bluuebunny/crossref_metadata_2025 huggingface dataset:
Vapur: A Search Engine to Find Related Protein - Compound Pairs in COVID-19 Literature
Authors: Köksal Abdullatif , Dönmez Hilal , Özçelik Rıza , Ozkirimli Elif , Özgür Arzucan
Published: September 2020

Coronavirus Disease of 2019 (COVID-19) created dire consequences globally and triggered an intense scientific effort from different domains. The resulting publications created a huge text collection in which finding the studies related to a biomolecule of interest is challenging for general purpose search engines because the publications are rich in domain specific terminology. Here, we present Vapur: an online COVID-19 search engine specifically designed to find related protein - chemical pairs. Vapur is empowered with a relation-oriented inverted index that is able to retrieve and group studies for a query biomolecule with respect to its related entities. The inverted index of Vapur is automatically created with a BioNLP pipeline and integrated with an online user interface. The online interface is designed for the smooth traversal of the current literature by domain researchers and is publicly available athttps://tabilab.cmpe.boun.edu.tr/vapur/.
Structural and Functional Brain-wide Alterations in A350V IQSEC2 Mutant Mice Displaying Autistic-like Behavior
Authors: Lichtman Daniela , Bergmann Eyal , Kavushansky Alexandra , Cohen Nadav , Levy Nina S. , Levy Andrew P. , Kahn Itamar
Published: September 2020

IQSEC2 is an X-linked gene which is associated with autism spectrum disorder (ASD), intellectual disability and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of IQSEC2 (A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cortex and hippocampus. Moreover, using a data-driven approach we demonstrate that A350V mice present alterations in structure–function relations of the frontal, auditory, and visual networks. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three–chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to IQSEC2 mutations.

Significance Statement

Several recent studies have characterized the changes in the organization of brain networks in animal models of autism spectrum disorders (ASD). Here we assessed the effect of an A350V missense mutation in the IQSEC2 gene, which is associated with ASD, on brain-wide functional connectivity and its relation to social behavior deficits in A350V mice relative to controls. We found that the A350V IQSEC2 model results in disrupted functional connectivity of the anterior cingulate cortex and the dorsomedial striatum. Critically, disrupted increased corticostriatal functional connectivity is predictive of individual variability in social interaction only in A350V mice implicating this pathway in the pathophysiology of the A350V IQSEC2 mutation.
High-content analysis and Kinetic Image Cytometry identify toxic and epigenotoxic effects of HIV antiretrovirals on human iPSC-neurons and primary neural precursor cells
Authors: Smith Alyson S. , Ankam Soneela , Farhy Chen , Fiengo Lorenzo , Basa Ranor C.B. , Gordon Kara L. , Martin Charles T. , Terskikh Alexey V. , Jordan-Sciutto Kelly L. , Price Jeffrey H. , McDonough Patrick M.
Published: September 2020

Despite viral suppression due to combination antiretroviral therapy (cART), HIV-associated neurocognitive disorders (HAND) continue to affect half of people with HIV, suggesting that certain antiretrovirals (ARVs) may contribute to HAND. We examined the effects of nucleoside/nucleotide reverse transcriptase inhibitors tenofovir disproxil fumarate (TDF) and emtricitabine (FTC) and the integrase inhibitors dolutegravir (DTG) and elvitegravir (EVG) on viability, structure, and function of glutamatergic neurons (a subtype of CNS neuron involved in cognition) derived from human induced pluripotent stem cells (hiPSC-neurons), and primary human neural precursor cells (hNPCs), which are responsible for neurogenesis. Using automated digital microscopy and image analysis (high content analysis, HCA), we found that DTG, EVG, and TDF decreased hiPSC-neuron viability, neurites, and synapses after seven days of treatment. Analysis of hiPSC-neuron calcium activity using Kinetic Image Cytometry (KIC) demonstrated that DTG and EVG also decreased the frequency and magnitude of intracellular calcium transients. Longer ARV exposures and simultaneous exposure to multiple ARVs increased the magnitude of these neurotoxic effects. Using the Microscopic Imaging of Epigenetic Landscapes (MIEL) assay, we found that TDF decreased hNPC viability and changed the distribution of histone modifications that regulate chromatin packing, suggesting that TDF may reduce neuroprogenitor pools important for CNS development and maintenance of cognition in adults. This study establishes human preclinical assays that can screen potential ARVs for CNS toxicity to develop safer cART regimens and HAND therapeutics.
Developmental plasticity of texture discrimination following early vision loss in the marsupialMonodelphis domestica
Authors: Ramamurthy Deepa L. , Dodson Heather K. , Krubitzer Leah A.
Published: September 2020

Behavioral strategies that depend on sensory information are not immutable; rather they can be shaped by the specific sensory context in which animals develop. This behavioral plasticity depends on the remarkable capacity for the brain to reorganize in response to alterations in the sensory environment, particularly when changes in sensory input occur at an early age. To study this phenomenon, we utilize the short-tailed opossum, a marsupial that has been a valuable animal model to study developmental plasticity due to the extremely immature state of its nervous system at birth. Previous studies in opossums have demonstrated that removal of retinal inputs early in development results in profound alterations to cortical connectivity and functional organization of visual and somatosensory cortex; however, behavioral consequences of this plasticity are not well understood. We trained early blind (EB) and sighted control (SC) opossums to perform a two-alternative forced choice texture discrimination task. Whisker trimming caused an acute deficit in discrimination accuracy for both EB and SC animals indicating that they primarily used a whisker-based strategy to guide choices based on tactile cues – though performance recovered in days, suggesting a shift to the use of other body parts when whiskers were absent. Mystacial whiskers were important for performance in both groups; however, genal whiskers only contributed to performance in EB animals. EB opossums significantly outperformed SC opossums in discrimination accuracy, being more sensitive to textural differences by ~75 μm smaller. Our results support behavioral compensation following early blindness using tactile inputs, especially the whisker system.
Larazotide Acetate for Treatment of Celiac Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Abu-Zaid Ahmed , Alhaddab Noor Tariq , Alnujaidi Razan Abdulkarim , Alharbi Hadeel Abdulaziz , Alangari Fulwah , Alyahyawi Naseem , Kamal Aminah , Altowairqi Abdulaziz Khalaf , Alhabeeb Habeeb , Almustanyir Sami , Alyoubi Reem Abdullah
Published: September 2020

Purpose

The standard of care for treatment of celiac disease (CD) is a stringent lifetime glutenfree diet (GFD), which is very challenging. Larazotide acetate (AT-1001) is an anti-zonulin which functions as a gut permeability regulator for treatment of CD. We endeavored to conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) which studied the efficacy and safety of larazotide acetate in patients with CD.

Methods

We examined four databases from inception to 20-August-2020 using related keywords. We identified all relevant RCTs and judged their risk of bias. We pooled continuous outcomes as mean difference and dichotomous outcomes as risk ratio with 95% confidence interval under fixed-effects meta-analysis model.

Results

Four RCTs met our eligibility criteria, comprising 626 patients (larazotide acetate, n = 465, placebo, n = 161). Three and two studies reported outcomes of patients undergoing gluten challenge and GFD, respectively. For change in lactulose-to-mannitol ratio, the overall effect estimate did not reveal a significant difference between larazotide acetate and placebo groups. For change in total gastrointestinal symptom rating scale (GSRS), subgroup analysis showed that larazotide acetate significantly yielded better symptomatic improvement in the gluten challenge but not gluten free subgroup. Similar finding was found for change in celiac-disease GSRS (CD-GSRS) favoring the gluten challenge over gluten free subgroup. When compared to placebo, larazotide acetate favorably reduced the adverse event (AE) of gluten-related diarrhea in patients who underwent gluten challenge. Other AEs were comparable between both treatment groups.

Conclusions

Larazotide acetate is well-endured and superior to placebo in alleviating gastrointestinal symptoms.
NLRC5 regulates expression of MHC-I and provides a target for anti-tumor immunity in transmissible cancers
Authors: Ong Chrissie E. B. , Patchett Amanda L. , Darby Jocelyn M. , Chen Jinying , Liu Guei-Sheung , Lyons A. Bruce , Woods Gregory M. , Flies Andrew S.
Published: September 2020

Downregulation of major histocompatibility complex I (MHC-I) on tumor cells is a primary means of immune evasion by many types of cancer. Additionally, MHC-I proteins are a primary target of immune-mediated transplant rejection. Transmissible tumors that overcome allograft rejection mechanisms and evade anti-tumor immunity have killed thousands of wild Tasmanian devils (Sarcophilus harrisii). Interferon gamma (IFNG) upregulates surface MHC-I expression on devil facial tumor (DFT) cells but is not sufficient to induce tumor regressions. Transcriptome analysis of IFNG-treated DFT cells revealed strong upregulation ofNLRC5, a master regulator of MHC-I in humans and mice. To explore the role of NLRC5 in transmissible cancers, we developed DFT cell lines that constitutively overexpress NLRC5. Transcriptomic results suggest that the role of NLRC5 as a master regulator of MHC-I is conserved in devils. Furthermore, NLRC5 was shown to drive the expression of many components of the antigen presentation pathway. To determine if MHC-I is a target of allogeneic immune responses, we tested serum from devils with anti-DFT responses including natural DFT regressions against DFT cells. Antibody binding occurred with cells treated with IFNG and overexpressed NLRC5. However, CRISPR/Cas9-mediated knockout of MHC-I subunit beta-2-microglobulin (B2M) eliminated antibody binding to DFT cells. Consequently, MHC-I could be identified as a target for anti-tumor and allogeneic immunity and provides mechanistic insight into MHC-I expression and antigen presentation in marsupials. NLRC5 could be a promising target for immunotherapy and vaccines to protect devils from transmissible cancers and inform development of transplant and cancer therapies for humans.
A negative feedback loop of the TOR signaling moderates growth and enables rapid sensing of stress signals in plants
Authors: Jamsheer K Muhammed , Jindal Sunita , Sharma Mohan , Sharma Manvi , Sivaj Sreejath , Mannully Chanchal Thomas , Laxmi Ashverya
Published: September 2020

TOR kinase is a central coordinator of nutrient-dependent growth in eukaryotes. Maintaining optimal TOR signaling is critical for the normal development of organisms. However, the mechanisms involved in the maintenance of optimal TOR signaling are currently unknown in plants. In this study, we describe a negative feedback loop of TOR signaling helping in the adaptability of plants in changing environmental conditions. Using an interdisciplinary approach, we identified a plant-specific zinc finger protein FLZ8, as a regulator of TOR signaling in Arabidopsis. In sugar sufficiency, FLZ8 is upregulated by TOR-dependent and –independent histone modifications. FLZ8 negatively regulates TOR signaling by promoting antagonistic SnRK1α1 signaling and bridging the interaction of SnRK1α1 with RAPTOR, a crucial accessory protein of TOR. This negative feedback loop moderates the TOR-growth signaling axis in the favorable condition and helps in the rapid activation of stress signaling in unfavorable conditions establishing its importance in the adaptability of plants.
Secreted and cell surface proteome analysis of pathogenicCorynebacterium diphtheriaereveals proteins relevant to virulence
Authors: Goring Andrew K. , Chen Yu , Clubb Robert T. , Loo Joseph A.
Published: September 2020

Corynebacterium diphtheriaeis responsible for the severe upper respiratory tract disease, diphtheria, which can be fatal in healthy individuals without proper treatment. Its interaction with the infected host is crucial to its virulence, secreting diphtheria toxin and a variety of machinery to acquire nutrients for further import into the cell. Additionally, it shares a conserved iron import mechanism with related pathogenic actinobacteria such asMycobacterium tuberculosis, and contains sortase-mediated anchored cell wall proteins similar to other gram-positive bacteria. Information obtained from secreted and cell-surface proteomes are relevant for the study of diphtheria and related bacterial infections. Mass spectrometry-based proteomics measurements on samples of pathogenicCorynebacterium diphtheriaeculture supernatant and cell-surface digested proteins identified greater than 3 times more proteins than a previous similar study. The diphtheria toxin was identified, as well as pathologically relevant proteins involved in iron-uptake and cell adhesion. For instance, 17 proteins predicted to be on the iron-regulated DtxR promoter were identified in cells grown under different iron concentrations, opening the door to performing comparative quantitative proteomics studies on samples where iron sources are modulated. Results of this study serve as a repository for future studies on pathogenicC. diphtheriaeuptake.
A heterologous in-cell assay for investigating intermicrovillar adhesion complex interactions and function
Authors: Weck Meredith L. , Crawley Scott W. , Tyska Matthew J.
Published: September 2020

Solute transporting epithelial cells build arrays of microvilli on their apical surface to increase membrane scaffolding capacity and enhance function potential. In epithelial tissues such as the kidney and gut, microvilli are length-matched and assembled into tightly packed ‘brush borders’, which are organized by ∼50 nm thread-like links that form between the distal tips of adjacent protrusions. Composed of protocadherins CDHR2 and CDHR5, adhesion links are stabilized at the tips by a cytoplasmic tripartite module containing the scaffolds USH1C and ANKS4B, and the actin-based motor, MYO7B. As several questions about the formation and function of this ‘intermicrovillar adhesion complex’ remain open, we devised a system that allows one to study individual binary interactions between specific complex components and MYO7B. Our approach employs a chimeric myosin consisting of the motor domain of MYO10 fused to the cargo-binding tail domain of MYO7B. When expressed in HeLa cells, which do not normally produce adhesion complex proteins, this motor exhibited robust trafficking to the tips of filopodia and was also able to transport individual components to these sites. Unexpectedly, the MYO10/MYO7B chimera was able to deliver CDHR2 and CDHR5 to distal tips in the absence USH1C or ANKS4B. Cells engineered to localize high levels of CDHR2 at filopodial tips acquired inter-filopodial adhesion and exhibited a striking dynamic length matching activity that aligned distal tips over time. These observations reveal a robust adhesion-dependent mechanism for matching the lengths of adjacent surface protrusions, and may offer insight on how epithelial cells minimize microvillar length variability.
EPH Receptor Tyrosine Kinases Regulate Epithelial Morphogenesis and Phosphorylate the PAR-3 Scaffold Protein to Modulate Downstream Signaling Networks
Authors: Banerjee Sara L. , Lavoie Noémie , Jacquet Kévin , Lessard Frédéric , Osornio-Hernandez Ana , Lavoie Josée N. , Elowe Sabine , Lambert Jean-Philippe , Laprise Patrick , Bisson Nicolas
Published: September 2020

The EPH family is the largest among receptor tyrosine kinases (RTKs) in humans. In contrast to other RTKs, EPH receptors (EPHRs) cognate ligands, ephrins, are tethered to the cell surface. This results in EPHR-ephrin signaling being mainly involved in short-range cell-cell communication events that regulate cell adhesion, migration and tissue boundary formation. Although EPHRs functions have been broadly studied, the molecular mechanisms by which they control these processes are far from being understood. To address this, we sought to identify new effector proteins acting downstream of EPHRs and determine their role in EPHR-regulated functions. To unravel EPHR-associated signaling complexes under native conditions, we applied a mass spectrometry-based approach, namely BioID proximity labeling. We obtained a composite proximity network from EPHA4, -B2, -B3 and -B4 receptors that comprises 395 proteins, most of which were not previously linked to EPH signaling. A gene ontology and pathway term analysis of the most common candidates highlighted cell polarity as a novel function associated with EPHR activity. We found that EPHA1 and EPHB4 expression is restricted to the basal and lateral membrane domains in polarized Caco-2 3D spheroidal cell cultures. We further discovered that their depletion impairs the compartmentalized distribution of polarity proteins as well as overall spheroid morphogenesis. Moreover, we examined the contribution of a number of candidates, selected from EPHR proximity networks, via loss-of-function in an EPHR-dependent cell segregation assay. We found that depletion of the signaling scaffold PAR-3 blocks cell sorting. We also delineated a signalling complex involving the C-terminal SRC kinase (CSK), whose recruitment to PAR-3 complexes is dependent on EPHR signals. Our work sheds a new light on EPHR signaling networks and describes conceptually novel the mechanisms by which EPHRs signal at the membrane to contribute to the regulation of cellular phenotypes.
Comparative mapping of crawling-cell morphodynamics in deep learning-based feature space
Authors: Imoto Daisuke , Saito Nen , Nakajima Akihiko , Honda Gen , Ishida Motohiko , Sugita Toyoko , Ishihara Sayaka , Katagiri Koko , Okimura Chika , Iwadate Yoshiaki , Sawai Satoshi
Published: September 2020

Navigation of fast migrating cells such as amoebaDictyosteliumand immune cells are tightly associated with their morphologies that range from steady polarized forms that support high directionality to those more complex and variable when making frequent turns. Model simulations are essential for quantitative understanding of these features and their origins, however systematic comparisons with real data are underdeveloped. Here, by employing deep-learning-based feature extraction combined with phase-field modeling framework, we show that a low dimensional feature space for 2D migrating cell morphologies obtained from the shape stereotype of keratocytes,Dictyosteliumand neutrophils can be fully mapped by interlinked signaling network of cell-polarization and protrusion dynamics. Our analysis links the data-driven shape analysis to the underlying causalities by identifying key parameters critical for migratory morphologies both normal and aberrant under genetic and pharmacological perturbations. The results underscore the importance of deciphering self-organizing states and their interplay when characterizing morphological phenotypes.
Early alphavirus replication dynamics in single cells reveal a passive basis for superinfection exclusion
Authors: Singer Zakary S. , Ambrose Pradeep M. , Danino Tal , Rice Charles M.
Published: September 2020

While decades of research have elucidated many steps in the alphavirus lifecycle, the earliest replication dynamics have remained unclear. This missing time window has obscured early replicase strand synthesis behavior and prevented elucidation of how the resulting activity gives rise to a superinfection exclusion environment, one of the fastest competitive phenotypes among viruses. Using quantitative live-cell and single-molecule imaging, we characterize the strand preferences of the viral replicasein situ, and measure protein kinetics in single cells over time. In this framework, we evaluate competition between alphaviruses, and uncover that early superinfection exclusion is actually not a binary and unidirectional process, but rather a graded and bidirectional viral interaction. In contrast to competition between other viruses, alphaviruses demonstrate a passive basis for superinfection exclusion, emphasizing the utility of analyzing viral kinetics within single cells.
Decapping complex is essential for functional P-body formation and is buffered by nuclear localization
Authors: Tishinov Kiril , Spang Anne
Published: September 2020

mRNA decay is a key step in regulating the cellular proteome. Cytoplasmic mRNA is largely turned over in processing bodies (P-bodies). P-body units assemble to form P-body granules under stress conditions. How this assembly is regulated, however, remains still poorly understood. Here, we show that the translational repressor Scd6 and the decapping stimulator Edc3 act partially redundantly in P-body assembly by capturing the Dcp1/2 decapping complex and preventing it from becoming imported into the nucleus by the karyopherin ß Kap95. Nuclear Dcp1/2 does not drive mRNA decay and might be stored there as a ready releasable pool, indicating a dynamic equilibrium between cytoplasmic and nuclear Dcp1/2. Cytoplasmic Dcp1/2 is linked to Dhh1 via Edc3 and Scd6. Functional P-bodies are present at the endoplasmic reticulum where Dcp2 potentially acts to increase the local concentration of Dhh1 through interaction with Scd6 and Edc3 to drive phase separation and hence P-body formation.
Bioinformatics evaluation of the homologues ofSchistosoma mansonibiomarker proteins of bladder cancer in otherSchistosomaspecies
Authors: Folayowon JO , Adebayo AS , Isokpehi RD , Anumudu CI
Published: September 2020

Schistosomiasis remains a public health problem in developing countries. An ideal diagnostic test capable of detecting parasites as early as possible after the onset of infection is therefore highly desired. The identification of biomarker proteins associated with active infection and immune response may constitute the basis for the development of a successful diagnostic test. The aim of this study is to contribute to the development of protein biomarkers for schistosomiasis using a bioinformatics approach. The homologues of 36 previously identified urine biomarker proteins from aSchistosoma mansonidatabase, were identified in otherSchistosomaspecies using SMARTBLAST and analyzed for similarities and differences using multiple sequence alignment. Of the 36S. mansonibiomarker proteins, 29 had homologues with bothS. haematobiumandS. japonicumor either ofS. haematobiumandS. japonicum. Most of the 29S. mansonibiomarker proteins aligned with their homologues with many conserved regions. However, some vital biomarker proteins like venom allergen-like proteins, which had been proposed as a putative drug and vaccine target, showed more semi conserved regions in which the amino acids had similar shape but weakly similar properties. The predictions of 12 markers found in all three species also show that treatment of infections may possibly benefit from the investigational drug Artenimol and specific nutraceuticals or supplements. Experimental evaluation is needed to confirm the potential of the proteins as biomarkers for early diagnosis of schistosomiasis and associated bladder cancer.
RNA polymerases in strict endosymbiont bacteria with extreme genome reduction show distinct erosions that could result in limited and differential promoters’ recognition
Authors: Rangel-Chávez Cynthia Paola , Galán-Vásquez Edgardo , Pescador-Tapia Azucena , Delaye Luis , Martínez-Antonio Agustino
Published: September 2020

Strict endosymbiont bacteria with high degree of genome reduction retain smaller proteins and, in certain cases, lack complete functional domains compared to their free-living counterparts. Until now, the mechanisms underlying these genetic reductions are not well understood. However, it is thought that, in order to compensate for gene reduction, somehow hosts take over those vital functions that endosymbionts cannot perform. In the present study, the conservation of RNA polymerases, the essential machinery for gene expression, is analysed in bacteria with extreme genome reductions. For this purpose, comparative genomics, phylogenetic analysis and three-dimensional models of RNA polymerase subunits were done over four lineages of endosymbiotic proteobacteria with the smallest genomes known to date. Amino acids under positive selection in the α subunit and loss of motifs in other subunits of RNA polymerase were observed. According to three-dimensional models, sites under positive selection might compensate the loss of motifs in α subunit. In addition, variations in the σ subunit were identified, some of them already studied inE. colias a result of random mutagenesis. Amino acid changes in RNA polymerase suggest a possible modification in the binding specificity of the canonical −10 box (TATAAT) in some of these organisms. Furthermore, the β-flap helix domain is absent in someHodgkiniastrains, as observed in RNA pol II of Archaea, thus lacking the capacity to bind to the −35 box. Here, we propose several RNA polymerases models for endosymbiont bacteria with extremely reduced genomes. Evidence suggests that RNA polymerases of each endosymbiont bacteria follow a unique evolutionary path, without necessarily following the same path as a lineage, this is probably influenced by the intimate interactions sustained with other endosymbionts and its hosts.
Effects of gypenosides on enteroendocrine L-cell function and GLP-1 secretion
Authors: Patibandla Chinmai , Campbell Erin , Shu Xinhua , Shaw Angus M , Dolan Sharron , Patterson Steven
Published: September 2020

Glucagon-like peptide 1 (GLP-1) is an incretin hormone produced in gut L-cells, which regulates postprandial glucose-dependent insulin secretion, also known as the incretin effect. GLP-1 secretion may be reduced in type 2 diabetes mellitus, impacting on glycaemic regulation. Thus, methods to enhance endogenous GLP-1 secretion by use of natural GLP-1 secretagogues may improve glucose control in diabetes. Gypenosides (GYP) extracted from the plantGynostemma Pentaphyllum(Jiaogulan) are known for their glucose-lowering effects bothin vitroandin vivo, although their effect on GLP-1 secretion is unknown. Our results showed that GYP enhanced cell viability and significantly upregulated antioxidant gene Nrf2, Cat and Ho-1 expression. GYP did not affect glucokinase expression but downregulated proglucagon gene expression over 24h, although, cellular GLP-1 content was unchanged. Prohormone convertase 1 (Pcsk1) gene expression was unchanged by GYP over 24h, although protein levels were significantly downregulated, while prohormone convertase 2 (Pcsk2) mRNA and protein levels were significantly upregulated. Acute exposure to gypenosides enhanced calcium uptake and GLP-1 release from GLUTag cells both at low and high glucose concentrations. These results suggest that anti-diabetic properties of gypenosides are partly linked to their ability to stimulate GLP-1 secretion. Gypenosides enhance antioxidant gene expression and may protect L-cells from excess oxidative stress.
An fMRI study of initiation and inhibition of manual responses in people who stutter
Authors: Wiltshire Charlotte E. E. , Chesters Jennifer , Krishnan Saloni , Healy Máiréad P. , Watkins Kate E.
Published: September 2020

Developmental stuttering is a speech motor disorder characterised by difficulties initiating speech and frequent interruptions to the speech flow. Previous work suggests that people who stutter (PWS) have an overactive response suppression mechanism. Imaging studies of speech production in PWS consistently reveal greater activity of the right inferior frontal cortex, an area robustly implicated in inhibitory control of both manual and spoken responses. Here, we used a manual response version of the stop-signal task during fMRI to investigate neural differences related to response initiation and inhibition in PWS. Behaviourally, PWS were slower to respond to ‘go’ stimuli than people who are typically fluent (PWTF), but there was no difference in stop-signal reaction time. Our fMRI results were consistent with these behavioural results. The fMRI analysis revealed the expected networks associated with manual response initiation and inhibition in both groups. However, all contrasts between the two groups were characterised by overactivity in PWS relative to PWTF. This overactivity was significantly different for the initiation of responses (i.e. the ‘go’ trials) but not for response inhibition (i.e. the ‘stop’ trials). One explanation of these results is that PWS are consistently in a heightened inhibition state, i.e. areas of the inhibition network are more active, generally. This interpretation is consistent with predictions from the global response suppression hypothesis.
Volatiles fromSerratia marcescens, S. proteamaculans, andBacillus subtilisInhibit Growth ofRhizopus stoloniferand Other Fungi
Authors: Carter-House Derreck , Chung Joshua , McDonald Skylar , Mauck Kerry , Stajich Jason E
Published: September 2020

The common soil bacteriaSerratia marcescens, Serratia proteamaculans, andBacillus subtilisproduce small molecular weight volatile compounds that are fungi-static against multiple species, including the zygomycete moldRhizopus stolonifer(Mucoromycota) and the model filamentous moldNeurospora crassa(Ascomycota). The compounds or the bacteria can be exploited in development of biological controls to prevent establishment of fungi on food and surfaces. Here, we quantified and identified bacteria-produced volatiles using headspace sampling and gas chromatography-mass spectrometry. We found that each bacterial species in culture has a unique volatile profile consisting of dozens of compounds. Using multivariate statistical approaches, we identified compounds in common or unique to each species. Our analysis suggested that three compounds, dimethyl trisulfide, anisole, and 2-undecanone, are characteristic of the volatiles emitted by these antagonistic bacteria. We developed bioassays for testing inhibition of each compound and found dimethyl trisulfide and anisole were the most potent. This work establishes a pipeline for translating volatile profiles of cultured bacteria into high quality candidate fungistatic compounds which may be useful in combination as antifungal control products.

IMPORTANCE

Bacteria may benefit by producing fungistatic volatiles that limit fungal growth providing a mechanism to exclude competitors for resources. Volatile production is potentially mediating long distance biological control and competitive in-teractions among microbes, but the specific bioactive compounds are poorly characterized. This work provides evidence that fungistatic compounds in complex blends can be identified using machine-learning and multivariate approaches. This is the first step in identifying pathways responsible for fungistatic volatile production in order to phenotype and select natural strains for biocontrol ability, or engineer bacteria with relevant pathways.
Direct observation of RAG recombinase recruitment to chromatin and theIgHlocus in live pro-B cells
Authors: Lovely Geoffrey A , Braikia Fatima-Zohra , Singh Amit , Schatz David G. , Murre Cornelis , Liu Zhe , Sen Ranjan
Published: September 2020

The RAG1 and RAG2 proteins introduce double-strand DNA breaks at antigen-receptor loci in developing lymphocytes to initiate V(D)J recombination. How RAG proteins find the correct target locus in a vast excess of non-specific chromatin is not known. Here we measured dynamics of RAG1/RAG2 interactions with chromatin in living pro-B cells. We found that the majority of RAG1 or RAG1/RAG2 complex is in a fast 3D diffusive state, and the residual slow diffusive (bound) fraction was determined by a non-core portion of RAG1, and the PHD domain of RAG2. The RAG proteins exhibited distinct dynamics at theIgHlocus. In particular, RAG2 increased the probability of RAG1 binding toIgH, a property that likely explains its non-catalytic role in V(D)J recombination. Our observations reveal how RAG finds its targets in developing B cells.

One Sentence Summary

Single-molecule imaging of the RAG recombinase reveals its search strategy for chromatin, H3K4me3 and antibody gene loci in living cells.
Enhancing design thinking approaches to innovation through gamification
Authors: Patrício Rui , Moreira Antonio Carrizo , Zurlo Francesco
Published: September 2020

Purpose

The paper aims to explore the relationship between gamification and design thinking approach to innovation in the context of the early stage of innovation process (ESoIP). Design thinking is conceptually appropriate to support innovative, complex and uncertain business environments. Still, its practices have demonstrated some difficulties in managing the ESoIP, such as lack of structure and clarity around goals. This paper argues that gamification can enhance and complement design thinking in the management of firms' ESoIP.

Design/methodology/approach

Given the need to achieve a deeper understanding of the linkages between gamification and design thinking, the paper follows an exploratory theory building approach for this complex reality of innovation. The case study research method was conducted in three firms (Trivalor, Novartis and Microsoft) that applied a gamification approach to the ESoIP.

Findings

The results demonstrate that gamification has the power to enhance and complement design thinking practices by getting tasks more organized and improving coordination and employees' engagement in the innovation process.

Practical implications

The paper provides critical managerial contributions on how firms can use gamification to improve design thinking approaches to ESoIP. Its consequences are also crucial to innovation, R&D, and product/service development managers interested in using gamification to support the ideation and concept development of new solutions complementing traditional design thinking approaches.

Originality/value

Merging the gamification and design thinking approaches is novel, particularly on firms' ESoIP. The paper provides a comprehensive discussion of design thinking shortcomings and the role that gamification can play in overcoming them.
Consumer segmentation and preference for indigenous chicken products
Authors: Bannor Richard Kwasi , Abele Steffen , Kuwornu John K.M. , Oppong-Kyeremeh Helena , Yeboah Ernest Darkwah
Published: September 2020

Purpose

This study examined consumer preference and willingness to pay a premium price for indigenous chicken products in Ghana.

Design/methodology/approach

Data were obtained from 240 consumers in Ghana through the administration of a structured questionnaire. Probit regression was used to examine the factors influencing consumer preference for indigenous chicken products in Ghana. Ordered probit regression was employed to examine the factors influencing the percentage premium price a consumer is willing to pay for indigenous chicken products whereas the cluster analysis was used to segment the consumers.

Findings

Different sets of factors were identified to have influenced the decision to purchase indigenous chicken products and the willingness to pay for a premium price. In total, four market segments were identified in this study: shopper consumer segment, the conventional or ethnocentric consumer segment, the privilege consumer segment and the pleasure-seeker consumer segment.

Research limitations/implications

The important factors to learn from this study are the following: examining the critical success factors for the promotion of indigenous chicken products in Ghana is an excellent opportunity for future research. Second, the choice of locally-produced exotic breeds/strains of chicken meat has not been examined in this study. Therefore, a comparative study of consumer preference of the locally-produced exotic breeds/strains of chicken in Ghana is another great opportunity for further research.

Originality/value

Regardless of the seemly opportunities in regional marketing, Ghana has not leveraged on this to promote a regional marketing brand for its local products – like indigenous chicken products – over imported chicken products. Besides, regionalism studies on agricultural products have received less attention in Ghana; therefore, this study contributes to a better understanding of consumer choice of indigenous chicken products, potentially, and the marketing of regional food products in Ghana.
The role of reputation in the business cooperation process: multiple case studies in small and medium-sized enterprises
Authors: Franco Mário , Haase Heiko
Published: September 2020

Purpose

This study aims to identify the main reasons for forming a cooperation agreement in the context of small and medium-sized enterprises (SMEs) and understand the role of reputation in this business process.

Design/methodology/approach

To achieve these objectives, a qualitative research approach was adopted, specifically the case study method. The context of analysis studied here was formed of five SMEs (cases) located in an inland region of Portugal. Data-collecting instruments were individual interviews and documentary analysis, and the data treatment technique was content analysis.

Findings

From the results obtained, it is concluded that SMEs have different reasons for entering a cooperation agreement and that the criterion of reputation, in the partner selection process, was quite frequently mentioned. In addition, the study found trust to be another important criterion when choosing a partner. This means that besides the resources a partner may possess, the most important aspect is that there should be mutual trust.

Practical implications

This study seeks to help SME managers to characterise and understand the phenomenon of cooperation and show the main criteria to consider when choosing their partner(s).

Originality/value

This study is innovative because it will help to characterise and understand business cooperation in SMEs and contribute to choosing a suitable partner, so that SMEs can achieve good performance, major market expansion and improve relations with their partners, in an increasingly competitive environment.
Characteristics and outcomes of patients with COVID‐19 admitted to ICU in a tertiary hospital in Stockholm, Sweden
Authors: Larsson Emma , Brattström Olof , Agvald‐Öhman Christina , Grip Jonathan , Campoccia Jalde Francesca , Strålin Kristoffer , Nauclér Pontus , Oldner Anders , Konrad David , Persson Björn P. , Eriksson Lars I. , Mårtensson Johan ,   Karolinska Intensive Care COVID‐19 Study Group
Published: September 2020

Background

Information on characteristics and outcomes of intensive care unit (ICU) patients with COVID‐19 remains limited. We examined characteristics, clinical course and early outcomes of patients with COVID‐19 admitted to ICU.

Methods

We included all 260 patients with COVID‐19 admitted to nine ICUs at the Karolinska University Hospital (Stockholm, Sweden) between 9 March and 20 April 2020. Primary outcome was in‐hospital mortality among patients with definite outcomes (discharged from ICU or death), as of 30 April 2020 (study end point). Secondary outcomes included ICU length of stay, the proportion of patients receiving mechanical ventilation and renal replacement therapy, and hospital discharge destination.

Results

Of 260 ICU patients with COVID‐19, 208 (80.0%) were men, the median age was 59 (IQR 51‐65) years, 154 (59.2%) had at least one comorbidity, and the median duration of symptoms preceding ICU admission was 11 (IQR 8‐14) days. Sixty‐two (23.8%) patients remained in ICU at study end point. Among the 198 patients with definite outcomes, ICU length of stay was 12 (IQR, 6‐18) days, 163 (82.3%) received mechanical ventilation, 28 (14.1%) received renal replacement therapy, 60 (30.3%) died, 62 (31.3%) were discharged home, 47 (23.7%) were discharged to ward, and 29 (14.6%) were discharged to another health care facility. On multivariable logistic regression analysis, older age and admission from the emergency department was associated with higher mortality.

Conclusion

This study presents detailed data on clinical characteristics and early outcomes of consecutive patients with COVID‐19 admitted to ICU in a large tertiary hospital in Sweden.
Levothyroxine and subclinical hypothyroidism in patients with recurrent pregnancy loss
Authors: Yoshihara Hiroyuki , Sugiura‐Ogasawara Mayumi , Goto Shinobu , Kitaori Tamao
Published: September 2020

Problem

The association between subclinical hypothyroidism (SCH) and recurrent pregnancy loss (RPL) remains unclear. We evaluated whether SCH affects subsequent live births and whether levothyroxine is effective in improving the live birth rate in patients with RPL.

Method of study

This observational cohort study included 1418 pregnancies of 1014 patients with a history of 2 or more pregnancy losses, who were euthyroid or had hypothyroidism, and had at least one subsequent pregnancy outcome. Some patients with SCH, as defined as a TSH >2.5 mIU/L, were treated with levothyroxine, and these comprised the levothyroxine group. The prevalence of SCH, subsequent live birth rates per patient and per pregnancy were compared among patients with SCH treated with and without levothyroxine and patients with euthyroid.

Results

The prevalence of SCH was 14.4%. Subsequent live birth rates were 75.0% for the levothyroxine group, 68.6% for the untreated SCH group, and 70.1% for the euthyroid group. After excluding miscarriages with abnormal karyotypes, live birth rates were 89.2%, 90.0%, and 91.1%. The adjusted odds ratio (95%CI) was 0.95 (0.23‐3.83) after controlling covariables when comparing SCH patients with and without treatment. The live birth rates per pregnancy were 93.1%, 85.7%, and 90.9%, respectively. The adjusted OR was 0.95 (0.23‐3.83).

Conclusion

Levothyroxine has no effect on improving the live birth rate in patients with RPL associated with SCH. Treatment in patients with RPL and SCH raised TSH levels (2.5‐10mIU/L) might not be beneficial in improving the live birth rate.
Situating Saudi Arabia in China's Belt and Road Initiative
Authors: Fulton Jonathan
Published: September 2020

Saudi Arabia's geostrategic location and role as a Middle East regional power, combined with its ambitious Saudi Vision 2030 development plan, make it an important Belt and Road Initiative (BRI) partner for China, which has become Saudi Arabia's largest trading partner. Despite mutual interests, the role of the United States as the dominant power in the Persian Gulf region means that the Sino‐Saudi Arabia relationship must be managed in such a way that it does not directly challenge Washington. This article argues that China has followed a strategic hedging approach in developing its relations with Saudi Arabia, focusing on the economic and developmental goals of the BRI and Saudi Vision 2030 to avoid antagonizing the United States (US) while taking advantage of US regional security commitments.
Beyond MAP: A guide to dimensions of rainfall variability for tropical ecology
Authors: Schwartz Naomi B. , Lintner Benjamin R. , Feng Xue , Powers Jennifer S.
Published: September 2020

Tropical ecologists have long recognized rainfall as the key climate filter shaping tropical ecosystem structure and function across space and time. Still, tropical ecologists have historically had a limited toolkit for characterizing rainfall, largely relying on simple metrics like mean annual precipitation (MAP) and dry season length to characterize rainfall regimes that vary along many more dimensions. Here, we review methods for quantifying dimensions of rainfall variability on multiple time scales, with a focus on ecological applications of these methods. We also discuss key considerations for tropical ecologists looking to use rainfall metrics that better align with hypothesized biological or ecological mechanisms or that more effectively describe rainfall variability in the systems we study and provide a toolkit (R scripts and gridded datasets) to do so. We argue that incorporating more sophisticated approaches to quantify rainfall variability into study design and statistical analyses will enhance our understanding of past, ongoing, and future changes in tropical ecosystems.

Abstract in Spanish is available with online material.
Juggling options: Manipulation ease determines primate optimal fruit‐size choice
Authors: Dias da Silva Renann H. P. , Castro Sa Matheus J. , Baccaro Fabricio B. , Tománek Pavel , Barnett Adrian A.
Published: September 2020

Optimal foraging theory predicts that animals will seek simultaneously to minimize food processing time and maximize energetic gain. To test this hypothesis, we evaluated whether a specialist seed‐predator primate forages optimally when choosing among variable‐sized thick‐husked fruits. Our objects of study were the golden‐backed uacari (Cacajao ouakary, Pitheciidae) and single‐seeded pods of the macucu tree (Aldina latifolia, Fabaceae). We predict that golden‐backed uacari will consume fruits of the size class that requires the least time to obtain, handle, and ingest. We used scan sampling, ad libitum to record feeding observations, and measured fruits, their penetrability, and the size of taxidermized C. ouakary hands. To test whether uacaris selected for optimal characteristics, we compared 8 metrics from 75 eaten and 105 uneaten seeds/fruits collected. Uacaris selected fruits of medium size and weight disproportionately to their abundance. Processing large fruits took six times longer than did medium‐sized fruits, but seeds were only four times as large, that is, for energetic yield per unit time, thus choosing medium‐sized pods was optimal. Disproportionate selection by C. ouakary of fruits of medium size and mass in relation to their abundance suggests active sub‐sampling of the available weight–size continuum. This selectivity probably maximizes trade‐offs between the energy derived from a seed, and time and energy expended in processing fruit to access this, so following optimal foraging theory predictions. The greater time spent processing large pods is attributed to difficulties manipulating objects five to seven times the size of the animal's palm and one‐sixth its own body weight.