bluuebunny/crossref_metadata_2025 huggingface dataset:
DPre: computational identification of differentiation bias and genes underlying cell type conversions
Authors: Steffens Simon , Fu Xiuling , He Fangfang , Li Yuhao , Babarinde Isaac A , Hutchins Andrew P
Published: October 2019

Cells are generally resistant to cell type conversions, but can be converted by the application of growth factors, chemical inhibitors and ectopic expression of genes. However, it remains difficult to accurately identify the destination cell type or differentiation bias when these techniques are used to alter cell type. Consequently, there is demand for computational techniques that can help researchers understand both the cell type and differentiation bias. While advanced tools identifying cell types exist for single cell data and the deconvolution of mixed cell populations, the problem of exploring partially differentiated cells of indeterminate transcriptional identity has not been addressed. To fill this gap, we developed driver-predictor, which relies on scoring per gene transcriptional similarity between RNA-Seq datasets to reveal directional bias of differentiation. By comparing against large cell type transcriptome libraries or a desired target expression profile, the tool enables the user to visualize both the changes in transcriptional identity as well as the genes accounting for the cell type changes. This software will be a powerful tool for researchers to explore in vitro experiments that involve cell type conversions.

Availability and implementation

Source code is open source under the MIT license and is freely available on https://github.com/LoaloaF/DPre.

Supplementary information

Supplementary data are available at Bioinformatics online.
High-Dose Cytomegalovirus (CMV) Hyperimmune Globulin and Maternal CMV DNAemia Independently Predict Infant Outcome in Pregnant Women With a Primary CMV Infection
Authors: Nigro Giovanni , Adler Stuart P ,   Congenital Cytomegalic Disease Collaborating Group, Lasorella Stefania , Iapadre Giulia , Maresca Maria , Mareri Arianna , Di Paolantonio Claudia , Catenaro Milena , Tambucci Renato , Mattei Ivan , Carta Gaspare , D’Alfonso Angela , Patacchiola Felice , Aurora Fioroni Maria , Manganaro Lucia , Giancotti Antonella , Pancallo Daniela , Lauri Silvia , Liuzzi Giuseppina , Di Renzo Gian Carlo , Della Torre Benedetta , Lupi Carla , Calvario Agata , Vimercati Antonella , Carbonara Sergio , Gussetti Nadia , Pisano Pasquale
Published: October 2019

Background

After primary maternal cytomegalovirus (CMV) infection during pregnancy, infants are at risk for disease.

Methods

Factors predictive of infant outcome were analyzed in a database of 304 pregnant women with primary infection. These women were enrolled between 2010 and 2017 and delivered 281 infants, of whom 108 were CMV infected. Long term follow-up occurred for 173 uninfected and 106 infected infants at age 4 years (range, 1–8 years). One hundred fifty-seven women were treated with an average of 2 doses (range, 1–6 doses) of high-dose hyperimmune globulin (HIG: 200 mg/kg/infusion). We used a regression model to define predictors of fetal infection, symptoms at birth, and long-term sequelae; 31 covariates were tested.

Results

Four factors predicted fetal infection: a 1.8-fold increase (30% vs 56%) in the rate of congenital infection without HIG (adjusted odds ratio [AOR], 5.2; P < .0001), a 1.8-fold increase (32% vs 56%) associated with maternal viral DNAemia prior to HIG administration (AOR, 3.0; P = .002), abnormal ultrasounds (AOR, 59; P = .0002), and diagnosis of maternal infection by seroconversion rather than avidity (AOR, 3.3; P = .007). Lack of HIG and abnormal ultrasounds also predicted symptoms (P = .001). Long-term sequelae were predicted by not receiving HIG (AOR, 13.2; P = .001), maternal infection in early gestation (odds ratio [OR], 0.9; P = .017), and abnormal ultrasounds (OR, 7.6; P < .003). Prevalence and copy/number of DNAemia declined after HIG.

Conclusions

Maternal viremia predicts fetal infection and neonatal outcome. This may help patient counseling. High-dose HIG may prevent fetal infection and disease and is associated with the resolution of DNAemia.
Water temperature during winter may control striped bass recruitment during spring by affecting the development time of copepod nauplii
Authors: Millette N C , Pierson J J , North E W
Published: October 2019

Striped bass (Morone saxatilis) are anadromous fish that support an important fishery along the east coast of North America. In Chesapeake Bay, strong juvenile recruitment of striped bass can occur when larvae overlap with high concentrations of their zooplankton prey, but the mechanisms fostering the temporal overlap are unknown. Here, the influence of winter temperature on the peak abundances of a key prey, Eurytemora carolleeae, was estimated with a temperature-dependent developmental model. The role of these peaks in regulating striped bass recruitment was explored in three nursery areas: upper Chesapeake Bay, Choptank River, and Patuxent River. Model results indicated that cold winters delay the timing and increase the size of peak E. carolleeae spring abundance. When the model output was used in regression relationships with striped bass juvenile recruitment and freshwater discharge, the regression models explained up to 78% of annual recruitment variability. Results suggests that cold, wet winters could increase the chance of a match between striped bass larvae and high concentrations of their prey. This mechanistic link between winter temperatures and striped bass production, acting through prey dynamics, could further understanding of fish recruitment variability and indicates that warmer winters could negatively affect some striped bass populations.
Quantifying long-term discards from Queensland’s (Australia) east Coast otter trawl fishery
Authors: Wang Na , Courtney Anthony J , Campbell Matthew J , Yang Wen-Hsi
Published: October 2019

This article estimated the weight of annual discards in the Queensland east coast otter trawl fishery. Discards data were analysed using three generalized linear mixed models to derive adjusted discard rates, expressed as kg per retained catch, kg per boat day, and kg per area swept by trawls, respectively. Model explanatory terms included trawl fishing sector, presence/absence of bycatch reduction devices (BRDs), lunar phase, and whether the data were obtained from commercial vessels during their normal fishing activities or during research charters. Adjusted discard rates were then used to derive three estimates of annual discards and the average used to examine a long-term discard trends from 1988 to 2014. Total discards declined significantly from a peak of approximately 67 000 t in 1997 to approximately 21 000 t from 2011 to 2014, largely due to a decline in fishing effort, and to a lesser degree, the effects of BRDs that were mandated in the fishery in the early 2000s.
Knowledge as Property Rights Under the Ratchet Effect of Innovation
Authors: Tan Teck Yong
Published: October 2019

This paper studies how reduced oversight creates an incentive for process innovation. With incomplete contracts, tight monitoring of workers creates a ratchet effect of innovation. Under reduced oversight, a worker accrues private knowledge about his innovation, which serves as a substitute for its inalienable property rights. The resulting asymmetric information generates an information rent for the worker, which feeds back as an innovation incentive ex ante. A weak early production incentive is required to complement it. Innovations are generally underutilized ex post, and mildly successful innovations are not distinguished from failed innovation attempts.
Female Combatants in Postconflict Processes: Understanding the Roots of Exclusion
Authors: Henshaw Alexis Leanna
Published: October 2019

Research on contemporary internal armed conflicts has consistently shown that women are active in most armed insurgencies, in groups with varied ideologies, and in every region of the world. However, scholarship from feminist security studies shows that, not only are women still generally underrepresented in peace processes, but women affiliated with rebel groups in particular are more likely to be excluded from disarmament, demobilization, and reintegration (DDR) efforts. Closing this gap is a necessary next step for improving the security of women. This article draws on feminist theory and feminist security studies literature to highlight four factors that contribute to the exclusion of insurgent women from DDR efforts: attributions of agency, gendered hierarchy within groups, the tendency to collapse complex intersectionalities, and the pressure for patriarchal reordering after conflict. Drawing on selected cases, I illustrate each of these factors at work and discuss the implications for female ex-combatants, policy-makers, and scholars.
The endgame of gas giant formation: accretion luminosity and contraction post-runaway
Authors: Ginzburg Sivan , Chiang Eugene
Published: October 2019

Giant planets are thought to form by runaway gas accretion on to solid cores. Growth must eventually stop running away, ostensibly because planets open gaps (annular cavities) in their surrounding discs. Typical models stop runaway by artificially capping the accretion rate and lowering it to zero over an arbitrarily short time-scale. In reality, post-runaway accretion persists as long as the disc remains. During this final and possibly longest phase of formation, when the planet is still emerging from the disc, its mass can more than double, and its radius contracts by orders of magnitude. By drawing from the theory of how gaps clear, we find that post-runaway accretion luminosities diverge depending on disc viscosity: luminosities fall in low-viscosity discs but continue to rise past runaway in high-viscosity discs. This divergence amounts to a factor of 102 by the time the disc disperses. Irrespective of the specifics of how planets interact with discs, the observed luminosity and age of an accreting planet can be used to calculate its instantaneous mass, radius, and accretion rate. We perform this exercise for the planet candidates embedded within the discs orbiting PDS 70, HD 163296, and MWC 758, inferring masses of 1–10 MJ, accretion rates of 0.1–10 MJ Myr−1, and radii of 1–10 RJ. Our radii are computed self-consistently from the planet’s concurrent contraction and accretion and do not necessarily equal the value of 2RJ commonly assumed; in particular, the radius depends on the envelope opacity as R ∝ κ0.5.
Contralateral Interhemispheric Transcallosal Transchoroidal Approach for Resection of a Tumor in the Lateral Wall of the Third Ventricle: 2-Dimensional Operative Video
Authors: Hendricks Benjamin K , Spetzler Robert F
Published: October 2019

Third ventricular tumors pose a surgical challenge, given the intricate surrounding anatomy and depth of the surgical field. A surgical approach to these lesions can involve several different trajectories, the selection of which is dependent on the location of the tumor. Approaches include transforaminal, translamina terminalis, interforniceal, occipital transtentorial, endoscopic transventricular, transchoroidal, and supracerebellar infratentorial. This patient had a metastatic lesion within the lateral wall of the third ventricle. The selection of the surgical approach was dependent on the laterality of the tumor. The foramen of Monro was identified, and landmarks were confirmed. The choroid plexus could then be retracted medially, and the choroidal sulcus was identified. The sulcus was entered laterally to minimize the risk of transgressing the fornix. The tumor was identified along the lateral third ventricular wall, and the plane between the tumor and normal plane was readily created. The tumor was then removed entirely, and postoperative imaging demonstrated a complete resection. The patient gave informed consent for surgery and video recording. Institutional review board approval was deemed unnecessary. Used with permission from Barrow Neurological Institute, Phoenix, Arizona.
Interpersonal Dyadic Influences of Pain Catastrophizing Between Caregivers and Children With Chronic Pain
Authors: Parker Delana M. , Birnie Kathryn A. , Yoon Isabel A. , Bhandari Rashmi P.
Published: October 2019

Objectives:

Pain catastrophizing is an important predictor of pain-related outcomes. Caregiver and child levels of catastrophizing about child chronic pain are associated cross-sectionally, yet predictive associations testing interpersonal influences within caregiver-child dyads are lacking. The present study tested caregiver and child influences on partner catastrophizing about child pain over a period of 1 month following initiation of interdisciplinary pain treatment and examined whether the change in pain catastrophizing was associated with child pain interference.

Materials and Methods:

A total of 113 caregiver-child dyads (M
age=14.41) completed measures at the time of initiating care at a pediatric tertiary outpatient pain management clinic (baseline) and ∼1 month later. Caregivers and children independently reported on catastrophizing about child pain and child pain interference at baseline and 1-month follow-up.

Results:

Caregiver and child pain catastrophizing decreased over 1 month following initial interdisciplinary pain evaluation, with average scores remaining in the moderate to high range. Change in caregiver, but not child, catastrophizing about child pain was predicted by partner baseline pain catastrophizing. Decreases in catastrophizing about child pain were associated with within-person improvement in ratings of child pain interference.

Discussion:

In the short period following initial pain evaluation, caregivers and children evidenced reductions in pain catastrophizing, which were associated with increased child function. Findings highlight the important role of child cognitive-affective responses to pain in influencing caregiver catastrophizing about child pain. Understanding the individual contributions children and caregivers make to interpersonal pain processes will inform future family-level clinical interventions.
Language Skills in Children Born Preterm (<30 Wks' Gestation) Throughout Childhood: Associations With Biological and Socioenvironmental Factors
Authors: Nguyen Thi-Nhu-Ngoc , Spencer-Smith Megan , Pascoe Leona , Treyvaud Karli , Lee Katherine J. , Thompson Deanne K. , Cheong Jeanie L. Y. , Doyle Lex W. , Anderson Peter J.
Published: October 2019

Objective:

To examine the individual and collective contribution of biological and socioenvironmental factors associated with language function at 2, 5, 7, and 13 years in children born preterm (<30 weeks' gestation or <1250 g birth weight).

Methods:

Language function was assessed as part of a prospective longitudinal study of 224 children born preterm at 2, 5, 7, and 13 years using age-appropriate tools. Language Z-scores were generated based on a contemporaneous term-born control group. A selection of biological factors (sex, small for gestational age, bronchopulmonary dysplasia, infection, and qualitatively defined brain injury) and early socioenvironmental factors at age 2 years (primary income earner employment status and type, primary caregiver education level, English as a second language, parental mental health history, parent sensitivity and facilitation, and parent-child synchrony) was chosen a priori. Associations were assessed using univariable and multivariable linear regression models applied to outcomes at each time point.

Results:

Higher primary caregiver education level, greater parent-child synchrony, and parent sensitivity were independently associated with better language function across childhood. Socioenvironmental factors together explained an increasing percentage of the variance (9%–18%) in language function from 2 to 13 years of age. In comparison, there was little evidence for associations between biological factors and language function, even during early childhood years.

Conclusion:

This study highlights the importance of socioenvironmental factors over biological factors for language development throughout childhood. Some of these socioenvironmental factors are potentially modifiable, and parent-based interventions addressing parenting practices and education may benefit preterm children's language development.
Lifetime estrogen exposure and cognition in late life: the Cache County Study
Authors: Matyi Joshua M. , Rattinger Gail B. , Schwartz Sarah , Buhusi Mona , Tschanz JoAnn T.
Published: October 2019

Objective:

Prevalence of Alzheimer's disease (AD) is higher for women, possibly influenced by sex-dependent effects of the estrogen. We examined the association between estrogen and cognitive decline in over 2,000 older adult women in a 12-year population-based study in Cache County, Utah.

Methods:

The baseline sample included 2,114 women (mean age = 74.94 y, SD = 6.71) who were dementia-free at baseline and completed a women's health questionnaire, asking questions regarding reproductive history and hormone therapy (HT). Endogenous estrogen exposure (EEE) was calculated taking the reproductive window (age at menarche to age at menopause), adjusted for pregnancy and breastfeeding. HT variables included duration of use, HT type (unopposed; opposed), and time of HT initiation. A modified version of the Mini-Mental State Examination (3MS) was administered at four triennial waves to assess cognitive status. Linear mixed-effects models examined the relationship between estrogen exposure and 3MS score over time.

Results:

EEE was positively associated with cognitive status (β = 0.03, P = 0.054). In addition, longer duration of HT use was positively associated with cognitive status (β = 0.02, P = 0.046) and interacted with age; older women had greater benefit compared with younger women. The timing of HT initiation was significantly associated with 3MS (β = 0.55, P = 0.048), with higher scores for women who initiated HT within 5 years of menopause compared with those initiating HT 6-or-more years later.

Conclusions:

Our results suggest that longer EEE and HT use, especially in older women, are associated with higher cognitive status in late life.
Cannabinoid effects on responses to quantitative sensory testing among individuals with and without clinical pain: a systematic review
Authors: Mun Chung Jung , Letzen Janelle E. , Peters Erica N. , Campbell Claudia M. , Vandrey Ryan , Gajewski-Nemes Julia , DiRenzo Dana , Caufield-Noll Christine , Finan Patrick H.
Published: October 2019

There has been an explosion of interest in the utility of cannabinoids as potential analgesics. This systematic review critically synthesizes the evidence for cannabinoid analgesic effects on quantitative sensory testing outcomes in both healthy adults and patients with chronic noncancer pain. Our systematic review protocol is preregistered on PROSPERO (CRD42018117367). An electronic search was made in PsycINFO, Cochrane, Google Scholar, Embase, and Pubmed of all literature published until August 2018. Of the 1217 studies found from the search, a total 39 placebo-controlled studies that met the eligibility criteria were synthesized for this study. Because of substantial heterogeneity of study designs, populations, cannabinoid compounds, and quantitative sensory testing outcomes, meta-analysis was not conducted. More consistent evidence of cannabinoid analgesia was observed for inhaled cannabis than synthetic cannabinoids. Analgesic effects were most commonly observed in tests of cold pain sensitivity, and hyperalgesic effects were most commonly observed in tests of electrical stimulation. Patterns of findings from studies with healthy subjects did not substantively differ from those with chronic noncancer pain. However, these observations are qualified by the high degree of inconsistency across studies and methodological heterogeneity. We offer recommendations for future studies to improve study rigor and reproducibility.
Evolutionary history of dimethylsulfoniopropionate (DMSP) demethylation enzyme DmdA in marine bacteria
Authors: Hernández Laura , Vicens Alberto , Eguiarte Luis Enrique , Souza Valeria , Anda Valerie De , González José M.
Published: October 2019

Dimethylsulfoniopropionate (DMSP), an osmolyte produced by oceanic phytoplankton, is predominantly degraded by bacteria belonging to theRoseobacterlineage and other marineAlphaproteobacteriavia DMSP-dependent demethylase A protein (DmdA). To date, the evolutionary history of DmdA gene family is unclear. Some studies indicate a common ancestry between DmdA and GcvT gene families and a co-evolution betweenRoseobacterand the DMSP-producing-phytoplankton around 250 million years ago (Mya). In this work, we analyzed the evolution of DmdA under three possible evolutionary scenarios: 1) a recent common ancestor of DmdA and GcvT, 2) a coevolution betweenRoseobacterand the DMSP-producing-phytoplankton, and 3) pre-adapted enzymes to DMSP prior toRoseobacterorigin. Our analyses indicate that DmdA is a new gene family originated from GcvT genes by duplication and functional divergence driven by positive selection before a coevolution betweenRoseobacterand phytoplankton. Our data suggest thatRoseobacteracquireddmdAby horizontal gene transfer prior to exposition to an environment with higher DMSP. Here, we propose that the ancestor that carried the DMSP demethylation pathway genes evolved in the Archean, and was exposed to a higher concentration of DMSP in a sulfur rich atmosphere and anoxic ocean, compared to recentRoseobacterecoparalogs (copies performing the same function under different conditions), which should be adapted to lower concentrations of DMSP.
Runx1 promotes scar deposition and inhibits myocardial proliferation and survival during zebrafish heart regeneration
Authors: Koth Jana , Wang Xiaonan , Killen Abigail C. , Stockdale William T. , Potts Helen G. , Jefferson Andrew , Bonkhofer Florian , Riley Paul R. , Patient Roger , Göttgens Berthold , Mommersteeg Mathilda T.M.
Published: October 2019

Runx1 is a transcription factor that plays a key role in determining the proliferative and differential state of multiple cell-types, during both development and adulthood. Here, we report how runx1 is specifically upregulated at the injury site during zebrafish heart regeneration, but unexpectedly, absence of runx1 results in enhanced regeneration. Using single cell sequencing, we found that the wild-type injury site consists of Runx1-positive endocardial cells and thrombocytes that induce expression of smooth muscle and collagen genes without differentiating into myofibroblasts. Both these populations are absent in runx1 mutants, resulting in a less collagenous and fibrinous scar. The reduction in fibrin in the mutant is further explained by reduced myofibroblast formation and by upregulation of components of the fibrin degradation pathway, including plasminogen receptor Annexin 2A as well as downregulation of plasminogen activator inhibitor serpine1 in myocardium and endocardium, resulting in increased levels of Plasminogen. In addition, we find enhanced myocardial proliferation as well as increased myocardial survival in the mutant. Our findings suggest that Runx1 controls the regenerative response of multiple cardiac cell-types and that targeting Runx1 is a novel therapeutic strategy to induce endogenous heart repair.
Structure of SWI/SNF chromatin remodeller RSC bound to a nucleosome
Authors: Wagner Felix R. , Dienemann Christian , Wang Haibo , Stützer Alexandra , Tegunov Dimitry , Urlaub Henning , Cramer Patrick
Published: October 2019

Chromatin remodelling complexes of the SWI/SNF family function in the formation of nucleosome-depleted regions and transcriptionally active promoters in the eukaryote genome. The structure of the Saccharomyces cerevisiae SWI/SNF family member RSC in complex with a nucleosome substrate reveals five protein modules and suggests key features of the remodelling mechanism. A DNA-interacting module grasps extra-nucleosomal DNA and helps to recruit RSC to promoters. The ATPase and arm modules sandwich the nucleosome disc with their ‘SnAC’ and ‘finger’ elements, respectively. The translocase motor engages with the edge of the nucleosome at superhelical location +2 to pump DNA along the nucleosome, resulting in a sliding of the histone octamer along DNA. The results elucidate how nucleosome-depleted regions are formed and provide a basis for understanding human chromatin remodelling complexes of the SWI/SNF family and the consequences of cancer mutations that frequently occur in these complexes.
Malaria parasite immune evasion and adaptation to its mosquito host is influenced by the acquisition of multiple blood meals
Authors: Kwon Hyeogsun , Reynolds Rebekah A. , Simões Maria L. , Dimopoulos George , Smith Ryan C.
Published: October 2019

A minimum of two blood meals are required for a mosquito to acquire and transmit malaria, yet Anopheles mosquitoes frequently obtain additional blood meals during their adult lifespan. To determine the impact of subsequent blood-feeding on parasite development in Anopheles gambiae, we examined rodent and human Plasmodium parasite infection with or without an additional non-infected blood meal. We find that an additional blood meal significantly reduces P. berghei immature oocyst numbers, yet does not influence mature oocysts that have already begun sporogony. This is in contrast to experiments performed with the human parasite, P. falciparum, where an additional blood meal does not affect oocyst numbers. These observations are reproduced when mosquitoes were similarly challenged with an artificial protein meal, suggesting that parasite losses are due to the physical distension of the mosquito midgut. We provide evidence that feeding compromises the integrity of the midgut basal lamina, enabling the recognition and lysis of immature P. berghei oocysts by the mosquito complement system. Moreover, we demonstrate that additional feeding promotes P. falciparum oocyst growth, suggesting that human malaria parasites exploit host resources provided with blood-feeding to accelerate their growth. This contrasts experiments with P. berghei, where the size of surviving oocysts is independent of an additional blood meal. Together, these data demonstrate differences in the ability of Plasmodium species to evade immune detection and adapt to utilize host resources at the oocyst stage, representing an additional, yet unexplored component of vectorial capacity that has important implications for transmission of malaria.
Temperature dependence of platelet metabolism
Authors: Jóhannsson F. , Yurkovich J.T. , Guðmundsson S. , Sigurjónsson Ó. E. , Rolfsson Ó.
Published: October 2019

Temperature plays a fundamental role in biology, influencing cellular function, affecting chemical reaction rates, molecular structures, and interactions. While the temperature dependence of many biochemical reactions is well definedin vitro, the effect of temperature on metabolic function at the network level is not well understood but remains an important challenge in optimizing the storage of cells and tissues at lower temperatures. Here, we have used time-course metabolomics data and systems biology approaches to characterize the effects of storage temperature on human platelets (PLTs) in platelet additive solution. We observed that changes to the metabolome with storage time do not simply scale with temperature but instead display complex temperature dependence, with only a small subset of metabolites following an Arrhenius-type. Investigation of PLT energy metabolism through integration with computational modeling revealed that oxidative metabolism is more sensitive to temperature changes than is glycolysis. The increased contribution of glycolysis to ATP turnover at lower temperature indicates a stronger glycolytic phenotype with decreasing storage temperature. More broadly, these results demonstrate that the temperature dependence of the PLT metabolic network is not uniform, suggesting that efforts to improve the health of stored PLTs could be targeted at specific pathways.

Statement of Significance

The temperature dependence of cellular metabolism is difficult to study due to regulatory events that are activated upon deviation from the optimal temperature range. Platelets are blood components used in transfusion medicine but also serve as a model cell to study human energy metabolism in the absence of genetic regulation. We investigated changes in platelet metabolism at temperatures spanning from 4 °C-37 °C using a quantitative metabolic systems biology approach as opposed to assessing individual reactions. We found that energy producing metabolic pathways have different temperature sensitivities. The results define the metabolic response to temperature on the metabolic pathway level and are of importance for understanding the cryopreservation of human platelets and more complex human cells used in cellular therapy.
PRIGSA2: Improved version of Protein Repeat Identification by Graph Spectral Analysis
Authors: Chakrabarty Broto , Parekh Nita
Published: October 2019

Tandemly repeated structural motifs in proteins form highly stable structural folds and provide multiple binding sites associated with diverse functional roles. The tertiary structure and function of these proteins are determined by the type and copy number of the repeating units. Each repeat type exhibits a unique pattern of intra- and inter-repeat unit interactions that is well-captured by the topological features in the network representation of protein structures. Here we present an improved version of our graph based algorithm, PRIGSA, with structure-based validation and filtering steps incorporated for accurate detection of tandem structural repeats. The algorithm integrates available knowledge on repeat families with de novo prediction to detect repeats in single monomer chains as well as in multimeric protein complexes. Three levels of performance evaluation are presented: comparison with state-of-the-art algorithms on benchmark dataset of repeat and non-repeat proteins, accuracy in the detection of members of 13 known repeat families reported in UniProt and execution on the complete Protein Data Bank to show its ability to identify previously uncharacterized proteins. A ∼3-fold increase in the coverage of the members of 13 known families and 3,408 novel uncharacterized structural repeat proteins are identified on executing it on PDB. URL: http://bioinf.iiit.ac.in/PRIGSA2/.
Optimized double emulsion flow cytometry with high-throughput single droplet isolation
Authors: Brower Kara K. , Carswell-Crumpton Catherine , Klemm Sandy , Cruz Bianca , Kim Gaeun , Calhoun Suzanne G.K. , Nichols Lisa , Fordyce Polly M.
Published: October 2019

Droplet microfluidics has made large impacts in diverse areas such as enzyme evolution, chemical product screening, polymer engineering, and single-cell analysis. However, while droplet reactions have become increasingly sophisticated, phenotyping droplets by a fluorescent signal and sorting them to isolate variants-of-interest remains a field-wide bottleneck. Here, we present an optimized double emulsion workflow, sdDE-FACS, that enables high-throughput phenotyping, selection, and sorting of droplets using standard flow cytometers. Using a 130 μm nozzle, we demonstrate robust post-sort recovery of intact droplets, with little to no shear-induced droplet breakage, at high sort frequency (12-14 kHz) across two industry-standard FACS instruments. We report the first quantitative plate statistics for double emulsion droplet isolation and demonstrate single droplet recovery with >70% efficiency. In addition, we establish complete downstream recovery of nucleic acids from single, sorted double emulsion droplets, an advance in droplet sorting comparable with the capabilities of single-cell FACS. This work resolves several hurdles in the field of high-throughput droplet analysis and paves the way for a variety of new droplet assays, including rare variant isolation and multiparameter single-cell analysis, marrying the full power of flow cytometry with droplet microfluidics.
Nucleotide inhibition of the pancreatic ATP-sensitive K+ channel explored with patch-clamp fluorometry
Authors: Usher Samuel G. , Ashcroft Frances M. , Puljung Michael C.
Published: October 2019

Pancreatic ATP-sensitive K+ channels (KATP) comprise four inward rectifier subunits (Kir6.2), each associated with a sulphonylurea receptor (SUR1). ATP/ADP binding to Kir6.2 shuts KATP. Mg-nucleotide binding to SUR1 stimulates KATP. In the absence of Mg2+, SUR1 increases the apparent affinity for nucleotide inhibition at Kir6.2 by an unknown mechanism. We simultaneously measured channel currents and nucleotide binding to Kir6.2. Fits to combined data sets suggest that KATPcloses with only one nucleotide molecule bound. A Kir6.2 mutation (C166S) that increases channel activity did not affect nucleotide binding, but greatly perturbed the ability of bound nucleotide to inhibit KATP. Mutations at position K205 in SUR1 affected both nucleotide affinity and the ability of bound nucleotide to inhibit KATP. This suggests a dual role for SUR1 in KATPinhibition, both in directly contributing to nucleotide binding and in stabilising the nucleotide-bound closed state.
NOX4 regulates TGFβ-induced proliferation and self-renewal in glioblastoma stem cells
Authors: García-Gómez P , Dadras M , Bellomo C , Mezheyeuski A , Tzavlaki K , Moren A , Caja L
Published: October 2019

Glioblastoma (GBM) is the most aggressive and common glioma subtype with a median survival of 15 months after diagnosis. Current treatments have limited therapeutic efficacy, thus more effective approaches are needed. The glioblastoma tumoral mass is characterized by a small cellular subpopulation, the Glioblastoma stem cells (GSCs), which has been held accountant for initiation, invasion, proliferation, relapse and resistance to chemo- and radiotherapy. Targeted therapies against GSCs are crucial, and so is the understanding of the molecular mechanisms that govern the GSCs. Transforming growth factor β (TGFβ), platelet growth factor (PDGF) signalling and Reactive Oxygen Species (ROS) production govern and regulate cancer-stem cell biology. In this work, we focus on the role of the NADPH oxidase 4 (NOX4) downstream of TGFβ signalling in the GSCs. NOX4 utilises NADPH to generate ROS; TGFβ induces NOX4 expression, thus increasing ROS production. Interestingly, NOX4 itself regulates GSC self-renewal and modulates Since TGFβ regulates PDGFB in GSC, we analysed how PDGFB modulates NOX4 expression and increases ROS production. Both TGFβ and PDGF signalling regulate GSC proliferation in a NOX4/ROS-dependent manner. The transcription factor NRF2, involved in the transcriptional regulation of antioxidant and metabolic responses, is regulated by both TGFβ and NOX4. This results in an antioxidant response, which positively contributes to GSC self-renewal and proliferation. In conclusion, this work functionally establishes NOX4 as a key mediator of GSC biology.
Volumetric fluorescence imaging in a human eye model by oblique scanning laser ophthalmoscope (oSLO): a feasibility study
Authors: Shao Wenjun , Song Weiye , Yi Ji
Published: October 2019

Fluorescence retinal imaging, such as fluorescein angiography, indocyanine green angiography, and autofluorescence imaging, are valuable tools in ophthalmology and vision science. However, these clinical imaging modalities provideen faceview of the retina, with limited capability to discriminate retinal layers over a large field-of-view (FOV). We recently developed a novel retinal imaging method, oblique scanning laser ophthalmoscopy (oSLO), to provide volumetric retinal fluorescence imaging without any depth sectioning. OSLO breaks the coaxial alignment of the excitation and detection, to produce a cross-sectional view on retina using the natural ocular optics. In this paper, we demonstrated oSLO in a realistic human eye model and showed the feasibility for futurein vivohuman retinal imaging. A new optical design was implemented to significantly simplify our previous oSLO systems. We overcame the limitation by the small numerical aperture (NA) of the human eye, by integrating a pair of cylindrical lens in the remote focusing system. We experimentally showed that the current setup can achieve a FOV of ∼3×6×0.8 mm3, and the transverse and axial resolutions of 7 and 41 µm, respectively. The capability of volumetric fluorescence imaging over a large FOV in the human retina could lead to new clinical imaging paradigms for retinal diseases.
Targeting cardiac myocyte Na+-K+ pump function with β3 adrenergic agonist in rabbits and patients with severe congestive heart failure
Authors: Fry Natasha AS , Liu Chia-Chi , Garcia Alvaro , Hamilton Elisha J , Galougahi Keyvan Karimi , Kim Yeon Jae , Harris Jacqueline L , Nelson Gregory IC , Whalley David W , Bundgaard Henning , Rasmussen Helge H
Published: October 2019

Background

Reported one- and two-year mortality for patients with advanced heart failure (HF) treated medically are ~75% and nearly 100%. In such patients, reversible cellular abnormalities are potential treatment targets and a raised cytosolic Na+ concentration that impairs their myocardial contractility is one potential target. β3 adrenoceptor (β3 AR) agonists stimulate the myocyte Na+-K+ pump.

Methods

We induced severe HF in rabbits by coronary ligation and measured indices of organ congestion after treatment with β3 AR agonists. Na+-K+ pump current was measured in voltage-clamped myocytes isolated from non-infarct myocardium. To assess if β3 ARs might add benefit to optimised guideline-directed medical treatment we report outcomes of giving the β3 AR agonist mirabegron to patients hospitalized with advanced, treatment-refractory stage D HF.

Results

Treatment of rabbits after coronary ligation with β3 AR agonist reversed a decreased myocyte Na+-K+ pump current and significantly reduced organ congestion and prevalence of ascites. Oral treatment with mirabegron rapidly improved signs and symptoms of 9 patients with advanced HF and improvement of ≥1 NYHA Class was maintained early post-discharge with continued treatment. One patient died from HF at 16 months, 4 died from other causes at 2 – 30 months and 4 remain alive at 38 ± 4 months with NYHA Class II symptoms.

Conclusions

Parallel β3 AR agonist-induced reversal of Na+-K+ pump inhibition and severe HF in rabbits identify pump inhibition as a treatment target, and changed in-hospital clinical trajectory and post-discharge course more favorable than expected suggest efficacy of mirabegron in advanced human HF.
Branched evolution and genomic intratumor heterogeneity in the pathogenesis of cutaneous T-cell lymphoma
Authors: Iyer Aishwarya , Hennessey Dylan , O’Keefe Sandra , Patterson Jordan , Wang Weiwei , Wong Gane Ka-Shu , Gniadecki Robert
Published: October 2019

Mycosis fungoides (MF) is a slowly progressive cutaneous T-cell lymphoma (CTCL) for which there is no cure. In the early plaque stage the disease is indolent, but development of tumors heralds an increased risk of metastasis and death. Previous research into the genomic landscape of CTCL revealed a complex pattern of >50 driver mutations implicated in more than a dozen of signaling pathways. However, the genomic mechanisms governing disease progression and treatment resistance remain unknown. Building on our previous discovery of the clonotypic heterogeneity of MF, we hypothesized that this lymphoma does not progress in a linear fashion as currently thought, but comprises heterogeneous mutational subclones. We sequenced exomes of 49 cases of MF and identified 28 previously unreported putative driver genes. MF exhibited extensive intratumoral heterogeneity (ITH) of a median of six subclones showing branched pattern of phylogenetic relationships. Stage progression was correlated with an increase in ITH and redistribution of mutations from the stem to the clades. The pattern of clonal driver mutations was highly variable with no consistent mutations between patients. A similar intratumoral heterogeneity was detected in leukemic CTCL (Sézary syndrome). Based on these findings we propose a model of the pathogenesis of MF comprising neutral, divergent evolution of cancer subclones and discuss how ITH impacts the efficacy of targeted drug therapies and immunotherapies of CTCL.
ADHD symptoms and their neurodevelopmental correlates in children born very preterm
Authors: Montagna Anita , Karolis Vjaceslavs , Batalle Dafnis , Counsell Serena , Rutherford Mary , Arulkumaran Sophie , Happe Francesca , Edwards David , Nosarti Chiara
Published: October 2019

This study investigated the association between attention-deficit/hyperactivity disorder (ADHD) symptomatology in preschool-aged children who were born very preterm (<32 weeks) and cognitive outcomes, clinical risk and socio-demographic characteristics. 119 very preterm children who participated in the Evaluation of Preterm Imaging Study at term-equivalent age were assessed at a mean age of 4.5 years. Parents completed the ADHD Rating Scale IV, a norm-referenced checklist that evaluates ADHD symptomatology according to diagnostic criteria, and the Behavior Rating Inventory of Executive Function-Preschool version. Children completed the Wechsler Preschool and Primary Scales of Intelligence and the Forward Digit Span task. Longitudinal data including perinatal clinical, qualitative MRI classification, socio-demographic variables and neurodevelopmental disabilities were investigated in relation to ADHD symptomatology. All results were corrected for multiple comparisons using false discovery rate. Results showed that although the proportion of very preterm children with clinically significant ADHD did not differ from normative data after excluding those with neurodevelopmental disabilities, 32.7% met criteria for subthreshold ADHD inattentive type and 33.6% for combined type, which was higher than the expected 20% in normative samples. Higher ADHD symptom scores (all) were associated with greater executive dysfunction (inhibitory self-control, flexibility, and emergent metacognition, corrected p<0.001 for all tests). Higher inattentive ADHD symptom scores were associated with lower IQ (ρ=-0.241, p=0.036) and higher perinatal clinical risk (more days on mechanical ventilation (ρ=0.206, p=0.025) and more days on parenteral nutrition (ρ=0.223, p=0.015)). Higher hyperactive ADHD symptom scores instead were associated with lower socio-economic status (ρ=0.278, p=0.002). These results highlight the importance of monitoring and supporting the development of very preterm children throughout the school years, as subthreshold ADHD symptoms represent risk factors for psychosocial problems and for receiving a future clinical diagnosis of ADHD.
Intracellular Neutralization of Ricin Toxin by Single Domain Antibodies Targeting the Active Site Pocket
Authors: Rudolph Michael J. , Czajka Timothy F. , Davis Simon A. , Thi Nguyen Chi My , Li Xiao-ping , Tumer Nilgun E. , Vance David J. , Mantis Nicholas J.
Published: October 2019

The extreme potency of the plant toxin, ricin, is due to its enzymatic subunit, RTA, which inactivates mammalian ribosomes with near perfect efficiency. Here we characterized, at the functional and structural levels, seven alpaca single-domain antibodies (VHHs) previously reported to recognize epitopes in proximity to RTA’s active site. Three of the VHHs, V2A11, V8E6 and V2G10, were potent inhibitors of RTAin vitroand protected Vero cells from ricin when expressed as intracellular antibodies (“intrabodies”). Crystal structure analysis revealed that the complementarity-determining region 3 (CDR3) elements of V2A11 and V8E6 penetrate RTA’s active site and interact with key catalytic residues. V2G10, in contrast, sits atop the enzymatic pocket and occludes substrate accessibility. The other four VHHs also penetrated/occluded RTA’s active site, but lacked sufficient binding affinities to outcompete RTA-ribosome interactions. Intracellular delivery of high-affinity, single-domain antibodies may offer a new avenue in the development of countermeasures against ricin toxin.
Identification of continuous-time hybrid “Box–Jenkins” systems with multiple unknown time delays using two-stage parameter estimation algorithm
Authors: Ghoul Yamna
Published: October 2019

Purpose

This study/paper aims to present a separable identification algorithm for a multiple input single output (MISO) continuous time (CT) hybrid “Box–Jenkins”.

Design/methodology/approach

This paper proposes an optimal method for the identification of MISO CT hybrid “Box–Jenkins” systems with unknown time delays by using the two-stage recursive least-square (TS-RLS) identification algorithm.

Findings

The effectiveness of the proposed scheme is shown with application to a simulation example.

Originality/value

A two-stage recursive least-square identification method is developed for multiple input single output continuous time hybrid “Box–Jenkins” system with multiple unknown time delays from sampled data. The proposed technique allows the division of the global CT hybrid “Box–Jenkins” system into two fictitious subsystems: the first one contains the parameters of the system model, including the multiple unknown time delays, and the second contains the parameters of the noise model. Then the TS-RLS identification algorithm can be applied easily to estimate all the parameters of the studied system.
Emerging destination mobility
Authors: Gbollie Charles , Gong Shaoying
Published: October 2019

Purpose

The purpose of this paper is to explore the push-pull factors and motivations of African and Asian international students in Chinese universities.

Design/methodology/approach

Concurrent mixed methods (qualitative and quantitative) design was used. The quantitative component included 537 Africans and Asians from five notable universities, while the qualitative aspect consisted of 30 participants in Wuhan and few other cities in China.

Findings

Findings revealed availability of scholarship opportunities, China’s flexibility (visa and program entry) and perception of better education quality as important push-pull factors. It also discovered several new pull factors, including citizens’ attitude and good report, development potential and hospitality and receptiveness, while career development and entertainment were found to be the most and least significant motivational factors, respectively. The study also found a significant relationship between push-pull factors and study abroad motivation (SAM) as well as cross-cultural differences between African and Asian students.

Research limitations/implications

Most of the participants were drawn from Wuhan city. Hence, the findings cannot be outrightly generalized to other contexts.

Practical implications

This research provides valuable knowledge for policy makers, higher education institutions, international students and other stakeholders in China to inform better student experience.

Originality/value

There was no study found that combines push-pull factors and SAM or comparatively investigates African and international students in China. Knowledge about sojourners push-pull factors and motivations, their relationship and cross-cultural differences is essential for evidence-based interventions.
The impact of corporate governance on earnings quality: evidence from Peru
Authors: Melgarejo Mauricio
Published: October 2019

Purpose

The purpose of this paper is to explore whether firms with good corporate governance practices in countries with high levels of political and economic uncertainty, such as Peru, present a higher quality of accounting information.

Design/methodology/approach

This study uses a multivariate regression analysis to investigate the impact of good corporate governance practices on the quality of accounting information for the firms listed in the Lima Stock Exchange (LSE).

Findings

Firms included in the Good Corporate Governance Index, in the LSE, present more value relevant, more persistent and more conservative accounting reports. These results hold after controlling for a self-selection bias.

Originality/value

It is the first paper to explore the impact of good corporate practices on earnings quality in Peru. Also, this study uses a two-state regression methodology to control for the self-selection bias in the sample.