bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of knowledge graph embedding approaches for drug-drug interaction prediction in realistic settings
Authors: Celebi Remzi , Uyar Huseyin , Yasar Erkan , Gumus Ozgur , Dikenelli Oguz , Dumontier Michel
Published: December 2019

Background

Current approaches to identifying drug-drug interactions (DDIs), include safety studies during drug development and post-marketing surveillance after approval, offer important opportunities to identify potential safety issues, but are unable to provide complete set of all possible DDIs. Thus, the drug discovery researchers and healthcare professionals might not be fully aware of potentially dangerous DDIs. Predicting potential drug-drug interaction helps reduce unanticipated drug interactions and drug development costs and optimizes the drug design process. Methods for prediction of DDIs have the tendency to report high accuracy but still have little impact on translational research due to systematic biases induced by networked/paired data. In this work, we aimed to present realistic evaluation settings to predict DDIs using knowledge graph embeddings. We propose a simple disjoint cross-validation scheme to evaluate drug-drug interaction predictions for the scenarios where the drugs have no known DDIs.

Results

We designed different evaluation settings to accurately assess the performance for predicting DDIs. The settings for disjoint cross-validation produced lower performance scores, as expected, but still were good at predicting the drug interactions. We have applied Logistic Regression, Naive Bayes and Random Forest on DrugBank knowledge graph with the 10-fold traditional cross validation using RDF2Vec, TransE and TransD. RDF2Vec with Skip-Gram generally surpasses other embedding methods. We also tested RDF2Vec on various drug knowledge graphs such as DrugBank, PharmGKB and KEGG to predict unknown drug-drug interactions. The performance was not enhanced significantly when an integrated knowledge graph including these three datasets was used.

Conclusion

We showed that the knowledge embeddings are powerful predictors and comparable to current state-of-the-art methods for inferring new DDIs. We addressed the evaluation biases by introducing drug-wise and pairwise disjoint test classes. Although the performance scores for drug-wise and pairwise disjoint seem to be low, the results can be considered to be realistic in predicting the interactions for drugs with limited interaction information.
Cloning, characterization of TaGS3 and identification of allelic variation associated with kernel traits in wheat (Triticum aestivum L.)
Authors: Yang Jian , Zhou Yanjie , Zhang Yu’e , Hu Weiguo , Wu Qiuhong , Chen Yongxing , Wang Xicheng , Guo Guanghao , Liu Zhiyong , Cao Tingjie , Zhao Hong
Published: December 2019

Background

Grain weight is an important yield component. Selection of advanced lines with heavy grains show high grain sink potentials and strong sink activity, which is an increasingly important objective in wheat breeding programs. Rice OsGS3 has been identified as a major quantitative trait locus for both grain weight and grain size. However, allelic variation of GS3 has not been characterized previously in hexaploid wheat.

Results

We cloned 2445, 2393, and 2409 bp sequences of the homologs TaGS3-4A, TaGS3-7A, and TaGS3-7D in wheat ‘Changzhi 6406’, a cultivar that shows high grain weight. The TaGS3 genes each contained five exons and four introns, and encoded a deduced protein of 170, 169, and 169 amino acids, respectively. Phylogenetic analysis of plant GS3 protein sequences revealed GS3 to be a monocotyledon-specific gene and the GS3 proteins were resolved into three classes. The length of the atypical Gγ domain and the cysteine-rich region was conserved within each class and not conserved between classes. A single-nucleotide polymorphism in the fifth exon (at position 1907) of TaGS3-7A leads to an amino acid change (ALA/THR) and showed different frequencies in two pools of Chinese wheat accessions representing extremes in grain weight. Association analysis indicated that the TaGS3-7A-A allele was associated with higher grain weight in the natural population. The TaGS3-7A-A allele was favoured in global modern wheat cultivars but the allelic frequency varied among different wheat-production regions of China, which indicated that this allele is of potential utility to improve wheat grain weight in certain wheat-production areas of China.

Conclusions

The novel molecular information on wheat GS3 homologs and the KASP functional marker designed in this study may be useful in marker-assisted breeding for genetic improvement of wheat.
Genetic diversity of Listeria monocytogenes strains in ruminant abortion and rhombencephalitis cases in comparison with the natural environment
Authors: Papić Bojan , Pate Mateja , Félix Benjamin , Kušar Darja
Published: December 2019

Background

Listeria monocytogenesis the causative agent of listeriosis, a serious disease affecting both animals and humans. Here, multilocus sequence typing (MLST) was used to characterize the genetic diversity ofListeria monocytogenesstrains isolated from the natural environment and animal clinical cases in Europe. The prevalence of clonal complexes (CCs) obtained was compared according to (i) the origin of isolation – clinical cases vs. natural environment – and (ii) the clinical form of animal listeriosis – rhombencephalitis vs. abortion. To this aim, two datasets were constructed. The clinical dataset consisted of 350 animal clinical isolates originating from France and Slovenia and supplemented with isolates from Switzerland and Great Britain. The natural environment dataset consisted of 253 isolates from the natural environment originating from Slovenia and supplemented with isolates from nine other European countries.

Results

For the clinical cases, CC1, CC4-CC217 and CC412 were the most prevalent in rhombencephalitis and CC1, CC37 and CC4-CC217 in abortion. The hypervirulent CC1 and CC4-CC217 prevailed in both datasets. These results indicated that livestock is constantly exposed to hypervirulent CCs. CC1 was significantly associated with a clinical origin, whereas CC9, CC29 and CC14 were associated with the natural environment. CC1 was predominant among rhombencephalitis cases both in cattle and small ruminants, and its prevalence did not differ significantly between these two groups. A novel association of CC37 and CC6 with abortion cases was revealed.

Conclusions

Here, we show that CC1 and CC4-CC217 are prevalent in isolates of environmental and animal clinical origin, suggesting that ruminants are frequently exposed to hypervirulent CCs. The presence of CC4 in two mastitis cases calls for further attention due to direct threat to the consumer. We showed several associations between CCs and the origin of isolation or clinical form of listeriosis, e.g. CC37 and CC6 with abortion. This study improves our understanding of the population structure ofL. monocytogenesisolates from the natural environment and animal clinical cases. Moreover, it provides a basis for future studies aiming to determine the underlying mechanisms of phenotypic traits of interest.
Native-valve Enterococcus hirae endocarditis: a case report and review of the literature
Authors: Pinkes Mary E. , White Catherine , Wong Cynthia S.
Published: December 2019

Background

Enterococcus hirae is rarely identified in humans and may be a commensal pathogen in psittacine birds. We present the fifth known case of E. hirae endocarditis.

Case presentation

A 64-year-old Caucasian female presented with fever, hypotension, atrial fibrillation with rapid ventricular response, and a two-week history of lightheadedness. Her previous medical history included COPD, recurrent DVT, atrial fibrillation (on warfarin), hypertension, hypothyroidism, and Hodgkin’s lymphoma. Physical exam was notable for expiratory wheezes and a 2/6 systolic ejection murmur at the right sternal border. 2D echocardiogram revealed severe aortic stenosis. The patient underwent right and left heart catheterization, where she was found to have severe aortic stenosis and mild pulmonary hypertension. She subsequently underwent minimally invasive aortic valve replacement with a bovine pericardial valve, bilateral atrial cryoablation, and clipping of the left atrial appendage. Her aortic valve was found to have a bicuspid, thickened appearance with calcifications, multiple small vegetations, and a root abscess beneath the right coronary cusp. With a new suspicion of infective endocarditis, the patient was placed on broad-spectrum IV antibiotics. Intra-operative blood cultures were negative. A tissue culture from the aortic valve vegetations identified Enterococcus hirae susceptible to ampicillin through MALDI-TOF. Antibiotic treatment was then switched to IV ampicillin and ceftriaxone; she declined aminoglycoside treatment due to toxicity concerns. The patient had an uncomplicated postoperative course and was discharged with 6 weeks of antibiotics. To date, she continues to be followed with no signs of relapsing disease.

Conclusions

To our knowledge, this case constitutes the fifth known case of E. hirae endocarditis, and the second case to have been identified with MALDI-TOF and treated with ampicillin and ceftriaxone. This case reinforces the efficacy of ampicillin and ceftriaxone for the treatment of E. hirae endocarditis.
Homozygous variants in the HEXB and MBOAT7 genes underlie neurological diseases in consanguineous families
Authors: Khan Shazia , Rawlins Lettie E. , Harlalka Gaurav V. , Umair Muhammad , Ullah Asmat , Shahzad Shaheen , Javed Muhammad , Baple Emma L. , Crosby Andrew H. , Ahmad Wasim , Gul Asma
Published: December 2019

Background

Neurological disorders are a common cause of morbidity and mortality within Pakistani populations. It is one of the most important challenges in healthcare, with significant life-long socio-economic burden.

Methods

We investigated the cause of disease in three Pakistani families in individuals with unexplained autosomal recessive neurological conditions, using both genome-wide SNP mapping and whole exome sequencing (WES) of affected individuals.

Results

We identified a homozygous splice site variant (NM_000521:c.445 + 1G > T) in the hexosaminidase B (HEXB) gene confirming a diagnosis of Sandhoff disease (SD; type II GM2-gangliosidosis), an autosomal recessive lysosomal storage disorder caused by deficiency of hexosaminidases in a single family. In two further unrelated families, we identified a homozygous frameshift variant (NM_024298.3:c.758_778del; p.Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7) as the likely cause of disease. MBOAT7 gene variants have recently been identified as a cause of intellectual disability (ID), seizures and autistic features.

Conclusions

We identified two metabolic disorders of lipid biosynthesis within three Pakistani families presenting with undiagnosed neurodevelopmental conditions. These findings enabled an accurate neurological disease diagnosis to be provided for these families, facilitating disease management and genetic counselling within this population. This study consolidates variation within MBOAT7 as a cause of neurodevelopmental disorder, broadens knowledge of the clinical outcomes associated with MBOAT7-related disorder, and confirms the likely presence of a regionally prevalent founder variant (c.758_778del; p.Glu253_Ala259del) in Pakistan.
Broadening the phenotype of the TWNK gene associated Perrault syndrome
Authors: Fekete Bálint , Pentelényi Klára , Rudas Gabor , Gál Anikó , Grosz Zoltán , Illés Anett , Idris Jimoh , Csukly Gabor , Domonkos Andor , Molnar Maria Judit
Published: December 2019

Background

Perrault syndrome is a genetically heterogenous, very rare disease, characterized clinically by sensorineural hearing loss, ovarian dysfunction and neurological symptoms. We present the case of a 33 years old female patient with TWNK-associated Perrault syndrome. The TWNK gene is coding the mitochondrial protein Twinkle and currently there are only two reports characterizing the phenotype of TWNK-associated Perrault syndrome. None of these publications reported about special brain MRI alterations and neuropathological changes in the muscle and peripheral nerves.

Case presentation

Our patients with TWNK-dependent Perrault syndrome had severe bilateral hypoacusis, severe ataxia, polyneuropathy, lower limb spastic paraparesis with pyramidal signs, and gonadal dysgenesis. Psychiatric symptoms such as depression and paranoia were present as well. Brain MRI observed progressive cerebellar hyperintensive signs associated with cerebellar, medulla oblongata and cervical spinal cord atrophy. Light microscopy of the muscle biopsy detected severe neurogenic lesions. COX staining was centrally reduced in many muscle fibers. Both muscle and sural nerve electron microscopy detected slightly enlarged mitochondria with abnormal cristae surrounded by lipid vacuoles. In the sural nerve, dystrophic axons had focally uncompacted myelin lamellae present. Genetic investigation revealed multiple mtDNA deletion and compound heterozygous mutations of the TWNK gene (c.1196 A > G, c.1358 G > A).

Conclusion

This study demonstrates that TWNK associated Perrault syndrome has a much broader phenotype as originally published. The coexistence of severe hypoacusis, spastic limb weakness, ataxia, polyneuropathy, gonadal dysgensia, hyperintense signals in the cerebellum and the presence of the mtDNA multiple deletion could indicate the impairment of the TWNK gene. This is the first report about pyramidal tract involvement and cerebellar MRI alteration associated with TWNK-related Perrault syndrome.
Perinephric urinoma following spontaneous renal rupture in the third trimester of pregnancy: a case report and brief review of the literature
Authors: Chen Ya , Yan Yun Fang , Zhang Ying , Carroll Xianming , Li Hui Rong , Tao Li , Sun Mei Guo , Leeper-Woodford Sandra
Published: December 2019

Background

Spontaneous formation of urinoma is a rare condition, especially for pregnant women. We report a patient in the third trimester of pregnancy with a spontaneous renal rupture who then develops a urinoma from urine leaking into the perinephric space.

Case presentation

A 23-year-old primagravida was diagnosed with a spontaneous renal rupture and acute left loin pain accompanied by hematuria when she was 35 weeks pregnant. A sub-capsular perinephric cyst then developed to a size of 319 × 175 × 253 mm, and because of discomfort to the patient, we performed Cesarean section. After a healthy male newborn was delivered, fluid was suctioned from a large perirenal cyst that had an estimated size of 300 × 200 × 300 mm. A percutaneous nephrostomy tube was left in the cyst until CT showed no remaining fluid. In the six-month follow-up, the patient showed no perirenal extravasation according to an ultrasound scan, and the urine analysis and renal function tests were normal.

Conclusion

Close follow-up should be recommended for the patient who has renal rupture after conservative therapy, especially for pregnant woman. CT or MRI should be considered in addition to utilizing ultrasound in the management of pregnant women who present with urinomas. Percutaneous nephrostomy is suggested as an appropriate treatment for large urinomas.
A scoping review of the literature on the current mental health status of physicians and physicians-in-training in North America
Authors: Mihailescu Mara , Neiterman Elena
Published: December 2019

Background

This scoping review summarizes the existing literature regarding the mental health of physicians and physicians-in-training and explores what types of mental health concerns are discussed in the literature, what is their prevalence among physicians, what are the causes of mental health concerns in physicians, what effects mental health concerns have on physicians and their patients, what interventions can be used to address them, and what are the barriers to seeking and providing care for physicians. This review aims to improve the understanding of physicians’ mental health, identify gaps in research, and propose evidence-based solutions.

Methods

A scoping review of the literature was conducted using Arksey and O’Malley’s framework, which examined peer-reviewed articles published in English during 2008–2018 with a focus on North America. Data were summarized quantitatively and thematically.

Results

A total of 91 articles meeting eligibility criteria were reviewed. Most of the literature was specific to burnout (n = 69), followed by depression and suicidal ideation (n = 28), psychological harm and distress (n = 9), wellbeing and wellness (n = 8), and general mental health (n = 3). The literature had a strong focus on interventions, but had less to say about barriers for seeking help and the effects of mental health concerns among physicians on patient care.

Conclusions

More research is needed to examine a broader variety of mental health concerns in physicians and to explore barriers to seeking care. The implication of poor physician mental health on patients should also be examined more closely. Finally, the reviewed literature lacks intersectional and longitudinal studies, as well as evaluations of interventions offered to improve mental wellbeing of physicians.
Campbelltown – Changing our Future: study protocol for a whole of system approach to childhood obesity in South Western Sydney
Authors: Maitland Nicola , Williams Mandy , Jalaludin Bin , Allender Steven , Strugnell Claudia , Brown Andrew , Hayward Joshua , Crooks Nicholas , Tredoux Jaimie , Li Vincy , Wardle Karen
Published: December 2019

Background

In Australia, around 67% of adults and 25% of children (5–17 years) are currently overweight or obese (Australian Bureau of Statistics, 4364.0.55.001 - National Health Survey: First Results, 2017–18, 2018). The Campbelltown – Changing our Future study will translate ‘a whole of system’ approach, previously trialed in rural communities in Victoria and the Australian Capital Territoty, to Campbelltown Local Government Area (LGA), a socioeconomically and ethnically diverse urban community in south western Sydney, NSW.

Methods

The study intervention will use a five-step approach; 1 – set up a childhood obesity monitoring system by collecting baseline data from children in primary schools across Campbelltown LGA to give a local context to the community when developing the systems map; 2 - key stakeholders develop systems maps which inform the development of the interventions; 3 - key stakeholders and community groups identify priority areas for action and form working groups; 4 - implementation of the interventions; 5 - evaluation of the interventions. The study will adopt a longitudinal pre/post design with repeated measures at baseline, 2 years and 4 years. Both qualitative and quantitative methods will be used to collect and analyse the data.

Discussion

Addressing childhood overweight and obesity is complex and requires a multifaceted intervention. This approach has the capacity to impact a range of factors that influence childhood overweight and obesity utilising existing capacity of multiple partners with broad community reach. Findings will develop local responses which capture the complexity of obesity at a community level and further our understanding of the interrelationships and relative importance of local factors impacting childhood overweight and obesity. This study aims to provide evidence for systems methods and approaches suitable for adaption and scaling and may provide evidence of successful community intervention elements.
Efficacy of glucocorticoids for the treatment of macrolide refractory mycoplasma pneumonia in children: meta-analysis of randomized controlled trials
Authors: Kim Hwan Soo , Sol In Suk , Li Donghe , Choi Miyoung , Choi Yun Jung , Lee Kyung Suk , Seo Ju Hee , Lee Yong Ju , Yang Hyeon-Jong , Kim Hyun Hee
Published: December 2019

Background

Mycoplasma pneumoniae is one of the most common pathogens causing community acquired pneumonia in children. Although the rate of macrolide-refractory Mycoplasma pneumoniae (MRMP) has increased, systemic glucocorticoids as a treatment option has not been validated yet. The purpose of this study was to assess the efficacy of glucocorticoids add-on in the treatment of MRMP in children through systematic review and meta-analysis.

Methods

Data sources

A systematic literature search was conducted using ten electronic bibliographic databases including English, Korean, Chinese and Japanese languages, up to March 8, 2018.

Study selection

The study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and selected randomized control trials which compared the efficacy of glucocorticoids add-on to macrolide in the treatment of MRMP in children.

Data extraction

Two independent reviewers extracted: primary outcomes as hospital days, fever duration, and change in C-reactive protein (CRP) and main analysis was performed through meta-analysis with random effects model.

Results

Twenty-four unique randomized controlled trials met the inclusion criteria. The mean length of hospital stay in glucocorticoids treatment group was significantly shorter than that in conventional macrolide-treatment group (Weighted mean difference (WMD) = − 4.03 days). The mean length of fever duration was significantly shorter in the glucocorticoid treatment group in comparison with the conventional treatment group (WMD = -3.32 days). Level of CRP after treatment was significantly lower in the glucocorticoid treatment group than that in the conventional treatment group (WMD = -16.03). Sensitivity analysis and subgroup analysis showed no significant improvement in heterogeneity. As limitations of the study, most of the studies included were from a single country and we were unable to control for heterogeneity across interventions, lack of standardized measures, and different time points of assessments across studies.

Conclusions

Glucocorticoid add-on treatment for MRMP can significantly shorten the duration of fever and hospital stay and decrease the level of CRP. These results should be confirmed by adequately powered studies in the future.
Biochemical and nutritional characterization of the medfly gut symbiont Enterobacter sp. AA26 for its use as probiotics in sterile insect technique applications
Authors: Azis Konstantinos , Zerva Ioanna , Melidis Paraschos , Caceres Carlos , Bourtzis Kostas , Ntougias Spyridon
Published: December 2019

Background

Enterobacter sp. AA26 was recently isolated from the midgut of Ceratitis capitata (Wiedemann) and it was shown to have positive effects in rearing efficiency when used as larval probiotics. In this study, biomass production was carried out in bench-scale bioreactors to elucidate the biokinetic properties of Enterobacter sp. AA26 and its nutritional value.

Results

Strain AA26 is a psychrotolerant, halotolerant, facultatively anaerobic bacterium with broad pH range for growth (pH 4 to 10.2), which possessed the typical biochemical profile of Enterobacter spp. The specific oxygen uptake rate (SOUR) was calculated as 63.2 ± 1.26 and 121 ± 1.73 mg O2 g− 1 VSS h− 1, with the yield coefficients in acetate and glucose being equal to 0.62 ± 0.03 and 0.67 ± 0.003 g biomass produced/g substrate consumed, respectively. The maximum specific growth rate (μmax) of strain AA26 grown in fill-and-draw bioreactors at 20 °C and 35 °C was 0.035 and 0.069 h− 1, respectively. Strain AA26 grew effectively in agro-industrial wastewaters, i.e. cheese whey wastewater (CWW), as alternative substrate for replacing yeast-based media. Biomass of strain AA26 could provide all the essential amino acids and vitamins for the artificial rearing of C. capitata. Greater intracellular α- and β-glucosidase activities were observed during growth of strain AA26 in CWW than in yeast-based substrate, although the opposite pattern was observed for the respective extracellular activities (p < 0.01). Low protease activity was exhibited in cells grown in yeast-based medium, while no lipase activities were detected.

Conclusions

The ability of strain AA26 to grow in agro-industrial wastes and to provide all the essential nutrients can minimize the cost of commercial media used for mass rearing and large scale sterile insect technique applications.
“How do we use the time?” – an observational study measuring the task time distribution of nurses in psychiatric care
Authors: Glantz Andreas , Örmon Karin , Sandström Boel
Published: December 2019

Background

The nurse’s primary task in psychiatric care should be to plan for the patient’s care in cooperation with the patient and spend the time needed to build a relationship. Psychiatric care nurses however claim that they lack the necessary time to communicate with patients. To investigate the validity of such claims, this time-motion study aimed at identifying how nurses working at inpatient psychiatric wards distribute their time between a variety of tasks during a working day.

Methods

During the period of December 2015 and February 2016, a total of 129 h and 23 min of structured observations of 12 nurses were carried out at six inpatient wards at one psychiatric clinic in southern Sweden. Time, frequency of tasks and number of interruptions were recorded and analysed using descriptive statistics.

Results

Administering drugs or medications accounted for the largest part of the measured time (17.5%) followed by indirect care (16%). Relatively little time was spent on direct care, the third largest category in the study (15.3%), while an unexpectedly high proportion of time (11.3%) was spent on ward related tasks. Nurses were also interrupted in 75% of all medication administering tasks.

Conclusions

Nurses working in inpatient psychiatric care spend little time in direct contact with the patients and medication administration is interrupted very often. As a result, it is difficult to establish therapeutic relationships with patients. This is an area of concern for both patient safety and nurses’ job satisfaction.
Correction to: Potential cost-savings from the use of the biosimilars filgrastim, infliximab and insulin glargine in Canada: a retrospective analysis
Authors: Mansell Kerry , Bhimji Hishaam , Eurich Dean , Mansell Holly
Published: December 2019

In the original publication of this article [1], there is a mistake in the Fig. 2a, 2b, and 2c.
Maternal milk and fecal microbes guide the spatiotemporal development of mucosa-associated microbiota and barrier function in the porcine neonatal gut
Authors: Liu Hongbin , Zeng Xiangfang , Zhang Guolong , Hou Chengli , Li Ning , Yu Haitao , Shang Lijun , Zhang Xiaoya , Trevisi Paolo , Yang Feiyun , Liu Zuohua , Qiao Shiyan
Published: December 2019

Background

The early-life microbiota exerts a profound and lifelong impact on host health. Longitudinal studies in humans have been informative but are mostly based on the analysis of fecal samples and cannot shed direct light on the early development of mucosa-associated intestinal microbiota and its impact on GI function. Using piglets as a model for human infants, we assess here the succession of mucosa-associated microbiota across the intestinal tract in the first 35 days after birth.

Results

Although sharing a similar composition and predicted functional profile at birth, the mucosa-associated microbiome in the small intestine (jejunum and ileum) remained relatively stable, while that of the large intestine (cecum and colon) quickly expanded and diversified by day 35. Among detected microbial sources (milk, vagina, areolar skin, and feces of sows, farrowing crate, and incubator), maternal milk microbes were primarily responsible for the colonization of the small intestine, contributing approximately 90% bacteria throughout the first 35 days of the neonatal life. Although maternal milk microbes contributed greater than 90% bacteria to the large intestinal microbiota of neonates upon birth, their presence gradually diminished, and they were replaced by maternal fecal microbes by day 35. We found strong correlations between the relative abundance of specific mucosa-associated microbes, particularly those vertically transmitted from the mother, and the expression levels of multiple intestinal immune and barrier function genes in different segments of the intestinal tract.

Conclusion

We revealed spatially specific trajectories of microbial colonization of the intestinal mucosa in the small and large intestines, which can be primarily attributed to the colonization by vertically transmitted maternal milk and intestinal microbes. Additionally, these maternal microbes may be involved in the establishment of intestinal immune and barrier functions in neonates. Our findings strengthen the notion that studying fecal samples alone is insufficient to fully understand the co-development of the intestinal microbiota and immune system and suggest the possibility of improving neonatal health through the manipulation of maternal microbiota.
Growth of the facultative chemolithoautotroph Ralstonia eutropha on organic waste materials: growth characteristics, redox regulation and hydrogenase activity
Authors: Poladyan Anna , Blbulyan Syuzanna , Sahakyan Mayramik , Lenz Oliver , Trchounian Armen
Published: December 2019

Background

The chemolithoautotrophic β-proteobacteriumRalstonia eutrophaH16 (Cupriavidus necator) is one of the most studied model organisms for growth on H2and CO2.R. eutrophaH16 is also a biologically significant bacterium capable of synthesizing O2-tolerant [NiFe]-hydrogenases (Hyds), which can be used as anode biocatalysts in enzyme fuel cells. For heterotrophic growth ofR. eutropha, various sources of organic carbon and energy can be used.

Results

Growth, bioenergetic properties, and oxidation–reduction potential (ORP) kinetics were investigated during cultivation ofR. eutrophaH16 on fructose and glycerol or lignocellulose-containing brewery spent grain hydrolysate (BSGH). BSGH was used as carbon and energy source byR. eutrophaH16, and the activities of the membrane-bound hydrogenase (MBH) and cytoplasmic, soluble hydrogenase (SH) were measured in different growth phases. Growth ofR. eutrophaH16 on optimized BSGH medium yielded ~ 0.7 g cell dry weight L−1with 3.50 ± 0.02 (SH) and 2.3 ± 0.03 (MBH) U (mg protein)−1activities. Upon growth on fructose and glycerol, a pH drop from 7.0 to 6.7 and a concomitant decrease of ORP was observed. During growth on BSGH, in contrast, the pH and ORP stayed constant. The growth rate was slightly stimulated through addition of 1 mM K3[Fe(CN)6], whereas temporarily reduced growth was observed upon addition of 3 mM dithiothreitol. The overall andN,N′-dicyclohexylcarbodiimide-sensitive ATPase activities of membrane vesicles were ~ 4- and ~ 2.5-fold lower, respectively, upon growth on fructose and glycerol (FGN) compared with only fructose utilization (FN). Compared to FN, ORP was lower upon bacterial growth on FGN, GFN, and BSGH.

Conclusions

Our results suggest that reductive conditions and low ATPase activity might be signals for energy depletion, which, in turn, leads to increased hydrogenase biosynthesis to overcome this unfavorable situation. Addition of fructose or microelements have no, or a negative, influence on hydrogenase activity. Organic wastes (glycerol, BSGH) are promising carbon and energy sources for the formation of biomass harboring significant amounts of the biotechnologically relevant hydrogenases MBH and SH. The results are valuable for using microbial cells as producers of hydrogenase enzymes as catalysts in enzymatic fuel cells.
Substantially improving the enantioconvergence of PvEH1, a Phaseolus vulgaris epoxide hydrolase, towards m-chlorostyrene oxide by laboratory evolution
Authors: Zong Xun-Cheng , Li Chuang , Xu Yao-Hui , Hu Die , Hu Bo-Chun , Zang Jia , Wu Min-Chen
Published: December 2019

Background

Epoxide hydrolase can regioselectively catalyze the oxirane ring-opening hydrolysis of rac-epoxides producing the corresponding chiral diols. In our laboratory, a gene named pveh1 encoding an EH from Phaseolus vulgaris was cloned. Although the directed modification of PvEH1 was carried out, the mutant PvEH1Y3 showed a limited degree of enantioconvergence towards racemic (rac-) m-chlorostyrene oxide (mCSO).

Results

PvEH1 and PvEH1Y3 were combinatively subjected to laboratory evolution to further enhance the enantioconvergence of PvEH1Y3 towards rac-mCSO. Firstly, the substrate-binding pocket of PvEH1 was identified using a CAVER 3.0 software, and divided into three zones. After all residues in zones 1 and 3 were subjected to leucine scanning, two E. coli transformants, E. coli/pveh1Y149L and /pveh1P184L, were selected, by which rac-mCSO was transformed into (R)-m-chlorophenyl-1,2-ethanediol (mCPED) having 55.1% and 27.2% eep. Secondly, two saturation mutagenesis libraries, E. coli/pveh1Y149X and /pveh1P184X (X: any one of 20 residues) were created at sites Y149 and P184 of PvEH1. Among all transformants, both E. coli/pveh1Y149L (65.8% αS and 55.1% eep) and /pveh1P184W (66.6% αS and 59.8% eep) possessed the highest enantioconvergences. Finally, the combinatorial mutagenesis was conducted by replacements of both Y149L and P184W in PvEH1Y3, constructing E. coli/pveh1Y3Z2, whose αS reached 97.5%, higher than that (75.3%) of E. coli/pveh1Y3. In addition, the enantioconvergent hydrolysis of 20 mM rac-mCSO was performed by E. coli/pveh1Y3Z2, giving (R)-mCPED with 95.2% eep and 97.2% yield.

Conclusions

In summary, the enantioconvergence of PvEH1Y3Z2 was successfully improved by laboratory evolution, which was based on the study of substrate-binding pocket by leucine scanning. Our present work introduced an effective strategy for the directed modification of enantioconvergence of PvEH1.
Optimization of an in vivo model to study immunity to Plasmodium falciparum pre-erythrocytic stages
Authors: Flores-Garcia Yevel , Herrera Sonia M. , Jhun Hugo , Pérez-Ramos Daniel W. , King C. Richter , Locke Emily , Raghunandan Ramadevi , Zavala Fidel
Published: December 2019

Background

The circumsporozoite protein (CSP) of Plasmodium is a key surface antigen that induces antibodies and T-cells, conferring immune protection in animal models and humans. However, much of the work on CSP and immunity has been developed based on studies using rodent or non-human primate CSP antigens, which may not be entirely translatable to CSP expressed by human malaria parasites, especially considering the host specificity of the different species.

Methods

Using a genetically engineered strain of Plasmodium berghei that expresses luciferase, GFP and the Plasmodium falciparum orthologue of CSP, the effect of laboratory preparation, mosquito treatment and mouse factors on sporozoite infectivity was assessed using an in vivo bioluminescence assay on mice. This assay was compared with a PCR-based protection assay using an already described monoclonal antibody that can provide sterile protection against sporozoite challenge.

Results

Bioluminescence assay demonstrated similar detection levels of the quantity and kinetics of liver-stage infection, compared to PCR-based detection. This assay was used to evaluate treatment of sporozoite and delivery method on mouse infectivity, as well as the effects of age, sex and strain of mice. Finally, this assay was used to test the protective capacity of monoclonal antibody AB317; results strongly recapitulate the findings of previous work on this antibody.

Conclusions

The PbGFP-Luc line and in vivo bioluminescence imaging provide highly sensitive read-outs of liver-stage infection in mice, and this method can be useful to reliably evaluate potency of pre-erythrocytic interventions.
Intracluster correlation coefficients in the Greater Mekong Subregion for sample size calculations of cluster randomized malaria trials
Authors: Peerawaranun Pimnara , Landier Jordi , Nosten Francois H. , Nguyen Thuy-Nhien , Hien Tran Tinh , Tripura Rupam , Peto Thomas J. , Phommasone Koukeo , Mayxay Mayfong , Day Nicholas P. J. , Dondorp Arjen , White Nick , von Seidlein Lorenz , Mukaka Mavuto
Published: December 2019

Background

Sample size calculations for cluster randomized trials are a recognized methodological challenge for malaria research in pre-elimination settings. Positively correlated responses from the participants in the same cluster are a key feature in the estimated sample size required for a cluster randomized trial. The degree of correlation is measured by the intracluster correlation coefficient (ICC) where a higher coefficient suggests a closer correlation hence less heterogeneity within clusters but more heterogeneity between clusters.

Methods

Data on uPCR-detectedPlasmodium falciparumandPlasmodium vivaxinfections from a recent cluster randomized trial which aimed at interrupting malaria transmission through mass drug administrations were used to calculate the ICCs for prevalence and incidence ofPlasmodiuminfections. The trial was conducted in four countries in the Greater Mekong Subregion, Laos, Myanmar, Vietnam and Cambodia. Exact and simulation approaches were used to estimate ICC values for both the prevalence and the incidence of parasitaemia. In addition, the latent variable approach to estimate ICCs for the prevalence was utilized.

Results

The ICCs for prevalence ranged between 0.001 and 0.082 for all countries. The ICC from the combined 16 villages in the Greater Mekong Subregion were 0.26 and 0.21 forP.falciparumandP. vivaxrespectively. The ICCs for incidence of parasitaemia ranged between 0.002 and 0.075 for Myanmar, Cambodia and Vietnam. There were very high ICCs for incidence in the range of 0.701 to 0.806 in Laos during follow-up.

Conclusion

ICC estimates can help researchers when designing malaria cluster randomized trials. A high variability in ICCs and hence sample size requirements between study sites was observed. Realistic sample size estimates for cluster randomized malaria trials in the Greater Mekong Subregion have to assume high between cluster heterogeneity and ICCs. This work focused on uPCR-detected infections; there remains a need to develop more ICC references for trials designed around prevalence and incidence of clinical outcomes. Adequately powered trials are critical to estimate the benefit of interventions to malaria in a reliable and reproducible fashion.

Trial registration: ClinicalTrials.govNCT01872702. Registered 7 June 2013. Retrospectively registered.https://clinicaltrials.gov/ct2/show/NCT01872702
Intrafractional 6D head movement increases with time of mask fixation during stereotactic intracranial RT-sessions
Authors: Mangesius Julian , Seppi Thomas , Weigel Rocco , Arnold Christoph Reinhold , Vasiljevic Danijela , Goebel Georg , Lukas Peter , Ganswindt Ute , Nevinny-Stickel Meinhard
Published: December 2019

Background

The present study investigates the intrafractional accuracy of a frameless thermoplastic mask used for head immobilization during stereotactic radiotherapy. Non-invasive masks cannot completely prohibit head movements. Previous studies attempted to estimate the magnitude of intrafractional inaccuracy by means of pre- and postfractional measurements only. However, this might not be sufficient to accurately map also intrafractional head movements.

Materials and methods

Intrafractional deviation of mask-fixed head positions was measured in five patients during a total of 94 fractions by means of close-meshed repeated ExacTrac measurements (every 1.4 min) conducted during the entire treatment session. A median of six (range: 4 to 11) measurements were recorded per fraction, delivering a dataset of 453 measurements.

Results

Random errors (SD) for the x, y and z axes were 0.27 mm, 0.29 mm and 0.29 mm, respectively. Median 3D deviation was 0.29 mm. Of all 3D intrafractional motions, 5.5 and 0.4% exceeded 1 mm and 2 mm, respectively. A moderate correlation between treatment duration and mean 3D displacement was determined (rs = 0.45). Mean 3D deviation increased from 0.21 mm (SD = 0.26 mm) in the first 2 min to a maximum of 0.53 mm (SD = 0.31 mm) after 10 min of treatment time.

Conclusion

Pre- and post-treatment measurement is not sufficient to adequately determine the range of intrafractional head motion. Thermoplastic masks provide both reliable interfractional and intrafractional immobilization for image-guided stereotactic hypofractionated radiotherapy. Greater positioning accuracy may be obtained by reducing treatment duration (< 6 min) and applying intrafractional correction.

Trial registration

Clinicaltrials.gov, NCT03896555, Registered 01 April 2019 - retrospectively registered.
Intramedullary nailing for pertrochanteric fractures of proximal femur: a consecutive series of 323 patients treated with two devices
Authors: Catania Pompeo , Passaretti Daniele , Montemurro Giorgio , Ripanti Simone , Carbone Stefano , Candela Vittorio , Carnovale Michele , Gumina Stefano , Pallotta Francecsco
Published: December 2019

Introduction

Pertrochanteric fractures (PFs) frequently affect the lower limb of osteoporotic patients and represent an important cause of morbidity and mortality in the elderly. In this prospective randomized controlled trial, we have compared functional and radiological results and complications of patients affected by PFs treated with two intramedullary proximal femoral nails.

Materials

We enrolled 323 subjects with PFs, classified according to AO/OTA system as 31.A1 (pertrochanteric simple) and 31.A2 (pertrochanteric multifragmentary). Patients were divided into two groups according to the osteosynthesis devices: group A, Elos-Intrauma® nail (155 cases) and group B, Gamma 3-Stryker® nail (168 cases). Pre-operatively, the baseline characteristics of each patient (gender, age, weight and BMI) were collected. Intraoperative blood loss, subjective pain by visual analogue scale (VAS), esthetic satisfaction, functional scores of the hip by Harris Hip Score (HHS), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) were noted. The post-operative degree of fracture reduction was assessed. Each patient had a minimum follow-up of 12 months.

Results

The study group was composed of 106 male and 217 female with an average age of 85.4 (range, 65–90, standard deviation (SD) 5.95) years. No statistical differences about sex and age distribution were noted between the two groups. Group A reported lower intraoperative blood loss, 45 ml vs 51 ml, respectively (p < 0.001). There was not any statistical difference about operative time. Group A had a better reduction of fracture (p = 0.0347). The greatest difference was detectable comparing subgroups 31.A2 (p = 0.032). There were no statistical differences about complication frequency and the overall rate was 25% (80 cases). Finally, there was no difference in terms of VAS, HHS, and WOMAC score between the two groups on each follow-up. Patients of group A showed a higher subjective satisfaction index at 1 post-operative year, 7.42 (SD 1.19) vs 6.45 (SD 1.35) of group B (p < 0.001).

Conclusion

Elos® nail is a reliable device on a short-term follow-up and represents an alternative choice to the Gamma 3® nail, a well-known and appreciated system for over 25 years.
Biofilm production of coagulase-negative staphylococci isolated from rescued wild animals in the Republic of Korea
Authors: Lee Sangjun , Hwang Jehwi , Kim Jongwoon , Lee Joonyeop , Kim Hong-Cheul , Rhim Haerin , Han Jae-Ik
Published: December 2019

Biofilm production is a well-known causative factor of catheter- and medical device-related sepsis. Its high prevalence in coagulase-negative staphylococci (CoNS) has recently been reported. Information on biofilm production in CoNS isolated from wild animals is lacking. Herein, we studied the biofilm formation capabilities of CoNS isolated from rescued wild animals in the Republic of Korea. Swab samples were collected from the conjunctiva, nasal cavity, perianal area, and rectum for mammals while the sampling was done from the conjunctiva, oral mucosa, pericloacal area, and cloaca for birds. Isolation of CoNS was based on morphological and biochemical analyses along with molecular typing. Biofilm production was analyzed using 96-well plate based quantitative adherence assays. The studies demonstrated that CoNS of mammalian origin have higher biofilm-producing ability (70.4%) than the isolates from birds (62.5%). In particular, all methicillin-resistant (MR) CoNS isolated from mammals were capable of biofilm formation while only 63.3% of MR CoNS isolated from birds could produce biofilms. The MR CoNS isolated from mammals also had a significantly higher ability to form biofilms (100%) than methicillin susceptible CoNS (60.0%) than those isolates from birds. The findings show that wild animals may act as reservoirs as well as possible transmitters of biofilm-mediated antibiotic resistant genes.
Up-regulation of IGF2BP2 by multiple mechanisms in pancreatic cancer promotes cancer proliferation by activating the PI3K/Akt signaling pathway
Authors: Xu Xiaodong , Yu Yan , Zong Ke , Lv Pengwei , Gu Yuantin
Published: December 2019

Background

The survival of pancreatic cancer patients remains poor. However, the underlying molecular mechanism and new therapeutic target of pancreatic cancer are still needed to be found. Many studies have shown that the IGF2 mRNA-binding protein 2 (IGF2BP2) plays oncogenic roles in cancers. However, the clinical significance, role and molecular mechanisms of IGF2BP2 in pancreatic cancer remain unclear.

Methods

The expression of IGF2BP2 and miR-141 was detected in pancreatic cancer, and clinical significances were analyzed by statistical analysis. The function of IGF2BP2 and miR-141 was determined in vitro and in vivo, and the underlying mechanism was investigated. The gene copy number variation (CNV) of IGF2BP2 was analyzed based on The Cancer Genome Atlas (TCGA) dataset. microRNAs (miRNAs) regulating IGF2BP2 were predicted by online tools and confirmed by experiments.

Results

IGF2BP2 is overexpressed in pancreatic cancer tissues compared with control tissues. Upregulation of IGF2BP2 predicts shorter overall survival (OS) in pancreatic cancer patients by statistical analysis. IGF2BP2 overexpression is partially due to genomic amplification. Bioinformatics analyses and validation experiments showed that IGF2BP2 is a direct target of miR-141. A negative correlation between IGF2BP2 mRNA expression and the expression of miR-141 was observed in pancreatic cancer tissues and more importantly, reexpression of miR-141 rescued the oncogenic role of IGF2BP2. Moreover, upregulating IGF2BP2 expression promotes pancreatic cancer cell growth by activating the PI3K/Akt signaling pathway in vitro and in vivo.

Conclusions

We comprehensively reveal the oncogenic role of IGF2BP2 in pancreatic cancer carcinogenesis and confirm that genomic amplification and the silencing of miR-141 contribute to its activation. Our findings highlight that IGF2BP2 may be a promising molecular target for the treatment of pancreatic cancer.
OnTAD: hierarchical domain structure reveals the divergence of activity among TADs and boundaries
Authors: An Lin , Yang Tao , Yang Jiahao , Nuebler Johannes , Xiang Guanjue , Hardison Ross C. , Li Qunhua , Zhang Yu
Published: December 2019

The spatial organization of chromatin in the nucleus has been implicated in regulating gene expression. Maps of high-frequency interactions between different segments of chromatin have revealed topologically associating domains (TADs), within which most of the regulatory interactions are thought to occur. TADs are not homogeneous structural units but appear to be organized into a hierarchy. We present OnTAD, an optimized nested TAD caller from Hi-C data, to identify hierarchical TADs. OnTAD reveals new biological insights into the role of different TAD levels, boundary usage in gene regulation, the loop extrusion model, and compartmental domains. OnTAD is available at https://github.com/anlin00007/OnTAD.