bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in hepatitis C virus seroprevalence and associated risk factors among men who have sex with men in Montréal: results from three cross-sectional studies (2005, 2009, 2018)
Authors: Delaunay Charlotte Laniece , Cox Joseph , Klein Marina B. , Lambert Gilles , Grace Daniel , Lachowsky Nathan , Maheu-Giroux Mathieu
Published: January 2020

Introduction

To eliminate the hepatitis C virus (HCV) by 2030, Canada must adopt a micro-elimination approach targeting priority populations, including gay, bisexual, and other men who have sex with men (MSM). HCV prevalence and risk factors among MSM populations are context-dependent, and accurately describing these indicators at the local level is essential if we want to design appropriate, targeted prevention and treatment interventions. We aimed first to estimate and investigate temporal trends in HCV seroprevalence between 2005-2018 among Montréal MSM, and then to identify the socio-economic, behavioural, and biological factors associated with HCV exposure among this population.

Methods

We used data from three bio-behavioural cross-sectional surveys conducted among Montréal MSM in 2005 (n=1,795), 2009 (n=1,258), and 2018 (n=1,086). To ensure comparability of seroprevalence estimates across time, we standardized the 2005 and 2009 time-location samples to the 2018 respondent-driven sample. Time trends overall and stratified by HIV status, history of injection drug use (IDU), and age were examined. Modified Poisson regression analyses with generalized estimating equations were used to identify factors associated with HCV seropositivity pooling all surveys. We used multiple imputation by chained equations for all missing values.

Results

Standardized HCV seroprevalence among all MSM remained stable from 7% (95% confidence interval (CI): 3-10%) in 2005, to 8% (95%CI: 1-9%) in 2009, and 8% (95%CI: 4-11%) in 2018. This apparent stability hides diverging temporal trends in seroprevalence between age groups, with a decrease among MSM <30 years old, and an increase among MSM aged ≥45 years. History of IDU was the strongest predictor for HCV seropositivity (adjusted prevalence ratio: 8.0; 95%CI: 5.5-11.5), and no association was found between HCV seroprevalence and the sexual risk factors studied (condomless anal sex with men of serodiscordant/unknown HIV status, number of sexual partners, and group sex), nor with biological markers of syphilis.

Conclusions

HCV seroprevalence remained stable among Montréal MSM between 2005-2018. Unlike other settings where HCV infection was strongly associated with sexual risk factors among MSM subgroups, IDU was the preeminent risk factor for HCV seropositivity. Understanding the intersection of IDU contexts, practices, and populations is essential to prevent HCV transmission among MSM.
A Pilot Study of an Esophageal Cooling Device During Radiofrequency Ablation for Atrial Fibrillation
Authors: Clark Brad , Alvi Nazia , Hanks Joseph , Suprenant Brad
Published: January 2020

Background

Esophageal thermal injury is a risk of ablation of the posterior left atrium despite various devices utilized to date.

Objective

Evaluate the potential of a commercially-available esophageal cooling device to provide esophageal protection during left atrial catheter ablation.

Methods

In this pilot study, we randomized 6 patients undergoing catheter ablation for atrial fibrillation. Three patients received standard of care for our site (use of a single-sensor temperature probe, with adjunct iced-water instillation for any temperature increases >1°C). Three patients received standard ablation after placement of the esophageal cooling device using a circulating water temperature of 4°C. All patients underwent transesophageal echocardiogram (TEE) and esophagogastroduodenoscopy (EGD) on the day prior to ablation followed by EGD on the day after.

Results

In the 3 control patients, one had no evidence of esophageal mucosal damage, one had diffuse sloughing of the esophageal mucosa and multiple ulcerations, and one had a superficial ulcer with large clot. Both patients with lesions were classified as Zargar 2a. In the 3 patients treated with the cooling device, one had no evidence of esophageal mucosal damage, one had esophageal erythema (Zargar 1), and one had a solitary Zargar 2a lesion. At 3-month follow-up, 1 patient in each group had recurrence of atrial fibrillation.

Conclusions

The extent of esophageal injury was less severe with a commercially available esophageal cooling device than with reactive instillation of ice-cold water. This pilot study supports further evaluation with a larger clinical trial.
Crystal structures of full length DENV4 NS2B-NS3 reveal the dynamic interaction between NS2B and NS3
Authors: Phoo Wint Wint , Sahili Abbas El , Zhang ZhenZhen , Chen Ming Wei , Liew Chong Wai , Lescar Julien , Vasudevan Subhash G. , Luo Dahai
Published: January 2020

Flavivirus is a genus of emerging and re-emerging arboviruses which include many significant human pathogens. Non-structural protein 3 (NS3), a multifunctional protein with N-terminal protease and C-terminal helicase, is essential in viral replication. The NS3 protease together with NS2B cofactor is an attractive antiviral target. A construct with an artificial glycine linker connecting the NS2B cofactor and NS3 protease has been used for structural, biochemical and drug-screening studies. The effect of this linker on dynamics and enzymatic activity of the protease was studied by several biochemical and NMR methods but the findings remained inconclusive. Here, we designed constructs of NS2B cofactor joined to full length DENV4 NS3 in three different manners, namelybNS2B47NS3 (bivalent),eNS2B47NS3(enzymatically cleavable) andgNS2B47NS3 (glycine-rich G4SG4 linker). We report the first crystal structures of linked and unlinked full-length NS2B-NS3 enzyme in its free state and also in complex with Bovine Pancreatic Trypsin Inhibitor (BPTI). These structures demonstrate that the NS2B-NS3 protease mainly adopts a closed conformation. BPTI binding is not essential to but favors the closed conformation by interacting with both NS2B and NS3. The artificial linker between NS2B and NS3 tends to induce the open conformation and interfere with the protease activity. This negative impact on the enzyme structure and function is restricted to the protease domain as the ATPase activities of these constructs are not affected.
Experience-dependent modulation of the visual evoked potential: testing effect sizes, retention over time, and associations with age in 415 healthy individuals
Authors: Valstad Mathias , Moberget Torgeir , Roelfs Daniël , Slapø Nora B. , Timpe Clara M.F. , Beck Dani , Richard Geneviève , Sofie Sæther Linn , Haatveit Beathe , Andre Skaug Knut , Egil Nordvik Jan , Hatlestad-Hall Christoffer , Einevoll Gaute T. , Mäki-Marttunen Tuomo , Westlye Lars T. , Jönsson Erik G. , Andreassen Ole A. , Elvsåshagen Torbjørn
Published: January 2020

Experience-dependent modulation of the visual evoked potential (VEP) is a promising proxy measure of synaptic plasticity in the cerebral cortex. However, existing studies are limited by small to moderate sample sizes as well as by considerable variability in how VEP modulation is quantified. In the present study, we used a large sample (n = 415) of healthy volunteers to compare different quantifications of VEP modulation with regards to effect sizes and retention of the modulation effect over time. We observed significant modulation for VEP components C1 (Cohen’sd= 0.53), P1 (d= 0.66), N1 (d= −0.27), N1b (d= −0.66), but not P2 (p = 0.1), and in one time-frequency cluster (~30 Hz and ~70 ms post-stimulus;d= −0.48), 2-4 minutes after 2 Hz prolonged visual stimulation. For components N1 (d= −0.21) and N1b (d= −0.38), as well for the time-frequency cluster (d= −0.33), this effect was retained after 54-56 minutes. Moderate to high correlations (ρ= [0.39, 0.69]) between modulation at different postintervention blocks revealed a relatively high temporal stability in the modulation effect for each VEP component. However, different VEP components also showed markedly different temporal retention patterns. Finally, P1 modulation correlated positively with age (t = 5.26), and was larger for female participants (t = 3.91), with no effects of either age or sex on N1 and N1b potentiation. These results provide strong support for VEP modulation, and especially N1b modulation, as a robust measure of synaptic plasticity, but underscore the need to differentiate between components, and to control for demographic confounders.
A ballistic pollen dispersal strategy hidden in stylar oscillation
Authors: Ito Shuto , Rajabi Hamed , Gorb Stanislav N
Published: January 2020

Asteraceae, the most successful flowering plant family, is adapted to the vast range of ecological niches. Their adaptability is partially based on their strong ability of reproduction. The initial, yet challenging, step for plant reproduction is to transport pollen to flower-visiting pollinators. Using quantitative experiments and numerical simulations, here we show that the common floral feature of Asteraceae, a pollen-bearing style, serves as a ballistic lever for catapulting pollen grains to pollinators. This is likely to be a pollination strategy to propel pollen to blind spots of pollinators’ bodies, which are beyond the physical reach of the styles. Our results suggest that the specific morphology and length of the floret, as well as the pollen adhesion, avoid pollen waste by catapulting pollen within a certain range equal to the size of a flowerhead. The insights into the functional floral oscillation may shed light on the superficially unremarkable, but ubiquitous functional floral design of Asteraceae.
Evolution of transmissible spongiform encephalopathy and the prion protein gene (PRNP) in mammals
Authors: Buchanan Brittaney L. , Zink Robert M.
Published: January 2020

Wildlife managers are concerned with transmissible spongiform encephalopathies (TSEs) as they are currently incurable, always fatal, and have the potential to cross species boundaries. Although a wide range of mammals exhibit TSEs, it is currently unclear whether they are evolutionarily clustered or if TSE+ species are randomly distributed phylogenetically. We tested whether mammalian species with TSEs are phylogenetically underdispersed on a tree derived from 102 PRNP sequences obtained from the Orthologous Mammalian Markers database. We determined that the PRNP tree was topologically congruent with a species tree for these same 102 taxa constructed from 20 aligned gene sequences, excluding the PRNP sequence. Searches in Google Scholar were done to determine whether a species is known to have expressed a TSE. TSEs were present in a variety of orders excluding Chiroptera, Eulipotyphyla, and Lagomorpha and no marine mammals (Artiodactyla) were recorded to have a TSE. We calculated the phylogenetic signal of binary traits (D-Value) to infer if the phylogenetic distribution of TSEs are conserved or dispersed. The occurrence of TSEs in both trees is non-random (Species tree D-value = 0.291; PRNP tree D-value = 0.273), and appears to have arisen independently in the recent history of different mammalian groups. Our findings suggest that the evolution of TSEs develops in groups of species irrespective of PRNP genotype. The evolution of TSEs merits continued exploration at a more in-depth phylogenetic level, as well as the search for genetic combinations that might underlie TSE diseases.
Long-read Assays Shed New Light on the Transcriptome Complexity of a Viral Pathogen and on Virus-Host Interaction
Authors: Tombácz Dóra , Prazsák István , Maróti Zoltán , Moldován Norbert , Csabai Zsolt , Balázs Zsolt , Dénes Béla , Kalmár Tibor , Snyder Michael , Boldogkői Zsolt
Published: January 2020

Characterization of global transcriptomes using conventional short-read sequencing is challenging because of the insensitivity of these platforms to transcripts isoforms, multigenic RNA molecules, and transcriptional overlaps, etc. Long-read sequencing (LRS) can overcome these limitations by reading full-length transcripts. Employment of these technologies has led to the redefinition of transcriptional complexities in reported organisms. In this study, we applied LRS platforms from Pacific Biosciences and Oxford Nanopore Technologies to profile the dynamic vaccinia virus (VACV) transcriptome and assess the effect of viral infection on host gene expression. We performed cDNA and direct RNA sequencing analyses and revealed an extremely complex transcriptional landscape of this virus. In particular, VACV genes produce large numbers of transcript isoforms that vary in their start and termination sites. A significant fraction of VACV transcripts start or end within coding regions of neighboring genes. We distinguished five classes of host genes according to their temporal responses to viral infection. This study provides novel insights into the transcriptomic profile of a viral pathogen and the effect of the virus on host gene expression.

Author Summary

Viral transcriptomes that are determined using conventional (first- and second-generation) sequencing techniques are incomplete because these platforms are inefficient or fail to distinguish between types of transcripts and transcript isoforms. In particular, conventional sequencing techniques fail to distinguish between parallel overlapping transcripts, including alternative polycistronic transcripts, transcriptional start site (TSS) and transcriptional end site (TES) isoforms, and splice variants and RNA molecules that are produced by transcriptional read-throughs. Long-read sequencing (LRS) can provide complete sets of RNA molecules, and can therefore be used to assemble complete transcriptome atlases of organisms. Although vaccinia virus (VACV) does not produce spliced RNAs, its transcriptome contains large numbers of TSSs and TESs for individual viral genes and has a high degree of polycistronism, together leading to enormous complexity. In this study, we applied single molecule real-time and nanopore-based cDNA and direct-RNA sequencing methods to investigate transcripts of VACV and the host organism.
Heterogeneity of proteome dynamics between connective tissue phases of adult tendon
Authors: Simpson Deborah , Choi Howard , Wang Ding , Prescott Mark , Pitsillides Andrew A. , Dudhia Jayesh , Clegg Peter D. , Ping Peipei , Thorpe Chavaunne T.
Published: January 2020

Maintenance of connective tissue integrity is fundamental to sustain function, requiring protein turnover to repair damaged tissue. However, connective tissue proteome dynamics remain largely undefined, as do differences in turnover rates of individual proteins in the collagen and glycoprotein phases of connective tissue extracellular matrix (ECM). Here, we investigate proteome dynamics in the collagen and glycoprotein phases of connective tissues by exploiting the spatially distinct fascicular (collagen-rich) and interfascicular (glycoprotein-rich) ECM phases of tendon. Using isotope labelling, mass spectrometry and bioinformatics, we calculate turnover rates of individual proteins within rat Achilles tendon and its ECM phases. Our results demonstrate complex proteome dynamics in tendon, with ~1000-fold differences in protein turnover rates, and overall faster protein turnover within the glycoprotein-rich interfascicular matrix compared to the collagen-rich fascicular matrix. These data provide insights into the complexity of proteome dynamics in tendon, likely required to maintain tissue homeostasis.
Different forms of fear extinction are supported by distinct cortical substrates
Authors: Lay Belinda P. P. , Pitaru Audrey , Boulianne Nathan , Esber Guillem R. , Iordanova Mihaela D.
Published: January 2020

Understanding how learned fear can be reduced is at the heart of treatments for anxiety disorders. Tremendous progress has been made in this regard through extinction training in which an expected aversive outcome is omitted. However, current progress almost entirely rests on this single paradigm, resulting in a very specialized knowledgebase at the behavioural and neural level of analysis. Here, we used a paradigm-independent approach to show that different methods that lead to reduction in learned fear are dissociated in the cortex. We report that the infralimbic cortex has a very specific role in fear reduction that depends on the omission of aversive events but not on overexpectation. The orbitofrontal cortex, a structure generally overlooked in fear, is critical for downregulating fear when fear is inflated or overexpected, but not when an aversive event is omitted.
Breast cancer-secreted factors induce atrophy and reduce basal and insulin-stimulated glucose uptake by inhibiting Rac1 activation in rat myotubes
Authors: Ali Mona Sadek , Bitsch-Olsen Stine , Frank Emma , Battey Edmund , Perla Mirela , Themsen Scott Sebastian Birch , Raun Steffen Henning , Jong Steven de , Sylow Lykke
Published: January 2020

Background

Metabolic disorders are prevalent in women with breast cancer, increasing mortality and cancer recurrence rates. Despite clinical implications, the cause of breast cancer-associated metabolic dysfunction remains poorly understood. Skeletal muscle is crucial for insulin-stimulated glucose uptake, thus key to whole-body glucose homeostasis. In this study, we determined the effect of breast cancer cell-conditioned media on skeletal muscle glucose uptake in response to insulin.

Method

L6 myotubes overexpressing myc-tagged GLUT4 (GLUT4myc-L6) were incubated with 40% conditioned media from tumorigenic MCF7 or BT474, or non-tumorigenic control MCF10A breast cells. Mass-spectrometry-based proteomics was applied to detect molecular rewiring in response to breast cancer in the muscle. Expression of myogenesis and inflammation markers, GLUT4 translocation, [3H]-2-deoxyglucose (2DG) uptake, and intramyocellular insulin signalling were determined.

Results

Breast cancer cell-conditioned media induced proteomic changes in pathways related to sarcomere organisation, actin filament binding, and vesicle trafficking, disrupted myogenic differentiation, activated an inflammatory response via NF-κB, and induced muscle atrophy. Basal and insulin-stimulated GLUT4 translocation and 2DG uptake were reduced in myotubes treated with breast cancer cell-conditioned media compared to the control. Insulin signalling via the Rho GTPase Rac1 was blocked in breast cancer-treated myotubes, while Akt-TBC1D4 signalling was unaffected.

Conclusion

Conditioned media from MCF7 and BT474 breast cancer cells reduced skeletal muscle glucose uptake via inhibition of GLUT4 translocation and intramyocellular insulin signalling by selectively blocking Rac1 activation and inducing inflammation. These findings indicate that the rewiring of skeletal muscle proteome, inflammation, and insulin signalling could play a role in metabolic dysfunction in patients with breast cancer.
Transcriptomic Organization of Human Posttraumatic Stress Disorder
Authors: Girgenti Matthew J. , Wang Jiawei , Ji Dingjue , Cruz Dianne ,   Traumatic Stress Brain Research Study Group,   the Million Veteran Program, Stein Murray B. , Gelernter Joel , Young Keith , Huber Bertrand R. , Williamson Douglas E. , Friedman Matthew J. , Krystal John H. , Zhao Hongyu , Duman Ronald S.
Published: January 2020

Posttraumatic stress disorder (PTSD) affects approximately 8% of the general population, with higher rates in extreme stress groups, including combat veterans or victims of sexual assault. Despite extensive study of the neurobiological correlates of PTSD, little is known about its molecular substrates. Here differential gene expression and network analyses of 4 prefrontal cortex (PFC) postmortem subregions of male and female PTSD subjects demonstrates extensive remodeling of the transcriptomic landscape. The data revealed a highly connected down-regulated set of interneuron transcripts in the most significant gene network associated with PTSD and integration of this data with genotype data from the largest PTSD GWAS identified the interneuron synaptic geneELFN1as conferring significant genetic liability for PTSD. We also identified marked sexual dimorphism in the transcriptomic signatures that could contribute to the higher rates of PTSD in women. Comparison with a matched major depressive disorder (MDD) cohort revealed significant divergence between the molecular profiles of subjects with PTSD and depression despite their high comorbidity. Our analysis provides convergent systems-level evidence of genomic networks within the PFC that contribute to the pathophysiology of PTSD in humans.
Tomato wall-associated kinase SlWak1 acts in an Fls2- and Fls3-dependent manner to promote apoplastic immune responses toPseudomonas syringae
Authors: Zhang Ning , Pombo Marina A , Rosli Hernan G , Martin Gregory B.
Published: January 2020

Wall-associated kinases (Waks) are known to be important components of plant immunity against various pathogens includingPseudomonas syringaepv. tomato (Pst) although their molecular mechanisms are largely unknown. In tomato,SlWak1has been implicated in immunity because its transcript abundance increases significantly in leaves after treatment with the flagellin-derived peptides flg22 and flgII-28, which activate the receptors Fls2 and Fls3, respectively. We generated twoSlWak1tomato mutants (Δwak1) using CRISPR/Cas9 and investigated the role ofSlWak1in tomato-Pstinteractions. PTI activated in the apoplast by flg22 or flgII-28 was compromised in Δwak1 plants but PTI at the leaf surface was unaffected. The Δwak1 plants developed fewer callose deposits than wild-type plants but retained the ability to generate reactive oxygen species and activate MAPKs in response to flg22 and flgII-28. The induction ofWak1gene expression by flg22 and flgII-28 was greatly reduced in a tomato mutant lacking Fls2 and Fls3 but induction ofFls3gene expression by flgII-28 was unaffected in Δwak1 plants. AfterPstinoculation, Δwak1 plants developed disease symptoms more slowly than Δfls2.1/fls2.2/fls3 mutant plants, although both plants ultimately were similarly susceptible. SlWak1 co-immunoprecipitated with both Fls2 and Fls3 independently of flg22/flgII-28 or Bak1. These observations suggest that SlWak1 acts in a complex with Fls2/Fls3 and plays an important role at later stages of the PTI in the apoplast.
Object-based analyses in FIJI/ImageJ to measure local RNA translation sites in neurites in response to Aβ1-42 oligomers
Authors: Gamarra María , Blanco-Urrejola Maite , Batista Andreia F.R. , Imaz Josune , Baleriola Jimena
Published: January 2020

Subcellular protein delivery is especially important in signal transduction and cell behavior, and is typically achieved by localization signals within the protein. However, protein delivery can also rely on localization of mRNAs that are translated at target sites. Although once considered heretical, RNA localization has proven to be highly conserved in eukaryotes.

RNA localization and localized translation are especially relevant in polarized cells like neurons where neurites extend dozens to hundreds of centimeters away from the soma. Local translation confers dendrites and axons the capacity to respond to their environment in an acute manner without fully relying on somatic signals. The relevance of local protein synthesis in neuron development, maintenance and disease has not been fully acknowledged until recent years, partly due to the limited amount of locally produced proteins. For instance, in hippocampal neurons levels of newly-synthesized somatic proteins can be more than 20-30 times greater than translation levels of neuritic proteins. Thus local translation events can be easily overlooked under the microscope.

Here we describe an object-based analysis used to visualize and quantify local RNA translation sites in neurites. Newly-synthesized proteins are tagged with puromycin and endogenous RNAs labelled with SYTO. After imaging, signals corresponding to neuritic RNAs and proteins are filtered with a Laplacian operator to enhance the edges. Resulting pixels are converted into objects and selected by automatic masking followed by signal smoothing. Objects corresponding to RNA or protein and colocalized objects (RNA and protein) are quantified along individual neurites. Colocalization between RNA and protein in neurites correspond to newly-synthesized proteins arising from localized RNAs and represent localized translation sites. To test the validity of our analyses we have compared control neurons to Aβ1-42-treated neurons. Aβ is involved in the pathology of Alzheimer’s disease and was previously reported to induce local translation in axons and dendrites which in turn contributes to the disease. We have observed that Aβ increases the synthesis of neuritic proteins as well as the fraction of translating RNAs in distal sites of the neurite, suggesting an induction of local protein synthesis. Our results thus confirm previous reports and validate our quantification method.
Acute oral toxicity and risks of exposure to the neonicotinoid thiamethoxam, and other classes of systemic insecticide, for the Common Eastern Bumblebee (Bombus impatiens)
Authors: Mundy-Heisz Kayla A. , Prosser Ryan S. , Raine Nigel E.
Published: January 2020

The Common Eastern Bumblebee (Bombus impatiens) is native to North America with an expanding range across Eastern Canada and the USA. This species is commercially produced primarily for greenhouse crop pollination and is a common and abundant component of the wild bumblebee fauna in agricultural, suburban and urban landscapes. However, there is a dearth of pesticide toxicity information about North American bumblebees. The present study determines the acute oral toxicity (48-hour LD50) of cyantraniliprole (>0.54 μg/bee), flupyradifurone (>1.7 μg/bee), sulfoxaflor (0.0194 μg/bee), and thiamethoxam (0.0012 μg/bee). Compared with published honey bee (Apis mellifera) LD50 values, the present study shows that thiamethoxam and sulfoxaflor are 4.2x and 7.5x more acutely toxic toB. impatiens, whereas flupyradifurone is more acutely toxic toA. mellifera. The current rule of thumb for toxicity extrapolation beyond the honey bee as a model species, termed 10x safety factor, may be sufficient for bumblebee acute oral toxicity. A comparison of three risk assessment equations suggested that the Standard Risk Approach (SRA) and Fixed Dose Risk Approach (FDRA) provide more nuanced levels of risk evaluation compared to the European Plant Protection Organization (EPPO) Hazard Quotient (HQ), primarily because SRA and FDRA take into account real world variability in pollen and nectar pesticide residues and the chances that bees are exposed to them.
Most commonly mutated genes in High Grade Serous Ovarian Carcinoma are nonessential for ovarian surface epithelial stem cell transformation
Authors: Yamulla Robert J. , Nalubola Shreya , Flesken-Nikitin Andrea , Nikitin Alexander Yu. , Schimenti John C.
Published: January 2020

High grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological cancer and the 5th leading cause of cancer-related deaths of women in the USA. Disease-associated mutations have been identified by the Cancer Genome Atlas Research Network. However, aside from mutations in TP53 or alterations in the RB1 pathway that are extremely common in HGSOC, the contributions of other mutation combinations have been difficult to assess experimentally or with genomic data alone. Previous research identified ALDH+ stem cells of the ovarian surface epithelium (OSE) as one of the putative cells of HGSOC origin. Here, we performed combinatorial CRISPR mutagenesis of 20 putative HGSOC driver genes to identify mutation combinations that transformed OSE stem cells (OSE-SC) and non-stem cells (OSE-NS). Overrepresented mutations and mutation combinations were identified in all transformants and were investigated directly in targeted assays. Our results support the OSE stem cell theory of HGSOC initiation and suggest that most commonly mutated genes in HGSOC have no effect on OSE-SC transformation initiation. We suggest a model in which combined disruption of RB1 and PTEN, in addition to TP53 deficiency, constitutes a core set of mutations required for efficient transformation in vitro. A few previously uncharacterized mutation combinations further enhanced transformation but may have done so via TP53-related mechanisms. Together, our results identify mutation combinations that are critical for OSE-SC transformation and may contribute to more accurate modeling of HGSOC development. Our cancer driver screening methodology may also serve as a model for high throughput functional assessment of commonly mutated genes uncovered in other cancers by large scale sequencing.
Layer and rhythm specificity for predictive routing
Authors: Bastos André M. , Lundqvist Mikael , Waite Ayan S. , Kopell Nancy , Miller Earl K.
Published: January 2020

In predictive coding, experience generates predictions that attenuate the feeding forward of predicted stimuli while passing forward unpredicted “errors”. Different models have different neural implementations of predictive coding. We recorded spikes and local field potentials from laminar electrodes in five cortical areas (V4, LIP, area 7A, FEF, and PFC) while monkeys performed a task that modulated visual stimulus predictability. Pre-stimulus predictions were associated with increased alpha/beta (8-30 Hz) power/coherence that fed back the cortical hierarchy primarily via deep-layer cortex. Unpredictable stimuli were associated with increases in spiking and in gamma-band (40-90 Hz) power/coherence that fed forward up the cortical hierarchy via superficial-layer cortex. Area 7A uniquely showed increases in high-beta (~22-28 Hz) power/coherence to unpredicted stimuli. These results suggest that predictive coding may be implemented via lower-frequency alpha/beta rhythms that “prepare” pathways processing predicted inputs by inhibiting feedforward gamma rhythms and associated spiking.
Sex dependent compensatory mechanisms to preserve blood pressure homeostasis in PGI2receptor deficient mice
Authors: Tang Soon Yew , Anderson Seán T. , Meng Hu , Sarantopoulou Dimitra , Ricciotti Emanuela , Hennessy Elizabeth J. , Grant Gregory R. , FitzGerald Garret A.
Published: January 2020

Inhibitors of microsomal prostaglandin E synthase-1 (mPges-1) are in the early phase of clinical development. Deletion of mPges-1 confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing prostaglandin (PG) E2, but increasing biosynthesis of prostacyclin (PGI2). In hyperlipidemic mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2accounts for its anti-atherogenic effect. However, the impact of mPges-1 depletion on blood pressure (BP) in this setting remains unknown.

To address how differential effects on PGE2and PGI2might modulate salt-evoked BP responses in the absence of mPges-1, we generated mice lacking the I prostanoid (Ipr) receptor or mPges-1 on a hyperlipidemic background caused by deletion of the low density lipoprotein receptor (Ldlr KOs). Here, mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr KO mice, whereas, despite the direct vasodilator properties of PGI2, Ipr deletion suppressed it. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1 KO mice. Suppression of PGE2biosynthesis was enough to explain the exaggerated BP response to salt loading by either mPges-1/Ldlr depletion or by an MPGES-1 inhibitor in mice expressing human mPGES-1. However, the lack of a hypertensive response to salt in Ipr-deficient mice was attributable to reactive activation of the atrial natriuretic peptide pathway. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high salt diet. This is attributable to the protective effect of estrogen in Ldlr KO mice and in Ipr /Ldlr DKOs. Thus, estrogen compensates for a deficiency in PGI2to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In males, by contrast, augmented formation of ANP plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hyperlipidemic males on a high salt diet might be at risk of a hypertensive response to mPGES-1 inhibitors.
Neural correlates of winning and losing fights in poison frog tadpoles
Authors: Fischer Eva K , Alvarez Harmony , Lagerstrom Katherine M , McKinney Jordan E , Petrillo Randi , Ellis Gwen , O’Connell Lauren A
Published: January 2020

Aggressive competition for resources among juveniles is documented in many species, but the neural mechanisms regulating this behavior in young animals are poorly understood. In poison frogs, increased parental care is associated with decreased water volume of tadpole pools, resource limitation, and aggression. Indeed, the tadpoles of many poison frog species will attack, kill, and cannibalize other tadpoles. We examined the neural basis of conspecific aggression in Dyeing poison frog (Dendrobates tinctorius) tadpoles by comparing individuals that won aggressive encounters, lost aggressive encounters, or did not engage in a fight. We first compared patterns of generalized neural activity using immunohistochemical detection of phosphorylated ribosomes (pS6) as a proxy for neural activation associated with behavior. We found increased neural activity in the medial pallium and preoptic area of loser tadpoles, suggesting the amphibian homologs of the mammalian hippocampus and preoptic area may facilitate loser-associated behaviors. Nonapeptides (arginine vasotocin and mesotocin) and dopamine have been linked to aggression in other vertebrates and are located in the preoptic area. We next examined neural activity specifically in nonapeptide- and tyrosine-hydroxylase-positive cells using double-label immunohistochemistry. We found increased neural activity specifically in the preoptic area nonapeptide neurons of winners, whereas we found no differences in activity of dopaminergic cells among behavioral groups. Our findings suggest the neural correlates of aggression in poison frog tadpoles are similar to neural mechanisms mediating aggression in adults and juveniles of other vertebrate taxa.
The roles of aridification and sea level changes in the diversification and persistence of freshwater fish lineages
Authors: Buckley Sean J , Brauer Chris , Unmack Peter , Hammer Michael , Beheregaray Luciano B.
Published: January 2020

While the influence of Pleistocene climatic changes on divergence and speciation has been well-documented across the globe, complex spatial interactions between hydrology and eustatics over longer timeframes may also determine species evolutionary trajectories. Within the Australian continent, glacial cycles were not associated with changes in ice cover and instead largely resulted in fluctuations from moist to arid conditions across the landscape. Here, we investigate the role of hydrological and coastal topographic changes brought about by Plio-Pleistocene climatic changes on the biogeographic history of a small Australian freshwater fish, the southern pygmy perchNannoperca australis. Using 7,958 ddRAD-seq (double digest restriction-site associated DNA) loci and 45,104 filtered SNPs, we combined phylogenetic, coalescent and species distribution analyses to investigate the relative roles of aridification, sea level and tectonics and their associated biogeographic changes across southeast Australia. Sea-level changes since the Pliocene and reduction or disappearance of large waterbodies throughout the Pleistocene were determining factors in strong divergence across the clade, including the initial formation and maintenance of a cryptic species,N.‘flindersi’. Isolated climatic refugia and fragmentation due to lack of connected waterways maintained the identity and divergence of inter- and intraspecific lineages. Our historical findings suggest that predicted increases in aridification and sea level due to anthropogenic climate change might result in markedly different demographic impacts, both spatially and across different landscape types.
A cell atlas of human thymic development defines T cell repertoire formation
Authors: Park Jong-Eun , Botting Rachel A. , Conde Cecilia Domínguez , Popescu Dorin-Mirel , Lavaert Marieke , Kunz Daniel J. , Stephenson Emily , Ragazzini Roberta , Tuck Elizabeth , Wilbrey-Clark Anna , Ferdinand John R. , Webb Simone , Maunder Daniel , Vandamme Niels , Mahbubani Krishnaa , Polanski Krzysztof , Mamanova Lira , Fuller Andrew , Filby Andrew , Reynolds Gary , Dixon David , Saeb-Parsy Kourosh , Lisgo Steven , Henderson Deborah , Vento-Tormo Roser , Meyer Kerstin B. , Saeys Yvan , Bonfanti Paola , Behjati Sam , Clatworthy Menna R. , Taghon Tom , Haniffa Muzlifah , Teichmann Sarah A.
Published: January 2020

The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We utilised single-cell RNA-sequencing (scRNA-seq) to create a cell census of the human thymus and to reconstruct T-cell differentiation trajectories and T-cell receptor (TCR) recombination kinetics. Using this approach, we identified and locatedin situnovel CD8αα+T-cell populations, thymic fibroblast subtypes and activated dendritic cell (aDC) states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and suggests later commitment of the CD8+T-cell lineage. Taken together, our data provide a comprehensive atlas of the human thymus across the lifespan with new insights into human T-cell development.
AP-XPS beamline, a platform for operando science at Pohang Accelerator Laboratory
Authors: Kim Geonhwa , Yu Youngseok , Lim Hojoon , Jeong Beomgyun , Lee Jouhahn , Baik Jaeyoon , Mun Bongjin Simon , Kim Ki-jeong
Published: January 2020

Beamline 8A (BL 8A) is an undulator-based soft X-ray beamline at Pohang Accelerator Laboratory. This beamline is aimed at high-resolution ambient-pressure X-ray photoelectron spectroscopy (AP-XPS), soft X-ray absorption spectroscopy (soft-XAS) and scanning photoemission microscopy (SPEM) experiments. BL 8A has two branches, 8A1 SPEM and 8A2 AP-XPS, that share a plane undulator, the first mirror (M1) and the monochromator. The photon beam is switched between the two branches by changing the refocusing mirrors after the monochromator. The acceptance angle of M1 is kept glancing at 1.2°, and Pt is coated onto the mirrors to achieve high reflectance, which ensures a wide photon energy range (100–2000 eV) with high resolution at a photon flux of ∼1013 photons s−1. In this article, the main properties and performance of the beamline are reported, together with selected experiments performed on the new beamline and experimental system.
Dichloridobis[2-(pyridin-2-yl-κN)-1H-benzimidazole-κN
3]nickel(II) monohydrate
Authors: MacNeil Connor S. , Ogweno Aloice O. , Ojwach Stephen O. , Hayes Paul G.
Published: January 2020

In the title complex, [NiCl2(C12H9N3)2]·H2O, a divalent nickel atom is coordinated by two 2-(pyridin-2-yl)-1H-benzimidazole ligands in a slightly distorted octahedral environment defined by four N donors of two N,N′-chelating ligands, along with two cis-oriented anionic chloride donors. The title complex crystallized with a water molecule disordered over two positions. In the crystal, a combination of O—H...Cl, O—H.·O and N—H...Cl hydrogen bonds, together with C—H...O, C—H...Cl and C—H...π interactions, links the complex molecules and the water molecules to form a supramolecular three-dimensional framework. The title complex is isostructural with the cobalt(II) dichloride complex reported previously [Das et al. (2011). Org. Biomol. Chem. 9, 7097–7107].
Bis(4-phenyl-2-sulfanylidene-2,3-dihydro-1,3-thiazol-3-ido-κ2
S
2,N)(4-phenyl-1,3-thiazole-2-thiolato-κS
2)bismuth
Authors: Stammler Hans-Georg , Imran Muhammad
Published: January 2020

The title compound, [Bi(C9H6NS2)3], was prepared by reacting BiCl3 and 2-mercapto-4-phenylthiazole (LH) at room temperature in a stoichiometric ratio of 1:4. The molecular structure reveals a slightly distorted square-pyramidal environment around the BiIII atom. Two of the three monoanionic ligands L
− coordinate in an N,S-bidentate mode, while one shows a monodentate mode through an S atom. There are no significant intermolecular interactions present in the crystal.
Personality traits and intrapreneurial behaviour
Authors: Alam Muhammad Zubair , Kousar Shazia , Shabbir Aiza , Kaleem Muhammad Ali
Published: January 2020

Purpose

Intrapreneurship is rapidly concerning organizations to tailor their operations and strategies for competitive advantage. Research on intrapreneurial dimensions is in the developing stage, requiring more rigorous methods of investigation and application in various contexts. This study aims to focus on individual level intrapreneurship by examining the association of personality traits (PTs) on intrapreneurial behaviour (IB) moderated by knowledge sharing behaviour (KSB) and comparison of employees in engineering and functional departments.

Design/methodology/approach

A survey has been conducted for data collection using a structured questionnaire. Partial least squares structural equation modelling has been used for hypotheses testing, moderation and multi-group analysis on a sample of 534 respondents.

Findings

Results reveal that PTs exerted a positive influence on IB. The impact of PTs on IB was more pronounced in the employees of functional departments. KSB moderates positively in the relationship between PTs and IB. Both groups significantly differ in dimensions of PTs.

Practical implications

Organizations can do little to improve PTs of employees, which impacts on intrapreneurship in organizations. However, KSB in organizations can be improved by adopting various measures. KSB eventually promotes innovation in organizations resulting in an overall competitive advantage for firms.

Originality/value

This is the first study that contributes theoretically in intrapreneurship literature by providing insights on PTs impacting IB incorporating KSB and comparing the diverse group of employees.
Sustainable open innovation to address a grand challenge
Authors: Bogers Marcel , Chesbrough Henry , Strand Robert
Published: January 2020

Purpose

This paper describes the case of how the Danish beer manufacturer, Carlsberg, developed the Green Fiber Bottle as part of its sustainability program through an open innovation approach in collaboration with complementary partners. It thereby illustrates how a grand challenge associated with sustainability can be effectively addressed through open innovation and reveals the opportunities and challenges that emerge in that context.

Design/methodology/approach

The paper summarizes some key elements of the case and, in particular, discusses some of the lessons learned, which can be further explored in future research, practice, and policy.

Findings

The case suggests a number of key issues that are relevant when attempting to address grand challenges, in general, and sustainability in the food and beverage (F&B) industry, in particular, namely: leveraging open innovation in the face of sustainability as a grand challenge; sustainability beyond a solid business case; opportunities and challenges in the face of new business models; the importance of early wins for addressing societal challenges for signals and scaling; and the importance of the Nordic context and long-term vision.

Originality/value

The case describes a recent (and to some extent still ongoing) initiative of how a particular F&B company has explored new approaches to developing its sustainability program. Therefore, it highlights some of the unique characteristics of this case. This paper also lays the groundwork for the establishment of “Sustainable Open Innovation” as a domain in its own right.
Internationalization and family firm performance
Authors: Debicki Bart J. , Miao Chao , Qian Shanshan
Published: January 2020

Purpose

The purpose of this paper is to evaluate the effect of internationalization on performance in family firms, as well as the potential impact of moderators on this relationship.

Design/methodology/approach

This paper is a meta-analysis of the impact of internationalization on performance in family firms, as well as the role of several moderators shaping this relationship, based on 29 studies.

Findings

The findings indicate a significant positive effect of internationalization on family firm performance. This relationship was stronger in family firms with lower family ownership. Several methodological moderators were significant, such as the means of measuring performance and internationalization. The results also point to several cultural moderators, such as individualism, masculinity, low uncertainty avoidance and short-term orientation, which positively influence the main effect.

Originality/value

The authors provide discussions of the results, their practical and theoretical implications, as well as avenues for future research.
Power and area-efficient register designs involving EHO algorithm
Authors: Sabu Neethu Anna , K. Batri
Published: January 2020

Purpose

This paper aims to design three low-power and area-efficient serial input parallel output (SIPO) register designs, namely, transistor count reduction technique shift register (TCRSR), series stacking in TCR shift register (S-TCRSR) and forced stacking of transistor in TCR shift register (FST in TCRSR). Shift registers (SR) are the basic building blocks of all types of digital applications. The performance of all the designs has been improved through one of the metaheuristic algorithms named elephant herding optimization (EHO) algorithm and hence suited for low-power very large scale integration (VLSI) applications. It is for the first time that the EHO algorithm is implemented in memory elements.

Design/methodology/approach

The registers together with clock network consume 18-36 percentage of the total power consumption of a microprocessor. The proposed designs are implemented using low-power and high-performance double edge-triggered D flip-flops with least count of clocked transistors involving transmission gate. The second and third register designs are developed from the modified version of the first one employing series and forced stacking, thereby reducing static power because of sub-threshold leakage current. The performance parameters such as power-delay-product (PDP) and leakage power are further optimized using the EHO algorithm. A greater reduction in power is achieved in all the designs by utilizing the EHO algorithm.

Findings

All the designs are simulated at a supply voltage of 1 V/500 MHz when the input switching activity is 25 percentage in Cadence Virtuoso using 45 nm CMOS technology. Nine recently proposed SR designs are simulated in the same conditions, and the performance has been compared with the proposed ones. The simulated results prove the excellence of proposed designs in different performance parameters like leakage power, energy-delay-product (EDP), PDP, layout area compared with the recent designs. The PDPdq value has a reduction of 95.9per cent (TCRSR), 96.6per cent (S-TCRSR) and 97per cent (FST in TCRSR) with that of a conventional shift register (TGSR).

Originality/value

The performance of proposed low-power SR designs is enhanced using EHO algorithm. The optimized performance results have been compared with a few optimization algorithms. It is for the first time that EHO algorithm is implemented in memory elements.