the Örebro Musculoskeletal Screening Questionnaire and muscle endurance measured by the sit-to-stand test. A number of explorative analyses will also be conducted.Ethics and disseminationSheppHeartCABG is approved by the regional ethics committee (no. H-4-2014-109) and the Danish Data Protection Agency (no. 30-1309) and is performed in accordance with good clinical practice and the Declaration of Helsinki in its latest form. Positive, neutral and negative results of the trial will be submitted to international peer-reviewed journals. Furthermore, results will be presented at national and international conferences relevant to the subject fields.Trial registration numberNCT02290262; pre-results.
From the geometry of box spaces to the geometry and measured couplings of groups
Authors: Das Kajal 
Published: January 2017

In this paper, we prove that if two “box spaces” of two residually finite groups are coarsely equivalent, then the two groups are “uniform measured equivalent” (UME). More generally, we prove that if there is a coarse embedding of one box space into another box space, then there exists a “uniform measured equivalent embedding” (UME-embedding) of the first group into the second one. This is a reinforcement of the easier fact that a coarse equivalence (resp.ã coarse embedding) between the box spaces gives rise to a coarse equivalence (resp.ã coarse embedding) between the groups. We deduce new invariants that distinguish box spaces up to coarse embedding and coarse equivalence. In particular, we obtain that the expanders coming from [Formula: see text] cannot be coarsely embedded inside the expanders of [Formula: see text], where [Formula: see text] and [Formula: see text]. Moreover, we obtain a countable class of residually finite groups which are mutually coarse-equivalent but any of their box spaces are not coarse-equivalent.
Theoretical Framework About Relational Capability on Inter-Organizational Cooperation
Authors: Alves Fernanda Salvador , Segatto Andréa Paula , De-Carli Eduardo 
Published: January 2017

The inter-organizational cooperation (IOC) is based on the use of consensual ways to seek a common goal. It requires a strategic vision of organizations to enable purchases and allocate resources to improve the performance and create learning. In addition, IOC may be able to pool resources, skills and values looking for maintaining competitiveness. The organizations must develop ‘Relational Capabilities’ (RC) for their cooperative success. Such skills are learning, involving structural interaction, development of specific assets and cooperative behavior. Authors present a typology of dimensions and characteristics to understanding the construct. From these aspects, the research proposes a theoretical framework for understanding and allowing the assessment of the RC construct, in the IOC. To elaborate it, the studies mentioned above were regrouped by similarities, in the pursuit of joint and complementary, to develop a new framework of components from the dimensions proposed. The results were five dimensions: coordination, cultural, knowledge, technology and coadaptation, which were formed by components. It is possible to believe that the evaluation of RC in inter-organizational relationships can identify factors that influence the success of alliances that should be improved or developed by empirical disclosure of the results. Therefore, the partnership objectives are met as full as possible.
Correlation between discharge timings of pairs of motor units reveals the presence but not the proportion of common synaptic input to motor neurons
Authors: Rodriguez-Falces Javier , Negro Francesco , Farina Dario 
Published: January 2017

We investigated whether correlation measures derived from pairs of motor unit (MU) spike trains are reliable indicators of the degree of common synaptic input to motor neurons. Several 50-s isometric contractions of the biceps brachii muscle were performed at different target forces ranging from 10 to 30% of the maximal voluntary contraction relying on force feedback. Forty-eight pairs of MUs were examined at various force levels. Motor unit synchrony was assessed by cross-correlation analysis using three indexes: the output correlation as the peak of the cross-histogram (ρ) and the number of synchronous spikes per second (CIS) and per trigger (E). Individual analysis of MU pairs revealed that ρ, CIS, and E were most often positively associated with discharge rate (87, 85, and 76% of the MU pairs, respectively) and negatively with interspike interval variability (69, 65, and 62% of the MU pairs, respectively). Moreover, the behavior of synchronization indexes with discharge rate (and interspike interval variability) varied greatly among the MU pairs. These results were consistent with theoretical predictions, which showed that the output correlation between pairs of spike trains depends on the statistics of the input current and motor neuron intrinsic properties that differ for different motor neuron pairs. In conclusion, the synchronization between MU firing trains is necessarily caused by the (functional) common input to motor neurons, but it is not possible to infer the degree of shared common input to a pair of motor neurons on the basis of correlation measures of their output spike trains. NEW & NOTEWORTHY The strength of correlation between output spike trains is only poorly associated with the degree of common input to the population of motor neurons. The synchronization between motor unit firing trains is necessarily caused by the (functional) common input to motor neurons, but it is not possible to infer the degree of shared common input to a pair of motor neurons on the basis of correlation measures of their output spike trains.