bluuebunny/crossref_metadata_2025 huggingface dataset:
Saponin, Polyphenol, Flavonoid content and α-glucosidase Inhibitory Activity, Antioxidant Potential of Launaea sarmentosa Leaves grown in Ben Tre province, Vietnam
Authors: Them Le Thi , Tuong Nguyen Dung Phu , Thi Nhat Trinh Pham , Tong Hung Quach , Tuong Vi Le Nguyen , Trong Tuan Nguyen , Duc Lam Tri , Thuy Nguyen Van , Dung Le Tien
Published: July 2019

Launaea sarmentosa (Willd) Schultz-Bip.ex Kuntze, a creeping herb, belongs to family Asteraceae. It is distributed in sandy coasts of India, Sri Lanka, Malaysia, East Africa and Vietnam. In Vietnamese folk medicine, whole plant possess tonic, soporific, diuretic, laxative properties and the roots are used to benefit milk for mothers after childbirth, instead of Lactuca indica. Up to now, the phytochemicals and bioactivities of this plant are not yet been examined. The present study was designed to investigate the saponin, polyphenol and flavonoid contents as well as α-glucosidase inhibitory and antioxidant activities of the leaves of L. sarmentosa. Preliminary phytochemical screening of this plant were found to give positive reactions for flavonoid, saponin, alkaloid, tannin, and steroid compounds. The result of quantitative determination showed that the leaves contains high amount of polyphenol compounds (290.90 mg GAEs/g extract), lower amount of flavonoids (85.47 mg QEs/g extract) and the saponin content was found to be 10.8 % (per dry weight). As expected, the ethanol extract had a antioxidant potential with IC50 value of 24.15 μg/mL in DPPH experiment, compared to that of vitamin C. Meanwhile, the α-glucosidase inhibitory assay showed inhibited enzyme activity with IC50 value of 67.09 μg/ml.
Effect of Zn on microstructure evolution of Mg-Gd-Y-Nd-Zn-Zr alloy during heat treatment
Authors: Li T , Chen D J , Liu W , Yuan J W , Qu J
Published: July 2019

The effect of Zn on the microstructure evolution of Mg-7Gd-3Y-1Nd-xZn-0.5Zr (x=1.0, 2.0) (wt.%) alloys during homogenization and ageing heat treatment has been investigated systemically. The results indicate that as-cast 1 Zn alloy is composed mainly of α-Mg, Mg5(RE, Zn) eutectic phase, (Mg, Zn)3RE eutectic phase, stacking faults and block-like compounds rich in RE. Increasing of Zn content result in the disappearance of Mg5(RE, Zn) eutectic phase, but the volume fraction of 14H-typ LPSO phase is increasing, which has made it even more difficult to dissolve into the matrix during homogenization. After homogenization at 520 °C for 48 h, the 14H LPSO phase remains in the alloys with 2 wt.% Zn, but only compounds rich in RE can be seen in the alloy with 1 wt.%Zn. After ageing at 240°C for 18 h, the coherent β′ phase can be found both in 1Zn and 2Zn alloys, resulting in the increase of mechanical properties. The β′, β1 and stacking faults can be found in 1Zn and 2Zn alloys after ageing at 240°C for 100 h. However, it can be concluded that Zn can suppress the formation of LPSO phases but impede the precipitation of β′ and β1 during the aging process. The as-aged alloy with 1% Zn addition shows the optimal mechanical properties.
Experimental study on process of carbon fiber composites based on high temperature epoxy system curing
Authors: Liu Mingfan , Tong Zhipei , Gao Lei , Zhang Peng , Cheng Yongqi , Sun Yousong
Published: July 2019

The carbon fiber reinforced composite materials used in sliding friction pairs was studied in the paper. A type resin matrix of epoxy CYD-128 with 4-4’ Diamond dipheny methane(DDM) was prepared, and the curing dynamics parameters under different heating rates were studied by DSC thermal analysis, the curing step as 100°C/2h+160°C/2h was assured according to the β extrapolation method; The exsistance and the content change of the characteristic functional groups in the cured epoxy resin were analysed by the Infrared spectrum of the cured epoxy resin; The carbon fibers were processed with vacuum impregnation technology after glued, and the tensile fracture of the sample was observed as well as the micro morphology by SEM. The tests showed that the tensile strength of carbon fiber composite had grown 18.9% and the compression strength increased 25.9% by vacuum impregnation, and the carbon fibers were closely combined with the epoxy resin.
Innovative Application of Digitized Design in Traditional Manufacturing: An Example in the Powder Metallurgy Industry
Authors: Jih-Sheng Lo , Lee Kim C K , Shyh-Chour Huang
Published: July 2019

This research began with a series of in-depth interview with experts in the field of powder metallurgy, combined with literature review, a design process with a checklist of design quality for powder metallurgy cultural and creative products was established. We first verified this design process with the checklist by applying it to improve the design of an existing powder metallurgy cultural and creative product. Then we designed three cultural and creative products based on the established design process with the checklist of design quality and chose an icon of Hakka Lion among them to prepare a toolset and finished the test production of a sample, which all of our interviewed experts deemed as having excellent quality. Therefore, this research verified that the traditional technology of powder metallurgy could not only be utilized to produce mechanical parts, but it can also be applied in the cultural and creative industry to produce high value-added artifacts that are typically full of very complex curvature surfaces. In addition, the design process with the checklist of design quality for powder metallurgy cultural and creative products was also verified to be applicable. Besides, this research also introduced the technology of digitized design to the design and manufacturing process of an old powder metallurgy manufacturer successfully. Through which we enhanced the integrity and efficiency of this production process significantly. Hope that the result of this research will be helpful for the powder metallurgy industry in Miao-li County of Taiwan to find a way out.
Design of Curling Sports Service Robot
Authors: Chunlai Tian , Qideng Chen , Quanquan Feng , Sichun Luo
Published: July 2019

In order to implement handling and unmanned maintenance for curling in sports, a service robot is designed in this paper. It could save professional labor costs and improve work efficiency for the curling sports service with strong usability. Through analysis on the curling’s feature, the mechanical model of the service robot is established by three-dimensional CAD software. The robot consists two functional sub robots. One is the curling handling robot and the other one is the curling maintenance robot. The design includes the robotic arm systems, maintenance systems, intelligent identification, industrial CT inspection systems and pneumatic control systems. Referred to the mechanical structure of the excavator, the mechanical arm movement is driven by the cylinder. The handling curling has strong stability. The maintenance system adopts a circular layout design. The simulated motion of the design is carried out with the rationality of mechanical structure analyzed. It can make reasonable serve sports and improve work efficiency significantly.
The Control Method of Pigging Slug Flow for Multiphase Subsea Pipeline
Authors: Meng Li , Hao Xu
Published: July 2019

This paper analyses the causes of the large number of slug flows by OLGA software and analyses its control methods. It can be seen from the simulation that closing the high-production gas well to control the pigging flow rate and venting time can effectively control the volume of the pigging slug flow, thereby reducing the volume of the slug flow trap and reducing the platform area, thereby reducing the overall engineering investment.
Resource use for older people hospitalised due to injury in a Canadian integrated trauma system: a retrospective multicenter cohort study
Authors: Farhat Imen , Moore Lynne , Porgo Teegwendé Valérie , Patton Marie-Pier , Tardif Pier-Alexandre , Truchon Catherine , Berthelot Simon , Stelfox Henry T , Gabbe Belinda J , Lauzier François , Turgeon Alexis F , Clément Julien
Published: July 2019

Background

Injuries represent one of the leading causes of preventable morbidity and mortality. For countries with ageing populations, admissions of injured older patients are increasing exponentially. Yet, we know little about hospital resource use for injured older patients. Our primary objective was to evaluate inter-hospital variation in the risk-adjusted resource use for injured older patients. Secondary objectives were to identify the determinants of resource use and evaluate its association with clinical outcomes.

Methods

We conducted a multicenter retrospective cohort study of injured older patients (≥65 years) admitted to any trauma centres in the province of Quebec (2013–2016, N = 33,184). Resource use was estimated using activity-based costing and modelled with multilevel linear models. We conducted separate subgroup analyses for patients with trauma and fragility fractures.

Results

Risk-adjusted resource use varied significantly across trauma centres, more for older patients with fragility fractures (intra-class correlation coefficients [ICC] = 0.093, 95% CI [0.079, 0.102]) than with trauma (ICC = 0.047, 95% CI = 0.035–0.051). Risk-adjusted resource use increased with age, and the number of comorbidities, and varied with discharge destination (P < 0.001). Higher hospital resource use was associated with higher incidence of complications for trauma (Pearson correlation coefficient [r] = 0.5, 95% CI = 0.3–0.7) and fragility fractures (r = 0.5, 95% CI = 0.3–0.7) and with higher mortality for fragility fractures (r = 0.4, 95% CI = 0.2–0.6).

Conclusions

We observed significant inter-hospital variations in resource use for injured older patients. Hospitals with higher resource use did not have better clinical outcomes. Hospital resource use may not always positively impact patient care and outcomes. Future studies should evaluate mechanisms, by which hospital resource use impacts care.
Widespread FUS mislocalization is a molecular hallmark of amyotrophic lateral sclerosis
Authors: Tyzack Giulia E , Luisier Raphaelle , Taha Doaa M , Neeves Jacob , Modic Miha , Mitchell Jamie S , Meyer Ione , Greensmith Linda , Newcombe Jia , Ule Jernej , Luscombe Nicholas M , Patani Rickie
Published: July 2019

Mutations causing amyotrophic lateral sclerosis (ALS) clearly implicate ubiquitously expressed and predominantly nuclear RNA binding proteins, which form pathological cytoplasmic inclusions in this context. However, the possibility that wild-type RNA binding proteins mislocalize without necessarily becoming constituents of cytoplasmic inclusions themselves remains relatively unexplored. We hypothesized that nuclear-to-cytoplasmic mislocalization of the RNA binding protein fused in sarcoma (FUS), in an unaggregated state, may occur more widely in ALS than previously recognized. To address this hypothesis, we analysed motor neurons from a human ALS induced-pluripotent stem cell model caused by the VCP mutation. Additionally, we examined mouse transgenic models and post-mortem tissue from human sporadic ALS cases. We report nuclear-to-cytoplasmic mislocalization of FUS in both VCP-mutation related ALS and, crucially, in sporadic ALS spinal cord tissue from multiple cases. Furthermore, we provide evidence that FUS protein binds to an aberrantly retained intron within the SFPQ transcript, which is exported from the nucleus into the cytoplasm. Collectively, these data support a model for ALS pathogenesis whereby aberrant intron retention in SFPQ transcripts contributes to FUS mislocalization through their direct interaction and nuclear export. In summary, we report widespread mislocalization of the FUS protein in ALS and propose a putative underlying mechanism for this process.
The Demographic Transition and the Position of Women: a Marriage Market Perspective
Authors: Bhaskar V
Published: July 2019

Secular trends in cohort size cause large marriage market imbalances due to the age gap at marriage between men and women. Positive cohort growth adversely affects women in South Asia and sub-Saharan Africa. Secular decline improves their position in East Asia. I show that the age gap at marriage will not adjust in order to equilibrate the marriage market in response to persistent imbalances, even though it accommodates transitory shocks. This implies large distributional consequences on the sexes, and may increase dowries. I also analyse transition dynamics between steady states and examine how age gaps and transfers adjust in the transition.
QTL analysis of naturalSaccharomyces cerevisiaeisolates reveals unique alleles involved in lignocellulosic inhibitor tolerance
Authors: de Witt R N , Kroukamp H , Van Zyl W H , Paulsen I T , Volschenk H
Published: July 2019

Decoding the genetic basis of lignocellulosic inhibitor tolerance in Saccharomyces cerevisiae is crucial for rational engineering of bioethanol strains with enhanced robustness. The genetic diversity of natural strains present an invaluable resource for the exploration of complex traits of industrial importance from a pan-genomic perspective to complement the limited range of specialised, tolerant industrial strains. Natural S. cerevisiae isolates have lately garnered interest as a promising toolbox for engineering novel, genetically encoded tolerance phenotypes into commercial strains. To this end, we investigated the genetic basis for lignocellulosic inhibitor tolerance of natural S. cerevisiae isolates. A total of 12 quantitative trait loci underpinning tolerance were identified by next-generation sequencing linked bulk-segregant analysis of superior interbred pools. Our findings corroborate the current perspective of lignocellulosic inhibitor tolerance as a multigenic, complex trait. Apart from a core set of genetic variants required for inhibitor tolerance, an additional genetic background-specific response was observed. Functional analyses of the identified genetic loci revealed the uncharacterised ORF, YGL176C and the bud-site selection XRN1/BUD13 as potentially beneficial alleles contributing to tolerance to a complex lignocellulosic inhibitor mixture. We present evidence for the consideration of both regulatory and coding sequence variants for strain improvement.
Skp1 isoforms are differentially modified by a dual function prolyl 4-hydroxylase/N-acety lglucosaminyltransferase in a plant pathogen
Authors: van der Wel Hanke , Gas-Pascual Elisabet , West Christopher M
Published: July 2019

Skp1 is hydroxylated by an O2-dependent prolyl hydroxylase (PhyA) that contributes to O2-sensing in the social amoeba Dictyostelium and the mammalian pathogen Toxoplasma gondii. HO-Skp1 is subject to glycosylation and the resulting pentasaccharide affects Skp1 conformation in a way that influences association of Skp1 with F-box proteins, and potentially the assembly of E3(SCF) ubiquitin ligase complexes that mediate the polyubiquitination of target proteins that are degraded in the 26S-proteasome. To investigate the conservation and specificity of these modifications, we analyzed proteins from the oomycete Pythium ultimum, an important crop plant pathogen. Putative coding sequences for Pythium’s predicted PhyA and first glycosyltransferase in the predicted five-enzyme pathway, a GlcNAc-transferase (Gnt1), predict a bifunctional enzyme (Phgt) that, when expressed in Dictyostelium, rescued a knockout of phyA but not gnt1. Though recombinant Phgt was also unable to glycosylate Dictyostelium HO-Skp1, it could hydrolyze UDP-GlcNAc and modify a synthetic hydroxypeptide from Dictyostelium Skp1. Pythium encodes two highly similar Skp1 isoforms, but only Skp1A was efficiently hydroxylated and glycosylated in vitro. While kinetic analysis revealed no evidence for processive processing of Skp1, the physical linkage of the two activities implies dedication to Skp1 in vivo. These findings indicate a widespread occurrence of the Skp1 modification pathway across protist phylogeny, suggest that both Gnt1 and PhyA are specific for Skp1 and indicate that the second Skp1 provides a bypass mechanism for O2-regulation in Pythium and other protists that conserve this gene.
Instruments for the Assessment of Behavioral and Psychosocial Functioning in Duchenne and Becker Muscular Dystrophy; a Systematic Review of the Literature
Authors: Hellebrekers Danique M J , Lionarons Judith M , Faber Catharina G , Klinkenberg Sylvia , Vles Johan S H , Hendriksen Jos G M
Published: July 2019

Objective

This systematic review aims to provide an overview of instruments used to assess behavioral and psychosocial functioning of patients with Duchenne and Becker muscular dystrophy, as well as to review the psychometric properties and applicability of these instruments.

Methods

Five databases (Embase, Psyc.info, ERIC, Pubmed/Medline, and Cochrane) were searched from inception to June, 2018. Potential articles were rated by two independent reviewers. A predefined PROSPERO form (CRD42017074518) was used to extract data from included articles.

Results

Sixty-one instruments were used in 54 studies. The Child Behavior Checklist is commonly used, but it lacks disease specific psychometric information. Sixteen instruments that contained disease specific psychometric information were included for final evaluation. The results displayed three instruments that are potentially valid for screening of psychosocial problems: The Psychosocial Adjustment and Role Skills Scale 3rd edition, the Pediatric Quality of Life Inventory Generic module, and the Life Satisfaction Index for Adolescents with Duchenne muscular dystrophy. Appropriate instruments for screening of behavioral problems may be: the Strengths and Difficulties Questionnaire, the Generalized Anxiety Disorder-7 item questionnaire, and the Patient Health Questionnaire-9 item questionnaire.

Conclusions

Further research on psychometric properties of screening instruments is crucial to ascertain a gold standard for clinical and research purposes. Meanwhile, for definite diagnostics purposes we recommend a multimethod, multisource, multisetting assessment in this high-risk population.
Companion-driven evolution of massive stellar binaries
Authors: Rose Sanaea C , Naoz Smadar , Geller Aaron M
Published: July 2019

At least $70\, {\rm per\, cent}$ of massive OBA-type stars reside in binary or higher order systems. The dynamical evolution of these systems can lend insight into the origins of extreme phenomena such as X-ray binaries and gravitational wave sources. In one such dynamical process, the Eccentric Kozai–Lidov (EKL) mechanism, a third companion star alters the secular evolution of a binary system. For dynamical stability, these triple systems must have a hierarchical configuration. We explore the effects of a distant third companion’s gravitational perturbations on a massive binary’s orbital configuration before significant stellar evolution has taken place (≤10 Myr). We include tidal dissipation and general relativistic precession. With large (38 000 total) Monte Carlo realizations of massive hierarchical triples, we characterize imprints of the birth conditions on the final orbital distributions. Specifically, we find that the final eccentricity distribution over the range of 0.1–0.7 is an excellent indicator of its birth distribution. Furthermore, we find that the period distributions have a similar mapping for wide orbits. Finally, we demonstrate that the observed period distribution for approximately 10-Myr-old massive stars is consistent with EKL evolution.
The distinct stellar metallicity populations of simulated Local Group dwarfs
Authors: Genina Anna , Frenk Carlos S , Benítez-Llambay Alejandro , Cole Shaun , Navarro Julio F , Oman Kyle A , Fattahi Azadeh
Published: July 2019

A number of Local Group dwarf galaxies are known to have two spatially segregated stellar metallicity populations, a centrally concentrated metal-rich population, and a more extended metal-poor population. In this work we discuss mechanisms that lead to the formation of two spatially segregated metallicity populations. Using a set of high-resolution hydrodynamical simulations of Local Group-like environments, we select a sample of satellite and field galaxies, spanning the stellar mass range 106–109 M⊙, that exhibit bimodality in their metallicity distributions. Among those, we identify a subsample with a strong spatial segregation in the two populations. We find three distinct mechanisms for their formation. In field dwarfs and in a small fraction of satellites, a merger causes the metal-poor stars to migrate to larger radii and encourages the available gas to sink to the centre of the dwarf. Most of the gas is subsequently blown out of the halo through star formation feedback, but the remaining gas is consumed in the formation of a metal-rich population. In the exclusive case of satellites that have retained some of their gas at infall, it is the compression of this gas by ram pressure near pericentre that triggers the formation of metal-rich stars, whilst simultaneously preventing star formation at larger radii through stripping. Additionally, in a small number of field and satellite dwarfs, interactions with gaseous filaments and other galaxies can result in the formation of a metal-rich population. Regardless of the formation mechanism, a history of mergers typically enhances the spatial segregation.
TERC promotes cellular inflammatory response independent of telomerase
Authors: Liu Haiying , Yang Yiding , Ge Yuanlong , Liu Juanhong , Zhao Yong
Published: July 2019

TERC is an RNA component of telomerase. However, TERC is also ubiquitously expressed in most human terminally differentiated cells, which don’t have telomerase activity. The function of TERC in these cells is largely unknown. Here, we report that TERC enhances the expression and secretion of inflammatory cytokines by stimulating NK-κB pathway in a telomerase-independent manner. The ectopic expression of TERC in telomerase-negative cells alters the expression of 431 genes with high enrichment of those involved in cellular immunity. We perform genome-wide screening using a previously identified ‘binding motif’ of TERC and identify 14 genes that are transcriptionally regulated by TERC. Among them, four genes (LIN37, TPRG1L, TYROBP and USP16) are demonstrated to stimulate the activation of NK-κB pathway. Mechanistically, TERC associates with the promoter of these genes through forming RNA–DNA triplexes, thereby enhancing their transcription. In vivo, expression levels of TERC and TERC target genes (TYROBP, TPRG1L and USP16) are upregulated in patients with inflammation-related diseases such as type II diabetes and multiple sclerosis. Collectively, these results reveal an unknown function of TERC on stimulating inflammatory response and highlight a new mechanism by which TERC modulates gene transcription. TERC may be a new target for the development of anti-inflammation therapeutics.
The Pol IV largest subunit CTD quantitatively affects siRNA levels guiding RNA-directed DNA methylation
Authors: Wendte Jered M , Haag Jeremy R , Pontes Olga M , Singh Jasleen , Metcalf Sara , Pikaard Craig S
Published: July 2019

In plants, nuclear multisubunit RNA polymerases IV and V are RNA Polymerase II-related enzymes that synthesize non-coding RNAs for RNA-directed DNA methylation (RdDM) and transcriptional gene silencing. Here, we tested the importance of the C-terminal domain (CTD) of Pol IV’s largest subunit given that the Pol II CTD mediates multiple aspects of Pol II transcription. We show that the CTD is dispensable for Pol IV catalytic activity and Pol IV termination-dependent activation of RNA-DEPENDENT RNA POLYMERASE 2, which partners with Pol IV to generate dsRNA precursors of the 24 nt siRNAs that guide RdDM. However, 24 nt siRNA levels decrease ∼80% when the CTD is deleted. RNA-dependent cytosine methylation is also reduced, but only ∼20%, suggesting that siRNA levels typically exceed the levels needed for methylation of most loci. Pol IV-dependent loci affected by loss of the CTD are primarily located in chromosome arms, similar to loci dependent CLSY1/2 or SHH1, which are proteins implicated in Pol IV recruitment. However, deletion of the CTD does not phenocopy clsy or shh1 mutants, consistent with the CTD affecting post-recruitment aspects of Pol IV activity at target loci.
Copepod carcasses in the subtropical convergence zone of the Sargasso Sea: implications for microbial community composition, system respiration and carbon flux
Authors: Tang Kam W , Backhaus Liv , Riemann Lasse , Koski Marja , Grossart Hans-Peter , Munk Peter , Nielsen Torkel Gissel
Published: July 2019

The oligotrophic subtropical gyre covers a vast area of the Atlantic Ocean. Decades of time-series monitoring have generated detailed temporal information about zooplankton species and abundances at fixed locations within the gyre, but their live/dead status is often omitted, especially in the dynamic subtropical convergence zone (STCZ) where the water column stratification pattern can change considerably across the front as warm and cold water masses converge. We conducted a detailed survey in the North Atlantic STCZ and showed that over 85% of the copepods were typically concentrated in the upper 200 m. Copepod carcasses were present in all samples and their proportional numerical abundances increased with depth, reaching up to 91% at 300–400 m. Overall, 14–19% of the copepods within the upper 200 m were carcasses. Shipboard experiments showed that during carcass decomposition, microbial respiration increased, and the bacterial community associated with the carcasses diverged from that in the ambient water. Combining field and experimental data, we estimated that decomposing copepod carcasses constitute a negligible oxygen sink in the STCZ, but sinking carcasses may represent an overlooked portion of the passive carbon sinking flux and should be incorporated in future studies of carbon flux in this area.
Predictors of successful discontinuation of biologic and targeted synthetic DMARDs in patients with rheumatoid arthritis in remission or low disease activity: a systematic literature review
Authors: Schlager Lukas , Loiskandl Michaela , Aletaha Daniel , Radner Helga
Published: July 2019

Objective

To systematically review possible predictors of successful discontinuation of biologic or targeted synthetic DMARDs (b/tsDMARDs) in RA patients in remission or low disease activity.

Methods

MEDLINE database and Cochrane Library were scanned for studies that discontinued b/tsDMARDs in remission/low disease activity and searched for predictors of successful discontinuation. Additionally, EULAR and ACR meeting abstracts were hand searched.

Results

Thirty-four studies with a total of 5724 patients were included. Predictors of successful b/tsDMARD discontinuation were (number of studies): low disease activity (n = 13), better physical function (n = 6), low or absence of rheumatoid factor (n = 5) or ACPA (n = 3), low levels of CRP (n = 3) or ESR (n = 3), shorter disease duration (n = 3), low signals of disease activity by ultrasound (n = 3). Only one study with high risk of bias was identified on tsDMARD discontinuation.

Conclusion

Several predictors of successful bDMARD discontinuation were identified. Although studies are heterogeneous, these predictors may inform clinical decision making in patients who are considered for a potential bDMARD discontinuation.
Methodological considerations when analysing and interpreting real-world data
Authors: Stürmer Til , Wang Tiansheng , Golightly Yvonne M , Keil Alex , Lund Jennifer L , Jonsson Funk Michele
Published: July 2019

In the absence of relevant data from randomized trials, nonexperimental studies are needed to estimate treatment effects on clinically meaningful outcomes. State-of-the-art study design is imperative for minimizing the potential for bias when using large healthcare databases (e.g. claims data, electronic health records, and product/disease registries). Critical design elements include new-users (begin follow-up at treatment initiation) reflecting hypothetical interventions and clear timelines, active-comparators (comparing treatment alternatives for the same indication), and consideration of induction and latent periods. Propensity scores can be used to balance measured covariates between treatment regimens and thus control for measured confounding. Immortal-time bias can be avoided by defining initiation of therapy and follow-up consistently between treatment groups. The aim of this manuscript is to provide a non-technical overview of study design issues and solutions and to highlight the importance of study design to minimize bias in nonexperimental studies using real-world data.
Prevalence and Pattern of Congenital Anomalies in a Tertiary Hospital in Central Vietnam
Authors: Giang Hoang Thi Nam , Bechtold-Dalla Pozza Susanne , Ulrich Sarah , Linh Le Khac , Tran Hoang Thi
Published: July 2019

Background

Burden and pattern of congenital anomalies are insufficiently reported in Vietnam. This study aims to determine the prevalence and pattern of congenital anomalies in neonates in a tertiary hospital in central Vietnam.

Methods

A prospective cross-sectional study recruited all newborns with congenital anomalies in Da Nang Hospital for Women and Children—where nearly 60% neonates in the city are delivered.

Results

Over a 1-year period, 551 out of 14 335 registered live births were found to have congenital anomalies, equivalent to an overall prevalence of 384.4 per 10 000 live births. Congenital heart defects were the most common type (52.3%) with the prevalence of 200.9 per 10 000 live births, followed by anomalies of musculoskeletal system, digestive system.

Conclusions

This study revealed a high prevalence of congenital anomalies with the most common type being congenital heart defects in central Vietnam compared to both higher income countries and resource-limited settings.
Clinical and epidemiologic profile of venomous snakebites in Chongqing Wuling mountainous area, western China
Authors: Chen Xi , He Hongmei , Cai Hongke
Published: July 2019

Background

In China, venomous snakebites are an important medical emergency and cause of hospital admission, but few studies have looked at the clinical and epidemiologic profile of human snakebite victims.

Methods

We conducted a retrospective study of 440 snakebite cases encountered at a single hospital in the Chongqing Wuling mountainous area of western China from July 2004 to August 2018. Data were collected from the electronic medical record system.

Results

The majority of bite victims were male (58.4%), 41–60 y of age (37.9%) and the bites occurred during the daytime (51.1%) in July–September (62.5%). The lower limbs were the most vulnerable sites to snakebites (73.9%). The most common local toxicity consisted of pain (86.1%), oedema (78.4%) and bleeding (35.9%). Of the systemic toxicities, haematuria (14.3%) and ophthalmoplegia (9.5%) were common. The majority (86.4%) of individuals presented to the hospital within 6 h.

Conclusions

This study describes the clinical and epidemiologic profile of venomous snakebites in the Chongqing Wuling mountainous area of western China. Multicentre prospective studies were needed in the entire country of China.
Canker and Wood Rot Pathogens Present in Young Apple Trees and Propagation Material in the Western Cape of South Africa
Authors: Havenga Minette , Gatsi Greg M. , Halleen Francois , Spies Christoffel F. J. , van der Merwe Rhona , Mostert Lizel
Published: July 2019

Canker and wood rot pathogens cause dieback and, in severe cases, the death of young apple trees. Recently, a higher occurrence of cankers was observed on 1-year-old apple trees in the Western Cape Province of South Africa. This study aimed to assess the phytosanitary status of nursery trees and propagation material as possible inoculum sources for canker pathogens. Thirteen 1-year-old apple orchards showing canker or dieback symptoms were sampled. Certified nursery apple trees were collected from four nurseries as well as scion and rootstock mother plant material. Isolations were made from the discoloration observed in the vascular tissue of the plant parts and from asymptomatic material. Possible canker and wood rot species were identified with PCR and sequence comparisons of the relevant gene regions and phylogenetic analyses. Similar canker and wood rot species were isolated from 1-year-old diseased apple trees, nursery apple trees, and the propagation material. Forty-five fungal species associated with canker or wood rot symptoms were identified. The top five most abundant fungal species found causing disease on commercial 1-year-old trees were also found in high numbers causing latent infection in certified apple nursery trees. These species were Didymosphaeria rubi-ulmifolii sensu lato, Diplodia seriata, Schizophyllum commune, Didymella pomorum, and Coniochaeta fasciculata, with D. rubi-ulmifolii sensu lato being the dominant species in both sampling materials. In all, 65% of certified nursery apple trees, 5% of scion shoots used for budding, and 21% of rooted rootstock cuttings from layer blocks had latent infections of canker and wood rot pathogens. Pathogenicity trials were conducted with isolates of 39 species, inoculated onto 2-year-old branches of 14-year-old Golden Delicious trees. All species caused lesions that were significantly longer than the control. This study confirmed the presence of canker and wood rot pathogens in apple propagation material as well as certified nursery apple trees, which will aid the improvement of management practices in nurseries.
Imaging live bacteria at the nanoscale: comparison of immobilisation strategies
Authors: Benn Georgina , Pyne Alice L. B. , Ryadnov Maxim G. , Hoogenboom Bart W
Published: July 2019

Atomic force microscopy (AFM) provides an effective, label-free technique enabling the imaging of live bacteria under physiological conditions with nanometre precision. However, AFM is a surface scanning technique, and the accuracy of its performance requires the effective and reliable immobilisation of bacterial cells onto substrates. Here, we compare the effectiveness of various chemical approaches to facilitate the immobilisation of Escherichia coli onto glass cover slips in terms of bacterial adsorption, viability and compatibility with correlative imaging by fluorescence microscopy. We assess surface functionalisation using gelatin, poly-L-lysine, Cell-Tak™, and Vectabond®. We describe how bacterial immobilisation, viability and suitability for AFM experiments depend on bacterial strain, buffer conditions and surface functionalisation. We demonstrate the use of such immobilisation by AFM images that resolve the porin lattice on the bacterial surface; local degradation of the bacterial cell envelope by an antimicrobial peptide (Cecropin B); and the formation of membrane attack complexes on the bacterial membrane.
Functional maturation of human neural stem cells in a 3D bioengineered brain model enriched with fetal brain-derived matrix
Authors: Sood Disha , Cairns Dana M. , Dabbi Jayanth M. , Ramakrishnan Charu , Deisseroth Karl , Black Lauren D. , Santaniello Sabato , Kaplan David L.
Published: July 2019

Brain extracellular matrix (ECM) is often overlooked in vitro brain tissue models, despite its instructive roles during development. Using developmental stage-sourced brain ECM in reproducible 3D bioengineered culture systems, we demonstrate enhanced functional differentiation of human induced neural stem cells (hiNSCs) into healthy neurons and astrocytes. Particularly, fetal brain tissue-derived ECM supported long-term maintenance of differentiated neurons, demonstrated by morphology, gene expression and secretome profiling. Astrocytes were evident within the second month of differentiation, and reactive astrogliosis was inhibited in brain ECM-enriched cultures when compared to unsupplemented cultures. Functional maturation of the differentiated hiNSCs within fetal ECM-enriched cultures was confirmed by calcium signaling and unsupervised cluster analysis. Additionally, the study identified native biochemical cues in decellularized ECM with notable comparisons between fetal and adult brain-derived ECMs. The development of novel brain-specific biomaterials for generating mature in vitro brain models provides an important path forward for interrogation of neuron-glia interactions.
Meta-gene markers predict meningioma recurrence with high accuracy
Authors: Zador Zsolt , Landry Alexander , Haibe-Kains Benjamin , Cusimano Michael D.
Published: July 2019

Background

Meningiomas, the most common adult brain tumors, recur in up to half of cases[1–3]. This requires timely intervention and therefore accurate risk assessment of recurrence is essential. Our current practice relies heavily on histological grade and extent of surgical excision to predict meningioma recurrence. However, prediction accuracy can be as poor as 50% for low or intermediate grade tumors, which constitute more than 90% of all cases. Moreover, attempts to find molecular markers, particularly for predicting recurrence of intermediate tumors have been impeded by low[4] or heterogenous[5–8] genetic signal. We therefore sought to apply systems-biology approaches to transcriptomic data to better predict meningioma recurrence.

Methods

We apply gene co-expression networks to a cohort of 252 adult patients from the publicly-available genetic repository Gene Expression Omnibus. Resultant gene clusters (“modules”) were represented by the first principle component of their expression levels, and their ability to predict recurrence assessed with a logistic regression model. External validation was done using an independent merged cohort of 108 patients using the same modules. We used the bioinformatics database DAVID[9] to examine the gene ontology associations of each module.

Results

Using gene co-expression analysis, we were able predict tumor recurrence with high accuracy using a single module which mapped to cell cycle-related functions (AUC of 0.81 ± 0.09 in external validation). Further, the module maintained its accuracy with removal of up to 20 of it’s most individually predictive genes, suggesting robustness against noise at the single gene level.

Conclusions

With the easy accessibility of gene panels in healthcare diagnostics, our results offer a basis for routine molecular testing in meningioma management.
MethylNet: An Automated and Modular Deep Learning Approach for DNA Methylation Analysis
Authors: Levy Joshua J. , Titus Alexander J. , Petersen Curtis L. , Chen Youdinghuan , Salas Lucas A. , Christensen Brock C.
Published: July 2019

Background

DNA methylation (DNAm) is an epigenetic regulator of gene expression programs that can be altered by environmental exposures, aging, and in pathogenesis. Traditional analyses that associate DNAm alterations with phenotypes suffer from multiple hypothesis testing and multi-collinearity due to the high-dimensional, continuous, interacting and non-linear nature of the data. Deep learning analyses have shown much promise to study disease heterogeneity. DNAm deep learning approaches have not yet been formalized into user-friendly frameworks for execution, training, and interpreting models. Here, we describe MethylNet, a DNAm deep learning method that can construct embeddings, make predictions, generate new data, and uncover unknown heterogeneity with minimal user supervision.

Results

The results of our experiments indicate that MethylNet can study cellular differences, grasp higher order information of cancer sub-types, estimate age and capture factors associated with smoking in concordance with known differences.

Conclusion

The ability of MethylNet to capture nonlinear interactions presents an opportunity for further study of unknown disease, cellular heterogeneity and aging processes.
SynToxProfiler: an approach for top drug combination selection based on integrated profiling of synergy, toxicity and efficacy
Authors: Ianevski Aleksandr , Kononov Alexander , Timonen Sanna , Aittokallio Tero , Giri Anil K
Published: July 2019

Drug combinations are becoming a standard treatment of many complex diseases due to their capability to overcome resistance to monotherapy. Currently, in the preclinical drug combination screening, the top hits for further study are often selected based on synergy alone, without considering the combination efficacy and toxicity effects, even though these are critical determinants for the clinical success of a therapy. To promote the prioritization of drug combinations based on integrated analysis of synergy, efficacy and toxicity profiles, we implemented a web-based open-source tool, SynToxProfiler (Synergy-Toxicity-Profiler). When applied to 20 anti-cancer drug combinations tested both in healthy control and T-cell prolymphocytic leukemia (T-PLL) patient cells, as well as to 77 anti-viral drug pairs tested on Huh7 liver cell line with and without Ebola virus infection, SynToxProfiler was shown to prioritize synergistic drug pairs with higher selective efficacy (difference between efficacy and toxicity level) as top hits, which offers improved likelihood for clinical success.
Domain-centric dissection and classification of prokaryotic poly(3-hydroxyalkanoate) synthases
Authors: Liu Zhanzhong , Zhu Zuobin , Yang Jianye , Wu Sheng , Liu Qinghua , Wang Mengmeng , Cheng Huiling , Yan Jiawei , Wang Liang
Published: July 2019

Although many enzymes and multiple pathways involve in Polyhydroxyalkanoates (PHAs) synthesis, PHA synthases play a determinant role in the process, which include three subunits of PhaC, PhaE, and PhaR. Currently, PHA synthases are categorized into four classes according to its primary sequences, substrate specificity, and subunit composition. However, theoretical analysis of PHA synthases from the domain perspective has not been performed. In this study, we dissected PHA synthases thoroughly through analysis of domain organization. Both referenced bacterial and archaeal proteomes were then screened for the presence and absence of different PHA synthases along NCBI taxonomy ID-based phylogenetic tree. In addition, sequences annotated as bacterial and archaeal PhaCs in UniProt database were also analyzed for domain organizations and interactions. In sum, the in-silico study provided a better understanding of the domain features of PHA synthases in prokaryotes, which also assisted in the production of PHA polymers with optimized chemical properties.
Evaluating the Potential of Younger Cases and Older Controls Cohorts to Improve Discovery Power in Genome-wide Association Studies of Late-onset Diseases
Authors: Oliynyk Roman Teo
Published: July 2019

For more than a decade, genome-wide association studies have been making steady progress in discovering the causal gene variants that contribute to late-onset human diseases. Polygenic late-onset diseases in an aging population display the risk allele frequency decrease at older ages, caused by individuals with higher polygenic risk scores becoming ill proportionately earlier and bringing about a change in the distribution of risk alleles between new cases and the as-yet-unaffected population. This phenomenon is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes, while for late-onset diseases with relatively lower prevalence and heritability, exemplified by cancers, the effect is significantly lower. Computer simulations have determined that genome-wide association studies of the late-onset polygenic diseases showing high cumulative incidence together with high initial heritability will benefit from using the youngest possible age-matched cohorts. Moreover, rather than using age-matched cohorts, study cohorts combining the youngest possible cases with the oldest possible controls may significantly improve the discovery power of genome-wide association studies.
Autocatalytic chemical networks preceded proteins and RNA in evolution
Authors: Xavier Joana C. , Hordijk Wim , Kauffman Stuart , Steel Mike , Martin William F.
Published: July 2019

Modern cells embody metabolic networks containing thousands of elements and form autocatalytic molecule sets that produce copies of themselves. How the first self-sustaining metabolic networks arose at life’ s origin is a major open question. Autocatalytic molecule sets smaller than metabolic networks were proposed as transitory intermediates at the origin of life, but evidence for their role in prebiotic evolution is lacking. Here we identify reflexively autocatalytic food-generated networks (RAFs)—self-sustaining networks that collectively catalyze all their reactions—embedded within microbial metabolism. RAFs in the metabolism of ancient anaerobic autotrophs that live from H2 and CO2 generate amino acids and bases, the monomeric components of protein and RNA, and acetyl-CoA, but amino acids and bases do not generate metabolic RAFs, indicating that small-molecule catalysis preceded polymers in biochemical evolution. RAFs uncover intermediate stages in the origin of metabolic networks, narrowing the gaps between early-Earth chemistry and life.
Isolation of secreted proteins fromDrosophilaovaries and embryos throughin vivoBirA-mediated biotinylation
Authors: Stevens Leslie M. , Zhang Yuan , Volnov Yuri , Chen Geng , Stein David S.
Published: July 2019

The extraordinarily strong non-covalent interaction between biotin and avidin (kD = 10-14-10-16) has permitted this interaction to be used in a wide variety of experimental contexts. The Biotin Acceptor Peptide (BAP), a 15 amino acid motif that can be biotinylated by theE. coliBirA protein, has been fused to proteins of interest, making them substrates forin vivobiotinylation. Here we report on the construction and characterization of a modified BirA bearing signals for secretion and endoplasmic reticulum (ER) retention, for use in experimental contexts requiring biotinylation of secreted proteins. When expressed in theDrosophilafemale germline or ovarian follicle cells under Gal4-mediated transcriptional control, the modified BirA protein could be detected and shown to be enzymatically active in ovaries and progeny embryos. Surprisingly, however, it was not efficiently retained in the ER, and instead appeared to be secreted. To determine whether this secreted protein, now designated secBirA, could biotinylate secreted proteins, we generated BAP-tagged versions of two secretedDrosophilaproteins, Torsolike (Tsl) and Gastrulation Defective (GD), which are normally expressed maternally and participate in embryonic pattern formation. Both Tsl-BAP and GD-BAP were shown to exhibit normal patterning activity. Co-expression of Tsl-BAP together with secBirA in ovarian follicle cells resulted in its biotinylation, which permitted its isolation from both ovaries and progeny embryos using Avidin-coupled affinity matrix. In contrast, co-expression with secBirA in the female germline did not result in detectable biotinylation of GD-BAP, possibly because the C-terminal location of the BAP tag made it inaccessible to BirAin vivo. Our results indicate that secBirA directs biotinylation of proteins bound for secretionin vivo, providing access to powerful experimental approaches for secreted proteins of interest. However, efficient biotinylation of target proteins may vary depending upon the location of the BAP tag or other structural features of the protein.