bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal and neonatal outcomes in pregnant women with psoriasis and psoriatic arthritis: a systematic review and meta-analysis
Authors: Xie Wenhui , Huang Hong , Ji Lanlan , Zhang Zhuoli
Published: April 2021

Objective

Psoriasis and PsA are inflammatory diseases that affect women in their reproductive years. We aimed to investigate whether maternal psoriasis and PsA are associated with adverse pregnancy outcomes.

Methods

We searched multiple electronic databases from inception to 3 August 2020, and reference lists of selected articles. Observational studies reporting at least one pregnancy outcome in women with psoriasis or PsA with a comparator of general population or healthy subjects were included. Data were pooled by random-effects models and expressed as odds ratio (OR) and 95% CI.

Results

Overall, 16 studies were included in the meta-analysis. The pooled analyses showed pregnant women with psoriatic diseases have a significantly higher risk of adverse maternal outcomes compared with the general population [caesarean delivery: 1.33 (1.17, 1.52); preterm birth: 1.32 (1.15, 1.52); (pre)eclampsia: 1.28 (1.14, 1.43); gestational diabetes: 1.19 (1.10, 1.30); gestational hypertension: 1.30 (1.18, 1.44)]. However, no statistically increased risks of fetal complications were observed in women with psoriatic diseases [small for gestational age: 1.02 (0.93, 1.11); low birth weight: 1.15 (0.93, 1.42); congenital malformations: 1.03 (0.93, 1.14); Apgar score <7: 1.07 (0.81, 1.39); neonatal mortality: 1.13 (0.90, 1.43); stillbirth: 1.19 (0.95, 1.50)]. Subgroup analysis found similar results in women with either psoriasis or PsA regarding maternal outcomes, and the magnitude of risk estimates seems to be greater in PsA, though without statistical difference.

Conclusions

Pregnant women with psoriasis and PsA have excess risk of adverse maternal events, but not adverse neonatal events. Close monitoring of the mothers’ clinical status before and during pregnancy is decidedly required in daily practice.
Characterization of Virulence Phenotypes of Soybean Cyst Nematode (Heterodera glycines) Populations in North Dakota
Authors: Chowdhury Intiaz Amin , Yan Guiping , Plaisance Addison , Markell Samuel
Published: April 2021

Soybean cyst nematode (SCN; Heterodera glycines) continues to be the greatest threat to soybean production in the United States. Because host resistance is the primary strategy used to control SCN, knowledge of SCN virulence phenotypes (HG types) is necessary for choosing sources of resistance for SCN management. To characterize SCN virulence phenotypes in North Dakota, a total of 419 soybean fields across 22 counties were sampled during 2015, 2016, and 2017. SCN was detected in 42% of the fields sampled, and population densities in these samples ranged from 30 to 92,800 eggs and juveniles per 100 cm3 of soil. The SCN populations from some of the infested fields were virulence-phenotyped with seven soybean indicator lines and a susceptible check (‘Barnes’) using the HG type tests. Overall, 73 SCN field populations were successfully virulence-phenotyped. The HG types detected in North Dakota were HG types 0 (frequency rate: 36%), 7 (27%), 2.5.7 (19%), 5.7 (11%), 1.2.5.7 (4%), and 2.7 (2%). However, before this study only HG type 0 was detected in North Dakota. The designation of each of these HG types detected was also validated by repeating the HG type tests for 33 arbitrarily selected samples. This research for the first time reports several new HG types detected in North Dakota and confirms that the virulence of SCN populations is shifting and overcoming resistance, highlighting the necessity of using different resistance sources, rotating resistance sources, and identifying novel resistance sources for SCN management in North Dakota.
Regular physical activity-related awareness and knowledge in Portugal: results from a population-based survey
Authors: Guedes-Estevez Estefania , Costa Ana Rute , Moura-Ferreira Pedro , Lunet Nuno , Morais Samantha
Published: April 2021

Background:

Previous studies have shown that adequate physical activity (PA, defined as any bodily movement that requires energy expenditure) related awareness and knowledge is crucial to promote regular PA. Therefore, this study aims to characterize PA awareness and knowledge, and to quantify its association with sociodemographic characteristics, health literacy and frequency of exercise.

Methods:

In a cross-sectional study conducted in 2012, a total of 1624 Portuguese-speaking residents of mainland Portugal (16–79 years old) were assessed through face-to-face interviews using a structured questionnaire. Adjusted prevalence ratios, calculated using Poisson regression, were used to quantify associations with PA awareness and knowledge.

Results:

The most reported benefits of PA were “reduces abdominal fat accumulation” (95.8%), “reduces myocardial infarction risk” (92.9%) and “improves bone health” (90.7%), these were less referred by older participants, while more often identified by those who exercise daily. The most referred barrier for people to not practice PA regularly was “lack of time” (33.9%) with differences observed by sex, age, education, employment and health literacy. Over two-thirds of participants correctly identified at least 2 of 3 PAs (“running”, “soccer” and “tennis”) that require the most energy, particularly males, those with higher health literacy and who exercise twice or more times a week.

Conclusions:

An adequate PA-related awareness and knowledge was observed, and differences according to age, health literacy levels and frequency of exercise were found. As such, awareness-raising interventions to increase regular PA through improving physical literacy and motivation should focus on older adults, those with limited health literacy and who do not exercise.
Patient-Led Research Collaborative: embedding patients in the Long COVID narrative
Authors: McCorkell Lisa , S. Assaf Gina , E. Davis Hannah , Wei Hannah , Akrami Athena
Published: April 2021

A large subset of patients with coronavirus disease 2019 (COVID-19) are experiencing symptoms well beyond the claimed 2-week recovery period for mild cases. These long-term sequelae have come to be known as Long COVID. Originating out of a dedicated online support group, a team of patients formed the Patient-Led Research Collaborative and conducted the first research on Long COVID experience and symptoms. This article discusses the history and value of patient-centric and patient-led research; the formation of Patient-Led Research Collaborative as well as key findings to date; and calls for the following: the acknowledgement of Long COVID as an illness, an accurate estimate of the prevalence of Long COVID, publicly available basic symptom management, care, and research to not be limited to those with positive polymerase chain reaction and antibody tests, and aggressive research and investigation into the pathophysiology of symptoms.
Orofacial pain in 1916 patients with early or moderate Parkinson disease
Authors: O'Neill Francis , Kobylecki Christopher , Carrasco Roberto , Hu Michele T. , Grosset Donald , Silverdale Monty ,   on behalf of the UK Parkinson's Pain Study Collaboration
Published: April 2021

Introduction:

Several studies have reported that some types of orofacial pain are more common in patients with Parkinson disease (PD) than the general population.

Objectives:

In this study, we aimed to investigate the prevalence of self-reported orofacial pain in a larger group of patients with PD than has been previously studied.

Methods:

We analysed data from 1916 participants with PD in a cross-sectional study recruited to the UK Parkinson's Pain Study who had detailed assessments of pain, motor, and nonmotor symptoms. The King's Parkinson's Pain scale was used to quantify different subtypes of pain.

Results:

A total of 139 (7.3%) patients reported the presence of some form of orofacial pain. Burning mouth syndrome was reported in 32 (1.7%), whereas chewing pain was found in 38 (2.0%) and grinding pain in 78 (4.0%). Orofacial pain was significantly more common in females (10.4%) than males (5.9%). Multiple logistic regression analysis showed a significant association between orofacial pain and pain severity, neuropathic pain, and oral motor and nonmotor dysfunction.

Conclusion:

In our study, population cohort of early patients with PD found prevalence of orofacial pain conditions similar to that in the general population.
GABAergic retinal ganglion cells regulate innate defensive responses
Authors: Cai Danrui , Luo Xue , Shen Kejiong , Shen Yin
Published: April 2021

Gamma-aminobutyric acid (GABA) is regarded as the most important inhibitory neurotransmitter in the central nervous system, including the retina. However, the roles of GABA-immunolabeled retinal ganglion cells (RGCs) have not been explored. Here, we report the expression of GABAergic RGCs that project to many brain areas in mice, including the superior colliculus. Selective ablation of the superior colliculus-projecting GABAergic RGCs, leaving other GABAergic RGCs intact, reduces the looming stimulus-induced defensive response without affecting image-forming functions; it also significantly enhances glucose metabolism in the superior colliculus, as determined by [18F]-fluorodeoxyglucose PET (FDG PET). Our findings demonstrate that superior colliculus-projecting GABAergic RGCs control the visually active defensive response by regulating superior colliculus neurons.
Impaired HA-specific T follicular helper cell and antibody responses to influenza vaccination are linked to inflammation in humans
Authors: Hill Danika L , Innocentin Silvia , Wang Jiong , James Eddie A , Lee James C , Kwok William W , Zand Martin , Carr Edward J , Linterman Michelle A
Published: April 2021

Antibody production following vaccination can provide protective immunity to subsequent infection from pathogens such as influenza. However, circumstances where antibody formation is impaired after vaccination, such as in older people, require us to better understand the cellular and molecular mechanisms that underpin successful vaccination in order to improve vaccine design for at risk groups. Here, by studying the breadth of anti-hemagglutinin (HA) IgG, serum cytokines, and B and T cell responses by flow cytometry before and after influenza vaccination, we show that formation of circulating T follicular helper cells (cTfh) cells are the best predictor of high titre antibody responses. Using MHC class II tetramers we demonstrate that HA-specific cTfh cells can derived from pre-existing memory CD4+T cells and have a diverse TCR repertoire. In older people, the differentiation of HA-specific cells into cTfh cells was impaired. This age-dependent defect in cTfh cell formation was not due to a contraction of the TCR repertoire, but rather was linked with an increased inflammatory gene signature in cTfh cells. Together this suggests that strategies that temporarily dampen inflammation at the time of vaccination may be a viable strategy to boost optimal antibody generation upon immunisation of older people.

One sentence summary

Antibody production upon vaccination requires antigen-specific cTfh cells whose formation is suppressed by pro-inflammatory cytokine signalling.
High coverage COVID-19 mRNA vaccination rapidly controls SARS-CoV-2 transmission in Long-Term Care Facilities
Authors: De Salazar Pablo M , Link Nicholas , Lamarca Karuna , Santillana Mauricio
Published: April 2021

Residents of Long-Term Care Facilities (LTCFs) represent a major share of COVID-19 deaths worldwide. Measuring the vaccine effectiveness among the most vulnerable in these settings is essential to monitor and improve mitigation strategies.

We evaluated the early effect of the administration of BNT162b2 mRNA vaccines to individuals older than 64 years residing in LTCFs in Catalonia, a region of Spain. We monitored all the SARS-CoV-2 documented infections and deaths among LTCFs residents from February 6th to March 28th, 2021, the subsequent time period after which 70% of them were fully vaccinated. We developed a modeling framework based on the relation between community and LTFCs transmission during the pre-vaccination period (July -December 2020) and compared the true observations with the counterfactual model predictions. As a measure of vaccine effectiveness, we computed the total reduction in SARS-CoV-2 documented infections and deaths among residents of LTCFs over time, as well as the reduction on the detected transmission for all the LTCFs.

We estimated that once more than 70% of the LTCFs population were fully vaccinated, 74% (58%-81%, 90% CI) of COVID-19 deaths and 75% (36%-86%, 90% CI) of all expected documented infections among LTCFs residents were prevented. Further, detectable transmission among LTCFs residents was reduced up to 90% (76-93%, 90%CI) relative to that expected given transmission in the community.

Our findings provide evidence that high-coverage vaccination is the most effective intervention to prevent SARS-CoV-2 transmission and death among LTCFs residents. Conditional on key factors such as vaccine roll out, escape and coverage --across age groups--, widespread vaccination could be a feasible avenue to control the COVID-19 pandemic.
ddPCR Reveals SARS-CoV-2 Variants in Florida Wastewater
Authors: Gering Eben , Colbert Jacob , Schmedes Sarah , Duncan George , Lopez Joe , Motes Jessy , Weiss James , Azarian Taj , Tekin Omer , Blanton Jason
Published: April 2021

Wastewater was screened for the presence of functionally significant mutations in SARS-CoV-2 associated with emerging variants of concern (VOC) by ddPCR, and results accorded with sequencing of clinical samples from the same region. We propose that PCR-based screening of wastewater can provide a powerful tool for rapid and inexpensive screening of large population segments for VOC-associated mutations and can hone complementary sampling and sequencing of direct (human) test material to track emerging VOC.
The PUPPY Study – Protocol for a Longitudinal Mixed Methods Study Exploring Problems Coordinating and Accessing Primary Care for Attached and Unattached Patients Exacerbated During the COVID-19 Pandemic Year
Authors: Marshall Emily Gard , Breton Mylaine , Cossette Benoît , Isenor Jennifer E , Mathews Maria , Ayn Caitlyn , Smithman Mélanie Ann , Stock David , Frymire Eliot , Edwards Lynn , Green Michael
Published: April 2021

Background

The COVID-19 pandemic significantly disrupted primary care in Canada, with many walk-in clinics and family practices initially closing or being perceived as inaccessible, pharmacies remaining open with restrictions on patient interactions, rapid uptake of virtual care, and reduced referrals for lab tests, diagnostics, and specialist care. The PUPPY Study (Problems Coordinating and Accessing Primary Care for Attached and Unattached Patients Exacerbated During the COVID-19 Pandemic Year) seeks to understand the impact of COVID-19 across the quadruple aim of primary care, with particular focus on the impacts on patients without attachment to a regular provider and those with chronic health conditions.

Objective

The PUPPY Study objective is to understand the impact of COVID-19 across the quadruple aim of primary care.

Methods

The PUPPY study builds on an existing research program exploring patients’ access and attachment to primary care, pivoted to adapt to the emerging COVID-19 context. We will undertake a longitudinal mixed methods study to understand critical gaps in primary care access and coordination, comparing data pre- and post-pandemic in three Canadian provinces (Quebec, Ontario, and Nova Scotia). Multiple data sources will be used including: a policy review; qualitative interviews with primary care policymakers, providers (i.e., family physicians, nurse practitioners, and pharmacists), and patients (N=120); and medication prescribing and healthcare billings. The findings will inform the strengthening of primary care during and beyond the COVID-19 pandemic.

Results

Funding was provided by the Canadian Institutes of Health Research COVID-19 Rapid Funding Opportunity Grant. Ethical approval to conduct this study was granted in Ontario (Queens Health Sciences & Affiliated Teaching Hospitals Research Ethics Board, file number 6028052; Western University Health Sciences Research Ethics Board, project 116591; University of Toronto Health Sciences Research Ethics Board, protocol number 40335), Québec (Centre intégré universitaire de santé et de services sociaux de l’Estrie, project number 2020-3446) and Nova Scotia (Nova Scotia Health Research Ethics Board, file number 1024979).

Conclusions

This is the first study of its kind exploring the impacts of COVID-19 on primary care systems, with particular focus on the issues of patient’s attachment and access to primary care. Through a multi-stakeholder, cross-jurisdictional approach, the PUPPY Study will generate findings and implications for future policy and practice.
Risk factors associated with respiratory infectious disease-related presenteeism: a rapid review
Authors: Daniels Sarah , Wei Hua , Han Yang , Catt Heather , Denning David W. , Hall Ian , Regan Martyn , Verma Arpana , Whitfield Carl A. , van Tongeren Martie
Published: April 2021

Background

Workplace transmission is a significant contributor to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks. Previous studies have found that infectious illness presenteeism could contribute to outbreaks in occupational settings and identified multiple occupational and organisational risk factors. Amid the COVID-19 pandemic, it is imperative to investigate presenteeism particularly in relation to respiratory infectious disease (RID). Hence, this rapid review aims to determine the prevalence of RID-related presenteeism, including COVID-19, and examines the reported reasons and associated risk factors.

Methods

The review followed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) search approach and focused on studies published in English and Chinese. Database searches included MEDLINE, EMBASE, Web of Science, China Knowledge Resource Integrated Database (CNKI) and preprint databases MedRxiv and BioRxiv.

Results

The search yielded 54 studies, of which four investigated COVID-19-related presenteeism. Prevalence of work presenteeism ranged from 14.1% to 55% for confirmed RID, and 6.6% to 100% for those working with suspected or subclinical RID. The included studies demonstrated that RID-related presenteeism is associated with occupation, sick pay policy, age, gender, health behaviour and perception, vaccination, peer pressure and organisational factors such as presenteeism culture.

Conclusions

This review demonstrates that presenteeism or non-adherence to isolation guidance is a real concern and can contribute to workplace transmissions and outbreaks. Policies which would support workers financially and improve productivity, should include a range of effective non-pharmaceutical inventions such as workplace testing, promoting occupational health services, reviewing pay and bonus schemes and clear messaging to encourage workers to stay at home when ill. Future research should focus on the more vulnerable and precarious occupational groups, and their inter-relationships, to develop comprehensive intervention programs to reduce RID-related presenteeism.
Self-regulation of stress-related large-scale brain network balance using real-time fMRI Neurofeedback
Authors: Krause Florian , Kogias Nikos , Krentz Martin , Lührs Michael , Goebel Rainer , Hermans Erno J.
Published: April 2021

It has recently been shown that acute stress affects the allocation of neural resources between large-scale brain networks, and the balance between the executive control network and the salience network in particular. Maladaptation of this dynamic resource reallocation process is thought to play a major role in stress-related psychopathology, suggesting that stress resilience may be determined by the retained ability to adaptively reallocate neural resources between these two networks. Actively training this ability could hence be a potentially promising way to increase resilience in individuals at risk for developing stress-related symptomatology. Using real-time functional Magnetic Resonance Imaging, the current study investigated whether individuals can learn to self-regulate stress-related large-scale network balance. Participants were engaged in a bidirectional and implicit real-time fMRI neurofeedback paradigm in which they were intermittently provided with a visual representation of the difference signal between the average activation of the salience and executive control networks, and tasked with attempting to self-regulate this signal. Our results show that, given feedback about their performance over three training sessions, participants were able to (1) learn strategies to differentially control the balance between SN and ECN activation on demand, as well as (2) successfully transfer this newly learned skill to a situation where they (a) did not receive any feedback anymore, and (b) were exposed to an acute stressor in form of the prospect of a mild electric stimulation. The current study hence constitutes an important first successful demonstration of neurofeedback training based on stress-related large-scale network balance – a novel approach that has the potential to train control over the central response to stressors in real-life and could build the foundation for future clinical interventions that aim at increasing resilience.

Highlights

Acute stress affects the allocation of neural resources between large-scale brain networks

We provide a first successful demonstration of neurofeedback training based on stress-related large-scale brain networks

Novel approach has the potential to train control over central response to stressors in real-life

Could build foundation for future clinical interventions to increase resilience
RNA labelling in live plants reveals single cell transcriptional dynamics: application to phosphate signaling
Authors: Hani Sahar , Cuyas Laura , David Pascale , Secco David , Whelan James , Thibaud Marie-Christine , Merret Rémy , Mueller Florian , Pochon Nathalie , Javot Hélène , Faklaris Orestis , Maréchal Eric , Bertrand Edouard , Nussaume Laurent
Published: April 2021

Plants are sessile organisms constantly adapting to ambient fluctuations through spatial and temporal transcriptional responses. Here, we implemented the latest generation RNA imaging system and combined it with microfluidics to visualize transcriptional regulation in living Arabidopsis plants. This enabled quantitative measurements of the transcriptional activity of single loci in single cells, real time and changing environmental conditions. Using phosphate responsive genes as model, we found that active genes displayed high transcription initiation rates (∼3s) and frequently clustered together in endoreplicated cells. We observed gene bursting and large allelic differences in single cells, revealing that at steady-state, intrinsic noise dominated extrinsic variations. Moreover, we established that transcriptional repression triggered in roots by phosphate, a crucial macronutrient limiting plant development, occurred with unexpected fast kinetics (∼minutes) and striking heterogeneity between neighboring cells. Access to single cell RNA polymerase II dynamics within live plants will benefit future studies of signaling processes.
Estimating the age of poorly dated fossil specimens and deposits using a total-evidence approach and the fossilized birth-death process
Authors: Barido-Sottani Joëlle , Żyła Dagmara , Heath Tracy A.
Published: April 2021

Bayesian total-evidence approaches under the fossilized birth-death model enable biologists to combine fossil and extant data while accounting for uncertainty in the ages of fossil specimens, in an integrative phylogenetic analysis. Fossil age uncertainty is a key feature of the fossil record as many empirical datasets may contain a mix of precisely dated and poorly dated fossil specimens or deposits. In this study, we explore whether reliable age estimates for fossil specimens can be obtained from Bayesian total-evidence phylogenetic analyses under the fossilized birth-death model. Through simulations based on the example of the Baltic amber deposit, we show that estimates of fossil ages obtained through such an analysis are accurate, particularly when the proportion of poorly dated specimens remains low and the majority of fossil specimens have precise dates. We confirm our results using an empirical dataset of living and fossil penguins by artificially increasing the age uncertainty around some fossil specimens and showing that the resulting age estimates overlap with the recorded age ranges. Our results are applicable to many empirical datasets where classical methods of establishing fossil ages have failed, such as the Baltic amber and the Gobi Desert deposits.
Recovery of silver fir (Abies albaMill.) seedlings from ungulate browsing mirrors soil nitrogen availability
Authors: Csilléry Katalin , Buchmann Nina , Brendel Oliver , Gessler Arthur , Glauser Alexandra , Kupferschmid Andrea Doris
Published: April 2021

Abies albahas a high potential for mitigating climate change in European mountain forests, yet, its natural regeneration is severely limited by ungulate browsing. Here, we simulated browsing in a common garden experiment to study growth and physiological traits, measured from bulk needles, using a randomized block design with two levels of browsing severity and seedlings originating from 19 populations across Switzerland. Genetic factors explained most variation in growth (on average, 51.5%) and physiological traits (10.2%) under control conditions, while heavy browsing considerably reduced the genetic effects on growth (to 30%), but doubled those on physiological traits related to C storage. While browsing reduced seedling height, it also lowered seedlings’ water use efficiency (decreasedδ13C) and N supply by mycorrhizal fungi as indicated by an increase inδ15N. Different populations reacted differently to browsing stress, and for Height, Starch andδ15N, population differences appeared to be the result of natural selection. We found that the fastest growing populations, originating from the warmest regions, decreased their needle starch level the most as a reaction to heavy browsing, suggesting a potential genetic underpinning for a growth-storage trade-off. Further, we found that seedlings originating from mountain populations growing on steep slopes had a significantly lower N discrimination in the common garden than those originating from flat areas, indicating that they have been selected to grow on N poor, potentially drained, soils. This finding was corroborated by the fact that N concentration in adult needles was lower on steep slopes than on flat ground, strongly indicating that steep slopes are the most N poor environments. Seedlings from these poor environments generally had a low growth rate and high storage, thus might be slower to recover from browsing stress than fast growing provenances from the warm environments with developed soils, such as the Swiss plateau.
Peripheral Neuronal Activation Shapes the Microbiome and Alters Gut Physiology
Authors: Griffiths Jessica A. , Yoo Bryan B. , Thuy-Boun Peter , Cantu Victor , Weldon Kelly , Challis Collin , Sweredoski Michael J. , Chan Ken Y. , Thron Taren M. , Sharon Gil , Moradian Annie , Humphrey Gregory , Zhu Qiyun , Shaffer Justin , Wolan Dennis W. , Dorrestein Pieter C. , Knight Rob , Gradinaru Viviana , Mazmanian Sarkis K.
Published: April 2021

The gastrointestinal (GI) tract is extensively innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia, which together regulate gut physiology. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Herein, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites, as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+or TH+neurons increases fecal output, while only ChAT+activation results in increased colonic migrating motor complexes and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally-activated ENS neurons differentially regulate the gut microbiome and GI physiology in mice, without involvement of signals from the brain.
Dynamic Causal Modeling of Neural Responses to an Orofacial Pneumotactile Velocity Array
Authors: Wang Yingying , Custead Rebecca , Oh Hyuntaek , Barlow Steven M.
Published: April 2021

The effective connectivity of neuronal networks during orofacial pneumotactile stimulation with different velocities is still unknown. The present study aims to characterize the effectivity connectivity elicited by three different saltatory velocities (5, 25, and 65 cm/s) over the lower face using dynamic causal modeling on functional magnetic resonance imaging data of twenty neurotypical adults. Our results revealed the contralateral SI and SII as the most likely sources of the driving inputs within the sensorimotor network for the pneumotactile stimuli, suggesting parallel processing of the orofacial pneumotactile stimuli. The 25 cm/s pneumotactile stimuli modulated forward interhemispheric connection from the contralateral SII to the ipsilateral SII, suggesting a serial interhemispheric connection between the bilateral SII. Moreover, the velocity pneumotactile stimuli influenced the contralateral M1 through both contralateral SI and SII, indicating that passive pneumotactile stimulation may positively impact motor function rehabilitation. Furthermore, the slow velocity 5 cm/s pneumotactile stimuli modulated both forward and backward connections between the right cerebellar lobule VI and the contralateral left SI, SII, and M1, while the medium velocity 25 cm/s pneumotactile stimuli modulated both forward and backward connections between the right cerebellar lobule VI and the contralateral left SI and M1. Our findings suggest that the right cerebellar lobule VI plays a role in the sensorimotor network through feedforward and feedback neuronal pathways.
Coherent waves of myelin plasticity during motor-skill learning
Authors: Azzaritto Michela , Ziegler Gabriel , Huber Eveline , Grabher Patrick , Callaghan Martina , Thompson Alan , Friston Karl , Weiskopf Nikolaus , Killeen Tim , Freund Patrick
Published: April 2021

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal dependencies of these changes, and their microstructural underpinnings, remain unclear. Eighteen healthy males received training in a computer- controlled motion game 4 times a week, for 4 weeks. Performance improvements were observed in all trained participants. Serial myelin-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related myelin-sensitive microstructural changes in the grey and white matter across the corticospinal system and hippocampus. Interestingly, analysis of the trajectory of these transient changes revealed a time-shifted choreography across white and grey matter of the corticospinal system as well as with changes in the hippocampus. Crucially, in the cranial corticospinal tracts, myelin-sensitive changes during training in the posterior part of the limb of the internal capsule were of greater magnitude in lower-limb trainees compared to upper limb trainees. Motor skill learning is depended on coherent waves of plasticity within a corticospinal-hippocampal loop.
Peptidylarginine deiminase IV (PADI4) is not essential for cell-autonomous HSC maintenance and normal haematopoiesis
Authors: Young Christine , Russell John R. , Lawson Hannah , Mapperley Christopher , Kranc Kamil R. , Christophorou Maria A.
Published: April 2021

Peptidylarginine deiminases (PADIs, or PADs) are emerging as key regulators of human physiology and pathophysiology. The nuclear deiminase PADI4 regulates embryonic stem cell pluripotency, however its role in adult stem cells is unknown. PADI4 is expressed most highly in the bone marrow (BM), where it is found as part of a self-renewal-associated gene signature and shown to modulate the function of critical transcriptional regulators such as Tal1 and c-Myc, suggesting that it regulates haematopoietic development or regeneration. We investigated the functional significance of PADI4 in haematopoietic stem cell (HSC) biology and normal haematopoiesis. We employed two conditional mouse models of tissue-specificPadi4ablation, wherePadi4was completely deleted either after the emergence of HSCs, or acutely in the BM of adult mice. We found that loss of PADI4 does not significantly affect HSC self-renewal or differentiation potential upon injury or serial transplantation, nor does it lead to exhaustion or premature ageing of HSCs. Thus, surprisingly, PADI4 is dispensable for cell-autonomous HSC maintenance, differentiation and haematopoietic regeneration. This work has important implications for the clinical use of PADI4 inhibitors as therapeutic agents in autoimmunity and cancer.

Key Points

PADI4 is dispensable for steady-state and post-transplantation haematopoiesis

HSCs do not require intrinsic PADI4 activity to respond to haematopoietic injury

PADI4 deficiency does not lead to premature HSC ageing or exhaustion
Cortical tracking of unheard formant modulations derived from silently presented lip movements and its decline with age
Authors: Suess Nina , Hauswald Anne , Reisinger Patrick , Rösch Sebastian , Keitel Anne , Weisz Nathan
Published: April 2021

The integration of visual and auditory cues is crucial for successful processing of speech, especially under adverse conditions. Recent reports have shown that when participants watch muted videos of speakers, the phonological information about the acoustic speech envelope is tracked by the visual cortex. However, the speech signal also carries much richer acoustic details, e.g. about the fundamental frequency and the resonant frequencies, whose visuo-phonological transformation could aid speech processing. Here, we investigated the neural basis of the visuo-phonological transformation processes of these more fine-grained acoustic details and assessed how they change with ageing. We recorded whole-head magnetoencephalography (MEG) data while participants watched silent intelligible and unintelligible videos of a speaker. We found that the visual cortex is able to track the unheard intelligible modulations of resonant frequencies and the pitch linked to lip movements. Importantly, only the processing of intelligible unheard formants decreases significantly with age in the visual and also in the cingulate cortex. This is not the case for the processing of the unheard speech envelope, the fundamental frequency or the purely visual information carried by lip movements. These results show that unheard spectral fine-details (along with the unheard acoustic envelope) are transformed from a mere visual to a phonological representation. Aging affects especially the ability to derive spectral dynamics at formant frequencies. Since listening in noisy environments should capitalize on the ability to track spectral fine-details, our results provide a novel focus on compensatory processes in such challenging situations.
Iron-sulfur clusters are involved in post-translational arginylation
Authors: Van Verna , Brown Janae B. , Rosenbach Hannah , Mohamed Ijaz , Ejimogu Nna-Emeka , Bui Toan S. , Szalai Veronika A. , Chacón Kelly N. , Span Ingrid , Smith Aaron T.
Published: April 2021

Eukaryotic arginylation is an essential post-translational modification that both modulates protein stability and regulates protein half-life through the N-degron pathway. Arginylation is catalyzed by a family of enzymes known as the arginyl-tRNA transferases (ATE1s), which are conserved across the eukaryotic domain. Despite its conservation and importance, little is known regarding the structure, mechanism, and regulation of ATE1s. In this work, we have discovered that ATE1s bind a previously unknown iron-sulfur cluster that is conserved across evolution. We have extensively characterized the nature of this iron-sulfur cluster, and we show that the presence of the iron-sulfur cluster is linked to alterations in arginylation efficacy. Finally, we demonstrate that the ATE1 iron-sulfur cluster is oxygen sensitive, which could be a molecular mechanism of the N-degron pathway to sense oxidative stress. Thus, our data provide the framework of a cluster-based paradigm of ATE1 regulatory control.
Interpretable, scalable, and transferrable functional projection of large-scale transcriptome data using constrained matrix decomposition
Authors: Panchy Nicholas , Watanabe Kazuhide , Hong Tian
Published: April 2021

Large-scale transcriptome data, such as single-cell RNA-sequencing data, have provided unprecedented resources for studying biological processes at the systems level. Numerous dimensionality reduction methods have been developed to visualize and analyze these transcriptome data. In addition, several existing methods allow inference of functional variations among samples using gene sets with known biological functions. However, it remains challenging to analyze transcriptomes with reduced dimensions that are interpretable in terms of dimensions’ directionalities, transferrable to new data, and directly expose the contribution of individual genes. In this study, we used gene set non-negative principal component analysis (gsPCA) and non-negative matrix factorization (gsNMF) to analyze large-scale transcriptome datasets. We found that these methods provide low-dimensional information about the progression of biological processes in a quantitative manner, and their performances are comparable to existing functional variation analysis methods in terms of distinguishing multiple cell states and samples from multiple conditions. Remarkably, upon training with a subset of data, these methods allow predictions of locations in the functional space using data from experimental conditions that are not exposed to the models. Specifically, our models predicted the extent of progression and reversion for cells in the epithelial-mesenchymal transition (EMT) continuum. These methods revealed conserved EMT program among multiple types of single cells and tumor samples. Finally, we demonstrate this approach is broadly applicable to data and gene sets beyond EMT and provide several recommendations on the choice between the two linear methods and the optimal algorithmic parameters. Our methods show that simple constrained matrix decomposition can produce to low-dimensional information in functionally interpretable and transferrable space, and can be widely useful for analyzing large-scale transcriptome data.
In vitroreconstitution of Sgk3 activation by phosphatidylinositol-3-phosphate
Authors: Pokorny Daniel , Truebestein Linda , Fleming Kaelin D. , Burke John E. , Leonard Thomas A.
Published: April 2021

Serum- and glucocorticoid-regulated kinase 3 (Sgk3) is activated by the phospholipid phosphatidylinositol-3-phosphate (PI3P) downstream of growth factor signaling and by Vps34-mediated PI3P production on endosomes. Upregulation of Sgk3 activity has recently been linked to a number of human cancers. Here, we show that Sgk3 is regulated by a combination of phosphorylation and allosteric activation by PI3P. We demonstrate that PI3P binding induces large conformational changes in Sgk3 associated with its activation, and that the PI3P binding pocket of the PX domain of Sgk3 is sequestered in its inactive conformation. Finally, we reconstituted Sgk3 activation via Vps34-mediated PI3P synthesis on phosphatidylinositol liposomesin vitro. In addition to defining the mechanism of Sgk3 activation by PI3P, our findings open up potential therapeutic avenues in allosteric inhibitor development to target Sgk3 in cancer.
eIF2α integrates proteotoxic signals both from ER and cytoplasm: Hsp70-Bag3 module regulates HRI-dependent phosphorylation of eIF2α
Authors: Patel Shivani , Kumar Santosh , Hesin Arkadi , Yaglom Julia , Sherman Michael Y.
Published: April 2021

The major heat shock protein Hsp70 has been implicated in many stages of cancer development. These effects are mediated by a scaffold protein Bag3 that binds to Hsp70 and links it to components of multiple cancer-related signaling pathways. Accordingly, the Hsp70-Bag3 complex has been targeted by small molecules, which showed strong anti-cancer effects. Here, our initial question was how JG-98, an allosteric inhibitor of Hsp70 that blocks its interaction with Bag3, causes cell death. Breast epithelial cells MCF10A transformed with a single oncogene Her2 showed higher sensitivity to JG-98 then parental MCF10A cells. RNA expression analysis showed that this enhanced sensitivity correlated with higher induction of the UPR genes. Indeed, depletion of the pro-apoptotic UPR responsive transcription factor CHOP significantly protected cells from JG-98. Surprisingly, only the eIF2α-associated branch of the UPR was activated by JG-98, suggesting that the response was not related to the ER proteotoxicity. Indeed, it was dependent on activation of a distinct cytoplasmic eIF2α kinase HRI. HRI-dependent phosphorylation of eIF2α was also activated by the cytoplasmic proteotoxicity via Hsp70-Bag3 complex, which directly associates with HRI. Dissociation of Hsp70-Bag3 complex led to Bag3-dependent degradation of HRI via autophagy. Therefore, eIF2α integrates proteotoxicity signals from both ER and cytoplasm, and the cytoplasmic response mediates cytotoxicity of the Hsp70-Bag3 inhibitors.
Intergenic ORFs as elementary structural modules ofde novogene birth and protein evolution
Authors: Papadopoulos Chris , Callebaut Isabelle , Gelly Jean-Christophe , Hatin Isabelle , Namy Olivier , Renard Maxime , Lespinet Olivier , Lopes Anne
Published: April 2021

The noncoding genome plays an important role inde novogene birth and in the emergence of genetic novelty. Nevertheless, how noncoding sequences’ properties could promote the birth of novel genes and shape the evolution and the structural diversity of proteins remains unclear. Therefore, by combining different bioinformatic approaches, we characterized the fold potential diversity of the amino acid sequences encoded by all intergenic ORFs (Open Reading Frames) ofS. cerevisiaewith the aim of (i) exploring whether the large structural diversity observed in proteomes is already present in noncoding sequences, and (ii) estimating the potential of the noncoding genome to produce novel protein bricks that can either give rise to novel genes or be integrated into pre-existing proteins, thus participating in protein structure diversity and evolution. We showed that amino acid sequences encoded by most yeast intergenic ORFs contain the elementary building blocks of protein structures. Moreover, they encompass the large structural diversity of canonical proteins with strikingly the majority predicted as foldable. Then, we investigated the early stages ofde novogene birth by identifying intergenic ORFs with a strong translation signal in ribosome profiling experiments and by reconstructing the ancestral sequences of 70 yeastde novogenes. This enabled us to highlight sequence and structural factors determiningde novogene emergence. Finally, we showed a strong correlation between the fold potential ofde novoproteins and the one of their ancestral amino acid sequences, reflecting the relationship between the noncoding genome and the protein structure universe.
FAN1 nuclease activity affects CAG expansion and age at onset of Huntington’s disease
Authors: McAllister Branduff , Donaldson Jasmine , Binda Caroline S. , Powell Sophie , Chughtai Uroosa , Edwards Gareth , Stone Joseph , Lobanov Sergey , Elliston Linda , Schuhmacher Laura-Nadine , Rees Elliott , Menzies Georgina , Ciosi Marc , Maxwell Alastair , Chao Michael J. , Hong Eun Pyo , Lucente Diane , Wheeler Vanessa , Lee Jong-Min , MacDonald Marcy E. , Long Jeffrey D. , Aylward Elizabeth H. , Landwehrmeyer G. Bernhard , Rosser Anne E. ,   REGISTRY Investigators of the European Huntington’s disease network, Paulsen Jane S. ,   PREDICT-HD Investigators of the Huntington Study Group, Williams Nigel M. , Gusella James F. , Monckton Darren G. , Allen Nicholas D. , Holmans Peter , Jones Lesley , Massey Thomas H.
Published: April 2021

The age at onset of motor symptoms in Huntington’s disease (HD) is driven byHTTCAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier onset HD. Nuclease activities of these variants correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion comparable to those observed with completeFAN1knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.