bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic variation and evolutionary analysis ofPepino mosaic virusin Sicily: insights into the dispersion and epidemiology
Authors: Davino S. , Panno S. , Iacono G. , Sabatino L. , D'Anna F. , Iapichino G. , Olmos A. , Scuderi G. , Rubio L. , Tomassoli L. , Capodici G. , Martinelli F. , Davino M.
Published: July 2016

Pepino mosaic virus(PepMV) is a highly infectious potexvirus that causes a severe disease in tomato (Solanum lycopersicum) crops worldwide. In Sicily, the first outbreak was detected in a single greenhouse in 2005 and it was promptly eradicated. However, in 2008, a large number of greenhouses were simultaneously affected, and it was impossible to eradicate or control the virus. This study addressed the dispersion and the genetic diversity of PepMVisolates obtained from the outbreak in Sicily, in comparison with worldwide PepMVisolates, to gain insight into the factors determining the evolution and epidemiology of the virus. A total of 1800 samples from plants with and without symptoms were collected in the Sicilian provinces of Agrigento, Caltanissetta, Palermo, Ragusa, Siracusa and Trapani. Three isolates collected at different times were biologically characterized. The incidence of the virus increased rapidly from 13% in 2011 to 63% in 2013, and phylogenetic analysis showed that all Sicilian isolates of PepMVbelonged to theCH2 strain, one of the six strains previously described. Nucleotide diversity of the Sicilian isolates was low, thus suggesting rapid spread and genetic stability.
The effects of respiratory sinus arrhythmia on anger reactivity and persistence in major depression
Authors: Ellis Alissa J. , Shumake Jason , Beevers Christopher G.
Published: July 2016

The experience of anger during a depressive episode has recently been identified as a poor prognostic indicator of illness course. Given the clinical implications of anger in major depressive disorder (MDD), understanding the mechanisms involved in anger reactivity and persistence is critical for improved intervention. Biological processes involved in emotion regulation during stress, such as respiratory sinus arrhythmia (RSA), may play a role in maintaining negative moods. Clinically depressed (MDD; n = 49) and nondepressed (non‐MDD; n = 50) individuals were challenged with a stressful computer task shown to increase anger, while RSA (high frequency range 0.15–0.4 Hz) was collected. RSA predicted future anger, but was unrelated to current anger. That is, across participants, low baseline RSA predicted anger reactivity during the task, and in depressed individuals, those with low RSA during the task had a greater likelihood of anger persistence during a recovery period. These results suggest that low RSA may be a psychophysiological process involved in anger regulation in depression. Low RSA may contribute to sustained illness course by diminishing the repair of angry moods.
Dissecting the U, M, S and C genomes of wild relatives of bread wheat (Aegilops spp.) into chromosomes and exploring their synteny with wheat
Authors: Molnár István , Vrána Jan , Burešová Veronika , Cápal Petr , Farkas András , Darkó Éva , Cseh András , Kubaláková Marie , Molnár‐Láng Márta , Doležel Jaroslav
Published: July 2016

Goat grasses (Aegilops spp.) contributed to the evolution of bread wheat and are important sources of genes and alleles for modern wheat improvement. However, their use in alien introgression breeding is hindered by poor knowledge of their genome structure and a lack of molecular tools. The analysis of large and complex genomes may be simplified by dissecting them into single chromosomes via flow cytometric sorting. In some species this is not possible due to similarities in relative DNA content among chromosomes within a karyotype. This work describes the distribution of GAA and ACG microsatellite repeats on chromosomes of the U, M, S and C genomes of Aegilops, and the use of microsatellite probes to label the chromosomes in suspension by fluorescence in situ hybridization (FISHIS). Bivariate flow cytometric analysis of chromosome DAPI fluorescence and fluorescence of FITC‐labelled microsatellites made it possible to discriminate all chromosomes and sort them with negligible contamination by other chromosomes. DNA of purified chromosomes was used as a template for polymerase chain reation (PCR) using Conserved Orthologous Set (COS) markers with known positions on wheat A, B and D genomes. Wheat–Aegilops macrosyntenic comparisons using COS markers revealed significant rearrangements in the U and C genomes, while the M and S genomes exhibited structure similar to wheat. Purified chromosome fractions provided an attractive resource to investigate the structure and evolution of the Aegilops genomes, and the COS markers assigned to Aegilops chromosomes will facilitate alien gene introgression into wheat.
Relationship between transfusion volume and outcomes in children undergoing noncardiac surgery
Authors: Goobie Susan M. , DiNardo James A. , Faraoni David
Published: July 2016

BACKGROUND

The objective of this study was to assess the relationship between the volume of red blood cells (RBCs) transfused and outcomes in children undergoing noncardiac surgery.

STUDY DESIGN AND METHODS

Children undergoing noncardiac surgery recorded in the 2012 and 2013 American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) pediatric databases were included. Outcomes included 30‐day mortality and the incidence of major postoperative complications. Children who received RBC transfusions were further classified into four subgroups based on the volume transfused. We used multivariable logistic regression analysis and propensity‐matched analysis to match each child who received a transfusion with a nontransfused control and to compare the incidences of 30‐day mortality and adverse postoperative outcomes.

RESULTS

After propensity‐matched analysis, there were 4496 children in the group that received transfusion volumes from 1 to 19 mL/kg, 1557 in the group that received volumes from 20 to 39 mL/kg, 506 in the group that received from 40 to 59 mL/kg, and 412 in the group that received ≥60 mL/kg. Children who received RBC transfusion volumes from 40 to 59 mL/kg and ≥60 mL/kg had an increased risk for 30‐day mortality of 7.3% versus 1.4% (p < 0.001) and 11.2% versus 2.9% (p = 0.005), respectively, compared with their matched controls. No statistical difference was reported for children who were exposed to transfusion volumes from 20 to 39 mL/kg (3.3% vs 1.3%; p = 0.021), or from 1 to 19 mL/kg (1.4% vs. 1.2%; p = 0.691). Although no effect was observed on the incidence of postoperative renal failure or wound complications, RBC transfusions were associated with an increased incidence of postoperative infection when the volume transfused exceeded 20 mL/kg.

CONCLUSIONS

RBC transfusion is associated with an increased incidence of 30‐day mortality and postoperative infections in children undergoing noncardiac surgery, and there is a correlation between the volume of red blood cells transfused and the incidences of adverse outcomes. Potential associations related to the reason to transfuse, the cause of the bleeding, or the actual blood products themselves need to be studied in further prospective trials.
Canine acute leukaemia: 50 cases (1989–2014)
Authors: Bennett A. L. , Williams L. E. , Ferguson M. W. , Hauck M. L. , Suter S. E. , Lanier C. B. , Hess P. R.
Published: July 2016

Acute leukaemia (AL) is a bone marrow malignancy of hematopoietic progenitors that historically is poorly responsive to treatment. With the widespread adoption of dose‐intense chemotherapy, more human patients attain long‐term survivals, but whether comparable progress has been made in canineALis unknown. To investigate this question, medical records from three academic veterinary hospitals were reviewed. Fifty dogs met the criteria forAL, having excess circulating or marrow blasts, a major cytopenia(s), and no substantial lymphadenopathy. Thirty‐six dogs received cytotoxic chemotherapy; 23 achieved a complete or partial response for a median of 56 days (range, 9–218). With failure or relapse, 14 dogs were rescued. Median survival with treatment was poor at 55 days (range, 1–300). Untreated (n = 6) and palliatively‐treated (n = 8) dogs lived a median of 7.5 days. Most dogs developed chemoresistance within weeks of initiating treatment, and consequently, survival times forALremain disappointingly short.
Activation of autonomic thermoeffectors preceding the decision to behaviourally thermoregulate in resting humans
Authors: Schlader Zachary J. , Coleman Gregory L. , Sackett James R. , Sarker Suman , Chapman Christopher L. , Johnson Blair D.
Published: July 2016

New Findings

What is the central question of this study?

Do increases in metabolic heat production and sweat rate precede the initiation of thermoregulatory behaviour in resting humans exposed to cool and warm environments?

What is the main finding and its importance?

Thermoregulatory behaviour at rest in cool and warm environments is preceded by changes in vasomotor tone in glabrous and non‐glabrous skin, but not by acute increases in metabolic heat production or sweat rate. These findings suggest that sweating and shivering are not obligatory for thermal behaviour to be initiated in humans.

We tested the hypothesis that acute increases in metabolic heat production and sweating precede the initiation of thermoregulatory behaviour in resting humans exposed to cool and warm environments. Twelve healthy young subjects passively moved between 17 and 40°C rooms when they felt ‘too cool’ (C→W) or ‘too warm’ (W→C). Skin and internal (intestinal) temperatures, metabolic heat production, local sweat rate (forearm and chest) and cutaneous vascular conductance (CVC; forearm and fingertip) were measured continually. Compared with pretest baseline (31.8 ± 0.3°C), skin temperature was higher at C→W (32.0 ± 0.7°C; P = 0.01) and W→C (34.5 ± 0.5°C; P < 0.01). Internal temperature did not differ (P = 0.12) between baseline (37.2 ± 0.3°C), C→W (37.2 ± 0.3°C) and W→C (37.0 ± 0.3°C). Metabolic heat production was not different from baseline (40 ± 9 W m−2) at C→W (39 ± 7 W m−2; P = 0.50). Forearm (0.06 ± 0.01 mg cm−2 min−1) and chest (0.04 ± 0.02 mg cm−2 min−1) sweat rate at W→C did not differ from baseline (forearm, 0.05 ± 0.02 mg cm−2 min−1 and chest, 0.04 ± 0.02 mg cm−2 min−1; P ≥ 0.23). Forearm CVC was not different from baseline (0.30 ± 0.21 perfusion units (PU) mmHg−1) at C→W (0.24 ± 0.11 PU mmHg−1; P = 0.17), but was higher at W→C (0.65 ± 0.33 PU mmHg−1; P < 0.01). Fingertip CVC was different from baseline (2.6 ± 2.0 PU mmHg−1) at C→W (0.70 ± 0.42 PU mmHg−1; P < 0.01) and W→C (4.49 ± 1.66 PU mmHg−1; P < 0.01). Thermoregulatory behaviour at rest in cool and warm environments is preceded by changes in vasomotor tone in glabrous and non‐glabrous skin, but not by acute increases in metabolic heat production or sweat rate.
The effect of microphone wind noise on the amplitude modulation of wind turbine noise and its mitigation
Authors: Kendrick Paul , von Hünerbein Sabine , Cox Trevor J.
Published: July 2016

Microphone wind noise can corrupt outdoor recordings even when wind shields are used. When monitoring wind turbine noise, microphone wind noise is almost inevitable because measurements cannot be made in still conditions. The effect of microphone wind noise on two amplitude modulation (AM) metrics is quantified in a simulation, showing that even at low wind speeds of 2.5 m/s errors of over 4 dBA can result. As microphone wind noise is intermittent, a wind noise detection algorithm is used to automatically find uncorrupted sections of the recording, and so recover the true AM metrics to within ±2/±0.5 dBA.
Specific but not Global Cognitive Functions are Associated with Gait Initiation in Older Adults
Authors: Boripuntakul Sirinun , Sungkarat Somporn
Published: July 2016

The objective of this study was to examine the association between cognitive ability and gait initiation performance in older adults. Global and specific cognitive functions and spatiotemporal gait parameters during gait initiation were assessed in 60 older adults. Multivariate linear regression was conducted to determine the association between cognitive functions and gait initiation parameters. Results showed that global cognitive function was not associated with any of the spatiotemporal parameters. Poorer performance on measures of executive function and language ability were associated with shorter step length, narrower step width, and longer step time. In addition, poorer performance on test of visuospatial ability was associated with longer step time. In conclusion, specific but not global cognitive functions were associated with gait initiation performance. Clinical gait examination should incorporate gait initiation and cognitive assessments. Rehabilitation strategies aimed at improving cognition and gait initiation performance may be beneficial for preventing falls.
Increasing the Energy Expenditure of Seated Activities in Older Adults with a Portable Elliptical Device
Authors: Lerma Nicholas L. , Swartz Ann M. , Rowley Taylor W. , Maeda Hotaka , Strath Scott J.
Published: July 2016

Background:

The ill-health effects of sedentary behavior are becoming well-documented, yet older adults spend 70–80% of waking hours sedentary.

Purpose:

To determine if a portable elliptical device increases energy expenditure (EE) while performing popular seated activities.

Methods:

Twenty older adults (68.1 ± 1.4 years) participated to compare the measured EE between seated rest and three randomized seated pedaling activities: computer use, reading, TV viewing. Each pedaling activity included 5-min of self-selected paced/no resistance (SSP) and externally paced/added resistance pedaling (Paced).

Results:

A significant increase in EE existed during SSP (+1.44 ± 0.12 kcal/min) and Paced (+2.19 ± 0.09 kcal/min) pedaling relative to Seated Rest (p < .001). EE during the Paced activities was significantly greater than all SSP activities (p <.01).

Conclusion:

Extrapolating these results, pedaling at a SSP for an hour while performing seated activities is equivalent to the net EE of walking 1.6 miles. Future home-based effectiveness and feasibility should be explored.
Short- and Long-Term Effects of Concurrent Strength and HIIT Training in Octogenarians with COPD
Authors: Guadalupe-Grau Amelia , Aznar-Laín Susana , Mañas Asier , Castellanos Juan , Alcázar Julián , Ara Ignacio , Mata Esmeralda , Daimiel Rosa , García-García Francisco José
Published: July 2016

To investigate the short- and long-term effects of concurrent strength and high-intensity interval training (HIIT) on octogenarian COPD patients, nine males (age = 84.2 ± 2.8 years, BMI = 29.3 ± 2.3) with low to severe COPD levels (2.1 ± 1.5 BODE index) underwent a supervised 9-week strength and HIIT exercise program. Training had a significant (p < .05) impact on senior fitness test scores (23–45%), 30-m walking speed (from 1.29 ± 0.29–1.62 ± 0.33 m/s), leg and chest press 1RM (38% and 45% respectively), maximal isometric strength (30–35%), and 6-min walking test (from 286.1 ± 107.2–396.2 ± 106.5 m), and tended to increase predicted forced vital capacity by 14% (p = .07). One year after the intervention all training-induced gains returned to their preintervention values except for the chest press 1RM (p <.05). Short-term concurrent strength and HIIT training increases physical fitness in the oldest-old COPD patients, and has potential long-term benefits.
Fine-grained dengue forecasting using telephone triage services
Authors: Abdur Rehman Nabeel , Kalyanaraman Shankar , Ahmad Talal , Pervaiz Fahad , Saif Umar , Subramanian Lakshminarayanan
Published: July 2016

Calling patterns on a health hotline can accurately forecast dengue cases, 2 to 3 weeks ahead of time, at a subcity level.
Conservation of protein abundance patterns reveals the regulatory architecture of the EGFR-MAPK pathway
Authors: Shi Tujin , Niepel Mario , McDermott Jason E. , Gao Yuqian , Nicora Carrie D. , Chrisler William B. , Markillie Lye M. , Petyuk Vladislav A. , Smith Richard D. , Rodland Karin D. , Sorger Peter K. , Qian Wei-Jun , Wiley H. Steven
Published: July 2016

Abundance of most EGFR-MAPK pathway proteins is conserved across cell types, revealing adaptors as rate-limiting nodes.
Science Signaling
Podcast for 12 July 2016: Adaptor proteins limit signaling
Authors: Wiley H. Steven , VanHook Annalisa M.
Published: July 2016

Adaptor proteins, not core signaling components, control the flow of information downstream of the epidermal growth factor receptor.
Impact of Infectious Diseases Consultation on Clinical Outcomes of Patients with Staphylococcus aureus Bacteremia in a Community Health System
Authors: Turner R. Brigg , Valcarlos Elena , Won Regina , Chang Eric , Schwartz Jacqueline
Published: July 2016

Staphylococcus aureus
bacteremia (SAB) causes high rates of morbidity and death. Several studies in academic health settings have demonstrated that consultations from infectious diseases specialists improve the quality of care and clinical outcomes for SAB. Few data that describe the impact in resource-limited settings such as community hospitals are available. This retrospective cohort study evaluated the adherence to quality-of-care indicators and the clinical outcomes for SAB in a five-hospital community health system (range of 95 to 272 available beds per hospital), for patients with versus without infectious diseases consultation (IDC). IDC was provided if requested by the attending physician. The primary outcome was the incidence of treatment failure, defined as 30-day in-hospital death or 90-day SAB recurrence. Other outcomes included adherence to quality-of-care indicators. A total of 473 adult patients with SAB were included, with 369 (78%) receiving IDC. We identified substantial differences in baseline characteristics between the IDC group and the no-IDC group, including greater incidences of complicated bacteremia and intravenous drug users in the IDC group, with similar rates of severe illness (measured by Pitt bacteremia scores). Adherence to quality-of-care indicators was greater for patients with IDC (
P
< 0.001). After adjustment for other predicting variables, IDC was associated with a lower rate of treatment failure (adjusted odds ratio, 0.42 [95% confidence interval, 0.20 to 0.86];
P
= 0.018). IDC provided better quality of care and better clinical outcomes for patients with SAB who were treated at small, resource-limited, community hospitals.
Nonprescription Antimicrobial Use in a Primary Care Population in the United States
Authors: Zoorob Roger , Grigoryan Larissa , Nash Susan , Trautner Barbara W.
Published: July 2016

Community antimicrobial resistance rates are high in communities with frequent use of nonprescription antibiotics. Studies addressing nonprescription antibiotic use in the United States have been restricted to Latin American immigrants. We estimated the prevalence of nonprescription antibiotic use in the previous 12 months as well as intended use (intention to use antibiotics without a prescription) and storage of antibiotics and examined patient characteristics associated with nonprescription use in a random sample of adults. We selected private and public primary care clinics that serve ethnically and socioeconomically diverse patients. Within the clinics, we used race/ethnicity-stratified systematic random sampling to choose a random sample of primary care patients. We used a self-administered standardized questionnaire on antibiotic use. Multivariate regression analysis was used to identify independent predictors of nonprescription use. The response rate was 94%. Of 400 respondents, 20 (5%) reported nonprescription use of systemic antibiotics in the last 12 months, 102 (25.4%) reported intended use, and 57 (14.2%) stored antibiotics at home. These rates were similar across race/ethnicity groups. Sources of antibiotics used without prescriptions or stored for future use were stores or pharmacies in the United States, “leftover” antibiotics from previous prescriptions, antibiotics obtained abroad, or antibiotics obtained from a relative or friend. Respiratory symptoms were common reasons for the use of nonprescription antibiotics. In multivariate analyses, public clinic patients, those with less education, and younger patients were more likely to endorse intended use. The problem of nonprescription use is not confined to Latino communities. Community antimicrobial stewardship must include a focus on nonprescription antibiotics.
Critical Role of Alpha-Toxin and Protective Effects of Its Neutralization by a Human Antibody in Acute Bacterial Skin and Skin Structure Infections
Authors: Le Vien T. M. , Tkaczyk Christine , Chau Sally , Rao Renee L. , Dip Etyene Castro , Pereira-Franchi Eliane P. , Cheng Lily , Lee Sally , Koelkebeck Holly , Hilliard Jamese J. , Yu Xiang Qing , Datta Vivekananda , Nguyen Vien , Weiss William , Prokai Laszlo , O'Day Terrence , Stover C. Kendall , Sellman Bret R. , Diep Binh An
Published: July 2016

Methicillin-resistant
Staphylococcus aureus
(MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to
S. aureus
superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI and show that those infected with a mutant deficient in expression of alpha-toxin (Δ
hla
) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Δ
hla
strains developed ABSSSI that mimic the severe infections that occur in humans, including the large central dermonecrotic core surrounded by erythema, induration, and marked subcutaneous hemorrhage. More importantly, immunoprophylaxis with MEDI4893*, an anti-alpha-toxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the Δ
hla
mutant, indicating that this toxin could be completely neutralized during infection. Thus, this study illustrates a potential high standard for the development of new immunotherapeutic agents in which a toxin-neutralizing antibody provides protection to the same degree achieved with a toxin gene knockout. When MEDI4893* was administered as adjunctive therapy with a subtherapeutic dose of linezolid, the combination was significantly more efficacious than either agent alone in reducing the severity of ABSSSI.
Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity
Authors: Nankabirwa Joaniter I. , Conrad Melissa D. , Legac Jennifer , Tukwasibwe Stephen , Tumwebaze Patrick , Wandera Bonnie , Brooker Simon J. , Staedke Sarah G. , Kamya Moses R. , Nsobya Sam L. , Dorsey Grant , Rosenthal Philip J.
Published: July 2016

Dihydroartemisinin-piperaquine (DP) offers prolonged protection against malaria, but its impact on
Plasmodium falciparum
drug sensitivity is uncertain. In a trial of intermittent preventive treatment in schoolchildren in Tororo, Uganda, in 2011 to 2012, monthly DP for 1 year decreased the incidence of malaria by 96% compared to placebo; DP once per school term offered protection primarily during the first month after therapy. To assess the impact of DP on selection of drug resistance, we compared the prevalence of key polymorphisms in isolates that emerged at different intervals after treatment with DP. Blood obtained monthly and at each episode of fever was assessed for
P. falciparum
parasitemia by microscopy. Samples from 160 symptomatic and 650 asymptomatic episodes of parasitemia were assessed at 4 loci (N86Y, Y184F, and D1246Y in
pfmdr1
and K76T in
pfcrt
) that modulate sensitivity to aminoquinoline antimalarials, utilizing a ligase detection reaction-fluorescent microsphere assay. For
pfmdr1
N86Y and
pfcrt
K76T, but not the other studied polymorphisms, the prevalences of mutant genotypes were significantly greater in children who had received DP within the past 30 days than in those not treated within 60 days (86Y, 18.0% versus 8.3% [
P
= 0.03]; 76T, 96.0% versus 86.1% [
P
= 0.05]), suggesting selective pressure of DP. Full sequencing of
pfcrt
in a subset of samples did not identify additional polymorphisms selected by DP. In summary, parasites that emerged soon after treatment with DP were more likely than parasites not under drug pressure to harbor
pfmdr1
and
pfcrt
polymorphisms associated with decreased sensitivity to aminoquinoline antimalarials. (This study has been registered at ClinicalTrials.gov under no. NCT01231880.)
Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams
Authors: Momper Jeremiah D. , Capparelli Edmund V. , Wade Kelly C. , Kantak Anand , Dhanireddy Ramasubbareddy , Cummings James J. , Nedrelow Jonathan H. , Hudak Mark L. , Mundakel Gratias T. , Natarajan Girija , Gao Jamie , Laughon Matt , Smith P. Brian , Benjamin Daniel K.
Published: July 2016

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.
Evaluation of Antibiotics Active against Methicillin-Resistant Staphylococcus aureus Based on Activity in an Established Biofilm
Authors: Meeker Daniel G. , Beenken Karen E. , Mills Weston B. , Loughran Allister J. , Spencer Horace J. , Lynn William B. , Smeltzer Mark S.
Published: July 2016

We used
in vitro
and
in vivo
models of catheter-associated biofilm formation to compare the relative activity of antibiotics effective against methicillin-resistant
Staphylococcus aureus
(MRSA) in the specific context of an established biofilm. The results demonstrated that, under
in vitro
conditions, daptomycin and ceftaroline exhibited comparable activity relative to each other and greater activity than vancomycin, telavancin, oritavancin, dalbavancin, or tigecycline. This was true when assessed using established biofilms formed by the USA300 methicillin-resistant strain LAC and the USA200 methicillin-sensitive strain UAMS-1. Oxacillin exhibited greater activity against UAMS-1 than LAC, as would be expected, since LAC is an MRSA strain. However, the activity of oxacillin was less than that of daptomycin and ceftaroline even against UAMS-1. Among the lipoglycopeptides, telavancin exhibited the greatest overall activity. Specifically, telavancin exhibited greater activity than oritavancin or dalbavancin when tested against biofilms formed by LAC and was the only lipoglycopeptide capable of reducing the number of viable bacteria below the limit of detection. With biofilms formed by UAMS-1, telavancin and dalbavancin exhibited comparable activity relative to each other and greater activity than oritavancin. Importantly, ceftaroline was the only antibiotic that exhibited greater activity than vancomycin when tested
in vivo
in a murine model of catheter-associated biofilm formation. These results emphasize the need to consider antibiotics other than vancomycin, most notably, ceftaroline, for the treatment of biofilm-associated
S. aureus
infections, including by the matrix-based antibiotic delivery methods often employed for local antibiotic delivery in the treatment of these infections.
Inhibition and Dispersal of Pseudomonas aeruginosa Biofilms by Combination Treatment with Escapin Intermediate Products and Hydrogen Peroxide
Authors: Santiago Ariel J. , Ahmed Marwa N. A. , Wang Shu-Lin , Damera Krishna , Wang Binghe , Tai Phang C. , Gilbert Eric S. , Derby Charles D.
Published: July 2016

Escapin is an
l
-amino acid oxidase that acts on lysine to produce hydrogen peroxide (H
2
O
2
), ammonia, and equilibrium mixtures of several organic acids collectively called escapin intermediate products (EIP). Previous work showed that the combination of synthetic EIP and H
2
O
2
functions synergistically as an antimicrobial toward diverse planktonic bacteria. We initiated the present study to investigate how the combination of EIP and H
2
O
2
affected bacterial biofilms, using
Pseudomonas aeruginosa
as a model. Specifically, we examined concentrations of EIP and H
2
O
2
that inhibited biofilm formation or fostered disruption of established biofilms. High-throughput assays of biofilm formation using microtiter plates and crystal violet staining showed a significant effect from pairing EIP and H
2
O
2
, resulting in inhibition of biofilm formation relative to biofilm formation in untreated controls or with EIP or H
2
O
2
alone. Similarly, flow cell analysis and confocal laser scanning microscopy revealed that the EIP and H
2
O
2
combination reduced the biomass of established biofilms relative to that of the controls. Area layer analysis of biofilms posttreatment indicated that disruption of biomass occurs down to the substratum. Only nanomolar to micromolar concentrations of EIP and H
2
O
2
were required to impact biofilm formation or disruption, and these concentrations are significantly lower than those causing bactericidal effects on planktonic bacteria. Micromolar concentrations of EIP and H
2
O
2
combined enhanced
P. aeruginosa
swimming motility compared to the effect of either EIP or H
2
O
2
alone. Collectively, our results suggest that the combination of EIP and H
2
O
2
may affect biofilms by interfering with bacterial attachment and destabilizing the biofilm matrix.
High Level of Spinosad Production in the Heterologous Host Saccharopolyspora erythraea
Authors: Huang Jun , Yu Zhen , Li Mei-Hong , Wang Ji-Dong , Bai Hua , Zhou Jun , Zheng Yu-Guo
Published: July 2016

Spinosad, a highly effective insecticide, has an excellent environmental and mammalian toxicological profile. Global market demand for spinosad is huge and growing. However, after much effort, there has been almost no improvement in the spinosad yield from the original producer,
Saccharopolyspora spinosa
. Here, we report the heterologous expression of spinosad using
Saccharopolyspora erythraea
as a host. The native erythromycin polyketide synthase (PKS) genes in
S. erythraea
were replaced by the assembled spinosad gene cluster through iterative recombination. The production of spinosad could be detected in the recombinant strains containing the whole biosynthesis gene cluster. Both metabolic engineering and UV mutagenesis were applied to further improve the yield of spinosad. The final strain, AT-ES04PS-3007, which could produce spinosad with a titer of 830 mg/liter, has significant potential in industrial applications.

IMPORTANCE
This work provides an innovative and promising way to improve the industrial production of spinosad. At the same time, it also describes a successful method of heterologous expression for target metabolites of interest by replacing large gene clusters.
Structural Basis for Recombinatorial Permissiveness in the Generation of Anaplasma marginale Msp2 Antigenic Variants
Authors: Graça Telmo , Silva Marta G. , Kostyukova Alla S. , Palmer Guy H.
Published: July 2016

Sequential expression of outer membrane protein antigenic variants is an evolutionarily convergent mechanism used by bacterial pathogens to escape host immune clearance and establish persistent infection. Variants must be sufficiently structurally distinct to escape existing immune effectors yet retain the core structural elements required for localization and function within the outer membrane. We examined this balance usingAnaplasma marginale, which generates antigenic variants in the outer membrane protein Msp2 using gene conversion. The overwhelming majority of Msp2 variants expressed during long-term persistent infection are mosaics, derived by recombination of oligonucleotide segments from multiple alleles to form unique hypervariable regions (HVR). As a result, the mosaics are not under long-term selective pressure to encode a functional protein; consequently, we hypothesized that the Msp2 HVR is structurally permissive for mosaic expression. Using an integrated approach of predictive modeling with determination of the native Msp2 protein structure and function, we demonstrate that structured elements, most notably, β-sheets, are significantly concentrated in the highly conserved N- and C-terminal domains. In contrast, the HVR is overwhelmingly a random coil, with the structured α-helices and β-sheets being confined to the genomically defined structural tethers that separate the antigenically variable microdomains. This structure is supported by the surface exposure of the HVR microdomains and the slow diffusion-type porin function in native Msp2. Importantly, the predominance of the random coil provides plasticity for the formation of functional HVR mosaics and realization of the full potential of segmental gene conversion to dramatically expand the variant repertoire.
Spermidine Inversely Influences Surface Interactions and Planktonic Growth in Agrobacterium tumefaciens
Authors: Wang Yi , Kim Sok Ho , Natarajan Ramya , Heindl Jason E. , Bruger Eric L. , Waters Christopher M. , Michael Anthony J. , Fuqua Clay
Published: July 2016

In bacteria, the functions of polyamines, small linear polycations, are poorly defined, but these metabolites can influence biofilm formation in several systems. Transposon insertions in an ornithine decarboxylase (
odc
) gene in
Agrobacterium tumefaciens
, predicted to direct synthesis of the polyamine putrescine from ornithine, resulted in elevated cellulose. Null mutants for
odc
grew somewhat slowly in a polyamine-free medium but exhibited increased biofilm formation that was dependent on cellulose production. Spermidine is an essential metabolite in
A. tumefaciens
and is synthesized from putrescine in
A. tumefaciens
via the stepwise actions of carboxyspermidine dehydrogenase (CASDH) and carboxyspermidine decarboxylase (CASDC). Exogenous addition of either putrescine or spermidine to the
odc
mutant returned biofilm formation to wild-type levels. Low levels of exogenous spermidine restored growth to CASDH and CASDC mutants, facilitating weak biofilm formation, but this was dampened with increasing concentrations. Norspermidine rescued growth for the
odc
, CASDH, and CASDC mutants but did not significantly affect their biofilm phenotypes, whereas in the wild type, it stimulated biofilm formation and depressed spermidine levels. The
odc
mutant produced elevated levels of cyclic diguanylate monophosphate (c-di-GMP), exogenous polyamines modulated these levels, and expression of a c-di-GMP phosphodiesterase reversed the enhanced biofilm formation. Prior work revealed accumulation of the precursors putrescine and carboxyspermidine in the CASDH and CASDC mutants, respectively, but unexpectedly, both mutants accumulated homospermidine; here, we show that this requires a homospermidine synthase (
hss
) homologue.

IMPORTANCE
Polyamines are small, positively charged metabolites that are nearly ubiquitous in cellular life. They are often essential in eukaryotes and more variably in bacteria. Polyamines have been reported to influence the surface-attached biofilm formation of several bacteria. In
Agrobacterium tumefaciens
, mutants with diminished levels of the polyamine spermidine are stimulated for biofilm formation, and exogenous provision of spermidine decreases biofilm formation. Spermidine is also essential for
A. tumefaciens
growth, but the related polyamine norspermidine exogenously rescues growth and does not diminish biofilm formation, revealing that the growth requirement and biofilm control are separable. Polyamine control of biofilm formation appears to function via effects on the cellular second messenger cyclic diguanylate monophosphate, regulating the transition from a free-living to a surface-attached lifestyle.
Origin and time evolution of subduction polarity reversal from plate kinematics of Southeast Asia
Authors: von Hagke Christoph , Philippon Mélody , Avouac Jean-Philippe , Gurnis Michael
Published: July 2016

We present a regional model of plate geometry and kinematics of Southeast Asia since the Late Cretaceous, embedded in a global plate model. The model involves subduction polarity reversals and sheds new light on the origin of the subduction polarity reversal currently observed in Taiwan. We show that this subduction zone reversal is inherited from subduction of the proto–South China Sea plate and owes its current location to triple junction migration and slab rollback. This analysis sheds new light on the plate tectonic context of the Taiwan orogeny and questions the hypothesis that northern Taiwan can be considered an older, more mature equivalent of southern Taiwan.
The minimum scale of grooving on faults
Authors: Candela Thibault , Brodsky Emily E.
Published: July 2016

At the field scale, nearly all fault surfaces contain grooves generated as one side of the fault slips past the other. Grooves are so common that they are one of the key indicators of principal slip surfaces. Here, we show that at sufficiently small scales, grooves do not exist on fault surfaces. A transition to isotropic roughness occurs at 4–500 μm. Although the scale of the transition can vary even between locales on a single fault, the aspect ratio of the roughness at the transition is well defined for a given fault. We interpret the transition between grooved and ungrooved scales as a transition in deformation mode of asperities on the slip surface. Grooves can form when a hard indenter slides past a softer surface. At small scales, the asperities appear to yield plastically and therefore do not generate grooves as hard indenters. The plastic yielding can be a consequence of the high shear strains required to deform the surfaces at small scales where the aspect ratio (roughness) is high. The transition to plastic yielding is predicted to occur at a specific aspect ratio for each fault, as observed. The new observation both shows a limit to one of the most commonly observed features of faults and suggests a change in the mode of failure of faults as a function of scale.
Structural segmentation controlled the 2015 Mw 7.8 Gorkha earthquake rupture in Nepal
Authors: Hubbard Judith , Almeida Rafael , Foster Anna , Sapkota Soma Nath , Bürgi Paula , Tapponnier Paul
Published: July 2016

The ongoing collision of India with Asia is partly accommodated by slip on the Main Himalayan Thrust (MHT). The 25 April 2015, Mw 7.8 Gorkha earthquake is the most recent major event to rupture the MHT, which dips gently northward beneath central Nepal. Although the geology of the range has been studied for decades, fundamental aspects of its deep structure remain disputed. Here, we develop a structural cross section and a three-dimensional, geologically informed model of the MHT that are consistent with seismic observations from the Gorkha earthquake. A comparison of our model to a detailed slip inversion data set shows that the slip patch closely matches an oval-shaped, gently dipping fault surface bounded on all sides by steeper ramps. The Gorkha earthquake rupture seems to have been limited by the geometry of that fault segment. This is a significant step forward in understanding the deep geometry of the MHT and its effect on earthquake nucleation and propagation. Published models of fault locking do not correlate with the slip patch or our fault model in the vicinity of the earthquake, further suggesting that fault geometry was the primary control on this event. Our result emphasizes the importance of adequately constraining subsurface fault geometry in megathrusts in order to better assess the sizes and locations of future earthquakes.
Temporal and genetic link between incremental pluton assembly and pulsed porphyry Cu-Mo formation in accretionary orogens
Authors: Rezeau Hervé , Moritz Robert , Wotzlaw Jörn-Frederik , Tayan Rodrik , Melkonyan Rafael , Ulianov Alexey , Selby David , d’Abzac François-Xavier , Stern Richard A.
Published: July 2016

Economically important porphyry Cu-Mo deposits (PCDs) are generally hosted by upper-crustal plutons of variable chemical compositions related to distinct geodynamic settings. The absolute timing and duration of pluton assembly and PCD formation are critical to understanding the genetic relationship between these interrelated processes. Here, we present new comprehensive zircon U-Pb and molybdenite Re-Os ages that tightly constrain the timing and duration of pluton assembly and the age of mineralization in one of the largest ore-bearing plutons of the central Tethyan metallogenic belt, the Meghri-Ordubad pluton, southern Armenia and Nakhitchevan, Lesser Caucasus. This composite pluton was incrementally assembled during three compositionally distinct magmatic episodes over ∼30 m.y., comprising Middle Eocene (48.9–43.1 Ma) calc-alkaline subduction-related magmatism lasting 5.8 ± 0.8 m.y., followed by postsubduction Late Eocene–Middle Oligocene (37.8–28.1 Ma) shoshonitic magmatism over 9.7 ± 0.9 m.y., and Late Oligocene–Early Miocene (26.6–21.2 Ma) adakitic magmatism consisting of shoshonitic dikes and high-K calc-alkaline granodioritic magmas emplaced over 5.4 ± 0.4 m.y. Despite the distinct geodynamic settings and magma compositions, each intrusive suite culminated in the formation of variably sized PCDs, including the giant Oligocene Kadjaran porphyry Cu-Mo deposit associated with high-Sr/Y shoshonitic magmas. Complementary in situ zircon hafnium (εHfzircon = +8 to +11.3) and oxygen (δ18Ozircon = +4.6‰ to +6.0‰) isotope data support a mantle-dominated magma source with limited crustal contribution and/or cannibalization of young and juvenile lower-crustal cumulates. We conclude that, independent of geodynamic setting and magma composition, long-lived (5–10 m.y.) incremental mantle-derived magmatism is a prerequisite to form fertile magmatic-hydrothermal systems, and especially giant PCDs.
Impact of obesity on hospital complications and mortality in hospitalized patients with hyperglycemia and diabetes
Authors: Alexopoulos Anastasia-Stefania , Fayfman Maya , Zhao Liping , Weaver Jeff , Buehler Lauren , Smiley Dawn , Pasquel Francisco J , Vellanki Priyathama , Haw J Sonya , Umpierrez Guillermo E
Published: July 2016

Objective

Obesity is associated with increased risk of diabetes, hypertension and cardiovascular mortality. Several studies have reported increased length of hospital stay and complications; however, there are also reports of obesity having a protective effect on health, a phenomenon coined the ‘obesity paradox’. We aimed to investigate the impact of overweight and obesity on complications and mortality in hospitalized patients with hyperglycemia and diabetes.

Research design and methods

This retrospective analysis was conducted on 29 623 patients admitted to two academic hospitals in Atlanta, Georgia, between January 2012 and December 2013. Patients were subdivided by body mass index into underweight (body mass index <18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2) and obese (>30 kg/m2). Hyperglycemia was defined as a blood glucose >10 mmol/L during hospitalization. Hospital complications included a composite of pneumonia, acute myocardial infarction, respiratory failure, acute kidney injury, bacteremia and death.

Results

A total of 4.2% were underweight, 29.6% had normal weight, 30.2% were overweight, and 36% were obese. 27.2% of patients had diabetes and 72.8% did not have diabetes (of which 75% had hyperglycemia and 25% had normoglycemia during hospitalization). A J-shaped curve with higher rates of complications was observed in underweight patients in all glycemic groups; however, there was no significant difference in the rate of complications among normal weight, overweight, or obese patients, with and without diabetes or hyperglycemia.

Conclusions

Underweight is an independent predictor for hospital complications. In contrast, increasing body mass index was not associated with higher morbidity or mortality, regardless of glycemic status. There was no evidence of an obesity paradox among inpatients with diabetes and hyperglycemia.
Breast feeding and the weekend effect: an observational study
Authors: Fitzsimons Emla , Vera-Hernández Marcos
Published: July 2016

Objective

To compare the incidence of breast feeding by day of week of birth.

Design

Retrospective database study using 16 508 records from the 2005 and 2010 Infant Feeding Surveys.

Setting

England and Wales, UK.

Participants

Mothers of a sample of births from among all registered births in the periods August–September 2005 and August–October 2010.

Main outcome measure

Incidence of breast feeding after birth.

Results

Among babies of mothers who left full-time education aged 16 or under, the incidence of breast feeding was 6.7 percentage points lower (95% CI 1.4 to 12.1 percentage points) for those born on Saturdays than for those born on Mondays–Thursdays. No such differences by day of week of birth were observed among babies of mothers who left school aged 17 or over.

Conclusions

Breastfeeding policy should take into account differences in breast feeding by day of week of birth, which are apparent among low-educated mothers. Further research is needed to ascertain the reason for this finding.