bluuebunny/crossref_metadata_2025_split huggingface dataset:
Klebsiella pneumoniae Major Porins OmpK35 and OmpK36 Allow More Efficient Diffusion of β-Lactams than Their Escherichia coli Homologs OmpF and OmpC
Authors: Sugawara Etsuko , Kojima Seiji , Nikaido Hiroshi 
Published: September 2016

ABSTRACTKlebsiella pneumoniae, one of the most important nosocomial pathogens, is becoming a major problem in health care because of its resistance to multiple antibiotics, including cephalosporins of the latest generation and, more recently, even carbapenems. This is largely due to the spread of plasmid-encoded extended-spectrum β-lactamases. However, antimicrobial agents must first penetrate the outer membrane barrier in order to reach their targets, and hydrophilic and charged β-lactams presumably diffuse through the porin channels. Unfortunately, the properties ofK. pneumoniaeporin channels are largely unknown. In this study, we made clean deletions ofK. pneumoniaeporin genesompK35andompK36and examined the antibiotic susceptibilities and diffusion rates of β-lactams. The results showed that OmpK35 and OmpK36 produced larger more permeable channels than theirEscherichia colihomologs OmpF and OmpC; OmpK35 especially produced a diffusion channel of remarkably high permeability toward lipophilic (benzylpenicillin) and large (cefepime) compounds. These results were also confirmed by expressing various porins in anE. colistrain lacking major porins and the major multidrug efflux pump AcrAB. Our data explain why the development of drug resistance inK. pneumoniaeis so often accompanied by the mutational loss of its porins, especially OmpK35, in addition to the various plasmid-carried genes of antibiotic resistance, because even hydrolysis by β-lactamases becomes inefficient in producing high levels of resistance if the bacterium continues to allow a rapid influx of β-lactams through its wide porin channels.IMPORTANCEIn Gram-negative bacteria, drugs must first enter the outer membrane, usually through porin channels. Thus, the quantitative examination of influx rates is essential for the assessment of resistance mechanisms, yet no such studies exist for a very important nosocomial pathogen,Klebsiella pneumoniae. We found that the larger channel porin of this organism, OmpK35, produces a significantly larger channel than itsEscherichia colihomolog, OmpF. This makes unmodifiedK. pneumoniaestrains more susceptible to relatively large antibiotics, such as the third- and fourth-generation cephalosporins. Also, even the acquisition of powerful β-lactamases is not likely to make them fully resistant in the presence of such an effective influx process, explaining why so many clinical isolates of this organism lack porins.
Incentivising practice with take-home laparoscopic simulators in two UK Core Surgical Training programmes
Authors: Nicol Laura G , Walker Kenneth G , Cleland Jennifer , Partridge Roland , Moug Susan J 
Published: September 2016

IntroductionPractice using simulators has been validated as a mean for surgical trainees to improve basic laparoscopic skills and free their attention for higher cognitive functions. However, mere provision of equipment does not result in frequent practice. This study assesses one approach to incentivising practice within core surgical training programmes and leads to further recommendations.Methods30 core surgical trainees (CST) starting laparoscopic-based specialties were recruited from East and West of Scotland CST programmes and given take-home laparoscopic simulators, with six training modules. Attainment of target metric scores generated an eCertificate, to be rewarded by progression in the live theatre. Questionnaires assessed confounding variables and explored CSTs’ anxieties about laparoscopy.Results27 trainees (90%) agreed to participate (mean age 28 years, range 24–25; 17 males). 13 CSTs (48%) were in the first year of surgical training. 11 (41%) had no previous simulation experience and 7 (32%) CSTs played video games >3 hours/week. 12 of 27 trainees (44%) completed ≥1 task and 7 completed all (26%).Performances improved in some participants, but overall engagement with the programme was poor. Reasons given included poor internet connectivity, busy rotations and examinations. CSTs who engaged in the study significantly reduced their anxiety (mean 4.96 vs 3.56, p<0.05).ConclusionsThe provision of take-home laparoscopic simulators with accompanying targets did not successfully incentivise CSTs to practise. However, the subgroup who did engage with the project reported performance improvements and significantly reduced anxiety. Proposals to overcome barriers to practising in simulation, including obligatory simulation-based assessments, are discussed.
Dietary sugars versus glucose tablets for first-aid treatment of symptomatic hypoglycaemia in awake patients with diabetes: a systematic review and meta-analysis
Authors: Carlson Jestin N , Schunder-Tatzber Susanne , Neilson Christine J , Hood Natalie 
Published: September 2016

BackgroundWhile glucose tablets have been advocated for treating symptomatic hypoglycaemia in awake patients, dietary sugars may be more convenient. We performed a systematic review to compare the impact of these treatment options on the relief of symptomatic hypoglycaemia, time to resolution of symptoms, blood glucose levels, complications and hospital length of stay.MethodWe searched PubMed, Embase and the Cochrane Library through 28 June 2016 and assessed the quality of evidence using the Grades of Recommendation, Assessment, Development and Evaluation approach. Reference lists from a subset of the resulting articles were mined for additional, potentially eligible papers. We calculated the risk ratio (RR) of each treatment option for the preselected outcomes of interest.ResultsOf the 1774 identified papers, four studies met the inclusion criteria; three randomised controlled trials totalling 502 hypoglycaemic events treated with dietary sugars and 223 with glucose tablets and one observational study with 13 events treated with dietary sugars and 9 with glucose tablets. The dietary forms of sugar included sucrose, fructose, orange juice, jelly beans, Mentos, cornstarch hydrolysate, Skittles and milk. In the pooled analysis, patients treated with dietary sugars had a lower resolution of symptoms 15 min after treatment compared with glucose tablets (RR 0.89, 95% CI 0.83 to 0.95).ConclusionsWhen compared with dietary sugars, glucose tablets result in a higher rate of relief of symptomatic hypoglycaemia 15 min after ingestion and should be considered first, if available, when treating symptomatic hypoglycaemia in awake patients.
Social mobility and inflammatory and metabolic markers at older ages: the English Longitudinal Study of Ageing
Authors: Na-Ek Nat , Demakakos Panayotes 
Published: September 2016

BackgroundSince our knowledge of the associations between socioeconomic position (SEP) over the life course and inflammatory and metabolic markers, which are excellent predictors of cardiovascular disease, remains limited, we examined the association between social mobility over the life course and these markers at older ages.MethodsOur study used cross-sectionally collected data from 6142 participants aged 50 years and older from the English Longitudinal Study of Ageing. We estimated linear and logistic models of the associations between social mobility, using information on childhood and adult SEP, C reactive protein (CRP), fibrinogen, glycated haemoglobin (HbA1c) and high-density lipoprotein (HDL) cholesterol. Our models were gradually adjusted for age, sex, chronic diseases, obesity, physical activity, alcohol consumption, smoking status and depressive symptoms.ResultsParticipants who experienced upward social mobility had higher CRP, fibrinogen and HbA1c levels compared with those who had stable high SEP over the life course, but lower compared with those who experienced downward social mobility or had stable low SEP. They also had lower HDL levels compared with those who had stable high SEP or downwardly mobile. Adjustment for covariates partially explained the associations between social mobility and CRP and HDL, and fully explained those between social mobility and fibrinogen and HbA1c.ConclusionsSocial mobility is associated with inflammatory and metabolic markers at older ages with some of the observed associations persisting after accounting for covariates. Upward social mobility appears to partially reverse the damaging effect of childhood social disadvantage on inflammatory profiles in older ages.
Systematic screening for cardiovascular risk at pharmacies
Authors: Rohla Miklos , Haberfeld Heinz , Sinzinger Helmut , Kritz Harald , Tscharre Maximilian , Freynhofer Matthias K , Huber Kurt , Weiss Thomas W 
Published: September 2016

BackgroundEarly identification and treatment of cardiovascular risk factors (CVRFs) is essential to prevent excess morbidity, mortality and healthcare-related costs. We sought to investigate whether an active screening programme at pharmacies could identify a significant proportion of patients with previously undetected CVRFs.Methods and resultsBetween April and July 2013, 184 pharmacies in Lower Austria enrolled a total of 6800 participants, in whom body mass index (BMI), blood pressure (BP), total cholesterol and blood glucose were measured. Mean age was 58±17 years and 67.8% were women. 21% of men and 16% of women had a BMI≥30 kg/m2. The crude prevalence of diabetes mellitus (DM) was 7%, hypercholesterolaemia was identified in 57%, and 44% had elevated BP. Among fasting individuals (n=1814), DM was found in 18%. In total, 30% were confronted with a CVRF they were previously unaware of, and pharmacists recommended 45% of all participants to actively consult a physician. A first-time diagnosis of a CVRF was most frequent in the age groups between 25 and 64 (32% of participants).ConclusionsThis pharmacy-based approach for cardiovascular risk screening found similar overall prevalences of CVRFs as reported by national surveys, but revealed underdiagnoses, particularly in lower age groups. A previously unknown CVRF was identified in every third individual, frequently prompting the pharmacists to recommend the consultation of a physician. An active screening approach at pharmacies might therefore serve as an effective alternative to the public preventive medical examination, particularly in younger age groups.
A review and new data on neotectonic evolution of active faults in the Kachchh Basin, Western India: legacy of post-Deccan Trap tectonic inversion
Authors: Maurya D. M. , Chowksey Vikas , Patidar A. K. , Chamyal L. S. 
Published: September 2016

Abstract

The Kachchh Basin, located in Gujarat (India) at the western trailing edge of the Indian plate, comprises several east–west trending seismically active faults. The Kachchh Basin evolved in two major stages. The first is the rift stage, which correlates with the break-up and separation of the Indian plate in the Late Triassic–Early Cretaceous and synrift sedimentation. The second is the post-Deccan Trap inversion stage, when the basin was periodically uplifted along the existing east–west trending intrabasinal master faults: the Katrol Hill Fault, the Kachchh Mainland Fault, the South Wagad Fault, the Gedi Fault and the Island Belt Fault. The inversion of basin was initiated by the onset of a compressive stress regime in response to the collision of the Indian plate with the Eurasian plate in the far north during the Early Eocene. This is shown by the tilting of the Deccan Trap lava flows along with the underlying Mesozoic sequence and the associated intrusive bodies that occupy the core portions of domal and anticlinal flexures bounded by major fault lines. Seismotectonic data on the prolonged aftershock sequence after the 2001 Bhuj earthquake (M
w
7.7) reveal continuous low-to-moderate seismic activity along multiple faults covering a large area, now identified as the Kachchh Seismic Zone. This article reviews the neotectonic perspective of the active faults with the prime objective of delineating the post-Deccan Trap inversion phase of the Kachchh Basin, with an emphasis on neotectonism with regard to modern seismic activity. The datasets presented are primarily field-based neotectonic data from active fault zones that cover aspects of the tectonic geomorphology, Quaternary stratigraphy, near-surface fault traces and the nature of the fault in the shallow subsurface based on ground-penetrating radar studies. We also attempt a comparative neotectonic evaluation of each active fault in the Kachchh Basin and discuss the constraints for evolving a viable neotectonic model of the basin.
UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models
Authors: DeRyckere Deborah , Lee-Sherick Alisa B. , Huey Madeline G. , Hill Amanda A. , Tyner Jeffrey W. , Jacobsen Kristen M. , Page Lauren S. , Kirkpatrick Gregory G. , Eryildiz Fatma , Montgomery Stephanie A. , Zhang Weihe , Wang Xiaodong , Frye Stephen V. , Earp H. Shelton , Graham Douglas K. 
Published: September 2016

Abstract
Purpose: MERTK tyrosine kinase is ectopically expressed in 30% to 50% of acute lymphoblastic leukemias (ALL) and more than 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MERTK tyrosine kinase inhibitor, for treatment of acute leukemia.
Experimental Design: Preclinical in vitro and in vivo assays using cell lines and primary leukemia patient samples were used to evaluate antileukemic effects of UNC2025.
Results: UNC2025 potently inhibited prosurvival signaling, induced apoptosis, and reduced proliferation and colony formation in MERTK-expressing ALL and AML cell lines and patient samples. Approximately 30% of primary leukemia patient samples (78 of 261 total) were sensitive to UNC2025. Sensitive samples were most prevalent in the AML, T-ALL, and minimally differentiated (M0) AML subsets. UNC2025 inhibited MERTK in bone marrow leukemia cells and had significant therapeutic effects in xenograft models, with dose-dependent decreases in tumor burden and consistent two-fold increases in median survival, irrespective of starting disease burden. In a patient-derived AML xenograft model, treatment with UNC2025 induced disease regression. In addition, UNC2025 increased sensitivity to methotrexate in vivo, suggesting that addition of MERTK-targeted therapy to current cytotoxic regimens may be particularly effective and/or allow for chemotherapy dose reduction.
Conclusions: The broad-spectrum activity mediated by UNC2025 in leukemia patient samples and xenograft models, alone or in combination with cytotoxic chemotherapy, supports continued development of MERTK inhibitors for treatment of leukemia. Clin Cancer Res; 23(6); 1481–92. ©2016 AACR.
Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer
Authors: Chen Ying , Camacho Sandra Catalina , Silvers Thomas R. , Razak Albiruni R.A. , Gabrail Nashat Y. , Gerecitano John F. , Kalir Eva , Pereira Elena , Evans Brad R. , Ramus Susan J. , Huang Fei , Priedigkeit Nolan , Rodriguez Estefania , Donovan Michael , Khan Faisal , Kalir Tamara , Sebra Robert , Uzilov Andrew , Chen Rong , Sinha Rileen , Halpert Richard , Billaud Jean-Noel , Shacham Sharon , McCauley Dilara , Landesman Yosef , Rashal Tami , Kauffman Michael , Mirza Mansoor R. , Mau-Sørensen Morten , Dottino Peter , Martignetti John A. 
Published: September 2016

Abstract
Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer.
Experimental Design: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor.
Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor–mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexor-treated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all.
Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer. Clin Cancer Res; 23(6); 1552–63. ©2016 AACR.
The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma
Authors: Keane Colm , Gould Clare , Jones Kimberley , Hamm David , Talaulikar Dipti , Ellis Jonathan , Vari Frank , Birch Simone , Han Erica , Wood Peter , Le-Cao Kim-Anh , Green Michael R. , Crooks Pauline , Jain Sanjiv , Tobin Josh , Steptoe Raymond J. , Gandhi Maher K. 
Published: September 2016

Abstract
Purpose: To investigate the relationship between the intra-tumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo diffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival.
Experimental Design: We performed high-throughput unbiased TCRβ sequencing on a population-based cohort of 92 patients with DLBCL treated with conventional (i.e., non-checkpoint blockade) frontline “R-CHOP” therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString. The primary endpoints were 4-year overall survival (OS) and progression-free survival (PFS).
Results: The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (P &lt; 0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS rate of 60.0% [95% confidence interval (CI), 31.7%–79.6%], compared with 79.8% in patients with a low dominant clone (95% CI, 66.7%–88.5%; P = 0.005). A highly dominant clone also predicted inferior 4-year PFS rate of 46.6% (95% CI, 22.5%–76.6%) versus 72.6% (95% CI, 58.8%–82.4%, P = 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV+ DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell diversity was associated with significantly elevated PD-1, PD-L1, and PD-L2 immune checkpoint molecules.
Conclusions: Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy. Clin Cancer Res; 23(7); 1820–8. ©2016 AACR.
Reduced Left Lateralization of Language in Congenitally Blind Individuals
Authors: Lane Connor , Kanjlia Shipra , Richardson Hilary , Fulton Anne , Omaki Akira , Bedny Marina 
Published: September 2016

Abstract
Language processing depends on a left-lateralized network of frontotemporal cortical regions. This network is remarkably consistent across individuals and cultures. However, there is also evidence that developmental factors, such as delayed exposure to language, can modify this network. Recently, it has been found that, in congenitally blind individuals, the typical frontotemporal language network expands to include parts of “visual” cortices. Here, we report that blindness is also associated with reduced left lateralization in frontotemporal language areas. We analyzed fMRI data from two samples of congenitally blind adults (n = 19 and n = 13) and one sample of congenitally blind children (n = 20). Laterality indices were computed for sentence comprehension relative to three different control conditions: solving math equations (Experiment 1), a memory task with nonwords (Experiment 2), and a “does this come next?” task with music (Experiment 3). Across experiments and participant samples, the frontotemporal language network was less left-lateralized in congenitally blind than in sighted individuals. Reduction in left lateralization was not related to Braille reading ability or amount of occipital plasticity. Notably, we observed a positive correlation between the lateralization of frontotemporal cortex and that of language-responsive occipital areas in blind individuals. Blind individuals with right-lateralized language responses in frontotemporal cortices also had right-lateralized occipital responses to language. Together, these results reveal a modified neurobiology of language in blindness. Our findings suggest that, despite its usual consistency across people, the neurobiology of language can be modified by nonlinguistic experiences.
Neotropical spittlebugs related to Neaenini (Hemiptera, Cercopidae) and the origins of subfamily Cercopinae
Authors: HAMILTON K.G. ANDREW 
Published: September 2016

The Central American tribe Neaenini, originally comprising only the monobasic genus Neaenus Fowler, was thought to be transitional between Cercopinae and Aphrophorinae. The genus is here enlarged by 5 (1 unnamed) additional species including 2 in a distinctive new subgenus Neaniskus. Keys are presented to 5 species of Neaenus, to 12 allied Neotropical genera and their 57 species: 12 of Tomaspisinella Lallemand, 1927 (=Hemitomaspis Lallemand, 1949, syn.nov. and 3 distinctive new subgenera Meretricula, Merinx and Merulatomus), 14 species of Microsargane Fowler, 1897 (=Ecothera Melichar, 1915, syn.nov., with 2 distinctive new subgenera Microrhaphe and Microtholia) and 31 species of Zuata Fennah, together with 2 species of Helioptera gen. nov. and 6 monobasic genera (Liparonotum gen. nov., Marcion Fennah, Menytes gen. nov., Microclimax gen. nov., Microlaqueus gen. nov. and Simorhina Jacobi). The small Neotropical genera Tomaspisina Distant and Olcotomaspis Lallemand (with 2 new combinations and subgenus Hyalotomaspis Lallemand, stat.nov.) appear to be allied to the large old-world genus Phymatostetha Stål rather than to any new-world Cercopinae. A check list is presented to these 13 genera and their 76 species (of which 30 are new to science and 5 of Zuata are new synonyms). Males are described for 5 species previously known from females but males of 9 (in 6 genera) are still unknown. Male genitalia define a new tribe of Cercopinae, Microsarganini (Microsargane was formerly placed in Aphrophorinae) that also includes Liparonotum, Microclimax and Microlaqueus. Almost half of the genera are monobasic without synapomorphies to Aphrophorinae, suggesting that these genera (including several genera resembling both Aphrophorinae and Cercopinae) represent relict lineages at the base of the subfamily Cercopinae.