bluuebunny/crossref_metadata_2025_split huggingface dataset:
Key Enzymes of the Semiphosphorylative Entner-Doudoroff Pathway in the Haloarchaeon Haloferax volcanii: Characterization of Glucose Dehydrogenase, Gluconate Dehydratase, and 2-Keto-3-Deoxy-6-Phosphogluconate Aldolase
Authors: Sutter Jan-Moritz , Tästensen Julia-Beate , Johnsen Ulrike , Soppa Jörg , Schönheit Peter 
Published: June 2016

ABSTRACT

The halophilic archaeon
Haloferax volcanii
has been proposed to degrade glucose via the semiphosphorylative Entner-Doudoroff (spED) pathway. So far, the key enzymes of this pathway, glucose dehydrogenase (GDH), gluconate dehydratase (GAD), and 2-keto-3-deoxy-6-phosphogluconate (KDPG) aldolase (KDPGA), have not been characterized, and their functional involvement in glucose degradation has not been demonstrated. Here we report that the genes HVO_1083 and HVO_0950 encode GDH and KDPGA, respectively. The recombinant enzymes show high specificity for glucose and KDPG and did not convert the corresponding C
4
epimers galactose and 2-keto-3-deoxy-6-phosphogalactonate at significant rates. Growth studies of knockout mutants indicate the functional involvement of both GDH and KDPGA in glucose degradation. GAD was purified from
H. volcanii
, and the encoding gene,
gad
, was identified as HVO_1488. GAD catalyzed the specific dehydration of gluconate and did not utilize galactonate at significant rates. A knockout mutant of GAD lost the ability to grow on glucose, indicating the essential involvement of GAD in glucose degradation. However, following a prolonged incubation period, growth of the Δ
gad
mutant on glucose was recovered. Evidence is presented that under these conditions, GAD was functionally replaced by xylonate dehydratase (XAD), which uses both xylonate and gluconate as substrates. Together, the characterization of key enzymes and analyses of the respective knockout mutants present conclusive evidence for the
in vivo
operation of the spED pathway for glucose degradation in
H. volcanii
.

IMPORTANCE
The work presented here describes the identification and characterization of the key enzymes glucose dehydrogenase, gluconate dehydratase, and 2-keto-3-deoxy-6-phosphogluconate aldolase and their encoding genes of the proposed semiphosphorylative Entner-Doudoroff pathway in the haloarchaeon
Haloferax volcanii
. The functional involvement of the three enzymes was proven by analyses of the corresponding knockout mutants. These results provide evidence for the
in vivo
operation of the semiphosphorylative Entner-Doudoroff pathway in haloarchaea and thus expand our understanding of the unusual sugar degradation pathways in the domain
Archaea
.
Clostridium difficile
Infection
Authors: Shin Jae Hyun , Chaves-Olarte Esteban , Warren Cirle A. 
Published: June 2016

ABSTRACT

Clostridium difficile
is an anaerobic, Gram-positive, spore-forming, toxin-secreting bacillus that has long been recognized to be the most common etiologic pathogen of antibiotic-associated diarrhea.
C. difficile
infection (CDI) is now the most common cause of health care–associated infections in the United States and accounts for 12% of these infections (Magill SS et al.,
N Engl J Med
370:
1198–1208, 2014). Among emerging pathogens of public health importance in the United States, CDI has the highest population-based incidence, estimated at 147 per 100,000 (Lessa FC et al.,
N Engl J Med
372:
825–834, 2015). In a report on antimicrobial resistance,
C. difficile
has been categorized by the Centers for Disease Control and Prevention as one of three “urgent” threats (
http://www.cdc.gov/drugresistance/threat-report-2013/
). Although
C. difficile
was first described in the late 1970s, the past decade has seen the emergence of hypertoxigenic strains that have caused increased morbidity and mortality worldwide. Pathogenic strains, host susceptibility, and other regional factors vary and may influence the clinical manifestation and approach to intervention. In this article, we describe the global epidemiology of CDI featuring the different strains in circulation outside of North America and Europe where strain NAP1/027/BI/III had originally gained prominence. The elderly population in health care settings has been disproportionately affected, but emergence of CDI in children and healthy young adults in community settings has, likewise, been reported. New approaches in management, including fecal microbiota transplantation, are discussed.
Mobilization of Carbapenemase-Mediated Resistance in
Enterobacteriaceae
Authors: Mathers Amy 
Published: June 2016

ABSTRACT

There has been a dramatic increase in the last decade in the number of carbapenem-resistant
Enterobacteriaceae
, often leaving patients and their providers with few treatment options and resultant poor outcomes when an infection develops. The majority of the carbapenem resistance is mediated by bacterial acquisition of one of three carbapenemases (
Klebsiella pneumoniae
carbapenemase [KPC], oxacillinase-48-like [OXA-48], and the New Delhi metallo-β-lactamase [NDM]). Each of these enzymes has a unique global epidemiology and microbiology. The genes which encode the most globally widespread carbapenemases are typically carried on mobile pieces of DNA which can be freely exchanged between bacterial strains and species via horizontal gene transfer. Unfortunately, most of the antimicrobial surveillance systems target specific strains or species and therefore are not well equipped for examining genes of drug resistance. Examination of not only the carbapenemase gene itself but also the genetic context which can predispose a gene to mobilize within a diversity of species and environments will likely be central to understanding the factors contributing to the global dissemination of carbapenem resistance. Using the three most prevalent carbapenemase genes as examples, this chapter highlights the potential impact the associated genetic mobile elements have on the epidemiology and microbiology for each carbapenemase. Understanding how a carbapenemase gene mobilizes through a bacterial population will be critical for detection methods and ultimately inform infection control practices. Understanding gene mobilization and tracking will require novel approaches to surveillance, which will be required to slow the spread of this emerging resistance.
Emerging Fungal Infections in the Pacific Northwest: The Unrecognized Burden and Geographic Range of
Cryptococcus gattii
and
Coccidioides immitis
Authors: Lockhart Shawn R. , McCotter Orion Z. , Chiller Tom M. 
Published: June 2016

ABSTRACT

Both
Cryptococcus gattii
and
Coccidioides
can cause debilitating diseases if not identified early. It is imperative that clinicians recognize these diseases and begin treatment quickly when necessary. In order to have these two mycoses in their differential diagnosis, clinicians, microbiologists, and public health officials must be aware of the expanding geographic boundary in the case of
Coccidioides immitis
and the new emergence in the case of
C. gattii
. Accordingly, there is now mandatory reporting for cases of
C. gattii
and
C. immitis
in both Washington and Oregon, and the Centers for Disease Control and Prevention keeps a repository of available isolates. Through the One Health initiative, clinicians, veterinarians, and public health officials are collaborating to better understand the emergence and expanding geographic range of these extremely important fungal diseases.
Increasing access to care for sick newborns: evidence from the Ghana Newhints cluster-randomised controlled trial
Authors: Manu Alexander , Hill Zelee , ten Asbroek Augustinus HA , Soremekun Seyi , Weobong Benedict , Gyan Thomas , Tawiah-Agyemang Charlotte , Danso Samuel , Amenga-Etego Seeba , Owusu-Agyei Seth , Kirkwood Betty R 
Published: June 2016

ObjectivesTo evaluate the impact of Newhints community-based surveillance volunteer (CBSV) assessments and referrals on access to care for sick newborns and on existing inequities in access.DesignWe evaluated a prospective cohort nested within the Newhints cluster-randomised controlled trial.SettingCommunity-based intervention involving more than 750 000, predominantly rural, population in seven contiguous districts in the Brong-Ahafo Region, Ghana.ParticipantsParticipants were recently delivered women (from more than 120 000 women under surveillance) and their 16 168 liveborn babies. Qualitative in-depth interviews with referral narratives (IDIs) were conducted with 92 mothers, CBSVs and health facility front-desk and maternity/paediatrics ward staff.InterventionsNewhints trained and effectively supervised 475 CBSVs (existing within the Ghana Health Service) in 49 of 98 supervisory zones (clusters) to assess and refer newborns with any of the 10-key-danger signs to health facilities within the first week after birth; promote independent care seeking for sick newborns and problem-solve around barriers between November 2008 and December 2009.Primary outcomesThe main evaluation outcomes were rates of compliance with referrals and independent care seeking for newborn illnesses.ResultsOf 4006 sampled, 2795 (69.8%) recently delivered women received CBSV assessment visits and 279 (10.0%) newborns were referred with danger signs. Compliance with referrals was unprecedentedly high (86.0%) with women in the poorest quintile (Q1) complying better than the least poor (Q5):87.5%(Q1) vs 69.7%(Q5); p=0.038. Three-quarters went to hospitals; 18% were admitted and 58% received outpatient treatment. Some (24%) mothers were turned away at facilities and follow-on IDIs showed that some of these untreated babies subsequently died. Independent care seeking for severe newborn illness increased from 55.4% in control to 77.3% in Newhints zones, especially among Q1 where care seeking almost doubled (95.0% vs 48.6%; RR=1.94 (1.32, 2.84); p=0.001). Rates were the highest among rural residents but urban residents complied quicker.ConclusionsHome visits are feasible and a potentially pro-poor approach to link sick newborns to facilities. Its effectiveness in improving survival hinges on matched improvement in facility quality of care.Trial registration numberNCT00623337.
Latest trends in ADHD drug prescribing patterns in children in the UK: prevalence, incidence and persistence
Authors: Beau-Lejdstrom Raphaelle , Douglas Ian , Evans Stephen J W , Smeeth Liam 
Published: June 2016

ObjectivesTo investigate attention deficit and hyperactivity disorder (ADHD) drug prescribing in children under 16 years old in the UK between 1992 and 2013.MethodsAll patients under 16 registered in the Clinical Practice Research Datalink (CPRD) with a minimum of 1 year of observation time and who received at least one prescription of any ADHD drug between 1 January 1992 and 31 December 2013.Trends in prevalence and incidence of use of ADHD drugs in children were calculated between 1995 and 2013 and persistence in new users was estimated.ResultsThe prevalence of ADHD drug use in children under 16 increased 34-fold overall, rising from 1.5 95% CI (1.1 to 2.0) per 10 000 children in 1995 to 50.7 95% CI (49.2 to 52.1) per 10 000 children in 2008 then stabilising to 51.1 95% CI (49.7 to 52.6) per 10 000 children in 2013. The rate of new users increased eightfold reaching 10.2 95% CI (9.5 to 10.9) per 10 000 children in 2007 then decreasing to 9.1 95% CI (8.5 to 9.7) per 10 000 children in 2013. Although prevalence and incidence increased rather steeply after 1995, this trend seems to halt from 2008 onwards. We identified that 77%, 95% CI (76% to 78%) of children were still under treatment after 1 year and 60% 95% CI (59% to 61%) after 2 years.ConclusionsThere was a marked increase in ADHD drug use among children in the UK from 1992 until around 2008, with stable levels of use since then. UK children show relatively long persistence of treatment with ADHD medications compared to other countries.
Identification of depression in women during pregnancy and the early postnatal period using the Whooley questions and the Edinburgh Postnatal Depression Scale: protocol for the Born and Bred in Yorkshire: PeriNatal Depression Diagnostic Accuracy (BaBY PaNDA) study
Authors: Littlewood Elizabeth , Ali Shehzad , Ansell Pat , Dyson Lisa , Gascoyne Samantha , Hewitt Catherine , Keding Ada , Mann Rachel , McMillan Dean , Morgan Deborah , Swan Kelly , Waterhouse Bev , Gilbody Simon 
Published: June 2016

IntroductionPerinatal depression is well recognised as a mental health condition but <50% of cases are identified by healthcare professionals in routine clinical practice. The Edinburgh Postnatal Depression Scale (EPDS) is often used to detect symptoms of postnatal depression in maternity and child services. The National Institute for Health and Care Excellence (NICE) recommends 2 ‘ultra-brief’ case-finding questions (the Whooley questions) to aid identification of depression during the perinatal period, but this recommendation was made in the absence of any validation studies in a perinatal population. Limited research exists on the acceptability of these depression case-finding instruments and the cost-effectiveness of routine screening for perinatal depression.Methods and analysisThe diagnostic accuracy of the Whooley questions and the EPDS will be determined against a reference standard (the Client Interview Schedule—Revised) during pregnancy (around 20 weeks) and the early postnatal period (around 3–4 months post partum) in a sample of 379 women. Further outcome measures will assess a range of psychological comorbidities, health-related quality of life and resource utilisation. Women will be followed up 12 months postnatally. The sensitivity, specificity and predictive values of the Whooley questions and the EPDS will be calculated against the reference standard at 20 weeks pregnancy and 3–4 months post partum. Acceptability of the depression case-finding instruments to women and healthcare professionals will involve in-depth qualitative interviews. An existing decision analytic model will be adapted to determine the cost-effectiveness of routine screening for perinatal depression.Ethics and disseminationThis study is considered low risk for participants. Robust protocols will deal with cases where risk of depression, self-harm or suicide is identified. The protocol received favourable ethical opinion from the North East—York Research Ethics Committee (reference: 11/NE/0022). The study findings will be published in peer-reviewed journals and presented at relevant conferences.
E-msNSP: Efficient Negative Sequential Patterns Mining Based on Multiple Minimum Supports
Authors: Xu Tiantian , Dong Xiangjun , Xu Jianliang , Gong Yongshun 
Published: June 2016

Mining negative sequential patterns (NSP) has been an important research area in data mining and knowledge discovery and it is much more challenging than mining positive sequential patterns (PSP) due to the computational complexity and search space. Only a few methods have been proposed to mine NSP and most of them only use single minimum support, which implicitly assumes that all items in the database are of the same nature or of similar frequencies in the database. This is often not the case in real-life applications. There are several methods to mine sequential patterns with multiple minimum supports (MMS), but these methods only consider PSP and do not handle NSP. So in this paper, we propose a new method, called e-msNSP, to mine NSP with multiple minimum supports. We also solve the problem of how to set up the minimum support to a sequence with negative item(s). E-msNSP consists of three major steps: (i) using the improved MS-GSP method to mine PSP with multiple minimum supports and storing all positive sequential candidates’ (PSC) related information simultaneously; (ii) using the same method in e-NSP to generate negative sequential candidates (NSC) based on above mined PSP; (iii) calculating the support of these NSC based only on the corresponding PSP and then getting NSP. To the best of our knowledge, e-msNSP is the first method to mine NSP with MMS and does not impose strict constraints. Experimental results show that the e-msNSP is highly effective and efficient.
Designing L-serine targeted molecularly imprinted polymer via theoretical investigation
Authors: Singh Ambareesh Kumar , Singh Meenakshi 
Published: June 2016

Molecular imprinting is one of few general, nonbiological methods for creating molecular receptors, but the progress in molecular imprinting calls for the predictive tools capable of understanding molecular level complexities of these processes. Thus, computational chemistry which predicts the suitability of functional monomer in designing the sensor for a particular analyte was attempted to design an amino acid (L-serine) sensor based on the molecular imprinting approach using density functional theory (DFT). Here, the computations were carried out to check the feasibility of best suited monomers for imprinting an amino acid (L-serine) in water and allied solvents. DFT method was utilized at B3LYP/6-31[Formula: see text]G(d,p) level to optimize template, monomers and template-monomer complexes and basis set superposition error (BSSE) was corrected by means of the counterpoise (CP) method for complexes in gas phase. All monomers can be utilized for imprinting. 2-vinyl pyridine and acrylamide were found to be good for imprinting serine in water but toluene was found to be good porogen for imprinting serine with functional monomer acrylamide. This study will aid in designing a water-compatible MIP sensor for serine molecules, which could be a biomarker for certain neurological disorders.
Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer
Authors: Guo Xingjun , Zheng Lei , Jiang Jianxin , Zhao Yan , Wang Xin , Shen Ming , Zhu Feng , Tian Rui , Shi Chengjian , Xu Meng , Li Xu , Peng Feng , Zhang Hang , Feng Yechen , Xie Yu , Xu Xiaodong , Jia Wei , He Ruizhi , Xie Chencheng , Hu Jun , Ye Dawei , Wang Min , Qin Renyi 
Published: June 2016

Abstract
Purpose: We sought to find new immune-based treatments for pancreatic cancer.
Experimental Design: We detected IL18 expression in plasma and specimens from patients with pancreatic cancer. We then investigated whether IL18 had a therapeutic effect for pancreatic cancer in vitro and in vivo and any underlying mechanisms.
Results: Higher plasma IL18 was associated with longer overall survival (OS), but higher IL18 in pancreatic cancer tissues was associated with shorter OS and increased invasion and metastasis. Recombinant IL18 alone had no antitumor effect in the syngeneic mice with orthotopically transplanted tumors and promoted tumors in immunocompromised mice; it also facilitated immune responses in vitro and in vivo by augmenting the activity of cytotoxic T cells and NK cells in peripheral blood and lymph nodes. However, IL18 promoted the proliferation and invasion of pancreatic cancer cells, in vitro and in vivo, through the NF-κB pathway. Nevertheless, by coadministrating IL18 with BAY11-7082, an NF-κB inhibitor, we were able to prevent the procancerous effects of IL18 and prolong the survival time of the mice.
Conclusions: IL18 has both cancer-promoting and cancer-suppressing functions. Although its single-agent treatment has no therapeutic effect on pancreatic cancer, when combined with the NF-κB pathway inhibitor, IL18 improved survival in a murine pancreatic cancer model. Our study implies the possibility of a combinational immunotherapy that uses IL18 and targets NF-κB pathway. Clin Cancer Res; 22(23); 5939–50. ©2016 AACR.
Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma
Authors: Fatkhutdinov Nail , Sproesser Katrin , Krepler Clemens , Liu Qin , Brafford Patricia A. , Herlyn Meenhard , Aird Katherine M. , Zhang Rugang 
Published: June 2016

Abstract
The majority of patients with melanoma harbor mutations in the BRAF oncogene, thus making it a clinically relevant target. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression-free survival of only 6 to 7 months. Previously, we reported high expression of ribonucleotide reductase M2 (RRM2), which is rate-limiting for de novo dNTP synthesis, as a poor prognostic factor in patients with mutant BRAF melanoma. In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed marked recurrence. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell-cycle arrest.
Implications: Inhibition of RRM2 converts the transient response of melanoma cells to BRAFi to a stable response and may be a novel combinatorial strategy to prolong therapeutic response of patients with melanoma. Mol Cancer Res; 14(9); 767–75. ©2016 AACR.
Comparative Effectiveness of Cardiac Resynchronization Therapy Among Patients With Heart Failure and Atrial Fibrillation
Authors: Khazanie Prateeti , Greiner Melissa A. , Al-Khatib Sana M. , Piccini Jonathan P. , Turakhia Mintu P. , Varosy Paul D. , Masoudi Frederick A. , Curtis Lesley H. , Hernandez Adrian F. 
Published: June 2016

Background—
Atrial fibrillation is common in patients with heart failure, but outcomes of patients with both conditions who receive cardiac resynchronization therapy with defibrillator (CRT-D) compared with an implantable cardioverter-defibrillator (ICD) alone are unclear.

Methods and Results—
Using the National Cardiovascular Data Registry’s ICD Registry linked with Medicare claims, we identified 8951 patients with atrial fibrillation who were eligible for CRT-D and underwent first-time device implantation for primary prevention between April 2006 and December 2009. We used Cox proportional hazards models and inverse probability-weighted estimates to compare outcomes with CRT-D versus ICD alone. Cumulative incidence of mortality (744 [33%] for ICD; 1893 [32%] for CRT-D) and readmission (1788 [76%] for ICD; 4611 [76%] for CRT-D) within 3 years and complications within 90 days were similar between groups. After inverse weighting for the probability of receiving CRT-D, risks of mortality (hazard ratio, 0.83; 95% confidence interval, 0.75–0.92), all-cause readmission (hazard ratio, 0.86; 95% confidence interval, 0.80–0.92), and heart failure readmission (hazard ratio, 0.68; 95% confidence interval, 0.62–0.76) were lower with CRT-D compared with ICD alone. There was no significant difference in the 90-day complication rate (hazard ratio, 0.88; 95% confidence interval, 0.60–1.29). We observed hospital-level variation in the use of CRT-D among patients with atrial fibrillation.

Conclusions—
Among eligible patients with heart failure and atrial fibrillation, CRT-D was associated with lower risks of mortality, all-cause readmission, and heart failure readmission, as well as with a similar risk of complications compared with ICD alone.