bluuebunny/crossref_metadata_2025 huggingface dataset:
Injury, Sleep, and Functional Outcome in Hospital Patients With Traumatic Brain Injury
Authors: Williams Ellita T. , Buchanan Diana Taibi , Buysse Daniel J. , Thompson Hilaire J.
Published: April 2019

Problem: Uninterrupted nighttime sleep is associated with better cognition and functional outcomes in healthy adults, but the relationship between sleep and functional outcome in individuals hospitalized with severe traumatic brain injury (TBI) remains to be clarified. Objective: The aims of this study were to (1) describe nighttime rest-activity variables—wake bouts (counts), total wake time (minutes), and sleep efficiency (SE) (percentage; time asleep/time in bed)—in people on a neuroscience step-down unit (NSDU) post-TBI and (2) describe the association between injury and nighttime rest-activity on post-TBI functional outcome (using Functional Independence Measure [FIM] at discharge from inpatient care). Methods: This study is a cross-sectional, descriptive pilot study. We recruited participants from the NSDU (n = 17 [age: mean (SD), 63.4 (17.9)]; 82% male, 94% white) who wore wrist actigraphy (source of nighttime rest-activity variables) for up to 5 nights. For injury variables, we used Glasgow Coma Scale (GCS) score and Injury Severity Score (ISS). We used Spearman ρ and regression to measure associations. Results: Glasgow Coma Scale mean (SD) score was 8.8 (4.9), ISS mean (SD) score was 23.6 (6.7), and FIM mean (SD) score was 48 (14.5). Averages of nighttime rest-activity variables (8 PM–7 AM) were as follows: SE, 73% (SD, 16); wake bouts, 41 counts (SD, 18); total wake time, 74 minutes (SD, 47). Correlations showed significance between FIM and GCS (P = .005) and between SE and GCS (P = .015). GCS was the only statistically significant variable associated with FIM (P = .013); we eliminated other variables from the model as nonsignificant (P > .10). Sleep efficiency and FIM association was nonsignificant (P = .40). In a separate model (ISS, GCS, and SE [dependent variable]), GCS was significant (P = .04), but ISS was not (P = .25). Conclusion: Patients with severe TBI on the NSDU have poor actigraphic sleep at night. GCS has a stronger association to functional outcome than nighttime rest-activity variables.
The Effect of Low Back Pain on Daily Activities and Sleep Quality in Patients With Lumbar Disc Herniation: A Pilot Study
Authors: Kose Gulsah , Tastan Sevinc , Temiz Nail Caglar , Sari Melek , Izci Yusuf
Published: April 2019

The aim of this study was to determine the effect of low back pain on the daily activities and sleep quality of patients with lumbar disc herniation. This cross-sectional study was performed between January and July 2015 in 77 patients. A visual analog scale (VAS), the Oswestry Disability Index (ODI), and the Pittsburgh Sleep Quality Index were used for patient assessment. The mean (SD) ODI score was 58.84 (9.51), and the mean (SD) VAS score of patients was 73.26 (24.37) mm. The VAS and ODI scores increased with age. This disability was mainly observed during weight lifting (67.6%), walking (48.1%), and standing (50.7%). A positive correlation was found between VAS score and ODI (r = 0.49, P < .001) and Pittsburgh Sleep Quality Index (r = 0.23, P = .039) scores. In patients with lumbar disc herniation, disability in activities of daily living and sleep quality are directly affected by low back pain and increase with pain intensity. Findings of this study provide useful information for healthcare professionals.
Changing pattern of chronic hepatitis C in renal transplant patients over 20 years
Authors: Emori Christini T. , Uehara Sílvia N.O. , Carvalho-Filho Roberto J. , Amaral Ana Cristina , de Souza e Silva Ivonete S. , Lanzoni Valéria P. , Moreira Sílvia R. , Silva-Souza Ana Lúcia , Gama Raimundo A. , Nunes Eunice J.S. , Leopércio Ana Paula.S. , Appel Flávia , Silva Antônio Eduardo B. , Medina-Pestana José O. , Ferraz Maria L.G.
Published: April 2019

Background

The prevalence and clinical epidemiological profile of hepatitis C virus (HCV) infection have changed over time.

Aim

This study aimed to evaluate these changes in renal transplant recipients (RTx) comparing two different decades.

Materials and methods

RTx with HCV referred to RTx from 1993 to 2003 (A) and from 2004 to 2014 (B) were studied retrospectively. The demographic and clinical characteristics and different outcomes were compared between groups A and B. Variables that were statistically different were tested for inclusion in a multivariate Cox proportional hazard model predicting patient survival within the group.

Results

Among 11 715 RTx, the prevalence of HCV was 7% in A and 4.9% in B. In the more recent period (B), the mean age was older (46.2 vs. 39.5 years), with more males (72 vs. 60.7%), larger number of deceased donors (74 vs. 55%), higher percentage of previous RTx (27 vs. 13.7%), less frequent history of blood transfusion (81 vs. 89.4%), lower prevalence of hepatitis B virus coinfection (4.7 vs. 21.4%), and higher percentage of cirrhotic patients (13 vs. 5%). Patients of group B more frequently underwent treatment of HCV (29 vs. 9%), less frequently used azathioprine (38.6 vs. 60.7%) and cyclosporine (11.8 vs. 74.7%), and more frequently used tacrolimus (91 vs. 27.3%). In the outcomes, graft loss showed no difference between periods; however, decompensation was more frequent (P = 0.007) and patients’ survival was lower in the more recent period (P = 0.032) compared with the earlier one.

Conclusion

The profile of RTx with HCV has changed over the last 20 years. Despite a decrease in the prevalence of HCV, new clinical challenges have emerged, such as more advanced age and a higher prevalence of cirrhosis.
Impact of pretransplant antibodies on outcomes after heart transplantation
Authors: Nunoda Shinichi
Published: April 2019

Purpose of review

Since the discovery of human leukocyte antigen (HLA) in the 1950s, there has been great interest in the role of antibodies in posttransplant rejection. The development of the lymphocyte toxicity test by Terasaki et al. in the 1960s was the first step toward understanding the role of antibodies in posttransplant rejection.

Recent findings

Subsequently, various organs have been transplanted and improving posttransplant outcomes have become a focus of research. In particular, methods to measure antibodies that affect posttransplant outcomes, including anti-HLA antibodies, and methods to desensitize patients from specific antibodies have been explored. One recent method for measuring antibodies is called the solid-phase assay, which uses purified HLA fixed to microbeads. This assay does not use donor lymphocytes and allows clinicians to test the reactivity of patient serum against a panel of antibodies. It has also enabled the identification of specific anti-HLA antibodies using a single HLA.

In addition to advances in methods to measure and analyze anti-HLA antibodies, the clinical impact of non-HLA antibodies has also received much attention recently.
Differential Intraoperative Effect of Liver Transplant in Different Inborn Errors of Metabolism
Authors: Porta Francesco , Romagnoli Renato , Busso Marta , Tandoi Francesco , Spada Marco
Published: April 2019

Liver transplant (LT) is a therapeutic option for a growing number of inborn errors of metabolism (IEM), including some disorders not confined to the liver. Clinical advantages of LT in maple syrup urine disease (MSUD), methylmalonic acidemia (MMA), and argininosuccinic aciduria (ASA) have been reported. However, no information on the early metabolic effect of LT after portal reperfusion is available in these disorders. Here we describe the intraoperative differential metabolic outcome of LT in MSUD, MMA, and ASA. In these IEM, LT promptly cleared toxic metabolites to safe concentrations. In MSUD, leucine concentration reached physiological concentration within 12 hours after portal reperfusion. In MMA and ASA, LT allowed faster clearance of methylmalonate and argininosuccinate, respectively, both dropping by ~90% within the first hour after portal reperfusion. The early biochemical benefits of LT in MSUD, MMA, and ASA demonstrate its immediate effectiveness in protecting patients from intercurrent metabolic decompensations.
Frequency and Determinants of Invasive Fungal Infections in Children With Solid and Hematologic Malignancies in a Nonallogeneic Stem Cell Transplantation Setting: A Narrative Review
Authors: Ruijters Veerle J. , Oosterom Natanja , Wolfs Tom F.W. , van den Heuvel-Eibrink Marry M. , van Grotel Martine
Published: April 2019

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in children with cancer. An overview of studies on the frequency and determinants of IFI in pediatric oncology patients in nonallogeneic stem cell transplantation settings is lacking. We performed a literature review in Pubmed and Embase, and included 13 prospective and 23 retrospective studies. The IFI frequency (proven/probable based on EORTC criteria) in nonallogeneic stem cell transplantation pediatric cancer patients ranged between 1.0% and 38.0%, with the highest frequencies reported in hematologic malignancies. The most common fungal species seen in the studied population was Candida, followed by Aspergillus. IFI are not well investigated in solid tumor patients. Significant recurrent determinants from univariate analysis were the diagnosis acute myeloid leukemia, (prolonged) neutropenia and an older age (above 10 years). The only 2 significant determinants based on multivariate analysis were the preceding number of days of broad-spectrum antibiotics (odds ratio, 1.05; 95% confidence interval, 1.02-1.07; P=0.0006) and the number of days of corticosteroids (odds ratio, 1.05; 95% confidence interval, 1.02-1.09; P=0.005), that were both based on a group of acute myeloid leukemia patients only. Future studies are necessary to determine the frequency and determinants of IFI in pediatric oncology including a representative number of solid tumor patients.
Medicolegal Investigation for Cremation Clearance
Authors: Gill James R. , Olko Holly G. , DeJoseph Maura E.
Published: April 2019

This study on cremation clearance examines whether physical inspections detect more unnatural unreported deaths than medicolegal investigations without inspections. We reviewed all deaths reported to the medical examiner for cremation clearance during 2 distinct years and compared subsequent amendments of death certificates after 2 different investigative methodologies (1 with and 1 without physical inspection). Of 10,367 deaths in 2012, there were 86 deaths (0.83%) in which the investigation with physical inspection resulted in amendments to the death certificate. Of 11,906 deaths in 2016 without physical inspection, there were 153 that resulted in amendments (1.3%) including 2 homicides. For the detection of accidents, there was no statistically significant difference (χ2= 0.8119,P= 0.367552). For cremation investigations, the work effort and costs of performing physical inspections do not appear justified given the similar detection rates (approximately 1%) for unnatural deaths among the 2 groups. Both methods, however, do detect unreported unnatural deaths.
Development of a Quality Improvement Curriculum in a Pediatric Emergency Medicine Fellowship
Authors: Carney Kevin P. , Topoz Irina , Vu Tien T. , Mistry Rakesh D. , DiStefano Michael
Published: April 2019

Quality improvement (QI) is a science of systematic analysis and improvement of health care delivery systems. Working knowledge of QI models is imperative to professional development of future pediatric emergency medicine practitioners. The Accreditation Council for Graduate Medical Education has established a list of QI and patient safety expectations for trainees. In order to address educational needs in this area, we have created a novel QI curriculum for pediatric emergency medicine fellows that include didactic sessions, active participation in QI projects, and mentorship by QI faculty. As a part of the curriculum, fellows are required to participate in variety of QI and patient safety activities, such as Morbidity and Mortality conferences, QI and Patient Case Review committees, and Clinical Care Guideline work groups. As a measure of success, fellows who have participated in this curriculum have shared their successful QI work at the local and national levels. This goal of this report is to share our experience in order to provide other institutions a framework for their own curriculum development.
Tenure and Turnover Among State Health Officials From the SHO-CASE Survey: Correlates and Consequences of Changing Leadership
Authors: Menachemi Nir , Danielson Elizabeth C. , Tilson Hugh A. , Yeager Valerie A. , Sellers Katie , Halverson Paul K. ,   for the SHO-CASE Steering Committee
Published: April 2019

Objective:

To examine characteristics associated with tenure length of State Health Officials (SHOs) and examine reasons and consequences for SHO turnover.

Design:

Surveys of current and former SHOs linked with secondary data from the United Health Foundation.

Setting:

Original survey responses from SHOs in the United States.

Participants:

Respondents included SHOs who served between 1973 and 2017.

Main Outcome Measures:

Tenure length and consequences of SHO turnover.

Results:

Average completed tenure among SHOs was 5.3 years (median = 4) and was shorter in recent time periods compared with decades prior. Older age at appointment (β = −0.109, P = .005) and those holding a management degree (β = −1.835, P = .017) and/or a law degree (β = −3.553, P < .001) were each associated with shorter SHO tenures. State Health Officials from states in the top quartile for health rankings had significantly longer average tenures (β = 1.717, P = .036). Many former SHOs believed that their tenure was too short and reported that their departure had either a significant or very large effect on their agency's ability to fulfill its mission.

Conclusions:

State Health Official tenures have become shorter over time and continue to be shorter than industry chief executive officers and best practice recommendations from organizational researchers. States have an opportunity to consider and address how factors within their control influence the stability of the SHO position.
Reduced Biventricular Volumes and Myocardial Dysfunction Long-term After Pediatric Heart Transplantation Assessed by CMR
Authors: Latus Heiner , Hachmann Pauline , Voges Inga , Mueller Simon , Gummel Kerstin , Reich Bettina , Sarikouch Samir , Peters Brigitte , Mazhari Nona , Behnke-Hall Kachina , Jux Christian , Apitz Christian , Thul Josef , Akintuerk Hakan , Bauer Juergen , Schranz Dietmar
Published: April 2019

Background.

Long-term cardiac remodeling after heart transplantation (HT) in children has been insufficiently characterized. The aim of our study was to evaluate ventricular size in HT patients using cardiovascular magnetic resonance (CMR) imaging, to find underlying factors related to potentially abnormal cardiac dimensions and to study its impact on functional class and ventricular function.

Methods.

Seventy-five pediatric HT recipients (age 14.0 ± 4.2 y) were assessed by using CMR 11.2 ± 5.4 years after HT. Right ventricular (RV) and left ventricular (LV) volumes and mass were derived from short-axis cine images and myocardial strain/strain rate was assessed using myocardial feature tracking technique. Results were compared with a healthy reference population (n = 79, age 13.7 ± 3.7 y).

Results.

LV end-diastolic ventricular volumes were smaller (64 ± 12 versus 84 ± 12 mL/m2; P < 0.001) while mass-to-volume ratio (0.86 ± 0.18 versus 0.65 ± 0.11; P < 0.001) and heart rate (92 ± 14 versus 78 ± 13 beats/min; P < 0.001) were higher in HT patients. LV-ejection fraction (EF) was preserved (66% ± 8% versus 64% ± 6%; P = 0.18) but RV-EF (58 ± 7 versus 62% ± 4%, P = 0.004), LV systolic longitudinal strain (−12 ± 6 versus −15% ± 5%; P = 0.05), diastolic strain rate (1.2 ± 0.6 versus 1.5 ± 0.6 1/s; P = 0.03), and intra and interventricular synchrony were lower in the HT group. Smaller LV dimensions were primarily related to longer follow-up time since HT (β = −0.38; P < 0.001) and were associated with worse functional class and impaired ventricular systolic and diastolic performance.

Conclusions.

Cardiac remodeling after pediatric HT is characterized by reduced biventricular size and increased mass-to-volume ratio. These adverse changes evolve gradually and are associated with impaired functional class and ventricular dysfunction suggesting chronic maladaptive processes affecting allograft health.
Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation
Authors: Vanhove Bernard , Poirier Nicolas , Soulillou Jean-Paul , Blancho Gilles
Published: April 2019

Nephrotoxicity of calcineurin inhibitors and uncontrolled effector function of alloreactive T lymphocytes are main drivers of transplant dysfunctions. T lymphocytes either directly damage tissues or indirectly promote inflammation and antibody responses. Beside inhibitors of calcium-dependent pathways and antimetabolites, modulators of T-cell costimulation are elected pharmacological tools to enable interference with immune-mediated transplant dysfunctions. CD28 and CTLA-4 are major costimulatory and coinhibitory cell surface signaling molecules interacting with CD80/86, known to be critically important for immune response of committed T cells and regulation. Initial bench to beside translation, 2 decades ago, resulted in the development of belatacept CTLA-4 fused with an immunoglobulin Fc domain, a biologic inhibiting interaction of both CD28 and CTLA-4 with CD80/86. Despite proven effectiveness in inhibiting alloimmune responses, clinical use of belatacept in kidney transplantation revealed a substantially high incidence of acute, cell-mediated rejection. The cause of belatacept-resistant graft rejection was allocated to elevated pretransplant frequencies of CD28+ memory T cells. Owing to different requirements in CD28 costimulatory and CTLA-4 coinhibitory signals to control naive and memory T cells, selective antagonists of CD28–CD80/86 interactions have been developed on the rationale that preservation of CTLA-4-mediated regulatory mechanisms would result in a better control of alloreactivity and would represent a regulatory T-cell–compatible immunosuppression. After the successful testing of selective CD28 antagonists in First In Human studies, this review delineates how this shift in paradigm performed in preclinical transplantation models and evaluates its clinical potential.
Post-treatment human papillomavirus antibody kinetics in cervical cancer patients
Authors: Piontek Till , Harmel Christoph , Pawlita Michael , Carow Katrin , Schröter Juliane , Runnebaum Ingo B. , Dürst Matthias , Graw Frederik , Waterboer Tim
Published: April 2019

Antibodies to the E6 and E7 oncoproteins of high-risk human papillomavirus (HPV) types are strongly associated with HPV-driven cancer, while antibodies against the capsid protein L1 are considered cumulative exposure markers. To test the hypothesis that L1 antibody levels are stable over time, whereas E6 and E7 levels undergo decay after cervical cancer (CxCa) treatment, we performed multiplex serology for HPV16 and 18 antigens E6, E7 and L1 in a post-treatment study of 184 patients with invasive CxCa that were characterized with a median follow-up time of 725 days, and 2–12 sera per patient. Antibody titers significantly decreased within the first six months for HPV16 E6 and E7 but not L1, and stabilized for the following 12 months on a high level, with few patients showing seroreversion. Of 67 patients seropositive for HPV16 E6 at diagnosis, 28 (41.8%) showed a decrease in antibody titers of at least 50% within the first 18 months. Similarly, of 50 HPV16 E7 seropositives, 33 (66.0%) showed decreasing antibody levels, whereas antibody decay was less frequent for HPV16 L1 (12 of 47, 25.5%). Using a power-law mathematical model to characterize antibody decay kinetics, the mean (±s.e.) durations to a 50% reduction in antibody titers within individual patients were estimated to be 56.9 (±26.1) and 56.3 (±19.0) days for HPV16 E6 and E7, respectively. In summary, HPV16 E6 and E7 antibodies undergo a slow but significant decrease in antibody titers within the first 6–18 months following CxCa treatment. However, larger studies are needed to confirm the utility of serology for prediction of disease progression and time to relapse based on antibody decay kinetics.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.
The scope of viral causation of human cancers: interpreting virus density from an evolutionary perspective
Authors: Ewald Paul W. , Swain Ewald Holly A.
Published: April 2019

Most known oncogenic viruses of humans use DNA as their genomic material. Research over the past quarter century has revealed that their oncogenicity results largely from direct interference with barriers to oncogenesis. In contrast to viruses that have been accepted causes of particular cancers, candidate viral causes tend to have fewer viral than cellular genomes in the tumours. These low viral loads have caused researchers to conclude that the associated viruses are not primary causes of the associated cancers. Consideration of differential survival, reproduction and infiltration of cells in a tumour suggest, however, that viral loads could be low even when viruses are primary causes of cancer. Resolution of this issue has important implications for human health because medical research tends to be effective at preventing and controlling infectious diseases. Mathematical models may clarify the problem and help guide future research by assessing whether low viral loads are likely outcomes of the differential survival, reproduction, and infiltration of cells in a tumour and, more generally, the extent to which viruses contribute to cancer.

This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.
Complement in human pre-implantation embryos: attack and defense
Authors: Reichhardt Martin P. , Lundin Karolina , Lokki A. Inkeri , Recher Gaëlle , Vuoristo Sanna , Katayama Shintaro , Tapanainen Juha , Kere Juha , Meri Seppo , Tuuri Timo
Published: April 2019

It is essential for early human life that immunological responses to developing embryos are tightly regulated. An imbalance in the activation and regulation of the human complement system occurs in pregnancy complications, such as pre-eclampsia and recurrent miscarriage. We hereby present the first full analysis of the expression and deposition of complement molecules in human pre-implantation embryos. Thus far, immunological imbalance has been considered in stages of pregnancy following implantation. We here show that complement activation and deposition takes place on developing human embryos already at the pre-implantation stage. Using confocal microscopy, we observed deposition of activation products such as C1q, C3 and C5 on healthy developing embryos, which highlights the need for strict complement regulation. The early embryos express the complement membrane inhibitors CD46, CD55 and CD59 and bind the soluble regulators C4bp and factor H. These findings show that complement targets human embryos, and indicate potential adverse pregnancy outcomes, if regulation of activation fails. In addition, single-cell RNA sequencing of embryos at oocyte, zygote, 4-cell and 8-cell stages showed expression of complement genes, e.g. C1s, C2, C3, C5, factor B and factor D. This shows that the embryonic cells themselves have the capacity to express C3 and C5, which may become activated and function as mediators of cellular signaling. The specific local embryonic expression of complement components, regulators, and deposition of activation products on the surface of embryos suggests that complement has immunoregulatory functions and may impact cellular homeostasis and differentiation at the earliest stage of human life.

Statement of significance

While canonical functions of the complement system relate to pathogen-defence, it is known to drive certain immune pathologies. The work here described shows, for the first time, expression and localization of a full range of complement molecules in human pre-implantation embryos. We demonstrate complement attack against early embryos, and show presence of embryonic defence mechanisms. Furthermore, we reveal early embryonic production of complement activators, suggesting non-canonical roles in cell signalling and development. Our findings thus reveal a fundamental role for complement at the earliest stages of human embryogenesis. Our data opens up for future studies into the role of complement, both in relation to infertility and pregnancy complications, as well as basic cellular processes during early human development.
Praziquantel activates a schistosome transient receptor potential channel
Authors: Park Sang-Kyu , McCusker Paul , Dosa Peter I. , Chan John D. , Marchant Jonathan S.
Published: April 2019

The anthelmintic drug praziquantel (PZQ) is used to treat schistosomiasis, a neglected tropical disease that affects over 200 million people. The target of PZQ in the blood fluke responsible for this disease is unknown. Here, we demonstrate that PZQ activates a transient receptor potential (TRP) channel found in parasitic schistosomes and other PZQ-sensitive parasites.
The limbic circuit for response vigour
Authors: Porr Bernd , Gomes Pedro , Andreassen Thor
Published: April 2019

Motivation can be defined as the amount of energy an animal puts into actions to achieve goals. This not a static property but can be learned. Recently, abstract models have been developed for this kind of learning which propose that tonic dopamine is responsible to energise behaviour. However the underlying circuitry is still not understood and it is still unclear how tonic dopamine acts on the motor system to energise behaviour. In this paper we present a limbic system model of response invigoration which is based on neurophysiological data and anatomical connections. We argue that the indirect pathway from NAcc core D2 neurons via the ventral pallidum to the SNr conveys response vigour, while the direct pathway from NAcc core D1 neurons is responsible for action selection. Once this detailed anatomically mapped circuit has been established we then condense this realistic model into an abstract model which then shows that tonic DA acts in a multiplicative way on the motor output and thus is able to energise behaviour. We demonstrate the model with both a simulated and real robot experiment.
Noise-Reducing Negative-Feedback Optogenetic Circuits in Mammalian Cells
Authors: Guinn Michael Tyler , Balázsi Gábor
Published: April 2019

Gene autorepression is widely present in nature and is also employed in synthetic biology, partly to reduce gene expression noise in cells. Optogenetic systems have recently been employed for controlling gene expression levels in mammalian cells, but most have utilized activator-based proteins, neglecting negative feedback. Here, we engineer optogenetic negative-feedback gene circuits in mammalian cells to achieve noise-reduction for precise gene expression control. We build a toolset of these noise-reducing Light-Inducible Tuner (LITer) gene circuits using the TetR repressor fused with a Tet-Inhibitory peptide (TIP) or a degradation tag through the light-sensitive LOV2 protein domain. These LITers provide nearly a range of 4-fold gene expression control and up to five-fold noise reduction from existing optogenetic systems. Moreover, we use the LITer gene circuit architecture to control gene expression of the cancer oncogene KRAS(G12V) and study its downstream effects through phospho-ERK levels and cellular proliferation. Overall, these novel LITer optogenetic platforms should enable precise spatiotemporal perturbations for studying multicellular phenotypes in developmental biology, oncology, and other biomedical fields of research.
Predicting the partition of behavioral variability in speed perception with naturalistic stimuli
Authors: Chin Benjamin M. , Burge Johannes
Published: April 2019

A core goal of visual neuroscience is to predict human perceptual performance from natural signals. Performance in any natural task can be impacted by at least three sources of uncertainty: stimulus variability, internal noise, and sub-optimal computations. Determining the relative importance of these factors has been a focus of interest for decades, but most successes have been achieved with simple tasks and simple stimuli. Drawing quantitative links directly from natural signals to perceptual performance has proven a substantial challenge. Here, we develop an image-computable (pixels in, estimates out) Bayesian ideal observer that makes optimal use of the statistics relating image movies to speed. The optimal computations bear striking resemblance to descriptive models proposed to account for neural activity in area MT. We develop a model based on the ideal, stimulate it with naturalistic signals, predict the behavioral signatures of each performance-limiting factor, and test the predictions in an interlocking series of speed discrimination experiments. The critical experiment collects human responses to repeated presentations of each unique image movie. The model, highly constrained by the earlier experiments, tightly predicts human response consistency without free parameters. This result implies that human observers use near-optimal computations to estimate speed, and that human performance is near-exclusively limited by natural stimulus variability and internal noise. The results demonstrate that human performance can be predicted from a task-specific statistical analysis of naturalistic stimuli, show that image-computable ideal observer analysis can be generalized from simple to natural stimuli, and encourage similar analyses in other domains.
Lethal mutagenesis of Rift Valley fever virus induced by favipiravir
Authors: Borrego Belén , de Ávila Ana I. , Domingo Esteban , Brun Alejandro
Published: April 2019

Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks paying a considerable toll of human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic and emerging RNA virus infections of humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies, and a decrease of specific infectivity, hallmarks of lethal mutagenesis.
SICaRiO: Short Indel Call filteRing with bOosting
Authors: Bhuyan Md Shariful Islam , Pe’er Itsik , Rahman M. Sohel
Published: April 2019

Despite impressive improvement in the next-generation sequencing technology, reliable detection of indels is still a difficult endeavour. Recognition of true indels is of prime importance in many applications, such as, personalized health care, disease genomics, population genetics etc. Recently, advanced machine learning techniques have been successfully applied to classification problems with large-scale data. In this paper, we present SICaRiO, a gradient boosting classifier for reliable detection of true indels, trained with gold-standard dataset from genome-in-a-bottle (GIAB) consortium. Our filtering scheme significantly improves the performance of each variant calling pipeline used in GIAB and beyond. SICaRiO uses genomic features which can be computed from publicly available resources, hence, we can apply it on any indel callsets not having sequencing pipeline-specific information (e.g., read depth). This study also sheds lights on prior genomic contexts responsible for indel calling error made by sequencing platforms. We have compared prediction difficulty for three indel categories over different sequencing pipelines. We have also ranked genomic features according to their predictivity in determining false indel calls.
Robust and replicable measurement for prepulse inhibition of the acoustic startle response
Authors: Miller Eric A. , Kastner David B. , Grzybowski Michael N. , Dwinell Melinda R. , Geurts Aron M. , Frank Loren M.
Published: April 2019

Measuring animal behavior in the context of experimental manipulation is critical for modeling and understanding neuro-psychiatric disease. Prepulse inhibition of the acoustic startle response (PPI) is a behavioral paradigm used extensively for this purpose, but the results of PPI studies are often inconsistent. As a result, the utility of this metric remains uncertain. Here we deconstruct the phenomenon of PPI. We first confirm several limitations of the traditional PPI metric, including that the underlying startle response has a non-Gaussian distribution and that the traditional PPI metric changes with different stimulus condition. We then develop a novel model that reveals PPI to be a combination of the previously appreciated scaling of the startle response, as well as a scaling of sound perception. Using our model, we find no evidence for differences in PPI in a rat model of Fragile-X Syndrome (FXS) compared to wild-type controls. These results in the rat provide a reliable methodology that could be used to clarify inconsistent PPI results in mice and humans. In addition, we find robust differences between wild-type male and female rats. Our model allows us to understand the nature of these differences, and we find that both the startle-scaling and sound-scaling components of PPI are a function of the baseline startle response. Males and females differ specifically in the startle-scaling, but not the sound-scaling, component of PPI. These findings establish a robust experimental and analytical approach that has the potential to provide a consistent biomarker of brain function.
Phenotypic and Genetic Markers of Psychopathology in a Population-Based Sample of Older Adults
Authors: Gard Arianna M. , Ware Erin B. , Hyde Luke W. , Schmitz Lauren , Faul Jessica , Mitchell Colter
Published: April 2019

Although psychiatric phenotypes are hypothesized to organize into a two-factor internalizing – externalizing structure, few studies have evaluated the structure of psychopathology in older adults, nor explored whether genome-wide polygenic scores (PGSs) are associated with psychopathology in a domain-specific manner. We used data from 6,216 individuals of European ancestry from the Health and Retirement Study, a large population-based sample of older adults in the United States. Confirmatory factor analyses were applied to validated measures of psychopathology and PGSs were derived from well-powered GWAS. Genomic SEM was implemented to construct latent PGSs for internalizing, externalizing, and general psychopathology. Phenotypically, the data were best characterized by a single general factor of psychopathology, a factor structure that was replicated across genders and age groups. Although externalizing PGSs (cannabis use, antisocial behavior, alcohol dependence, ADHD) were not associated with any phenotypes, PGSs for MDD, neuroticism, and anxiety disorders were associated with both internalizing and externalizing phenotypes. Moreover, the latent internalizing PGS and the latent one-factor PGS, derived using weights from Genomic SEM, explained 1% more variance in the general factor of psychopathology than any of the individual PGSs. Results support the following conclusions: genetic risk factors for and phenotypic markers of psychiatric disorders are transdiagnostic in European ancestries, GWAS-derived PGSs fail to capture genetic variation associated with disease specificity in European ancestries, and blunt phenotypic measurement in GWAS may preclude our ability to evaluate the structure and specificity of genetic contributions to psychiatric disorders.
Dorsal-to-ventral neocortical expansion is physically primed by ventral streaming of early embryonic preplate neurons
Authors: Saito Kanako , Okamoto Mayumi , Watanabe Yuto , Noguchi Namiko , Nagasaka Arata , Nishina Yuta , Shinoda Tomoyasu , Sakakibara Akira , Miyata Takaki
Published: April 2019

Mammalian neocortex exhibits a disproportionally “luxurious” representation of somatotopies in its lateral region, which depends on dorsal-to-ventral expansion of the pallium during development. Despite recent studies elucidating the molecular mechanisms underlying the cortical arealization/patterning, we know very little about how the cortex expands ventrally and the nature of the underlying force-generating events. We found that neurons born earliest (at embryonic day 10 [E10]) in the mouse pallium migrated ventrally and then extended corticofugal axons, which together formed a morphogenetic flow of the preplate that persists until E13. These neurons exerted pulling and pushing forces at the process and the soma, respectively. Ablation of these E10-born neurons attenuated both deflection of radial glial fibers (by E13) and extension of the cortical plate (by E14), which should occur ventrally, and subsequently shrank the postnatal neocortical map dorsally. This previously unrecognized preplate stream physically primes neocortical expansion and somatotopic map formation.
Object Colours, Material Properties and Animal Signals
Authors: Wilkins Lucas , Osorio Daniel
Published: April 2019

Colour is commonly regarded as an absolute measure of object properties, but most work on visual communication signals is concerned with colour differences, typically scaled by just noticeable differences (JNDs). Object colour solids represent the colour gamut of reflective materials for an eye. The geometry of colour solids reveals general relationships between colours and object properties which can explain why certain colours are significant to animals and evolve as signals. We define a measure of colour vividness, such that points on the surface are maximally vivid and the ‘grey’ centre is minimally vivid. We show that a vivid colour for one animal is likely to vivid for others, and highly vivid colours are less easily mimicked than less vivid colours. Further, vivid colours such as black, white, red, blue and light, unsaturated shades are produced pure or orderly materials. This kind of material needs to created and maintained against entropic processes that would otherwise degrade or destroy them. Vivid coloration is therefore indicative of ecological affordance or biological function, so that it is valuable to have attentional biases towards these colours regardless of any specific significance.
Signalling involving MET and FAK supports cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases
Authors: Zhang Chi , Stockwell Simon R. , Elbanna May , Ketteler Robin , Freeman Jamie , Al-Lazikani Bissan , Eccles Suzanne , De Haven Brandon Alexis , Raynaud Florence , Hayes Angela , Clarke Paul A. , Workman Paul , Mittnacht Sibylle
Published: April 2019

Deregulation of the cyclin-dependent kinases 4 and 6 (CDK4/6) is highly prevalent in cancer yet inhibitors against these kinases currently show use in restricted tumour contexts. The extent to which cancers depend on CDK4/6 and what may undermine such dependency is poorly understood. Here we report that signalling engaging the MET proto-oncogene receptor tyrosine kinase/focal adhesion kinase (FAK) axis leads to CDK4/6-independent CDK2-activation, involving as a critical mechanistic events loss of the CDK inhibitor p21CIP1 and gain of its regulator, the ubiquitin ligase subunit SKP2. Combined inhibition of MET/FAK and CDK4/6 eliminates proliferation capacity of cancer cells in culture, and enhances tumour growth inhibition in vivo. Activation of the MET/FAK axis is known to arise through cancer extrinsic and intrinsic cues. Our work predicts that such cues support cell division independent of the activity of the cell cycle-regulating CDK4/6 kinases and identifies MET/FAK as a tractable route to broaden the utility of CDK4/6 inhibitor-based therapies in the clinic.
Fragile X Mental Retardation Protein regulates R-loop formation and prevents global chromosome fragility
Authors: Chakraborty Arijita , Jenjaroenpun Piroon , McCulley Andrew , Li Jing , El Hilali Sami , Haarer Brian , Hoffman Elizabeth A. , Belak Aimee , Thorland Audrey , Hehnly Heidi , Chen Chun-long , Kuznetsov Vladimir A. , Feng Wenyi
Published: April 2019

Fragile X syndrome (FXS) is the most prevalent inherited intellectual disability caused by mutations in the Fragile X Mental Retardation 1 (FMR1) gene. The protein product of FMR1, FMRP, is known as a translational repressor whose nuclear function is not understood. Here we report that FMRP is a genome maintenance protein. We show that FX cells exhibit elevated level of chromosome breaks, both spontaneous and replication stress-induced. We demonstrate that FMRP is required for abating R-loop accumulation, thereby preventing chromosome breakage. Through mapping FMRP-bound chromatin loci in normal cells and correlating with FX-specific chromosome breaks, we identified novel FXS-susceptible genes. We show that FX cells have reduced expression of the uridine diphosphoglucuronosyl transferase 1 family enzymes, suggesting defective xenobiotics glucuronidation and consequential neurotoxicity in FXS.
Tunability of DNA polymerase stability during eukaryotic DNA replication
Authors: Lewis Jacob S. , Spenkelink Lisanne M. , Schauer Grant D. , Yurieva Olga , Mueller Stefan H. , Natarajan Varsha , Kaur Gurleen , Maher Claire , Kay Callum , O’Donnell Michael E. , van Oijen Antoine M.
Published: April 2019

Structural and biochemical studies have revealed the basic principles of how the replisome duplicates genomic DNA, but little is known about its dynamics during DNA replication. We reconstitute the 34 proteins needed to form the S. cerevisiae replisome and show how changing local concentrations of the key DNA polymerases tunes the ability of the complex to efficiently recycle these proteins or to dynamically exchange them. Particularly, we demonstrate redundancy of the Pol α DNA polymerase activity in replication and show that Pol α primase and the lagging-strand Pol δ can be re-used within the replisome to support the synthesis of large numbers of Okazaki fragments. This unexpected malleability of the replisome might allow it to deal with barriers and resource challenges during replication of large genomes.
Synaptic control of DNA-methylation involves activity-dependent degradation of DNMT3a1 in the nucleus
Authors: Bayraktar Gonca , Yuanxiang PingAn , Gomes Guilherme M , Confettura Aessandro D , Raza Syed A , Stork Oliver , Tajima Shoji , Yildirim Ferah , Kreutz Michael R.
Published: April 2019

DNA-methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3a1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDAR drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3a1 and results in deficits of promoter methylation of activity-dependent genes, synaptic plasticity as well as memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively the data show that GluN2A containing NMDAR control synapse-to-nucleus signaling that links plasticity-relevant signals to activity-dependent DNA-methylation involved in memory formation.
D-Cycloserine as Adjunct to Brief Computerised CBT for Spider Fear: Effects on Fear, Behaviour, and Cognitive Biases
Authors: Kappelmann Nils , Suesse Mareike , Steudte-Schmiedgen Susann , Kaldewaij Reinoud , Browning Michael , Michael Tanja , Rinck Mike , Reinecke Andrea
Published: April 2019

In anxiety disorders, cognitive behavioural therapy (CBT) improves information-processing biases such as implicit fear evaluations and avoidance tendencies, which predicts treatment response, so they might constitute important treatment targets. This study investigated (i) whether information-processing biases changed following single-session computerised CBT for spider fear, and (ii) whether this effect could be augmented by administration of D-cycloserine (DCS). Spider-fearful individuals were randomized to receiving 250mg of DCS (n=21) or placebo (n=17) and spider fear was assessed using self-report, behavioural, and information-processing (Extrinsic Affective Simon Task & Approach Avoidance Task) measures. Linear mixed-effects analyses indicated improvements on self-report and behavioural spider fear following CBT, but not on cognitive bias measures. There was no evidence of an augmentation effect of DCS on any outcome. Cognitive biases at 1-day were not predictive of 1-month follow-up spider fear. These findings provide no evidence for information-processing biases relating to CBT response or augmentation with DCS.
sMode of action of the antimicrobial peptide Mel4 is independent of Staphylococcus aureus cell membrane permeability
Authors: Yasir Muhammad , Dutta Debarun , Willcox Mark D.P.
Published: April 2019

Mel4 is a novel cationic peptide with potent activity against Gram-positive bacteria. The current study examined the anti-staphylococcal mechanism of action of Mel4 and its precursor peptide melimine. The interaction of peptides with lipoteichoic acid (LTA) and with the cytoplasmic membrane using DiSC(3)-5, Sytox green, Syto-9 and PI dyes were studied. Release of ATP and DNA/RNA from cells exposed to the peptides were determined. Bacteriolysis and autolysin-activated cell death were determined by measuring decreases in OD620nm and killing of Micrococcus luteus cells by cell-free media. Both peptides bound to LTA and rapidly dissipated the membrane potential (within 30 seconds) without affecting bacterial viability. Disturbance of the membrane potential was followed by the release of ATP (50% of total cellular ATP) by melimine and by Mel4 (20%) after 2 minutes exposure (p<0.001). Mel4 resulted in staphylococcal cells taking up PI with 3.9% cells predominantly stained after 150 min exposure, whereas melimine showed 34% staining. Unlike melimine, Mel4 did not release DNA/RNA. Cell-free media from Mel4 treated cells hydrolysed peptidoglycan and produced greater zones of inhibition against M. luteus lawn than melimine treated samples. These findings suggest that pore formation is unlikely to be involved in Mel4-mediated membrane destabilization for Staphylococcci, since there was no significant Mel4-induced PI staining and DNA/RNA leakage. It is likely that the S. aureus killing mechanism of Mel4 involves the release of autolysins followed by cell death. Whereas, membrane interaction is the primary bactericidal activity of melimine, which includes membrane depolarisation, pore formation, release of cellular contents leading to cell death.

This work is original, has not been published and is not being considered for publication elsewhere. Part of this manuscript has been presented as a poster presentation in Gordon Research Conference Italy in 2019. There are no conflicts of interest for any of the authors that could have influenced the results of this work. Prof. Mark Willcox holds the patent the for the melimine peptide.