bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Epidemiology of Plasmodium falciparum kelch13 Mutations in Senegal Determined by Using Targeted Amplicon Deep Sequencing
Authors: Talundzic Eldin , Ndiaye Yaye D. , Deme Awa B. , Olsen Christian , Patel Dhruviben S. , Biliya Shweta , Daniels Rachel , Vannberg Fredrik O. , Volkman Sarah K. , Udhayakumar Venkatachalam , Ndiaye Daouda 
Published: January 2017

ABSTRACT

The emergence of
Plasmodium falciparum
resistance to artemisinin in Southeast Asia threatens malaria control and elimination activities worldwide. Multiple polymorphisms in the
P. falciparum kelch
gene found in chromosome 13 (
Pfk13
) have been associated with artemisinin resistance. Surveillance of potential drug resistance loci within a population that may emerge under increasing drug pressure is an important public health activity. In this context,
P. falciparum
infections from an observational surveillance study in Senegal were genotyped using targeted amplicon deep sequencing (TADS) for
Pfk13
polymorphisms. The results were compared to previously reported
Pfk13
polymorphisms from around the world. A total of 22
Pfk13
propeller domain polymorphisms were identified in this study, of which 12 have previously not been reported. Interestingly, of the 10 polymorphisms identified in the present study that were also previously reported, all had a different amino acid substitution at these codon positions. Most of the polymorphisms were present at low frequencies and were confined to single isolates, suggesting they are likely transient polymorphisms that are part of naturally evolving parasite populations. The results of this study underscore the need to identify potential drug resistance loci existing within a population, which may emerge under increasing drug pressure.
Ribosomal Mutations Conferring Macrolide Resistance in Legionella pneumophila
Authors: Descours Ghislaine , Ginevra Christophe , Jacotin Nathalie , Forey Françoise , Chastang Joëlle , Kay Elisabeth , Etienne Jerome , Lina Gérard , Doublet Patricia , Jarraud Sophie 
Published: January 2017

ABSTRACTMonitoring the emergence of antibiotic resistance is a recent issue in the treatment of Legionnaires' disease. Macrolides are recommended as first-line therapy, but resistance mechanisms have not been studied inLegionellaspecies. Our aim was to determine the molecular basis of macrolide resistance inL. pneumophila. Twelve independent lineages from a common susceptibleL. pneumophilaancestral strain were propagated under conditions of erythromycin or azithromycin pressure to produce high-level macrolide resistance. Whole-genome sequencing was performed on 12 selected clones, and we investigated mutations common to all lineages. We reconstructed the dynamics of mutation for each lineage and demonstrated their involvement in decreased susceptibility to macrolides. The resistant mutants were produced in a limited number of passages to obtain a 4,096-fold increase in erythromycin MICs. Mutations affected highly conserved 5-amino-acid regions of L4 and L22 ribosomal proteins and of domain V of 23S rRNA (G2057, A2058, A2059, and C2611 nucleotides). The early mechanisms mainly affected L4 and L22 proteins and induced a 32-fold increase in the MICs of the selector drug. Additional mutations related to 23S rRNA mostly occurred later and were responsible for a major increase of macrolide MICs, depending on the mutated nucleotide, the substitution, and the number of mutated genes among the threerrlcopies. The major mechanisms of the decreased susceptibility to macrolides inL. pneumophilaand their dynamics were determined. The results showed that macrolide resistance could be easily selected inL. pneumophilaand warrant further investigations in both clinical and environmental settings.
Mutation in an Unannotated Protein Confers Carbapenem Resistance in Mycobacterium tuberculosis
Authors: Kumar Pankaj , Kaushik Amit , Bell Drew T. , Chauhan Varsha , Xia Fangfang , Stevens Rick L. , Lamichhane Gyanu 
Published: January 2017

ABSTRACT

β-Lactams are the most widely used antibacterials. Among β-lactams, carbapenems are considered the last line of defense against recalcitrant infections. As recent developments have prompted consideration of carbapenems for treatment of drug-resistant tuberculosis, it is only a matter of time before
Mycobacterium tuberculosis
strains resistant to these drugs will emerge. In the present study, we investigated the genetic basis that confers such resistance. To our surprise, instead of mutations in the known β-lactam targets, a single nucleotide polymorphism in the
Rv2421c-Rv2422
intergenic region was common among
M. tuberculosis
mutants selected with meropenem or biapenem. We present data supporting the hypothesis that this locus harbors a previously unidentified gene that encodes a protein. This protein binds to β-lactams, slowly hydrolyzes the chromogenic β-lactam nitrocefin, and is inhibited by select penicillins and carbapenems and the β-lactamase inhibitor clavulanate. The mutation results in a W62R substitution that reduces the protein's nitrocefin-hydrolyzing activity and binding affinities for carbapenems.
Inhibition by Avibactam and Clavulanate of the β-Lactamases KPC-2 and CTX-M-15 Harboring the Substitution N
132
G in the Conserved SDN Motif
Authors: Ourghanlian Clément , Soroka Daria , Arthur Michel 
Published: January 2017

ABSTRACT

The substitution N
132
G in the SDN motif of class A β-lactamases from rapidly growing mycobacteria was previously shown to impair their inhibition by avibactam but to improve the stability of acyl-enzymes formed with clavulanate. The same substitution was introduced in KPC-2 and CTX-M-15 to assess its impact on β-lactamases from
Enterobacteriaceae
and evaluate whether it may lead to resistance to the ceftazidime-avibactam combination. Kinetic parameters for the inhibition of the β-lactamases by avibactam and clavulanate were determined by spectrophotometry using nitrocefin as the substrate. The substitution N
132
G impaired (>1,000-fold) the efficacy of carbamylation of KPC-2 and CTX-M-15 by avibactam. The substitution improved the inhibition of KPC-2 by clavulanate due to reduced deacylation, whereas the presence or absence of N
132
G resulted in the inhibition of CTX-M-15 by clavulanate. The hydrolysis of amoxicillin and nitrocefin by KPC-2 and CTX-M-15 was moderately affected by the substitution N
132
G, but that of ceftazidime, ceftaroline, and aztreonam was drastically reduced. Isogenic strains producing KPC-2 and CTX-M-15 were constructed to assess the impact of the substitution N
132
G on the antibacterial activities of β-lactam–inhibitor combinations. For amoxicillin, the substitution resulted in resistance and susceptibility for avibactam and clavulanate, respectively. For ceftazidime, ceftaroline, and aztreonam, the negative impact of the substitution on β-lactamase activity prevented resistance to the β-lactam–avibactam combinations. In conclusion, the N
132
G substitution has profound effects on the substrate and inhibition profiles of class A β-lactamases, which are largely conserved in distantly related enzymes. Fortunately, the substitution does not lead to resistance to the ceftazidime-avibactam combination.
SseK1 and SseK3 Type III Secretion System Effectors Inhibit NF-κB Signaling and Necroptotic Cell Death in Salmonella-Infected Macrophages
Authors: Günster Regina A. , Matthews Sophie A. , Holden David W. , Thurston Teresa L. M. 
Published: January 2017

ABSTRACT

Within host cells such as macrophages,
Salmonella enterica
translocates virulence (effector) proteins across its vacuolar membrane via the SPI-2 type III secretion system. Previously, it was shown that when expressed ectopically, the effectors SseK1 and SseK3 inhibit tumor necrosis factor alpha (TNF-α)-induced NF-κB activation. In this study, we show that ectopically expressed SseK1, SseK2, and SseK3 suppress TNF-α-induced, but not Toll-like receptor 4- or interleukin-induced, NF-κB activation. Inhibition required a DXD motif in SseK1 and SseK3, which is essential for the transfer of
N
-acetylglucosamine to arginine residues (arginine-GlcNAcylation). During macrophage infection, SseK1 and SseK3 inhibited NF-κB activity in an additive manner. SseK3-mediated inhibition of NF-κB activation did not require the only known host-binding partner of this effector, the E3-ubiquitin ligase TRIM32. SseK proteins also inhibited TNF-α-induced cell death during macrophage infection. Despite SseK1 and SseK3 inhibiting TNF-α-induced apoptosis upon ectopic expression in HeLa cells, the percentage of infected macrophages undergoing apoptosis was SseK independent. Instead, SseK proteins inhibited necroptotic cell death during macrophage infection. SseK1 and SseK3 caused GlcNAcylation of different proteins in infected macrophages, suggesting that these effectors have distinct substrate specificities. Indeed, SseK1 caused the GlcNAcylation of the death domain-containing proteins FADD and TRADD, whereas SseK3 expression resulted in weak GlcNAcylation of TRADD but not FADD. Additional, as-yet-unidentified substrates are likely to explain the additive phenotype of a
Salmonella
strain lacking both SseK1 and SseK3.
Identification of a Residue (Glu60) in TRAP Required for Inducing Efficient Transcription Termination at the
trp
Attenuator Independent of Binding Tryptophan and RNA
Authors: McAdams Natalie M. , Patterson Andrea , Gollnick Paul 
Published: January 2017

ABSTRACT

Transcription of the tryptophan (
trp
) operon in
Bacillus subtilis
is regulated by an attenuation mechanism. Attenuation is controlled by the

t

rp
R
NA-binding
a
ttenuation
p
rotein (TRAP). TRAP binds to a site in the 5′ leader region of the nascent
trp
transcript in response to the presence of excess intracellular tryptophan. This binding induces transcription termination upstream of the structural genes of the operon. In prior attenuation models, the role of TRAP was only to alter the secondary structure of the leader region RNA so as to promote formation of the
trp
attenuator, which was presumed to function as an intrinsic terminator. However, formation of the attenuator alone has been shown to be insufficient to induce efficient termination, indicating that TRAP plays an additional role in this process. To further examine the function of TRAP, we performed a genetic selection for mutant TRAPs that bind tryptophan and RNA but show diminished termination at the
trp
attenuator. Five such TRAP mutants were obtained. Four of these have substitutions at Glu60, three of which are Lys (E60K) substitutions and the fourth of which is a Val (E60V) substitution. The fifth mutant obtained contains a substitution at Ile63, which is on the same β-strand of TRAP as Glu60. Purified E60K TRAP binds tryptophan and RNA with properties similar to those of the wild type but is defective at inducing termination at the
trp
attenuator
in vitro
.

IMPORTANCE
Prior models for attenuation control of the
B. subtilis trp
operon suggested that the only role for TRAP is to bind to the leader region RNA and alter its folding to induce formation of an intrinsic terminator. However, several recent studies suggested that TRAP plays an additional role in the termination mechanism. We hypothesized that this function could involve residues in TRAP other than those required to bind tryptophan and RNA. Here we obtained TRAP mutants with alterations at Glu60 that are deficient at inducing termination in the leader region while maintaining tryptophan and RNA binding properties similar to those of the WT protein. These studies provide additional evidence that TRAP-mediated transcription termination at the
trp
attenuator is neither intrinsic nor Rho dependent.
Quantifying the rise of the Himalaya orogen and implications for the South Asian monsoon
Authors: Ding Lin , Spicer R.A. , Yang Jian , Xu Qiang , Cai Fulong , Li Shun , Lai Qingzhou , Wang Houqi , Spicer T.E.V. , Yue Yahui , Shukla A. , Srivastava G. , Khan M. Ali , Bera S. , Mehrotra R. 
Published: January 2017

Abstract
We reconstruct the rise of a segment of the southern flank of the Himalaya-Tibet orogen, to the south of the Lhasa terrane, using a paleoaltimeter based on paleoenthalpy encoded in fossil leaves from two new assemblages in southern Tibet (Liuqu and Qiabulin) and four previously known floras from the Himalaya foreland basin. U-Pb dating of zircons constrains the Liuqu flora to the latest Paleocene (ca. 56 Ma) and the Qiabulin flora to the earliest Miocene (21–19 Ma). The proto-Himalaya grew slowly against a high (∼4 km) proto–Tibetan Plateau from ∼1 km in the late Paleocene to ∼2.3 km at the beginning of the Miocene, and achieved at least ∼5.5 km by ca. 15 Ma. Contrasting precipitation patterns between the Himalaya-Tibet edifice and the Himalaya foreland basin for the past ∼56 m.y. show progressive drying across southern Tibet, seemingly linked to the uplift of the Himalaya orogen.
Temperature and volume of global marine sediments
Authors: LaRowe Douglas E. , Burwicz Ewa , Arndt Sandra , Dale Andrew W. , Amend Jan P. 
Published: January 2017

Abstract
Marine sediments contribute significantly to global element cycles on multiple time scales. This is due in large part to microbial activity in the shallower layers and abiotic reactions resulting from increasing temperatures and pressures at greater depths. Quantifying the rates of these diagenetic changes requires a three-dimensional description of the physiochemical properties of marine sediments. In a step toward reaching this goal, we have combined global data sets describing bathymetry, heat conduction, bottom-water temperatures, and sediment thickness to quantify the three-dimensional distribution of temperature in marine sediments. This model has revealed that ∼35% of sediments are above 60 °C, conditions that are suitable for petroleum generation. Furthermore, significant microbial activity could be inhibited in ∼25% of marine sediments, if 80 °C is taken as a major thermal barrier for subsurface life. In addition to a temperature model, we have calculated new values for the total volume (3.01 × 108 km3) and average thickness (721 m) of marine sediments, and provide the only known determination of the volume of marine-sediment pore water (8.46 × 107 km3), equivalent to ∼6.3% of the volume of the ocean. The results presented here can be used to help quantify the rates of mineral transformations, lithification, catagenesis, and the extent of life in the subsurface on a global scale.
Coupling leeside grainfall to avalanche characteristics in aeolian dune dynamics
Authors: Nield Joanna M. , Wiggs Giles F.S. , Baddock Matthew C. , Hipondoka Martin H.T. 
Published: January 2017

Abstract
Avalanche (grainflow) processes are fundamental drivers of dune morphodynamics and are typically initiated by grainfall accumulations. In sedimentary systems, however, the dynamism between grainfall and grainflow remains unspecified because simple measurements are hampered by the inherent instability of lee slopes. Here, for the first time, terrestrial laser scanning is used to quantify key aspects of the grainfall process on the lee (slip face) of a barchan sand dune. We determine grainfall zone extent and flux and show their variability under differing wind speeds. The increase in the downwind distance from the brink of peak grainfall under stronger winds provides a mechanism that explains the competence of large avalanches to descend the entire lee slope. These findings highlight important interactions between wind speed, grainfall, and subsequent grainflow that influence dune migration rates and are important for correct interpretation of dune stratigraphy.
Effect of Electroacupuncture on the Expression of Agrin and Acetylcholine Receptor Subtypes in Rats with Tibialis Anterior Muscular Atrophy Induced by Sciatic Nerve Injection Injury
Authors: Yu Jianqi , Wang Meng , Liu Junying , Zhang Xiaoming , Yang Shengbo 
Published: January 2017

Objective To investigate the effects of electroacupuncture (EA) on mRNA and protein expression of agrin, acetylcholine receptor (AChR)-ε and AChR-γ in a rat model of tibialis anterior muscle atrophy induced by sciatic nerve injection injury, and to examine the underlying mechanism of action. Methods Fifty-four adult Sprague-Dawley rats were divided into four groups: healthy control group (CON, n=6); sciatic nerve injury group (SNI, n=24), comprising rats euthanased at 1, 2, 4 and 6 weeks, respectively, after penicillin injection-induced SNI (n=6 each); CON+EA group (n=12), comprising healthy rats euthanased at 4 and 6 weeks (after 2 and 4 weeks, respectively, of EA at GB30 and ST36); and SNI+EA group, comprising rats euthanased at 4 and 6 weeks (after 2 and 4 weeks, respectively, of EA). The sciatic nerve functional index (SFI), tibialis anterior muscle weight, muscle fibre cross-sectional area (CSA), and changes in agrin, AChR-ε, and AChR-γ expression levels were analysed. Results Compared with the control group (CON), SNI rats showed decreased SFI. The weight of the tibialis anterior muscle and muscle fibre CSA decreased initially and recovered slightly over time. mRNA/protein expression of agrin and AChR-ε were downregulated and AChR-γ expression was detectable (vs zero expression in the CON/CON+EA groups). There were no significant differences in CON+EA versus CON groups. However, the SNI+EA group exhibited significant improvements compared with the untreated SNI group (p<0.05). Conclusions EA may alleviate tibialis anterior muscle atrophy induced by sciatic nerve injection injury by upregulating agrin and AChR-ε and downregulating AChR-γ.
Adherence to guidelines for creatinine and potassium monitoring and discontinuation following renin–angiotensin system blockade: a UK general practice-based cohort study
Authors: Schmidt Morten , Mansfield Kathryn E , Bhaskaran Krishnan , Nitsch Dorothea , Sørensen Henrik Toft , Smeeth Liam , Tomlinson Laurie A 
Published: January 2017

ObjectivesTo examine adherence to serum creatinine and potassium monitoring and discontinuation guidelines following initiation of treatment with ACE inhibitors (ACEI) or angiotensin receptor blockers (ARBs); and whether high-risk patients are monitored.DesignA general practice-based cohort study using electronic health records from the UK Clinical Practice Research Datalink and Hospital Episode Statistics.SettingUK primary care, 2004–2014.Subjects223 814 new ACEI/ARB users.Main outcome measuresProportion of patients with renal function monitoring before and after ACEI/ARB initiation; creatinine increase ≥30% or potassium levels >6 mmol/L at first follow-up monitoring; and treatment discontinuation after such changes. Using logistic regression models, we also examined patient characteristics associated with these biochemical changes, and with follow-up monitoring within the guideline recommendation of 2 weeks after treatment initiation.Results10% of patients had neither baseline nor follow-up monitoring of creatinine within 12 months before and 2 months after initiation of an ACEI/ARB, 28% had monitoring only at baseline, 15% only at follow-up, and 47% both at baseline and follow-up. The median period between the most recent baseline monitoring and drug initiation was 40 days (IQR 12–125 days). 34% of patients had baseline creatinine monitoring within 1 month before initiating therapy, but <10% also had the guideline-recommended follow-up test recorded within 2 weeks. Among patients experiencing a creatinine increase ≥30% (n=567, 1.2%) or potassium level >6 mmol/L (n=191, 0.4%), 80% continued treatment. Although patients with prior myocardial infarction, hypertension or baseline potassium >5 mmol/L were at high risk of ≥30% increase in creatinine after ACEI/ARB initiation, there was no evidence that they were more frequently monitored.ConclusionsOnly one-tenth of patients initiating ACEI/ARB therapy receive the guideline-recommended creatinine monitoring. Moreover, the vast majority of the patients fulfilling postinitiation discontinuation criteria for creatinine and potassium increases continue on treatment.
Prevalence of diabetic retinopathy among 13473 patients with diabetes mellitus in China: a cross-sectional epidemiological survey in six provinces
Authors: Liu Yan , Song Yifan , Tao Liyuan , Qiu Weiqiang , Lv Huibin , Jiang Xiaodan , Zhang Mingzhou , Li Xuemin 
Published: January 2017

ObjectiveTo describe the prevalence and severity of diabetic retinopathy (DR) and sight-threatening DR (STDR) among Chinese adults with diabetes.Design, setting and participantsA cross-sectional epidemiological survey across Mainland China (N=13 473). Participants were diagnosed with diabetes mellitus by physicians and transferred to our screening clinics (1/3 from hospital patients, 1/3 from city residents, the other 1/3 from rural residents). 2 fundus photographs were taken of each eye with a colourful, non-mydriatic and non-stereoscopic camera and were graded according to the UK guidelines.Main outcomes and measuresThe prevalence and severity of DR and STDR.ResultsOf the 13 473 participants with diabetes participating in the study, 4591 had DR and 1769 had STDR, for an overall prevalence of 34.08% (95% CI 33.28% to 34.88%) and 13.13% (95% CI 12.56% to 13.70%), respectively. Among these, gradable photographs were available for 12 780 participants (94.86%). Participants who were aged >65 years were less likely to suffer from DR or STDR (p<0.001; age distribution). No gender-related differences were present (p>0.05). Participants with STDR suffered from more severe visual impairment compared with those without STDR (p<0.001). The prevalence of DR and STDR in the northern region was higher than in the southern region (p<0.001). The prevalence of DR was closely related to duration of disease (OR 2.63; 95% CI 2.42 to 2.86; p<0.001) and diabetes onset age (OR 0.38; 95% CI 0.35 to 0.41; p<0.001).ConclusionsThe prevalence of DR and STDR in Mainland China appeared a little high, and varied according to area. Non-proliferative DR was more common, but STDR needed prompt treatment, especially in economically less developed areas. This study highlights the necessity for DR screening and treatment in Mainland China.
Cost-effectiveness of a pragmatic structured education intervention for the prevention of type 2 diabetes: economic evaluation of data from the Let's Prevent Diabetes cluster-randomised controlled trial
Authors: Leal J , Ahrabian D , Davies M J , Gray L J , Khunti K , Yates T , Gray A M 
Published: January 2017

ObjectivesPrevention of type 2 diabetes mellitus (TD2M) is a priority for healthcare systems. We estimated the cost-effectiveness compared with standard care of a structured education programme (Let's Prevent) targeting lifestyle and behaviour change to prevent progression to T2DM in people with prediabetes.DesignCost-effectiveness analysis alongside randomised controlled trial.Setting44 general practices in Leicestershire, England.Participants880 participants with prediabetes randomised to receive either standard care or a 6-hour group structured education programme with follow-up sessions in a primary care setting.Main outcome measureIncremental cost utility from the UK National Health Service (NHS) perspective. Quality of life and resource use measured from baseline and during the 36 months follow-up using the EuroQoL EQ-5D and 15D instruments and an economic questionnaire. Outcomes measured using quality-adjusted life years (QALYs) and healthcare costs calculated in 2012–2013 prices.ResultsAfter accounting for clustering and missing data, the intervention group was found to have a net gain of 0.046 (95% CI −0.0171 to 0.109) QALYs over 3 years, adjusted for baseline utility, at an additional cost of £168 (95% CI −395 to 732) per patient compared with the standard care group. The incremental cost-effectiveness ratio is £3643/QALY with an 86% probability of being cost-effective at a willingness to pay threshold of £20 000/QALY.ConclusionsThe education programme had higher costs and higher quality of life compared with the standard care group. The Let's Prevent programme is very likely to be cost-effective at a willingness to pay threshold of £20 000/QALY gained.Trial registration numberISRCTN80605705.