bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimization of a Meropenem-Tobramycin Combination Dosage Regimen against Hypermutable and Nonhypermutable Pseudomonas aeruginosa via Mechanism-Based Modeling and the Hollow-Fiber Infection Model
Authors: Landersdorfer Cornelia B. , Rees Vanessa E. , Yadav Rajbharan , Rogers Kate E. , Kim Tae Hwan , Bergen Phillip J. , Cheah Soon-Ee , Boyce John D. , Peleg Anton Y. , Oliver Antonio , Shin Beom Soo , Nation Roger L. , Bulitta Jürgen B. 
Published: January 2018

ABSTRACTHypermutablePseudomonas aeruginosastrains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild-type strain and its isogenic hypermutable PAOΔmutSstrain (MICmeropenemof 1.0 mg/liter and MICtobramycinof 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ∼108.4CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAOΔmutSstrain in the HFIM, all monotherapies resulted in rapid regrowth to >108.7CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log10bacterial killing followed by regrowth to >6 log10CFU/ml by day 5 and high-level resistance (MICmeropenem, 32 mg/liter; MICtobramycin, 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log10bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4 log10over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutableP. aeruginosastrain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.
Draft Genome Sequences of Novel
Pseudomonas
,
Flavobacterium
, and
Sediminibacterium
Species Strains from a Freshwater Ecosystem
Authors: Pinto Federica , Tett Adrian , Armanini Federica , Asnicar Francesco , Boscaini Adriano , Pasolli Edoardo , Zolfo Moreno , Donati Claudio , Salmaso Nico , Segata Nicola 
Published: January 2018

ABSTRACT

Freshwater ecosystems represent 0.01% of the water on Earth, but they support 6% of global biodiversity that is still mostly uncharacterized. Here, we describe the genome sequences of three strains belonging to novel species in the
Pseudomonas
,
Flavobacterium
, and
Sediminibacterium
genera recovered from a water sample of Lake Garda, Italy.
Complete Genome Sequence of
Dietzia
sp. Strain WMMA184, a Marine Coral-Associated Bacterium
Authors: Braun Doug R. , Chevrette Marc G. , Acharya Deepa , Currie Cameron R. , Rajski Scott R. , Ritchie Kim B. , Bugni Tim S. 
Published: January 2018

ABSTRACT

Dietzia
sp. strain WMMA184 was isolated from the marine coral
Montastraea faveolata
as part of ongoing drug discovery efforts. Analysis of the 4.16-Mb genome provides information regarding interspecies interactions as it pertains to the regulation of secondary metabolism and natural product biosynthesis potential.
Deep brain stimulation in the caudal zona incerta versus best medical treatment in patients with Parkinson’s disease: a randomised blinded evaluation
Authors: Blomstedt Patric , Stenmark Persson Rasmus , Hariz Gun-Marie , Linder Jan , Fredricks Anna , Häggström Björn , Philipsson Johanna , Forsgren Lars , Hariz Marwan 
Published: January 2018

BackgroundSeveral open-label studies have shown good effect of deep brain stimulation (DBS) in the caudal zona incerta (cZi) on tremor, including parkinsonian tremor, and in some cases also a benefit on akinesia and axial symptoms. The aim of this study was to evaluate objectively the effect of cZi DBS in patients with Parkinson’s disease (PD).Method25 patients with PD were randomised to either cZi DBS or best medical treatment. The primary outcomes were differences between the groups in the motor scores of the Unified Parkinson’s Disease Rating Scale (UPDRS-III) rated single-blindly at 6 months and differences in the Parkinson’s Disease Questionnaire 39 items (PDQ-39). 19 patients, 10 in the medical arm and 9 in the DBS arm, fulfilled the study.ResultsThe DBS group had 41% better UPDRS-III scores off-medication on-stimulation compared with baseline, whereas the scores of the non-surgical patients off-medication were unchanged. In the on-medication condition, there were no differences between the groups, neither at baseline nor at 6 months. Subitems of the UPDRS-III showed a robust effect of cZi DBS on tremor. The PDQ-39 domains ‘stigma’ and ‘ADL’ improved only in the DBS group. The PDQ-39 summary index improved in both groups.ConclusionThis is the first randomised blinded evaluation of cZi DBS showing its efficacy on PD symptoms. The most striking effect was on tremor; however, the doses of dopaminergic medications could not be decreased. cZi DBS in PD may be an addition to existing established targets, enabling tailoring the surgery to the needs of the individual patient.
Features of GBA-associated Parkinson’s disease at presentation in the UK Tracking Parkinson’s study
Authors: Malek Naveed , Weil Rimona S , Bresner Catherine , Lawton Michael A , Grosset Katherine A , Tan Manuela , Bajaj Nin , Barker Roger A , Burn David J , Foltynie Thomas , Hardy John , Wood Nicholas W , Ben-Shlomo Yoav , Williams Nigel W , Grosset Donald G , Morris Huw R 
Published: January 2018

ObjectivesTo examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson’s disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function.MethodsWe prospectively recruited patients with PD in the Tracking Parkinson’s study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson’s Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia.ResultsWe studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher’s disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage.ConclusionsOur study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA-PD.Clinical trial registrationNCT02881099; Results.
Deep brain stimulation of the ventral striatal area for poststroke pain syndrome: a magnetoencephalography study
Authors: Gopalakrishnan Raghavan , Burgess Richard C. , Malone Donald A. , Lempka Scott F. , Gale John T. , Floden Darlene P. , Baker Kenneth B. , Machado Andre G. 
Published: January 2018

Poststroke pain syndrome (PSPS) is an often intractable disorder characterized by hemiparesis associated with unrelenting chronic pain. Although traditional analgesics have largely failed, integrative approaches targeting affective-cognitive spheres have started to show promise. Recently, we demonstrated that deep brain stimulation (DBS) of the ventral striatal area significantly improved the affective sphere of pain in patients with PSPS. In the present study, we examined whether electrophysiological correlates of pain anticipation were modulated by DBS that could serve as signatures of treatment effects. We recorded event-related fields (ERFs) of pain anticipation using magnetoencephalography (MEG) in 10 patients with PSPS preoperatively and postoperatively in DBS OFF and ON states. Simple visual cues evoked anticipation as patients awaited a painful (PS) or nonpainful stimulus (NPS) to the nonaffected or affected extremity. Preoperatively, ERFs showed no difference between PS and NPS anticipation to the affected extremity, possibly due to loss of salience in a network saturated by pain experience. DBS significantly modulated the early N1, consistent with improvements in affective networks involving restoration of salience and discrimination capacity. Additionally, DBS suppressed the posterior P2 (aberrant anticipatory anxiety) while enhancing the anterior N1 (cognitive and emotional regulation) in responders. DBS-induced changes in ERFs could potentially serve as signatures for clinical outcomes. NEW & NOTEWORTHY We examined the electrophysiological correlates of pain affect in poststroke pain patients who underwent deep brain stimulation (DBS) targeting the ventral striatal area under a randomized, controlled trial. DBS significantly modulated early event-related components, particularly N1 and P2, measured with magnetoencephalography during a pain anticipatory task, compared with baseline and the DBS-OFF condition, pointing to possible mechanisms of action. DBS-induced changes in event-related fields could potentially serve as biomarkers for clinical outcomes.
Three members of a peptide family are differentially distributed and elicit differential state-dependent responses in a pattern generator-effector system
Authors: Dickinson Patsy S. , Armstrong Matthew K. , Dickinson Evyn S. , Fernandez Rebecca , Miller Alexandra , Pong Sovannarath , Powers Brian W. , Pupo-Wiss Alixander , Stanhope Meredith E. , Walsh Patrick J. , Wiwatpanit Teerawat , Christie Andrew E. 
Published: January 2018

C-type allatostatins (AST-Cs) are pleiotropic neuropeptides that are broadly conserved within arthropods; the presence of three AST-C isoforms, encoded by paralog genes, is common. However, these peptides are hypothesized to act through a single receptor, thereby exerting similar bioactivities within each species. We investigated this hypothesis in the American lobster, Homarus americanus, mapping the distributions of AST-C isoforms within relevant regions of the nervous system and digestive tract, and comparing their modulatory influences on the cardiac neuromuscular system. Immunohistochemistry showed that in the pericardial organ, a neuroendocrine release site, AST-C I and/or III and AST-C II are contained within distinct populations of release terminals. Moreover, AST-C I/III-like immunoreactivity was seen in midgut epithelial endocrine cells and the cardiac ganglion (CG), whereas AST-C II-like immunoreactivity was not seen in these tissues. These data suggest that AST-C I and/or III can modulate the CG both locally and hormonally; AST-C II likely acts on the CG solely as a hormonal modulator. Physiological studies demonstrated that all three AST-C isoforms can exert differential effects, including both increases and decreases, on contraction amplitude and frequency when perfused through the heart. However, in contrast to many state-dependent modulatory changes, the changes in contraction amplitude and frequency elicited by the AST-Cs were not functions of the baseline parameters. The responses to AST-C I and III, neither of which is COOH-terminally amidated, are more similar to one another than they are to the responses elicited by AST-C II, which is COOH-terminally amidated. These results suggest that the three AST-C isoforms are differentially distributed in the lobster nervous system/midgut and can elicit distinct behaviors from the cardiac neuromuscular system, with particular structural features, e.g., COOH-terminal amidation, likely important in determining the effects of the peptides.NEW & NOTEWORTHY Multiple isoforms of many peptides exert similar effects on neural circuits. In this study we show that each of the three isoforms of C-type allatostatin (AST-C) can exert differential effects, including both increases and decreases in contraction amplitude and frequency, on the lobster cardiac neuromuscular system. The distribution of effects elicited by the nonamidated isoforms AST-C I and III are more similar to one another than to the effects of the amidated AST-C II.
TRIM59 Promotes Gliomagenesis by Inhibiting TC45 Dephosphorylation of STAT3
Authors: Sang Youzhou , Li Yanxin , Song Lina , Alvarez Angel A. , Zhang Weiwei , Lv Deguan , Tang Jianming , Liu Feng , Chang Zhijie , Hatakeyama Shigetsugu , Hu Bo , Cheng Shi-Yuan , Feng Haizhong 
Published: January 2018

Abstract
Aberrant EGFR signaling is a common driver of glioblastoma (GBM) pathogenesis; however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T-cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells. Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation.
Significance: These findings identify a novel component of the EGFR/STAT3 signaling axis in the regulation of glioma tumorigenesis. Cancer Res; 78(7); 1792–804. ©2018 AACR.
Morphological and molecular characterisation of two new Hemicycliophora species (Tylenchida: Hemicycliophoridae) with a revision of the taxonomic status of some known species and a phylogeny of the genus
Authors: Van den Berg Esther , Tiedt Louwrens R. , Liébanas Gracia , Chitambar John J. , Stanley Jason D. , Inserra Renato N. , Castillo Pablo , Subbotin Sergei A. 
Published: January 2018

Summary
Hemicycliophora presently contains 132 valid species of sheath nematodes. Within several samples obtained from surveys in Canada, South Africa, Spain and the USA, we distinguished six valid and six putative unidentified species by integrating the results of morphological and molecular analyses. Valid species included: H. californica, H. gracilis, H. parvana, H. poranga, H. raskii, and H. signata. The putative unidentified species were indicated as Hemicycliophora sp. 10, sp. 12, sp. 15, sp. 16, sp. 17, and sp. 18. Two new species of sheath nematodes from Spain and the USA were described and named as H. onubensis sp. n. and H. robbinsi sp. n., respectively. Hemicycliophora wyei is proposed as a junior synonym of H. parvana and H. ripa is proposed as a junior synonym of H. poranga. Eighteen valid and 13 unidentified species of sheath nematodes were characterised using the partial COI mtDNA gene. A total of 94 new sequences of which 77 were for the COI mtDNA gene were obtained in this study. Phylogenetic relationships within Hemicycliophora, using the D2-D3 expansion segments of 28S rDNA, ITS rRNA and COI gene sequences, are presented as inferred from Bayesian analysis.
On the Dynamics of Adjustment in the f-Plane Shallow Water Adjoint System
Authors: Morgan Michael C. 
Published: January 2018

Analytic results and numerical experimentation reveal that a “backward” integration of the adjoint of the shallow water system linearized about a basic state at rest on an f plane is characterized by a radiation of gravity wave–like structures and the emergence of a steady adjoint state. The earlier adjoint states are linked to the prescribed adjoint state (i.e., the adjoint forcing) through the locally conserved dynamical adjoint variables of the shallow water system: the sensitivity to “balanced height” ([Formula: see text]) and the sensitivity to potential vorticity (PV) [Formula: see text]. The sensitivity to balanced height is determined by the prescribed adjoint sensitivity forcings for the flow, [Formula: see text] and [Formula: see text], and height (fluid depth), [Formula: see text]: [Formula: see text]− ( g/ f)([Formula: see text]). The sensitivity to PV is diagnosed from the inversion of an elliptic operator relating the sensitivity to PV to the distribution of [Formula: see text]. The sensitivity to PV determines the long-time ( t → ∞), steady behavior of the adjoint sensitivity to height, [Formula: see text]= −( f/ H2)[Formula: see text]. In the vicinity of the initial adjoint forcing, the long-time, steady-state behavior of the adjoint system (linearized about a state at rest) is characterized by nondivergent sensitivities to the flow that resemble geostrophic balance: [Formula: see text]= (1/ H)[Formula: see text]/∂ y and [Formula: see text]= (1/ H)[Formula: see text]/∂ x. The process by which this long-time, nondivergent, adjoint state emerges is termed adjoint adjustment. For the system considered, sensitivities to the ageostrophic and irrotational components of the flow vanish for the adjusted state near the prescribed adjoint forcing.
The Transformation of Salinity Variance: A New Approach to Quantifying the Influence of Straining and Mixing on Estuarine Stratification
Authors: Li Xiangyu , Geyer W. Rockwell , Zhu Jianrong , Wu Hui 
Published: January 2018

AbstractThe roles of straining and dissipation in controlling stratification are derived analytically using a vertical salinity variance method. Stratification is produced by converting horizontal variance to vertical variance via straining, that is, differential advection of horizontal salinity gradients, and stratification is destroyed by the dissipation of vertical variance through turbulent mixing. A numerical model is applied to the Changjiang estuary in order to demonstrate the salinity variance balance and how it reveals the factors controlling stratification. The variance analysis reveals that dissipation reaches its maximum during spring tide in the Changjiang estuary, leading to the lowest stratification. Stratification increases from spring tide to neap tide because of the increasing excess of straining over dissipation. Throughout the spring–neap tidal cycle, straining is almost always larger than dissipation, indicating a net excess of production of vertical variance relative to dissipation. This excess is balanced on average by advection, which exports vertical variance out of the estuarine region into the plume. During neap tide, tidal straining shows a general tendency of destratification during the flood tide and restratification during ebb, consistent with the one-dimensional theory of tidal straining. During spring tide, however, positive straining occurs during flood because of the strong baroclinicity induced by the intensified horizontal salinity gradient. These results indicate that the salinity variance method provides a valuable approach for examining the spatial and temporal variability of stratification in estuaries and coastal environments.
Autonomous Sampling of Ocean Submesoscale Fronts with Ocean Gliders and Numerical Model Forecasting
Authors: Flexas Mar M. , Troesch Martina I. , Chien Steve , Thompson Andrew F. , Chu Selina , Branch Andrew , Farrara John D. , Chao Yi 
Published: January 2018

ABSTRACTSubmesoscale fronts arising from mesoscale stirring are ubiquitous in the ocean and have a strong impact on upper-ocean dynamics. This work presents a method for optimizing the sampling of ocean fronts with autonomous vehicles at meso- and submesoscales, based on a combination of numerical forecast and autonomous planning. This method uses a 48-h forecast from a real-time high-resolution data-assimilative primitive equation ocean model, feature detection techniques, and a planner that controls the observing platform. The method is tested in Monterey Bay, off the coast of California, during a 9-day experiment focused on sampling subsurface thermohaline-compensated structures using a Seaglider as the ocean observing platform. Based on model estimations, the sampling “gain,” defined as the magnitude of isopycnal tracer variability sampled, is 50% larger in the feature-chasing case with respect to a non-feature-tracking scenario. The ability of the model to reproduce, in space and time, thermohaline submesoscale features is evaluated by quantitatively comparing the model and glider results. The model reproduces the vertical (~50–200 m thick) and lateral (~5–20 km) scales of subsurface subducting fronts and near-bottom features observed in the glider data. The differences between model and glider data are, in part, attributed to the selected glider optimal interpolation parameters and to uncertainties in the forecasting of the location of the structures. This method can be exported to any place in the ocean where high-resolution data-assimilative model output is available, and it allows for the incorporation of multiple observing platforms.
Forecasting West African Heat Waves at Subseasonal and Seasonal Time Scales
Authors: Batté Lauriane , Ardilouze Constantin , Déqué Michel 
Published: January 2018

Abstract
Early indication of an increased risk of extremely warm conditions could help alleviate some of the consequences of severe heat waves on human health. This study focuses on boreal spring heat wave events over West Africa and the Sahel and examines the long-range predictability and forecast quality of these events with two coupled forecasting systems designed at Météo-France, both based on the CNRM-CM coupled global climate model: the operational seasonal forecasting System 5 and the experimental contribution to the World Weather Research Programme/World Climate Research Programme (WWRP/WCRP) subseasonal-to-seasonal (S2S) project. Evaluation is based on past reforecasts spanning 22 years, from 1993 to 2014, compared to reference data from reanalyses. On the seasonal time scale, skill in reproducing interannual anomalies of heat wave duration is limited at a gridpoint level but is significant for regional averages. Subseasonal predictability of daily humidity-corrected apparent temperature drops sharply beyond the deterministic range. In addition to reforecast skill measures, the analysis of real-time forecasts for 2016, both in terms of anomalies with respect to the reforecast climatology and using a weather-type approach, provides additional insight on the systems’ performance in giving relevant information on the possible occurrence of such events.