bluuebunny/crossref_metadata_2025 huggingface dataset:
Metformin use and risk of cancer in patients with type 2 diabetes: a cohort study of primary care records using inverse probability weighting of marginal structural models
Authors: Farmer Ruth E , Ford Deborah , Mathur Rohini , Chaturvedi Nish , Kaplan Rick , Smeeth Liam , Bhaskaran Krishnan
Published: January 2019

Background

Previous studies provide conflicting evidence on whether metformin is protective against cancer. When studying time-varying exposure to metformin, covariates such as body mass index (BMI) and glycated haemoglobin (HbA1c) may act as both confounders and causal pathway variables, and so cannot be handled adequately by standard regression methods. Marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) can correctly adjust for such confounders. Using this approach, the main objective of this study was to estimate the effect of metformin on cancer risk compared with risk in patients with T2DM taking no medication.

Methods

Patients with incident type 2 diabetes (T2DM) were identified in the Clinical Practice Research Datalink (CPRD), a database of electronic health records derived from primary care in the UK. Patients entered the study at diabetes diagnosis or the first point after this when they had valid HbA1c and BMI measurements, and follow-up was split into 1-month intervals. Logistic regression was used to calculate IPTW; then the effect of metformin on all cancers (including and excluding non-melanoma skin cancer) and breast, prostate, lung, colorectal and pancreatic cancers was estimated in the weighted population.

Results

A total of 55 629 T2DM patients were alive and cancer-free at their study entry; 2530 people had incident cancer during a median follow-up time of 2.9 years [interquartile range (IQR) 1.3–5.4 years]. Using the MSM approach, the hazard ratio (HR) for all cancers, comparing treatment with metformin with no glucose-lowering treatment, was 1.02 (0.88–1.18). Results were robust to a range of sensitivity analyses and remained consistent when estimating the treatment effect by length of exposure. We also found no evidence of a protective effect of metformin on individual cancer outcomes.

Conclusions

We find no evidence that metformin has a causal association with cancer risk.
Changes in millennial adolescent mental health and health-related behaviours over 10 years: a population cohort comparison study
Authors: Patalay Praveetha , Gage Suzanne H
Published: January 2019

Background

There is evidence that mental health problems are increasing and substance use behaviours are decreasing. This paper aimed to investigate recent trends in mental ill health and health-related behaviours in two cohorts of UK adolescents in 2005 and 2015.

Methods

Prevalences in mental health (depressive symptoms, self-harm, anti-social behaviours, parent-reported difficulties) and health-related behaviours (substance use, weight, weight perception, sleep, sexual intercourse) were examined at age 14 in two UK birth cohorts; Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5627, born 1991–92) and Millennium Cohort Study (MCS, N = 11 318, born 2000–02). Prevalences and trend estimates are presented unadjusted and using propensity score matching and entropy balancing to account for differences between samples.

Results

Depressive symptoms (9% to 14.8%) and self-harm (11.8% to 14.4%) were higher in 2015 compared with 2005. Parent-reported emotional difficulties, conduct problems, hyperactivity and peer problems were higher in 2015 compared with 2005 (5.7–8.9% to 9.7–17.7%). Conversely, substance use (tried smoking, 9.2% to 2.9%; tried alcohol, 52.1% to 43.5%, cannabis, 4.6% to 3.9%), sexual activity (2% to 0.9%) and anti-social behaviours (6.2–40.1% to 1.6–27.7%) were less common or no different. Adolescents in 2015 were spending less time sleeping (<8 h 5.7% to 11.5%), had higher body mass index (BMI) (obese, 3.8% to 7.3%) and a greater proportion perceived themselves as overweight (26.5% to 32.9%). The findings should be interpreted bearing in mind limitations in ability to adequately harmonize certain variables and account for differences in attrition rates and generalizability of the two cohorts.

Conclusions

Given health-related behaviours are often cited as risk factors for poor mental health, our findings suggest relationships between these factors might be more complex and dynamic in nature than currently understood. Substantial increases in mental health difficulties, BMI and poor sleep-related behaviours highlight an increasing public health challenge.
Evaluation of a mandatory phishing training program for high-risk employees at a US healthcare system
Authors: Gordon William J , Wright Adam , Glynn Robert J , Kadakia Jigar , Mazzone Christina , Leinbach Elizabeth , Landman Adam
Published: January 2019

Objective

The study sought to understand the impact of a phishing training program on phishing click rates for employees at a single, anonymous US healthcare institution.

Materials and Methods

We stratified our population into 2 groups: offenders and nonoffenders. Offenders were defined as those that had clicked on at least 5 simulated phishing emails and nonoffenders were those that had not. We calculated click rates for offenders and nonoffenders, before and after a mandatory training program for offenders was implemented.

Results

A total of 5416 unique employees received all 20 campaigns during the intervention period; 772 clicked on at least 5 emails and were labeled offenders. Only 975 (17.9%) of our set clicked on 0 phishing emails over the course of the 20 campaigns; 3565 (65.3%) clicked on at least 2 emails. There was a decrease in click rates for each group over the 20 campaigns. The mandatory training program, initiated after campaign 15, did not have a substantial impact on click rates, and the offenders remained more likely to click on a phishing simulation.

Discussion

Phishing is a common threat vector against hospital employees and an important cybersecurity risk to healthcare systems. Our work suggests that, under simulation, employee click rates decrease with repeated simulation, but a mandatory training program targeted at high-risk employees did not meaningfully decrease the click rates of this population.

Conclusions

Employee phishing click rates decrease over time, but a mandatory training program for the highest-risk employees did not decrease click rates when compared with lower-risk employees.
Goal-Directed and Habitual Control in Smokers
Authors: Luijten Maartje , Gillan Claire M , de Wit Sanne , Franken Ingmar H A , Robbins Trevor W , Ersche Karen D
Published: January 2019

Introduction

Harmful behavior such as smoking may reflect a disturbance in the balance of goal-directed and habitual control. Animal models suggest that habitual control develops after prolonged substance use. In this study, we investigated whether smokers (N = 49) differ from controls (N = 46) in the regulation of goal-directed and habitual behavior. It was also investigated whether individual differences in nicotine dependence levels were associated with habitual responding.

Methods

We used two different multistage instrumental learning tasks that consist of an instrumental learning phase, subsequent outcome devaluation, and a testing phase to measure the balance between goal-directed and habitual responding. The testing phases of these tasks occurred after either appetitive versus avoidance instrumental learning. The appetitive versus aversive instrumental learning stages in the two different tasks modeled positive versus negative reinforcement, respectively.

Results

Smokers and nonsmoking controls did not differ on habitual versus goal-directed control in either task. Individual differences in nicotine dependence within the group of smokers, however, were positively associated with habitual responding after appetitive instrumental learning. This effect seems to be due to impaired stimulus-outcome learning, thereby hampering goal-directed task performance and tipping the balance to habitual responding.

Conclusions

The current finding highlights the importance of individual differences within smokers. For future research, neuroimaging studies are suggested to further unravel the nature of the imbalance between goal-directed versus habitual control in severely dependent smokers by directly measuring activity in the corresponding brain systems.

Implications

Goal-directed versus habitual behavior in substance use and addiction is highly debated. This study investigated goal-directed versus habitual control in smokers. The findings suggest that smokers do not differ from controls in goal-directed versus habitual control. Individual differences in nicotine dependence within smokers, however, were positively associated with habitual responding after appetitive instrumental learning. This effect seems to be due to impaired stimulus-outcome learning, thereby hampering goal-directed task performance and tipping the balance to habitual responding. These findings add to the ongoing debate on habitual versus goal-directed control in addiction and emphasize the importance of individual differences within smokers.
Frameworks and guidance to support ethical public health practice
Authors: Viens A M , Vass Caroline
Published: January 2019

This article reports and reflects on an element of a recent survey of UK public health professionals, specifically in relation to the Public Health Knowledge and Skills Framework (PHSKF) and the ethical requirements that underpin public health practice. Only 38.4% of respondents reported accessing the PHKSF and a mere 13.7% reported accessing the accompanying background paper on ethical public health practice. Given that ethical practice underpins the PHSKF, it is concerning that so few respondents are familiar with the PHSKF and one of the source documents. While issuing frameworks and guidance is one way to support public health practice, there is a further need for greater integration of skills and knowledge around ethical public health practice within education and training initiatives.
Heritability of Cerebral Blood Flow and the Correlation to Schizophrenia Spectrum Disorders: A Pseudo-continuous Arterial Spin Labeling Twin Study
Authors: Legind Christian S , Broberg Brian V , Brouwer Rachel , Mandl René C W , Ebdrup Bjørn H , Anhøj Simon J , Jensen Maria H , Hilker Rikke , Fagerlund Birgitte , Hulshoff Pol Hilleke E , Glenthøj Birte Y , Rostrup Egill
Published: January 2019

Whether aberrant cerebral blood flow (CBF) in schizophrenia is affected by genetic influences, and consequently a potential marker for genetic susceptibility, is unknown. Our aims were to determine the heritability of CBF in thalamic, frontal, and striatal areas, and to ascertain if associations with disease were under genetic influence. Monozygotic (MZ) twin pairs concordant (n = 2) or discordant (n = 20) for schizophrenia spectrum disorders (ICD-10 F2x.x), matched on sex and age with dizygotic (DZ; n = 20) and healthy control pairs (MZ: n = 27; DZ: n = 18; total: n = 181 individuals), were recruited via the National Danish Twin Register. CBF in thalamus, frontal lobes, and putamen was measured with pseudo-continuous arterial spin labeling on a 3 T magnetic resonance scanner. Twin statistics were performed with structural equation modeling. CBF in the frontal lobes was heritable (h2 = 0.44, 95% CI [0.22–0.60]) but not correlated to disease. CBF correlated to schizophrenia spectrum disorders in the left thalamus (r = 0.17, [0.03–0.31]; P = 0.02), as well as in the left putamen (r = 0.19, [0.05–0.32]; P = 0.007) and the right putamen (r = 0.18, [0.03–0.32]; P = 0.02). When restricting the sample to schizophrenia (F20.x) only, shared genetic influences between CBF in the left putamen and schizophrenia liability (phenotypic correlation = 0.44, [0.28–0.58], P < 0.001) were found. Our results provide heritability estimates of CBF in the frontal lobes, and we find CBF in thalamus and putamen to be altered in schizophrenia spectrum disorders. Furthermore, shared genetic factors influence schizophrenia liability and striatal perfusion. Specifically, higher perfusion in the left putamen may constitute a marker of genetic susceptibility for schizophrenia.
An educational module to explore CRISPR technologies with a cell-free transcription-translation system
Authors: Collias Daphne , Marshall Ryan , Collins Scott P , Beisel Chase L , Noireaux Vincent
Published: January 2019

Within the last 6 years, CRISPR-Cas systems have transitioned from adaptive defense systems in bacteria and archaea to revolutionary genome-editing tools. The resulting CRISPR technologies have driven innovations for treating genetic diseases and eradicating human pests while raising societal questions about gene editing in human germline cells as well as crop plants. Bringing CRISPR into the classroom therefore offers a means to expose students to cutting edge technologies and to promote discussions about ethical questions at the intersection of science and society. However, working with these technologies in a classroom setting has been difficult because typical experiments rely on cellular systems such as bacteria or mammalian cells. We recently reported the use of an E. coli cell-free transcription-translation (TXTL) system that simplifies the demonstration and testing of CRISPR technologies with shorter experiments and limited equipment. Here, we describe three educational modules intended to expose undergraduate students to CRISPR technologies using TXTL. The three sequential modules comprise (i) designing the RNAs that guide DNA targeting, (ii) measuring DNA cleavage activity in TXTL and (iii) testing how mutations to the targeting sequence or RNA backbone impact DNA binding and cleavage. The modules include detailed protocols, questions for group discussions or individual evaluation, and lecture slides to introduce CRISPR and TXTL. We expect these modules to allow students to experience the power and promise of CRISPR technologies in the classroom and to engage with their instructor and peers about the opportunities and potential risks for society.
Salivary IgG levels in neonatal calves and its association to serum IgG: an observational pilot study
Authors: Johnsen Julie Føske , Chincarini Matteo , Sogstad Åse Margrethe , Sølverød Liv , Vatne Marie , Mejdell Cecilie Marie , Hänninen Laura
Published: January 2019

The diagnosis of inadequate transfer of colostrum immunoglobulin G (IgG) to calf serum, often known as failure of passive transfer (<10 g/L IgG1 at 24 to 48 h), necessitates blood sampling from the calf and in some instances the presence of a veterinarian. Sampling saliva is both less invasive and easy for the producer. Previous research has shown that quantification of saliva IgG is possible in juvenile and adult cattle. The objectives of this observational pilot study were to investigate whether IgG can be quantified in neonatal calf saliva, if it is correlated to serum IgG concentrations, and if the indirect quantification of saliva IgG is achievable by use of a digital refractometer. Paired blood and saliva samples were collected from 20 healthy dairy calves aged 1 to 3 d. In these samples, IgG was quantified directly with single radial immunodiffusion and indirectly by use of a digital refractometer indicating Brix % (a subsample of n = 12 saliva samples). A strong positive correlation (r = 0.7, P < 0.001) between saliva IgG (mean ± SD; 0.2 ± 0.11 g/L) and serum IgG (32.1 ± 11.94 g/L) was found. Saliva IgG ranged from the lowest detectable value, 0.1 g/L (n = 6 samples) to 0.6 g/L. Saliva Brix (1.2 ± 0.69%) was not significantly correlated to serum IgG (n = 12, r = 0.43, P = 0.155); however, it was significantly correlated to saliva IgG (n = 12, r = 0.7, P = 0.018) and Brix in serum (n = 12, r = 0.7, P = 0.013). We conclude that IgG was quantifiable in most of the saliva samples. For saliva IgG to be of any value with regards to detecting failure of passive transfer, future studies should investigate methods that can detect IgG <0.1 g/L. The results indicate that saliva IgG can be used to predict serum IgG at levels above 10 g/L, which may warrant further exploration of the use of saliva in the surveillance of failure of passive transfer. The results of the current pilot study did not support the potential usage of a Brix % refractometer to quantify saliva IgG.
Unexpected diversity of Hyboserica chafers in South African forest remnants: cladistic analysis, new species and the new genus Leoserica (Coleoptera: Scarabaeidae: Melolonthinae)
Authors: Fabrizi Silvia , Eberle Jonas , Ahrens Dirk
Published: January 2019

A taxonomic revision of Hyboserica uncovers an unexpected diversity of species from Southern African forest remnants. The work results in the description of a new genus, Leoserica gen. nov., a new combination, a new synonymy and 32 new species are described. The lectotypes of Serica capensis and Triodonta caffra are designated. The habitus and male genitalia of all revised species are illustrated. A species distribution map and an identification key to the species are provided. Phylogenetic analysis reveals a deep split into one very diverse eastern clade that is distributed north to Zimbabwe, and one western clade that is restricted to the fynbos of the Cape Region.
Outcomes Analysis of Gynecologic Oncologic Reconstruction
Authors: Block Lisa M. , Hartmann Emily C. , King Jason , Chakmakchy Saygin , King Timothy , Bentz Michael L.
Published: January 2019

Background:

Defects resulting from gynecologic oncology resections can range from small external defects to total exenterations, requiring complex pelvic reconstruction. We aim to investigate the patient and surgical factors that influence complication rates, reoperation rates, and length of stay. We hypothesize that this patient cohort will have high complication and reoperation rates that are likely most affected by their medical and extirpative surgery factors, with less direct impact from their reconstructive surgery procedures.

Methods:

All cases of reconstruction following resection of a gynecological oncology tumor at the University of Wisconsin Hospital over the last 14 years were reviewed. Forty-three patients were identified who required 66 flaps for reconstruction.

Results:

Mean follow-up period was 19 months. Overall complication rate was 65% and reoperation rate was 33%. Plastic surgery flap-specific complication and reoperation rates were 47% and 19%, respectively, and were not significantly associated with any patient risk factors. Flap reconstruction subtype was not associated with time to complete healing, complication rate, or reoperation. Prior chemotherapy was significantly correlated with increased rate of overall complication (P = 0.0253) and reoperation (P = 0.0448), but prior radiation was not. Mean hospital stay was 11 days (SD ± 9 d). Factors found to be significantly associated with an increase in hospitalization length were increasing number of comorbidities (P = 0.021), exenteration defects (P = 0.0122), myocutaneous flap reconstruction (P = 0.0003), radiation (P = 0.0004), and chemotherapy P = 0.0035).

Conclusion:

This patient cohort has an overall high complication and reoperation rate; however, increasingly complex reconstruction is not associated with significant differences in complication rates or reoperation.
Opioid Use Disorder in Pregnancy
Authors: SANJANWALA AALOK R. , HARPER LORIE M.
Published: January 2019

Opioid use disorders during pregnancy are a major risk factor for pregnancy-associated deaths. Women with opioid use disorders also experience increases in the incidence of cardiac arrest, renal failure, cesarean delivery, and blood transfusion. As such there is a tremendous need by obstetricians to understand and treat opiate use as a holistic public health problem with its own unique risk factors, and management strategies. Universal screening with brief intervention and referral, referral to psychotherapy, and pharmacotherapy are all recommended strategies for opioid use disorder in pregnancy.
The Effect of Marked Nasal Septal Deviation on Left Ventricular Function and Blood Markers
Authors: Karataş Mehmet , Taşolar Hakan
Published: January 2019

Objectives:

This study aimed to assess the effect of nasal septoplasty in patients with marked nasal septal deviation (MNSD) on subjective perception of nasal patency, echocardiography, and hematologic parameters.

Methods:

Seventy-nine consecutive patients (mean age, 29.9 ± 9.7 years; 57 men and 22 women) at least 18 years old were diagnosed as MNSD consistent with presenting symptom of chronic nasal obstruction lasting at least 3 months. Complete blood count measurement to assess mean platelet volume (MPV) and neutrophil to lymphocyte ratio (NLR), the Nasal Obstruction Symptom Evaluation (NOSE) questionnaire, and echocardiography were performed for all patients just before and at postoperative third month of septoplasty.

Results:

The MPV (0.021), NLR (<0.001), and NOSE (<0.001) were all significantly decreased, and global longitudinal strain (GLS) value (<0.001) were also significantly increased at postoperative third month. Correlation analysis also indicated that ΔNLRwas positively correlated with ΔGLS(r = 0.385,P < 0.001), and ΔNOSE(r = 0.436,P < 0.001), and correlated negatively with the ΔMPV(r = –0.302,P = 0.024). ΔGLSwas also positively correlated with the ΔNOSE(r = 0.769,P < 0.001).

Conclusion:

Septoplasty for MNSD could provide not only alleviation of otorhinolaryngologic symptoms but also improvement in subclinical left ventricular systolic dysfunction and decline in MPV and NLR levels.
Seizures Following Cranioplasty: Risk Factors and Prevention Exploration
Authors: Zhang Jian , Liu Xianghui , Zhou Jun , Zhang Zhiying , Fu Meizhi , Guo Yunlin , Li Gang
Published: January 2019

Background:

The aim of this study was to identify risk factors and explore the possible prevention measures for seizures following cranioplasty.

Methods:

The authors performed a retrospective review of 142 consecutive patients who underwent cranioplasty following craniectomy for trauma or cerebral hemorrhage in Dezhou People's Hospital between January 2010 and January 2017. Patients who were diagnosed with aneurysms, arteriovenous malformations, cerebral infarction, and tumors (14), had seizures prior to cranioplasty (9) and those lost to follow-up (7) were excluded. Patients did not use antiepilepsy drugs from treatment of postcranioplasty seizures. The median follow-up time was 51.11 ± 31.59 months (range: 17–98 months). Analyses were performed on a database tracking age, sex, reason for craniectomy, operative time, time between operations, presence of dural substitute, diabetic status, hypertensive status, tobacco use, alcohol use, location of cranioplasty, classification, time and times of seizures following cranioplasty development.

Results:

One hundred twelve patients met study criteria. The overall rate of seizures following cranioplasty was 35.7% (40 out of 112 patients). There were no statistically significant associations between postcranioplasty seizures and sex, age, location of cranioplasty, cranioplasty materials, or dural substitute used in craniectomy. Postcranioplasty seizure frequency differed significantly according to reasons for depressive craniectomy. The incidence of postcranioplasty seizures was significantly higher in the first year than in later years. Incidence decreased progressively in subsequent years.

Conclusion:

Incidence of seizures following cranioplasty was associated with the reason for depressive craniectomy.
Proof simplification and automated theorem proving
Authors: Kinyon Michael
Published: January 2019

The proofs first generated by automated theorem provers are far from optimal by any measure of simplicity. In this paper, I describe a technique for simplifying automated proofs. Hopefully, this discussion will stimulate interest in the larger, still open, question of what reasonable measures of proof simplicity might be.

This article is part of the theme issue ‘The notion of ‘simple proof’ - Hilbert's 24th problem’.
Prolegomena to any theory of proof simplicity
Authors: Pambuccian Victor
Published: January 2019

By looking at concrete examples from elementary geometry, we analyse the manner in which the simplicity of proofs could be defined. We first find that, when presented with two proofs coming from mutually incompatible sets of assumptions, the decision regarding which one is simplest can be made, if at all, only on the basis of reasoning outside of the formal aspects of the axiom systems involved. We then show that, if the axiom system is fixed, a measure of proof simplicity can be defined based on the number of uses of axioms deemed to be deep or valuable, and prove a number of new results regarding the need to use at least three times some axioms in the proof of others. One such major example is Pappus implies Desargues, which is shown to require three uses of Pappus. A similar situation is encountered with Veblen's proof that the outer form of the Pasch axiom implies the inner form thereof. The outer form needs to be used at least three times in any such proof. We also mention the likely conflicting requirements of directness of a proof and the length of a proof.

This article is part of the theme issue ‘The notion of ‘simple proof’ - Hilbert's 24th problem’.
scSLAM-seq reveals core features of transcription dynamics in single cells
Authors: Erhard Florian , Baptista Marisa A.P. , Krammer Tobias , Hennig Thomas , Lange Marius , Arampatzi Panagiota , Jürges Christopher , Theis Fabian J. , Saliba Antoine-Emmanuel , Dölken Lars
Published: January 2019

Current single-cell RNA sequencing approaches gives a snapshot of a cellular phenotype but convey no information on the temporal dynamics of transcription. Moreover, the stochastic nature of transcription at molecular level is not recovered. Here, we present single-cell SLAM-seq (scSLAM-seq), which integrates metabolic RNA labeling, biochemical nucleoside conversion and single-cell RNA-seq to directly measure total transcript levels and transcriptional activity by differentiating newly synthesized from pre-existing RNA for thousands of genes per single cell. scSLAM-seq recovers the earliest virus-induced changes in cytomegalovirus infection and reveals a so far hidden phase of viral gene expression comprising promiscuous transcription of all kinetic classes. It depicts the stochastic nature of transcription and demonstrates extensive gene-specific differences. These range from stable transcription rates to on-off dynamics which coincide with gene-/promoter-intrinsic features (Tbp-TATA-box interactions and DNA methylation). Gene but not cell-specific features thus explain the heterogeneity in transcriptomes between individual cells and the transcriptional response to perturbations.
Genomewide Analyses of Psychological Resilience in US Army Soldiers
Authors: Stein Murray B. , Choi Karmel W. , Jain Sonia , Campbell-Sills Laura , Chen Chia-Yen , Gelernter Joel , He Feng , Heeringa Steven G. , Maihofer Adam X. , Nievergelt Caroline M. , Nock Matthew K. , Ripke Stephan , Sun Xiaoying , Kessler Ronald C. , Smoller Jordan W. , Ursano Robert J.
Published: January 2019

Though a growing body of preclinical and translational research is illuminating a biological basis for resilience to stress, little is known about the genetic basis of psychological resilience in humans. We conducted genomewide association studies (GWAS) of self-assessed (by questionnaire) and outcome-based (incident mental disorders from pre- to post-deployment) resilience among European (EUR) ancestry soldiers in the Army Study To Assess Risk and Resilience in Servicemembers (STARRS). Self-assessed resilience (N=11,492) was found to have significant common-variant heritability (h2=0.162, se=0.050, p=5.37e-4), and to be significantly negatively genetically correlated with neuroticism (rg= −0.388, p=0.0092). GWAS results from the EUR soldiers revealed a genomewide significant locus (4 SNPs in LD; top SNP: rs4260523, p=5.654e-09) on an intergenic region on Chr 4 upstream from DCLK2 (Doublecortin-Like Kinase 2), a member of the doublecortin (DCX) family of kinases that promote survival and regeneration of injured neurons. A second gene, KLHL36 (Kelch Like Family Member 36) was detected at gene-wise genomewide significance (p=1.89e-06). A polygenic risk score derived from the self-assessed resilience GWAS was not significantly associated with outcome-based resilience. In very preliminary results, genomewide significant association with outcome-based resilience was found for one locus (top SNP: rs12580015) on Chr 12 downstream from SLC15A5 (solute carrier family 15 member 5) in the small group (N=581) of subjects exposed to the highest level of deployment stress. The further study of genetic determinants of resilience has the potential to illuminate the molecular bases of stress-related psychopathology and potentially point to new avenues for therapeutic intervention.
Interdependent photo- and chemosensory systems regulate larval settlement in a marine sponge
Authors: Say Tahsha E. , Degnan Sandie M.
Published: January 2019

Marine pelagic larvae from throughout the animal kingdom use a hierarchy of environmental cues to identify a suitable benthic habitat on which to settle and metamorphose into the reproductive phase of the life cycle. The majority of larvae are induced to settle by biochemical cues (1) and many species have long been known to preferentially settle in the dark (2). Combined, these data suggest that larval responses to light and biochemical cues may be linked, but this is yet to be explored at the molecular level. Here, we track vertical position of larvae of the sponge Amphimedon queenslandica to show that they descend to the benthos at twilight, by which time they are competent to respond to biochemical cues (3), consistent with them naturally settling in the dark. We then conduct larval settlement assays under three different light regimes (natural day-night, constant dark or constant light), and use transcriptomics on individual larvae to identify candidate molecular pathways underlying the different settlement responses that we observe. We find that constant light prevents larval settlement in response to biochemical cues, likely via actively repressing chemostransduction; this is consistent with the sustained upregulation of a photosensory cryptochrome and two putative inactivators of G-protein signalling in the constant light only. We hypothesise that photo- and chemosensory systems may be hierarchically integrated into ontogeny to regulate larval settlement via nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) signalling in this sponge that belongs to one of the earliest branching of the extant animal lineages.

Significance statement

In the ocean, successful recruitment of pelagic larvae into reproductive adult populations enables the survival and connectivity of benthic communities. The majority of invertebrate larvae are induced to settle by biochemical cues, and multiple species preferentially settle in the dark. Here, we explore, for the first time, interactions between light and biochemical cues at behavioural and molecular levels during larval ontogeny in a sponge. We find that light perturbs ontogenetic changes in gene expression and prevents settlement in response to biochemical cues, demonstrating strong interdependencies between photo- and chemosensory systems. Sponges are one of the earliest-branching of the extant animal phyletic lineages, and a valuable comparative model for understanding the origin and evolution of the pelago-benthic life cycle.
Lipid rafts increase to facilitate ectoderm lineage specification of differentiating embryonic stem cells
Authors: Xu Chen , Cao Bo , Huo Ying-dong , Niu Gang , Zhang Michael Q , Mai Zi-lin , Lu Xi-bin , Niu Han-ben , Chen Dan-ni , Ni Yan-xiang
Published: January 2019

Lipid rafts are packed nanoscopic domains on plasma membrane and essential signalling platforms for transducing extracellular stimuli into cellular responses. Although depletion of raft component glycoshpingolipids causes abnormality particularly in ectoderm layer formation, it remains unclear whether rafts play a role in lineage determination, a critical but less-known stage in lineage commitment. Here, inducing mouse embryonic stem cell (mESC) differentiation with retinoic acid (RA), we observed lipid rafts increased since early stage, especially in ectoderm-like cells. Stochastic optical reconstruction microscopy characterized at super-resolution the distinct raft features in mESCs and the derived differentiated cells. Furthermore, RA-induced commitment of ectoderm-like cells was significantly diminished not only by genetic ablation of rafts but by applying inhibitor for glycosphingolipids or cholesterol at early differentiation stages. Meanwhile, raft inhibition delayed RA-induced pluripotency exit, an early step required for differentiation. Therefore, lipid rafts increase and facilitate ectoderm lineage specification as well as pluripotency exit during mESC differentiation.
Learning in visual regions as support for the bias in future value-driven choice
Authors: Jahfari Sara , Theeuwes Jan , Knapen Tomas
Published: January 2019

Reinforcement learning can bias decision-making towards the option with the highest expected outcome. Cognitive learning theories associate this bias with the constant tracking of stimulus values and the evaluation of choice outcomes in the striatum and prefrontal cortex. Decisions however first require processing of sensory input, and to-date, we know far less about the interplay between learning and perception. This fMRI study (N=43), relates visual BOLD responses to value-beliefs during choice, and, signed prediction errors after outcomes. To understand these relationships, which co-occurred in the striatum, we sought relevance by evaluating the prediction of future value-based decisions in a separate transfer phase where learning was already established. We decoded choice outcomes with a 70% accuracy with a supervised machine learning algorithm that was given trial-by-trial BOLD from visual regions alongside more traditional motor, prefrontal, and striatal regions. Importantly, this decoding of future value-driven choice outcomes again highligted an important role for visual activity. These results raise the intriguing possibility that the tracking of value in visual cortex is supportive for the striatal bias towards the more valued option in future choice.
Capturing site-specific heterogeneity with large-scale N-glycoproteome analysis
Authors: Riley Nicholas M. , Hebert Alexander S. , Westphall Michael S. , Coon Joshua J.
Published: January 2019

Protein glycosylation is a highly important, yet a poorly understood protein post-translational modification. Thousands of possible glycan structures and compositions create potential for tremendous site heterogeneity and analytical challenge. A lack of suitable analytical methods for large-scale analyses of intact glycopeptides has ultimately limited our abilities to both address the degree of heterogeneity across the glycoproteome and to understand how it contributes biologically to complex systems. Here we show that N-glycoproteome site-specific microheterogeneity can be captured via large-scale glycopeptide profiling with methods enabled by activated ion electron transfer dissociation (AI-ETD), ultimately characterizing 1,545 N-glycosites (>5,600 unique N-glycopeptides) from mouse brain tissue. Moreover, we have used this large-scale glycoproteomic data to develop several new visualizations that will prove useful for analyzing intact glycopeptides in future studies. Our data reveal that N-glycosylation profiles can differ between subcellular regions and structural domains and that N-glycosite heterogeneity manifests in several different forms, including dramatic differences in glycosites on the same protein.
Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors
Authors: Zhu Li , Narloch Jessica L. , Onkar Sayali , Joy Marion , Luedke Catherine , Hall Allison , Kim Rim , Pogue-Geile Katherine , Sammons Sarah , Nayyar Naema , Chukwueke Ugonma , Brastianos Priscilla K. , Anders Carey K. , Soloff Adam C. , Vignali Dario AA , Tseng George C. , Emens Leisha A. , Lucas Peter C. , Blackwell Kimberly L. , Oesterreich Steffi , Lee Adrian V.
Published: January 2019

The interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TIL) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs have a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain (BRM) METs by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study.
Automated pupillometry to detect command following in neurological patients: A proof-of-concept study
Authors: Vassilieva Alexandra , Olsen Markus Harboe , Peinkhofer Costanza , Knudsen Gitte Moos , Kondziella Daniel
Published: January 2019

Background

Levels of consciousness in patients with acute and chronic brain injury are notoriously underestimated. Paradigms based on electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) may detect covert consciousness in unresponsive patients but are subject to logistical challenges and the need for advanced statistical analysis.

Methods

To assess the feasibility of automated pupillometry for the detection of command following, we enrolled 20 healthy volunteers and 48 patients with a wide range of neurological disorders, including 7 patients in the intensive care unit (ICU), who were asked to engage in mental arithmetic.

Results

Fourteen of 20 (70%) healthy volunteers and 17 of 43 (39.5%) neurological patients, including 1 in the ICU, fulfilled prespecified criteria for command following by showing pupillary dilations during ≥4 of 5 arithmetic tasks. None of the 5 sedated and unconscious ICU patients passed this threshold.

Conclusions

Automated pupillometry combined with mental arithmetic appears to be a promising paradigm for the detection of covert consciousness in people with brain injury. We plan to build on this study by focusing on non-communicating ICU patients in whom the level of consciousness is unknown. If some of these patients show reproducible pupillary dilation during mental arithmetic, this would suggest that the present paradigm can reveal conscious awareness in unresponsive patients in whom standard investigations have failed to detect signs of covert consciousness.
Distinct role of flexible and stable encoding in sequential working memory
Authors: Lee Hyeonsu , Choi Woochul , Park Youngjin , Paik Se-Bum
Published: January 2019

The serial-position effect in working memory is considered important for studying how a sequence of sensory information can be retained and manipulated simultaneously in neural memory circuits. Here, via a precise analysis of the primacy and recency effects in human psychophysical experiments, we propose that stable and flexible coding take distinct roles of retaining and updating information in working memory, and that their combination induces serial-position effects spontaneously. We found that stable encoding retains memory to induce the primacy effect, while flexible encoding used for learning new inputs induces the recency effect. A model simulation based on human data, confirmed that a neural network with both flexible and stable synapses could reproduce the major characteristics of serial-position effects. Our new prediction, that the control of resource allocation by flexible-stable coding balance can modulate memory performance in sequence-specific manner, was supported by pre-cued memory performance data in humans.
“Skull base meningiomas have a distinct immune landscape.”
Authors: Zador Zsolt , Landry Alexander P. , Balas Michael , Cusimano Michael D.
Published: January 2019

Modulation of tumor microenvironment is an emerging frontier for new therapeutics. However in meningiomas, the most frequent adult brain tumor, the correlation of microenvironment with tumor phenotype is scarcely studied. We applied a variety of systems biology approaches to bulk tumor transcriptomics to explore the immune environments of both skull base and convexity (hemispheric) meningiomas. We hypothesized that the more benign biology of skull base meningiomas parallels the relative composition and activity of immune cells that oppose tumor growth and/or survival. We firstly applied gene co-expression networks to tumor bulk transcriptomics from 107 meningiomas (derived from 3 independent studies) and found immune processes to be the sole biological mechanism correlated with anatomical location while correcting for tumour grade. We then derived tumor immune cell fractions from bulk transcriptomics data and examined the immune cell-cytokine interactions using a network-based approach. We demonstrate that oncolytic M1 macrophages dominate skull base meningiomas while mast cells, known to play a role in oncogenesis, show greater activity in convexity tumors. Our results are the first to suggest the importance of tumor microenvironment in meningioma biology in the context of anatomic location and immune landscape. These findings may help better inform surgical decision making and yield location-specific therapies through modulation of immune microenvironment.
A curated collection of transcriptome datasets to investigate the molecular mechanisms of immunoglobulin E-mediated atopic diseases
Authors: Huang Susie S. Y. , Ali Fatima Al , Boughorbel Sabri , Toufiq Mohammed , Chaussabel Damien , Garand Mathieu
Published: January 2019

Prevalence of allergies has reached ~50% of industrialized populations and with children under ten being the most susceptible. However, the combination of the complexity of atopic allergy susceptibility/development and environmental factors has made identification of gene biomarkers challenging. The amount of publicly accessible transcriptomic data presents an unprecedented opportunity for mechanistic discoveries and validation of complex disease signatures across studies. However, this necessitates structured methodologies and visual tools for the interpretation of results. Here, we present a curated collection of transcriptomic datasets relevant to immunoglobin E (IgE)-mediated atopic diseases (ranging from allergies to primary immunodeficiencies). 30 datasets from the Gene Expression Omnibus (GEO), encompassing 1761 transcriptome profiles, were made available on the Gene Expression Browser (GXB), an online and open-source web application that allows for the query, visualization, and annotation of metadata. The thematic compositions, disease categories, sample number, and platforms of the collection are described. Ranked gene lists and sample grouping are used to facilitate data visualization/interpretation and are available online via GXB (http://ige.gxbsidra.org/dm3/geneBrowser/list). Dataset validation using associated publications showed good concordance in GXB gene expression trend and fold-change.

Database URL: http://ige.gxbsidra.org/dm3/geneBrowser/list
DISPOT: A simple knowledge-based protein domain interaction statistical potential
Authors: Narykov Oleksandr , Korkin Dmitry
Published: January 2019

Motivation

The complexity of protein-protein interactions (PPIs) is further compounded by the fact that an average protein consists of two or more domains, structurally and evolutionary independent subunits. Experimental studies have demonstrated that an interaction between a pair of proteins is not carried out by all domains constituting each protein, but rather by a select subset. However, finding which domains from each protein mediate the corresponding PPI is a challenging task.

Results

Here, we present Domain Interaction Statistical POTential (DISPOT), a simple knowledge-based statistical potential that estimates the propensity of an interaction between a pair of protein domains, given their SCOP family annotations. The statistical potential is derived based on the analysis of more than 352,000 structurally resolved protein-protein interactions obtained from DOMMINO, a comprehensive database on structurally resolved macromolecular interactions

Availability and implementation

DISPOT is implemented in Python 2.7 and packaged as an open-source tool. DISPOT is implemented in two modes, basic and auto-extraction. The source code for both modes is available on Github: (https://github.com/KorkinLab/DISPOT) and standalone docker images on DockerHub: (https://cloud.docker.com/u/korkinlab/repository/docker/korkinlab/dispot).
Multiple selection signatures in farmed Atlantic salmon adapted to different environments across Hemispheres
Authors: López M.E. , Linderoth T. , Norris A. , Lhorente J.P. , Neira R. , Yáñez J.M.
Published: January 2019

1.

Domestication of Atlantic salmon started approximately forty years ago, using both artificial and natural selection strategies. Such selection methods are likely to have imposed distinctive selection signatures on the salmon genome. Therefore, identifying differences in selection signatures may give insights into the mechanism of selection and candidate genes of biological and productive interest. Here, we used two complementary haplotype-based statistics, the within-population integrated Haplotype Score test (|iHS|) and the cross-population Extended Haplotype Homozygosity test (XP-EHH) to compare selection signatures in four populations of Atlantic salmon with a common genetic origin. Using |iHS| we found 24, 14, 16 and 26 genomic regions under selection in Pop-A, Pop-B, Pop-C, and Pop-D, respectively. While using the XP-EHH test we identified 27, 25 and 15 potential selection regions in Pop-A/Pop-B, Pop-A/Pop-C and Pop-A/Pop-D, respectively. These genomic regions harbor important genes suchigf1randsh3rf1which have been associated with growth related traits in other species. Our results contribute to the detection of candidate genes of interest and help to understand the evolutionary and biological mechanisms for controlling complex traits under selection in Atlantic salmon.