bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene-environment interactions in face categorisation: experience with a nanny and oxytocin receptor genotype interact to reduce face categorization reaction times
Authors: Neoh Michelle Jin Yee , Setoh Peipei , Bizzego Andrea , Tandiono Moses , Foo Jia Nee , Esposito Gianluca
Published: December 2020

Human faces are relevant stimuli that capture attention, provide information about group belonging and elicit automatic prepared responses. While early experiences with other race faces plays a critical role in acquiring face expertise, the exact mechanism through which it exerts its influence is still to be elucidated. In particular, the influence of genetic factors and the role of a multi-ethnic context has not been explored. The aim of this study was to investigate how caregiving experiences with nannies and oxytocin receptor gene (OXTR) genotypes interact in regulating other-race categorisation mechanisms in adults. Information about single nucleotide polymorphisms of the OXTR (rs53576) and experiences with own- and other-race nannies was collected from 89 Singaporean adults, who completed a visual categorization task of face stimuli (Chinese or Javanese). Participants were grouped into A/A homozygotes and G-carriers and assigned a score to account for the type of nanny experience. A General Linear Model was used to estimate the effect of nanny experience, genetic group and their interaction on categorization reaction time. A significant main effect of the nanny experience (p<.001) and of the interaction between genetic group and experience (p=.008) was found. Post-hoc analysis revealed a significant negative correlation between nanny experience and reaction time for A/A homozygotes (r=−0.52, p<.001) but no significant correlation for G-carriers. In summary, a significant gene-environment interaction on face categorization was found. This finding appears to represent an indirect pathway through which genes and experiences interact to shape mature social sensitivity in human adults.

Highlights

Early nanny experience interacts with oxytocin receptor genotype in affecting the speed of face categorisation.

Individuals with other-race nanny experience show faster categorisation response times. Gene-environment interactions are present in face categorisation.
DOT1L interaction partner AF10 controls patterning of H3K79 methylation and RNA polymerase II to maintain cell identity
Authors: Wille Coral K. , Neumann Edwin N. , Deshpande Aniruddha J. , Sridharan Rupa
Published: December 2020

Histone 3 Lysine 79 methylation (H3K79me) is enriched on gene bodies proportional to gene expression levels, and serves as a strong barrier for reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). DOT1L is the sole histone methyltransferase that deposits all three orders - mono, di, and tri methylation – at H3K79. Here we leverage genetic and chemical approaches to parse the specific functions of the higher orders of H3K79me in maintaining cell identity. DOT1L interacts with AF10 (Mllt10) which recognizes unmodified H3K27 and boosts higher order H3K79 methylation. AF10 deletion evicts higher order H3K79me2/3, and reorganizes H3K79me1 to the transcription start site, to facilitate iPSC formation in the absence of steady state transcriptional changes. Instead, AF10 loss redistributes RNA polymerase II to a uniquely pluripotent pattern at highly expressed, rapidly transcribed housekeeping genes. Taken together, we reveal a mechanism for higher order histone methylation located at the gene body in reinforcing cell identity.
Molecular insights into substrate recognition and discrimination by the N-terminal domain of Lon AAA+ protease
Authors: Tzeng Shiou-Ru , Tseng Yin-Chu , Lin Chien-Chu , Hsu Chia-Ying , Huang Shing-Jong , Kuo Yi-Ting , Chang Chung-I
Published: December 2020

The Lon AAA+ proteases (LonA) is a ubiquitous ATP-dependent proteolytic machine, which selectively degrades damaged proteins or native proteins carrying exposed motifs (degrons). Here we characterize the structural basis for substrate recognition and discrimination by the N-terminal domain(NTD) of LonA. The results reveal that the six NTDs are attached to the hexameric LonA chamber by flexible linkers such that the formers tumble independently of the latter. Further spectral analyses show that the NTD selectively interacts with unfolded proteins, protein aggregates, and degron-tagged proteins by two hydrophobic patches of its N-lobe, but not intrinsically disordered substrate, α-casein. Moreover, the NTD selectively binds to protein substrates when they are thermally induced to adopt unfolded conformations. Collectively, our findings demonstrate that NTDs enable LonA to perform protein quality control to selectively degrade proteins in damaged states and suggest that substrate discrimination and selective degradation by LonA are mediated by multiple NTD interactions.

Impact Statement

The N-terminal domains enable Lon protease to discriminate and capture selected protein species for degradation by exposed hydrophobic patches and flexible linkages to the hexameric core complex.
Temporal Microbial Community Dynamics within a Unique Acid Saline Lake
Authors: Ghori Noor-ul-Huda , Wise Michael. J. , Whiteley Andrew. S.
Published: December 2020

Lake Magic is one of the acidic hypersaline lakes (ca. 1 km in diameter) present within the Yilgarn Craton in WA. This unique lake exhibits extremely low pH (<1.6) coupled to very high salinity (32% TDS) with the highest concentration of aluminium (1774 mg/L) and silica (510 mg/L) in the world. Previous studies on Lake Magic diversity has revealed that the lake hosts acidophilic, acidotolerant, halophilic and halotolerant bacterial species. These studies provide indicators of the population residing within the lake. However, they do not emphasize the survival mechanisms adopted by the resident microorganisms and how the diversity of microbial populations residing within the lake changes during the dynamic stages of flooding, evapo-concentration and desiccation. We have studied the bacterial and fungal diversity in Lake Magic via amplicon sequencing and functional analysis through different stages of the lake in a span of one year, in the salt and sediment layer. Our results highlight that the diversity in Lake Magic is strongly driven by the pH and salt concentrations at different stages of the lake. The microbial community becomes more specialised in specific functions during more extreme stages. This also suggests that microbial interactions are involved in stabilising the ecosystem and is responsible for the resistance and resilience of these communities as the interactions of these microbes create a safe haven for other microbes to survive during more extreme stages.
Conformational dynamics of auto-inhibition in the ER calcium sensor STIM1
Authors: van Dorp Stijn , Qiu Ruoyi , Choi Ucheor B. , Wu Minnie M. , Yen Michelle , Kirmiz Michael , Brunger Axel T. , Lewis Richard S.
Published: December 2020

The dimeric ER Ca2+sensor STIM1 controls store-operated Ca2+entry (SOCE) through the regulated binding of its CRAC activation domain (CAD) to Orai channels in the plasma membrane. In resting cells, the STIM1 CC1 domain interacts with CAD to suppress SOCE, but the structural basis of this interaction is unclear. Using single-molecule Förster resonance energy transfer (smFRET) and protein crosslinking approaches, we show that CC1 interacts dynamically with CAD in a domain-swapped configuration with an orientation predicted to sequester its Orai- binding region adjacent to the ER membrane. Following ER Ca2+depletion and release from CAD, cysteine crosslinking indicates that the two CC1 domains become closely paired along their entire length in the active Orai-bound state. These findings provide a structural basis for the dual roles of CC1: sequestering CAD to suppress SOCE in resting cells and propelling it towards the plasma membrane to activate Orai and SOCE after store depletion.
Developmental accumulation of gene body and transposon non-CpG methylation in the zebrafish brain
Authors: Ross Samuel E , Hesselson Daniel , Bogdanovic Ozren
Published: December 2020

DNA methylation predominantly occurs at CG dinucleotides in vertebrate genomes; however, non-CG methylation (mCH) is also detectable in vertebrate tissues, most notably in the nervous system. In mammals it is well established that mCH is targeted to CAC trinucleotides by DNMT3A during nervous system development where it is enriched in gene bodies and associated with transcriptional repression. However, the conservation of developmental mCH accumulation and its deposition by DNMT3A is largely unexplored and has yet to be functionally demonstrated in other vertebrates. In this study, by analyzing DNA methylomes and transcriptomes of zebrafish brains, we identified enrichment of mCH at CAC trinucleotides (mCAC) at defined transposon motifs as well as in developmentally downregulated genes associated with developmental and neural functions. We further generated and analyzed DNA methylomes and transcriptomes of developing zebrafish larvae and demonstrated that, like in mammals, mCH accumulates during post-embryonic brain development. Finally, by employing CRISPR/Cas9 technology, we unraveled a conserved role for Dnmt3a enzymes in developmental mCAC deposition. Overall, this work demonstrates the evolutionary conservation of developmental mCH dynamics and highlights the potential of zebrafish as a model to study mCH regulation and function during normal and perturbed development.
Is mRNA decapping activity of ApaH like phosphatases (ALPH’s) the reason for the loss of cytoplasmic ALPH’s in all eukaryotes but Kinetoplastida?
Authors: Castañeda Londoño Paula Andrea , Banholzer Nicole , Bannermann Bridget , Kramer Susanne
Published: December 2020

Background

ApaH like phosphatases (ALPHs) originate from the bacterial ApaH protein and are present in eukaryotes of all eukaryotic super-groups; still, only two proteins have been functionally characterised. One is ALPH1 from the KinetoplastidTrypanosoma bruceithat we recently found to be the mRNA decapping enzyme of the parasite. mRNA decapping by ALPHs is unprecedented in eukaryotes, which usually use nudix hydrolases, but the bacterial ancestor protein ApaH was recently found to decap non-conventional caps of bacterial mRNAs. These findings prompted us to explore whether mRNA decapping by ALPHs is restricted to Kinetoplastida or more widespread among eukaryotes.

Results

We screened 824 eukaryotic proteomes with a newly developed Python-based algorithm for the presence of ALPHs and used the data to refine phylogenetic distribution, conserved features, additional domains and predicted intracellular localisation of ALPHs. We found that most eukaryotes have either no ALPH (500/824) or very short ALPHs, consisting almost exclusively of the catalytic domain. These ALPHs had mostly predicted non-cytoplasmic localisations, often supported by the presence of transmembrane helices and signal peptides and in two cases (one in this study) by experimental data. The only exceptions were ALPH1 homologues from Kinetoplastida, that all have unique C-terminal and mostly unique N-terminal extension, and at least theT. bruceienzyme localises to the cytoplasm. Surprisingly, despite of these non-cytoplasmic localisations, ALPHs from all eukaryotic super-groups hadin vitromRNA decapping activity.

Conclusions

ALPH was present in the last common ancestor of eukaryotes, but most eukaryotes have either lost the enzyme since, or use it exclusively outside the cytoplasm in organelles in a version consisting of the catalytic domain only. While our data provide no evidence for the presence of further mRNA decapping enzymes among eukaryotic ALPHs, the broad substrate range of ALPHs that includes mRNA caps provides an explanation for the selection against the presence of a cytoplasmic ALPH protein as a mean to protect mRNAs from unregulated degradation. Kinetoplastida succeeded to exploit ALPH as their mRNA decapping enzyme, likely using the Kinetoplastida-unique N- and C-terminal extensions for regulation.
Nuclear myocardial perfusion studies do not predict vascular or myocardial architecture in advanced heart failure
Authors: Farris Stephen , Don Creighton , Soine Laurie , Lombardi William , Caldwell James , Stempien-Otero April
Published: December 2020

Objectives

To determine predictors of tissue that would benefit from improved blood flow in subjects with advanced heart disease.

Background

Advanced regeneration and percutaneous revascularization strategies including revascularization of chronic total occlusions (CTO) are being used to potentially restore myocardial function in the growing population of patients with advanced heart disease. Predictors of myocardial recovery in this population have not been established.

Methods

Cardiac tissue was collected from 27 subjects undergoing LVAD or cardiac transplantation who had nuclear perfusion imaging prior to procedure. Histologic analysis for fibrosis, vascular density and inflammation was performed and correlated with nuclear perfusion images from the same areas. In a subset of subjects, correlations of nuclear perfusion with TIMI flow by coronary arteriography was also performed.

Results

Areas of both normal and abnormal epicardial coronary blood flow had a large variation in radiotracer uptake. There were no statistically significant correlations between uptake of radiotracer at rest and degree of cardiac fibrosis, vascular density or inflammation and the matched area of myocardium. Fibrosis varied from 5-50% in areas with severe defects and areas of normal radiotracer uptake. Endothelial density correlated with inflammation in end-stage heart disease.

Conclusions

Radiotracer uptake poorly predicted both areas of severe fibrosis that will not benefit from increased blood flow and areas of minimal fibrosis that may recover. Correlation of inflammation and endothelial density support a hypothesis that inflammatory cytokines augment vascularity in myocardium. Novel strategies to improve function in advanced heart disease are in need of better markers of recovery.
Deep Learning to Estimate Cardiac Magnetic Resonance-Derived Left Ventricular Mass
Authors: Khurshid Shaan , Friedman Samuel , Pirruccello James P. , Di Achille Paolo , Diamant Nathaniel , Anderson Christopher D. , Ellinor Patrick T. , Batra Puneet , Ho Jennifer E. , Philippakis Anthony , Lubitz Steven A.
Published: December 2020

Background

Cardiac magnetic resonance (CMR) is the gold standard for left ventricular hypertrophy (LVH) diagnosis. CMR-derived LV mass can be estimated using proprietary algorithms (e.g., inlineVF), but their accuracy and availability may be limited.

Objective

To develop an open-source deep learning model to estimate CMR-derived LV mass.

Methods

Within participants of the UK Biobank prospective cohort undergoing CMR, we trained two convolutional neural networks to estimate LV mass. The first (ML4Hreg) performed regression informed by manually labeled LV mass (available in 5,065 individuals), while the second (ML4Hseg) performed LV segmentation informed by inlineVF contours. We compared ML4Hreg, ML4Hseg, and inlineVF against manually labeled LV mass within an independent holdout set using Pearson correlation and mean absolute error (MAE). We assessed associations between CMR-derived LVH and prevalent cardiovascular disease using logistic regression adjusted for age and sex.

Results

We generated CMR-derived LV mass estimates within 38,574 individuals. Among 891 individuals in the holdout set, ML4Hsegreproduced manually labeled LV mass more accurately (r=0.864, 95% CI 0.847-0.880; MAE 10.41g, 95% CI 9.82-10.99) than ML4Hreg(r=0.843, 95% CI 0.823-0.861; MAE 10.51, 95% CI 9.86-11.15, p=0.01) and inlineVF (r=0.795, 95% CI 0.770-0.818; MAE 14.30, 95% CI 13.46-11.01, p<0.01). LVH defined using ML4Hsegdemonstrated the strongest associations with hypertension (odds ratio 2.76, 95% CI 2.51-3.04), atrial fibrillation (1.75, 95% CI 1.37-2.20), and heart failure (4.53, 95% CI 3.16-6.33).

Conclusions

ML4Hsegis an open-source deep learning model providing automated quantification of CMR-derived LV mass. Deep learning models characterizing cardiac structure may facilitate broad cardiovascular discovery.
Fronto-limbic neural variability as a transdiagnostic correlate of emotion dysregulation
Authors: Kebets Valeria , Favre Pauline , Houenou Josselin , Polosan Mircea , Aubry Jean-Michel , Van De Ville Dimitri , Piguet Camille
Published: December 2020

Background

Emotion dysregulation is central to the development and maintenance of psychopathology, and is common across many psychiatric disorders. Neurobiological models of emotion dysregulation involve the fronto-limbic brain network, including in particular the amygdala and prefrontal cortex (PFC). Neural variability has recently been suggested as an index of cognitive flexibility. We hypothesized that within-subject neural variability in the fronto-limbic network would be related to inter-individual variation in emotion dysregulation in the context of low affective control.

Methods

In a multi-site cohort (N= 166, 93 females) of healthy individuals and individuals with emotional dysregulation (attention deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), and borderline personality disorder (BPD)), we applied partial least squares (PLS), a multivariate data-driven technique, to derive latent components yielding maximal covariance between blood-oxygen level-dependent (BOLD) signal variability at rest and emotion dysregulation, as expressed by affective lability, depression and mania scores.

Results

PLS revealed one significant latent component (r= 0.62,p= 0.001), whereby greater emotion dysregulation was associated with increased neural variability in the amygdala, hippocampus, ventromedial, dorsomedial and dorsolateral PFC, insula and motor cortex, and decreased neural variability in occipital regions. This spatial pattern bears a striking resemblance to the fronto-limbic network, which is thought to subserve emotion regulation, and is impaired in individuals with ADHD, BD, and BPD.

Conclusions

Our work supports emotion dysregulation as a transdiagnostic dimension with neurobiological underpinnings that transcend diagnostic boundaries, and adds evidence to neural variability being a relevant proxy of neural efficiency.
The effect of remote ischemic preconditioning on postoperative cardiac and inflammatory biomarkers in pancreatic surgery: a randomized controlled trial
Authors: van Zeggeren Laura , Visser Remco A. , Vernooij Lisette M. , Dijkstra Ineke M. , Bosma Madeleen , Molenaar Izaak Q. , van Santvoort Hjalmar C. , Noordzij Peter G.
Published: December 2020

Background

Cardiac and inflammatory biomarkers have been associated with adverse outcome after major abdominal surgery. Remote ischemic preconditioning (RIPC) may protect organs from ischemic insults during and after cardiac surgery, but the effect in major abdominal surgery is largely unknown.

Objective

To study the effect of RIPC on cardiac and inflammatory biomarkers in patients undergoing pancreatic resection.

Methods

Single-center, double-blind, randomized controlled trial in ninety patients undergoing elective pancreatic resection between March 2017 and February 2019. Three cycles of upper-limb ischemia and reperfusion (each 5 minutes) were applied before surgery. The primary endpoint was the maximum postoperative high-sensitive cardiac troponin (hs-cTn) T concentration within 48 hours after surgery. Secondary endpoints were postoperative myocardial injury (PMI, defined as a postoperative hs-cTnT ≥14 ng L-1), the maximum concentration of interleukin (IL)-6 within 48 hours after surgery, and postoperative complications within 30-days of surgery.

Results

RIPC did not reduce the maximum hs-cTnT concentration after surgery (12.6 ng L-1 vs 16.6 ng L-1 in the control group (P=0.23), nor did it lessen the incidence of PMI (15 (33.3%) patients in the RIPC group versus 19 (42.2%) controls, P=0.93). The maximum postoperative IL-6 concentration was 239 pg mL-1 [115-360] in the RIPC group, as compared to 317 pg mL-1 [174-909] in the control group (P=0.13). A postoperative complication occurred in 23 (51%) RIPC patients and 24 (53%) controls.

Conclusions

Remote ischemic preconditioning did not reduce the maximum postoperative hs-cTnT concentration. Postoperative myocardial injury, IL-6 concentrations and postoperative complications were not statistically different between RIPC patients and controls.

Trial Registration

Clinicaltrials.gov identifier NCT03460938

Funding

Funding for biomarker analysis was provided by Roche Diagnostics. Roche Diagnostics had no role in design and conduct of the study, analysis and interpretation of the data, preparation and approval of the manuscript.

Article summary

Strengths and limitations of this study

Well-designed clinical trial in a selected group of high-risk abdominal surgery patients.

Serial assessment of high-sensitive cardiac troponin T and interleukin-6 concentrations.

Postoperative cardiac biomarker concentrations were relatively low.

This trial was not primarily designed to detect differences in IL-6 concentrations and postoperative complications.
Mental health among pregnant women during the pandemic in Sweden– a mixed methods approach using data from the Mom2B mobile application for research
Authors: Fransson Emma , Karalexi Maria , Kimmel Mary , Bränn Emma , Kollia Natasa , van Zoest Vera , Nordling Eira , Papadopoulos Fotios C , Skalkidou Alkistis
Published: December 2020

Public health emergencies such as the coronavirus (SARS-CoV-2) pandemic have significant impact on mental health, and have been shown to impact on already prevalent affective disorders during and after pregnancy. The aim of this study was to utilize modern tools to assess depressive and anxiety symptoms, as well as wellbeing and life changes in pregnant women during the pandemic in Sweden, where no lockdown has been in place.

Data from the Mom2B, a national ongoing mobile application-based study of pregnant and newly-delivered women were utilized. Participants (n= 1345) filled out self-report screeners of depression, anxiety and wellbeing. Questions about COVID symptoms and effects on life and health care were added from March 2020. Movement data was collected using the phone’s GPS sensor. Mood scores were compared with throughout the months of 2020 and to the levels of a previous collected material. Highest levels of depression and anxiety were evident in April and October 2020. Symptoms were higher among those feeling socially isolated, but not for those infected or with symptomatic family members. Wellbeing and mobility were strongly positively correlated and were lowest in April. Women reported on cancelled healthcare appointments and worry about their partners being absent from the delivery.

The Mom2B application enabled gathering information at a national level in real-time as the pandemic has been evolving. Levels of perinatal affective symptoms and low wellbeing were elevated compared with previous years as well as with months with fewer cases of SARS-Cov-2. Similar applications can help healthcare providers and governmental bodies to in real time monitor high-risk groups during crises, as well as to adjust measures and the support offered.

Funding

This project was funded by the Uppsala Region to AS, the Swedish Association of Local Authorities and Regions (SKR) to the department of Obstetrics and Gynecology, Akademiska University Hospital, the Swedish Research Council (Grant number 2020-01965) to AS, as well as the Fredrik and Inger Thuring’s Foundation to EF.
The Influence of Phenotyping Method on Structural Neuroimaging Associations with Depression in UK Biobank
Authors: Harris Mathew A. , Cox Simon R. , de Nooij Laura , Barbu Miruna C. , Adams Mark J. , Shen Xueyi , Deary Ian J. , Lawrie Stephen M. , McIntosh Andrew M. , Whalley Heather C.
Published: December 2020

Background

Depression is assessed in many different ways, with large population studies often relying on minimal phenotyping approaches. Genetic results suggest that more formal clinical diagnoses and simpler self-report measures of depression show some core similarities, but also important differences. It is not yet clear whether this is also the case for neuroimaging measures.

Methods

We studied 39,300 UK Biobank imaging participants (20,701 female; aged 44.6 to 82.3 years, M = 64.1, SD = 7.5) with structural neuroimaging (T1 and DTI) and depression data. Depression phenotypes included a minmal single-item self-report measure, an intermediate symptom-based measure of ‘probable’ depression, and a more clinically robust measure based on DSM-IV criteria. We tested i) associations between brain structural measures and each depression phenotype, and ii) the effects of depression phenotype on these associations.

Results

Small depression-brain structure associations (β < 0.1) were significant after FDR correction for many global and regional metrics for all three phenotypes. The most consistent imaging associations across depression phenotypes were for measures of white matter integrity. There were small but significant effects of phenotype definition primarily for cortical thickness, which showed stronger negative associations with Self-reported Depression than the symptom-based measures.

Conclusion

Similar to previous genetic studies, we found some consistent associations indicating a core component of depression across phenotypes, and some additional associations that were phenotype-specific. Although these specific results did not relate to depth of phenotyping as expected, effects of phenotype definition are still an important consideration for future depression research.
Global Warming and Neurological Practice: Systematic Review
Authors: Peinkhofer C , Amiri M , Othman MH , De Vecchi T , Nersesjan V , Kondziella D
Published: December 2020

Background

Climate change, including global warming, is expected to cause poorer global health and a rise in the number of environmental refugees. As neurological disorders account for a major share of worldwide morbidity and mortality, climate change and global warming are also destined to alter neurological practice; however, to what extent and by which mechanisms is unknown. We aimed to collect the available information on the effects of ambient temperatures and human migration on the epidemiological and clinical manifestations of major neurological disorders.

Methods

We searched PubMed and Scopus from January 1, 2000 to November 30, 2020 for human studies published in English addressing the influence of ambient temperatures and human migration on Alzheimer’s and non-Alzheimer’s dementia, epilepsy, headache and migraine, multiple sclerosis, Parkinson’s disease, stroke, and tick-borne encephalitis (as a model disease for neuroinfections). The protocol was pre-registered at PROSPERO (2020 CRD42020147543).

Results

101 studies met inclusion criteria, but we were unable to identify a single study addressing how global warming and human migration will change neurological practice. Still, extracted data suggested multiple ways by which these aspects might alter neurological morbidity and mortality in the future.

Conclusion

Significant heterogeneity exists across studies with respect to methodology, outcome measures, control of confounders and study design, but there is enough evidence to suggest climate change will affect the neurological practice of all major neurological disorders. Adequately designed studies to address this issue are urgently needed, which will require concerted efforts from the neurological community.
Tau-first subtype of Alzheimer’s disease consistently identified across in vivo and post mortem studies
Authors: Aksman Leon M. , Oxtoby Neil P. , Scelsi Marzia A. , Wijeratne Peter A. , Young Alexandra L. , Alves Isadora Lopes , Barkhof Frederik , Alexander Daniel C. , Altmann Andre ,   the ADNI
Published: December 2020

Alzheimer’s disease (AD) is marked by the spread of misfolded amyloid-β and tau proteins throughout the brain. While it is commonly believed that amyloid-β abnormality drives the cascade of AD pathogenesis, several in vivo and post mortem studies indicate that in some subjects localized tau-based neurofibrillary tangles precede amyloid-β pathology. This suggests that there may be multiple distinct subtypes of protein aggregation pathways within AD, with potentially different demographic, cognitive and comorbidity profiles. We investigated this hypothesis, applying data-driven disease progression subtyping models to post mortem immunohistochemistry and in vivo positron emission tomography (PET) and cerebrospinal fluid (CSF) based measures of protein pathologies in two large observational cohorts. We consistently identified both amyloid-first and tau-first AD subtypes, where tau-first subjects had higher levels of soluble TREM2 compared to amyloid-first subjects. Our work provides insight into AD progression that may be valuable for interventional trials targeting amyloid-β and tau.
A systems biology analysis of lipolysis and fatty acid release from adipocytesin vitroand from adipose tissuein vivo
Authors: Lövfors William , Ekström Jona , Jönsson Cecilia , Strålfors Peter , Cedersund Gunnar , Nyman Elin
Published: December 2020

Lipolysis and the release of fatty acids to supply energy fuel to other organs, such as between meals, during exercise, and starvation, are fundamental functions of the adipose tissue. The intracellular lipolytic pathway in adipocytes is activated by adrenaline and noradrenaline, and inhibited by insulin. Circulating fatty acids are elevated in type 2 diabetic individuals. The mechanisms behind this elevation are not fully known, and to increase the knowledge a link between the systemic circulation and intracellular lipolysis is key. However, data on lipolysis and knowledge fromin vitrosystems have not been linked to correspondingin vivodata and knowledgein vivo. Here, we use mathematical modelling to provide such a link. We examine mechanisms of insulin action by combiningin vivoandin vitrodata into an integrated mathematical model that can explain all data. Furthermore, the model can describe independent data not used for training the model. We show the usefulness of the model by simulating new and more challenging experimental setupsin silico, e.g. the extracellular concentration of fatty acids during an insulin clamp, and the difference in such simulations between individuals with and without type 2 diabetes. Our work provides a new platform for model-based analysis of adipose tissue lipolysis, under both non-diabetic and type 2 diabetic conditions.
Water stress and nitrogen supply affect floral traits and pollination in the white mustard,Sinapis alba(Brassicaceae)
Authors: Akter Asma , Klečka Jan
Published: December 2020

Changes in environmental conditions are likely to have a complex effect on the growth of plants, their phenology, plant-pollinator interactions, and reproductive success. The current world is facing an ongoing climate change along with other human-induced environmental changes. Most research has focused on the impact of increasing temperature as a major driving force for climate change, but other factors may have important impacts on plant traits and pollination too and these effects may vary between different seasons. In addition, it is likely that the effects of multiple environmental factors, such as increasing temperature, water stress, and nitrogen enrichment are not independent. Therefore, we tested the impact of three key factors – season, water, and nitrogen supply – on plant traits, pollination, and seed production inSinapis alba(Brassicaceae). Plants were grown in three seasons with two levels of water and nitrogen supply in a factorial design. We collected data on multiple vegetative and floral traits and assessed the response of pollinators in the field. Additionally, we evaluated the effect of growing conditions on seed set in plants exposed to pollinators and in hand-pollinated plants. Our results show that water stress impaired vegetative growth, decreased flower production, reduced visitation by pollinators and seed set, while nitrogen availability played an important role in nectar production. Seasonality modulated the effect of water and nitrogen availability on vegetative and floral traits and strongly affected flowering phenology and flower production. We demonstrated that changes in water and nitrogen availability alter plant vegetative and floral traits, which impacts flower visitation and consequently plant reproduction. We conclude that ongoing environmental changes such as altered precipitation regimes and nitrogen enrichment may thus affect plant-pollinator interactions with negative consequences for the reproduction of wild plants and insect-pollinated crops.
Optimized guide RNA selection recommendations for usingspCas9 gene editing in human hematopoietic stem and progenitor cells
Authors: Verhagen Han J.M.P. , Kuijk Carlijn , Kokke Anne M. , Rutgers Laurens , van der Meulen Santhe A. , van Mierlo Gerard , Voermans Carlijn , van den Akker Emile
Published: December 2020

Ribonucleoproteins (RNPs) are frequently applied for therapeutic gene editing as well as fundamental research, because the method is fast, viral free, and does not rely on clonal selection.

We evaluated various parameters to genetically engineer human hematopoietic stem progenitor cells (HSPCs) usingspCas9-RNPs and achieve gene editing efficiencies up to 80%. We find that single guide RNA (sgRNA) design is critical to achieve high gene editing efficiencies. However, finding effective sgRNAs for HSPCs can be challenging, while the contribution of numerousin silicomodels is unclear.

Here we established a time- and cost-efficientin vitrotranscribed sgRNA screening model in K562 cells to identify sgRNAs that are effective in HSPCs using RNP delivery. We show that this simple screening method outperforms allin silicoprediction models. Our data demonstrates that mostin silicosgRNA prediction models are ineffective and we make recommendations to potentially improve their accuracy.

We report that gene editing is equally efficient in distinct CD34+HSPC subpopulations. Furthermore, no effects on cell proliferation, differentiation orin vitrohematopoietic lineage commitment were observed. Finally, no upregulation of p21 expression was found, suggesting unperturbed HSPC homeostasis.

Key points

In vitro transcribedsingle sgRNAs (IVTsgRNA) screening in K562 outperformsin silicomodeling

Hematopoietic stem and progenitor cells are equally targeted by Ribonucleoproteins (RNPs)

Hematopoietic stem and progenitor cells show no induction of p21 expression or effects on differentiation, proliferation and lineage commitment

Graphical abstract
An infectivity-enhancing site on the SARS-CoV-2 spike protein is targeted by COVID-19 patient antibodies
Authors: Liu Yafei , Soh Wai Tuck , Tada Asa , Arakawa Akemi , Matsuoka Sumiko , Nakayama Emi E. , Li Songling , Ono Chikako , Torii Shiho , Kishida Kazuki , Jin Hui , Nakai Wataru , Arase Noriko , Nakagawa Atsushi , Shindo Yasuhiro , Kohyama Masako , Nakagami Hironori , Tomii Keisuke , Ohmura Koichiro , Ohshima Shiro , Okada Masato , Matsuura Yoshiharu , Standley Daron M. , Shioda Tatsuo , Arase Hisashi
Published: December 2020

SARS-CoV-2 infection causes severe symptoms in a subset of patients, suggesting the presence of certain unknown risk factors. Although antibodies against the receptor-binding domain (RBD) of the SARS-CoV-2 spike have been shown prevent SARS-CoV-2 infection, the effects of antibodies against other spike protein domains are largely unknown. Here, we screened a series of anti-spike monoclonal antibodies from COVID-19 patients, and found that some of antibodies against the N-terminal domain (NTD) dramatically enhanced the binding capacity of the spike protein to ACE2, and thus increased SARS-CoV2 infectivity. Surprisingly, mutational analysis revealed that all the infectivity-enhancing antibodies recognized a specific site on the surface of the NTD. The antibodies against this infectivity-enhancing site were detected in all samples of hospitalized COVID-19 patients in the study. However, the ratio of infectivity-enhancing antibodies to neutralizing antibodies differed among patients. Furthermore, the antibodies against the infectivity-enhancing site were detected in 3 out of 48 uninfected donors, albeit at low levels. These findings suggest that the production of antibodies against SARS-CoV-2 infectivity-enhancing site could be considered as a possible exacerbating factors for COVID-19 and that a spike protein lacking such antibody epitopes may be required for safe vaccine development, especially for individuals with pre-existing enhancing antibodies.
Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19
Authors: Wilk Aaron J. , Lee Madeline J. , Wei Bei , Parks Benjamin , Pi Ruoxi , Martínez-Colón Giovanny J. , Ranganath Thanmayi , Zhao Nancy Q. , Taylor Shalina , Becker Winston ,   Stanford COVID-19 Biobank, Jimenez-Morales David , Blomkalns Andra L. , O’Hara Ruth , Ashley Euan A. , Nadeau Kari C. , Yang Samuel , Holmes Susan , Rabinovitch Marlene , Rogers Angela J. , Greenleaf William J. , Blish Catherine A.
Published: December 2020

Our understanding of protective vs. pathologic immune responses to SARS-CoV-2, the virus that causes Coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses reveal widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, with the most profound disturbances including a prominent neutrophil hyperactivation signature and monocytes with anti-inflammatory features. We further demonstrate that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.

One Sentence Summary

Single-cell profiling demonstrates multifarious dysregulation of innate immune phenotype associated with COVID-19 severity.
Automated hiPSC culture and sample preparation for 3D live cell microscopy
Authors: Coston Mackenzie E. , Gregor Benjamin W. , Arakaki Joy , Borensztejn Antoine , Do Thao P. , Fuqua Margaret A. , Haupt Amanda , Hendershott Melissa C. , Leung Winnie , Mueller Irina A. , Nelson Angelique M. , Rafelski Susanne M. , Swain-Bowden Madison J. , Tang W. Joyce , Thirstrup Derek J. , Wiegraebe Winfried , Yan Calysta , Gunawardane Ruwanthi N , Gaudreault Nathalie
Published: December 2020

Our goal is to identify and understand cellular behaviors using 3D live imaging of cell organization. To do this, we image human inducible pluripotent stem cell (hiPSC) lines expressing fluorescently tagged protein representing specific cellular organelles and structures. To produce large numbers of standardized cell images, we developed an automated hiPSC culture procedure, to maintain, passage and Matrigel coat 6-well plastic plates and 96-well glass plates compatible with high-resolution 3D microscopy. Here we describe this system including optimization procedures and specific values for plate movement, angle of tips, speed of aspiration and dispense, seeding strategies and timing of every step. We validated this approach through a side-by-side comparison of quality control results obtained from manual and automated methods. Additionally, we developed an automated image-based colony segmentation and feature extraction pipeline to predict cell count and select wells with consistent morphology for high resolution 3D microscopy.
A Framework to Analyse and Interpret Mouse Functional Genome by Prioritizing High Impact SNPs
Authors: Arslan Ahmed
Published: December 2020

The essential understanding of disease pathogenesis and enabling genetic findings to be used for developing new therapeutics, is missing in the identifications of genomic loci through whole genome association studies (GWAS). Here we describe a new computational method (mMap) that reduces this gap by characterizing the functional and regulatory impact of allelic variation. The method incorporates the precomputed annotations of 26 protein functional regions and eight regulatory regions and recover SNPs that fall/lie in these regions. After annotating SNPs to functional or regulatory data, method link them to biological functions and pathways, and predicts significantly disrupted biological regions, processes and pathways, by controlling false discovery through hypergeometric test. By doing so, the method limits data to human interpretation level by prioritizing SNPs that have the potential to mediate a biological phenotype. The method is applicable to procedures that rely on the understanding of the biological causal role of mouse SNPs and is available online. In two example mMap applications, including whole genomes SNPs data from 48 inbred mice strains, we identify biological mechanisms by which SNPs can regulate pathways to govern phenotypes by targeting different coding and regulatory regions, even in closely related strains.
Local microcircuitry of parasubiculum shows distinct and common features of excitatory and inhibitory connectivity
Authors: Sammons Rosanna P , Tzilivaki Alexandra , Schmitz Dietmar
Published: December 2020

The parasubiculum is located within the parahippocampal region, where it is thought to be involved in the processing of spatial navigational information. It contains a number of functionally specialised neuron types including grid cells, head direction cells and border cells, and provides input into layer 2 of the medial entorhinal cortex where grid cells are abundantly located. The local circuitry within the parasubiculum remains so far undefined but may provide clues as to the emergence of spatially tuned firing properties of neurons in this region. We used simultaneous patch-clamp recordings to determine the connectivity rates between the three major groups of neurons found in the parasubiculum. We find high rates of interconnectivity between the pyramidal class and interneurons, as well as features of pyramid to pyramid interactions indicative of a non-random network. The microcircuit that we uncover shares both similarities and divergences to those from other parahippocampal regions also involved in spatial navigation.
Dominant Remodeling of Cattle Rumen Microbiome bySchedonorus arundinaceus(Tall Fescue) KY-31 Carrying a Fungal Endophyte
Authors: Khairunisa Bela Haifa , Susanti Dwi , Loganathan Usha , Teutsch Christopher D. , Campbell Brian T. , Fiske David , Wilkinson Carol A. , Aylward Frank O. , Mukhopadhyay Biswarup
Published: December 2020

Tall fescue KY-31 feeds ~20% of the beef cattle in the United States. It carries a fungal endophyte that produces ergovaline, which causes toxicosis in cattle, leading to $2 billion revenue loss annually. The MaxQ cultivar of the grass is non-toxic, but less attractive economically. To develop ways of mitigating the toxicity, the rumen microbiome of cattle consuming KY-31 and MaxQ have been analyzed, principally for identifying ergovaline transforming microorganisms and often using fecal microbiome as a surrogate. We have hypothesized that KY-31 not only causes toxicosis, but also impacts rumen metabolism broadly, and tested the hypothesis by analyzing rumen microbiome compositions of cattle that grazed MaxQ with an intervening KY-31 grazing period with 16S rRNA-V4 element as identifier. We found that KY-31 remodeled the cellulolytic and saccharolytic communities substantially. This effect was not evident at whole microbiome levels but in the compositions of sessile and planktonic fractions. A move from MaxQ to KY-31 lowered the Firmicutes abundance in the sessile fraction and increased it in planktonic part and caused an opposite effect for Bacteroidetes, although the total abundances of these dominant rumen organisms remained unchanged. In the sessile fraction, the abundances ofFibrobacter, which degrades less degradable fibers, and certain cellulolytic Firmicutes such asPseudobutyrivibrioandButyrivibrio2, dropped, and these losses were apparently compensated by increased occurrences ofEubacteriumand specificRuminococcaceaeandLachnospiraceae. In planktonic fraction the Tenericutes’ abundance increased as saccharolytic Bacteroidetes’ level dropped. Several potential ergovaline degraders were enriched. A return to MaxQ restored the original Firmicutes and Bacteroidetes distributions. However, theFibrobacterandButyrivibrio2 abundances remained low and their substitutes maintained significant presence. The rumen microbiome was influenced minimally by animals’ fescue toxicosis and was distinct from previously reported fecal microbiomes in composition. In summary, KY-31 and MaxQ cultivars of tall fescue were digested in the cattle rumen with distinct consortia and the KY-31-specific features were dominant. The study highlighted the importance of analyzing sessile and planktonic fractions separately.
Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits
Authors: Whyte Carly E. , Singh Kailash , Burton Oliver T. , Aloulou Meryem , Moudra Alena , Roca Carlos P. , Naranjo Francisco J. , Lombard-Vadnais Félix , Kouser Lubna , Hochepied Tino , Halim Timotheus Y. F. , Schlenner Susan , Lesage Sylvie , Dooley James , Liston Adrian
Published: December 2020

Interleukin 2 (IL-2) is a key homeostatic cytokine, with potential therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical application has been hampered by pleiotropic functionality and wide-spread receptor expression, with unexpected adverse events during trials. To characterize the IL-2 homeostatic network, we developed a novel mouse strain allowing IL-2 production to be diverted. Rewiring of IL-2 production to diverse leukocyte sources allowed the identification of contextual influences over IL-2 impact. Network analysis identified a priority access for Tregs, and a competitive fitness cost induced among both Tregs and conventional CD4 T cells for IL-2 production. CD8 T cells and NK cells, by contrast, exhibited a preference for autocrine IL-2 production. IL-2 sourced from dendritic cells amplified the Treg circuit, while IL-2 produced by B cells induced two context-dependent circuits: dramatic expansion of CD8+Tregs and ILC2 cells. The former was associated with an unexpected concentration of rare CD8+Tregs in B cell zones, while the latter drove a downstream, IL-5-mediated, eosinophilic circuit. The source-specific effects demonstrate the contextual influence of IL-2 function and potentially explain unexpected adverse effects observed during clinical trials of exogenous IL-2. Targeted IL-2 production therefore has the potential to amplify or quench particular circuits in the IL-2 network, based on clinical desirability.

Graphical abstract
VCFShark: how to squeeze a VCF file
Authors: Deorowicz Sebastian , Danek Agnieszka
Published: December 2020

The VCF files with results of sequencing projects take a lot of space. We propose VCFShark squeezing them up to an order of magnitude better than the de facto standards (gzipped VCF and BCF).

Availability and Implementation

https://github.com/refresh-bio/vcfshark

Contact

sebastian.deorowicz@polsl.pl

Supplementary information

Supplementary data are available at publisher’s Web site.