bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroimaging Biomarkers at Baseline Predict Electroconvulsive Therapy Overall Clinical Response in Depression
Authors: Levy Anna , Taib Simon , Arbus Christophe , Péran Patrice , Sauvaget Anne , Schmitt Laurent , Yrondi Antoine
Published: January 2019

Objective

Major depressive disorder is a frequent and disabling disease and can be treated with antidepressant drugs. When faced with severe or resistant major depressive disorder, however, psychiatrists may resort to electroconvulsive therapy (ECT). Although very effective, the response falls short of 100%. A recent meta-analysis established clinical and biological predictive factors of the response to ECT. We decided to explore neuroimaging biomarkers that could be predictors of the ECT response.

Methods

We performed a systematic literature review up to January 1, 2018, using a Boolean combination of MeSH terms. We included 19 studies matching our inclusion criteria.

Results

Lower hippocampal, increased amygdala, and subgenual cingulate gyrus volumes were predictive for a better ECT response. Functional magnetic resonance imaging also found that the connectivity between the dorsolateral prefrontal cortex and posterior default-mode network is predictive of increased efficacy. Conversely, deep white matter hyperintensities in basal ganglia and Virchow-Robin spaces, medial temporal atrophy, ratio of left superior frontal to left rostral middle frontal cortical thickness, cingulate isthmus thickness asymmetry, and a wide range of gray and white matter anomalies were predictive for a poorer response.

Conclusions

Our review addresses the positive or negative predictive value of neuroimaging biomarkers for the ECT response, indispensable in a personalized medicine dynamic. These data could reduce the risk of nonresponders or resistance with earlier effective management. It might also help researchers elucidate the complex pathophysiology of depressive disorders and the functioning of ECT.
Survival of adult barn owls is linked to corticosterone levels
Authors: Béziers Paul , Korner-Nievergelt Fränzi , Jenni Lukas , Roulin Alexandre , Almasi Bettina
Published: January 2019

Glucocorticoid hormones, such as corticosterone, are fundamental in the translation of external stimuli into physiological adjustments that promote the survival of an organism in face of changes in its environment. At baseline levels, corticosterone is crucial in regulating daily life metabolism and energy expenditure, whereas the acute corticosterone response promotes short-term physiological and behavioral responses to unpredictable environmental challenges. Given their different physiological effects and their role in mediating fitness components, it is still unclear whether and how inter-individual variation in baseline corticosterone levels and acute stress-response levels can affect the survival of organisms. We used 13 years of capture-recapture and dead recovery data combined with 11 years of corticosterone measurements taken on breeding barn owls (Tyto alba) to investigate how survival probability varies in relation to baseline and stress-induced corticosterone levels. Our study shows that males with a higher level of both baseline and stress-induced corticosterone levels have a higher probability of surviving than individuals with lower corticosterone levels. In females, survival probability was higher in individuals presenting elevated stress-induced corticosterone levels but was not significantly associated to baseline corticosterone levels. Our results suggest that in the barn owl the stress-induced corticosterone response is a better proxy of adult survival than baseline corticosterone levels. Further studies investigating the link between corticosterone levels and different fitness components as well as the environmental factors (e.g. weather, development conditions, disease and predation risk) leading to such endocrine phenotypes are needed to identify the costs and benefits of presenting high and low corticosterone profiles.
Identification and mitigation of pervasive off-target activity in CRISPR-Cas9 screens for essential non-coding elements
Authors: Tycko Josh , Wainberg Michael , Marinov Georgi K. , Ursu Oana , Hess Gaelen T. , Ego Braeden K. , Aradhana  , Li Amy , Truong Alisa , Trevino Alexandro E. , Spees Kaitlyn , Yao David , Kaplow Irene M. , Greenside Peyton G. , Morgens David W. , Phanstiel Douglas H. , Snyder Michael P. , Bintu Lacramioara , Greenleaf William J. , Kundaje Anshul , Bassik Michael C.
Published: January 2019

Pooled CRISPR-Cas9 screens have recently emerged as a powerful method for functionally characterizing regulatory elements in the non-coding genome, but off-target effects in these experiments have not been systematically evaluated. Here, we conducted a genome-scale screen for essential CTCF loop anchors in the K562 leukemia cell line. Surprisingly, the primary drivers of signal in this screen were single guide RNAs (sgRNAs) with low specificity scores. After removing these guides, we found that there were no CTCF loop anchors critical for cell growth. We also observed this effect in an independent screen fine-mapping the core motifs in enhancers of the GATA1 gene. We then conducted screens in parallel with CRISPRi and CRISPRa, which do not induce DNA damage, and found that an unexpected and distinct set of off-targets also caused strong confounding growth effects with these epigenome-editing platforms. Promisingly, strict filtering of CRISPRi libraries using GuideScan specificity scores removed these confounded sgRNAs and allowed for the identification of essential enhancers, which we validated extensively. Together, our results show off-target activity can severely limit identification of essential functional motifs by active Cas9, while strictly filtered CRISPRi screens can be reliably used for assaying larger regulatory elements.
Knowledge, attitude and practices on dengue fever among paediatric and adult in-patients in Metro Manila, Philippines
Authors: M. Herbuela Von Ralph Dane , de Guzman Ferdinand S. , Sobrepeña Girly D. , F. Claudio Andrew Benedict , V. Tomas Angelica Cecilia , Arriola-delos Reyes Carmina M. , Regalado Rachele A. , Teodoro Mariama M. , Watanabe Kozo
Published: January 2019

Background

Knowledge, attitude and practice (KAP) studies have included mainly community-based samples, yet, investigation on in-patients with Dengue fever (DF) through hospital-based surveillance has not been done.

Methods

This study aimed to assess and compare the KAP, identify its determinants and protective factors among 250 clinically or serologically confirmed paediatric (n = 233) and adult patients (n = 17) with DF and 250 youth (n = 233) and adult (n = 17) controls.

Results

Paediatric patients with DF had significantly higher knowledge (P < 0.05) and practice (P < 0.05) domains mean scores than adult patients with DF and significantly lower practice mean scores than youth controls (P < 0.05). Being senior high school, days in the hospital and rash determined increased KAP among paediatric patients with DF while no significant determinants were found among adult patients with DF. Mosquito-eating fish, screen windows and Dengue vaccine were protective factors against DF, though, further studies should confirm these results. Moreover, there was a significant positive correlation between knowledge and attitude (P < 0.01) of paediatric patients with DF, however, similar with adult patients with DF, these domains did not correlate with their practices against DF.

Conclusion

This suggests that the translation of knowledge and attitude to better practices against DF was poor. Thus, it is necessary to structure health programs on models that facilitate behavioural change among children and adults.
RAI1 Regulates Activity-Dependent Nascent Transcription and Synaptic Scaling
Authors: Garay Patricia M. , Chen Alex , Tsukahara Takao , Kohen Rafi , Christian Althaus J. , Wallner Margarete A. , Giger Roman J. , Sutton Michael A. , Iwase Shigeki
Published: January 2019

Long-lasting forms of synaptic plasticity such as synaptic scaling are critically dependent on transcription. Activity-dependent transcriptional dynamics in neurons, however, have not been fully characterized, because most previous efforts relied on measurement of steady-state mRNAs. Here, we profiled transcriptional dynamics of primary neuronal cultures undergoing network activity shifts using nascent RNA sequencing. We found pervasive transcriptional changes, in which ~45% of expressed genes respond to network activity shifts. Notably, the majority of these genes respond to increases or decreases of network activity uniquely, rather than reciprocally. We further linked the chromatin regulator Retinoic acid induced 1 (RAI1), the Smith-Magenis Syndrome gene, to the specific transcriptional program driven by reduced network activity. Finally, we show that RAI1 is essential for homeostatic synaptic upscaling but not downscaling. These results demonstrate the utility of bona fide transcription profiling to discover mechanisms of activity-dependent chromatin remodeling that underlie normal and pathological synaptic plasticity.
Capturing multiple-type interactions into practical predictors of type replacement following HPV vaccination
Authors: Man Irene , Auranen Kari , Wallinga Jacco , Bogaards Johannes A.
Published: January 2019

Current HPV vaccines target a subset of the oncogenic human papillomavirus (HPV) types. If HPV types compete during infection, vaccination may trigger replacement by the non-targeted types. Existing approaches to assess the risk of type replacement have focussed on detecting competitive interactions between pairs of vaccine and non-vaccine types. However, methods to translate any inferred pairwise interactions into predictors of replacement have been lacking. In this paper, we develop practical predictors of type replacement in a multi-type setting, readily estimable from pre-vaccination longitudinal or cross-sectional prevalence data. The predictors we propose for replacement by individual non-targeted types take the form of weighted cross hazard ratios of acquisition versus clearance, or aggregate odds ratios of coinfection with the vaccine types. We elucidate how the hazard-based predictors incorporate potentially heterogeneous direct and indirect type interactions by appropriately weighting type-specific hazards and show when they are equivalent to the odds-based predictors. Additionally, pooling type-specific predictors proves to be useful for predicting increase in the overall non-vaccine-tvpe prevalence. Using simulations, we demonstrate good performance of the predictors under different interaction structures. We discuss potential applications and limitations of the proposed methodology in predicting type replacement, as compared to existing approaches.
The effectiveness and cost effectiveness of a hospital avoidance program in a residential aged care facility
Authors: Carter Hannah , Lee Xing , Dwyer Trudy , Jeffrey Dee , O’Neill Barbara , Doran Chris , Parkinson Lynne , Osborne Sonya , Reid-Searl Kerry , Graves Nicholas
Published: January 2019

Background

Residential aged care facility residents experience high rates of hospital admissions which are stressful, costly and often preventable.

Design

Prospective pre-post cohort study and decision model analysis

Intervention

A decision-support tool was implemented to enable nursing staff to detect, refer and quickly respond to early signals of a deteriorating resident. Advanced clinical skills training, new diagnostic equipment and guided support from clinical lead nurses and nurse practitioners was provided to support nursing staff in the delivery of appropriate sub-acute care.

Outcome measures

Rate of hospital admissions; length of stay; incremental cost per QALY; net monetary benefit.

Results

The hospital avoidance program was associated with a 19% reduction in annual hospital admissions and a 31% reduction in the average length of stay. When modelled in a cohort of 1,000 residents the program resulted in a total of 1,606 fewer hospital bed days per annum. This contributed to a total cost saving of $2.6 million and 0.62 incremental QALYs gained per 1,000 residents. The program had a positive net monetary benefit and was considered cost-effective, even when the willingness to pay for health care gains was set to zero. A probabilistic sensitivity analysis estimated that there was an 86% probability that the program was cost-effective after taking the uncertainty of the model inputs into account.

Conclusions

This study provides compelling evidence for the effectiveness and cost-effectiveness of a RACF nurse led sub-acute care program in preventing unnecessary hospital admissions.
Closely related Cryptococcus neoformans strains possess differential virulence both in humans and the mouse inhalation model
Authors: Mukaremera Liliane , MacDonald Tami R. , Nielsen Judith N. , Akampulira Andrew , Schutz Charlotte , Taseera Kabanda , Muzoora Conrad , Meintjes Graeme , Meya David B. , Boulware David R. , Nielsen Kirsten
Published: January 2019

Cryptococcal meningitis (CM) causes high rates of HIV-related mortality, yet Cryptococcus factors influencing patient outcome are not well understood. Pathogen-specific traits, such as the strain genotype and degree of antigen shedding, are associated with clinical outcome but the underlying biology remains elusive. In this study, we examined factors determining disease outcome in HIV-infected cryptococcal meningitis patients infected with C. neoformans strains with the same multi-locus sequence type. Both patient mortality and survival were observed during infections with the same sequence type. Disease outcome did not correlate with underlying patient immune deficiencies. Patient mortality was associated with higher antigen levels, fungal burden in the CSF, and low CSF fungal clearance. Virulence of a subset of clinical strains with the same sequence type were analyzed using the mouse inhalation model of cryptococcosis. We showed a strong correlation between human and mouse mortality rates, demonstrating the mouse inhalation model recapitulates human infection. Similar to human infection, the ability to multiply in vivo, demonstrated by high fungal burden in the lung and brain tissues, was associated with mouse mortality. Mortality rate was not associated with single C. neoformans virulence factors in vitro or in vivo; rather, a trend in mortality rate correlated with a suite of traits. These observations show that genotype similarities between C. neoformans strains do not necessarily translate into similar virulence either in the mouse model or in human patients. In addition, our results show that in vitro assays do not fully reproduce in vivo conditions that influence C. neoformans virulence.
A Simple Cross-Linking/Mass Spectrometry Workflow to Study System-Wide Protein Interactions
Authors: Götze Michael , Iacobucci Claudio , Ihling Christian , Sinz Andrea
Published: January 2019

We present a cross-linking/mass spectrometry (XLMS) workflow for performing proteome-wide cross-linking analyses within one week. The workflow is based on the commercially available MS-cleavable cross-linker disuccinimidyl dibutyric urea (DSBU) and can be employed by every lab having access to a mass spectrometer with tandem MS capabilities. We provide an updated version 2.0 of the freeware software tool MeroX, available at www.StavroX.com, that allows conducting fully automated and reliable studies delivering insights into protein-protein interaction networks and protein conformations at the proteome level. We exemplify our optimized workflow for mapping protein-protein interaction networks in Drosophila melanogaster embryos on a system-wide level. From cross-linked Drosophila embryo extracts, we detected 18,037 cross-link spectrum matches corresponding to 5,129 unique cross-linked residues in biological triplicate experiments at 5% FDR (3,098 at 1% FDR). Among these, 1,237 interprotein cross-linking sites were identified that contain valuable information on protein-protein interactions. The remaining 3,892 intra-protein cross-links yield information on conformational changes of proteins in their cellular environment.
Tau pathology in early Alzheimer’s disease disrupts selective neurophysiological network dynamics
Authors: Kocagoncu Ece , Quinn Andrew , Firouzian Azadeh , Cooper Elisa , Greve Andrea , Gunn Roger , Green Gary , Woolrich Mark W. , Henson Richard N. , Lovestone Simon ,   Deep and Frequent Phenotyping study team, Rowe James B.
Published: January 2019

The role of aggregation of misfolded Tau protein in the pathogenesis of Alzheimer’s disease is the subject of rapid biomarker development and new therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography (E/MEG) in combination with [18F]AV1451 PET scanning to quantify Tau-dependent network disruption. Using a graph theoretical approach to MEG connectivity, we quantified nodal measures of functional segregation, centrality and efficiency of information transfer. We correlated these metrics against the nodes’ uptake of [18F]AV1451. There were both regional- and frequency-specific effects of Tau levels on the efficiency of information transfer and network segregation in early AD. Tau correlated with temporal regional participation coefficient (in delta, theta, beta bands); and temporal lobar eigenvector centrality (in theta, alpha, beta bands), but greater eccentricity at higher frequencies (gamma). The results support the translational development of neurophysiological “signatures” as biomarkers of Alzheimer’s disease, with potential to facilitate experimental medicines studies.
Comprehensive analysis of RNA-seq kits for standard, low and ultra-low quantity samples
Authors: Palomares Marie-Ange , Dalmasso Cyril , Bonnet Eric , Derbois Céline , Brohard-Julien Solène , Ambroise Christophe , Battail Christophe , Deleuze Jean-François , Olaso Robert
Published: January 2019

High-throughput RNA-sequencing has become the gold standard method for whole-transcriptome gene expression analysis, and is widely used in numerous applications to study cell and tissue transcriptomes. It is also being increasingly used in a number of clinical applications, including expression profiling for diagnostics and alternative transcript detection. However, despite its many advantages, RNA sequencing can be challenging in some situations, for instance in cases of low input amounts or degraded RNA samples. Several protocols have been proposed to overcome these challenges, and many are available as commercial kits. In this study, we comprehensively test three recent commercial technologies for RNA-seq library preparation (TruSeq, SMARTer and SMARTer Ultra-Low) on human reference tissue preparations, using standard (1μg), low (100 and 10 ng) and ultra-low (< 1 ng) input amounts, and for mRNA and total RNA, stranded or unstranded. The results are analyzed using read quality and alignment metrics, gene detection and differential gene expression metrics. Overall, we show that the TruSeq kit performs well with an input amount of 100 ng, while the SMARTer kit shows degraded performance for inputs of 100 and 10 ng, and the SMARTer Ultra-Low kit performs relatively well for input amounts < 1 ng. All the results are discussed in detail, and we provide guidelines for biologists for the selection of a RNA-seq library preparation kit.
The reconstitution of body mass index in HIV positive subjects under antiretroviral treatment in Kinshasa
Authors: Tshima Guyguy Kabundi , Mulumba Paul Madishala
Published: January 2019

Objective

We aimed to evaluate BMI changes in HIV adults’ subjects in the first year of ART in malaria endemic areas.

Methods

We used linear regression analysis showing that the change in weight at 12 months (y) in a malaria-endemic area is related to malaria infection at admission and its different episodes as illustrated by equation: y = a + bxi + ε, where x is malaria on admission, i refers to episodes of clinical malaria infection during the year, b is the slope, a is a constant and ε are confounding factors such as tuberculosis or poor eating habits.

Results

We found a positive value for b (b = 0.697), and this shows that weight loss at 12 months is correlated with the diagnosis of severe malaria at admission. In other words, severe malaria eliminates the weight gained under ART.

Conclusions

Malaria is the leading cause of weight loss under ART.

Important recommendation for future:

This study suggests nutritional education based on local foods containing antioxidants to fight the oxidative stress generated by HIV and stimulated byPlasmodium falciparumduring febrile episodes. Oxidative stress is blocked by NADPHase which is a metalloenzyme based on selenium.

Thus, to prevent a weight loss or the occurrence of the protein-energy malnutrition among people living with HIV, it is necessary to use the nutritional education.

Objectif

Nous voulions évaluer les modifications de l’IMC chez les patients VIH adultes au cours de la première année du traitement antirétroviral dans une zone d’endémie palustre

Matériel et Méthodes

Nous avons utilisé une analyse de régression linéaire montrant que la variation de poids à 12 mois (y) dans une zone d’endémie palustre est liée à l’infection palustre à l’admission et à ses différents épisodes, comme l’illustre l’équation suivante: y = a + bxi + ε, où x est le paludisme à l’admission, i les épisodes de paludisme clinique survenus au cours de l’année, b est la pente, a est une constante et ε sont des facteurs de confusion tels que la tuberculose ou de mauvaises habitudes alimentaires..

Résultats

Nous avons trouvé une valeur positive pour b (b = 0,697), ce qui montre que la perte de poids à 12 mois est en corrélation avec le diagnostic de paludisme grave à l’admission. En d’autres termes, le paludisme grave élimine le poids gagné sous traitement antirétroviral.

Conclusions

Le paludisme est la principale cause de perte de poids sous ARV.

Recommandation importante pour l’avenir : Cette étude suggère une éducation nutritionnelle basée sur des aliments locaux contenant des anti-oxydants pour lutter contre le stress oxydatif généré par le VIH et stimulé par lePlasmodium falciparumlors des poussées fébriles. Le stress oxydatif est bloqué par la NADPHase qui est une métalloenzyme à base de sélénium. Ainsi, il est nécessaire d’utiliser l’éducation nutritionnelle pour prévenir la perte du poids sous ARV.
Effects of body mass index on relationship status, social contact, and socioeconomic position: Mendelian Randomization study in UK Biobank
Authors: Howe Laura D , Kanayalal Roshni , Beaumont Robin N , Davies Alisha R , Frayling Timothy M , Harrison Sean , Jones Samuel E , Sassi Franco , Wood Andrew R , Tyrrell Jessica
Published: January 2019

Objective

To assess whether body mass index (BMI) has a causal effect on social and socioeconomic factors, including whether both high and low BMI can be detrimental.

Design

Mendelian Randomization, using genetic variants for BMI to obtain unconfounded estimates, and non-linear Mendelian Randomization.

Setting

UK Biobank.

Participants

378,244 men and women of European ancestry, mean age 57 (SD 8 years).

Main outcome measures

Townsend deprivation index, income, age completed full time education, degree level education, job class, employment status, cohabiting relationship status, participation in leisure and social activities, visits from friends and family, and having someone to confide in.

Results

Higher BMI was causally associated with higher deprivation, lower income, fewer years of education, lower odds of degree-level education and skilled employment. For example, a 1 SD higher genetically-determined BMI (4.8kg/m2 in UK Biobank) was associated with £1,660 less income per annum [95%CI: £950, £2,380]. Non-linear Mendelian Randomization provided evidence that both low BMI (bottom decile, <22kg/m2) and high BMI (top seven deciles, >24.6kg/m2) can increase deprivation and reduce income. In men only, higher BMI was related to lower participation in leisure and social activities. There was no evidence of causal effects of BMI on visits from friends and family or in having someone to confide in. Non-linear Mendelian Randomization analysis showed that low BMI (bottom three deciles, <23.5kg/m2) reduces the odds of cohabiting with a partner or spouse for men, whereas high BMI (top two deciles, >30.7kg/m2) reduces the odds of cohabitation with a partner or spouse for women.

Conclusions

BMI affects social and socioeconomic outcomes, with both high and low BMI being detrimental for some measures of SEP. This suggests that in addition to health benefits, maintaining healthy ranges of BMI across the population could have benefits both for individuals and society.
Reproducibility of functional brain alterations in major depressive disorder: evidence from a multisite resting-state functional MRI study with 1,434 individuals
Authors: Xia Mingrui , Si Tianmei , Sun Xiaoyi , Ma Qing , Liu Bangshan , Wang Li , Meng Jie , Chang Miao , Huang Xiaoqi , Chen Ziqi , Tang Yanqing , Xu Ke , Gong Qiyong , Wang Fei , Qiu Jiang , Xie Peng , Li Lingjiang , He Yong ,   DIDA-Major Depressive Disorder Working Group
Published: January 2019

Resting-state functional MRI (R-fMRI) studies have demonstrated widespread alterations in brain function in patients with major depressive disorder (MDD). However, a clear and consistent conclusion regarding a repeatable pattern of MDD-relevant alterations is still limited due to the scarcity of large-sample, multisite datasets. Here, we address this issue by including a large R-fMRI dataset with 1,434 participants (709 patients with MDD and 725 healthy controls) from five centers in China. Individual functional activity maps that represent very local to long-range connections are computed using the amplitude of low-frequency fluctuations, regional homogeneity and distance-related functional connectivity strength. The reproducibility analyses involve different statistical strategies, global signal regression, across-center consistency, clinical variables, and sample size. We observed significant hypoactivity in the orbitofrontal, sensorimotor, and visual cortices and hyperactivity in the frontoparietal cortices in MDD patients compared to the controls. These alterations are not affected by different statistical analysis strategies, global signal regression and medication status and are generally reproducible across centers. However, these between-group differences are partially influenced by the episode status and the age of disease onset in patients, and the brain-clinical variable relationship exhibits poor cross-center reproducibility. Bootstrap analyses reveal that at least 400 subjects in each group are required to replicate significant alterations (an extent threshold of P<.05 and a height threshold of P<.001) at 50% reproducibility. Together, these results highlight reproducible patterns of functional alterations in MDD and relevant influencing factors, which provides crucial guidance for future neuroimaging studies of this disorder.
Ontological Dimensions of Cognitive-Neural Mappings
Authors: Bolt Taylor , Nomi Jason S. , Arens Rachel , Vij Shruti G. , Riedel Michael , Salo Taylor , Laird Angela R. , Eickhoff Simon B. , Uddin Lucina Q.
Published: January 2019

The growing literature reporting results of cognitive-neural mappings has increased calls for an adequate organizing ontology, or taxonomy, of these mappings. This enterprise is non-trivial, as relevant dimensions that might contribute to such an ontology are not yet agreed upon. We propose that any candidate dimensions should be evaluated on their ability to explain observed differences in functional neuroimaging activation patterns. In this study, we use a large sample of task-based functional magnetic resonance imaging (task-fMRI) results and a data-driven strategy to identify these dimensions. First, using a data-driven dimension reduction approach and multivariate distance matrix regression (MDMR), we quantify the variance among activation maps that is explained by existing ontological dimensions. We find that ‘task paradigm’ categories explain the most variance among task-activation maps than other dimensions, including latent cognitive categories. Surprisingly, ‘study ID’, or the study from which each activation map was reported, explained close to 50% of the variance in activation patterns. Using a clustering approach that allows for overlapping clusters, we derived data-driven latent activation states, associated with re-occurring configurations of the canonical fronto-parietal/salience, sensory-motor, and default mode network activation patterns. Importantly, with only four data-driven latent dimensions, one can explain greater variance among activation maps than all conventional ontological dimensions combined. These latent dimensions may inform a data-driven cognitive ontology, and suggest that current descriptions of cognitive processes and the tasks used to elicit them do not accurately reflect activation patterns commonly observed in the human brain.
Combinatorial Treatment Increases IKAP Levels in Human Cells Generated from Familial Dysautonomia Patients
Authors: Yannai Sivan , Zonszain Jonathan , Donyo Maya , Ast Gil
Published: January 2019

Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from a point mutation at the 5’ splice site of intron 20 in the IKBKAP gene. This mutation decreases production of the IKAP protein, and treatments that increase the level of the full-length IKBKAP transcript are likely to be of therapeutic value. We previously found that phosphatidylserine (PS), an FDA-approved food supplement, elevates IKAP levels in cells generated from FD patients. Here we demonstrate that combined treatment of cells generated from FD patients with PS and kinetin or PS and the histone deacetylase inhibitor trichostatin A (TSA) resulted in an additive elevation of IKAP compared to each drug alone. This indicates that the compounds influence different pathways. We also found that pridopidine enhances production of IKAP in cells generated from FD patients. Pridopidine has an additive effect on IKAP levels when used in combination with kinetin or TSA, but not with PS; suggesting that PS and pridopidine influence IKBKAP levels through the same mechanism. Indeed, we demonstrate that the effect of PS and pridopidine is through sigma-1 receptor-mediated activation of the BDNF signaling pathway. A combination treatment with any of these drugs with different mechanisms has potential to benefit FD patients.
Survival Analysis and Prognostic Factors of Time to First Domestic Violence after Marriage among Married Women in Africa
Authors: Fagbamigbe A. F. , Akintayo A. O. , Oshodi O. , Makinde F. T. , Babalola M. , Damilola E. A. , Enabor O. C.
Published: January 2019

Background

Domestic violence remains a public health challenge worldwide. Studies in the sub-Saharan Africa have shown high level of violence against women, especially from intimate partners. What is not known is how soon domestic violence happens after marriage among ever-married women. This study assessed the timing of first domestic violence among ever-married women and identified its determinants in Nigeria, Kenya, and Mozambique.

Data and Method

Data of 56440 ever-married women of reproductive age pooled from DHS conducted in Nigeria (2013), Kenya (2014) and Mozambique (2011) was used. The timing of first domestic violence was estimated as the period between marriage and the first experience of domestic violence. Ever-married women without violence experience were censored on the date of the survey. Survival analysis techniques were used to assess the timing and the factors influencing the timing p=0.05.

Result

The prevalence of domestic violence in Nigeria, Kenya and Mozambique was 12.1%, 7.5%, and 15.4% respectively. The median time to first domestic violence across the three countries was 3 years. We found a higher prevalence of violence among formerly married women than currently married women. Women who married before age 20 years have a significantly higher risk of experiencing violence (Nigeria: aHR= 2.36 (95% CI (1.97- 2.83), Kenya: aHR= 1.89 (95% CI (1.31- 2.73) and Mozambique: aHR=1.60 (95% CI (1.24 −2.12)) than older women. Women in poorer wealth quintile were at higher risk of violence across the three countries. Other factors associated with the timing of first domestic violence are respondents’, location of residence and educational attainment.

Conclusion

Domestic violence has remained high in Mozambique, Nigeria and Kenya. There was a significant relationship between timing of first domestic violence and whether or not a woman remains in a marriage. Education and delayed marriage could help reduce violence in marriage.
China’s Development Assistance for Health on Key Tropical Diseases: A SWOT Analysis
Authors: Li Hong-Mei , Ding Wei , Huang Lu-Lu , Ma Xue-Jiao , Qian Ying-Jun , Wang Duo-Quan , Xiao Ning , Guan Ya-Yi , Zhou Xiao-Nong
Published: January 2019

Background

WHO focused and gave priority on ten serious tropical diseases, while China has made remarkable achievements on tropical diseases control. In addition, China has a history of more than 60 years in the health assistance, however, its assistance for tropical diseases started late.

Methods

A qualitative questionnaire was distributed to inquiry the opinions of professionals on China’s health assistance on tropical diseases and published articles were searched to collect those data. SWOT analysis, as a tool of qualitative analysis, was used to classify and evaluate the current strengths, the weakness, the opportunities, and the threats of health assistance on tropical diseases in China.

Results

Based on SWOT analysis, the internal factors and external environments are obtained. The strengths are focused on China’s achievements on tropical diseases control, surveillance response system of tropical diseases, and human resources of public health; the weakness laid on sustainability of aid projects and funding, applicability of Chinese experience, and lack of composite talents; the opportunities are mainly in the global need of tropical diseases control, China’s health cooperation in Belt & Road and Africa, and the actively participating of international organizations in health assistance; as well as the threats are reflected in the complex international situation, domestic needs of tropical diseases control, and the significant gaps between China and developed countries.

Conclusion

The internal strengths and weaknesses of development assistance for health on tropical diseases are clearly presented in the SWOT framework, as well as the external opportunities and threats and corresponding coping strategies. In the era of global health, China should strengthen and improve the health assistance for tropical diseases.

Author summary

Tropical diseases are serious infections in tropical and sub-tropical regions, with billions of persons infected and millions of deaths every year, especially in Africa. WHO also called for global efforts to control and eliminate tropical diseases. In the era of global health, development assistance on tropical diseases is important to demonstrate the soft power of national diplomacy, and China has started its health assistance in 1963. In this paper, a qualitative questionnaire and published articles were combined to collect data, and then SWOT analysis was used to analyze the internal factors and external environment, that is the current strengths, the weakness, the opportunities, and the threats of the China’s Health Assistance on key tropical diseases. Based on those results, we put forward the countermeasures and suggestions for the future cooperation of tropical diseases. At the end of this paper, we call on Chinese professionals should make use of their own advantages and actively improve the global tropical diseases control.
The evolution of collective infectious units in viruses
Authors: Leeks Asher , Sanjuán Rafael , West Stuart A.
Published: January 2019

Viruses frequently spread among cells or hosts in groups, with multiple viral genomes inside the same infectious unit. These collective infectious units can consist of multiple viral genomes inside the same virion, or multiple virions inside a larger structure such as a vesicle. Collective infectious units deliver multiple viral genomes to the same cell simultaneously, which can have important implications for viral pathogenesis, antiviral resistance, and social evolution. However, little is known about why some viruses transmit in collective infectious units, whereas others do not. We used a simple evolutionary approach to model the potential costs and benefits of transmitting in a collective infectious unit. We found that collective infectious units could be favoured if cells infected by multiple viral genomes were significantly more productive than cells infected by just one viral genome, and especially if there were also efficiency benefits to packaging multiple viral genomes inside the same infectious unit. We also found that if some viral sequences are defective, then collective infectious units could evolve to become very large, but that if these defective sequences interfered with wild-type virus replication, then collective infectious units were disfavoured.
Accuracy of gene expression prediction from genotype data with PrediXcan varies across diverse populations
Authors: Mikhaylova Anna , Thornton Timothy
Published: January 2019

Predicting gene expression with genetic data has garnered significant attention in recent years. PrediXcan is one of the most widely used gene-based association methods for testing imputed gene expression values with a phenotype due to the invaluable insight the method has shown into the relationship between complex traits and the component of gene expression that can be attributed to genetic variation. The prediction models for PrediXcan, however, were obtained using supervised machine learning methods and training data from the Depression and Gene Network (DGN) and the Genotype-Tissue Expression (GTEx) data, where the majority of subjects are of European descent. Many genetic studies, however, include samples from multi-ethnic populations, and in this paper we assess the accuracy of gene expression predictions with PrediXcan in diverse populations. Using transcriptomic data from the GEUVADIS (Genetic European Variation in Health and Disease) RNA sequencing project and whole genome sequencing data from the 1000 Genomes project, we evaluate and compare the predictive performance of PrediXcan in an African population (Yoruban) and four European populations. Prediction results are obtained using a range of models from PrediXcan weight databases, and Pearson’s correlation coefficient is used to measure prediction accuracy. We demonstrate that the predictive performance of PrediXcan varies across populations (F-test p-value < 0.001), where prediction accuracy is the worst in the Yoruban sample compared to European samples. Moreover, the performance of PrediXcan varies not only among distant populations, but also among closely related populations as well. We also find that the qualitative performance of PrediXcan for the populations considered is consistent across all weight databases used.
Mix-and-inject XFEL crystallography reveals gated conformational dynamics during enzyme catalysis
Authors: Dasgupta Medhanjali , Budday Dominik , de Oliveira Saulo H.P. , Madzelan Peter , Marchany-Rivera Darya , Seravalli Javier , Hayes Brandon , Sierra Raymond G. , Boutet Sebastian , Hunter Mark , Alonso-Mori Roberto , Batyuk Alexander , Wierman Jennifer , Lyubimov Artem , Brewster Aaron S. , Sauter Nicholas K. , Applegate Gregory A. , Tiwari Virendra K. , Berkowitz David B. , Thompson Michael C. , Cohen Aina , Fraser James S. , Wall Michael E. , van den Bedem Henry , Wilson Mark A.
Published: January 2019

Summary Paragraph

Protein dynamics play an important role in enzyme catalysis1-4. Many enzymes form covalent catalytic intermediates that can alter enzyme structure and conformational dynamics5,6. How these changes in enzyme structure and dynamics facilitate passage along the reaction coordinate is a fundamental unanswered question in structural enzymology. Here, we use Mix-and-Inject Serial Femtosecond X-ray Crystallography (MISC) at an X-ray Free Electron Laser (XFEL)7-10, ambient temperature X-ray crystallography, computer simulations, and enzyme kinetics to characterize how covalent modification of the active site cysteine residue in isocyanide hydratase (ICH) alters the enzyme’s conformational ensemble throughout the catalytic cycle. With MISC, we directly observe formation of a thioimidate covalent intermediate during ICH catalysis. The intermediate exhibits changes in the active site electrostatic environment, disrupting a hydrogen bond and triggering a cascade of conformational changes in ICH. X-ray-induced formation of a cysteine-sulfenic acid at the catalytic nucleophile (Cys101-SOH) with conventional crystallography at ambient temperature induces similar conformational shifts, demonstrating that these enzyme motions result from cysteine modification. Computer simulations show how cysteine modification-gated structural changes allosterically propagate through the ICH dimer. Mutations at Gly150 that modulate helical mobility reduce ICH catalytic turnover and alter its pre-steady state kinetic behavior, establishing that helical mobility is important for ICH catalytic efficiency. Taken together, our results demonstrate the potential of mix-and-inject XFEL crystallography to capture otherwise elusive mechanistic details of enzyme catalysis and dynamics from microcrystalline samples7,11. This approach can connect conformational dynamics to function for the large class of systems that rely on covalently modified cysteine residues for catalysis or regulation, resolving long-standing questions about enzyme mechanism and functionally relevant non-equilibrium enzyme motions.
Investigating causal pathways between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization
Authors: Treur Jorien L , Demontis Ditte , Smith George Davey , Sallis Hannah ,   ADHD working group of the Psychiatric Genomics Consortium, Richardson Tom G , Wiers Reinout W , Børglum Anders D , Verweij Karin JH , Munafò Marcus R
Published: January 2019

Background

Attention-deficit hyperactivity disorder (ADHD) has consistently been associated with substance (ab)use, but the nature of this association is not fully understood. In view of preventive efforts, a vital question is whether there are causal effects, from ADHD to substance use and/or from substance use to ADHD.

Methods

We applied bidirectional Mendelian randomization using summary-level data from the largest available genome-wide association studies (GWASs) on ADHD, smoking (initiation, cigarettes/day, cessation, and a compound measure of lifetime smoking), alcohol use (drinks/week and alcohol use disorder), cannabis use (initiation and cannabis use disorder (CUD)) and coffee consumption (cups/day). Genetic variants robustly associated with the ‘exposure’ were selected as instruments and then identified in the ‘outcome’ GWAS. Effect estimates from individual genetic variants were combined with inverse-variance weighted regression and five sensitivity analyses were applied (weighted median, weighted mode, MR-Egger, generalized summary-data-based MR, and Steiger filtering).

Results

We found strong evidence that liability to ADHD increases likelihood of smoking initiation and also cigarettes per day among smokers, decreases likelihood of smoking cessation, and increases likelihood of cannabis initiation and CUD. In the other direction, there was evidence that liability to smoking initiation and CUD increase ADHD risk. There was no clear evidence of causal effects between liability to ADHD and alcohol or caffeine consumption.

Conclusions

We find evidence for causal effects of liability to ADHD on smoking and cannabis use, and of liability to smoking and cannabis use on ADHD risk, indicating bidirectional pathways. Further work is needed to explore causal mechanisms.
Characterization of the interactive effects of labile and recalcitrant organic matter on microbial growth and metabolism
Authors: Quigley Lauren N. M. , Edwards Abigail , Steen Andrew D. , Buchan Alison
Published: January 2019

Geochemical models typically represent organic matter (OM) as consisting of multiple, independent pools of compounds, each accessed by microorganisms at different rates. However, recent findings indicate that organic compounds can interact within microbial metabolisms. The relevance of interactive effects within marine systems is debated and a mechanistic understanding of its complexities, including microbe-substrate relationships, is lacking. As a first step toward uncovering mediating processes, the interactive effects of distinct pools of OM on the growth and respiration of marine bacteria, individual strains and a simple, constructed community of Roseobacter lineage members were tested. Isolates were provided with natural organic matter (NOM) and different concentrations (1, 4, 40, 400 μM-C) and forms of labile organic matter (acetate, casamino acids, tryptone, coumarate). The microbial response to the mixed substrate regimes was assessed using viable counts and respiration in two separate experiments. Two marine bacteria and a six-member constructed community were assayed with these experiments. Both synergistic and antagonistic growth responses were evident for all strains, but all were transient. The specific substrate conditions promoting a response, and the direction of that response, varied amongst species. These findings indicate that the substrate conditions that result in OM interactive effects are both transient and species-specific and thus influenced by both the composition and metabolic potential of a microbial community.
Nanoscopic Stoichiometry and Single-Molecule Counting
Authors: Nino Daniel , Djayakarsana Daniel , Milstein Joshua N.
Published: January 2019

Single-molecule localization microscopy (SMLM) has the potential to revolutionize proteomic and genomic analyses by providing information on the number and stoichiometry of proteins or nucleic acids aggregating at spatial scales below the diffraction limit of light. Here we present a method for molecular counting with SMLM built upon the exponentially distributed blinking statistics of photoswitchable fluorophores, with a focus on organic dyes. We provide a practical guide to molecular counting, highlighting many of the challenges and pitfalls, by benchmarking the method on fluorescently labeled, surface mounted DNA origami grids. The accuracy of the results illustrates SMLM’s utility for optical ‘-omics’ analysis.