bluuebunny/crossref_metadata_2025 huggingface dataset:
Global, regional, and national burden of migraine in 204 countries and territories, 1990 to 2019
Authors: Safiri Saeid , Pourfathi Hojjat , Eagan Arielle , Mansournia Mohammad Ali , Khodayari Mohammad Taghi , Sullman Mark J.M. , Kaufman Jay , Collins Gary , Dai Haijiang , Bragazzi Nicola Luigi , Kolahi Ali-Asghar
Published: April 2021

Data from the Global Burden of Disease Study 2019 were used to report the burden of migraine in 204 countries and territories during the period 1990 to 2019, through a systematic analysis of point prevalence, annual incidence, and years lived with disability (YLD). In 2019, the global age-standardised point prevalence and annual incidence rate of migraine were 14,107.3 (95% Uncertainty Interval [UI] 12,270.3-16,239) and 1142.5 (95% UI 995.9-1289.4) per 100,000, an increase of 1.7% (95% UI 0.7%-2.8%) and 2.1% (95% UI 1.1%-2.8%) since 1990, respectively. Moreover, the global age-standardised YLD rate in 2019 was 525.5 (95% UI 78.8-1194), an increase of 1.5% (95% UI –4.4% to 3.3%) since 1990. The global point prevalence of migraine in 2019 was higher in females and increased by age up to the 40 to 44 age group, then decreased with increased age. Belgium (22,400.6 [95% UI: 19,305.2-26,215.8]), Italy (20,337.7 [95% UI: 17,724.7-23,405.8]), and Germany (19,436.4 [95% UI: 16,806.2-22,810.3]) had the 3 highest age-standardised point prevalence rates for migraine in 2019. In conclusion, there were large intercountry differences in the burden of migraine, and this burden increased significantly across the measurement period. These findings suggest that migraine care needs to be included within the health system to increase population awareness regarding the probable risk factors and treatment strategies especially among young adults and middle-aged women, as well as to increase the data on migraines.
Albendazole-Induced Liver Injury
Authors: Piloiu Claudia , Dumitrascu Dan L.
Published: April 2021

Background:

Albendazole is an anthelmintic drug used worldwide for prophylactic or curative treatment. Side effects include diarrhea, abdominal pain, elevated levels of hepatic transaminases, dizziness, neutropenia, and alopecia.

Areas of Uncertainty:

The main question of the systematic review is if albendazole administration can cause liver injury or liver failure.

Data sources:

Two researchers conducted the search on PubMed and the key words used were: “albendazole,” “anthelmintic,” “drug-induced liver injury,” and “acute hepatitis.” Two new case reports were included in the systematic review.

Results:

Literature search concluded in 10 cases listed on PubMed. Another 2 new case reports from our experience are included in the systematic review. Most common symptoms presented are jaundice, anorexia, and vomiting after the single-use of albendazole or long-term usage. All cases presented high levels of transaminases, with remission after stopping the administration of albendazole. The treatment with albendazole was mostly given for liver hydatid cysts or empirically.

Conclusions:

Albendazole is a prescription-based drug used by most patients without medical advice, without knowing the risk of side effects. The anthelmintic drug may induce liver injury, even in small doses; in result, practitioners and patients should take this information in consideration.
Script Concordance and the Think-Aloud Approach Through the Lens of Cognitive Apprenticeship Theory
Authors: Tedesco-Schneck Mary
Published: April 2021

Background

Script concordance (SC) and the think-aloud (TA) approach informed by cognitive apprenticeship theory can promote clinical reasoning.

Purpose

The purpose of this study was to determine whether SC with the TA approach based on the tenets of cognitive apprenticeship theory facilitated clinical reasoning in senior-level prelicensure nursing students in a baccalaureate program.

Methods

This study was executed in a didactic pediatric nursing course using a quantitative, nonexperimental design. Creation of the SC/TA learning activity was grounded in cognitive apprenticeship theory and based on the SC testing/TA testing method.

Results

Repeated-measures analysis of variance revealed a difference (P = .001 and .003) between earlier and later SC scores for the fall 2018 cohort.

Conclusion

The SC/TA teaching/learning activity informed by cognitive apprenticeship theory offers a leveled approach to foster clinical reasoning in prelicensure nursing education.
Biobehavioral Aspects of the COVID-19 Pandemic: A Review
Authors: Hall Peter A. , Sheeran Paschal , Fong Geoffrey T. , Cheah Charissa S. L. , Oremus Mark , Liu-Ambrose Teresa , Sakib Mohammad N. , Butt Zahid A. , Ayaz Hasan , Jandu Narveen , Morita Plinio P.
Published: April 2021

Objective

This review highlights the scope and significance of the coronavirus disease 2019 (COVID-19) pandemic with a focus on biobehavioral aspects and critical avenues for research.

Methods

A narrative review of the published research literature was undertaken, highlighting major empirical findings emerging during the first and second waves of the COVID-19 pandemic.

Results

Interactions among biological, behavioral, and societal processes were prominent across all regions of the globe during the first year of the COVID-19 emergency. Affective, cognitive, behavioral, socioeconomic, and technological factors all played a significant role in the spread of infection, response precautions, and outcomes of mitigation efforts. Affective symptoms, suicidality, and cognitive dysfunction have been widely described consequences of the infection, the economic fallout, and the necessary public health mitigation measures themselves. The impact of COVID-19 may be especially serious for those living with severe mental illness and/or chronic medical diseases, given the confluence of several adverse factors in a manner that appears to have syndemic potential.

Conclusions

The COVID-19 pandemic has made clear that biological and behavioral factors interact with societal processes in the infectious disease context. Empirical research examining mechanistic pathways from infection and recovery to immunological, behavioral, and emotional outcomes is critical. Examination of how emotional and behavioral factors relate to the pandemic—both as causes and as effects—can provide valuable insights that can improve management of the current pandemic and future pandemics to come.
Positive Psychosocial Factors and Oxytocin in the Ovarian Tumor Microenvironment
Authors: Cuneo Michaela G. , Szeto Angela , Schrepf Andrew , Thaker Premal H. , Goodheart Michael , Cole Steve W. , Sood Anil K. , McCabe Philip M. , Mendez Armando J. , Lutgendorf Susan K.
Published: April 2021

Objective

Clinical ovarian cancer research shows relationships between psychosocial factors and disease-promoting aspects of the stress response (e.g., norepinephrine and cortisol). However, little is known about how psychosocial factors might relate to beneficial hormones in the ovarian tumor microenvironment. Here we examine relationships between psychosocial factors and tumor-associated oxytocin, a hormone linked to survival and antitumor processes in ovarian cancer.

Methods

Patients with ovarian cancer (n = 96) completed assessments of positive psychosocial factors (social support, positive affect, and purpose in life) and distress (perceived stress and depression) at the time of surgery. Levels of oxytocin and interleukin (IL) 6 in ascites fluid were obtained during surgery and analyzed by enzyme-linked immunosorbent assay. Multiple regression analyses adjusting a priori for patient age and disease stage examined associations between psychosocial factors and ascites oxytocin. IL-6 was used as a covariate in secondary analyses to examine the potentially confounding effects of inflammation in these relationships.

Results

Higher levels of positive affect (β = 0.22, p = .034), purpose in life (β = 0.31, p = .021), and social nurturance (β = 0.24, p = .024) were all related to higher levels of tumor-associated oxytocin at the time of surgery. In contrast, we found no effects for distress or social attachment. Relationships between oxytocin, purpose in life, and social nurturance were independent of IL-6, whereas positive affect was no longer significant with IL-6 in the model.

Conclusions

Tumor-associated oxytocin may be a previously uninvestigated link in the relationship between psychosocial factors and health in ovarian cancer. Future studies should examine causal mechanisms of relationships observed in this study.
The Health Behavior Model of Personality in the Context of a Public Health Crisis
Authors: Willroth Emily C. , Smith Angela M. , Shallcross Amanda J. , Graham Eileen K. , Mroczek Daniel K. , Ford Brett Q.
Published: April 2021

Objective

The US Centers for Disease Control and Prevention recommended behavioral measures to slow the spread of COVID-19, such as social distancing and wearing masks. Although many individuals comply with these recommendations, compliance has been far from universal. Identifying predictors of compliance is crucial for improving health behavior messaging and thereby reducing disease spread and fatalities.

Methods

We report preregistered analyses from a longitudinal study that investigated personality predictors of compliance with behavioral recommendations in diverse US adults across five waves from March to August 2020 (n = 596) and cross-sectionally in August 2020 (n = 405).

Results

Agreeableness—characterized by compassion—was the most consistent predictor of compliance, above and beyond other traits, and sociodemographic predictors (sample A, β = 0.25; sample B, β = 0.12). The effect of agreeableness was robust across two diverse samples and sensitivity analyses. In addition, openness, conscientiousness, and extraversion were also associated with greater compliance, but effects were less consistent across sensitivity analyses and were smaller in sample A.

Conclusions

Individuals who are less agreeable are at higher risk for noncompliance with behavioral mandates, suggesting that health messaging can be meaningfully improved with approaches that address these individuals in particular. These findings highlight the strong theoretical and practical utility of testing long-standing psychological theories during real-world crises.
Psychological Distress Reported by Primary Care Physicians in China During the COVID-19 Pandemic
Authors: Zeng Xin , Peng Tao , Hao Xiaofei , Zou Chuan , Lin Kai , Liao Xiaoyang , Chen Shanping , Hayhoe Benedict
Published: April 2021

Objective

Primary care physicians (PCPs) play a key role in responding to the COVID-19 epidemic. The objective of this study was to explore the influencing factors associated with self-reported psychological distress among a sample of PCPs in China in relation to COVID-19.

Methods

An online survey was distributed to a sample of PCPs in Chengdu city between February 10 and February 13, 2020. The survey consisted of three sections: demographic characteristics, COVID-19–related questions, and the General Health Questionnaire-12 (GHQ-12). After 5 months, a follow-up survey investigating the change of the GHQ-12 was conducted.

Results

A total of 712 PCPs completed the baseline survey (11.8% of those invited), 55.6% were female and 74.4% were aged between 30 and 49 years. High levels of psychological distress (GHQ-12 ≥3) were observed in 29.2% and were associated with low preparedness, high work impact, working with infected residents, personal life impact, and concerns, as well as older age and being married (p values < .05). Logistic regression analysis showed that psychological distress was associated with low preparedness (odds ratio [OR] = 0.91, 95% confidence interval [CI] = 0.87–0.96), high work impact (OR = 1.11, 95% CI = 1.03–1.20), personal life impact (OR = 1.12, 95% CI = 1.07–1.17), and safety-related concerns (OR = 1.09, 95% CI = 1.02–1.16). At the 5-month assessment point, high psychological distress was less frequent (21.8%).

Conclusions

COVID-19 has resulted in high levels of distress in approximately 30% of PCPs in China. Factors associated with high psychological distress levels include low preparedness and high levels of work impact, personal life impact, and concerns. These findings highlight the importance of enhancing psychological health throughout the course of infectious pandemics.
CanDIG: Secure Federated Genomic Queries and Analyses Across Jurisdictions
Authors: Dursi L. Jonathan , Bozoky Zoltan , de Borja Richard , Li Jimmy , Bujold David , Lipski Adam , Rashid Shaikh Farhan , Sethi Amanjeev , Memon Neelam , Naidoo Dashaylan , Coral-Sasso Felipe , Wong Matthew , Quirion P-O , Lu Zhibin , Agarwal Samarth , Pavlov Kat , Ponomarev Andrew , Husic Mia , Pace Krista , Palmer Samantha L. , Grover Stephanie A. , Hakgor Sevan , Siu Lillian L. , Malkin David , Virtanen Carl , Pugh Trevor J. , Jacques Pierre-Étienne , Joly Yann , Jones Steven J. M. , Bourque Guillaume , Brudno Michael
Published: April 2021

Rapid expansions of bioinformatics and computational biology have broadened the collection and use of -omics data including genomic, transcriptomic, methylomic and a myriad of other health data types, in the clinic and the laboratory. Both clinical and research uses of such data require co-analysis with large datasets, for which participant privacy and the need for data custodian controls must remain paramount. This is particularly challenging in multi-jurisdictional settings, such as Canada, where health privacy and security requirements are often heterogeneous. Data federation presents a solution to this, allowing for integration and analysis of large datasets from various sites while abiding by local policies.

The Canadian Distributed Infrastructure for Genomics platform (CanDIG) enables federated querying and analysis of -omics and health data while keeping that data local and under local control. It builds upon existing infrastructures to connect five health and research institutions across Canada, relies heavily on standards and tooling brought together by the Global Alliance for Genomics and Health (GA4GH), implements a clear division of responsibilities among its participants and adheres to international data sharing standards. Participating researchers and clinicians can therefore contribute to and quickly access a critical mass of -omics data across a national network in a manner that takes into account the multi-jurisdictional nature of our privacy and security policies. Through this, CanDIG gives medical and research communities the tools needed to use and analyze the ever-growing amount of -omics data available to them in order to improve our understanding and treatment of various conditions and diseases. CanDIG is being used to make genomic and phenotypic data available for querying across Canada as part of data sharing for five leading pan-Canadian projects including the Terry Fox Comprehensive Cancer Care Centre Consortium Network (TF4CN) and Terry Fox PRecision Oncology For Young peopLE (PROFYLE), and making data from provincial projects such as POG (Personalized Onco- Genomics) more widely available.
Microbial Rhodopsins are Increasingly Favored over Chlorophyll in High Nutrient Low Chlorophyll waters
Authors: Hassanzadeh Babak , Thomson Blair , Deans Fenella , Wenley Jess , Lockwood Scott , Currie Kim , Morales Sergio E. , Steindler Laura , Sañudo-Wilhelmy Sergio A. , Baltar Federico , Gómez-Consarnau Laura
Published: April 2021

Microbial rhodopsins are simple light-harvesting complexes that, unlike chlorophyll photosystems, have no iron requirements for their synthesis and phototrophic functions. Here we report the first environmental concentrations of rhodopsin along the Subtropical Frontal Zone off New Zealand, where Subtropical waters encounter the iron-limited Subantarctic High Nutrient Low Chlorophyll (HNLC) region. Rhodopsin concentrations were highest in HNLC waters where chlorophyll-aconcentrations were lowest. Furthermore, while the ratio of rhodopsin to chlorophyll-aphotosystems was on average 20 along the transect, this ratio increased to over 60 in HNLC waters. We further show that microbial rhodopsins are abundant in both picoplankton (0.2-3μm) and in the larger (>3μm) size fractions of the microbial community containing eukaryotic plankton and/or particle-attached prokaryotes. These findings suggest that rhodopsin phototrophy could be critical for microbial plankton to adapt to resource-limiting environments where photosynthesis and possibly cellular respiration are impaired.

Originality-Significance statement

High Nutrient Low Chlorophyll (HNLC) regimes cover approximately 30% of the global ocean surface and play a crucial role in the Earth’s carbon cycle. Here we show that microbial rhodopsins are particularly abundant in a HNLC region of the Subantarctic ocean, where chlorophyll abundance is relatively low and photosynthesis and respiration might be impaired due to iron limitation. These data suggest that rhodopsin phototrophy can contribute significantly to the energy budgets of HNLC regions, capturing meaningful amounts of light that cannot be channeled through photosynthesis.
Insight into Canary Island pine physiology provided by stable isotope patterns of water and plant tissues along an altitudinal gradient
Authors: Miranda José Carlos , Lehmann Marco M. , Saurer Matthias , Altman Jan , Treydte Kerstin
Published: April 2021

The Canary Islands, an archipelago east of Morocco’s Atlantic coast, present steep altitudinal gradients covering various climatic zones from hot deserts to subalpine Mediterranean, passing through fog-influenced cloud forests. Unlike the majority of the Canarian flora,Pinus canariensisgrow along most of these gradients, allowing the study of plant functioning in contrasting ecosystems. Here we assess the water sources (precipitation, fog) ofP. canariensisand its physiological behavior in its different natural environments. We analyzed carbon and oxygen isotope ratios of water and organics from atmosphere, soil and different plant organs and tissues (including 10-year annual time series of tree-ring cellulose) of six sites from 480 to 1990 m asl on the Canary island La Palma. We found a decreasing δ18O trend in source water that was overridden by an increasing δ18O trend in needle water, leaf assimilates and tree-ring cellulose with increasing altitude, suggesting site-specific tree physiological responses to relative humidity. Fog-influenced and fog-free sites showed similar δ13C values, suggesting photosynthetic activity to be limited by stomatal closure and irradiance at certain periods. Besides, we observed an18O-depletion (fog-free and timberline sites) and13C-depletion (fog-influenced and fog-free sites) in latewood compared to earlywood caused by seasonal differences in: (i) water uptake (i.e. deeper ground water during summer drought, fog water frequency and interception) and (ii) meteorological conditions (stem radial growth and latewood δ18O correlated with winter precipitation). In addition, we found evidence for foliar water uptake and strong isotopic gradients along the pine needle axis in water and assimilates. These gradients are likely the reason for an unexpected underestimation of pine needle water δ18O when applying standard leaf water δ18O models. Our results indicate that soil water availability and air humidity conditions are the main drivers of the physiological behavior of pine along the Canary Island’s altitudinal gradients.
Inhibition of MRN activity by a telomere protein motif
Authors: Khayat Freddy , Cannavo Elda , Alshmery Majedh , Foster William R. , Chahwan Charly , Maddalena Martino , Smith Christopher , Oliver Anthony W. , Watson Adam , Carr Antony M. , Cejka Petr , Bianchi Alessandro
Published: April 2021

The MRN complex (MRX inSaccharomyces cerevisiae) initiates the repair of DNA double-stranded breaks (DSBs) and activates the Tel1/ATM kinase, which orchestrates the DNA damage response (DDR). Telomeres prevent DDR activation at chromosome ends, partly by keeping MRN-ATM in check. We show that the multiple activities of the MRX complex are disabled by telomeric protein Rif2 through the action of a short motif (MIN,MRN/X-inhibitory motif) at the N-terminal end of the protein. MIN executes telomeric suppression of Tel1, DDR and and non-homologous end joining (NHEJ) via direct biding to the N-terminal region of Rad50. A combination of biochemical and genetic data suggests that Rif2 promotes a transition within the MRX complex that is not conductive for endonuclease activity, DNA-end tethering or Tel1 kinase activation. We suggests that the MIN motif operates in theRIF2paralogORC4(Origin Recognition Complex 4) inK. lactisand in telomeric protein Taz1 inSchizoccharomyces pombe, which is not evolutionarily related to Orc4/Rif2. These results highlight a potential Achilles’ heel in Rad50, the regulatory subunit of MRN, which we suggest has been targeted by different telomeric factors in multiple fungal lineages, raising the possibility that analogous approaches might be deployed in other Eukaryotes as well.
Impact of fenbendazole resistance inAscaridia dissimilison the economics of production in turkeys
Authors: Collins James B. , Jordan Brian , Vidyashankar Anand N. , Castro Pablo Jimenez , Kaplan Ray M.
Published: April 2021

Feed conversion efficiency is among the most important factors affecting profitable production of poultry. Infections with parasitic nematodes can decrease efficiency of production, making parasite control through the use of anthelmintics an important component of health management. In ruminants and horses, anthelmintic resistance is highly prevalent in many of the most important nematode species, which greatly impacts their control. Recently, we identified resistance to fenbendazole in an isolate ofAscaridia dissimilis, the most common intestinal helminth of turkeys. Using this drug-resistant isolate, we investigated the impact that failure to control infections has on weight gain and feed conversion in growing turkeys. Birds were infected on Day 0 with either a fenbendazole-susceptible or -resistant isolate, and then half were treated with fenbendazole (SafeGuard®Aquasol) at 4- and 8-weeks post infection. Feed intake and bird weight were measured for each pen weekly throughout the study, and feed conversion rate was calculated. Necropsy was performed on birds from each treatment group to assess worm burdens at weeks 7 and 9 post infection. In the birds infected with the susceptible isolate, fenbendazole-treated groups had significantly better feed conversion as compared to untreated groups. In contrast, there were no significant differences in feed conversion between the fenbendazole-treated and untreated groups in the birds infected with the resistant isolate. At both weeks 7 and 9, worm burdens were significantly different between the treated and untreated birds infected with the drug-susceptible isolate, but not in the birds infected with the drug-resistant isolate. These significant effects on feed conversion were seen despite having a rather low worm establishment in the birds. Overall, these data indicate thatA. dissimiliscan produce significant reductions in feed conversion, and that failure of treatment due to the presence of fenbendazole-resistant worms can have a significant economic impact on turkey production. Furthermore, given the low worm burdens and an abbreviated grow out period of this study, the levels of production loss we measured may be an underestimate of the true impact that fenbendazole-resistant worms may have on a commercial operation.
An automated feeding system for the African killifish reveals effects of dietary restriction on lifespan and allows scalable assessment of associative learning
Authors: McKay Andrew , Costa Emma K. , Chen Jingxun , Hu Chi-Kuo , Chen Xiaoshan , Bedbrook Claire N. , Khondker Rishad C. , Thielvoldt Mike , Singh Param Priya , Wyss-Coray Tony , Brunet Anne
Published: April 2021

The African turquoise killifish is an exciting new vertebrate model for aging studies. A significant challenge for any model organism is the control over its diet in space and time. To address this challenge, we created an automated and networked fish feeding system. Our automated feeder is designed to be open-source, easily transferable, and built from widely available components. Compared to manual feeding, our automated system is highly precise and flexible. As a proof-of-concept for the feeding flexibility of these automated feeders, we define a favorable regimen for growth and fertility for the African killifish and a dietary restriction regimen where both feeding time and quantity are reduced. We show that this dietary restriction regimen extends lifespan in males (but not in females) and impacts the transcriptomes of killifish livers in a sex-specific manner. Moreover, combining our automated feeding system with a video camera, we establish a quantitative associative learning assay to provide an integrative measure of cognitive performance for the killifish. The ability to precisely control food delivery in the killifish opens new areas to assess lifespan and cognitive behavior dynamics and to screen for dietary interventions and drugs in a scalable manner previously impossible with traditional vertebrate model organisms.
Quantification of durable CRISPR-based gene silencing activity
Authors: Nakamura Muneaki , Ivec Alexis , Gao Yuchen , Qi Lei S.
Published: April 2021

Development of CRISPR-based technologies for regulating gene expression stands to provide novel methods for the study and engineering of biological behavior. New tools capable of inducing long-lasting changes in gene expression will increase the utility of these techniques, providing durable effects from one-time doses of reagents. We describe here a reporter system for quantifying the ability of CRISPR-based effectors to induce stable gene repression. We observe a continuous gradation of the ability of these effectors to silence gene expression, depending on the domain composition and configuration. We also report the creation of a single CRISPR protein capable of producing durable gene silencing. This assay should allow for the continued development of enhanced gene repression tools which will be useful in a wide array of biological research and engineering applications.
Effect of rapamycin on mitochondria and lysosomes in fibroblasts from patients with mtDNA mutations
Authors: Cheema Nashwa , Cameron Jessie M. , Hood David A.
Published: April 2021

Maintaining mitochondrial function and dynamics is crucial for cellular health. In muscle, defects in mitochondria result in severe myopathies where accumulation of damaged mitochondria causes deterioration and dysfunction. Importantly, understanding the role of mitochondria in disease is a necessity to determine future therapeutics. One of the most common myopathies ismitochondrialencephalopathylacticacidosisstroke-like episodes (MELAS), which has no current treatment. Recently, MELAS patients treated with rapamycin exhibited improved clinical outcomes. However, the cellular mechanisms of rapamycin effects in MELAS patients are currently unknown. In this study, we used cultured skin fibroblasts as a window into the mitochondrial dysfunction evident in MELAS cells, as well as to study the mechanisms of rapamycin action, compared to control, healthy individuals. We observed that mitochondria from patients were fragmented, had a 3-fold decline in the average speed of motility, a 2-fold reduced mitochondrial membrane potential and a 1.5–2-fold decline in basal respiration. Despite the reduction in mitochondrial function, mitochondrial import protein Tim23 was elevated in patient cell lines. MELAS fibroblasts had increased MnSOD, p62 and lysosomal function when compared to healthy controls. Treatment of MELAS fibroblasts with rapamycin for 24 hrs resulted in increased mitochondrial respiration compared to control cells, a higher lysosome content, and a greater localization of mitochondria to lysosomes. Our studies suggest that rapamycin has the potential to improve cellular health even in the presence of mtDNA defects, primarily via an increase in lysosomal content.
Local Connectivity and Synaptic Dynamics in Mouse and Human Neocortex
Authors: Campagnola Luke , Seeman Stephanie C , Chartrand Thomas , Kim Lisa , Hoggarth Alex , Gamlin Clare , Ito Shinya , Trinh Jessica , Davoudian Pasha , Radaelli Cristina , Kim Mean-Hwan , Hage Travis , Braun Thomas , Alfiler Lauren , Andrade Juia , Bohn Phillip , Dalley Rachel , Henry Alex , Kebede Sara , Mukora Alice , Sandman David , Williams Grace , Larsen Rachael , Teeter Corinne , Daigle Tanya L. , Berry Kyla , Dotson Nadia , Enstrom Rachel , Gorham Melissa , Hupp Madie , Lee Samuel Dingman , Ngo Kiet , Nicovich Rusty , Potekhina Lydia , Ransford Shea , Gary Amanda , Goldy Jeff , McMillen Delissa , Pham Trangthanh , Tieu Michael , Siverts La’Akea , Walker Miranda , Farrell Colin , Schroedter Martin , Slaughterbeck Cliff , Cobb Charles , Ellenbogen Richard , Gwinn Ryder P , Keene C. Dirk , Ko Andrew L , Ojemann Jeffrey G , Silbergeld Daniel L , Carey Daniel , Casper Tamara , Crichton Kirsten , Clark Michael , Dee Nick , Ellingwood Lauren , Gloe Jessica , Kroll Matthew , Sulc Josef , Tung Herman , Wadhwani Katherine , Brouner Krissy , Egdorf Tom , Maxwell Michelle , McGraw Medea , Pom Christina Alice , Ruiz Augustin , Bomben Jasmine , Feng David , Hejazinia Nika , Shi Shu , Szafer Aaron , Wakeman Wayne , Phillips John , Bernard Amy , Esposito Luke , D’Orazi Florence D , Sunkin Susan , Smith Kimberly , Tasic Bosiljka , Arkhipov Anton , Sorensen Staci , Lein Ed , Koch Christof , Murphy Gabe , Zeng Hongkui , Jarsky Tim
Published: April 2021

To elucidate cortical microcircuit structure and synaptic properties we present a unique, extensive, and public synaptic physiology dataset and analysis platform. Through its application, we reveal principles that relate cell type to synapse properties and intralaminar circuit organization in the mouse and human cortex. The dynamics of excitatory synapses align with the postsynaptic cell subclass, whereas inhibitory synapse dynamics partly align with presynaptic cell subclass but with considerable overlap. Despite these associations, synaptic properties are heterogeneous in most subclass to subclass connections. The two main axes of heterogeneity are strength and variability. Cell subclasses divide along the variability axis, while the strength axis accounts for significant heterogeneity within the subclass. In human cortex, excitatory to excitatory synapse dynamics are distinct from those in mouse and short-term plasticity varies with depth across layers 2 and 3. With a novel connectivity analysis that enables fair comparisons between circuit elements, we find that intralaminar connection probability among cell subclasses exhibits a strong layer dependence.These and other findings combined with the analysis platform create new opportunities for the neuroscience community to advance our understanding of cortical microcircuits.
Towards a unified theory of the reference frame of the ventriloquism aftereffect
Authors: Lokša Peter , Kopčo Norbert
Published: April 2021

The ventriloquism aftereffect (VAE), observed as a shift in the perceived locations of sounds after audio-visual stimulation, requires reference frame alignment since hearing and vision encode space in different reference frames (head-centered vs. eye-centered). Previous experimental studies reported inconsistent results, observing either a mixture of head-centered and eye-centered frames, or a predominantly head-centered frame. Here, a computational model is introduced to examine these inconsistencies. Based on experimental data, the model uses the measured size of the ventriloquism effect to predict the VAE adaptation in the auditory spatial map. Versions of the model examine whether the adaptation is induced by visual signals in head-centered frame, eye-centered frame, by eye-gaze direction-dependent signals, or their combination, and whether some biases are induced by the saccade-to-auditory-target response method used in the experiments. The model is first evaluated on three separate data sets. It can predict them well even without explicit need for an eye-centered signals influencing VAE, suggesting that the reference frame of VAE is mainly head-centered. The model predictions are qualitatively similar but less accurate when all three data sets are combined, suggesting that interactions between individual neural mechanisms are more complex than the simple linear combination assumed in the model.
A nascent polypeptide sequence modulates DnaA translation elongation in response to nutrient availability
Authors: Felletti Michele , Romilly Cedric , Wagner E. Gerhart H. , Jonas Kristina
Published: April 2021

The ability to regulate DNA replication initiation in response to changing nutrient conditions is an important feature of most cell types. In bacteria, DNA replication is triggered by the initiator protein DnaA, which has long been suggested to respond to nutritional changes, nevertheless the underlying mechanisms remain poorly understood. Here, we report a novel mechanism that adjusts DnaA synthesis in response to nutrient availability inCaulobacter crescentus. By performing a detailed biochemical and genetic analysis of thednaAmRNA we identified a sequence downstream of thednaAstart codon that inhibits DnaA translation elongation upon carbon exhaustion. Our data show that the corresponding peptide sequence, but not the mRNA secondary structure or the codon choice, are critical for this response, suggesting that specific amino acids in the growing DnaA nascent chain tune translational efficiency. Our study provides new insights into DnaA regulation and highlights the importance of translation elongation as a regulatory target. We propose that nascent chain sequences, like the one described, might constitute a general strategy for modulating the synthesis rate of specific proteins under changing conditions.
Hydrogel-based slow release of a receptor-binding domain subunit vaccine elicits neutralizing antibody responses against SARS-CoV-2
Authors: Gale Emily C. , Powell Abigail E. , Roth Gillie A. , Meany Emily L. , Yan Jerry , Ou Ben S. , Grosskopf Abigail K. , Adamska Julia , Picece Vittoria C. T. M. , d’Aquino Andrea I. , Pulendran Bali , Kim Peter S. , Appel Eric A.
Published: April 2021

The development of effective vaccines that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID-19. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines because it is efficient to manufacture, highly stable, and a target for neutralizing antibodies. Unfortunately, RBD is poorly immunogenic. While most subunit vaccines are commonly formulated with adjuvants to enhance their immunogenicity, we found that clinically-relevant adjuvants Alum, AddaVax, and CpG/Alum were unable to elicit neutralizing responses following a prime-boost immunization. Here we show that sustained delivery of an RBD subunit vaccine comprising CpG/Alum adjuvant in an injectable polymer-nanoparticle (PNP) hydrogel elicited potent anti-RBD and anti-spike antibody titers, providing broader protection against SARS-CoV-2 variants of concern compared to bolus administration of the same vaccine and vaccines comprising other clinically-relevant adjuvant systems. Notably, a SARS-CoV-2 spike-pseudotyped lentivirus neutralization assay revealed that hydrogel-based vaccines elicited potent neutralizing responses when bolus vaccines did not. Together, these results suggest that slow delivery of RBD subunit vaccines with PNP hydrogels can significantly enhance the immunogenicity of RBD and induce neutralizing humoral immunity.
IL-21 and IFN-alpha have both opposite and redundant role on human innate precursors and memory B-cell differentiation
Authors: Boudigou Marina , Michée-Cospolite Magalie , Hémon Patrice , Grasseau Alexis , Dantec Christelle Le , Porchet Emmanuelle , Jamin Christophe , Devauchelle Valérie , Mignen Olivier , Cornec Divi , Pers Jacques-Olivier , Pottier Laëtitia Le , Hillion Sophie
Published: April 2021

Immunological memory is essential for effective immune protection upon antigen rechallenge. Memory B cells encompass multiple subsets, heterogeneous in terms of phenotypes, origins and precursors, anatomical localization, and functional responses. B-cell responses are conditioned by micro-environmental signals, including cytokines. Here, we analyzedin vitrothe effects of two cytokines implicated in B-cell differentiation, interferon-alpha (IFN-α) and interleukin (IL)-21, on the early functional response of four different mature B-cell subsets (IgD-CD27-naive, IgD+CD27+unswitched, IgD-CD27+switched and double-negative B cells). The dual response of naive and memory B cells to IL-21 allowed us to uncover a unique IgD+CD27-CD10-B-cell population (referred to as NARB+) characterized by the expression of marginal zone B-cell markers CD45RB and CD1c. Similar to memory B cells, NARB+cells were in a pre-activated state, allowing them to rapidly differentiate into plasmablasts upon innate signals while maintaining their susceptibility to IL-21 activation-induced apoptosis as observed for the naive compartment. Both in-depth phenotypic analysis of circulating B cells, and identification of these cells in spleen, tonsil and gut-associated lymphoid tissues, supported that NARB+are uncommitted precursors of human marginal zone B cells.
Mechanistic basis for understanding the dual activities of the bifunctionalAzotobacter vinelandiimannuronan C-5 epimerase and alginate lyase AlgE7
Authors: Gaardløs Margrethe , Heggeset Tonje Marita Bjerkan , Tøndervik Anne , Tezé David , Svensson Birte , Ertesvåg Helga , Sletta Håvard , Aachmann Finn Lillelund
Published: April 2021

The functional properties of alginates are dictated by the monomer composition and molecular weight distribution. Mannuronan C-5 epimerases determine the former by epimerizing β-D-mannuronic acid residues (M) into α-L-guluronic acid residues (G). The molecular weight is affected by alginate lyases, which cleave alginate chains through β-elimination. The reaction mechanisms for the epimerization and cleavage are similar and some enzymes can perform both. These dualistic enzymes share high sequence identity with mannuronan C-5 epimerases without lyase activity, and the mechanism behind their activity as well as the amino acids responsible for it are still unknown. In this study, we investigate mechanistic determinants of the bifunctional epimerase and lyase activity of AlgE7 fromAzotobacter vinelandii. Based on sequence analyses, a range of AlgE7 variants were constructed and subjected to activity assays and product characterization by NMR. Our results show that the lyase activity of AlgE7 is regulated by the type of ion present: Calcium promotes it, whereas NaCl reduces it. By using defined poly-M and poly-MG substrates, the preferred cleavage sites of AlgE7 were found to be M↓XM and G↓XM, where X can be either M or G. By studying AlgE7 mutants, R148 was identified as an important residue for the lyase activity, and the point mutant R148G resulted in an enzyme with only epimerase activity. Based on the results obtained in the present study we suggest a unified catalytic reaction mechanism for both epimerase and lyase activities where H154 functions as the catalytic base and Y149 as the catalytic acid.

Importance

Post-harvest valorisation and upgrading of algal constituents is a promising strategy in the development of a sustainable bioeconomy based on algal biomass. In this respect, alginate epimerases and lyases are valuable enzymes for tailoring of the functional properties of alginate, a polysaccharide extracted from brown seaweed with numerous applications in food, medicine and material industries. By providing a better understanding of the reaction mechanism and of how the two enzyme reactions can be altered by changes in reaction conditions, this study opens for further applications of bacterial epimerases and lyases in enzymatic tailoring of alginate polymers.
Photoswitchable epothilone-based microtubule stabilisers allow GFP-imaging-compatible, optical control over the microtubule cytoskeleton
Authors: Gao Li , Meiring Joyce C. M. , Heise Constanze , Rai Ankit , Müller-Deku Adrian , Akhmanova Anna , Thorn-Seshold Julia , Thorn-Seshold Oliver
Published: April 2021

Optical methods to modulate microtubule stability and dynamics are promising approaches to reach the micron- and millisecond-scale resolution needed to decrypt the diverse roles of the microtubule cytoskeleton in biology. However, such optical methods have until now focussed nearly exclusively on microtubule destabilisation. Here, we introduce “STEpos” as light-responsive epothilone reagents, designed to photoswitchably bind to tubulin and stabilise lateral contacts in the microtubule lattice. Using a novel styrylthiazole photoswitch, designed to allow the hydrogen-bonding that is key to epothilone potency, we have created the first set of GFP-orthogonal photoswitchable microtubule stabilisers. The STEpos can photocontrol microtubule polymerisation, cell division, and cellular microtubule dynamics with micron- and second-scale spatiotemporal precision. STEpos offer substantial improvements of potency, solubility, and ease-of-use compared to the only previous photopharmaceuticals for microtubule stabilisation. The intriguing structure-photoswitching-activity relationship insights from this work will also assist future developments of improved STEpo reagents, and we anticipate that these will contribute greatly to high-precision cytoskeleton research across the fields of biophysics, cargo transport, cell motility, cell division, development, and neuroscience.
A Bioinspired Glycopolymer for Capturing Membrane Proteins in Native-Like Lipid-Bilayer Nanodiscs
Authors: Danielczak Bartholomäus , Rasche Marie , Lenz Julia , Pérez Patallo Eugenio , Weyrauch Sophie , Mahler Florian , Agbadaola Michael Tope , Meister Annette , Babalola Jonathan Oyebamiji , Vargas Carolyn , Kolar Cenek , Keller Sandro
Published: April 2021

Amphiphilic copolymers that directly extract membrane proteins and lipids from cellular membranes to form nanodiscs combine the advantages of harsher membrane mimics with those of a native-like membrane environment. Among the few commercial polymers that are capable of forming nanodiscs, alternating diisobutylene/maleic acid (DIBMA) copolymers have gained considerable popularity as gentle and UV-transparent alternatives to aromatic polymers. However, their moderate hydrophobicities and high electric charge densities render all existing aliphatic copolymers rather inefficient under near-physiological conditions. Here, we introduce Glyco-DIBMA, a bioinspired glycopolymer that possesses increased hydrophobicity and reduced charge density but nevertheless retains excellent solubility in aqueous solutions. Glyco-DIBMA outperforms established aliphatic copolymers in that it solubilizes lipid vesicles of various compositions much more efficiently, thereby furnishing smaller, more narrowly distributed nanodiscs that preserve a bilayer architecture and exhibit rapid lipid exchange. We demonstrate the superior performance of Glyco-DIBMA in preparative and analytical applications by extracting a broad range of integral membrane proteins from cellular membranes and further by purifying a membrane-embedded voltage-gated K+channel, which was fluorescently labeled and analyzed with the aid of microfluidic diffusional sizing (MDS) directly within native-like lipid-bilayer nano-discs.
Microfluidic delivery of cutting enzymes for fragmentation of surface-adsorbed DNA molecules
Authors: Budassi Julia , Cho NaHyun , Del Valle Anthony , Sokolov Jonathan
Published: April 2021

We describe a method for fragmenting, in-situ, surface-adsorbed and immobilized DNAs on polymethylmethacrylate(PMMA)-coated silicon substrates using microfluidic delivery of the cutting enzyme DNase I. Soft lithography is used to produce polydimethylsiloxane (PDMS) gratings which form microfluidic channels for delivery of the enzyme. Bovine serum albumin (BSA) is used to reduce DNase I adsorption to the walls of the microchannels and enable diffusion of the cutting enzyme to a distance of 10mm. Due to the DNAs being immobilized, the fragment order is maintained on the surface. Possible methods of preserving the order for application to sequencing are discussed.
A Broadly Conserved Deoxycytidine Deaminase Protects Bacteria from Phage Infection
Authors: Severin Geoffrey B. , Hsueh Brian Y. , Elg Clinton A. , Dover John A. , Rhoades Christopher R. , Wessel Alex J. , Ridenhour Benjamin J. , Top Eva M. , Ravi Janani , Parent Kristin N. , Waters Christopher M.
Published: April 2021

The El Tor biotype ofVibrio choleraeis responsible for perpetuating the longest cholera pandemic in recorded history (1961-current). The genomic islands VSP-1 and -2 are two understudied genetic features that distinguish El Tor from previous pandemics. To understand their utility, we calculated the co-occurrence of VSP genes across bacterial genomes. This analysis predicted the previously uncharacterizedvc0175, herein renameddeoxycytidylatedeaminaseVibrio(dcdV), is in a gene network withdncV, a cyclic GMP-AMP synthase involved in phage defense. DcdV consists of two domains, a P-loop kinase and a deoxycytidylate deaminase, that are required for the deamination of dCTP and dCMP, inhibiting phage predation by corrupting cellular nucleotide concentrations. Additionally, DcdV is post-translationally inhibited by a unique noncoding RNA encoded 5’ of thedcdVlocus. DcdV homologs are conserved in bacteria and eukaryotes and our results identifyV. choleraeDcdV as the founding member of a previously undescribed bacterial phage defense system.
Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity
Authors: Correia Jorge C. , Kelahmetoglu Yildiz , Jannig Paulo R. , Schweingruber Christoph , Svaikovskaya Dasa , Zhengye Liu , Cervenka Igor , Oliveira Mariana , Nijssen Jik , Martínez-Redondo Vicente , Stec Michael , Khan Naveen , Lanner Johanna T. , Kleiner Sandra , Hedlund Eva , Ruas Jorge L.
Published: April 2021

Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN). Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics. Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA-sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift towards a slow MN identity. In muscle, NRTN increased capillary density, oxidative capacity, and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs, makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-1α1. This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity.

HIGHLIGHTS

NRTN is a myokine induced by physical exercise.

Muscle-derived NRTN promotes a slow motor neuron identity.

Muscle-derived NRTN enhances muscle oxidative metabolism.

NRTN improves systemic metabolism, exercise performance and motor coordination.