bluuebunny/crossref_metadata_2025 huggingface dataset:
Why high yield QTLs did not succeed in preventing yield stagnation in rice?
Authors: Xiong Dongliang
Published: May 2019

Rice plays a vital role in global food security, and its yield needs to be increased to meet escalating demand. Although many high yield quantitative trait loci (QTLs) have been identified in the last decades, rice grain yield in the main rice-producing countries is stagnating since the middle of the 1990s. By summarizing the yield performance of high-yielding QTL lines, we found that almost all the high-yielding QTL introduced lines had no practical usage in current high yield breeding programs, due mainly to their low absolute grain yield. Further analysis showed that scientists primarily focused on spikelets number per panicle alone rather than other yield traits, and, in most of the studies, the yield increase was referenced to very old cultivars. By analyzing the yield traits correlations across cultivars in both field and pot conditions, and yield traits correlations across different eco-sites using the same cultivars, we demonstrated that the rice high yield will be rarely achieved by using single-trait approaches due to the traits trade-offs. Building on this, several recommendations are provided to the next generation of biotechnological breeding in rice.
Identification of NAD-dependent xylitol dehydrogenase fromGluconobacter oxydansWSH-003
Authors: Liu Li , Zeng Weizhu , Du Guocheng , Chen Jian , Zhou Jingwen
Published: May 2019

Gluconobacter oxydansplays important role in conversion of D-sorbitol to L-sorbose, which is an essential intermediate for industrial-scale production of vitamin C. In the fermentation process, some D-sorbitol could be converted to D-fructose and other byproducts by uncertain dehydrogenases. Genome sequencing has revealed the presence of diverse genes encoding dehydrogenases inG. oxydans. However, the characteristics of most of these dehydrogenases remain unclear. Therefore, analyses of these unknown dehydrogenases could be useful for identifying those related to the production of D-fructose and other byproducts. Accordingly, dehydrogenases inG. oxydansWSH-003, an industrial strain used for vitamin C production, were examined. An NAD-dependent dehydrogenase, which was annotated as xylitol dehydrogenase 2, was identified, codon-optimized, and expressed inEscherichia coliBL21 (DE3) cells. The enzyme exhibited high preference for NAD+as the cofactor, while no activity with NADP+, FAD, or PQQ was noted. Although this enzyme presented high similarity with NAD-dependent xylitol dehydrogenase, it showed high activity to catalyze D-sorbitol to D-fructose. Unlike the optimum temperature and pH for most of the known NAD-dependent xylitol dehydrogenases (30°C–40°C and about 6–8, respectively), those for the identified enzyme were 57°C and 12, respectively. TheKmandVmaxof the identified dehydrogenase towards L-sorbitol were 4.92 μM and 196.08 μM/min, respectively. Thus, xylitol dehydrogenase 2 can be useful for cofactor NADH regeneration under alkaline conditions or its knockout can improve the conversion ratio of D-sorbitol to L-sorbose.

Importance

Production of L-sorbose from D-sorbitol byGluconobacter oxydansis the first step for industrial scale production of L-ascorbic acid.G. oxydanscontains a lot of different dehydrogenases, among which only several are responsible for the conversion of D-sorbitol to L-sorbose, while others may responsible for the accumulation of byproducts, thus decreased the yield of L-sorbose on D-sorbitol. Therefore, a new xylitol dehydrogenase has been identified from 44 dehydrogenases ofG.oxydans. Optimum temperature and pH of the xylitol dehydrogenase are different to most of the known ones. Knock-out of the dehydrogenase may improve the conversion ratio of D-sorbitol to L-sorbose. Besides, the enzyme exhibits high preference for NAD+and have potential to be used for cofactor regeneration.
Acute phase protein, α – 1- acid glycoprotein (AGP-1), has differential effects on TLR-2 and TLR-4 mediated responses
Authors: Sumanth Mosale Seetharam , Abhilasha Kandahalli Venkataranganayaka , Jacob Shancy Petsel , Chaithra Vyala Hanumanthareddy , Basrur Venkatesha , Willard Belinda , McIntyre Thomas M. , Prabhu K. Sandeep , Marathe Gopal K.
Published: May 2019

Alpha-1-acid glycoprotein (AGP-1) is a major positive acute phase glycoprotein with unknown functions that likely plays a role in inflammation. We tested its involvement in a variety of inflammatory responses using human AGP-1 purified to apparent homogeneity and confirmed its identity by immunoblotting and mass spectrometry. AGP-1 alone upregulated MAPK signaling in murine peritoneal macrophages. However, when given in combination with TLR ligands, AGP-1 selectively augmented MAPK activation induced by ligands of TLR-2 (Braun lipoprotein) but not TLR-4 (lipopolysaccharide).In vivotreatment of AGP-1 in a murine model of sepsis with or without TLR-2 or TLR-4 ligands, selectively potentiated TLR-2-mediated mortality, but was without significant effect on TLR-4-mediated mortality. Furthermore,in vitro, AGP-1 selectively potentiated TLR-2 mediated adhesion of human primary immune cell, neutrophils. Hence, our studies highlight a new role for the acute phase protein AGP-1 in sepsis via its interaction with TLR-2 signaling mechanisms to selectively promote responsiveness to one of the two major gram-negative endotoxins, contributing to the complicated pathobiology of sepsis.
Peptides derived of kunitz-type serine protease inhibitor as potential vaccine against experimental schistosomiasis
Authors: Hernández-Goenaga Juan , López-Abán Julio , Protasio Anna V. , Vicente Santiago Belén , del Olmo Esther , Vanegas Magnolia , Fernández-Soto Pedro , Alfonso Patarroyo Manuel , Muro Antonio
Published: May 2019

Schistosomiasis is a significant public health problem in sub-Saharan Africa, China, South-East Asia and regions of South and central America affecting about 189 million people. Kunitz-type serine protease inhibitors have been identified as important players in the interaction of other flatworm parasites with their mammalian hosts. Here, we evaluate the protective efficacy of chemically synthesized of T- and B-cell peptide epitopes derived from a kunitz protein fromSchistosoma mansoni. Putative kunitz-type protease inhibitor proteins were identified in theS. mansonigenome and their expression analyzed by RNA-seq. Gene expression analyses showed that the kunitz protein Smp_147730 (Syn. Smp_311670) was dramatically and significantly up-regulated in schistosomula and adult worms when compared to the invading cercariae. T- and B-cell epitopes were predicted using bioinformatics tools, chemically synthesized and formulated in the Adjuvant Adaptation (ADAD) vaccination system. BALB/c mice were vaccinated and challenged withS. mansonicercariae. Kunitz peptides were highly protective in vaccinated BALB/c mice showing significant reductions in recovery of adult females (89-91%), and in the numbers of eggs trapped in the livers (77-81%) and guts (57-77%) of mice. Moreover, liver lesions were significantly reduced in vaccinated mice (64-65%) compared to infected control mice. The vaccination regime was well tolerated with both peptides. We propose the use of these peptides, alone or in combination, as reliable candidates for vaccination against schistosomiasis.
Comparison of Vitek® 2, three different gradient strip tests and broth microdilution for detecting vanB-positive Enterococcus faecium isolates with low vancomycin MICs
Authors: Klare Ingo , Bender Jennifer K. , Fleige Carola , Kriebel Nancy , Hamprecht Axel , Gatermann Sören , Werner Guido
Published: May 2019

Objectives

In 2018, EUCAST issued a warning regarding unreliable results of gradient strip tests for confirming vancomycin resistance in enterococci. We compared the performance of various diagnostic standard and confirmatory tests to identify and determine vanB-type vancomycin resistance.

Methods

We analysed a collection of vanB-positive E. faecium isolates (n = 68) with low level vancomycin minimal inhibitory concentrations (MICs) and compared the performance of Vitek® 2 (bioMérieux), of broth microdilution and of three different gradient strip test providers (Oxoid, Liofilchem, bioMérieux). For the latter we compared the standard procedure vs. a protocol with increased inoculum, a rich agar medium and a longer incubation time (“macromethod”).

Results

The sensitivity of Vitek® 2 was 81% of vanB-isolates compared to 72% for broth microdilution and 61 – 63% for the three gradient strip tests using standard conditions. The “macromethod” substantially improved performance of all strip tests resulting in a sensitivity of 89 – 96% at 48h readout.

Conclusions

The “macromethod” provided the overall best performance for recognition of vanB E. faecium. We therefore propose to adapt the EUCAST warning and to recommend the “macromethod” with an additional 48h readout or a confirmation by a vanB-specific PCR from culture.
Mesenchymal expression of activated K-ras yields Noonan Syndrome-like bone defects that are rescued by mid-gestational MEK inhibition
Authors: Nedelcu Simona , Kobayashi Tatsuya , Stanciu Monica , Kronenberg Henry M. , Lees Jacqueline A.
Published: May 2019

Activating germline K-ras mutations cause Noonan syndrome (NS), which is characterized by several developmental deficits including cardiac defects, cognitive delays and skeletal abnormalities. NS patients have increased signaling through the MAPK pathway. To model NS skeletal defects and understand the effect of hyperactive K-ras signaling on normal limb development, we generated a mouse model in which activated K-rasG12D was expressed specifically in mesenchymal progenitors of the limb bud. These mice display short, abnormally mineralized long bones that phenocopy those of NS patients. This defect was first apparent at E14.5, and was characterized by a delay in bone collar formation. Coincident mutation of p53 had no effect on the K-rasG12D induced bone defect, arguing that it is does not result from senescence or apoptosis. Instead, our data revealed profound defects in the development of the committed osteoblasts; their appearance is delayed, concordant with the delay in bone collar formation, and they display an aberrant localization outside of the bone shaft. Additionally, we see growth plate defects including a reduction in the hypertrophic chondrocyte layer. Most importantly, we found that in utero delivery of a MEK inhibitor between E10.5 and E14.5 is sufficient to completely suppress the ability of activated K-ras to induce NS-like long bone defects in embryogenesis. These data define a critical point in mid-gestation in which elevated MAPK signaling impairs growth plate and bone collar formation and yield NS-like limb defects. Moreover, they offer insight into possible therapeutic strategies for skeletal defects in patients with Noonan Syndrome.

SIGNIFICANCE STATEMENT

Noonan syndrome is a genetic condition that is characterized by various developmental defects including skeletal abnormalities that lead to short stature. These patients carry mutations that activate Ras/MAPK signaling. We have generated a mouse model that recapitulates these Noonan Syndrome-like bone defects. Analysis of these animals establishes the developmental window in which bone formation goes awry, and reveals disruption of an early event that is critical for the longitudinal growth of bones. Additionally, we show that treatment with an inhibitor of Ras/MAPK signaling during this key developmental window is sufficient to completely suppress these Noonan Syndrome-like bone defects. This offers possible therapeutic strategies for skeletal defects in patients with Noonan Syndrome.
Cullin-5 adaptor SPSB1 controls NF-κB activation downstream of multiple signalling pathways
Authors: Georgana Iliana , de Motes Carlos Maluquer
Published: May 2019

Cullin-RING E3 ubiquitin ligases (CRLs) have emerged as critical regulators of many cellular functions including innate immunity and inflammation. CRLs form multiprotein complexes in which specific adaptor proteins recruit the substrates to be ubiquitylated. Here, we systematically depleted all predicted SOCS-box proteins – the substrate adaptors for the CRL5 family - and assessed the impact on the activation of the NF-κB pathway. Depletion of SPSB1 resulted in a significant increase in NF-κB activation, indicating the importance of SPSB1 as an NF-κB negative regulator. In agreement, overexpression of SPSB1 suppressed NF-κB activity in a potent, dose-dependent manner in response to various agonists. Conversely, the activation of IRF-3, AP-1 and STATs was unaffected by SPSB1, showing its specificity for NF-κB. Mechanistically, SPSB1 suppressed NF-κB activation induced via multiple pathways including Toll-like receptors and RNA and DNA sensing adaptors, but was unable to prevent the phosphorylation and degradation of IκB nor the translocation of p65 into the nucleus. This indicated that SPSB1 exerts its inhibitory activity downstream, or at the level, of the NF-κB heterodimer and in agreement, SPSB1 was found to co-precipitate with p65. Additionally, A549 cells stably expressing SPSB1 presented lower cytokine levels including type I interferon in response to cytokine stimulation and virus infection. Taken together, our results reveal novel regulatory mechanisms in inflammation and innate immune signalling and identify the prominent role of SPSB1 in controlling NF-κB activation, thus providing new opportunities for the therapeutic targeting of NF-κB transcriptional activity.
Quantifying E2F1 protein dynamics in single cells
Authors: Mathey-Prevot Bernard , Parker Bao-Tran , Im Carolyn , Hong Cierra , Dong Peng , Yao Guang , You Lingchong
Published: May 2019

The Rb/E2F pathway plays a central role in regulating cell-fate decisions and cell-cycle progression. The E2F1 protein, a major effector of the pathway, is regulated via a combination of transcriptional, translational and posttranslational constraints. Elucidating the regulation and impact of the Rb/E2F pathway requires direct measurement of E2F1 dynamics in single cells. To this end, we have engineered fluorescent E2F1 protein reporters to enable live detection and quantification in single cells. The reporter constructs expressed an E2F1-Venus fusion protein under the regulation of the mouse or human E2F1 promoter and contained or excluded the 3’UTR of the E2F1 gene, a sequence that contains miRNA regulatory regions that modulate expression of the protein. Expression of the reporter protein was highly dynamic during the cell cycle: there was no or little fluorescent signal in G0, but levels steadily increased during late G1 and peaked during mid to late S phase before returning to baseline before the onset of mitosis. The absence of the E2F1 3’UTR in the constructs led to considerably higher steady-state levels of the fusion protein, which although normally regulated, exhibited a slightly less complex dynamic profile during the cell cycle or genotoxic stress. Lastly, the presence or absence of Rb failed to impact in substantial ways the overall detection and levels of the reporters.
Symmetric arrangement of mitochondria:plasma membrane contacts between adjacent photoreceptor cells regulated by Opa1
Authors: Meschede Ingrid P. , Seabra Miguel C. , Futter Clare E. , Votruba Marcela , Cheetham Michael E. , Burgoyne Thomas
Published: May 2019

Mitochondria are known to play an essential role in photoreceptor function and wellbeing that enables normal healthy vision. Within photoreceptors they are elongated and extend most of the length inner segment, where they supply energy for protein synthesis and the phototransduction machinery in the outer segment as well as acting as a calcium store. Here we examined the arrangement of the mitochondria within the inner segment in detail using 3D electron microscopy techniques and show they are tethered to the plasma membrane in a highly specialised arrangement. This includes mitochondria running alongside each other in neighbouring inner segments, with evidence of alignment of the cristae openings. As the pathway by which photoreceptors meet their high energy demands is not fully understood, we propose this to be a mechanism to share metabolites and assist in maintaining homeostasis across the photoreceptor cell layer. In the extracellular space between photoreceptors, Müller glial processes were identified. Due to the often close proximity to the inner segment mitochondria, they may too play a role in the inner segment mitochondrial arrangement as well as metabolite shuttling. OPA1 is an important factor in mitochondrial homeostasis, including cristae remodelling; therefore, we examined the photoreceptors of a heterozygousOpa1knock-out mouse model. The cristae structure in theOpa1+/−photoreceptors was not greatly affected, but there were morphological abnormalities and a reduction in mitochondria in contact with the inner segment plasma membrane. This indicates the importance of key regulators in maintaining this specialised photoreceptor mitochondrial arrangement.
The conformational and mutational landscape of the ubiquitin-like marker for the autophagosome formation in cancer
Authors: Fas Burcu Aykac , Kumar Mukesh , Sora Valentina , Mashkoor Maliha , Lambrughi Matteo , Tiberti Matteo , Papaleo Elena
Published: May 2019

Autophagy is a cellular process to recycle damaged cellular components and its modulation can be exploited for disease treatments. A key autophagy player is a ubiquitin-like protein, LC3B. Compelling evidence attests the role of autophagy and LC3B in different cancer types. Many LC3B structures have been solved, but a comprehensive study, including dynamics, has not been yet undertaken. To address this knowledge gap, we assessed ten physical models for molecular dynamics for their capabilities to describe the structural ensemble of LC3B in solution using different metrics and comparison with NMR data. With the resulting LC3B ensembles, we characterized the impact of 26 missense mutations from Pan-Cancer studies with different approaches. Our findings shed light on driver or neutral mutations in LC3B, providing an atlas of its modifications in cancer. Our framework could be used to assess the pathogenicity of mutations by accounting for the different aspects of protein structure and function altered by mutational events.
A platform for semi-automated voluntary training of common marmosets for behavioral neuroscience: Voluntary training of common marmosets
Authors: Walker Jeffrey D. , Pirschel Friederice , Gidmark Nicholas , MacLean Jason N. , Hatsopoulos Nicholas G.
Published: May 2019

In most cases, behavioral neuroscience studies of the common marmoset employ adaptations of well-established methods used with macaque monkeys. However, in most cases these approaches do not readily generalize to marmosets indicating a need for alternatives. Here we present the development of one such alternate: a platform for semi-automated, voluntary in-home cage behavioral training that allows for the study of naturalistic behaviors. We describe the design and production of a modular behavioral training apparatus using CAD software and digital fabrication. We demonstrate that this apparatus permits voluntary behavioral training and data collection throughout the marmoset’s waking hours with little experimenter intervention. Further we demonstrate the use of this apparatus to reconstruct the kinematics of the marmoset’s upper limb movement during natural foraging behavior.

NEW AND NOTEWORTHY

The study of marmosets in neuroscience has grown rapidly and this model organism presents challenges that are unique to this primate species. Here we address those challenges with an innovative platform for semi-automated and voluntary training of common marmosets. The platform allows marmosets to train throughout their waking hours with little to no experimenter intervention. We describe the use of this platform to capture the kinematics of the upper limb during natural foraging behavior and to expand the opportunities for behavioral training beyond the limits of traditional behavioral training sessions. The platform is flexible and can be easily extended to incorporate other motor tasks (e.g. visually cued reaching or manipulandum based tasks) using CAD models and digital fabrication.
Symbiotic properties of a chimeric Nod‐independent photosynthetic Bradyrhizobium strain obtained by conjugative transfer of a symbiotic plasmid
Authors: Songwattana Pongpan , Tittabutr Panlada , Wongdee Jenjira , Teamtisong Kamonluck , Wulandari Dyah , Teulet Albin , Fardoux Joel , Boonkerd Nantakorn , Giraud Eric , Teaumroong Neung
Published: May 2019

The lateral transfer of symbiotic genes converting a predisposed soil bacteria into a legume symbiont has occurred repeatedly and independently during the evolution of rhizobia. We experimented the transfer of a symbiotic plasmid between Bradyrhizobium strains. The originality of the DOA9 donor is that it harbours a symbiotic mega‐plasmid (pDOA9) containing nod, nif and T3SS genes while the ORS278 recipient has the unique property of inducing nodules on some Aeschynomene species in the absence of Nod factors (NFs). We observed that the chimeric strain ORS278‐pDOA9* lost its ability to develop a functional symbiosis with Aeschynomene. indica and Aeschynomene evenia. The mutation of rhcN and nodB led to partial restoration of nodule efficiency, indicating that T3SS effectors and NFs block the establishment of the NF‐independent symbiosis. Conversely, ORS278‐pDOA9* strain acquired the ability to form nodules on Crotalaria juncea and Macroptillium artropurpureum but not on NF‐dependent Aeschynomene (A. afraspera and A. americana), suggesting that the ORS278 strain also harbours incompatible factors that block the interaction with these species. These data indicate that the symbiotic properties of a chimeric rhizobia cannot be anticipated due to new combination of symbiotic and non‐symbiotic determinants that may interfere during the interaction with the host plant.
C‐reactive protein assessment to predict early septic complications after laparoscopic bowel resection for endometriosis: a diagnostic study
Authors: Scattarelli A , Carriou M , Boulet L , Chati R , Coget J , Bridoux V , Tuech J‐J , Roman H
Published: May 2019

Objective

To assess the predictive value of C‐reactive protein (CRP) level for early septic complications after laparoscopic bowel resection for endometriosis.

Design

Retrospective study using data prospectively recorded in the CIRENDO database.

Setting

University tertiary referral centre.

Population

Three hundred and three women managed by segmental resection or disc excision for colorectal endometriosis in 40 consecutive months.

Methods

C‐reactive protein was routinely measured at postoperative days 4, 5, and 6. Bowel fistula, pelvic abscess, and pelvic infected haematoma were prospectively recorded.

Main outcome measures

A receiver operating characteristic (ROC) curve was built to assess the best cut off CRP value to predict early septic complications.

Results

The incidence of bowel fistula and pelvic abscess/infected hematoma were 2 and 7.9%, respectively. The CRP cut‐off value of 100 mg/l at postoperative day 4 predicts early septic pelvic complications (sensitivity, specificity, positive and negative predictive values of, respectively, 76, 83, 30.2, and 90.4%), and the area under the curve was 0.85 (95% CI 0.78–0.92).

Conclusion

Postoperative CRP monitoring is useful in the prediction of early septic pelvic complications following bowel endometriosis surgery, with possible impact on the management of postoperative outcomes and hospitalisation stay.

Tweetable abstract

Levels of CRP ≥100 mg/l at day 4 after bowel resection or excision for endometriosis are associated with early septic pelvic complications.
When Is the Averaging Effect Present in Auditor Judgments?
Authors: Lambert Tamara A. , Peytcheva Marietta
Published: May 2019

Auditing standards task auditors with collecting sufficient appropriate evidence to form audit judgments. Yet, cognitive psychology documents a robust finding in which people evaluate a bundle of relevant, directionally consistent evidence as though averaging the strength of the components. In consequence, a bundle of evidence may be viewed as weaker evidence than the bundle's strongest evidence item alone. We experimentally examine whether this averaging effect occurs in an audit context, and we test a potential moderator. In three independent mini‐cases, we ask auditor participants to make judgments about going concern, internal controls, and fraud risk. We present auditors with unfavorable audit evidence relevant to each judgment, manipulating whether we present a single strong evidence item or bundle it with a weaker evidence item. We also manipulate the auditor's initial impression of the client's state. We find that experienced auditors succumb to the averaging effect, making more strongly unfavorable judgments in response to the single evidence item than the bundle, and that this bias is reduced when the observed evidence is inconsistent with the auditor's initial impression. We interpret our results as consistent with the dual‐processing theory of cognition.
Market segmentation and supply‐chain predictability: evidence from China
Authors: Li Chenchen , Li Rui , Diao Xundi , Wu Chongfeng
Published: May 2019

We determine the industry‐level supply‐chain predictability in the Chinese stock market. Evidence is provided that a limited information model is gradually adaptive to the Chinese stock market in recent years, while several traditional measures of informed trading perform differently in the previous period. An innovative indicator of the mobile ratio volatility is also proposed here, which relates the increasing mobile trading behavior to this cross‐sectional predictability. Furthermore, we explain the asymmetry of customer and supplier momentum in this market.
How much does tax erode fund excess returns?
Authors: Chen Zhe , Gallagher David R. , Harman Graham , Warren Geoffrey J. , Xi Lihui
Published: May 2019

We model the tax drag from active fund management based on reported monthly holdings of active equity funds. Tax drag erodes 65 percent of the 0.74 percent excess return in Broad Market funds, but only 21 percent of the 1.80 percent excess return in Small‐Cap funds for Australian superannuation (pension) fund investors. Tax drag varies with investment style; market state, which is most detrimental during bull markets; and fund turnover. For high‐income individual investors, tax drag is exacerbated to the extent that active management only generates meaningful after‐tax excess return for Small‐Cap funds of certain styles.
Dog ownership at three months of age is associated with protection against food allergy
Authors: Marrs Tom , Logan Kirsty , Craven Joanna , Radulovic Suzana , McLean W.H.A. Irwin , Lack Gideon , Flohr Carsten , Perkin Michael R. ,   the EAT Study Team
Published: May 2019

Background

The prevention of food allergy is a key priority for reducing the burden of allergic disease. Environmental exposures modulate the risk of developing food allergy and some of this may be mediated by the infants’ developing microbiome. However, the role of potentially protective environmental exposures, such as pet ownership, is largely uninvestigated with respect to food allergy.

Methods

We performed a secondary cohort analysis in the Enquiring About Tolerance (EAT) study, which enrolled 1303 three‐month infants onto a randomized trial to prevent food allergy. A survey elicited domestic animal ownership and participants were examined for atopic dermatitis (AD) at enrolment. Sensitization to foods and aeroallergens were elicited by skin and serum testing at 3, 12 and 36 months. Food allergy status was determined by double‐blind placebo‐controlled food challenges between 1 and 3 years.

Results

Food allergy was diagnosed amongst 6.1% (68/1124) of participants with complete data. No significant relationships were demonstrated between food allergy and caesarean delivery, infections or antibiotic exposure in early life. After adjusting for familial atopic disease, maternal dog/cat sensitization and participant AD, living with dogs was associated with a 90% reduction in the odds of infants developing food allergy (adjusted odds ratio (aOR) 0.10 (confidence interval (CI) 0.01‐0.71), P = 0.02). None of the 49 infants living with at least two dogs developed food allergy, suggesting a dose‐response relationship (each dog owned aOR 0.12 (CI 0.02‐0.81), P = 0.03). No relationship was demonstrated between owning dogs or cats and the development of AD.

Conclusion

Dog ownership in infancy may prevent food allergy.
Mindful Emotion Regulation, Savouring and Proactive Behaviour: The Role of Supervisor Justice
Authors: Molina Agustin , O'Shea Deirdre
Published: May 2019

The global financial crisis and recession‐prompted budget cuts represent significant challenges to public sector organisations, limiting their ability to make changes to job design and increasing job demands. In such environments, primary interventions targeted at changing the job or the work are not always viable. In this research, we examine the effectiveness of a mindful emotion regulation (MER) intervention versus a “control” savouring nature (SN) intervention in terms of facilitating the investment of work engagement into proactive behaviours. We also examine how the job resource of supervisor justice impacts these relationships. We collected data from an Irish public sector organisation using a cluster randomised controlled trial design. The final sample comprised 108 participants (MER = 74; SN = 34). Results highlight the valuable role that job resources play as boundary conditions of psychological‐based interventions since the success of MER and SN depended on the participants’ perceptions of supervisor justice. When supervisor justice was high, a restorative SN exercise was effective in promoting proactive behaviours. When supervisor justice was low, a more complex cognitive and emotional exercise in the form of MER was required. We explain these results and consider their implications for future research.
Randomized study of individualized pharmacokinetically‐guided dosing of paclitaxel compared with body‐surface area dosing in Chinese patients with advanced non‐small cell lung cancer
Authors: Zhang Jie , Zhou Fei , Qi Huiwei , Ni Huijuan , Hu Qiong , Zhou Caicun , Li Yunying , Baburina Irina , Courtney Jodi , Salamone Salvatore J.
Published: May 2019

Aims

This prospective, randomized study was initiated to assess the impact of pharmacokinetically (PK)‐guided paclitaxel (PTX) dosing on toxicity and efficacy compared with body‐surface area (BSA)‐based dosing in Chinese non‐small cell lung cancer patients.

Methods

A total of 319 stage IIIB/IV non‐small cell lung cancer patients receiving first‐line chemotherapy were enrolled. Patients were randomized to receive 3‐weekly carboplatin plus PTX at a starting dose of 175 mg/m2 with subsequent PTX dosing based on either BSA or PK‐guided dosing targeting time above a PTX plasma concentration of 0.05 μmol/L (PTXTc > 0.05) between 26 and 31 hours. The primary safety endpoint was grade 4 haematological toxicity. The secondary endpoints were neuropathy, objective response rate, progression‐free survival and overall survival.

Results

In total, 275 (86%) patients completed ≥2 cycles of chemotherapy (140 in BSA arm and 135 in PK arm). In cycle 1, with the same PTX dose, average PTXTc > 0.05 was 37 hours (range = 18–57 hours). Over cycles 2–4, patients in the PK arm had significantly lower average PTX doses and exposure compared with the BSA arm (128 vs 161 mg/m2, P < .0001 and 29 vs 35 hours, P < .0001). PK‐guided dosing significantly reduced the cumulative incidence of grade 4 haematological toxicity (15% vs 24%, P = .004), grade 4 neutropenia (15% vs 23%, P = .009) and grade ≥ 2 neuropathy (8% vs 21%, P = .005). Objective response rate (32% vs 26%, P = .28) and overall survival (21.0 vs 24.0 months, P = .815) were similar in PK and BSA arms. Progression‐free survival was slightly improved in PK arm (4.67 vs 4.17 months, P = .026).

Conclusion

PK‐guided PTX dosing significantly reduced grade 4 haematological toxicities and grade ≥ 2 neuropathy without an adverse impact on clinical outcomes.
Empathy and defending behaviours in school bullying: The mediating role of motivation to defend victims
Authors: Longobardi Claudio , Borello Laura , Thornberg Robert , Settanni Michele
Published: May 2019

Background

The literature indicates that separate significant links exist in adolescence between empathy, cognitive and affective motivation to defend victims, and behavioural problems in bullying episode in schools.

Aims

The aim of the study was to investigate the relationship between empathy, motivation to defend, and defending behaviour in bullying situations. The hypothesis focuses on the possible role of autonomous motivation in the association between empathy and defending attitudes.

Samples and methods

Data were collected from 430 Italian adolescents (48.4% male, 51.6% female) who completed a questionnaire in their schools. The mean age of the participants was 13.1 years (SD = 2.1).

Results

Results showed that empathy significantly predicts defending behaviour and also has a significant effect on extrinsic, introjected, and intrinsic motivation to defend. Autonomous motivation, in turn, has a mediating role in the relationship between empathy and defending behaviour.

Conclusions

Our study suggests the importance of focusing on empathy and on developing autonomous motivation to defend in children, to raise spontaneous defending attitudes against bullying.
Management of advanced prostate cancer in a middle‐income country: real‐world consideration of the Advanced Prostate Cancer Consensus Conference 2017
Authors: Saad Marniza , Alip Adlinda , Lim Jasmine , Abdullah Matin Mellor , Chong Flora Li Tze , Chua Chong Beng , Ismail Fuad , Khong Rachael Kit‐Tsan , Lim Chun Sen , Loh Chit Sin , Malek Rohan , Mohd Ghani Khairul Asri , Md Noor Ibtisam , Md Yusoff Noor Ashani , Nasuha Noor Azam , Razack Azad , Soo Hoo Hwoei Fen , Sundram Murali , Tan Hui Meng , Thiagarajan Muthukkumaran , Teh Guan Chou , Voon Pei Jye , Ong Teng Aik
Published: May 2019

Objective

To examine the results of the Malaysian Advanced Prostate Cancer Consensus Conference (MyAPCCC) 2018, held for assessing the generalizability of consensus reached at the Advanced Prostate Cancer Consensus Conference (APCCC 2017) to Malaysia, a middle‐income country.

Methods

Six key sections were chosen: (1) high‐risk localized and locally advanced prostate cancer, (2) oligometastatic prostate cancer, (3) castration‐naïve prostate cancer, (4) castrate resistant prostate cancer, (5) use of osteoclast‐targeted therapy and (6) global access to prostate cancer drugs. There were 101 consensus questions, consisting of 91 questions from APCCC 2017 and 10 new questions from MyAPCCC 2018, selected and modified by the steering committee; of which, 23 questions were assessed in both ideal world and real‐world settings. A panel of 22 experts, comprising of 11 urologists and 11 oncologists, voted on 101 predefined questions anonymously. Final voting results were compared with the APCCC 2017 outcomes.

Results

Most voting results from the MyAPCCC 2018 were consistent with the APCCC 2017 outcomes. No consensus was achieved for controversial topics with little level I evidence, such as management of oligometastatic disease. No consensus was reached on using high‐cost drugs in castration‐naïve or castration‐resistant metastatic prostate cancer in real‐world settings. All panellists recommended using generic drugs when available.

Conclusions

The MyAPCCC 2018 voting results reflect the management of advanced prostate cancer in a middle‐income country in a real‐world setting. These results may serve as a guide for local clinical practices and highlight the financial challenges in modern healthcare.
Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23‐gene panel with utility for non‐invasive diagnosis and risk stratification
Authors: Ward Douglas G. , Gordon Naheema S. , Boucher Rebecca H. , Pirrie Sarah J. , Baxter Laura , Ott Sascha , Silcock Lee , Whalley Celina M. , Stockton Joanne D. , Beggs Andrew D. , Griffiths Mike , Abbotts Ben , Ijakipour Hanieh , Latheef Fathimath N. , Robinson Robert A. , White Andrew J. , James Nicholas D. , Zeegers Maurice P. , Cheng K. K. , Bryan Richard T.
Published: May 2019

Objectives

To develop a focused panel of somatic mutations (SMs) present in the majority of urothelial bladder cancers (UBCs), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SMs in urinary cell‐pellet (cp)DNA and cell‐free (cf)DNA as part of the development of a non‐invasive clinical assay.

Patients and Methods

A panel of SMs was validated by targeted deep‐sequencing of tumour DNA from 956 patients with UBC. In addition, amplicon and capture‐based targeted sequencing measured mutant allele frequencies (MAFs) of SMs in 314 urine cpDNAs and 153 urine cfDNAs. The association of SMs with grade, stage, and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SMs detected in tumour tissue and cpDNA and cfDNA was assessed.

Results

The panel comprised SMs in 23 genes: TERT (promoter), FGFR3, PIK3CA, TP53, ERCC2, RHOB, ERBB2, HRAS, RXRA, ELF3, CDKN1A, KRAS, KDM6A, AKT1, FBXW7, ERBB3, SF3B1, CTNNB1, BRAF, C3orf70, CREBBP, CDKN2A, and NRAS; 93.5–98.3% of UBCs of all grades and stages harboured ≥1 SM (mean: 2.5 SMs/tumour). RAS mutations were associated with better overall survival (P = 0.04). Mutations in RXRA, RHOB and TERT (promoter) were associated with shorter time to recurrence (P < 0.05). MAFs in urinary cfDNA and cpDNA were highly correlated; using a capture‐based approach, >94% of tumour SMs were detected in both cpDNA and cfDNA.

Conclusions

SMs are reliably detected in urinary cpDNA and cfDNA. The technical capability to identify very low MAFs is essential to reliably detect UBC, regardless of the use of cpDNA or cfDNA. This 23‐gene panel shows promise for the non‐invasive diagnosis and risk stratification of UBC.
Strain‐selective efficacy of sacubitril/valsartan on carotid fibrosis in response to injury in two inbred mouse strains
Authors: Korshunov Vyacheslav A. , Quinn Breandan , Faiyaz Abrar , Ahmed Rifat , Sowden Mark P. , Doyley Marvin M. , Berk Bradford C.
Published: May 2019

Background and Purpose

Sacubitril/valsartan (Sac/val) is more effective than valsartan in lowering BP and mortality in patients with heart failure. Here, we proposed that Sac/val treatment would be more effective in preventing pathological vascular remodelling in 129X1/SvJ (129X1), than in C57BL/6J (B6) inbred mice.

Experimental Approach

Sac/val (60 mg·kg−1·day−1) and valsartan (27 mg·kg−1·day−1) were given as prophylactic or therapeutic treatments, to 129X1 or B6 mice with carotid artery ligation for 14 days. Blood flow was measured by ultrasound. Ex vivo, carotid tissue was analysed with histological and morphometric techniques, together with RNA sequencing and gene ontology.

Key Results

Sac/val was more effective than valsartan in lowering BP in 129X1 compared with B6 mice. Liver expression of CYP2C9 and plasma cGMP levels were similar across treatments. A reduction in carotid thickening after prophylactic treatment with valsartan or Sac/val also resulted in significant arterial shrinkage in B6 mice. In 129X1 mice, Sac/val and prophylactic treatment with valsartan had no effect on carotid thickening but preserved carotid size. BP lowering significantly correlated with a decline in carotid stiffness (R2 = .37, P = .0096) in 129X1 but not in B6 mice. The gene expression signature associated with hyalurononglucosaminidase activity was down‐regulated in injured arteries after both regimens of Sac/val only in 129X1 mice. Administration of Sac/val but not valsartan significantly reduced deposition of hyaluronic acid and carotid fibrosis in 129X1 mice.

Conclusion and Implications

These results underscore the importance of the genetic background in the efficacy of the Sac/val on vascular fibrosis.
Human papillomavirus infection in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice
Authors: Chin‐Hong Peter V. , Reid Gail E. ,   the AST Infectious Diseases Community of Practice
Published: May 2019

These guidelines from the American Society of Transplantation Infectious Diseases Community of Practice update the epidemiology and management of human papillomavirus (HPV) infections in organ transplant recipients. HPV is one of the most common sexually transmitted infections and is associated with cancers of the anogenital region. Increasing evidence suggests an association with head and neck cancers as well. Solid organ transplant recipients have a higher risk of HPV infection than the general population. Infection manifests as premalignant lesions, warts, or cancer of the cervix, penis, vulva, scrotum, and anal canal. Most are asymptomatic initially, so diagnosis can be difficult without screening. A vaccine is available though not effective in preventing all cancer‐causing strains. Organ transplant recipients should be screened for HPV‐associated cancers and appropriate therapy initiated in a timely manner. Further studies are warranted to delineate the most effective screening methods and therapeutic modalities, including whether changes in immunosuppression are effective in attenuating disease.
Visual and proprioceptive recalibrations after exposure to a visuomotor rotation
Authors: Rand Miya K. , Heuer Herbert
Published: May 2019

Adaptation to a visuomotor rotation in a cursor‐control task is accompanied by proprioceptive recalibration, whereas the existence of visual recalibration is uncertain and has even been doubted. In the present study, we tested both visual and proprioceptive recalibration; proprioceptive recalibration was not only assessed by means of psychophysical judgments of the perceived position of the hand, but also by an indirect procedure based on movement characteristics. Participants adapted to a gradually introduced visuomotor rotation of 30° by making center‐out movements to remembered targets. In subsequent test trials, they made center‐out movements without visual feedback or observed center‐out motions of a cursor without moving the hand. In each test trial, they judged the endpoint of hand or cursor by matching the position of the hand or of a visual marker, respectively, moving along a semicircular path. This path ran through all possible endpoints of the center‐out movements. We observed proprioceptive recalibration of 7.3° (3.1° with the indirect procedure) and a smaller, but significant, visual recalibration of 1.3°. Total recalibration of 8.6° was about half as strong as motor adaptation, the adaptive shift of the movement direction. The evidence of both proprioceptive and visual recalibration was obtained with a judgment procedure that suggests that recalibration is restricted to the type of movement performed during exposure to a visuomotor rotation. Consequently, identical physical positions of the hand can be perceived differently depending on how they have been reached, and similarly identical positions of a cursor on a monitor can be perceived differently.
Epileptic negative myoclonus restricted to lower limbs in benign childhood focal epilepsy with vertex spikes
Authors: Gong P. , Xue J. , Qian P. , Yang H. , Liu X. , Zhang Y. , Jiang Y. , Yang Z.
Published: May 2019

Background and purpose

The aim was to determine the electroclinical findings in benign childhood focal epilepsy with vertex spikes (BEVS) with epileptic negative myoclonus (ENM) restricted to the lower limbs.

Methods

The electroencephalogram database of Peking University First Hospital and medical records of patients with BEVS and ENM restricted to the lower limbs were reviewed.

Results

Twenty‐seven patients with BEVS had ENM restricted to the lower limbs. Twelve started as ENM restricted to the lower limbs. The age at seizure onset ranged from 1.5 to 4.8 years. During the course, half of the 12 patients developed focal sensorimotor seizures and then were diagnosed as benign childhood epilepsy with centrotemporal spikes (BECTS), with BEVS (four cases) and without BEVS (two cases). Five of them had electrical status epilepticus during sleep (ESES) and met the diagnostic criteria of atypical benign partial epilepsy (ABPE). Fifteen of the 27 patients had ENM restricted to the lower limbs during the course. The age at seizure onset ranged from 1.3 to 9.8 years. All had ESES and were diagnosed as ABPE, 11 as ABPE with BEVS and four as ABPE evolving into BEVS.

Conclusions

Benign childhood focal epilepsy with vertex spikes (BEVS) might represent a specific epileptic syndrome of the continuum of benign childhood focal epilepsy. ENM restricted to the lower limbs was a special phenomenon in BEVS. BEVS could overlap with BECTS or evolve into BECTS and further into ABPE and vice versa. Ignorance of vertex spikes with associated ENM restricted to the lower limbs might lead to a misunderstanding of BEVS, a specific type of benign childhood focal epilepsy.
Premature mortality in persons with epilepsy and schizophrenia: A population‐based nationwide cohort study
Authors: Andersen Katrine M. , Petersen Liselotte V. , Vestergaard Mogens , Pedersen Carsten B. , Christensen Jakob
Published: May 2019

Objective

To determine the mortality for persons with epilepsy and schizophrenia by absolute and relative measures.

Methods

This is a population‐based nationwide cohort study of persons born in Denmark from 1960 to 1987 who were alive and residing in Denmark on their 25th birthday. We identified persons diagnosed with epilepsy and schizophrenia prior to their 25th birthday and followed them to death, emigration, or December 31, 2012, whichever came first. The primary outcome was overall mortality. Data were analyzed using Cox regressions.

Results

Persons were followed for 24 167 573 person years; the median was 15 years. The mortality rate ratio was 4.4 (95% confidence interval [CI] = 4.1‐4.7) for persons with epilepsy, 6.6 (95% CI = 6.1‐7.1) for persons with schizophrenia, and 12.8 (95% CI = 9.1‐18.1) for persons with both disorders, compared with persons without these disorders. The estimated cumulative mortality at the age of 50 years was 3.1% (95% CI = 3.0‐3.1) for persons without epilepsy and schizophrenia, 10.7% (95% CI = 9.7‐11.8) for persons with epilepsy, 17.4% (95% CI = 16.0‐18.8) for persons with schizophrenia, and 27.2% (95% CI = 15.7‐40.1) for persons with both disorders.

Significance

Persons with epilepsy and schizophrenia have very high mortality; more than one in four persons with both disorders died between the age of 25 and 50 years, indicating that these patients need special clinical attention.