bluuebunny/crossref_metadata_2025 huggingface dataset:
Itchy Patches on the Upper and Lower Extremities
Authors: Mitri Andia , Lake Eden
Published: September 2019

This is a case of a patient presenting with pruritic dark plaques that erupted on the upper extremities and the left inner thigh. The patient is otherwise asymptomatic with no other acute concerns. A multiple-choice question is presented and readers will be challenged to diagnose this patient based on the case presentation, symptoms, and patient history. An answer is given followed by a discussion of the diagnosis, clinical features, and therapeutic management.
Neuropathological Findings of Dementia Associated With Subjective Hearing Loss
Authors: Neff Ryan M. , Jicha Gregory , Westgate Philip M. , Hawk Greg S. , Bush Matthew L. , McNulty Beth
Published: September 2019

Objective:

The relationship between hearing loss and cognitive decline is of great importance with growing evidence of hearing loss as an independent modifiable risk factor for dementia. Our goal was to evaluate for differences in dementia neuropathology between subjective normal hearing and hearing loss subjects, as well as subjects who wore hearing aids.

Study Design:

Retrospective database.

Setting:

Tertiary academic center.

Patients:

Brain tissue analyzed from our Center on Aging. Demographics, subjective hearing status, hearing aid use, cognitive status, and dementia neuropathology documented.

Interventions:

Dementia neuropathology analyzed in brains of normal hearing and hearing loss subjects.

Main Outcome Measures:

Differences in dementia neuropathology between hearing groups. Groups were compared using logistic regression and analysis of covariance (ANCOVA).

Results:

Two-hundred and seventy-three subjects were included, 189 normal hearing and 84 subjective hearing loss subjects. No significant difference demonstrated in Alzheimer's disease neuropathology (p > 0.05) or pathologic stage (p = 0.2471). No significant difference observed in neuropathology of other major dementia types, specifically, presence of Lewy bodies (p > 0.05), Lewy body disease pathologic stage (p = 0.9778), or presence of micro-infarcts, macro-infarcts, or arteriosclerosis (p > 0.05). Hearing aid-wearing subjects had a lower prevalence of clinical dementia (39.1% versus 57.9%; p = 0.0208) with no significant difference in dementia neuropathology (p > 0.05).

Conclusion:

Subjective hearing loss was not found to be associated with significantly different dementia neuropathology, which counters hypotheses on hearing loss causing permanent neurodegeneration and cognitive decline. Hearing aid users were found to have a lower prevalence of dementia for similar levels of neurodegeneration, suggesting a potential neuroprotective effect of hearing aids.
Systematic review: role of elevated plasma von-Willebrand factor as predictor of mortality in patients with chronic liver disease
Authors: Eidelberg Andrew , Kirubakaran Richard , Nair Sukesh Chandran , Eapen Chundamannil Eapen , Elias Elwyn , Goel Ashish
Published: September 2019

In this systematic review, we aimed to assess role of plasma von-Willebrand factor (vWF), an endothelial activation marker, as prognostic marker in patients with chronc liver disease [cirrhosis and acute-on-chronic liver failure (ACLF)]. We searched published databases using predefined keywords to identify all studies up to June 2018, in which plasma vWF (antigen or activity assay) was used as prognostic marker predicting mortality in patients with chronic liver disease. Relevant extracted data from selected studies were narratively summarized. The individual study’s area under ROC curve for plasma vWF as a predictor of mortality was pooled and meta-analyzed. Six studies (cirrhosis: 5; ACLF: 1) with an aggregate data of 765 patients (cirrhosis: 715 patients; ACLF: 50 patients) were included. Baseline plasma vWF-antigen was an independent predictor of medium-term mortality in patients with cirrhosis (summary area under the curve: 0.74; 95% confidence interval: 0.70–0.79) with an optimal cutoff of 318% (216–390%; median, range) over a period of 25.6 months (23.6–33 months). Plasma vWF also predicted short-term (over 7 days) mortality in patients with ACLF. Plasma vWF levels correlated with Child’s score, model for end-stage liver disease (MELD) score and hepatic venous pressure gradient and performed as well as MELD score in predicting mortality in patients with cirrhosis and ACLF. Baseline plasma vWF level predicts mortality over a medium term (1–3 years) in cirrhosis and over a short term (1 week) in ACLF patients. The marked elevation of baseline plasma vWF levels in ACLF patients was associated with drastic truncation of survival when compared with cirrhosis patients.
Health Literacy Risk in Older Adults With and Without Mild Cognitive Impairment
Authors: Liu Yong B. , Chen Yan L. , Xue Hui P. , Hou Ping
Published: September 2019

Background

The relationship between an increasing elderly population and wide-ranging neurological conditions has led to heightened rates of cognitive function impairment. Some researchers have found that health literacy risk may be associated with cognitive impairment in older adults.

Objectives

The purpose of this study was to delineate the difference in health literacy risk between older adults with mild cognitive impairment and those with normal cognitive function.

Methods

We conducted a survey study to explore the health literacy risk in older adults with and without mild cognitive impairment. Data were collected from 412 subjects between 60 and 91 years of age (260 without and 152 with mild cognitive impairment) between June and December 2016 in China. Cognitive function was measured using the Mini-Mental Status Examination, Montreal Cognitive Assessment, Global Deterioration Scale, Activities of Daily Living, and Hamilton Depression Rating Scale. Health literacy was measured using the Chinese Citizen Health Literacy Questionnaire.

Results

The scores of total health literacy and its three dimensions (basic health knowledge and mind, basic skills, and health lifestyle and behavior) were lower in those with mild cognitive impairment. Older adults with normal cognitive function had adequate or marginal health literacy levels, whereas those with mild cognitive impairment had marginal or inadequate health literacy levels. Using multiple logistic regression analysis, we found that health literacy risk, education level, age, marital status, and body mass index were independent risk factors for mild cognitive impairment.

Discussion

These results suggest that low health literacy may be a predictor of mild cognitive impairment. Screening for lower health literacy risk should be included in multidimensional geriatric evaluation.
The Frequency and Prognostic Significance of the Histologic Type in Early-stage Ovarian Carcinoma
Authors: Leskela Susanna , Romero Ignacio , Cristobal Eva , Pérez-Mies Belén , Rosa-Rosa Juan M. , Gutierrez-Pecharroman Ana , Santón Almudena , Gonzalez Belén O. , López-Reig Raquel , Hardisson David , Vera-Sempere Francisco , Illueca Carmen , Vieites Begoña , López-Guerrero José A. , Palacios José , Poveda Andrés
Published: September 2019

The frequency and prognostic significance of the histologic type in early-stage ovarian cancer (OC) is not as well established as in advanced stages. In addition, histologic typing based only on morphologic features may be difficult, especially in high-grade tumors. In this study, we have analyzed a prospective cohort of 502 early-stage OCs to investigate their frequency, immunohistochemical characteristics, and survival of the 5 main histologic types. Histotype was assigned according to not only the morphologic features but also according to the expression pattern of WT1, p53, Napsin A, and progesterone receptors. In addition, an extended panel including p16, β-catenin, HER2, Arid1A, HINF1B, CK7, CDX2, and CK20 was used to refine the diagnosis in difficult cases. In this series, the frequency of the 5 major histologic types was as follows: endometrioid carcinoma, 32.7%; clear cell carcinoma, 25.1%; high-grade serous carcinoma (HGSC), 24.7%; mucinous carcinoma, 10.2%; low-grade serous carcinoma, 4.6%; and others, 2.8%. The combination of morphology and immunohistochemistry allowed the reclassification of 23% of OCs. The lowest concordance was found between samples initially diagnosed as endometrioid, but finally classified as high-grade serous tumors (22% error rate). Endometrioid carcinoma was the most favorable histologic type, whereas HGSC and low-grade serous carcinoma had the worst prognosis. Clear cell carcinoma with abnormal p53 immunostaining pattern also had poor prognosis. Although histologic grade was not a prognostic factor among early-stage endometrioid OCs, distinction between grade 3 endometrioid OC and HGSC is recommended, taking into account differences in prognosis and molecular alterations that can guide different treatments.
Adverse Histologic Features in Colorectal Nonpedunculated Malignant Polyps With Nodal Metastasis
Authors: Patel Natalie , Vyas Monika , Celli Romulo , Jain Dhanpat , Zhang Xuchen
Published: September 2019

Tumor differentiation, lymphovascular invasion, margin status, polyp shape, and size are important parameters of malignant polyps (pT1) indicating possible node metastasis, which justifies a surgery. However, the size, margin, and lymphovascular invasion are often unknown or difficult to assess in a piecemeal polypectomy from a nonpedunculated malignant polyp. The aim of the study was to identify adverse histologic features in nonpedunculated malignant polyps associated with an increased risk of nodal metastasis, which may warrant a colectomy procedure. A total of 24 node-positive and 18 node-negative nonpedunculated malignant polyps and their corresponding subsequent resection specimens from 2005 to 2018 were reviewed. Cases with node metastasis were more often positive for high-grade tumor budding (70.8% vs. 16.7%; P=0.0005), poorly differentiated clusters (54.2% vs. 22.2%; P=0.0369), and both high-grade tumor budding and poorly differentiated clusters (45.8% vs. 11.1%; P=0.0160) compared with controls without nodal metastasis. High-grade tumor budding, poorly differentiated clusters, and combined high-grade tumor budding and poorly differentiated clusters increased the risk of nodal metastasis, with odds ratio of 12.1, 4.1, and 14.3, respectively. Furthermore, nodal metastasis could be seen in subsequent colectomy specimen even in completely excised malignant polyps with adverse histologic features. Our findings indicate that high-grade tumor budding and poorly differentiated clusters are important adverse histologic risk features in predicting lymph node metastatic potential. These histologic features should be reported and it may warrant a colectomy when they are present.
Efficacy of Transcutaneous Electronic Nerve Stimulation in Postoperative Analgesia After Pulmonary Surgery
Authors: Zhou Jian , Dan Yuqing , Yixian Yanling , Lyu Mengyuan , Zhong Jiayi , Wang Zihuai , Zhu Yunke , Liu Lunxu
Published: September 2019

Objective

The aim of the study was to identify the analgesic efficacy and safety of transcutaneous electronic nerve stimulation in postoperative pain after pulmonary surgery.

Design

Electronic databases (PubMed, Embase, Web of Science, and CENTRAL) were systematically searched from their inception to June 2019. The continuous variables were pooled as the weighted mean difference with correlated 95% confidence interval. Results were recognized as significant when a P value is less than 0.05. Subgroup analyses, sensitivity analyses, and quality assessment were performed.

Results

Altogether, 10 studies were included. The pooled results indicated that transcutaneous electronic nerve stimulation group conferred lower pain intensity score on the first postoperative day (weighted mean difference = −0.93, 95% confidence interval = −1.56 to −0.30, P = 0.004), postoperative day 2 (weighted mean difference = −1.00, 95% confidence interval = −1.64 to −0.35, P = 0.002), postoperative day 3 (weighted mean difference = −0.92, 95% confidence interval = −1.76 to −0.09, P = 0.03), postoperative day 4 (weighted mean difference = −0.90, 95% confidence interval = −1.24 to −0.56, P < 0.001), and postoperative day 5 (weighted mean difference = −1.39, 95% confidence interval = −2.20 to −0.57, P < 0.001) compared with the placebo transcutaneous electronic nerve stimulation group. No publication bias was found. No significant discovery was obtained in sensitivity analyses.

Conclusions

Transcutaneous electronic nerve stimulation might be an effective supplementary analgesic regimen in multimodal analgesia to decrease pain intensity after pulmonary surgery.
A Quality Improvement Intervention to Reduce Necrotizing Enterocolitis in premature infants with Probiotic Supplementation
Authors: Rolnitsky Asaph , Ng Eugene , Asztalos Elizabeth , Shama Yasmin , Karol Dalia , Findlater Carla , Garsch Maren , Dunn Michael
Published: September 2019

Background:

Necrotizing Enterocolitis (NEC) is a severe intestinal inflammatory disease due to multifactorial causes that present in preterm infants. Compared with similar neonatal intensive care units, our NEC rate was increasing and prompted reduction by a quality improvement (QI) intervention.

Methods:

We aimed to reduce NEC rate by 30% by the end of 2016. We used the Institute of Healthcare Improvement model and typical QI tools, including teamwork, process organizing tools, and evidence-based review, to assist in our selection of supplementation of Lactobacillus reuteri probiotic. We used education, process mapping, process control statistics, and forcing mechanism to implement the changes. In addition to reducing NEC rates, our additional outcome measures were sepsis, mortality, sepsis evaluations, feeding intolerance, growth, days of both antimicrobials, and parenteral nutrition use. Process measures were compliance with probiotics supplementation policy and balancing measures were sepsis rates and feeding intolerance.

Results:

NEC rates decreased from 4.4% to the current 1.7%, and in a pre/post-intervention analysis, the results were significant in all patient subcategories. We did not demonstrate a reduction in mortality. No adverse events occurred. Feeding intolerance episodes and days nil-per-os decreased with no differences in growth at discharge. These results continued over 2 years, and this practice has already spread to several neonatal intensive care units in Ontario, Canada.

Conclusions:

We utilized QI methods and tools to implement a successful practice change of routine probiotic supplementation to reduce NEC rates in preterm infants. We suggest considering this intervention as a successful means to prevent this serious illness.
Microscopically Positive Resection Margins in Laparoscopic Gastric GIST Resection May Not Confer a Poorer Prognosis
Authors: Majinyang Song , Ruth Yeoh K.M. , Ahmed Saleem , Sanghvi Kaushal , Oo Aung M. , Nath Koura A. , Rao Jaideepraj , Shelat Vishal G.
Published: September 2019

Laparoscopic resection of gastrointestinal stromal tumor (GIST) has increased popularity with studies showing good outcomes for patients with tumors <5 cm, with a shorter hospital stay, lower blood loss, and morbidity. Our study aims to audit the clinical profile and surgical outcomes of GISTs, with an evaluation of laparoscopic versus open surgery and the prognostic role of positive R1 margins. In our retrospective study, 62 GIST patients who underwent surgery were included and further analysis was made for the 48 gastric GISTs patients. In total, 33 patients underwent laparoscopic gastric GIST resection, whereas the rest underwent open resection. There was no difference in operative duration but the blood loss was lesser and length of stay shorter in the laparoscopic group. The laparoscopic group had a higher incidence of R1 resection but none developed recurrence or metastasis during follow-up. Laparoscopic resection in the management of gastric GISTs resulted in higher R1 resection rates but this did not affect recurrence rates or overall survival.
Exploring the underwater silken architectures of caddisworms: comparative silkomics across two caddisfly suborders
Authors: Frandsen Paul B. , Bursell Madeline G. , Taylor Adam M. , Wilson Seth B. , Steeneck Amy , Stewart Russell J.
Published: September 2019

Caddisfly (Trichoptera) larvae assemble a variety of underwater structures using bioadhesive silk. The order is divided into two primary sub-orders distinguished by how the larvae deploy their silk. Foraging Integripalpia larvae construct portable tube cases. Annulipalpia larvae construct stationary retreats, some with suspended nets to capture food. To identify silk molecular adaptations that may have contributed to caddisfly diversification, we report initial characterization of silk from a net-spinner genus,
Parapsyche,
for comparison with the silk of a tube case-maker genus,
Hesperophylax
. Overall, general features of silk structure and processing are conserved across the sub-orders despite approximately 200 Ma of divergence: the H-fibroin proteins comprise repeating phosphoserine-rich motifs, naturally spun silk fibres contain approximately 1 : 1 molar ratios of divalent metal ions to phosphate, silk fibre precursors are stored as complex fluids of at least two types of complexes, and silk gland proteins contain only traces of divalent metal ions, suggesting metal ions that solidify the fibres are absorbed from the aqueous environment after silk extrusion. However, the number and arrangement of the repeating phosphoserine blocks differ between genera, suggesting molecular adaptation of H-fibroin through duplication and shuffling of conserved structural modules may correspond with the radiation of caddisflies into diverse environments.

This article is part of the theme issue ‘Transdisciplinary approaches to the study of adhesion and adhesives in biological systems’.
Novel delivery of cellular therapy to reduce ischaemia reperfusion injury in kidney transplantation
Authors: Thompson Emily R , Bates Lucy , Ibrahim Ibrahim K , Sewpaul Avinash , Stenberg Ben , McNeill Andrew , Figueiredo Rodrigo , Girdlestone Tom , Wilkins Georgina C , Irwin Ellen A , Tingle Samuel J , Scott William E , Lamos Henrique , Mellor Andrew L. , Roobrouck Valerie D. , Ting Anthony E. , Hosgood Sarah A , Nicholson Michael L , Fisher Andrew J , Ali Simi , Sheerin Neil S , Wilson Colin H
Published: September 2019

Ex-vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimise organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC®) possess potent immunomodulatory properties which could prove beneficial in minimising subsequent ischaemia reperfusion injury. We investigated the potential reconditioning capability of MAPC cells in kidney NMP.

Methods

Pairs (5) of human kidneys from the same donor were simultaneously perfused for 7 hours. The right or left kidney was randomly allocated to receive MAPC treatment. Serial samples of perfusate, urine and tissue biopsies were taken for comparison with the control paired kidney.

Results

MAPC-treated kidneys demonstrated improved urine output (p<0.01), decreased expression of the kidney injury biomarker NGAL (p<0.01), improved microvascular perfusion on contrast enhanced ultrasound (cortex p<0.05, medulla p<0.01), downregulation of IL-1β (p<0.05) and upregulation of IL-10 (p<0.05) and Indolamine-2, 3-dioxygenase (p<0.05). A mouse model of intraperitoneal chemotaxis demonstrated decreased neutrophil recruitment when stimulated with perfusate from MAPC-treated kidneys (p<0.01). Immunofluorescence revealed pre-labelled MAPC cells home to the perivascular space in the kidneys during NMP. MAPC therapy was not associated with detrimental physiological or embolic events.

Conclusion

We report the first successful delivery of cellular therapy to a kidney during NMP. Kidneys treated with MAPC cells demonstrate improvement in clinically relevant functional parameters and injury biomarkers. This novel method of cell therapy delivery provides an exciting opportunity to recondition organs prior to clinical transplantation.

One Sentence Summary

Ex-vivo reconditioning of human kidneys using Multipotent Adult Progenitor Cell therapy delivered during normothermic machine perfusion.
Changes in association between school foods and child and adolescent dietary quality during implementation of the Healthy, Hunger-Free Kids Act of 2010
Authors: Berger Aaron T. , Widome Rachel , Erickson Darin J. , Laska Melissa N. , Harnack Lisa J.
Published: September 2019

Purpose

To estimate the effect of Healthy, Hunger-Free Kids Act of 2010 (HHFKA) implementation on dietary quality of all US school-aged children and adolescents, and examine whether those effects differed by demographic group.

Methods

We used survey regression on 2007-2016 National Health and Nutrition Examination Survey (NHANES) data to estimate the proportion of energy intake from school foods and the association between school food intake and dietary quality, before and after HHFKA passage/implementation. To account for demographic changes in the US population over time, inverse probability weighting was employed. The product of the proportion of energy from school foods and the association between school food intake and dietary quality estimated the effect of HHFKA implementation on dietary quality.

Results

School food intake quantity remained stable during the study period. HHFKA implementation improved students’ dietary quality by 4.3 Healthy Eating Index-2010 (HEI) points (95% CI: 2.5, 6.1) on days when school foods were eaten, and by 1.3 HEI points (95% CI: 0.73, 1.8) averaged over all days annually.

Conclusions

HHFKA implementation improved the total dietary quality of US school students. US students would benefit from eating school meals in the post-HHFKA era, and HHFKA regulations should not be relaxed.
Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors
Authors: Teoh JiaJie , Subramanian Narayan , Pero Maria Elena , Bartolini Francesca , Amador Ariadna , Kanber Ayla , Williams Damian , Petri Sabrina , Yang Mu , Allen Andrew S. , Beal Jules , Haut Sheryl R. , Frankel Wayne N.
Published: September 2019

ARFGEF1 encodes a guanine exchange factor involved in intracellular vesicle trafficking, and is a candidate gene for childhood genetic epilepsies. To model ARFGEF1 haploinsufficiency observed in a recent Lennox Gastaut Syndrome patient, we studied a frameshift mutation (Arfgef1fs) in mice. Arfgef1fs/+ pups exhibit signs of developmental delay, and Arfgef1fs/+ adults have a significantly decreased threshold to induced seizures but do not experience spontaneous seizures. Histologically, the Arfgef1fs/+ brain exhibits a disruption in the apical lining of the dentate gyrus and altered spine morphology of deep layer neurons. In primary hippocampal neuron culture, dendritic surface and synaptic but not total GABAA receptors (GABAAR) are reduced in Arfgef1fs/+ neurons with an accompanying decrease in GABAAR-containing recycling endosomes in cell body. Arfgef1fs/+ neurons also display differences in the relative ratio of Arf6+:Rab11+:TrfR+ recycling endosomes. Although the GABAAR-containing early endosomes in Arfgef1fs/+ neurons are comparable to wildtype, Arfgef1fs/+ neurons show an increase in GABAAR-containing lysosomes in dendrite and cell body. Together, the altered endosome composition and decreased neuronal surface GABAAR results suggests a mechanism whereby impaired neuronal inhibition leads to seizure susceptibility.

Highlights

Arfgef1fs/+ mice have lower seizure threshold but no spontaneous seizure.

Arfgef1fs/+ neurons show reduced dendritic surface GABAAR.

Arfgef1fs/+ neurons have decreased GABAAR-containing recycling endosome accompanied with an increase in GABAAR-containing lysosomes.
Rapid detection of identity-by-descent tracts for mega-scale datasets
Authors: Shemirani Ruhollah , Belbin Gillian M. , Avery Christy L. , Kenny Eimear E. , Gignoux Christopher R. , Ambite José Luis
Published: September 2019

The ability to identify segments of genomes identical-by-descent (IBD) is a part of standard workflows in both statistical and population genetics. However, traditional methods for finding local IBD across all pairs of individuals scale poorly leading to a lack of adoption in very large-scale datasets. Here, we present iLASH, IBD by LocAlity-Sensitive Hashing, an algorithm based on similarity detection techniques that shows equal or improved accuracy in simulations compared to the current leading method and speeds up analysis by several orders of magnitude on genomic datasets, making IBD estimation tractable for hundreds of thousands to millions of individuals. We applied iLASH to the Population Architecture using Genomics and Epidemiology (PAGE) dataset of ∼52,000 multi-ethnic participants, including several founder populations with elevated IBD sharing, which identified IBD segments on a single machine in an hour (∼3 minutes per chromosome compared to over 6 days per chromosome for a state-of-the-art algorithm). iLASH is able to efficiently estimate IBD tracts in very large-scale datasets, as demonstrated via IBD estimation across the entire UK Biobank (∼500,000 individuals), detecting nearly 13 billion pairwise IBD tracts shared between ∼11% of participants. In summary, iLASH enables fast and accurate detection of IBD, an upstream step in applications of IBD for population genetics and trait mapping.
Causes and consequences of facultative sea crossing in a soaring migrant
Authors: Becciu Paolo , Rotics Shay , Horvitz Nir , Kaatz Michael , Fiedler Wolfgang , Zurell Damaris , Flack Andrea , Jeltsch Florian , Wikelski Martin , Nathan Ran , Sapir Nir
Published: September 2019

Studying the causes and consequences of route selection in animal migration is important for understanding the evolution of migratory systems and how they may be affected by environmental factors at various spatial and temporal scales. One key decision during migration is whether to cross “high transport cost” areas, or to circumvent them. Soaring birds may face this choice when encountering waterbodies where convective updrafts are weak or scarce. Crossing these waterbodies requires flying using energetically costly flapping flight, while circumventing them over land permits energetically cheap soaring.

We tested how several atmospheric factors (e.g., wind, thermal uplift) and geographic, seasonal and state-related factors (sex and age) affected route selection in migrating white storks (Ciconia ciconia). We used 196 GPS tracks of 70 individuals either crossing or circumventing the north-easternmost section of the Mediterranean Sea, over Iskenderun Bay in southern Turkey.

We found that westward and southward winds promoted a cross-bay journey in spring and autumn, respectively, acting as tailwinds. Also, overall weaker winds promoted a sea crossing in spring. Sea crossing was associated with flapping flight and higher values of Overall Dynamic Body Acceleration (ODBA) and resulted in higher ground speed than travel over land.

The combined environmental conditions and the effects of route selection on movement-related energy costs and speed were likely responsible for an increase in the time spent flying and distance travelled of migrating storks that decided to cross the bay during spring. Notably, daily travel distances of spring migrants crossing the bay were 60 kilometres longer than those of land-detouring birds, allowing them to reach their destination faster but likely incurring a higher energetic flight cost. No such benefit was found during autumn.

Our findings confirm that atmospheric conditions can strongly affect bird route selection. Consequently, migration timing, speed and movement-related energy expenditure differed considerably between the two migratory seasons and the two route choices, highlighting a time-energy trade-off in the migration of white storks.
Alpha Activity Reflects the Magnitude of an Individual Bias in Human Perception
Authors: Grabot Laetitia , Kayser Christoph
Published: September 2019

Biases in sensory perception can arise from both experimental manipulations and personal trait-like features. These idiosyncratic biases and their neural underpinnings are often overlooked in studies on the physiology underlying perception. A potential candidate mechanism reflecting such idiosyncratic biases could be spontaneous alpha band activity, a prominent brain rhythm known to influence perceptual reports in general. Using a temporal order judgement task, we here tested the hypothesis that alpha power reflects the overcoming of an idiosyncratic bias. Importantly, to understand the interplay between idiosyncratic biases and contextual (temporary) biases induced by experimental manipulations, we quantified this relation before and after temporal recalibration. Using EEG recordings in human participants (male and female), we find that pre-stimulus frontal alpha power correlates with the tendency to respond relative to an own idiosyncratic bias, with stronger alpha leading to responses matching the bias. In contrast, alpha power does not predict response correctness. These results also hold after temporal recalibration and are specific to the alpha band, suggesting that alpha band activity reflects, directly or indirectly, processes that help to overcome an individual’s momentary bias in perception. We propose that combined with established roles of parietal alpha in the encoding of sensory information frontal alpha reflects complementary mechanisms influencing perceptual decisions.

Significance statement

The brain is a biased organ, frequently generating systematically distorted percepts of the world, leading each of us to evolve in our own subjective reality. However, such biases are often overlooked or considered noise when studying the neural mechanisms underlying perception. We show that spontaneous alpha band activity predicts the degree of biasedness of human choices in a time perception task, suggesting that alpha activity indexes processes needed to overcome an individual’s idiosyncratic bias. This result provides a window onto the neural underpinnings of subjective perception, and offers the possibility to quantify or manipulate such priors in future studies.
Density dependence on multiple spatial scales maintains spatial variation in both abundance and traits
Authors: van Benthem Koen J. , Wittmann Meike J.
Published: September 2019

Population density affects fitness through various processes, such as mate finding and competition. The fitness of individuals in a population can in turn affect its density, making population density a key quantity linking ecological and evolutionary processes. Density effects are, however, rarely homogeneous. Different life-history processes can be affected by density over different spatial scales. In birds, for example, competition for food may depend on the number of birds nesting in the direct vicinity, while competition for nesting sites may occur over larger areas. Here we investigate how the effects of local density and of density in nearby patches can jointly affect the emergence of spatial variation in abundance as well as phenotypic diversification. We study a two-patch model that is described by coupled ordinary differential equations. The patches have no intrinsic differences: they both have the same fitness function that describes how an individual’s fitness depends on density in its own patch as well as the density in the other patch. We use a phase-space analysis, combined with a mathematical stability analysis to study the long-term behaviour of the system. Our results reveal that the mutual effect that the patches have on each other can lead to the emergence and long-term maintenance of a low and a high density patch. We then add traits and mutations to the model and show that different selection pressures in the high and low density patch can lead to diversification between these patches. Via eco-evolutionary feedbacks, this diversification can in turn lead to changes in the long-term population densities: under some parameter settings, both patches reach the same equilibrium density when mutations are absent, but different equilibrium densities when mutations are allowed. We thus show how, even in the absence of differences between patches, interactions between them can lead to differences in long-term population density, and potentially to trait diversification.
Mechanisms of distributed working memory in a large-scale network of macaque neocortex
Authors: Mejias Jorge F. , Wang Xiao-Jing
Published: September 2019

To elucidate the circuit mechanism of persistent neural activity underlying working memory that is distributed across multiple brain regions, we developed an anatomically constrained computational model of large-scale macaque cortex. We found that persistent activity may emerge from inter-areal reverberation, even in a regime where none of the isolated areas is capable of generating persistent activity. The persistent activity pattern along the cortical hierarchy indicates a robust bifurcation in space, characterized by a few association areas near dynamical criticality. A host of spatially distinct attractor states is found, potentially subserving various internal processes. The model yields testable predictions including the idea of counterstream inhibitory bias, and suggests experiments to differentiate local versus distributed mechanisms. Simulated lesion or optogenetic inactivation revealed that distributed activity patterns are resilient while dependent on a structural core. This work provides a theoretical framework for identifying large-scale brain mechanisms and computational principles of distributed cognitive processes.
Benchmarking analysis of deleterious SNP prediction tools on CYP2D6 enzyme
Authors: do Vale Ferreira Karla Cristina , Fialho Leonardo Ferreira , Franco Octávio Luiz , de Alencar Sérgio Amorim , Porto William Farias
Published: September 2019

The cytochrome P450 family is composed of hemeproteins involved in the metabolic transformation of endogenous and exogenous substances. The CYP2D6 enzyme is responsible for the metabolism of approximately 25% of clinically used drugs and is mainly expressed in the liver. The CYP2D6 gene is known to have a large number of Single Nucleotide Polymorphisms (SNPs) and the majority of them do not present clinical consequences. Nevertheless, these variations could modify the CYP2D6 enzyme’s function, resulting in poor metabolizing or ultra-extensive metabolizing phenotypes, when metabolism is slower or accelerated, respectively. Currently, there are several computational tools for predicting functional changes caused by genetic variations. Here, using 20 web servers, we evaluated the impact of 21 missense SNPs (6 neutral and 15 deleterious) previously validated by the literature. Only seven predictors presented sensitivity higher than 70%, while four showed specificity higher than 70% and only one reached the Matthews correlation coefficient of 0.39. Combinations of tools with greater sensitivity and specificity were made to improve the Matthews correlation coefficient, which increased the coefficient of five tools (Provean, FatHMM, SDM, PoPMuSiC and HotMuSiC). The results suggest that the most appropriate tool for CYP2D6 SNP prediction is FATHMM, which could aid in the classification of novel missense SNPs in this gene, providing the identification of mutations potentially associated with drug metabolism.
Mechanical and molecular parameters that influence the tendon differentiation potential of C3H10T1/2 cells in 2D- and 3D-culture systems
Authors: Gaut Ludovic , Bonnin Marie-Ange , Cacciapuoti Isabelle , Orpel Monika , Mericskay Mathias , Duprez Delphine
Published: September 2019

One of the main challenges in tendon field relies in the understanding of regulators of the tendon differentiation program. The optimum culture conditions that favor tendon cell differentiation are not identified. Mesenchymal stem cells present the ability to differentiate into multiple lineages in cultures under different cues ranging from chemical treatment to physical constraints. We analyzed the tendon differentiation potential of C3H10T1/2 cells, a murine cell line of mesenchymal stem cells, upon different 2D- and 3D-culture conditions. We observed that C3H10T1/2 cells cultured in 2D conditions on silicone substrate were more prone to tendon differentiation assessed with the expression of the tendon markersScx, Col1a1andTnmdas compared to cells cultured on plastic substrate. 3D fibrin environment was more favorable forScxandCol1a1expression compared to 2D-cultures. We also identified TGFβ2 as a negative regulator ofTnmdexpression in C3H10T1/2 cells in 2D- and 3D-cultures. Altogether, our results provide us with a better understanding of the culture conditions that promote tendon gene expression and identify mechanical and molecular parameters on which we could play to define the optimum culture conditions that favor tenogenic differentiation in mesenchymal stem cells.
Rest functional brain maturation during the first year of life
Authors: Lemaître Hervé , Augé Pierre , Saitovitch Ana , Vinçon-Leite Alice , Tacchella Jean-Marc , Fillon Ludovic , Calmon Raphael , Dangouloff-Ros Volodia , Lévy Raphaël , Grévent David , Brunelle Francis , Boddaert Nathalie , Zilbovicius Monica
Published: September 2019

The first year of life is a key period of brain development, characterized by dramatic structural and functional modifications. Here, we measured rest cerebral blood flow (CBF) modifications throughout babies’ first year of life using arterial spin labeling magnetic resonance imaging sequence in 52 infants, from 3 to 12 months of age. Overall, global rest CBF significantly increased during this age span. In addition, we found marked regional differences in local functional brain maturation. While primary sensorimotor cortices and insula showed early maturation, temporal and prefrontal region presented great rest CBF increase across the first year of life. Moreover, we highlighted a late and remarkably synchronous maturation of the prefrontal and posterior superior temporal cortices. These different patterns of regional cortical rest CBF modifications reflect a timetable of local functional brain maturation and are consistent with baby’s cognitive development within the first year of life.
Maternal care of heterozygous Dopamine Receptor D4 knockout mice: Differential susceptibility to early-life rearing conditions
Authors: Knop Jelle , van IJzendoorn Marinus H. , Bakermans-Kranenburg Marian J. , Joëls Marian , van der Veen Rixt
Published: September 2019

The differential susceptibility hypothesis proposes that individuals who are more susceptible to the negative effects of adverse rearing conditions may also benefit more from enriched environments. Evidence derived from human experiments suggests the lower efficacy dopamine receptor D4 (DRD4) 7-repeat as a main factor in exhibiting these for better and for worse characteristics. However, human studies lack the genetic and environmental control offered by animal experiments, complicating assessment of causal relations. To study differential susceptibility in an animal model, we exposed Drd4+/- mice and control litter mates to a limited nesting/bedding (LN), standard nesting (SN) or communal nesting (CN) rearing environment from postnatal day (P) 2-14. Puberty onset was examined from P24-P36 and adult females were assessed on maternal care towards their own offspring. In both males and females, LN reared mice showed a delay in puberty onset that was partly mediated by a reduction in body weight at weaning, irrespective of Drd4 genotype. During adulthood, LN reared females exhibited characteristics of poor maternal care, whereas dams reared in CN environments showed lower rates of unpredictability towards their own offspring. Differential susceptibility was observed only for licking/grooming levels of female offspring towards their litter; LN reared Drd4+/- mice exhibited the lowest and CN reared Drd4+/- mice the highest levels of licking/grooming. These results indicate that both genetic and early-environmental factors play an important role in shaping maternal care of the offspring for better and for worse.
Enhancement of drought tolerance on guinea grass by dry alginate macrobeads as inoculant of Bacillus strains
Authors: Mendoza-Labrador Jonathan , Romero-Perdomo Felipe , Hernández Juan-Pablo , Uribe Daniel , Buitrago Ruth Bonilla
Published: September 2019

Drought is responsible for almost 70% of total crop damage in tropical and subtropical countries. In the Colombian Caribbean, drought has caused low availability of Guinea grass (Megathyrsus maximus) in forage amount and quality, generating increase in production costs in livestock systems. In this study, we aimed at designing and evaluating dry macro-polymeric inoculants of Bacillus strains and used them successfully to mitigate drought effect on Guinea grass (M. maximus). We chose Bacillus sp XT13 and Bacillus megaterium XT14 strains, previously selected for their capacity to mitigate drought stress on Guinea grass. For the inoculant formulation process, a concentration of 3.2% alginate was used for both microorganisms, selecting the polymer-bacterium ratio of 70:30 for XT13 and 80:20 for XT14. The results of the experiments in greenhouse showed that drought had a negative effect on Guinea grass growth, but the PGPB application with or without macro-polymeric dry matrix improved plant growth significantly. We also observed that co-inoculation of the strains generated a greater beneficial effect than individual inoculation. Interestingly, co-inoculation of XT13 and XT14 under the dry macro-polymeric formulation increased biomass production of the aerial part (7.32%), root biomass, (25.3%), nutritional quality parameters, such as digestibility (3.32%), protein (20.3%); proline accumulation increased (21.06%) and both neutral digestible fiber (2.43%) and APX antioxidant activity (24.2%) decreased with respect to co-inoculation of both bacteria without formulation. These findings have shown that dry macrobeads immobilization has a significantly positive influence on the capacity of XT13 and XT14 bacterial strains to induce drought stress tolerance in Guinea grass.
KDML: a machine-learning framework for inference of multi-scale gene functions from genetic perturbation screens
Authors: Sailem Heba Z. , Rittscher Jens , Pelkmans Lucas
Published: September 2019

Characterising context-dependent gene functions is crucial for understanding the genetic bases of health and disease. To date, inference of gene functions from large-scale genetic perturbation screens is based on ad-hoc analysis pipelines involving unsupervised clustering and functional enrichment. We present Knowledge-Driven Machine Learning (KDML), a framework that systematically predicts multiple functions for a given gene based on the similarity of its perturbation phenotype to those with known function. As proof of concept, we test KDML on three datasets describing phenotypes at the molecular, cellular and population levels, and show that it outperforms traditional analysis pipelines. In particular, KDML identified an abnormal multicellular organisation phenotype associated with the depletion of olfactory receptors and TGFβ and WNT signalling genes in colorectal cancer cells. We validate these predictions in colorectal cancer patients and show that olfactory receptors expression is predictive of worse patient outcome. These results highlight KDML as a systematic framework for discovering novel scale-crossing and clinically relevant gene functions. KDML is highly generalizable and applicable to various large-scale genetic perturbation screens.
Selfing Maintains Flower Colour Polymorphism inL. arvensisDespite High Inbreeding Depression
Authors: Jiménez-López Francisco Javier , Ortiz Pedro Luis , Talavera María , Arista Montserrat
Published: September 2019

Flower colour polymorphism (FCP) is frequently associated with differences in pollinator attraction. FCP maintenance is intriguing, as positive directional selection by pollinators should result in the loss of polymorphism. Autonomous selfing could confer reproductive assurance when pollen is limited, and could be a mechanism for maintaining polymorphism unless inbreeding depression is high. We study the role of selfing in maintaining FCP inLysimachia arvensis, a species with blue and red morphs co-occurring in Mediterranean populations, where pollinators negatively select for the red morph. We experimentally assessed inbreeding depression in both morphs in two Mediterranean populations and genetic diversity was studied via AFLP and SSR microsatellites in 20 populations. Between-morph genetic differentiation was high and the red morph had a lower genetic diversity, mainly in the Mediterranean. Results also show strong phenological differences between selfed and outcrossed progeny, and a high ID of the red morph. The low genetic diversity of the red morph is in concordance with a reproductive system based predominantly on selfing. However, ID suggests a limited capacity for red morph recruitment, according to its low frequency in polymorphic populations. Genetic differentiation between morphs indicates a low gene flow between them, opening the possibility of reproductive isolation and speciation inLysimachia arvensis.
Interrogation of Enhancer Function by Enhanced CRISPR Epigenetic Editing
Authors: Li Kailong , Liu Yuxuan , Cao Hui , Zhang Yuannyu , Gu Zhimin , Liu Xin , Yu Andy , Kaphle Pranita , Dickerson Kathryn E. , Ni Min , Xu Jian
Published: September 2019

Tissue-specific gene expression requires coordinated control of gene-proximal and -distalcis-regulatory elements (CREs), yet functional analysis of gene-distal CREs such as enhancers remains challenging. Here we describe enhanced CRISPR/dCas9-based epigenetic editing systems, enCRISPRa and enCRISPRi, for multiplexed analysis of enhancer functionin situandin vivo. Using dual effectors capable of re-writing enhancer-associated chromatin modifications, we show that enCRISPRa and enCRISPRi modulate gene transcription by remodeling local epigenetic landscapes at sgRNA-targeted enhancers and associated genes. Comparing with existing methods, the new systems display more robust perturbation of enhancer activity and gene transcription with minimal off-targets. Allele-specific targeting of enCRISPRa to oncogenicTAL1super-enhancer modulatesTAL1expression and cancer progression in xenotransplants. Multiplexed perturbations of lineage-specific enhancers using an enCRISPRi knock-in mouse establishin vivoevidence for lineage-restricted essentiality of developmental enhancers during hematopoietic lineage specification. Hence, enhanced CRSIPR epigenetic editing provides opportunities for interrogating enhancer function in native biological contexts.