bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Celiac Disease in a Long‐term Study of a Spanish At‐genetic‐risk Cohort From the General Population
Authors: Fernández‐Fernández Sonia , Borrell Belén , Cilleruelo María L. , Tabares Ana , Jiménez‐Jiménez Juana , Rayo Ana I. , Perucho Teresa , García‐García Maria L.
Published: November 2018

Objectives:

To perform long‐term celiac disease (CD) screening in an HLA‐DQ2 (+) cohort from the general population and to assess the influence of risk genotypes on its development.

Methods:

In 2004, an HLA‐DQ2 (+) cohort was selected. After the first CD screening at age 2 to 3 years, we performed a follow‐up screening 8 to 10 years later. Antitransglutaminase 2 antibodies were determined using a rapid test kit. Results were confirmed by serum IgA antitransglutaminase 2 and IgA endomysial antibody determination. CD diagnosis was carried out by intestinal biopsies. Four HLA‐DQ2 genotypic groups were used: G1: DQ2.5/DQ2.5 (G1A) or DQ2.5/ DQ2.2 (G1B); G2: DQ2.2/DQ7.5 (DQ2.5 trans); G3: DQ2.5/ X; G4: DQ2.2/X.

Results:

CD prevalence after 10 years of follow‐up was 5.8% (95% confidence interval 3.8–8.7). One of every 3 HLA‐DQ2(+) children carried at least 1 haplotype DQ2.2 or DQ7. The homozygous genotype DQ2.5/DQ2.5 and the HLA‐DQ2.5 trans genotype increased CD risk 4‐ and 3‐fold, respectively. The homozygous genotype DQ2.5/ DQ2.2 did not increase the CD risk. Children carrying G1 or G2 genotypes were diagnosed with CD earlier and more frequently during the follow‐up compare with those carrying G3 or G4 genotypes. Approximately 81% of children with spontaneous antibody negativization after the first screening maintained negative antibodies.

Conclusions:

A repeated screening of at‐risk children during their follow‐up allowed us to diagnose new CD cases. In our cohort, HLA‐ DQ2.5 trans genotype conferred a higher risk in the development of CD than HLA‐ DQ2.5/DQ2.2. The majority of children with potential CD and CD autoimmunity at 10 years of age remained healthy.
Recanalization of Chronic Extrahepatic Portal Vein Obstruction in Pediatric Patients Using a Minilaparotomy Approach
Authors: Muratore Sydne , Flanagan Siobhan , Hunter David , Acton Robert
Published: November 2018

Purpose:

Extrahepatic portal vein obstruction (EHPVO) is the most frequent cause of portal hypertension in children. Some patients are not amenable to meso‐Rex bypass and alternative surgeries do not restore physiologic flow. We aim to demonstrate the feasibility and safety of minilaparotomy for recanalization of chronic EHPVO.

Methods:

This 2013–2015 single‐center, retrospective review included pediatric patients with chronic EHPVO who underwent minilaparotomy, mesenteric vein access, and attempted recanalization of the occluded portal vein. Outcomes included portal patency, resolution of variceal bleeding, size and number of varices, spleen size, and platelet count.

Results:

There were 6 EHPVO patients. The median age was 9.9 years and median duration of EHPVO was 7 years (3–16 years). EHPVO etiologies were liver transplantation (50%), idiopathic (33%), and umbilical vein catheterization (17%). Four patients (67%) had successful portal vein recanalization and stenting. At last follow‐up [median 3.1 years (2.2–4.3 years)] all successfully recanalized patients had patent portal vein stents and resolution of varices and variceal bleeding. The median reduction in spleen size was 26%, with improvement in platelet counts (50–310/μL). The 2 patients with an idiopathic etiology may have never had a main extrahepatic portal vein based on imaging, and both were unable to be recanalized.

Conclusions:

Recanalization and stenting of a prolonged occlusion of the portal vein via a minilaparotomy approach is feasible, safe, and may provide an alternative to shunt surgery or endoscopic therapy in selected patients.
Simple Electroencephalographic Treatment-Emergent Marker Can Predict Repetitive Transcranial Magnetic Stimulation Antidepressant Response—A Feasibility Study
Authors: Isserles Moshe , Daskalakis Zafiris J. , George Mark S. , Blumberger Daniel M. , Sackeim Harold A. , Shahaf Goded
Published: November 2018

Objectives

Prefrontal repetitive transcranial magnetic stimulation (rTMS) repeated daily for 4 to 6 weeks is used to treat major depressive disorder, but more than 50% of patients do not achieve significant response. Here we test the validity of a simple electroencephalographic (EEG) marker that predicts nonresponse to rTMS. Such a marker could potentially increase rTMS effectiveness by directing nonresponders to alternative treatments or by guiding early modification of stimulation parameters.

Methods

We retrospectively analyzed 2-channel EEG data captured in the OPT-TMS National Institute of Mental Health–sponsored, multicenter study. Cumulative Brain Engagement Index (cBEI), a measure derived from template matching that allows scoring EEG dynamics along treatment, was computed.

Results

Six hundred sixty-five EEG recordings were analyzed. In the rTMS group, the median cBEI was found to increase in the responder group but remained unchanged in the nonresponder group. The difference between the cBEI of the groups became statistically significant by the third valid EEG sample. Within 5 samples, 91% of the responders presented with a cBEI above a preset threshold. Within 9 samples, 17% of the nonresponders had a cBEI above the threshold.

Conclusions

This study demonstrates the feasibility of a simple-to-capture EEG marker as a treatment-emergent marker of response to rTMS treatment of depression. In the OPT-TMS study, discontinuing treatment when the cBEI dropped below the threshold between the fifth to ninth treatment potentially could have avoided administration of 485 (63%) of 765 treatments. Because the marker can be generated online, it would be of interest to evaluate, in future studies, whether it could be used to tune treatment parameters and improve remission rates.
Does women’s interpersonal anxiety track changes in steroid hormone levels?
Authors: Hahn Amanda C , DeBruine Lisa M , Pesce Lola A , Diaz Andrew , Aberson Christopher L , Jones Benedict C
Published: November 2018

Findings for progesterone and anxiety in non-human animals led to the hypothesis that women’s interpersonal anxiety will track changes in progesterone during the menstrual cycle. There have been few direct tests of this hypothesis, however. Consequently, we used a longitudinal design to investigate whether interpersonal anxiety (assessed using the anxious jealousy subscale of the relationship jealousy questionnaire) tracked changes in salivary steroid hormones during the menstrual cycle in a large sample of young adult women (N=383). We found no evidence for within-subject effects of progesterone, estradiol, their interaction or ratio, testosterone, or cortisol on anxious jealousy. There was some evidence that other components of jealousy (e.g., reactive jealousy) tracked changes in women’s cortisol, however. Collectively, these results provide no evidence for the hypothesis that interpersonal anxiety tracks changes in progesterone during the menstrual cycle.
Overcoming non-small cell lung cancer radiation resistance by modulating the tumor-immune ecosystem
Authors: Nizzero S. , Alfonso J.C.L. , Álvarez-Arenas A. , Mirzaev I. , Zervantonakis I.K. , Lewin T. , Rishi A. , Piretto E. , Joshi T.V. , Santiago D.N. , Karolak A. , Walker R. , Karreth F.A. , Torres-Roca J. , Enderling H.
Published: November 2018

Non-small-cell lung cancer is the leading cause of cancer death worldwide. Although radiotherapy is an effective treatment choice for early-stage cases, the 5-year survival rate of patients diagnosed in late-stages remains poor. Increasing evidence suggests that the local and systemic effects of radiotherapy dependent on the induced anti-tumor immune responses. We believe that an educated adaptation of radiotherapy plans based not only on the induced immune responses, but also on the tumor-immune ecosystem composition at the beginning of treatment might increase local tumor control. We propose two different mathematical models to evaluate the potential of the tumor-immune context to inform adaptation of treatment plans with the aim of improving outcomes.
Human Nerve-on-a-Chip. Engineering 3D functional human peripheral nerve in vitro
Authors: Sharma Anup D. , McCoy Laurie , Jacobs Elizabeth , Willey Hannah , Behn Jordan Q. , Ngyuen Hieu , Bolon Brad , Curley J. Lowry , Moore Michael J.
Published: November 2018

Development of “organ-on-a-chip” systems in the space of the nervous system is lagging because of lack of availability of human neuronal & glial cells and the structural complexity of the nervous system. Furthermore, a sizeable challenge in the drug development pipeline and an often-cited reason for failure in a vast number of clinical trials conducted for neuropathological ailments is the lack of translation from animal models. A preclinical in vitro model capable of mimicking the function and structure of the human nervous system is well desired. We present an in vitro biomimetic model of all-human peripheral nerve tissue capable of showing a robust neurite outgrowth (~5mm), myelination of human induced pluripotent stem cells (iPSCs)-derived neurons by primary human Schwann cells and evaluation of nerve conduction velocity (NCV), previously unrealized for any human cell-based in vitro system. This Human Nerve-on-a-chip (HNoaC) system is the first microphysiological system of human peripheral nerve which can be used for evaluating electrophysiological and histological metrics, which are gold-standard assessment techniques previously only possible with in vivo studies.
GSAP modulates γ-secretase specificity by inducing conformational change in PS1
Authors: Wong Eitan , Liao George P. , Chang Jerry , Xu Peng , Li Yue-Ming , Greengard Paul
Published: November 2018

The mechanism by which GSAP (γ-secretase activating protein) regulates γ-secretase activity has not yet been elucidated. Here, we show that knockout of GSAP in cultured cells directly reduces γ-secretase activity for Aβ production, but not for Notch1 cleavage, suggesting that GSAP may induce a conformational change contributing to the specificity of γ-secretase. Furthermore, using an active site directed photoprobe with double cross-linking moieties, we demonstrate that GSAP modifies the orientation and/or distance of PS1-NTF and PS1-CTF, a region containing the active site of γ-secretase. This work offers insight into how GSAP regulates γ-secretase specificity.
Rate variation in the evolution of non-coding DNA associated with social evolution in bees
Authors: Rubin Benjamin E.R. , Jones Beryl M. , Hunt Brendan G. , Kocher Sarah D.
Published: November 2018

The evolutionary origins of eusociality represent increases in complexity from individual to caste-based, group reproduction. These behavioral transitions have been hypothesized to go hand-in-hand with an increased ability to regulate when and where genes are expressed. Bees have convergently evolved eusociality up to five times, providing a framework to test this hypothesis. To examine potential links between putative gene regulatory elements and social evolution, we compare alignable, non-coding sequences in eleven diverse bee species, encompassing three independent origins of reproductive division of labor and two elaborations of eusocial complexity. We find that rates of evolution in a number of non-coding sequences correlate with key social transitions in bees. Interestingly, while we find little evidence for convergent rate changes associated with independent origins of social behavior, a number of molecular pathways exhibit convergent rate changes in conjunction with subsequent elaborations of social organization. We also present evidence that many novel non-coding regions may have been recruited alongside the origin of sociality in corbiculate bees; these loci could represent gene regulatory elements associated with division of labor within this group. Thus, our findings are consistent with the hypothesis that gene regulatory innovations are associated with the evolution of eusociality and illustrate how a thorough examination of both coding and non-coding sequence can provide a more complete understanding of the molecular mechanisms underlying behavioral evolution.
Candida albicanswhite and opaque cells exhibit distinct spectra of organ colonization in mouse models of infection
Authors: Takagi Julie , Singh-Babak Sheena D. , Lohse Matthew B. , Dalal Chiraj K. , Johnson Alexander D.
Published: November 2018

Candida albicans, a species of fungi, can thrive in diverse niches of its mammalian hosts; it is a normal resident of the GI tract and mucosal surfaces but it can also enter the bloodstream and colonize internal organs causing serious disease. The ability ofC. albicansto thrive in these different host environments has been attributed, at least in part, to its ability to assume different morphological forms. In this work, we examine one such morphological change known as white-opaque switching. White cells are the default state ofC. albicans, and most animal studies have been carried out exclusively with white cells. Here, we compared the proliferation of white and opaque cells in two murine models of infection and also monitored, using specially constructed strains, switching between the two states in the host. We found that white cells outcompeted opaque cells in many niches; however, we show for the first time that in some organs (specifically, the heart and spleen), opaque cells competed favorably with white cells and, when injected on their own, could colonize these organs. In environments where the introduced white cells outcompeted the introduced opaque cells, we observed high rates of opaque-to-white switching. We did not observe white-to-opaque switching in any of the niches we examined.
Brain neurosteroids are natural anxiolytics targeting α2 subunit γ-aminobutyric acid type-A receptors
Authors: Durkin Elizabeth J , Muessig Laurenz , Herlt Tanja , Lumb Michael J , Patel Ryan , Thomas Philip , Bright Damian P. , Jurd Rachel , Moss Stephen J , Dickenson Anthony H. , Cacucci Francesca , Smart Trevor G
Published: November 2018

Neurosteroids are naturally-occurring molecules in the brain that modulate neurotransmission. They are physiologically important since disrupting their biosynthesis precipitates neurological disorders, such as anxiety and depression. The endogenous neurosteroids, allopregnanolone and tetrahydro-deoxycorticosterone are derived from sex and stress hormones respectively, and exhibit therapeutically-useful anxiolytic, analgesic, sedative, anticonvulsant and antidepressant properties. Their main target is the γ-aminobutyric acid type-A inhibitory neurotransmitter receptor (GABAAR), whose activation they potentiate. However, whether specific GABAAR isoforms and neural circuits differentially mediate endogenous neurosteroid effects is unknown. By creating a knock-in mouse that removes neurosteroid potentiation from α2-GABAAR subunits, we reveal that this isoform is a key target for neurosteroid modulation of phasic and tonic inhibition, and is essential for the anxiolytic role of endogenous neurosteroids, but not for their anti-depressant or analgesic properties. Overall, α2-GABAAR targeting neurosteroids may act as selective anxiolytics for the treatment of anxiety disorders, providing new therapeutic opportunities for drug development.
Rehumanizing the homeless: Altered BOLD response following contact with an extreme outgroup
Authors: Kirk P. A. , Cohen A. O. , Sinnott-Armstrong W. , Harris L.T.
Published: November 2018

Dehumanized perception strips people of their humanity by ignoring their mental states. Evidence has accumulated to suggest many individuals do not spontaneously attribute mental states towards certain social groups, such as the homeless, and drug-addicted (Fiske et al., 2002, Harris & Fiske, 2006; 2007; 2011). These groups tend to elicit differential BOLD signal within areas associated with social cognition. To investigate the versatility of this response, two experiments were conducted: a mixed design study (20 participants); and a repeated-measures design (11 participants). These investigated the malleability of social cognition following a contact intervention with the homeless. Both experiments had participants make emotional judgements toward eight different social groups whilst under fMRI. The two studies found mixed evidence, demonstrating altered response to homeless people in regions such as the mPFC, Insula, IPL, and MTG following social contact. This lends some support to the use of contact as an effective intervention.
Comprehensive mass spectrometry-guided plant specialized metabolite phenotyping reveals metabolic diversity in the cosmopolitan plant family Rhamnaceae
Authors: Kang Kyo Bin , Ernst Madeleine , van der Hooft Justin J. J. , da Silva Ricardo R. , Park Junha , Medema Marnix H. , Sung Sang Hyun , Dorrestein Pieter C.
Published: November 2018

Plants produce a myriad of specialized metabolites to overcome their sessile habit and combat biotic as well as abiotic stresses. Evolution has shaped specialized metabolite diversity, which drives many other aspects of plant biodiversity. However, until recently, large-scale studies investigating specialized metabolite diversity in an evolutionary context have been limited by the impossibility to identify chemical structures of hundreds to thousands of compounds in a time-feasible manner. Here, we introduce a workflow for large-scale, semi-automated annotation of specialized metabolites, and apply it for over 1000 metabolites of the cosmopolitan plant family Rhamnaceae. We enhance the putative annotation coverage dramatically, from 2.5 % based on spectral library matches alone to 42.6 % of total MS/MS molecular features extending annotations from well-known plant compound classes into the dark plant metabolomics matter. To gain insights in substructural diversity within the plant family, we also extract patterns of co-occurring fragments and neutral losses, so-called Mass2Motifs, from the dataset; for example, only the Ziziphoid clade developed the triterpenoid biosynthetic pathway, whereas the Rhamnoid clade predominantly developed diversity in flavonoid glycosides, including 7-O-methyltransferase activity. Our workflow provides the foundations towards the automated, high-throughput chemical identification of massive metabolite spaces, and we expect it to revolutionize our understanding of plant chemoevolutionary mechanisms.
The functional brain favours segregated modular connectivity at old age unless targeted by neurodegeneration
Authors: Peraza Luis R , O’Brien John T , Blamire Andrew , Kaiser Marcus , Taylor John-Paul
Published: November 2018

Brain’s modular connectivity gives this organ resilience and adaptability. The ageing process alters the human brain, leading to modifications to its organised modularity and these changes are further accentuated by neurodegeneration, leading to disorganisation. To understand this further, we analysed modular variability—heterogeneity of modules—and modular dissociation—detachment from segregated connectivity—in two ageing cohorts and a mixed cohort of neurodegenerative diseases. Our results revealed that the brain follows a universal pattern of modular variability that matches highly active and metacognitive brain regions: the association cortices. We also proved that in ageing the brain moves towards a modular segregated structure despite presenting with increased modular heterogeneity—modules in older adults are not only segregated but their shape and size are more variable than in young adults. In the presence of neurodegeneration, the brain maintains its segregated connectivity globally but not locally; the modular brain shows patterns of differentiated pathology.
Inhibition of the 60S ribosome biogenesis GTPase LSG1 causes endoplasmic reticular disruption and cellular senescence
Authors: Pantazi Asimina , Quintanilla Andrea , Hari Priya , Tarrats Nuria , Parasyraki Eleftheria , Dix Flora Lucy , Patel Jaiyogesh , Chandra Tamir , Acosta Juan Carlos , Finch Andrew John
Published: November 2018

Cellular senescence is triggered by diverse stimuli and is characterised by long-term growth arrest and secretion of cytokines and chemokines (termed the SASP - senescence-associated secretory phenotype). Senescence can be organismally beneficial as it can prevent the propagation of damaged or mutated clones and stimulate their clearance by immune cells. However, it has recently become clear that senescence also contributes to the pathophysiology of aging through the accumulation of damaged cells within tissues. Here we describe that inhibition of the reaction catalysed by LSG1, a GTPase involved in the biogenesis of the 60S ribosomal subunit, leads to a robust induction of cellular senescence. Perhaps surprisingly, this was not due to ribosome depletion or translational insufficiency, but rather through perturbation of endoplasmic reticulum (ER) homeostasis and a dramatic upregulation of the cholesterol biosynthesis pathway. This cholesterol/ER signature is shared with several other forms of senescence and contributes to the cell cycle arrest in oncogene-induced senescence (OIS). Furthermore, targetting of LSG1 resulted in amplification of the cholesterol/ER signature and restoration of a robust cellular senescence response in transformed cells, suggesting potential therapeutic uses of LSG1 inhibition.
Integrating Culture-based Antibiotic Resistance Profiles with Whole-genome Sequencing Data for 11,087 Clinical Isolates
Authors: Galata Valentina , Laczny Cédric C. , Backes Christina , Hemmrich-Stanisak Georg , Schmolke Susanne , Franke Andre , Meese Eckart , Herrmann Mathias , Müller Lutz von , Plum Achim , Müller Rolf , Stähler Cord , Posch Andreas E. , Keller Andreas
Published: November 2018

Emerging antibiotic resistance is a major global health threat. The analysis of nucleic acid sequences linked to susceptibility phenotypes facilitates the study of genetic antibiotic resistance determinants to inform molecular diagnostics and drug development. We collected genetic data (11,087 newly sequenced whole genomes) and culture-based resistance profiles (10,991 of 11,087 isolates were comprehensively tested against 22 antibiotics in total) of clinical isolates including 18 main species spanning a time period of 30 years. Species and drug specific resistance patterns could be observed including increasing resistance rates forAcinetobacter baumanniito carbapenems and forEscherichia colito fluoroquinolones. Species-level pan-genomes were constructed to reflect the genetic repertoire of the respective species such as conserved essential genes and known resistance factors. Integrating phenotypes and genotypes through species-level pan-genomes allowed to infer gene-drug resistance associations using statistical testing. The isolate collection and the analysis results have been integrated into a resource, GEAR-base, available for academic research use free of charge athttps://gear-base.com.
Persistence of Fusarium oxysporum f. sp. fragariae in soil through asymptomatic colonization of rotation crops
Authors: Henry Peter M. , Pastrana Ana M. , Leveau Johan H.J. , Gordon Thomas R.
Published: November 2018

Asymptomatic plant colonization is hypothesized to enhance persistence of pathogenic forms of Fusarium oxysporum in the absence of a susceptible host. However, a correlation between pathogen populations on living plant tissues and soilborne populations after tillage has not been demonstrated. Living and dead tissues of broccoli, lettuce, spinach, wheat, cilantro, raspberry, and strawberry plants inoculated with Fusarium oxysporum f. sp. fragariae (the cause of Fusarium wilt of strawberry) were assayed to quantify the incidence of infection and extent of colonization by this pathogen. All crops could be infected by F. oxysporum f. sp. fragariae, but the extent of colonization varied between plant species. Pathogen population densities on non-living crown tissues incorporated into the soil matrix were typically greater than those observed on living tissues. Crop-dependent differences in the inoculum density of F. oxysporum f. sp. fragariae in soil were only observed after decomposition of crop residue. Forty-four weeks after plants were incorporated into the soil, F. oxysporum f. sp. fragariae soil population densities were positively correlated with population densities on plant tissue fragments recovered at the same timepoint. Results indicate that asymptomatic colonization can have a significant, long-term impact on soilborne populations of Fusarium wilt pathogens. Cultural practices, such as crop rotation, should be leveraged to favor pathogen population decline by planting hosts that do not support extensive population growth on living or decomposing tissues.
ReQTL – an allele-level measure of variation-expression genomic relationships
Authors: Spurr Liam , Alomran Nawaf , Słowiński Piotr , Li Muzi , Bousounis Pavlos , Zhang Qianqian , Sein Justin , Crandall Keith A. , Tsaneva-Atanasova Krasimira , Horvath Anelia
Published: November 2018

Motivation

By testing for association of DNA genotypes with gene expression levels, expression quantitative trait locus (eQTL) analyses have been instrumental in understanding how thousands of single nucleotide variants (SNVs) may affect gene expression. As compared to DNA genotypes, RNA genetic variation represents a phenotypic trait that reflects the actual allele content of the studied system. RNA genetic variation can be measured at expressed genome regions, and differs from the DNA genotype in sites subjected to regulatory forces. Therefore, assessment of correlation between RNA genetic variation and gene expression can reveal regulatory genomic relationships in addition to eQTLs.

Results

We introduce ReQTL, an eQTL modification which substitutes the DNA allele count for the variant allele frequency (VAF) at expressed SNV loci in the transcriptome. We exemplify the method on sets of RNA-sequencing data from human tissues obtained though the Genotype-Tissue Expression Project (GTEx) and demonstrate that ReQTL analyses show consistently high performance and sufficient power to identify both previously known and novel molecular associations. The majority of the SNVs implicated in significant cis-ReQTLs identified by our analysis were previously reported as significant cis-eQTL loci. Notably, trans ReQTL loci in our data were substantially enriched in RNA-editing sites. In summary, ReQTL analyses are computationally feasible and do not require matched DNA data, hence they have a high potential to facilitate the discovery of novel molecular interactions through exploration of the increasingly accessible RNA-sequencing datasets.

Availability and implementation

Sample scripts used in our ReQTL analyses are available with the Supplementary Material (ReQTL_sample_code).

Contact

horvatha@gwu.edu or lfspurr@gwmail.gwu.edu

Supplementary Information

Re_QTL_Supplementary_Data.zip
A multi-species repository of social networks
Authors: Sah Pratha , Méndez José David , Bansal Shweta
Published: November 2018

Social network analysis is an invaluable tool to understand the patterns, evolution, and consequences of sociality. Comparative studies over the spectrum of sociality across taxonomic groups are particularly valuable. Such studies however require quantitative information on social interactions across multiple species which is not easily available. We introduce the Animal Social Network Repository (ASNR) as the first multi-taxonomic repository that collates more than 650 social networks from 47 species, including those of mammals, reptiles, fish, birds, and insects. The repository was created by consolidating social network datasets from the literature on wild and captive animals into a consistent and easy-to-use network data format. The repository is archived at https://bansallab.github.io/asnr/. ASNR has tremendous research potential, including testing hypotheses in the fields of animal ecology, social behavior, epidemiology and evolutionary biology.
In for a penny, in for a pound: Examining motivated memory through the lens of retrieved context models
Authors: Talmi Deborah , Kavaliauskaite Deimante , Daw Nathaniel D.
Published: November 2018

When people encounter items that they believe will help them gain reward, they later remember them better than others. A recent model of emotional memory, the emotional Context Maintenance and Retrieval model (eCMR), predicts that these effects would be stronger when stimuli that predict high and low reward can compete with each other both during encoding and retrieval. We tested this prediction in two experiments. Participants were promised £1 for remembering some pictures, but only a few pence for remembering others. Their recall of the content of the pictures they saw was tested after one minute and in Experiment 2, also after 24 hours. Memory at immediate test showed effects of list composition. Recall of stimuli that predicted high reward was greater than of stimuli that predicted lower reward, but only when high- and low-reward items were studied and recalled together, not when they were studied and recalled separately. More high-reward items in mixed lists were forgotten over a 24-hour retention interval compared to items studied in other conditions, but reward did not modulate the forgetting rate, a null effect which should be replicated in a larger sample. These results confirm eCMR’s predictions, although further research is required to compare that model against alternatives.
BELLA: Berkeley Efficient Long-Read to Long-Read Aligner and Overlapper
Authors: Guidi Giulia , Ellis Marquita , Rokhsar Daniel , Yelick Katherine , Buluç Aydın
Published: November 2018

Recent advances in long-read sequencing enable the characterization of genome structure and its intra- and inter-species variation at a resolution that was previously impossible. Detecting overlaps between reads is integral to many long-read genomics pipelines, such as de novo genome assembly. While longer reads simplify genome assembly and improve the contiguity of the reconstruction, current long-read technologies come with high error rates. We present Berkeley Long-Read to Long-Read Aligner and Overlapper (BELLA), a novel algorithm for computing overlaps and alignments via sparse matrix-matrix multiplication that balances the goals of recall and precision, performing well on both.

We present a probabilistic model that demonstrates the feasibility of using short k-mers for detecting candidate overlaps. We then introduce a notion of reliable k-mers based on our probabilistic model. Combining reliable k-mers with our binning mechanism eliminates both the k-mer set explosion that would otherwise occur with highly erroneous reads and the spurious overlaps from k-mers originating in repetitive regions. Finally, we present a new method based on Chernoff bounds for separating true overlaps from false positives using a combination of alignment techniques and probabilistic modeling. Our methodologies aim at maximizing the balance between precision and recall. On both real and synthetic data, BELLA performs amongst the best in terms of F1 score, showing performance stability which is often missing for competitor software. BELLA’s F1 score is consistently within 1.7% of the top entry. Notably, we show improved de novo assembly results on synthetic data when coupling BELLA with the Miniasm assembler.
Longitudinal dentate nuclei iron concentration and atrophy in Friedreich ataxia: IMAGE-FRDA
Authors: Ward Phillip G. D. , Harding Ian H , Close Thomas G. , Corben Louise A , Delatycki Martin B , Storey Elsdon , Georgiou-Karistianis Nellie , Egan Gary F
Published: November 2018

Background

Friedreich ataxia is a recessively inherited, progressive neurological disease characterised by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of pathology in these structures.

Methods

Using in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n=20) and healthy controls (n=18) over a two-year period.

Results

The longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Moreover, atrophy was maximal in individuals early in the disease course, while the rate of iron concentration increased with disease progression.

Conclusions

Progressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.
Soil nutrient adequacy for optimal cassava growth, implications on cyanogenic glucoside production: a case of konzo-affected Mtwara region, Tanzania
Authors: Imakumbili Matema L.E. , Semu Ernest , Semoka Johnson M.R. , Abass Adebayo , Mkamilo Geoffrey
Published: November 2018

Soils in areas affected by konzo (a cassava cyanide intoxication paralytic disorder) are predominantly infertile and probably unable to supply cassava the nutrients it needs to achieve optimal growth. The soil nutrient levels in these areas, could also be influencing cyanogenic glucoside production in cultivated cassava, however there is hardly any knowledge on this. An assessment of soil nutrient levels on cassava fields in konzo-affected areas was therefore carried out to determine their adequacy for optimal cassava growth and how this influences cassava cyanogenic glucoside production. Konzo-affected Mtwara region, in Tanzania, was used as a case study area. Correlations between total hydrogen cyanide (HCN) levels in cassava roots and various soil nutrient levels on cassava fields were carried out and relationships between cyanide intoxication and soil nutrient levels on fields from which toxic cassava roots had been harvested were also investigated. The results showed that cassava grows under conditions of severe nutrient stress in the region. Soil nutrients found to be deficient on most fields, like potassium (mean = 0.09, SD = 0.05 cmol/kg), magnesium (mean = 0.26, SD = 0.14 cmol/kg) and zinc (mean = 1.34, SD = 0.26 mg/kg), are known to reduce cyanogenic glucoside levels in cassava roots when adequate in soils. Cyanogenic glucoside levels in cassava roots however increased by high levels soil phosphorous (rs = 0.486, p = 0.026 for all varieties) and sulphur (rs = 0.593, p = 0.032 and rs = 0.714, p = 0.047; for bitter and sweet cassava varieties, respectively) on these soils. The likelihood of cassava cyanide intoxication was also increased on fields with high pH and iron levels. High levels of sulphur and phosphorus, to very high levels of iron occurred on some fields. How soil nutrient supply influences cassava cyanogenic glucoside production in the konzo-affected areas was established.
Checkpoint adaptation in repair-deficient cells drives aneuploidy and resistance to genotoxic agents
Authors: Vydzhak Olga , Bender Katharina , Klermund Julia , Busch Anke , Reimann Stefanie , Luke Brian
Published: November 2018

Human cancers frequently harbour mutations in DNA repair genes, rendering the use of DNA damaging agents as an effective therapeutic intervention. As therapy-resistant cells often arise, it is important to better understand the molecular pathways that drive resistance in order to facilitate the eventual targeting of such processes. We employ repair-defective diploid yeast as a model to demonstrate that, in response to genotoxic challenges, nearly all cells eventually undergo checkpoint adaptation, resulting in the generation of aneuploid cells with whole chromosome losses that have acquired resistance to the initial genotoxic challenge. We demonstrate that adaptation inhibition, either pharmacologically, or genetically, drastically reduces the occurrence of resistant cells. Additionally, the aneuploid phenotypes of the resistant cells can be specifically targeted to induce cytotoxicity. We provide evidence that TORC1 inhibition with rapamycin, in combination with DNA damaging agents, can prevent both checkpoint adaptation and the continued growth of aneuploid resistant cells.
Occupancy patterns of 208 DNA-associated proteins in a single human cell type
Authors: Partridge E. Christopher , Chhetri Surya B. , Prokop Jeremy W. , Ramaker Ryne C. , Jansen Camden S. , Goh Say-Tar , Mackiewicz Mark , Newberry Kimberly M. , Brandsmeier Laurel A. , Meadows Sarah K. , Messer C. Luke , Hardigan Andrew A. , Dean Emma C. , Jiang Shan , Savic Daniel , Mortazavi Ali , Wold Barbara J. , Myers Richard M. , Mendenhall Eric M.
Published: November 2018

Genome-wide occupancy maps of transcriptional regulators are important for understanding gene regulation and its effects on diverse biological processes, but only a small fraction of the >1,600 transcription factors (TFs) encoded in the human genome has been assayed. Here we present data and analyses of ChIP-seq experiments for 208 DNA-associated proteins (DAPs) in the HepG2 hepatocellular carcinoma line, spanning nearly a quarter of its expressed TFs, transcriptional co-factors, and chromatin regulator proteins. The DAP binding profiles classify into major groups associated predominantly with promoters or enhancers, or with both. We confirm and expand the current catalog of DNA sequence motifs; 77 factors showed similar motifs to those previously described using in vivo and/or in vitro methods, and 17 yielded novel motifs. We also describe motifs corresponding to other TFs that co-enrich with the primary ChIP target. FOX family motifs are, for example, significantly enriched in ChIP-seq peaks of 37 other DAPs. We show that promoters and enhancers can be discriminated based on motif content and occupancy patterns. This large catalog reveals High Occupancy Target (HOT) regions at which many DAPs associate, although each contains motifs for only a minority of the numerous associated DAPs. These analyses provide a deeper and more complete overview of the gene regulatory networks that define this cell type.
The optimal odor-receptor interaction network is sparse in olfactory systems: Compressed sensing by nonlinear neurons with a finite dynamic range
Authors: Qin Shanshan , Li Qianyi , Tang Chao , Tu Yuhai
Published: November 2018

There are numerous different odorant molecules in nature but only a relatively small number of olfactory receptor neurons (ORNs) in brains. This “compressed sensing” challenge is compounded by the constraint that ORNs are nonlinear sensors with a finite dynamic range. Here, we investigate possible optimal olfactory coding strategies by maximizing mutual information between odor mixtures and ORNs’ responses with respect to the bipartite odor-receptor interaction network (ORIN) characterized by sensitivities between all odorant-ORN pairs. We find that the optimal ORIN is sparse – a finite fraction of sensitives are zero, and the nonzero sensitivities follow a broad distribution that depends on the odor statistics. We show that the optimal ORIN enhances performances of downstream learning tasks (reconstruction and classification). For ORNs with a finite basal activity, we find that having a basal-activity-dependent fraction of inhibitory odor-receptor interactions increases the coding capacity. All our theoretical findings are consistent with existing experiments and predictions are made to further test our theory. The optimal coding model provides a unifying framework to understand the peripheral olfactory systems across different organisms.
Alpha oscillations and travelling waves: signatures of predictive coding?
Authors: Alamia Andrea , VanRullen Rufin
Published: November 2018

Predictive coding is a key mechanism to understand the computational processes underlying brain functioning: in a hierarchical network, higher layers predict the activity of lower layers, and the unexplained residuals (i.e. prediction errors) are sent through. Because of its iterative nature, we wondered whether predictive coding could be related to brain oscillatory dynamics. First, we show that a simple 2-layers predictive coding model of visual cortex, with physiological communication delays between layers, naturally gives rise to alpha-band rhythms, similar to experimental observations. Then, we demonstrate that a multi-layer version of the same model can explain the occurrence of oscillatory travelling waves across layers, both feedforward (during visual stimulation) and backward (during rest). Remarkably, the predictions of our model are matched by the analysis of two independent EEG datasets, in which we observed oscillatory travelling waves in both directions.
Mechanism and resistance for antimycobacterial activity of a fluoroquinophenoxazine compound
Authors: Garcia Pamela K. , Annamalai Thirunavukkarasu , Wang Wenjie , Bell Raven , Le Duc , Pancorbo Paula Martin , Sikandar Sabah , Seddek Ahmed , Yu Xufen , Sun Dianqing , Uhlemann Anne-Catrin , Tiwari Purushottam B. , Leng Fenfei , Tse-Dinh Yuk-Ching
Published: November 2018

We have previously reported the inhibition of bacterial topoisomerase I activity by a fluoroquinophenoxazine compound (FP-11g) with a 6-bipiperidinyl lipophilic side chain that exhibited promising antituberculosis activity (MIC = 2.5 μM againstMycobacterium tuberculosis, SI = 9.8). Here, we found that the compound is bactericidal towardsMycobacterium smegmatis, resulting in greater than 5 Log10reduction in colony-forming units [cfu]/mL following a 10 h incubation at 1.25 μM (4X MIC) concentration. Growth inhibition (MIC = 50 μM) and reduction in cfu could also be observed against a clinical isolate ofMycobacterium abscessus.Stepwise isolation of resistant mutants ofM. smegmatiswas conducted to explore the mechanism of resistance. Mutations in the resistant isolates were identified by direct comparison of whole-genome sequencing data from mutant and wild-type isolates. These include mutations in genes likely to affect the entry and retention of the compound. FP-11g inhibitsMtbtopoisomerase I andMtbgyrase with IC50of 0.24 and 31.5 μM, respectively. Biophysical analysis showed that FP-11g binds DNA as an intercalator but the IC50for inhibition ofMtbtopoisomerase I activity is >10 fold lower than the compound concentrations required for producing negatively supercoiled DNA during ligation of nicked circular DNA. Thus, the DNA-binding property of FP-11g may contribute to its antimycobacterial mechanism, but that alone cannot account for the observed inhibition of Mtb topoisomerase I.
High-throughput micro-patterning platform reveals Nodal-dependent dissection of peri-gastrulation-associated versus pre-neurulation associated fate patterning
Authors: Tewary Mukul , Dziedzicka Dominika , Ostblom Joel , Prochazka Laura , Shakiba Nika , Woodford Curtis , Piccinini Elia , Vickers Alice , Louis Blaise , Rahman Nafees , Danovi Davide , Geens Mieke , Watt Fiona M. , Zandstra Peter W.
Published: November 2018

In vitromodels of post-implantation human development are valuable to the fields of regenerative medicine and developmental biology. Here, we report characterization of a robustin vitroplatform that enabled high-content screening of multiple human pluripotent stem cell (hPSC) lines for their ability to undergo peri-gastrulation-like fate patterning upon BMP4 treatment of geometrically-confined colonies and observed significant heterogeneity in their differentiation propensities along a gastrulation associable and neuralization associable axis. This cell line associated heterogeneity was found to be attributable to endogenous nodal expression, with upregulation of Nodal correlated with expression of a gastrulation-associated gene profile, and Nodal downregulation correlated with a neurulation-associated gene profile expression. We harness this knowledge to establish a platform of pre-neurulation-like fate patterning in geometrically confined hPSC colonies that arises due to a stepwise activation of reaction-diffusion and positional-information. Our work identifies a Nodal signalling dependent switch in peri-gastrulation versus pre-neurulation-associated fate patterning in hPSC cells, provides a technology to robustly assay hPSC differentiation outcomes, and suggests conserved mechanisms of self-organized fate specification in differentiating epiblast and ectodermal tissues.
A dynamic network model can explain temporal receptive fields in primary auditory cortex
Authors: Rahman Monzilur , Willmore Ben D. B. , King Andrew J. , Harper Nicol S.
Published: November 2018

Auditory neurons encode stimulus history, which is often modelled using a span of time-delays in a spectro-temporal receptive field (STRF). We propose an alternative model for the encoding of stimulus history, which we apply to extracellular recordings of neurons in the primary auditory cortex of anaesthetized ferrets. For a linear-non-linear STRF model (LN model) to achieve a high level of performance in predicting single unit neural responses to natural sounds in the primary auditory cortex, we found that it is necessary to include time delays going back at least 200 ms in the past. This is an unrealistic time span for biological delay lines. We therefore asked how much of this dependence on stimulus history can instead be explained by dynamical aspects of neurons. We constructed a neural-network model whose output is the weighted sum of units whose responses are determined by a dynamic firing-rate equation. The dynamic aspect performs low-pass filtering on each unit’s response, providing an exponentially decaying memory whose time constant is individual to each unit. We find that this dynamic network (DNet) model, when fitted to the neural data using STRFs of only 25 ms duration, can achieve prediction performance on a held-out dataset comparable to the best performing LN model with STRFs of 200 ms duration. These findings suggest that integration due to the membrane time constants or other exponentially-decaying memory processes may underlie linear temporal receptive fields of neurons beyond 25 ms.

AUTHOR SUMMARY

The responses of neurons in the primary auditory cortex depend on the recent history of sounds over seconds or less. Typically, this dependence on the past has been modelled by applying a wide span of time delays to the input, although this is likely to be biologically unrealistic. Real neurons integrate the history of their activity due to the dynamical properties of their cell membranes and other components. We show that a network with a realistically narrow span of delays and with units having dynamic characteristics like those found in neurons, succinctly models neural responses recorded from ferret primary auditory cortex. Because these integrative properties are widespread, our dynamic network provides a basis for modelling responses in other neural systems.