bluuebunny/crossref_metadata_2025 huggingface dataset:
Anterolateral entorhinal cortex thickness as a new biomarker for early detection of Alzheimer’s disease
Authors: Holbrook Andrew , Tustison Nicholas , Marquez Freddie , Roberts Jared , Yassa Michael A. , Gillen Daniel ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2019

Introduction

Loss of entorhinal cortex (EC) layer II neurons represents the earliest AD lesion in the brain. Research suggests differing functional roles between two EC subregions, the anterolateral EC (aLEC) and the posteromedial EC (pMEC).

Methods

We use joint label fusion to obtain aLEC and pMEC cortical thickness measurements from serial MRI scans of 775 ADNI-1 participants (219 healthy; 380 MCI; 176 AD) and use linear mixed-effects models to analyze longitudinal associations between cortical thickness, disease status and cognitive measures.

Results

Group status is reliability predicted by aLEC thickness, which also exhibits greater associations with cognitive outcomes than does pMEC thickness. Change in aLEC thickness is also associated with CSF amyloid and tau levels.

Discussion

Thinning of aLEC is a sensitive structural biomarker that changes over short durations in the course of AD and tracks disease severity – it is a strong candidate biomarker for detection of early AD.
Posttraumatic stress disorder is associated with alpha dysrhythmia across the visual cortex and the default mode network
Authors: Clancy Kevin J. , Andrzejewski Jeremy A. , Ding Mingzhou , Schmidt Norman B. , Li Wen
Published: November 2019

Background

Anomalies in default mode network (DMN) activity and alpha (8-12 Hz) oscillations have been independently observed in posttraumatic stress disorder (PTSD). Recent spatiotemporal analyses suggest that alpha oscillations support DMN functioning via inter-regional synchronization and sensory cortical inhibition. Therefore, we examined a unifying pathology of alpha deficits in the visual-cortex-DMN system in PTSD.

Methods

Patients with PTSD (N= 25) and two control groups—patients with Generalized Anxiety Disorder (N= 24) and healthy controls (N= 20)—underwent a standard eyes-open resting state (S-RS) and a modified resting state (M-RS) of passively viewing salient images (known to deactivate the DMN). High-density electroencephalogram (hdEEG) were recorded, from which intracortical alpha activity (power and connectivity/Granger causality) was extracted using the exact low-resolution electromagnetic tomography (eLORETA).

Results

Patients with PTSD (vs. controls) demonstrated attenuated alpha power in the visual cortex and key hubs of the DMN (posterior cingulate cortex/PCC and medial prefrontal cortex/mPFC) at both states, the severity of which further correlated with hypervigilance symptoms. With increased visual input (at M-RS vs. S-RS), patients with PTSD further demonstrated reduced alpha-frequency directed connectivity within the DMN (PCC→mPFC) and, importantly, from the visual cortex (VC) to both DMN hubs (VC→PCC and VC→mPFC), linking alpha deficits in the two systems.

Conclusions

These interrelated alpha deficits align with DMN hypoactivity/hypoconnectivity, sensory disinhibition, and hypervigilance in PTSD, representing a unifying neural underpinning of these anomalies. The identification of visual-cortex-DMN alpha dysrhythmia in PTSD further presents a novel therapeutic target, promoting network-based intervention of neural oscillations.
A wealth of opportunities: an ethnographic study on learning to deliver high-value, cost-conscious care
Authors: Stammen Lorette A. , Janssen Linda M.E. , Bressers Guusje , Driessen Erik W. , Stassen Laurents P.S. , Stalmeijer Renée E. , Scheele Fedde
Published: November 2019

Objective

Since physicians’ behaviour determines up to 80% of total healthcare expenditures, training residents to deliver high-value, cost-conscious care is essential. Residents acknowledge the importance of high-value, cost-conscious care-delivery, yet perceive training to be insufficient. We designed an observational study to gain insight into how the workplace setting relates to residents’ high-value, cost-conscious care-delivery.

Design

This ethnographic study builds on 175 hours of non-participant observations including informal interviews, 9 semi-structured interviews and document analysis.

Setting

Department of obstetrics and gynaecology in an academic hospital in the Netherlands. Population or sample: 21 gynaecology residents.

Methods

Iterative analysis process of fieldnotes, interview transcripts and documents, including open-coding, thematic analysis and axial analysis by a multidisciplinary research team.

Results

Residents rarely consider health care costs, and knowledge regarding costs is often absent. Senior consultants guide residents while balancing benefits, risks and costs, with or without explicating their decision-making process. Identified learning opportunities are elaboration on questions raised concerning high-value, cost-conscious care, checking information about costs that are used in discussions about high-value, cost-conscious care, and having a more open and explicit discussion about high-value, cost-conscious care.

Conclusion

Our study emphasizes that the opportunities and potential to train residents to deliver high-value, cost-conscious care in the workplace are present. The challenge resides in capitalizing on these opportunities. We suggest departments to consult external experts to facilitate discussions regarding high-value, cost-conscious care to contribute to informal learning and to create a workplace setting in which high-value, cost-conscious care-delivery is prioritized.

Funding

none
The prevalence of hepatitis C virus (HCV) infection in β-thalassemia patients in Pakistan: a systematic review and meta-analysis
Authors: Akhtar Sohail , Nasir Jamal Abdul , Shah Farrukh , Hinde Andrew
Published: November 2019

Objective

Hepatitis C virus (HCV) infection is the most commonly reported bloodborne infection in Pakistan. Frequent blood transfusions in β-thalassemia patients expose them to a high risk of HCV infection. The purpose of this paper is to summarize the current data on the prevalence of HCV infection among β-thalassemia patients in Pakistan by using a systematic review and meta–analysis.

Design

Systematic review and meta-analysis.

Participants

β-thalassemia patients in Pakistan.

Data sources

Following PRISMA guidelines, a comprehensive literature search in PubMed/MEDLINE and EMBASE was performed to identify published articles reporting on the prevalence of HCV among β-thalassemia patients in Pakistan. Only English language articles were considered. Two independent authors selected studies. The methodological quality of the included studies was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies.

Results

The search conceded a total of 138 studies, of which 27 studies were finally considered for meta-analysis. The pooled prevalence of HCV in β-thalassemia patients in Pakistan was 36.21% (95% CI: 28.98– 43.75%) based on 5,789 β-thalassemia patients, but there was considerable heterogeneity. Meta-analysis estimated the HCV prevalence among the β-thalassemia patients at 45.98 % (95% CI: 38.15–53.90%) in Punjab, 31.81% (95% CI: 20.27–44.59%) in Sindh, and 28.04% (95% CI: 13.58–45.26%) in Khyber Pakhtunkhwa. Meta–regression analysis showed that geographical location was a key source of heterogeneity.

Conclusions

The pooled prevalence of hepatitis C virus among β-thalassemia patients in Pakistan was 36.21%, but varies regionally within the country. The prevalence is higher than in neighboring countries. With the use of standard prevention procedures during blood transfusion, the risk of HCV transmission among β-thalassemia patients could be controlled hence prevalence of HCV in β-thalassemia patients could be reduced.

Strengths and limitations of this study

➢

This is the first systematic review and meta-analysis to estimate the pooled prevalence of HCV infection among the β-thalassemia patients in Pakistan

➢

We used of an extensive search strategy and adherence to predetermined inclusion and exclusion criteria.

➢

Strong and reliable methodological and statistical methods were used.

➢

Our analyses possessed a considerable amount of quantifiable heterogeneity.

➢

Not all regions in Pakistan were represented and most of the included studies were hospital-based, making it difficult to generalize the findings of this review.
Genetic variation near CXCL12 is associated with susceptibility to HIV-related non-Hodgkin lymphoma
Authors: Thorball Christian W. , Oudot-Mellakh Tiphaine , Hammer Christian , Santoni Federico A. , Niay Jonathan , Costagliola Dominique , Goujard Cécile , Meyer Laurence , Wang Sophia S. , Hussain Shehnaz K. , Theodorou Ioannis , Cavassini Matthias , Rauch Andri , Battegay Manuel , Hoffmann Matthias , Schmid Patrick , Bernasconi Enos , Günthard Huldrych F. , McLaren Paul J. , Rabkin Charles S. , Besson Caroline , Fellay Jacques
Published: November 2019

Human immunodeficiency virus (HIV) infection is associated with a substantially increased risk of non-Hodgkin lymphoma (NHL). High plasma viral load, low CD4+ T cell counts and absence of antiretroviral treatment (ART) are known predictive factors for NHL. Even in the era of suppressive ART, HIV-infected individuals remain at increased risk of developing NHL compared to the general population. To search for human genetic determinants of HIV-associated NHL, we performed case-control genome-wide association studies (GWAS) in three cohorts of HIV+ patients of European ancestry and meta-analyzed the results. In total, 278 cases and 1924 matched controls were included. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11). The G>A polymorphism creates a new transcription factor binding site for BATF and JUND. Analyses of topologically associating domains and promoter capture Hi-C data revealed significant interactions between the rs7919208 region and the promoter of CXCL12, also known as stromal-derived factor 1 (SDF-1). These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.
Mitochondrial DNA copy number and incident heart failure: The Atherosclerosis Risk in Communities (ARIC) study
Authors: Hong Yun Soo , Longchamps Ryan J. , Zhao Di , Castellani Christina A. , Loehr Laura R. , Chang Patricia P. , Matsushita Kunihiro , Grove Megan L. , Boerwinkle Eric , Arking Dan E. , Guallar Eliseo
Published: November 2019

Background

The association between mitochondrial DNA-copy number (mtDNA-CN) and incident heart failure (HF) in the general population is unclear.

Methods

We examined the association between mtDNA-CN and the risk of incident HF among 10,802 participants free of HF at baseline from the Atherosclerosis Risk in Communities (ARIC) study, a large bi-racial population-based cohort. mtDNA-CN was estimated using probe intensities on the Affymetrix Genome-Wide Human single nucleotide polymorphisms Array 6.0. Incident HF events were identified through hospital discharge codes from 1987 until 2005 and through adjudication by the ARIC HF Classification Committee since 2005.

Results

During a median follow-up of 23.1 years, there were 2,227 incident HF events (incidence rate 10.3 per 1000 person-years). In fully adjusted models, the hazard ratios (95% confidence intervals) for HF comparing the 2nd through 5th quintiles of mtDNA-CN to the 1st quintile were 0.91 (0.80–1.04), 0.82 (0.72–0.93), 0.81 (0.71–0.92), and 0.74 (0.65–0.85), respectively (P for trend < 0.001). In stratified analyses, the associations between mtDNA-CN and HF were similar across examined subgroups. The inverse association between mtDNA-CN and incident HF was stronger in HF with reduced ejection fraction (HFrEF) than in HF with preserved ejection fraction (HFpEF).

Conclusions

In this prospective cohort, mtDNA-CN was inversely associated with the risk of incident HF suggesting that reduced levels of mtDNA-CN, a biomarker of mitochondrial dysfunction, could reflect early susceptibility to HF.
Genome-wide association study of Buruli ulcer in rural Benin
Authors: Manry Jeremy , Vincent Quentin B. , Chrabieh Maya , Lorenzo Lazaro , Theodorou Ioannis , Ardant Marie-Françoise , Johnson Christian , Marion Estelle , Chauty Annick , Marsollier Laurent , Abel Laurent , Alcaïs Alexandre
Published: November 2019

Buruli ulcer, caused by Mycobacterium ulcerans, is the third mycobacterial disease worldwide characterized by devastating necrotizing skin lesions. The role of host genetics in susceptibility to Buruli ulcer has long been suggested. We conduct the first genome-wide association study of Buruli ulcer on a combined sample of 1,524 well characterized patients and controls from rural Benin. Two-stage analyses identify two novel associated loci located within lincRNA genes: rs9814705 in ENSG00000240095.1 (P = 2.85×10−7; odds ratio = 1.80 [1.43-2.27]), and rs76647377 in LINC01622 (P = 9.85×10−8; hazard ratio = 0.41 [0.28-0.60]). Furthermore, we replicate the protective effect of allele G of a missense variant located in ATG16L1, and previously shown to decrease bacterial autophagy (rs2241880, P = 0.003; odds ratio = 0.31 [0.14-0.68]). Our results suggest lincRNAs and the autophagy pathway as critical factors in the development of Buruli ulcer.
A Query Taxonomy Describes Performance of Patient-Level Retrieval from Electronic Health Record Data
Authors: Chamberlin Steven R. , Bedrick Steven D. , Cohen Aaron M. , Wang Yanshan , Wen Andrew , Liu Sijia , Liu Hongfang , Hersh William R.
Published: November 2019

Performance of systems used for patient cohort identification with electronic health record (EHR) data is not well-characterized. The objective of this research was to evaluate factors that might affect information retrieval (IR) methods and to investigate the interplay between commonly used IR approaches and the characteristics of the cohort definition structure.

We used an IR test collection containing 56 test patient cohort definitions, 100,000 patient records originating from an academic medical institution EHR data warehouse, and automated word-base query tasks, varying four parameters. Performance was measured using B-Pref. We then designed 59 taxonomy characteristics to classify the structure of the 56 topics. In addition, six topic complexity measures were derived from these characteristics for further evaluation using a beta regression simulation.

We did not find a strong association between the 59 taxonomy characteristics and patient retrieval performance, but we did find strong performance associations with the six topic complexity measures created from these characteristics, and interactions between these measures and the automated query parameter settings.

Some of the characteristics derived from a query taxonomy could lead to improved selection of approaches based on the structure of the topic of interest. Insights gained here will help guide future work to develop new methods for patient-level cohort discovery with EHR data.
Prevalence and associated occupational factors for low back pain among the bank employees in Dhaka City
Authors: Ali Mohammad , Ahsan Gias U. , Hossain Ahmed
Published: November 2019

Objective

Low Back Pain (LBP) is one of the common health problems among full-time office employees that causes employees absenteeism from work. The purpose of the study is to identify the association between occupational factors and LBP among full-time bank employees in Dhaka City.

Materials and Methods

We conducted a cross-sectional study with 593 full-time bank employees. The one-month complaints of LBP were administered by a musculoskeletal subscale of subjective health complaints by Eriksen et al. A logistic model was performed to identify variables associated with LBP, and a random forest technique was performed to identify the top 5 important variables.

Results

The one-month prevalence for LBP was found 36.6% among the bank employees and the prevalence was high (46.6%) for the 41 to 59-year-old age-group. The multiple logistic regression analysis indicates that age (41-59 years) (OR:2.11, CI=1.21-3.74), obesity (OR:2.06, CI=1.01-4.21) and long working hours (>9 hours) (OR:1.42, CI=1.01-2.0) are positively associated with LBP. Age and length of employment have a positive correlation of 0.87. The random forest technique identifies the top 5 important variables are, age, length of employment, long office hours, presence of chronic illness, and physical activity.

Conclusion

LBP is highly prevalent in full-time bank employees. The occupational factors like length of employment (>10 years) and long working hours (>9 hours) play a significant role in developing LBP among the bank employees. Moreover, the factors like age, chronic illness, obesity and physical activity should be taken into account in the prevention of LBP in bank employees.
Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome
Authors: Crockett Alexis M. , Ryan Sean K. , Vasquez Adriana Hernandez , Canning Caroline , Kanyuch Nickole , Kebir Hania , Ceja Guadalupe , Gesualdi James , Viaene Angela , Kapoor Richa , Benallegue Naïl , Anderson Stewart A. , Alvarez Jorge I.
Published: November 2019

Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia (SZ). As the blood brain barrier (BBB) is the immunological interface between the brain and the periphery, we investigated whether the BBB is intrinsically compromised in the most common genetic risk factor for SZ, the hemizygous deletion of chromosome 22q11.2 (22qDS). BBB-like endothelium (iBBB) differentiated from human 22qDS+SZ-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 (ICAM-1) was upregulated in 22qDS+SZ iBBB and 22qDS mice, indicating compromise of the BBB immune privilege. This immune imbalance resulted in increased migration/activation of leukocytes crossing the 22qDS+SZ iBBB. Finally, we found heightened astrocyte activation in murine and human 22qDS, suggesting that the BBB promotes astrocyte-mediated neuroinflammation. Overall, the barrier-promoting and immune privilege properties of the 22qDS BBB are compromised, and this might increase the risk for neuropsychiatric disease.
Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis
Authors: Magen Iddo , Yacovzada Nancy Sarah , Yanowski Eran , Coenen-Stass Anna , Grosskreutz Julian , Lu Ching-Hua , Greensmith Linda , Malaspina Andrea , Fratta Pietro , Hornstein Eran
Published: November 2019

Amyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative syndrome of the human motor neuron system, for which no effective treatment exists. Variability in the rate of disease progression limits the efficacy of ALS clinical trials, suggesting that developing of better biomarkers for prognosis will facilitate therapeutic progress. Here, we applied unbiased next-generation sequencing to investigate the potential of plasma cell-free microRNAs as biomarkers of ALS prognosis, in 252 patients with detailed clinical-phenotyping. First, we identified miRNAs, whose plasma levels remain stable over the course of disease in a longitudinal cohort of 22 patients. Next, we demonstrated that high levels of miR-181, a miRNA enriched in neurons of the brain and spinal cord, predicts a >2 fold risk of death in discovery cohort (126 patients) and an independent replication cohort (additional 122 patients). miR-181 performance is comparable with the established neurofilament light chain (NfL) biomarker and when combined together, miR-181+NfL establish a novel RNA-protein biomarker pair with superior prediction capacity of ALS prognosis. Therefore, plasma miR-181 predicts ALS disease course, and a novel miRNA-protein biomarker approach, based on miR-181+NfL, boosts precision of patient stratification and may greatly enhance the power of clinical trials.

One Sentence Summary

plasma miR-181 levels indicate high mortality risk in ALS patients.
Quantifying genetic heterogeneity between continental populations for human height and body mass index
Authors: Guo Jing , Bakshi Andrew , Wang Ying , Jiang Longda , Yengo Loic , Goddard Michael E , Visscher Peter M , Yang Jian
Published: November 2019

Genome-wide association studies (GWAS) in samples of European ancestry have identified thousands of genetic variants associated with complex traits in humans. However, it remains largely unclear whether these associations can be used in non-European populations. Here, we seek to quantify the proportion of genetic variation for a complex trait shared between continental populations. We estimated the between-population correlation of genetic effects at all SNPs (rg) or genome-wide significant SNPs (rg(GWS)) for height and body mass index (BMI) in samples of European (EUR;n= 49,839) and African (AFR;n= 17,426) ancestry. Thebetween EUR and AFR was 0.75 (s. e. = 0.035) for height and 0.68 (s. e. = 0.062) for BMI, and the correspondingwas 0.82 (s. e. = 0.030) for height and 0.87 (s. e. = 0.064) for BMI, suggesting that a large proportion of GWAS findings discovered in Europeans are likely applicable to non-Europeans for height and BMI. There was no evidence thatdiffers in SNP groups with different levels of between-population difference in allele frequency or linkage disequilibrium, which, however, can be due to the lack of power.
Meaning maps and saliency models based on deep convolutional neural networks are insensitive to image meaning when predicting human fixations
Authors: Pedziwiatr Marek A. , Kümmerer Matthias , Wallis Thomas S.A. , Bethge Matthias , Teufel Christoph
Published: November 2019

Eye movements are vital for human vision, and it is therefore important to understand how observers decide where to look. Meaning maps (MMs), a technique to capture the distribution of semantic importance across an image, have recently been proposed to support the hypothesis that meaning rather than image features guide human gaze. MMs have the potential to be an important tool far beyond eye-movements research. Here, we examine central assumptions underlying MMs. First, we compared the performance of MMs in predicting fixations to saliency models, showing that DeepGaze II – a deep neural network trained to predict fixations based on high-level features rather than meaning – outperforms MMs. Second, we show that whereas human observers respond to changes in meaning induced by manipulating object-context relationships, MMs and DeepGaze II do not. Together, these findings challenge central assumptions underlying the use of MMs to measure the distribution of meaning in images.
Remodeling of Crossbridges Controls Peptidoglycan Cross-linking Levels in Bacterial Cell Walls
Authors: Pidgeon Sean E. , Apostolos Alexis J. , Pires Marcos M.
Published: November 2019

Cell walls are barriers found in almost all known bacterial cells. These structures establish a controlled interface between the external environment and vital cellular components. A primary component of cell wall is a highly crosslinked matrix called peptidoglycan (PG). PG crosslinking, carried out by transglycosylases and transpeptidases, is necessary for proper cell wall assembly. Transpeptidases, targets of β-lactam antibiotics, stitch together two neighboring PG stem peptides (acyl-donor and acyl-acceptor strands). We recently described a novel class of cellular PG probes that were processed exclusively as acyl-donor strands. Herein, we have accessed the other half of the transpeptidase reaction by developing probes that are processed exclusively as acyl-acceptor strands. The critical nature of the crossbridge on the PG peptide was demonstrated in live bacterial cells and surprising promiscuity in crossbridge primary sequence was found in various bacterial species. Additionally, acyl-acceptor probes provided insight into how chemical remodeling of the PG crossbridge (e.g., amidation) can modulate crosslinking levels, thus establishing a physiological role of PG structural variations. Together, the acyl-donor and -acceptor probes will provide a versatile platform to interrogate PG crosslinking in physiologically relevant settings.

SYNOPSIS TOC
Whole-transcriptome RNA editing analysis in single cortical neurons links locus 15q11 with psychiatric illness
Authors: Ansell Brendan Robert E. , Thomas Simon N. , Bonelli Roberto , Munro Jacob E. , Freytag Saskia , Bahlo Melanie
Published: November 2019

BACKGROUND

Conversion of adenosine to inosine in RNA by ADAR enzymes occurs at thousands of sites in the human transcriptome, and is essential for healthy brain development. This ‘RNA editing’ process is dysregulated in many neuropsychiatric diseases, but is little understood at the level of individual neurons.

METHODS

We quantified RNA editing sites in full-length capture nuclear transcriptomes of 3055 neurons from six cortical regions of a neurotypical post-mortem female donor. Putative editing sites were intersected with sites in bulk human tissue transcriptomes including healthy and neuropsychiatric brain tissue, and sites identified in single nuclei from unrelated brain donors. Differential editing between cell types and cortical regions, and individual sites and genes therein, was quantified using linear models. Associations between gene expression and editing were also tested.

RESULTS

We identified 41,930 RNA editing sites with robust read coverage in at least ten neuronal nuclei. Most sites were located within Alu repeats in introns or 3’ UTRs, and approximately 80% were catalogued in published RNA editing databases. We identified 9285 putative novel RNA editing sites, 29% of which were also detectable neuronal transcriptomes from unrelated donors. Inhibitory neurons showed higher overall transcriptome editing than excitatory neurons. Among the strongest correlates of global editing rates were snoRNAs from the SNORD115 and SNORD116 cluster (15q11), known to modulate serotonin receptor processing and to colocalize with ADAR2. We identified 29 genes preferentially edited in excitatory neurons and 44 genes edited more heavily in inhibitory neurons including RBFOX1, its target genes and small nucleolar RNA-associated genes in the autism-associated Prader-Willi locus 15q11. These results provide cell-type and spatial context for 1730 and 910 sites that are also edited in the brains of schizophrenic and autistic patients respectively, and a reference for future studies of RNA editing in single brain cells from these cohorts.

CONCLUSIONS

RNA editing, including thousands of previously unreported sites, is robustly detectable in single neuronal nuclei, where gene editing differences are stronger between cell subtypes than between cortical regions. Insufficient editing of ASD-related genes in inhibitory neurons may manifest in the specific perturbation of these cells in autism.
Spike afterpotentials shape the in-vivo burst activity of principal cells in medial entorhinal cortex
Authors: Csordás Dóra É. , Fischer Caroline , Nagele Johannes , Stemmler Martin , Herz Andreas V.M.
Published: November 2019

Principal neurons in rodent medial entorhinal cortex (MEC) generate high-frequency bursts during natural behavior. While in vitro studies point to potential mechanisms that could support such burst sequences, it remains unclear whether these mechanisms are effective under in-vivo conditions. In this study, we focused on the membrane-potential dynamics immediately following action potentials, as measured in whole-cell recordings from male mice running in virtual corridors (Domnisoru et al., 2013). These afterpotentials consisted either of a hyperpolarization, an extended ramp-like shoulder, or a depolarization reminiscent of depolarizing afterpotentials (DAPs) recorded in vitro in MEC stellate and pyramidal neurons. Next, we correlated the afterpotentials with the cells’ propensity to fire bursts. All DAP cells with known location resided in Layer II, generated bursts, and their inter-spike intervals (ISIs) were typically between five and fifteen milliseconds. The ISI distributions of Layer-II cells without DAPs peaked sharply at around four milliseconds and varied only minimally across that group. This dichotomy in burst behavior is explained by cell-group-specific DAP dynamics. The same two groups of bursting neurons also emerged when we clustered extracellular spike-train autocorrelations measured in real two-dimensional arenas (Latuske et al., 2015). No difference in the spatial coding properties of the grid cells across all three groups was discernible. Layer III neurons were only sparsely bursting and had no DAPs. As various mechanisms for modulating the ion-channels underlying DAPs exist, our results suggest that the temporal features of MEC activity can be altered while maintaining the cells’ spatial tuning characteristics.

Significance Statement

Depolarizing afterpotentials (DAPs) are frequently observed in principal neurons from slice preparations of rodent medial entorhinal cortex (MEC), but their functional role in vivo is unknown. Analyzing whole-cell data from mice running on virtual tracks, we show that DAPs do occur during behavior. Cells with prominent DAPs are found in Layer II; their inter-spike intervals reflect DAP time-scales. In contrast, neither the rarely bursting cells in Layer III, nor the high-frequency bursters in Layer II, have a DAP. Extracellular recordings from mice exploring real two-dimensional arenas demonstrate that grid cells within these three groups have rather similar spatial coding properties. We conclude that DAPs shape the temporal but not the spatial response characteristics of principal neurons in MEC.

Author contributions

All authors designed research. DÉC, CF, and JN performed research and analyzed data (equal contribution). AVMH wrote and edited the paper with support from MS and the other authors.
Moving by thoughts alone? Amount of finger movement and pendulum length determine success in the Chevreul Pendulum Illusion
Authors: Cantergi Debora , Awasthi Bhuvanesh , Friedman Jason
Published: November 2019

Hand-held pendulums can seemingly oscillate on their own, without perceived conscious control. This illusion, named after Chevreul, is likely a result of ideomotor movements. While this phenomenon was originally assumed to have a supernatural basis, it has been accepted for over 150 years that the movements are self-generated. However, until now, recordings of the small movements that create these oscillations has not been performed. In this study, we examined the mechanism that produces these significant involuntary oscillations using a motion capture system. We determined that the Chevreul pendulum illusion is produced when the fingers holding the pendulum generate an oscillating frequency close to the resonant frequency of the pendulum. At an appropriate frequency, very small driving movements of the arm are sufficient to produce relatively large pendulum motion. Further, subjects that tended to move their fingers more were more successful in producing the illusion.
Allosteric Regulation of Vitamin K2 Biosynthesis in a Human Pathogen
Authors: Bashiri Ghader , Nigon Laura V. , Jirgis Ehab N. M. , Ho Ngoc Anh Thu , Stanborough Tamsyn , Dawes Stephanie S. , Baker Edward N. , Bulloch Esther M. M. , Johnston Jodie M.
Published: November 2019

Menaquinone (Vitamin K2) plays a vital role in energy generation and environmental adaptation in many bacteria, includingMycobacterium tuberculosis(Mtb). Although menaquinone levels are known to be tightly linked to the redox/energy status of the cell, the regulatory mechanisms underpinning this phenomenon are unclear. The first committed step in menaquinone biosynthesis is catalyzed by MenD, a thiamine diphosphate-dependent enzyme comprising three domains. Domains I and III form the MenD active site, but no function has yet been ascribed to domain II. Here we show the last cytosolicmetabolite in the menaquinone biosynthesis pathway (1,4-dihydroxy-2-napthoic acid, DHNA) binds to domain II ofMtb-MenD and inhibits enzyme activity. We identified three arginine residues (Arg97, Arg277 and Arg303) that are important for both enzyme activity and the feedback inhibition by DHNA: Arg277 appears to be particularly important for signal propagation from the allosteric site to the active site. This is the first evidence of feedback regulation of the menaquinone biosynthesis pathway in bacteria, unravelling a protein level regulatory mechanism for control of menaquinone levels within the cell.
Nonlinear stimulus representations in neural circuits with approximate excitatory-inhibitory balance
Authors: Baker Cody , Zhu Vicky , Rosenbaum Robert
Published: November 2019

Balanced excitation and inhibition is widely observed in cortical recordings. How does this balance shape neural computations and stimulus representations? This problem is often studied using computational models of neuronal networks in a dynamically balanced state. However, these balanced network models predict a linear relationship between stimuli and population responses, in contrast to the nonlinearity of cortical computations. We show that every balanced network architecture admits some stimuli that break the balanced state and these breaks in balance push the network into a “semi-balanced state” characterized by excess inhibition to some neurons, but an absence of excess excitation. The semi-balanced state is unavoidable in networks driven by multiple stimuli, consistent with experimental data, has a direct mathematical relationship to artificial neural networks, and permits nonlinear stimulus representations and nonlinear computations.
Bacterial glycogen provides short-term benefits in changing environments
Authors: Sekar Karthik , Linker Stephanie M. , Nguyen Jen , Grünhagen Alix , Stocker Roman , Sauer Uwe
Published: November 2019

Changing nutritional conditions challenge microbes and shape their evolutionary optimization. Here we investigated the role of glycogen in dynamic physiological adaptation of Escherichia coli to fluctuating nutrients following carbon starvation using real-time metabolomics. We found significant metabolic activity remaining after the depletion of environmental glucose that was linked to a rapid utilization of intracellular glycogen. Glycogen was depleted by 80% within minutes of glucose starvation and similarly replenished within minutes of glucose availability. These fast timescales of glycogen utilization correspond to the short-term benefits that glycogen provided to cells undergoing various physiological transitions. Cells capable of utilizing glycogen exhibited shorter lag times than glycogen mutants when starved between different carbon sources. The ability to utilize glycogen was also important for the transition between planktonic and biofilm lifestyles and enabled increased glucose uptake during pulses of limited glucose availability. While wild-type and mutant strains exhibited comparable growth rates in steady environments, mutants deficient in glycogen utilization grew more poorly in environments that fluctuated on minute-scales between carbon availability and starvation. Altogether, these results highlight an underappreciated role of glycogen to rapidly provide carbon and energy in changing environments, thereby increasing survival and competition capabilities in fluctuating and nutrient poor conditions.
Early-life gut dysbiosis linked to mass mortality in ostriches
Authors: Videvall Elin , Song Se Jin , Bensch Hanna M. , Strandh Maria , Engelbrecht Anel , Serfontein Naomi , Hellgren Olof , Olivier Adriaan , Cloete Schalk , Knight Rob , Cornwallis Charlie K.
Published: November 2019

Dysbiosis in the vertebrate gut microbiome has been associated with several diseases. However, it is unclear whether particular gut regions or specific time periods during ontogeny are responsible for the development of dysbiosis, especially in non-model organisms. Here we examine the microbiome associated with dysbiosis in different parts of the gastrointestinal tract (ileum, caecum, colon) in a long-lived bird with high juvenile mortality, the ostrich. Individuals that died of gut disease (n=68) had substantially different microbial composition from age-matched controls (n=50) throughout the gut. Several taxa were associated with mortality (Enterobacteriaceae, Peptostreptococcaceae, Porphyromonadaceae,Clostridium) and some with survival (Lachnospiraceae, Ruminococcaceae, Erysipelotrichaceae,Turicibacter). Repeated faecal sampling showed that pathobionts were already present shortly after hatching and proliferated in individuals with low diversity, resulting in mortality weeks later. The factors influencing seeding of the gut microbiota may therefore be key to understanding dysbiosis and host development.
Protein structure featurization via standard image classification neural networks
Authors: Sikosek Tobias
Published: November 2019

Many applications in the biomedical domain involve the detailed molecular and functional characterization of macro-molecules such as proteins. Where possible, this involves the knowledge of detailed 3D coordinates of every atom within a protein. At the same time, machine learning has become the basis of much innovation within this domain in recent years. There are, however, a few challenges in applying machine learning to 3D protein structures, such as variability in size and high dimensionality of the data. It would therefore be beneficial to be able to map every protein structure to a smaller fixed-dimensional representation that is directly learned from the structure without manual curation. In addition, it would be valuable for biomedical researchers if such approaches would require little method development and instead draw from cutting-edge research such as image classification via deep neural networks. Here, such an approach is outlined that first re-formats protein structures as 2D color images and then applies off-the-shelf neural networks for image classification. It is shown that such neural networks can be trained to effectively encode the CATH protein classification database and that feature vectors extracted from such networks, once trained, can be transferred to a completely new task that is likely to benefit from molecular protein information, namely that of small molecule binding.
Effects of an IgE receptor polymorphism acting on immunity, susceptibility to infection and reproduction in a wild rodent
Authors: Wanelik Klara M , Begon Mike , Bradley Janette E , Friberg Ida M , Jackson Joseph A , Taylor Christopher H , Paterson Steve
Published: November 2019

The genotype of an individual is an important predictor of their immune function, and subsequently, their ability to control or avoid infection and ultimately contribute offspring to the next generation. However, the same genotype, subjected to different intrinsic and/or extrinsic environments can also result in different phenotypic outcomes, which can be missed in controlled laboratory studies. Natural wildlife populations, which capture both genotypic and environmental variability, provide an opportunity to more fully understand the phenotypic expression of genetic variation. We identified a synonymous polymorphism in the high-affinity Immunoglobulin E (IgE) receptor (GC and non-GC haplotypes) that has sex-dependent effects on immune gene expression, susceptibility to infection and reproductive success of individuals in a natural population of field voles (Microtus agrestis). We found that the effect of the GC haplotype on the expression of immune genes differed between sexes. While males with the GC haplotype had upregulated more pro-inflammatory genes, including the cytokineIl33, females had upregulated more anti-inflammatory genes, including the cytokine inhibitorSocs3. Furthermore we found an effect of the GC haplotype on the probability of infection with a common microparasite, Babesia microti, in females - with females carrying the GC haplotype being more likely to be infected. Finally, we found an effect of the GC haplotype on reproductive success in males - with males carrying the GC haplotype having a lower reproductive success. This is a rare example of a polymorphism whose consequences we are able to follow across immunity, infection and reproduction for both males and females in a natural population.
Tumor microtubes connect pancreatic cancer cells in an Arp2/3 complex-dependent manner
Authors: Latario Casey J. , Schoenfeld Lori W. , Howarth Charles L. , Pickrell Laura E. , Begum Fatema , Fischer Dawn A. , Grbovic-Huezo Olivera , Leach Steven D. , Sanchez Yolanda , Smith Kerrington D. , Higgs Henry N.
Published: November 2019

Actin-based tubular connections between cells have been observed in many cell types. Termed “tunneling nanotubes (TNTs)”, “membrane nanotubes”, “tumor microtubes (TMTs)”, or “cytonemes”, these protrusions interconnect cells in dynamic networks. Structural features in these protrusions vary between cellular systems, including tubule diameter and presence of microtubules. We find tubular protrusions, which we classify as TMTs, in a pancreatic cancer cell line, DHPC-018. TMTs are present in DHPC-018-derived tumors in mice, as well as in a mouse model of pancreatic cancer and a sub-set of primary human tumors. DHPC-018 TMTs have heterogeneous diameter (0.39 – 5.85 μm, median 1.92 μm) and contain actin filaments, microtubules, and cytokeratin 19-based intermediate filaments. The actin filaments are cortical within the protrusion, as opposed to TNTs, in which filaments run down the center of the tube. TMTs are dynamic in length, but are long-lived (median > 60 min). Inhibition of actin polymerization, but not microtubules, results in TMT loss. A second class of tubular protrusion, which we term cell-substrate protrusion (CSP), has similar width range and cytoskeletal features but make contact with the substratum as opposed to another cell. Similar to previous work on TNTs, we find two assembly mechanisms for TMTs, which we term “pull-away” and “search-and-capture”. Inhibition of the Arp2/3 complex, an actin assembly factor, inhibits TMT assembly by both mechanisms. This work demonstrates that the actin architecture of TMTs is fundamentally different from that of TNTs, as well as demonstrating the role of Arp2/3 complex on TMT assembly.
The nuclear transport receptor TNPO1 binds macrophage immunometabolism regulator MACIR via a PY-NLS motif
Authors: McGauran Gavin , Dorris Emma , Borza Razvan , Morgan Niamh , Shields Denis C. , Matallanas David , Wilson Anthony G. , O’Connell David J.
Published: November 2019

Expression of the macrophage immunometabolism regulator gene (MACIR) is associated with severity of autoimmune disease pathology and the regulation of macrophage biology through unknown mechanisms. The 206 amino acid protein lacks homology to any characterized protein sequence and is a disordered protein according to structure prediction algorithms. Here we identify specific interactions of MACIR using a fragment complementation-based affinity pull down of cellular proteins prepared with a membrane solubilization buffer. Quantitative mass spectrometry showed enrichment of nuclear and mitochondrial proteins and of 63 significant interacting proteins, binding to the nuclear transport receptor TNPO1 and trafficking proteins UNC119 homolog A and B were validated by immunoprecipitation. Analysis of mutations in two candidate recognition motifs in the MACIR amino acid sequence confirmed TNPO1 binds via a PY-NLS motif (aa98-117). Characterizing nuclear MACIR activity in macrophage and fibroblasts is a priority with respect to developing strategies for treatment of autoimmune disease.
Genomic epidemiology of vancomycin resistantEnterococcus faecium(VREfm) in Latin America: Revisiting the global VRE population structure
Authors: Rios Rafael , Reyes Jinnethe , Carvajal Lina P. , Rincon Sandra , Panesso Diana , Planet Paul J. , Echeverri Aura M. , Dinh An , Kolokotronis Sergios-Orestis , Narechania Apurva , Tran Truc T. , Munita Jose M. , Murray Barbara E. , Arias Cesar A. , Diaz Lorena
Published: November 2019

The prevalence of vancomycin-resistantEnterococcus faeciumvaries across geographical regions yet little is known about its population structure in Latin America. Here, we provide a complete genomic characterization of 55 representative Latin American VREfmrecovered from 1998-2015 in 5 countries. We found that VREfmpopulation in the region is structured into two main clinical clades without geographical clustering. To place our regional findings in context, we reconstructed the global population structure of VREfmby including 285 genomes from 36 countries from 1946-2017. Our results differ from previous studies showing an early branching of animal related isolates and a further split of clinical isolates into two sub-clades, all within clade A. The overall phylogenomic structure was highly dependent on recombination (54% of the genome) and the split between clades A and B is estimated to have occurred more than 3585 years BP. Furthermore, while the branching of animal isolates and clinical clades was predicted to have occur ∼894 years BP, our molecular clock calculations suggest that the split within the clinical clade occurred around ∼371 years BP. By including isolates from Latin America, we present novel insights into the population structure of VREfmand revisit the evolution of this pathogen.
Towards a scaled-up T cell-mediated cytotoxicity assay in 3D cell culture using microscopy
Authors: Gottschalk Elinor , Czech Eric , Aksoy Bulent Arman , Aksoy Pinar , Hammerbacher Jeff
Published: November 2019

Three-dimensional (3D) cell culture systems with tumor spheroids are being adopted for research on the antitumor activity of drug treatments and cytotoxic T cells. Analysis of the cytotoxic effect on 3D tumor cultures within a 3D scaffold, such as collagen, is challenging. Image-based approaches often use confocal microscopy, which greatly limits the sample size of tumor spheroids that can be assayed. We explored a system where tumor spheroids growing in a collagen gel within a microfluidics chip can be treated with drugs or co-cultured with T cells. We attempted to adapt the system to measure the death of cells in the tumor spheroids directly in the microfluidics chip via automated widefield fluorescence microscopy. We were able to successfully measure drug-induced cytotoxicity in tumor spheroids, but had difficulties extending the system to measure T cell-mediated tumor killing.

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