bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Spiroindolone KAE609 Does Not Induce Dormant Ring Stages in Plasmodium falciparum Parasites
Authors: Chavchich Marina , Van Breda Karin , Rowcliffe Kerryn , Diagana Thierry T. , Edstein Michael D. 
Published: June 2016

ABSTRACT

In vitro
drug treatment with artemisinin derivatives, such as dihydroartemisinin (DHA), results in a temporary growth arrest (i.e., dormancy) at an early ring stage in
Plasmodium falciparum
. This response has been proposed to play a role in the recrudescence of
P. falciparum
infections following monotherapy with artesunate and may contribute to the development of artemisinin resistance in
P. falciparum
malaria. We demonstrate here that artemether does induce dormant rings, a finding which further supports the class effect of artemisinin derivatives in inducing the temporary growth arrest of
P. falciparum
parasites. In contrast and similarly to lumefantrine, the novel and fast-acting spiroindolone compound KAE609 does not induce growth arrest at the early ring stage of
P. falciparum
and prevents the recrudescence of DHA-arrested rings at a low concentration (50 nM). Our findings, together with previous clinical data showing that KAE609 is active against artemisinin-resistant K13 mutant parasites, suggest that KAE609 could be an effective partner drug with a broad range of antimalarials, including artemisinin derivatives, in the treatment of multidrug-resistant
P. falciparum
malaria.
Control of Clostridium difficile Physiopathology in Response to Cysteine Availability
Authors: Dubois Thomas , Dancer-Thibonnier Marie , Monot Marc , Hamiot Audrey , Bouillaut Laurent , Soutourina Olga , Martin-Verstraete Isabelle , Dupuy Bruno 
Published: June 2016

ABSTRACTThe pathogenicity ofClostridium difficileis linked to its ability to produce two toxins: TcdA and TcdB. The level of toxin synthesis is influenced by environmental signals, such as phosphotransferase system (PTS) sugars, biotin, and amino acids, especially cysteine. To understand the molecular mechanisms of cysteine-dependent repression of toxin production, we reconstructed the sulfur metabolism pathways ofC. difficilestrain 630in silicoand validated some of them by testingC. difficilegrowth in the presence of various sulfur sources. High levels of sulfide and pyruvate were produced in the presence of 10 mM cysteine, indicating that cysteine is actively catabolized by cysteine desulfhydrases. Using a transcriptomic approach, we analyzed cysteine-dependent control of gene expression and showed that cysteine modulates the expression of genes involved in cysteine metabolism, amino acid biosynthesis, fermentation, energy metabolism, iron acquisition, and the stress response. Additionally, a sigma factor (SigL) and global regulators (CcpA, CodY, and Fur) were tested to elucidate their roles in the cysteine-dependent regulation of toxin production. Among these regulators, onlysigLinactivation resulted in the derepression of toxin gene expression in the presence of cysteine. Interestingly, thesigLmutant produced less pyruvate and H2S than the wild-type strain. Unlike cysteine, the addition of 10 mM pyruvate to the medium for a short time during the growth of the wild-type andsigLmutant strains reduced expression of the toxin genes, indicating that cysteine-dependent repression of toxin production is mainly due to the accumulation of cysteine by-products during growth. Finally, we showed that the effect of pyruvate on toxin gene expression is mediated at least in part by the two-component system CD2602-CD2601.
Phenotypic Analysis Reveals that the 2010 Haiti Cholera Epidemic Is Linked to a Hypervirulent Strain
Authors: Satchell Karla J. F. , Jones Christopher J. , Wong Jennifer , Queen Jessica , Agarwal Shivani , Yildiz Fitnat H. 
Published: June 2016

ABSTRACT

Vibrio cholerae
O1 El Tor strains have been responsible for pandemic cholera since 1961. These strains have evolved over time, spreading globally in three separate waves. Wave 3 is caused by altered El Tor (AET) variant strains, which include the strain with the signature
ctxB7
allele that was introduced in 2010 into Haiti, where it caused a devastating epidemic. In this study, we used phenotypic analysis to compare an early isolate from the Haiti epidemic to wave 1 El Tor isolates commonly used for research. It is demonstrated that the Haiti isolate has increased production of cholera toxin (CT) and hemolysin, increased motility, and a reduced ability to form biofilms. This strain also outcompetes common wave 1 El Tor isolates for colonization of infant mice, indicating that it has increased virulence. Monitoring of CT production and motility in additional wave 3 isolates revealed that this phenotypic variation likely evolved over time rather than in a single genetic event. Analysis of available whole-genome sequences and phylogenetic analyses suggested that increased virulence arose from positive selection for mutations found in known and putative regulatory genes, including
hns
and
vieA
, diguanylate cyclase genes, and genes belonging to the
lysR
and
gntR
regulatory families. Overall, the studies presented here revealed that
V. cholerae
virulence potential can evolve and that the currently prevalent wave 3 AET strains are both phenotypically distinct from and more virulent than many El Tor isolates.
Human NOD2 Recognizes Structurally Unique Muramyl Dipeptides from Mycobacterium leprae
Authors: Schenk Mirjam , Mahapatra Sebabrata , Le Phuonganh , Kim Hee Jin , Choi Aaron W. , Brennan Patrick J. , Belisle John T. , Modlin Robert L. 
Published: June 2016

ABSTRACTThe innate immune system recognizes microbial pathogens via pattern recognition receptors. One such receptor, NOD2, via recognition of muramyl dipeptide (MDP), triggers a distinct network of innate immune responses, including the production of interleukin-32 (IL-32), which leads to the differentiation of monocytes into dendritic cells (DC). NOD2 has been implicated in the pathogenesis of human leprosy, yet it is not clear whetherMycobacterium leprae, which has a distinct MDP structure, can activate this pathway. We investigated the effect of MDP structure on the innate immune response, finding that infection of monocytes withM. lepraeinduces IL-32 and DC differentiation in a NOD2-dependent manner. The presence of the proximall-Ala instead of Gly in the common configuration of the peptide side chain ofM. lepraedid not affect recognition by NOD2 or cytokine production. Furthermore, amidation of thed-Glu residue did not alter NOD2 activation. These data provide experimental evidence that NOD2 recognizes naturally occurring structural variants of MDP.
A Subset of Protective γ9δ2T Cells Is Activated by Novel Mycobacterial Glycolipid Components
Authors: Xia Mei , Hesser Danny C. , De Prithwiraj , Sakala Isaac G. , Spencer Charles T. , Kirkwood Jay S. , Abate Getahun , Chatterjee Delphi , Dobos Karen M. , Hoft Daniel F. 
Published: June 2016

ABSTRACTγ9δ2T cells provide a natural bridge between innate and adaptive immunity, rapidly and potently respond to pathogen infection in mucosal tissues, and are prominently induced by both tuberculosis (TB) infection and bacillus Calmette Guérin (BCG) vaccination. Mycobacterium-expanded γ9δ2T cells represent only a subset of the phosphoantigen {isopentenyl pyrophosphate [IPP] and (E)-4-hydroxy-3-methyl-but-2-enylpyrophosphate [HMBPP]}-responsive γ9δ2T cells, expressing an oligoclonal set of T cell receptor (TCR) sequences which more efficiently recognize and inhibit intracellularMycobacterium tuberculosisinfection. Based on this premise, we have been searching forM. tuberculosisantigens specifically capable of inducing a unique subset of mycobacterium-protective γ9δ2T cells. Our screening strategy includes the identification ofM. tuberculosisfractions that expand γ9δ2T cells with biological functions capable of inhibiting intracellular mycobacterial replication. Chemical treatments ofM. tuberculosiswhole-cell lysates (MtbWL) ruled out protein, nucleic acid, and nonpolar lipids as theM. tuberculosisantigens inducing protective γ9δ2T cells. Mild acid hydrolysis, which transforms complex carbohydrate to monomeric residues, abrogated the specific activity ofM. tuberculosiswhole-cell lysates, suggesting that a polysaccharide was required for biological activity. Extraction of MtbWL with chloroform-methanol-water (10:10:3) resulted in a polar lipid fraction with highly enriched specific activity; this activity was further enriched by silica gel chromatography. A combination of mass spectrometry and nuclear magnetic resonance analysis of bioactive fractions indicated that 6-O-methylglucose-containing lipopolysaccharides (mGLP) are predominant components present in this active fraction. These results have important implications for the development of new immunotherapeutic approaches for prevention and treatment of TB.
A Sinorhizobium meliloti RpoH-Regulated Gene Is Involved in Iron-Sulfur Protein Metabolism and Effective Plant Symbiosis under Intrinsic Iron Limitation
Authors: Sasaki Shohei , Minamisawa Kiwamu , Mitsui Hisayuki 
Published: June 2016

ABSTRACT

In
Sinorhizobium meliloti
, RpoH-type sigma factors have a global impact on gene expression during heat shock and play an essential role in symbiosis with leguminous plants. Using mutational analysis of a set of genes showing highly RpoH-dependent expression during heat shock, we identified a gene indispensable for effective symbiosis. This gene, designated
sufT
, was located downstream of the
sufBCDS
homologs that specify the iron-sulfur (Fe/S) cluster assembly pathway. The identified transcription start site was preceded by an RpoH-dependent promoter consensus sequence. SufT was related to a conserved protein family of unknown molecular function, of which some members are involved in Fe/S cluster metabolism in diverse organisms. A
sufT
mutation decreased bacterial growth in both rich and minimal media, tolerance to stresses such as iron starvation, and activities of some Fe/S cluster-dependent enzymes. These results support the involvement of SufT in SUF (sulfur mobilization) system-mediated Fe/S protein metabolism. Furthermore, we isolated spontaneous pseudorevertants of the
sufT
mutant with partially recovered growth; each of them had a mutation in
rirA
. This gene encodes a global iron regulator whose loss increases the intracellular iron content. Deletion of
rirA
in the original
sufT
mutant improved growth and restored Fe/S enzyme activities and effective symbiosis. These results suggest that enhanced iron availability compensates for the lack of SufT in the maintenance of Fe/S proteins.

IMPORTANCE
Although RpoH-type sigma factors of the RNA polymerase are present in diverse proteobacteria, their role as global regulators of protein homeostasis has been studied mainly in the enteric gammaproteobacterium
Escherichia coli
. In the soil alphaproteobacterium
Sinorhizobium meliloti
, the
rpoH
mutations have a strong impact on symbiosis with leguminous plants. We found that
sufT
is a unique member of the
S. meliloti
RpoH regulon;
sufT
contributes to Fe/S protein metabolism and effective symbiosis under intrinsic iron limitation exerted by RirA, a global iron regulator. Our study provides insights into the RpoH regulon function in diverse proteobacteria adapted to particular ecological niches and into the mechanism of conserved Fe/S protein biogenesis.
Heterologous Expression of Der Homologs in an Escherichia coli der Mutant and Their Functional Complementation
Authors: Choi Eunsil , Kang Nalae , Jeon Young , Pai Hyun-Sook , Kim Sung-Gun , Hwang Jihwan 
Published: June 2016

ABSTRACT

The unique
Escherichia coli
GTPase Der (double Era-like GTPase), which contains tandemly repeated GTP-binding domains, has been shown to play an essential role in 50S ribosomal subunit biogenesis. The depletion of Der results in the accumulation of precursors of 50S ribosomal subunits that are structurally unstable at low Mg
2+
concentrations. Der homologs are ubiquitously found in eubacteria. Conversely, very few are conserved in eukaryotes, and none is conserved in archaea. In the present study, to verify their conserved role in bacterial 50S ribosomal subunit biogenesis, we cloned Der homologs from two gammaproteobacteria,
Klebsiella pneumoniae
and
Salmonella enterica
serovar Typhimurium; two pathogenic bacteria,
Staphylococcus aureus
and
Neisseria gonorrhoeae
; and the extremophile
Deinococcus radiodurans
and then evaluated whether they could functionally complement the
E. coli
der
-null phenotype. Only
K. pneumoniae
and
S
. Typhimurium Der proteins enabled the
E. coli der
-null strain to grow under nonpermissive conditions. Sucrose density gradient experiments revealed that the expression of
K. pneumoniae
and
S
. Typhimurium Der proteins rescued the structural instability of 50S ribosomal subunits, which was caused by
E. coli
Der depletion. To determine what allows their complementation, we constructed Der chimeras. We found that only Der chimeras harboring both the linker and long C-terminal regions could reverse the growth defects of the
der
-null strain. Our findings suggest that ubiquitously conserved essential GTPase Der is involved in 50S ribosomal subunit biosynthesis in various bacteria and that the linker and C-terminal regions may participate in species-specific recognition or interaction with the 50S ribosomal subunit.

IMPORTANCE
In
Escherichia coli
, Der (double Era-like GTPase) is an essential GTPase that is important for the production of mature 50S ribosomal subunits. However, to date, its precise role in ribosome biogenesis has not been clarified. In this study, we used five Der homologs from gammaproteobacteria, pathogenic bacteria, and an extremophile to elucidate their conserved function in 50S ribosomal subunit biogenesis. Among them,
Klebsiella pneumoniae
and
Salmonella enterica
serovar Typhimurium Der homologs implicated the participation of Der in ribosome assembly in
E. coli
. Our results show that the linker and C-terminal regions of Der homologs are correlated with its functional complementation in
E. coli der
mutants, suggesting that they are involved in species-specific recognition or interaction with 50S ribosomal subunits.
Emerging Tick-Borne Bacterial Pathogens
Authors: Kernif Tahar , Leulmi Hamza , Raoult Didier , Parola Philippe 
Published: June 2016

ABSTRACT
A vast number of novel tick-related microorganisms and tick-borne disease agents have been identified in the past 20 years, and more are being described due to several factors, from the curiosity of clinicians faced with unusual clinical syndromes to new tools used by microbiologists and entomologists. Borrelioses, ehrlichioses, anaplasmosis, and tick-borne rickettsial diseases are some of the emerging diseases that have been described throughout the world in recent years. In this article, we focus on the bacterial agents and diseases that have been recognized in the past 3 years and refer to major recent reviews of other recognized infections.
The Emergence of Enterovirus-D68
Authors: Messacar Kevin , Abzug Mark J. , Dominguez Samuel R. 
Published: June 2016

ABSTRACTEnterovirus-D68 (EV-D68) is a unique enterovirus, similar to human rhinoviruses, spread via the respiratory route and primarily causing respiratory disease. Increasing clusters of EV-D68 associated respiratory disease have been reported since 2008, with the largest reported outbreak occurring in North America in 2014. Epidemiologic data and biological plausibility support an association of EV-D68 with the neurologic condition, acute flaccid myelitis. Diagnosis requires EV-D68 specific PCR or viral sequencing of respiratory specimens. Treatment consists of supportive care, as there are no currently available effective vaccines or antiviral therapies. Further research is needed to prepare for future EV-D68 outbreaks of respiratory or neurologic disease.
Middle East Respiratory Syndrome (MERS)
Authors: Rasmussen Sonja A. , Watson Amelia K. , Swerdlow David L. 
Published: June 2016

ABSTRACTSince the identification of the first patients with Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, over 1,600 cases have been reported as of February 2016. Most cases have occurred in Saudi Arabia or in other countries on or near the Arabian Peninsula, but travel-associated cases have also been seen in countries outside the Arabian Peninsula. MERS-CoV causes a severe respiratory illness in many patients, with a case fatality rate as high as 40%, although when contacts are investigated, a significant proportion of patients are asymptomatic or only have mild symptoms. At this time, no vaccines or treatments are available. Epidemiological and other data suggest that the source of most primary cases is exposure to camels. Person-to-person transmission occurs in household and health care settings, although sustained and efficient person-to-person transmission has not been observed. Strict adherence to infection control recommendations has been associated with control of previous outbreaks. Vigilance is needed because genomic changes in MERS-CoV could result in increased transmissibility, similar to what was seen in severe acute respiratory syndrome coronavirus (SARS-CoV).
West Nile Virus Infection
Authors: Sejvar James J. 
Published: June 2016

ABSTRACTAlthough long recognized as a human pathogen, West Nile virus (WNV) emerged as a significant public health problem following its introduction and spread across North America. Subsequent years have seen a greater understanding of all aspects of this viral infection. The North American epidemic resulted in a further understanding of the virology, pathogenesis, clinical features, and epidemiology of WNV infection. Approximately 80% of human WNV infections are asymptomatic. Most symptomatic people experience an acute systemic febrile illness; less than 1% of infected people develop neuroinvasive disease, which typically manifests as meningitis, encephalitis, or anterior myelitis resulting in acute flaccid paralysis. Older age is associated with more severe illness and higher mortality; other risk factors for poor outcome have been challenging to identify. In addition to natural infection through mosquito bites, transfusion- and organ transplant–associated infections have occurred. Since there is no definitive treatment for WNV infection, protection from mosquito bites and other preventative measures are critical. WNV has reached an endemic pattern in North America, but the future epidemiologic pattern is uncertain.
West Africa 2013: Re-examining Ebola
Authors: Bausch Daniel G. , Rojek Amanda 
Published: June 2016

ABSTRACT
The outbreak of Ebola virus disease (EVD) that occurred from 2013 to 2016 in the West African countries of Guinea, Liberia, and Sierra Leone, with imported cases to three neighboring African countries as well as to the United States and Europe, constituted a major humanitarian disaster. The outbreak numbered over 28,500 cases, more than 10 times the number cumulatively registered from all previous EVD outbreaks combined, with at least 11,000 deaths, and resulted in billions of dollars of lost economic growth to an already impoverished region. The unprecedented scale of West Africa 2013 took the world by surprise and laid bare deficiencies in our response capacity to complex humanitarian disasters of highly infectious and lethal pathogens. However, the magnitude of West Africa 2013 also provided an, albeit unwelcome, unique opportunity and obligation to better understand the biology and epidemiology of EVD and, equally as important, the many scientific, economic, social, political, ethical, and logistical challenges in confronting emerging diseases in the modern era. Here we re-examine EVD, reviewing the unique challenges and scientific advances of West Africa 2013, contrasting them with the prior assumptions and classical teachings, identifying what they have taught us and what we still have to learn.
Positive effects on bone mineralisation and muscular fitness after 10 months of intense school-based physical training for children aged 8–10 years: the FIT FIRST randomised controlled trial
Authors: Larsen Malte Nejst , Nielsen Claus Malta , Helge Eva Wulff , Madsen Mads , Manniche Vibeke , Hansen Lone , Hansen Peter Riis , Bangsbo Jens , Krustrup Peter 
Published: June 2016

ObjectivesWe investigated whether musculoskeletal fitness of school children aged 8–10 years was affected by frequent intense PE sessions.Design and participants295 Danish school children aged 8–10 years were cluster randomised to a small-sided ball game group (SSG) (n=96, four schools, five classes), a circuit strength training group (CST) (n=83, four schools, four classes) or a control group (CON, n=116, two schools, five classes).InterventionSSG or CST was performed 3×40 min/week over 10 months. Whole-body dual-energy X-ray absorptiometry (DXA) scans were used to determine areal bone mineral density (aBMD), bone mineral content (BMC) and lean body mass (LBM). Flamingo balance, standing long jump and 20-m sprint tests were used to determine muscular fitness.ResultsAnalysis of baseline-to-10 months change scores showed between-group differences in favour of the interventions in whole-body aBMD (SSG vs CON: 8 mg/cm2, 95% CI 3 to 13; CST vs CON: 7 mg/cm2, 95% CI 2 to 13, p<0.05) and leg BMC (SSG vs CON: 11 g, 95% CI 4 to 18; CST vs CON: 11 g, 95% CI 3 to 18, p<0.05). SSG had higher change scores in leg aBMD compared with CON and CST (SSG vs CON: 19 mg/cm2, 95% CI 11 to 39, p<0.05; SSG vs CST: 12 mg/cm2, 95% CI 3 to 21, p<0.05), and CST had higher change scores in whole-body BMC compared with CON (CST vs CON: 25 g, 95% CI 10 to 39, p<0.05). Both training types resulted in higher change scores in postural balance (SSG vs CON: 2.4 fewer falls/min, 95% CI 0.3 to 4.5, CST vs CON: 3.6 fewer falls/min, 95% CI 1.3 to 5.9, p<0.05) and jump length (SSG vs CON: 10%, 95% CI 5 to 16%; CST vs CON: 9%, 95% CI 3 to 15%, p<0.05). No between-group differences were observed for sprint performance or LBM (p>0.05).ConclusionsIn conclusion, 3×40 min/week with SSG or CST over a full school year improves bone mineralisation and several aspects of muscular fitness of children aged 8–10 years, suggesting that well-organised intense physical education classes can contribute positively to develop musculoskeletal health in young children.Trial registration numberNCT02000492, post results.
Gender-based violence and absent fathers: a scoping review protocol
Authors: Sikweyiya Yandisa , Nduna Mzikazi , Khuzwayo Nelisiwe , Mthombeni Andile , Mashamba-Thompson Tivani Phosa 
Published: June 2016

IntroductionGender-based violence (GBV) and absent fathers are two epidemics that affect women and children in sub-Saharan Africa. However, the understanding of the complex links between GBV and absent fathers is currently inadequate. The aim of the study is to provide an overview of documented evidence that links GBV and absent fathers as well as identifies areas that require systematic review and where more primary research is needed.Methods and analysisThe search strategy for this scoping review study will involve electronic databases including: Academic Search Premier, Ingenta, Kluwer Online, PsycARTICLES (EBSCO), PsycINFO (EBSCO), Social Work Abstracts and Sociological Collection. The studies will be mapped in 2 stages: stage 1 will map studies descriptively by focus and method; stage 2 will involve additional inclusion criteria, quality assessment and data extraction undertaken by two reviewers in parallel. A thematic analysis of the studies will be carried out to extract relevant outcomes using NVIVO.DiscussionWe anticipate finding a large number of studies on GBV diagnostic interventions in sub-Saharan Africa which, once summarised, will be useful to guide future research. The protocol for the scoping review has been registered in PROSPERO.DisseminationThe study will be disseminated electronically and in print. It will also be presented to conferences related to GBV, Father Connections and Children's Health.PROSPERO registration numberCRD42015022094.