bluuebunny/crossref_metadata_2025 huggingface dataset:
Against Empathy: distinct correlates of empathy and compassion with burnout and affective symptoms in health professionals and students
Authors: Romani-Sponchiado Aline , Jordan Matthew R. , Stringaris Argyris , Salum Giovanni Abrahão
Published: September 2019

Concern for the well-being of medical professionals has increased considering the high rates of depression and suicidal ideation observed among medical students and residents. However, the causes of such psychological distress among health professionals are still unknown.
One possibility is that such negative outcomes arise from individual differences in how clinicians respond to the emotional states of their patients: while some tend respond with empathy (feeling what others feel), others tend respond with compassion (caring about what others feel). The aim of this study is to investigate the hypothesis that empathy is related to higher levels of burnout and affective symptoms, while compassion is related to lower levels of these outcomes.
We surveyed 464 undergraduate students and professionals in medicine (34.3%), psychology (47%) and nursing (18.8%), 79.7% female, with a median age of 23.3. The survey included the concern and perspective taking subscales from the Interpersonal Reactivity Index (IRI); empathy and behavioral contagion from the Empathy Index (EI); the depression, anxiety, and anger subscales from PROMIS; and the Medical Student Well-Being Index (MSWBI).
Empathy was associated with higher symptoms of burnout, depression, anxiety and anger; while higher levels of compassion were associated with lower levels of these outcomes.
Our findings provide new evidence that the well-being of medical professionals might be affected differently depending on socio-emotional traits relevant to emotional connection.
Natural Language Processing for Mimicking Clinical Trial Recruitment in Critical Care: A Semi-automated Simulation Based on the LeoPARDS Trial
Authors: Tissot Hegler , Shah Anoop , Agbakoba Ruth , Folarin Amos , Romao Luis , Brealey David , Harris Steve , Roguski Lukasz , Dobson Richard , Asselbergs Folkert
Published: September 2019

Clinical trials often fail on recruiting an adequate number of appropriate patients. Identifying eligible trial participants is a resource-intensive task when relying on manual review of clinical notes, particularly in critical care settings where the time window is short. Automated review of electronic health records has been explored as a way of identifying trial participants, but much of the information is in unstructured free text rather than a computable form. We developed an electronic health record pipeline that combines structured electronic health record data with free text in order to simulate recruitment into the LeoPARDS trial. We applied an algorithm to identify eligible patients using a moving 1-hour time window, and compared the set of patients identified by our approach with those actually screened and recruited for the trial. We manually reviewed clinical records for a random sample of additional patients identified by the algorithm but not identified for screening in the original trial. Our approach identified 308 patients, of whom 208 were screened in the actual trial. We identified all 40 patients with CCHIC data available who were actually recruited to LeoPARDS in our centre. The algorithm identified 96 patients on the same day as manual screening and 62 patients one or two days earlier. Analysis of electronic health records incorporating natural language processing tools could effectively replicate recruitment in a critical care trial, and identify some eligible patients at an earlier stage. If implemented in real-time this could improve the efficiency of clinical trial recruitment.
Cognitive functioning and lifetime Major Depressive Disorder in UK Biobank
Authors: De Nooij L , Harris MA , Adams MJ , Clarke T-K , Shen X , Cox SR , McIntosh AM , Whalley HC
Published: September 2019

Background

Cognitive impairment associated with lifetime Major Depressive Disorder (MDD) is well-supported by meta-analytic studies, but population-based estimates remain scarce. Previous UK Biobank studies have only shown limited evidence of cognitive differences related to probable MDD. Using updated cognitive and clinical assessments in UK Biobank, this study investigated population-level differences in cognitive functioning associated with lifetime MDD.

Methods

Associations between lifetime MDD and cognition (performance on six tasks and general cognitive functioning (g-factor)) were investigated in UK Biobank (N-range 7,457-14,836, age 45-81 years, 52% female), adjusting for demographics, education and lifestyle. Lifetime MDD classifications were based on the Composite International Diagnostic Interview. Within the lifetime MDD group, we additionally investigated relationships between cognition and (i) recurrence, (ii) current symptoms, (iii) severity of psychosocial impairment (while symptomatic), and (iv) concurrent psychotropic medication use.

Results

Lifetime MDD was robustly associated with a lower g-factor (β = −0.10, PFDR = 4.7×10−5), with impairments in attention, processing speed and executive functioning (β ≥ 0.06). Clinical characteristics revealed differential profiles of cognitive impairment among case individuals; those who reported severe psychosocial impairment and use of psychotropic medication performed worse on cognitive tests. Severe psychosocial impairment and reasoning showed the strongest association (β = −0.18, PFDR = 7.5×10−5).

Conclusions

Findings describe small but robust associations between lifetime MDD and lower cognitive performance within a population based sample. Overall effects were of modest effect size, suggesting limited clinical relevance. However, deficits within specific cognitive domains were more pronounced in relation to clinical characteristics, particularly severe psychosocial impairment.
RISK6, a universal 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response
Authors: Penn-Nicholson Adam , Mbandi Stanley Kimbung , Thompson Ethan , Mendelsohn Simon C. , Suliman Sara , Chegou Novel N. , Malherbe Stephanus T. , Darboe Fatoumatta , Erasmus Mzwandile , Hanekom Willem A. , Bilek Nicole , Fisher Michelle , Kaufmann Stefan H. E. , Winter Jill , Murphy Melissa , Wood Robin , Morrow Carl , Van Rhijn Ildiko , Moody Branch , Murray Megan , Andrade Bruno B. , Sterling Timothy R. , Sutherland Jayne , Naidoo Kogieleum , Padayatchi Nesri , Walzl Gerhard , Hatherill Mark , Zak Daniel , Scriba Thomas J. ,   the Adolescent Cohort Study team,   GC6-74 Consortium,   The ScreenTB and AE-TBC teams,   CAPRISA IMPRESS team,   RePORT Brazil Consortium,   Peruvian Household Contacts Cohort study group
Published: September 2019

Improved tuberculosis diagnostics and tools for monitoring treatment response are urgently needed. We developed a robust and simple, PCR-based host-blood transcriptomic signature, RISK6, for multiple applications: identifying individuals at risk of incident disease, as a screening test for subclinical or clinical tuberculosis, and for monitoring tuberculosis treatment. RISK6 utility was validated by blind prediction using quantitative real-time (qRT) PCR in seven independent cohorts.

Prognostic performance significantly exceeded that of previous signatures discovered in the same cohort. Performance for diagnosing subclinical and clinical disease in HIV-uninfected and HIV-infected persons, assessed by area under the receiver-operating characteristic curve, exceeded 85%. As a screening test for tuberculosis, the sensitivity at 90% specificity met or approached the benchmarks set out in World Health Organization target product profiles for non-sputum-based tests. RISK6 scores correlated with lung immunopathology activity, measured by positron emission tomography, and tracked treatment response, demonstrating utility as treatment response biomarker, while predicting treatment failure prior to treatment initiation. Performance of the test in capillary blood samples collected by finger-prick was noninferior to venous blood collected in PAXgene tubes. These results support incorporation of RISK6 into rapid, capillary blood-based point-of-care PCR devices for prospective assessment in field studies.
Mendelian Randomization with Instrumental Variable Synthesis (IVY)
Authors: Kuang Zhaobin , Cordova-Palomera Aldo , Sala Fred , Wu Sen , Dunnmon Jared , Re Chris , Priest James
Published: September 2019

Mendelian Randomization (MR) is an important causal inference method primarily used in biomedical research. This work applies contemporary techniques in machine learning to improve the robustness and power of traditional MR tools. By denoising and combining candidate genetic variants through techniques from unsupervised probabilistic graphical models, an influential latent instrumental variable is constructed for causal effect estimation. We present results on identifying relationships between biomarkers and the occurrence of coronary artery disease using individual-level real-world data from UK-BioBank via the proposed method. The approach, termed Instrumental Variable sYnthesis (IVY) is proposed as a complement to current methods, and is able to improve results based on allele scoring, particularly at moderate sample sizes.
Computer vision to automatically assess infant neuromotor risk
Authors: Chambers Claire , Seethapathi Nidhi , Saluja Rachit , Loeb Helen , Pierce Samuel , Bogen Daniel , Prosser Laura , Johnson Michelle J. , Kording Konrad P.
Published: September 2019

An infant’s risk of developing neuromotor impairment is primarily assessed through visual examination by specialized clinicians. Therefore, many infants at risk for impairment go undetected, particularly in under-resourced environments. There is thus a need to develop automated, clinical assessments based on quantitative measures from widely-available sources, such as video cameras. Here, we automatically extract body poses and movement kinematics from the videos of at-risk infants (N=19). For each infant, we calculate how much they deviate from a group of healthy infants (N=85 online videos) using Naïve Gaussian Bayesian Surprise. After pre-registering our Bayesian Surprise calculations, we find that infants that are at higher risk for impairments deviate considerably from the healthy group. Our simple method, provided as an open source toolkit, thus shows promise as the basis for an automated and low-cost assessment of risk based on video recordings.
Salt-free fractionation of complex isomeric mixtures of glycosaminoglycan oligosaccharides compatible with ESI-MS and microarray analysis
Authors: Liu Hao , Joshi Apoorva , Chopra Pradeep , Liu Lin , Boons Geert-Jan , Sharp Joshua S.
Published: September 2019

Heparin and heparan sulfate (Hp/HS) are linear complex glycosaminoglycans which are involved in diverse biological processes. The structural complexity brings difficulties in separation, making the study of structure-function relationships challenging. Here we present a separation method for Hp/HS oligosaccharide fractionation with cross-compatible solvent and conditions, combining size exclusion chromatography (SEC), ion-pair reversed phase chromatography (IPRP), and hydrophilic interaction chromatography (HILIC) as three orthogonal separation methods that do not require desalting or extensive sample handling. With this method, the final eluent is suitable for structure-function relationship studies, including tandem mass spectrometry and microarray printing. Our data indicate that high resolution is achieved on both IPRP and HILIC for Hp/HS isomers. In addition, the fractions co-eluted in IPRP could be further separated by HILIC, with both separation dimensions capable of resolving some isomeric oligosaccharides. We demonstrate this method using both unpurified reaction products from isomeric synthetic hexasaccharides and an octasaccharide fraction from enoxaparin, identifying isomers resolved by this multi-dimensional separation method. We demonstrate both structural analysis by MS, as well as functional analysis by microarray printing and screening using a prototypical Hp/HS binding protein: basic-fibroblast growth factor (FGF2). Collectively, this method provides a strategy for efficient Hp/HS structure-function characterization.
Case-control vs. case-only estimates of gene-environment interactions with common and misclassified clinical diagosis
Authors: Lobach Iryna , Sheng Ying , Lobach Siarhei , Zablotska Lydia , Huang Chiung-Yu
Published: September 2019

Genetic studies provide valuable information to assess if the effect of genetic variants varies by the non-genetic (“environmental”) variables, what is traditionally defined to be gene-environment interaction. A common complication is that multiple disease states present with the same set of symptoms, and hence share the clinical diagnosis. Because 1) disease states might have distinct genetic bases; and 2) frequencies of the disease states within the clinical diagnosis vary by the environmental variables, analyses of association with the clinical diagnosis as an outcome variable might result in false positive or false negative findings. We develop estimates for assessment of GxE in a case-only study and compare the case-control and case-only estimates. We report extensive simulation studies that evaluate empirical properties of the estimates and show the application to a study of Alzheimer’s disease.
Changes in ambient temperature are the prevailing cue in determiningBrachypodium distachyondiurnal gene regulation
Authors: MacKinnon Kirk J-M. , Cole Benjamin J. , Yu Chang , Coomey Joshua H. , Hartwick Nolan T. , Remigereau Marie-Stanislas , Duffy Tomás , Michael Todd P. , Kay Steve A. , Hazen Samuel P.
Published: September 2019

Plants are continuously exposed to diurnal fluctuations in light and temperature, and spontaneous changes in their physical or biotic environment. The circadian clock coordinates regulation of gene expression with a 24-hour period, enabling the anticipation of these events.

We used RNA sequencing to characterize theBrachypodium distachyontranscriptome under light and temperature cycles, as well as under constant conditions.

Approximately 3% of the transcriptome was regulated by the circadian clock, a smaller proportion reported in most other species. For most transcripts that were rhythmic under all conditions, including many known clock genes, the period of gene expression lengthened from 24 to 27 h in the absence of external cues. To functionally characterize the cyclic transcriptome inB. distachyon, we used Gene Ontology enrichment analysis, and found several terms significantly associated with peak expression at particular times of the day. Furthermore we identified sequence motifs enriched in the promoters of similarly-phased genes, some potentially associated with transcription factors.

When considering the overlap in rhythmic gene expression and specific pathway behavior, thermocycles was the prevailing cue that controlled diurnal gene regulation. Taken together, our characterization of the rhythmicB. distachyontranscriptome represents a foundational resource with implications in other grass species.
Draft genome sequence of a popular Indian tea genotype TV-1 [Camellia assamica L. (O). Kunze]
Authors: Mondal Tapan Kumar , Rawal Hukam Chand , Bera Biswajit , Kumar P. Mohan , Choubey Mrityunjay , Saha Gargi , Das Budhadeb , Bandyopadhyay Tanoy , Ilango R. Victor J. , Sharma Tilak Raj , Barua Anup , Radhakrishnan B. , Singh Nagendra Kumar
Published: September 2019

Camellia assamica L. (O). Kuntze. var. TV-1 from Assam, India is one of the most important tea cultivar of Indian Tea Industry which botanically belongs to Assam type and has distinct morphological as well as chemical constituent in leaf than China type of tea. We here present the first draft genome sequence of TV-1, assembled in 2.93 Gb size comprising of 14,824 scaffolds and covering 97.66% of the predicted genome size (3.0 Gb) as determined by flow cytometry. The N50 value, longest and average contig size for this draft genome was found to be as 538.96 Kb, 3.64 Mb and 197.99 Kb, respectively. There were 495,747 SSRs (Di- to Hexa-mers) in the genome and the repeat contents accounted for 71.87% of the genome. About 94.40% genome completeness was predicted with BUSCO, maximum among the published and reported tea genomes. The clustering of the assembled genome with Hi-C data resulted in 15 clusters ranging from the size of 631.46 Mb to 14.39 Mb and accounting 99.32% of assembled genome. This data will act as the starting point for unravelling the important genes and differentiating Indian tea from other commercially available tea varieties.
Long-term metabolic consequences of acute dioxin exposure differ between male and female mice
Authors: Hoyeck Myriam P , Blair Hannah , Ibrahim Muna , Solanki Shivani , Elsawy Mariam , Prakash Arina , Rick Kayleigh RC , Matteo Geronimo , O’Dwyer Shannon , Bruin Jennifer E
Published: September 2019

Exposure to environmental pollutants is consistently associated with increased diabetes risk in humans. In male mice, acute dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) exposure supresses insulin secretion. This study investigated the long-term effects of a single TCDD injection (20 µg/kg) on glucose metabolism and beta cell function in male and female mice. TCDD-exposed males displayed modest fasting hypoglycemia for ∼4 weeks post-injection, reduced fasting insulin levels for up to 6 weeks, increased insulin sensitivity, and decreased beta cell area. TCDD-exposed females also had long-term suppressed basal plasma insulin levels, and abnormal insulin secretion for up to 6 weeks. Unlike males, TCDD did not impact insulin sensitivity or beta cell area in females, but did cause transient glucose intolerance 4 weeks post-exposure. Our results show that a single exposure to dioxin can supress basal insulin levels long-term in both sexes, but effects on metabolism are sex-dependent.
BET inhibition prevents aberrant RUNX1 and ERG transcription in STAG2 mutant leukaemia cells
Authors: Antony Jisha , Gimenez Gregory , Taylor Terry , Khatoon Umaima , Day Robert , Morison Ian M. , Horsfield Julia A.
Published: September 2019

Mutations in the subunits of the cohesin complex, particularly in the STAG2 subunit, have been identified in a range of myeloid malignancies, but it is unclear how these mutations progress leukaemia. Here, we created isogenic K562 erythromyeloid leukaemia cells with and without the known leukemic STAG2 null mutation, R614*. STAG2 null cells acquired stem cell and extracellular matrix gene expression signatures that accompanied an adherent phenotype. Chromatin accessibility was dramatically altered in STAG2 null K562 cells, consistent with gene expression changes. Enhanced chromatin accessibility was observed at genes encoding hematopoietic transcription factors, ERG and RUNX1. Upon phorbol 12-myristate 13-acetate (PMA)-induced megakaryocytic differentiation, STAG2-null cells showed precocious spike in RUNX1 transcription from its P2 promoter. A similar precocious spike was observed in transcription of ERG. Interestingly, spikes in RUNX1-P2 and ERG only occurred as immediate early response to differentiation induction. Treatment of STAG2 null cells with enhancer-blocking BET inhibitor, JQ1, dampened precocious RUNX1 P2 expression and led to a complete loss of RUNX1 P1 and ERG transcription during PMA stimulation in both parental and STAG2 null K562 cells. These results suggest that precocious RUNX1 and ERG expression in STAG2 null cells is enhancer-driven. Furthermore, JQ1 treatment reduced stem cell-associated KIT expression in STAG2 null cells. We conclude that STAG2 depletion in leukemic cells amplifies an enhancer-driven transcriptional response to differentiation signals, and this characteristic is dampened by BET inhibition. The results have relevance to the development of therapeutic strategies for myeloid leukaemia
Road traffic delays and musculoskeletal health complaints among full-time bank employees: A cross-sectional study in Dhaka city
Authors: Ali Mohammad , Ahsan Gias U. , Uddin Zakir , Hossain Ahmed
Published: September 2019

Background

The factors of road traffic delays (RTDs) have significant consequences for both commuters’ health and the country’s economy as a whole. Addressing the musculoskeletal health complaints (MHCs) among full-time employees has not been fully explored. The current study investigates the association between RTDs-related factors and MHCs among bank employees.

Methods

We conducted a cross-sectional study among full-time employees from 32 banks in Dhaka city. Descriptive statistics summarized the gaps in the socio-demographic and RTDs-related factors on the one-month prevalence of MHCs. Random intercept logistic regression models were used to identify the associate factors of the MHCs.

Results

Out of 628 full-time bank employees, the one-month prevalence of MHCs was 57.7%. The MHCs are more prevalent among adults of age group 40-60 years (68%) than the age group 20-40 years (54%). The one-month prevalence of lower back pain (LBP) was highest (36.6%), followed by neck pain (22.9%) and upper back pain (21.2%). Multilevel logistic regression analysis of employees showed that the odds of MHCs were lower among male employees (AOR=0.42, 95% CI= 0.27, 0.64), car commuters (AOR = 0.38, 95% CI=0.19-0.76, reference: bus commuters) and rickshaw commuters (AOR=. = 0.39, 95% CI=0.22-0.69, reference: bus commuters). The MHCs were significantly higher among employees with following factors: obesity (AOR= 1.50, 95% CI= 1.02-2.21), prolonged commute time to the office (AOR = 7.48, 95% CI =3.64-15.38) and working extended-time in a day (AOR= 1.50, 95% CI= 1.02-2.21).

Conclusions

The study indicates a high burden of musculoskeletal health complaints among the employees in Dhaka city, and the most prevalent complaint was low back pain. Our study suggests that factors related to road traffic delays might act synergistically on developing musculoskeletal problems in full-time employees.
Temporal tuning of repetition suppression across the visual cortex
Authors: Fritsche Matthias , Lawrence Samuel J. D. , de Lange Floris P.
Published: September 2019

The visual system adapts to its recent history. A phenomenon related to this is repetition suppression (RS) - a reduction in neural responses to repeated compared to non-repeated visual input. An intriguing hypothesis is that the timescale over which RS occurs across the visual hierarchy is tuned to the temporal statistics of visual input features, which change rapidly in low-level areas but are more stable in higher-level areas. Here, we tested this hypothesis by studying the influence of the temporal lag between successive visual stimuli on RS throughout the visual system using fMRI. Twelve human volunteers engaged in four fMRI sessions in which we characterized the BOLD response to pairs of repeated and non-repeated natural images with inter-stimulus intervals (ISI) ranging from 50 to 1000 milliseconds to quantify the temporal tuning of RS along the posterior-anterior axis of the visual system. As expected, RS was maximal for short ISIs and decayed with increasing ISI. Furthermore, the overall magnitude of RS gradually increased from posterior to anterior visual areas. Crucially, however, and against our hypothesis, RS decayed at a similar rate in early and late visual areas. This finding challenges the prevailing view that the timescale of RS increases along the posterior-anterior axis of the visual system and suggests that RS is not tuned to temporal input regularities.
Microtubules deform the nucleus and force chromatin reorganization during early differentiation of human hematopoietic stem cells
Authors: Biedzinski S. , Faivre L. , Vianay B. , Delord M. , Blanchoin L. , Larghero J. , Théry M. , Brunet S.
Published: September 2019

Hematopoietic stem cells (HSC) can differentiate into all hematopoietic lineages to support hematopoiesis. Cells from the myeloid and lymphoid lineages fulfill distinct functions with specific shapes and intra-cellular architectures. The role of cytokines in the regulation of HSC differentiation has been intensively studied but our understanding of the potential contribution of inner cell architecture is relatively poor. Here we show that large invaginations are generated by microtubule constraints on the swelling nucleus of human HSCs during early commitment toward the myeloid lineage. These invaginations are associated with chromatin reorganization, local loss of H3K9 trimethylation and changes in expression of specific hematopoietic genes. This establishes the role of microtubules in defining the unique lobulated nuclear shape observed in myeloid progenitor cells and suggests that this shape is important to establish the gene expression profile specific to this hematopoietic lineage. It opens new perspectives on the implications of microtubule-generated forces, in the early specification of the myeloid lineage.
MicroRNAs Cause Accelerated Decay of Short-Tailed Target mRNAs
Authors: Eisen Timothy J. , Eichhorn Stephen W. , Subtelny Alexander O. , Bartel David P.
Published: September 2019

MicroRNAs (miRNAs) specify recruitment of deadenylases to mRNA targets. Despite this recruitment, we find that miRNAs have almost no effect on steady-state poly(A)-tail lengths of their targets in mouse fibroblasts, which motivates acquisition of pre-steady-state measurements of the effects of miRNAs on tail lengths, mRNA levels, and translational efficiencies. Effects on translational efficiency are minimal compared to effects on mRNA levels—even for newly transcribed target mRNAs. Effects on target mRNA levels accumulate as the mRNA population approaches steady state, whereas effects on tail lengths peak for recently transcribed target mRNAs and then subside. Computational modeling of this phenomenon reveals that miRNAs cause not only accelerated deadenylation of their targets but also accelerated decay of short-tailed target molecules. This unanticipated effect of miRNAs largely prevents short-tailed target mRNAs from accumulating despite accelerated target deadenylation. The net result is a nearly imperceptible change to the steady-state tail-length distribution of targeted mRNAs.

Highlights

miRNAs cause accelerated decay of short-tailed target molecules

This accelerated decay largely prevents accumulation of short-tailed target mRNAs

miRNAs are similarly effective on short-lived and long-lived target mRNAs

In 3T3 cells, miRNA effects on translation are negligible—even for nascent mRNA
Changes in life history and population size can explain relative neutral diversity levels on X and autosomes in extant human populations
Authors: Amster Guy , Murphy David A. , Milligan William M. , Sella Guy
Published: September 2019

In human populations, relative levels of neutral polymorphism on the X and autosomes differ markedly from each other and from the naive theoretical expectation of ¾. These differences have attracted considerable attention, with studies highlighting several potential causes, including male biased mutation and reproductive variance, historical changes in population size, and selection at linked loci. We revisit this question in light of our new theory about the effects of life history and given pedigree-based estimates of the dependence of human mutation rates on sex and age. We demonstrate that life history effects, particularly higher generation times in males than females, likely had multiple effects on human X-to-autosomes (X:A) polymorphism ratios, through the extent of male mutation bias, the equilibrium X:A ratios of effective population sizes, and differential responses to changes in population size. We also show that the standard approach of using divergence between species to correct for the male bias in mutation results in biased estimates of X:A effective population size ratios. We obtain alternative estimates using pedigree-based estimates of the male mutation bias, which reveal X:A ratios of effective population sizes to be considerably greater than previously appreciated. We then show that the joint effects of historical changes in life history and population size can explain X:A polymorphism ratios in extant human populations. Our results suggest that ancestral human populations were highly polygynous; that non-African populations experienced a substantial reduction in polygyny and/or increase in male-biased generation times around the out of Africa bottleneck; and that extant diversity levels were affected by fairly recent changes in sex-specific life history.

Significance Statement

All else being equal, the ratio of diversity levels on X and autosomes at selectively neutral sites should mirror the ratio of their numbers in the population and thus equal ¾. In reality, the ratios observed across human populations differ markedly from ¾ and from each other. Because from a population perspective, autosomes spend an equal number of generations in both sexes while the X spends twice as many generations in females, these departures from the naïve expectations likely reflect differences between male and female life histories and their effects on mutation processes. Indeed, we show that the ratios observed across human populations can be explained by demographic history, assuming plausible, sex-specific mutation rates, generation times and reproductive variances.
An alternative mechanism of early nodal clustering and myelination onset in GABAergic neurons of the central nervous system
Authors: Thetiot Melina , Freeman Sean A. , Roux Thomas , Dubessy Anne-Laure , Aigrot Marie-Stéphane , Rappeneau Quentin , Lejeune François-Xavier , Tailleur Julien , Sol-Foulon Nathalie , Lubetzki Catherine , Desmazieres Anne
Published: September 2019

In vertebrates, fast saltatory conduction along myelinated axons relies on the node of Ranvier. How nodes assemble on CNS neurons is not yet fully understood. We recently highlighted that clusters similar to nodes can form prior to myelin deposition in hippocampal GABAergic neurons and are associated with increased conduction velocity. Here, we used a live imaging approach to characterize the intrinsic mechanisms underlying the assembly of these early clusters. We first demonstrated that their components can partially pre-assemble prior to membrane targeting and determined the molecular motors involved in their trafficking. We then demonstrated the key role of the protein β2Nav for clustering initiation. We further unraveled the fate of these early clusters, by showing that they participate in node formation, but also have an unexpected role in guiding oligodendrocyte processes prior to myelin deposition. Altogether our results shed light on an alternative mechanism of nodal clustering and myelination onset.
The Dynamics of Cytoplasmic mRNA Metabolism
Authors: Eisen Timothy J. , Eichhorn Stephen W. , Subtelny Alexander O. , Lin Kathy S. , McGeary Sean E. , Gupta Sumeet , Bartel David P.
Published: September 2019

For all but a few mRNAs, the dynamics of metabolism are unknown. Here, we developed an experimental and analytical framework for examining these dynamics for mRNAs from thousands of genes. mRNAs of mouse fibroblasts exit the nucleus with diverse intragenic and intergenic poly(A)-tail lengths. Once in the cytoplasm, they have a broad (1000-fold) range of deadenylation rate constants, which correspond to cytoplasmic lifetimes. Indeed, with few exceptions, degradation appears to occur primarily through deadenylation-linked mechanisms, with little contribution from either endonucleolytic cleavage or deadenylation-independent decapping. Most mRNA molecules degrade only after their tail lengths fall below 25 nt. Decay rate constants of short-tailed mRNAs vary broadly (1000-fold) and are more rapid for short-tailed mRNAs that had previously undergone more rapid deadenylation. This coupling helps clear rapidly deadenylated mRNAs, enabling the large range in deadenylation rate constants to impart a similarly large range in stabilities.

Highlights

mRNAs enter the cytoplasm with diverse intra- and intergenic lengths

mRNA deadenylation rates span a 1000-fold range and correspond to mRNA half-lives

After their tails become short, mRNAs decay at rates that span a 1000-fold range

More rapidly deadenylated mRNAs decay more rapidly upon reaching short tail lengths
DeepCryoPicker: Fully Automated Deep Neural Network for Single Protein Particle Picking in cryo-EM
Authors: Al-Azzawi Adil , Ouadou Anes , Highsmith Max R , Tanner John J. , Duan Ye , Cheng Jianlin
Published: September 2019

Cryo-electron microscopy (Cryo-EM) is widely used in the determination of the three-dimensional (3D) structures of macromolecules. Particle picking from 2D micrographs remains a challenging early step in the Cryo-EM pipeline due to the diversity of particle shapes and the extremely low signal-to-noise ratio (SNR) of micrographs. Because of these issues, significant human intervention is often required to generate a high-quality set of particles for input to the downstream structure determination steps. Here we propose a fully automated approach (DeepCryoPicker) for single particle picking based on deep learning. It first uses automated unsupervised learning to generate particle training datasets. Then it trains a deep neural network to classify particles automatically. Results indicate that the DeepCryoPicker compares favorably with semi-automated methods such as DeepEM, DeepPicker and RELION, with the significant advantage of not requiring human intervention.
Structural neural connectivity analysis in zebrafish with restricted anterograde transneuronal viral labeling and quantitative brain mapping
Authors: Ma Manxiu , Kler Stanislav , Pan Y. Albert
Published: September 2019

The unique combination of small size, translucency, and powerful genetic tools makes larval zebrafish a uniquely useful vertebrate system to investigate normal and pathological brain structure and function. While functional connectivity can now be assessed (via fluorescent calcium or voltage reporters) at the whole-brain scale, it remains challenging to systematically determine structural connections and identify connectivity changes during development or disease. To address this, we developedTracer withRestrictedAnterogradeSpread (TRAS), a novel vesicular stomatitis virus (VSV)-based neural circuit labeling approach. TRAS makes use of replication-incompetent VSV (VSVΔG) and a helper virus (lentivirus) to enable anterograde transneuronal spread between efferent axons and their direct postsynaptic targets but restricts further spread to downstream areas. We integrated TRAS with the Z-Brain zebrafish 3D atlas for quantitative connectivity analysis and identified targets of the retinal and habenular efferent projections, in patterns consistent with previous reports. We compared retinofugal connectivity patterns between wild-type anddown syndrome cell adhesion molecule-like 1(dscaml1) mutant zebrafish and revealed differences in topographical distribution and potential changes in the retinofugal targeting of excitatory versus inhibitory retinorecipient cells. These results demonstrate the utility of TRAS for quantitative structural connectivity analysis that would be valuable for detecting novel efferent targets and mapping connectivity changes underlying neurological or behavioral deficits.
Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration
Authors: Wert Katherine J. , Velez Gabriel , Vijayalakshmi Kanchustambham , Shankar Vishnu , Sengillo Jesse D. , Zare Richard N. , Bassuk Alexander G. , Tsang Stephen H. , Mahajan Vinit B.
Published: September 2019

Neurodegenerative diseases are debilitating, incurable disorders caused by progressive neuronal cell death. Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in retinal photoreceptor cell death and progresses to the loss of the entire neural retinal network. We previously found that proteomic analysis of the adjacent vitreous serves as way to indirectly biopsy the neural retina and identify changes in the retinal proteome. We therefore analyzed protein expression in liquid vitreous biopsies from autosomal recessive retinitis pigmentosa (arRP) patients withPDE6Amutations and arRP mice withPde6ɑ mutations.Proteomic analysis of retina and vitreous samples identified molecular pathways affected at the onset of photoreceptor cell death. Based on affected molecular pathways, arRP mice were treated with a ketogenic diet or metabolites involved in fatty-acid synthesis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle. Dietary supplementation of a single metabolite, ɑ-ketoglutarate, increased docosahexaeonic acid (DHA) levels, provided neuroprotection, and enhanced visual function in arRP mice. A ketogenic diet delayed photoreceptor cell loss, while vitamin B supplementation had a limited effect. Finally, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) revealed restoration of key metabolites that correlated with our proteomic findings: pyrimidine and purine metabolism (uridine, dihydrouridine, and thymidine), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs vision and provides a neuroprotective effect on the photoreceptor cells and inner retinal network.

One Sentence Summary

The study shows protein and metabolite pathways affected during neurodegeneration and that replenishing metabolites provides a neuroprotective effect on the retina.
Animal biosynthesis of complex polyketides in a photosynthetic partnership
Authors: Torres Joshua P. , Lin Zhenjian , Winter Jaclyn M. , Krug Patrick J. , Schmidt Eric W.
Published: September 2019

Animals are rich sources of complex polyketides, including pharmaceuticals, cosmetics, and other products. Most polyketides are associated with microbial or plant metabolism1. For this reason, symbiotic bacteria or dietary organisms are often the true producers of compounds found in animals2,3. Although increasing evidence suggests that animals themselves make some compounds4–7, the origin of most polyketides in animals remains unknown. This problem makes it difficult to supply useful animal compounds as drugs and severely constrains our understanding of chemical diversity and the scope of biosynthesis in nature. Here, we demonstrate that animals produce microbe-like complex polyketides. We report a previously undocumented but widespread branch of fatty acid synthase- (FAS)-like proteins that have been retooled by evolution to synthesize complex products. One FAS-like protein uses only methylmalonyl-CoA as a substrate, otherwise unknown in animal lipid metabolism, and is involved in an intricate partnership between a sea slug and captured chloroplasts. The enzyme’s complex, methylated polyketide product results from a metabolic interplay between algal chloroplasts and animal host cells, and also likely facilitates the survival of both symbiotic partners, acting as a photoprotectant for plastids and an antioxidant for the slug8–12. Thus, we find that animals can unexpectedly synthesize a large and medically useful class of structurally complex polyketides previously ascribed solely to microbes, and can use them to promote symbiotic organelle maintenance. Because this represents an otherwise uncharacterized branch of polyketide and fatty acid metabolism, we anticipate a large diversity of animal polyketide products and enzymes awaiting discovery.
FARFAR2: Improved de novo Rosetta prediction of complex global RNA folds
Authors: Watkins Andrew M. , Das Rhiju
Published: September 2019

Methods to predict RNA 3D structures from sequence are needed to understand the exploding number of RNA molecules being discovered across biology. As assessed during community-wide RNA-Puzzles trials, Rosetta’s Fragment Assembly of RNA with Full-Atom Refinement (FARFAR) enables accurate prediction of complex folds, but it remains unclear how much human intervention and experimental guidance is needed to achieve this performance. Here, we present FARFAR2, a protocol integrating recent innovations with updated RNA fragment libraries and helix modeling. In 16 of 21 RNA-Puzzles revisited without experimental data or expert intervention, FARFAR2 recovers structures that are more accurate than the original models submitted by our group and other participants during the RNA-Puzzles trials. In five prospective tests, pre-registered FARFAR2 models for riboswitches and adenovirus VA-I achieved 3–8 Å RMSD accuracies. Finally, we present a server and three large model archives (FARFAR2-Classics, FARFAR2-Motifs, and FARFAR2-Puzzles) to guide future applications and advances.
Stimuli-responsive aggregation-induced fluorescence in a series of biphenyl-based Knoevenagel products: effects of substituent active methylene groups on π–π interactions
Authors: Sarma Parishmita , Patir Khemnath , Sarmah Kashyap Kumar , Gogoi Sonit Kumar , Thakuria Ranjit , Das Pranab Jyoti
Published: September 2019

A series of three biphenyl-based Knoevenagel products (denoted 1a, 1b, 1c) with active methylene groups has been synthesized. Compounds 1a and 1b show strong solid-state fluorescence, whereas 1c displays low emission. Effects of substituent groups in condensed phase packing of the molecules have been investigated and correlated with their photophysical properties. Interestingly, compound 1a exhibits mechanofluorochromism with emission color changes from yellow to green (wavelength shift of 40 nm) after mechanical grinding. Furthermore, fluorescence of 1a and 1b is turned off under alkaline conditions, making them potential candidates for aggregation-enhanced emission-based pH sensors.
Crystal structure and Hirshfeld surface analysis of 2-hydroxy-7-methoxy-1,8-bis(2,4,6-trichlorobenzoyl)naphthalene
Authors: Muto Toyokazu , Iida Kikuko , Noguchi Keiichi , Yonezawa Noriyuki , Okamoto Akiko
Published: September 2019

In the title compound, C25H12Cl6O4, the two carbonyl groups are oriented in a same direction with respect to the naphthalene ring system and are situated roughly parallel to each other, while the two 2,4,6-trichlorobenzene rings are orientated in opposite directions with respect to the naphthalene ring system: the carbonyl C—(C=O)—C planes subtend dihedral angles of 45.54 (15) and 30.02 (15)° to the naphthalene ring system are. The dihedral angles formed by the carbonyl groups and the benzene rings show larger differences, the C=O vectors being inclined to the benzene rings by 46.39 (16) and 79.78 (16)°. An intramolecular O—H...O=C hydrogen bond forms an S(6) ring motif. In the crystal, no effective intermolecular hydrogen bonds are found; instead, O...Cl and C...Cl close contacts are observed along the 21 helical-axis direction. The Hirshfeld surface analysis reveals several weak interactions, the major contributor being Cl...H/H...Cl contacts.
The crystal structure of the zwitterionic co-crystal of 2,4-dichloro-6-{[(3-hydroxypropyl)azaniumyl]methyl}phenolate and 2,4-dichlorophenol
Authors: Uprety Bhawna , Arderne Charmaine
Published: September 2019

The title compound, C10H13Cl2NO2·C6H4Cl2O, was formed from the incomplete Mannich condensation reaction of 3-aminopropan-1-ol, formaldehyde and 2,4-dichlorophenol in methanol. This resulted in the formation of a co-crystal of the zwitterionic Mannich base, 2,4-dichloro-6-{[(3-hydroxypropyl)azaniumyl]methyl}phenolate and the unreacted 2,4-dichlorophenol. The compound crystallizes in the monoclinic crystal system (in space group Cc) and the asymmetric unit contains a molecule each of the 2,4-dichlorophenol and 2,4-dichloro-6-{[(3-hydroxypropyl)azaniumyl]methyl}phenolate. Examination of the crystal structure shows that the two components are clearly linked together by hydrogen bonds. The packing patterns are most interesting along the b and the c axes, where the co-crystal in the unit cell packs in a manner that shows alternating aromatic dichlorophenol fragments and polar hydrogen-bonded channels. The 2,4-dichlorophenol rings stack on top of one another, and these are held together by π–π interactions. The crystal studied was refined as an inversion twin.
Estimating the price range and the effect of price bundling strategies
Authors: Dominique-Ferreira Sérgio , Antunes Cristina
Published: September 2019

Purpose

The purpose of this paper is to investigate and identify the price sensitivity of consumers of three- and five-star hotels and to determine the impact of bundling strategies on consumers’ price sensitivity.

Design/methodology/approach

To calculate price sensitivity, authors apply the van Westendorp’s price sensitivity meter (PSM). To understand the impact of bundling strategies, univariate and bivariate techniques are applied.

Findings

PSM results reveal the optimal prices and the range of acceptable prices for three- and five-star hotel. The bundling strategy results reveal that five-star customers are less sensitive to mixed-leader bundling. Regarding mixed-joint bundling, managers could improve sales through bundling strategies if they selected an attractive service (e.g. restaurants).

Practical implications

Findings assist hotel managers to understand the different price sensitivities, according to the hotel typology. Managers can manage prices without the risk of losing market share or revenue. The results help managers in deciding which bundling strategies they can create, as well as the services to be included to achieve highest profitability.

Originality/value

No research to date to the best of the authors’ knowledge has attempted to understand and compare the role of bundling strategies in three- and five-stars hotels. Moreover, no research has attempted to measure and compare customers’ price sensitivity of three- and five-stars hotels.
Negative outcomes of positive brand relationships
Authors: Jain Kokil , Sharma Isha
Published: September 2019

Purpose

This paper aims to understand how strong brand attachment can intensify the feeling of perceived betrayal, leading to brand hate after a negative experience with the brand. The study further investigates how consumers make causal attributions for negative experiences when strong brand attachment exists. The moderating effect of a narcissistic personality in the dissemination of negative electronic word of mouth (eWOM) following brand hate is also tested.

Design/methodology/approach

The study uses a within-the-subject repeated measures experimental design. A total of 202 college students were exposed to two treatments (high versus no brand attachment), involving a situation of product failure of a smart phone brand. A total of 135 responses were used to compare the outcomes of the two treatments using multivariate analysis. The data of high brand attachment treatment (N = 202) were used to test the proposed research model using partial least square-structural equation modelling.

Findings

The results suggest that having a strong positive relationship with the brand can generate stronger feelings of perceived betrayal and brand hate after the brand transgresses the consumer’s expectations. The results indicate that resentful customers can resort to eWOM after feeling betrayed, even though the prior relationship with the brand was strong.

Originality/value

This paper extends the work on perceived betrayal to study brand hate and proposes that brand hate can arise even if there is a strong brand attachment. It contributes to the growing body of literature on brand hate and its possible antecedents. Additionally, the study poses some crucial managerial implications for the brand managers by suggesting that strong brand relationships not always ensure loyalty or commitment and can lead to consequences that are damaging for the brand equity.