bluuebunny/crossref_metadata_2025 huggingface dataset:
Scientists’ opinion, attitudes, and consensus towards immunity passports
Authors: Aranzales Iván , Chan Ho Fai , Eichenberger Reiner , Hegselmann Rainer , Stadelmann David , Torgler Benno
Published: February 2021

Objectives

We measured attitudes towards “immunity passports” in the context of COVID-19 of a large sample of scientists. Consensus of scientists’ opinions on a different aspect of immunity passports was assessed.

Methods

We designed and implemented a survey to capture what scientists from around the world and different scientific background think about immunity certification. The survey was sent to the corresponding authors of scholarly articles published in the last five years in the top 20-ranked journals in each of the 27 subject areas between May and June 2020. Responses from 12,738 scientists were captured, and their distribution was tabulated by participants in health science and other fields. Consensus of responses was calculated using a variant of Shannon Entropy, made suitable for the ordinal response variables.

Results

Half of the scientists surveyed, regardless of academic background agree that a potential immunity passport program will be good for public health (50.2%) and the economy (54.4%), with 19.1% and 15.4% of participants disagree, respectively. A significant proportion of scientists raised concerns about immunity certification over fairness to others (36.5%) and social inequality (45.5%). There is little consensus in the different aspects of immunity passport among scientists. Overall, scientists with health background hold a more conservative view towards immunity certification.

Conclusions

Our findings suggest a lack of general agreement regarding the potential health and economic benefits, societal costs, and ethical issues of an immunity certification program within the scientific community. Given the relevant and important implications of immunity passport due to the increasing vaccine availability and efficacy, more attention should be given to the discussion of the design and implementation of immunity certification program.

Strengths and limitations of this study

First cross-disciplinary survey with a large and international sample size that enables mapping of scientists’ opinions and attitudes towards COVID-19 immunity certificates.

From the survey responses, we measured, reported, and compared the levels of consensus of scientists between health-related and non-health-related discipline.

Response rate and sample representativeness are moderate.
Effective subthalamic and pallidal deep brain stimulation – are we modulating the same network?
Authors: Sobesky Leon , Goede Lukas , Odekerken Vincent J.J. , Wang Qiang , Li Ningfei , Al-Fatly Bassam , Reich Martin , Volkmann Jens , de Bie Rob M.A. , Kühn Andrea A. , Horn Andreas
Published: February 2021

The subthalamic nucleus and internal pallidum are main target sites for deep brain stimulation in Parkinson’s disease. Multiple trials that investigated subthalamic versus pallidal stimulation were unable to settle on a definitive optimal target between the two. One reason could be that the effect is mediated via a common network. To test this hypothesis, we calculated connectivity profiles seeding from deep brain stimulation electrodes in 94 patients that underwent subthalamic treatment and 28 patients with pallidal treatment based on a normative connectome atlas calculated from 1,000 healthy subjects. In each cohort, we calculated connectivity profiles that were associated with optimal clinical improvements. The two maps showed striking similarity and were able to cross-predict outcomes in the respective other cohort (R = 0.38 at p < 0.001 & R = 0.35 at p = 0.027). Next, we calculated an agreement map which retained regions common of both target sites. Crucially, this map was able to explain an additional amount of variance in clinical improvements of either cohort when compared to the maps calculated on the two cohorts alone. Finally, we tested profiles and predictive utility of connectivity maps calculated from different motor symptom subscores with a specific focus on bradykinesia and rigidity. While our study is based on retrospective data and indirect connectivity metrics, it delivers empirical data to support the hypothesis of a largely overlapping network associated with effective deep brain stimulation in Parkinson’s disease irrespective of the specific target.
Vaccinating Australia: How long will it take?
Authors: Hanly Mark , Churches Tim , Fitzgerald Oisín , McIntyre C Raina , Jorm Louisa
Published: February 2021

The Australian Government’s COVID-19 vaccine rollout strategy is scheduled to commence in late February 2021 and aims to vaccinate the Australian adult population by the end of October 2021. The task of vaccinating some 20 million people within this timeframe presents considerable logistical challenges. Key to meeting this target is the rate of vaccine delivery: the number of vaccine doses that can be administered per day. In the opening phase, high priority groups will receive the Pfizer/BioNTech vaccine through hospital hubs at an initial rate of 80,000 doses per week. However, pending regulatory approval, the currently announced plan appears to be to distribute the AstraZeneca vaccine to the bulk of the popluation through a combination of general practices and community pharmacies. Here, we run a series of projections to estimate how long it will take to vaccinate the Australian population under different assumptions about the rate of vaccine administration as well as the schedule for second doses and prevalence of vaccine hesitancy. Our analysis highlights the ambitious rate of vaccine administration that will be neccessary to meet the Australian Government completion target of October 2021. A rate of 200,000 doses per day would comfortably meet that target; 80,000 doses a day would see roll-out extended until mid-2022. Speed is of the essence when it comes to vaccine rollout: protecting the population quickly will minimise the risk of sporadic and costly lockdowns lockdowns and the potential for small, local clusters getting out of control and sparking new epidemic waves. The government should gather all its resources to maximise the daily vaccination rate, ideally aiming to ramp up administration to at least 200,000 doses per day as quickly as possible. Quickly achieving and maintaining this pace will likely require dedicated large-scale vaccination sites that are capable of delivering thousands of doses a week in addition to the enthusiastic participation of GP practices and community pharmacies around the country. Lessons on the neccessary logistical planning, including coordination of delivery, ultra-cold-chain storage and staffing, can potentially be learned from Israel, where between 7,000 and 20,000 vaccinations per million population have been delivered daily throughout January.
Rapid vaccination and early reactive partial lockdown will minimize deaths from emerging highly contagious SARS-CoV-2 variants
Authors: Reeves Daniel B , Bracis Chloe , Swan David A. , Moore Mia , Dimitrov Dobromir , Schiffer Joshua T.
Published: February 2021

The goals of SARS-CoV-2 vaccination programs are to maximally reduce cases and deaths, and to limit the amount of time required under lockdown. Using a mathematical model calibrated to data from King County Washington but generalizable across states, we simulated multiple scenarios with different vaccine efficacy profiles, vaccination rates, and case thresholds for triggering and relaxing partial lockdowns. We assumed that a contagious variant is currently present at low levels. In all scenarios, it rapidly becomes dominant by early summer. Low case thresholds for triggering partial lockdowns during current and future waves of infection strongly predict lower total numbers of COVID-19 infections, hospitalizations and deaths in 2021. However, in regions with relatively higher current seroprevalence, there is a predicted delay in onset of a subsequent surge in new variant infections. For all vaccine efficacy profiles, increasing vaccination rate lowers the total number of infections and deaths, as well as the total number of days under partial lockdown. Due to variable current estimates of emerging variant infectiousness, vaccine efficacy against these variants, vaccine refusal, and future adherence to masking and physical distancing, we project considerable uncertainty regarding the timing and intensity of subsequent waves of infection. Nevertheless, under all plausible scenarios, rapid vaccination and early implementation of partial lockdown are the two most critical variables to save the greatest number of lives.
Modelling the Impact of Prevention and Treatment Interventions on HIV and Hepatitis C Virus Transmission Among People Who Inject Drugs in Kenya
Authors: Stone Jack , Fraser Hannah , Walker Josephine G , Mafirakureva Nyashadzaishe , Mundia Bernard , Cleland Charles , Kigen Bartilol , Musyoki Helgar , Waruiru Wanjiru , Ragi Allan , Bhattacharjee Parinita , Chhun Nok , Lizcano John , Akiyama Matthew J , Cherutich Peter , Kurth Ann , Luhmann Niklas , Vickerman Peter
Published: February 2021

Background

People who inject drugs (PWID) in Kenya have a high prevalence of HIV (14-26%) and HCV (11-36%). Needle and syringe programmes (NSP) and antiretroviral therapy (ART) have high coverage among PWID, while HCV treatment and opioid substitution therapy (OST) access is low.

Methods

A dynamic model of HIV (sexual and injecting-related) and HCV (injecting-related) transmission among PWID was calibrated using Bayesian methods to data from Nairobi and the Coastal region. We projected the impact of existing coverage levels of interventions (ART: 64-66%; OST: 4-7%; NSP: 54-56%) in each setting, and the impact over 2020-2030 of increasing the coverage of OST (50%) and NSP (75%; ‘full HR’), ART (UNAIDS 90-90-90 target), HCV treatment (1000 over 5 years), and reducing HIV sexual risk by 75%. We estimated HCV treatment levels needed to reduce HCV incidence by 90% with or without full HR.

Findings

Since 2013, HR has averted 15.1-20.6% (range in medians across settings) of HIV infections and 29.0-31.6% of HCV infections across Nairobi and the Coastal region, with most impact being due to NSP. Conversely, ART has only averted <5% of HIV infections since 2004 because of sub-optimal viral suppression (28-48%). Going forward, Full HR and ART could reduce HIV incidence by 58.2-62.0% and HCV incidence by 62.6-81.6% by 2030 across these settings. If sexual risk is also reduced, HIV incidence would reduce by 77.1-81.4%. Alongside full HR, treating 896 PWID over 2020-2025 could reduce HCV incidence by 90% by 2030.

Interpretation

Existing interventions have had moderate impact on HIV and HCV transmission in Kenya, but may have substantial impact if scaled-up. However, to achieve HIV and HCV elimination, reductions in sexual risk are needed and a scale-up in HCV treatment.

Funding

Global Fund, MDM
Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy
Authors: Oliveira da Silva MI , Santejo M , Babcock IW , Magalhães A , Minamide LS , Castillo E , Gerhardt E , Fahlbusch C , Swanson RA , Outeiro TF , Bamburg JR , Liz MA
Published: February 2021

Cognitive dysfunction and dementia are presently recognized as major complications in α-synucleinopathies, namely in Dementia with Lewy Bodies (DLB) and Parkinson’s disease with dementia (PDD). In these disorders, α-Synuclein (αSyn) accumulation affects severely the hippocampus by inducing synaptic dysfunction which culminates in cognitive impairment. To characterize the mechanisms underlying αSyn-induced neuronal dysfunction we analysed the effect of overexpression or extracellular administration of αSyn on hippocampal neurons. We observed that αSyn induces the dysregulation of the actin-binding protein cofilin and its assembly into rod structures in a mechanism mediated by the cellular prion protein (PrPC). Moreover, we unraveled cofilin pathology as mediator of αSyn-induced dendritic spine impairment in hippocampal neurons. Importantly, in a synucleinopathy mouse model with cognitive impairment we validated cofilin dysregulation and synaptic dysfunction at the same age when cognitive deficits were observed. Our data supports cofilin as a novel player on hippocampal synaptic dysfunction triggered by αSyn on Lewy Body dementias.
Combined influence of food availability and agricultural intensification on a declining aerial insectivore
Authors: Garrett Daniel R. , Pelletier Fanie , Garant Dany , Bélisle Marc
Published: February 2021

Aerial insectivores show worldwide population declines coinciding with shifts in agricultural practices. Increasing reliance on certain agricultural practices is thought to have led to an overall reduction in insect abundance that negatively affects aerial insectivore fitness. The relationship between prey availability and the fitness of insectivores may thus vary with the extent of agricultural intensity. It is therefore imperative to quantify the strength and direction of these associations. Here we used data from an 11-year study monitoring the breeding of Tree Swallows (Tachycineta bicolor) and the availability of Diptera (their main prey) across a gradient of agricultural intensification in southern Québec, Canada. This gradient was characterized by a shift in agricultural production, whereby landscapes composed of forage and pastures represented less agro-intensive landscapes and those focusing on large-scale arable row crop monocultures, such as corn (Zea mays) or soybean (Glycine max) that are innately associated with significant mechanization and agro-chemical inputs, represented more agro-intensive landscapes. We evaluated the landscape characteristics affecting prey availability, and how this relationship influences the fledging success, duration of the nestling period, fledgling body mass, and wing length as these variables are known to influence the population dynamics of this species. Diptera availability was greatest within predominately forested landscapes, while within landscapes dominated by agriculture, it was marginally greater in less agro-intensive areas. Of the measured fitness and body condition proxies, both fledging success and nestling body mass were positively related to prey availability. The impact of prey availability varied across the agricultural gradient as fledging success improved with increasing prey levels within forage landscapes yet declined in more agro-intensive landscapes. Finally, after accounting for prey availability, fledging success was lowest, nestling periods were the longest, and wing length of fledglings were shortest within more agro-intensive landscapes. Our results highlight the interacting roles that aerial insect availability and agricultural intensification have on the fitness of aerial insectivores, and by extension how food availability may interact with other aspects of breeding habitats to influence the population dynamics of predators.

Open Research

Data are not yet provided (option 4) as they are being used for other research projects. We affirm that data will be permanently archived if the paper is accepted for publication on the Dryad repository.
Identification of a Nervous System Gene Expression Signature in Colon Cancer Stem Cells Reveals a Role for Neural Crest RegulatorsEGR2andSOX2in Tumorigenesis
Authors: Regan Joseph L. , Schumacher Dirk , Staudte Stephanie , Steffen Andreas , Lesche Ralf , Toedling Joern , Jourdan Thibaud , Haybaeck Johannes , Golob-Schwarzl Nicole , Mumberg Dominik , Henderson David , Győrffy Balázs , Regenbrecht Christian R.A. , Keilholz Ulrich , Schäfer Reinhold , Lange Martin
Published: February 2021

Recent data support a hierarchical model of colon cancer driven by a population of cancer stem cells (CSCs). Greater understanding of the mechanisms that regulate CSCs may therefore lead to more effective treatments. Serial limiting dilution xenotransplantation assays of colon cancer patient-derived tumors demonstrated ALDHPositivecells to be enriched for tumorigenic self-renewing CSCs. In order to identify CSC modulators, we performed RNA-sequencing analysis of ALDHPositiveCSCs from a panel of colon cancer patient-derived organoids (PDOs) and xenografts (PDXs). These studies demonstrated CSCs to be enriched for embryonic and neural development gene sets. Functional analyses of genes differentially expressed in both ALDHPositivePDO and PDX CSCs demonstrated the neural crest stem cell (NCSC) regulator and wound response geneEGR2to be required for CSC tumorigenicity and to control expression of homeobox superfamily embryonic master transcriptional regulatorHOXgenes and the embryonic and neural stem cell regulatorSOX2. In addition, we identifyEGR2, HOXA2, HOXA4, HOXA5, HOXA7, HOXB2, HOXB3and the tumor suppressorATOH1as new prognostic biomarkers in colorectal cancer.
Unravelling the Physiological Correlates of Mental Workload Variations in Tracking and Collision Prediction Tasks: Implications for Air Traffic Controllers
Authors: John Alka Rachel , Singh Avinash K , Do Tien-Thong Nguyen , Eidels Ami , Nalivaiko Eugene , Gavgani Alireza Mazloumi , Brown Scott , Bennett Murray , Lal Sara , Simpson Ann M. , Gustin Sylvia M , Double Kay , Walker Frederick Rohan , Kleitman Sabina , Morley John , Lin Chin-Teng
Published: February 2021

Objective

We have designed tracking and collision prediction tasks to elucidate the differences in the physiological response to the workload variations in basic ATC tasks to untangle the impact of workload variations experienced by operators working in a complex ATC environment.

Background

Even though several factors influence the complexity of ATC tasks, keeping track of the aircraft and preventing collision are the most crucial.

Methods

Physiological measures, such as electroencephalogram (EEG), eye activity, and heart rate variability (HRV) data, were recorded from 24 participants performing tracking and collision prediction tasks with three levels of difficulty.

Results

The neurometrics of workload variations in the tracking and collision prediction tasks were markedly distinct, indicating that neurometrics can provide insights on the type of mental workload. The pupil size, number of blinks and HRV metric, root mean square of successive difference (RMSSD), varied significantly with the mental workload in both these tasks in a similar manner.

Conclusion

Our findings indicate that variations in task load are sensitively reflected in physiological signals, such as EEG, eye activity and HRV, in these basic ATC-related tasks.

Application

These findings have applicability to the design of future mental workload adaptive systems that integrate neurometrics in deciding not just ‘when’ but also ‘what’ to adapt. Our study provides compelling evidence in the viability of developing intelligent closed-loop mental workload adaptive systems that ensure efficiency and safety in ATC and beyond.

Précis

This article identifies the physiological correlates of mental workload variation in basic ATC tasks. The findings assert that neurometrics can provide more information on the task that contributes to the workload, which can aid in the design of intelligent mental workload adaptive system.
Hybrid multisite silicon neural probe with integrated flexible connector for interchangeable packaging
Authors: Novais Ashley , Calaza Carlos , Fernandes José , Fonseca Helder , Gaspar João , Jacinto Luis
Published: February 2021

Multisite neural probes are a fundamental tool to study brain function. Hybrid silicon/polymer neural probes, in particular, allow the integration of complex probe geometries, such as multi-shank designs, with flexible biocompatible cabling. Despite these advantages and benefiting from the highly reproducible fabrication methods on both silicon and polymer substrates, they have not been widely available. This paper presents the development, fabrication, characterization, and in vivo electrophysiological assessment of a hybrid multisite multi-shank silicon probe with a monolithically integrated polyimide flexible interconnect cable. The fabrication process was optimized on wafer level and several neural probes with 64 gold electrode sites equally distributed along 8 shanks with an integrated 8 μm-thick highly flexible polyimide interconnect cable were produce. To avoid the time-consuming bonding of the probe to definitive packaging, the flexible cable was designed to terminate in a connector pad that can mate with commercial zero-insertion force (ZIF) connectors for electronics interfacing. This allows great experimental flexibility since interchangeable packaging can be used according to experimental demands. High-density distributed in vivo electrophysiological recordings were obtained from the hybrid neural probes with low intrinsic noise and high signal-to-noise ratio (SNR).
PDAUG - a Galaxy based toolset for peptide library analysis, visualization, and machine learning modeling
Authors: Joshi Jayadev , Blankenberg Daniel
Published: February 2021

Computational methods based on initial screening and prediction of peptides for desired functions have been proven effective alternatives to the lengthy and expensive methods traditionally utilized in peptide research, thus saving time and effort. However, for many researchers, the lack of expertise in utilizing programming libraries and the lack of access to computational resources and flexible pipelines are big hurdles to adopting these advanced methods. To address these barriers, we have implemented the Peptide Design and Analysis Under Galaxy (PDAUG) package, a Galaxy based python powered collection of tools, workflows, and datasets for a rapid in-silico peptide library analysis. PDAUG offers tools for peptide library generation, data visualization, in-built and public database based peptide sequence retrieval, peptide feature calculation, and machine learning modeling. In contrast to the existing methods like standard programming libraries or rigid web-based tools, PDAUG offers a GUI based toolset thus providing flexibility to build and distribute reproducible pipelines and workflows without programming expertise. Additionally, this toolset facilitates researchers to combine PDAUG with hundreds of compatible existing Galaxy tools for limitless analytic strategies. Finally, we demonstrate the usability of PDAUG on predicting anticancer properties of peptides using four different feature sets and assess the suitability of various machine learning algorithms.
Redefining colorectal cancer classification and clinical stratification through a single-cell atlas
Authors: Khaliq Ateeq M. , Kurt Zeyneb , Grunvald Miles W. , Erdogan Cihat , Turgut Sevgi S. , Rand Tim , Khare Sonal , Borgia Jeffrey A. , Hayden Dana M. , Pappas Sam G. , Govekar Henry R. , Bhama Anuradha R. , Singh Ajaypal , Jacobson Richard A. , Kam Audrey E. , Zloza Andrew , Reiser Jochen , Catenacci Daniel V. , Turaga Kiran , Radovich Milan , Gupta Vineet , Al-Sabti Ram , Thyparambil Sheeno , Levy Mia A. , Subramanian Janakiraman , Kuzel Timothy M. , Sadanandam Anguraj , Hussain Arif , El-Rayes Bassel , Salahudeen Ameen A. , Masood Ashiq
Published: February 2021

Colorectal cancer (CRC), a disease of high incidence and mortality, has had few treatment advances owing to a large degree of inter- and intratumoral heterogeneity. Attempts to classify subtypes of colorectal cancer to develop treatment strategies has been attempted by Consensus Molecular Subtypes (CMS) classification. However, the cellular etiology of CMS classification is incompletely understood and controversial. Here, we generated and analyzed a single-cell transcriptome atlas of 49,859 CRC cells from 16 patients, validated with an additional 31,383 cells from an independent CRC patient cohort. We describe subclonal transcriptomic heterogeneity of CRC tumor epithelial cells, as well as discrete stromal populations of cancer-associated fibroblasts (CAFs). Within CRC CAFs, we identify the transcriptional signature of specific subtypes (CAF-S1 and CAF-S4) in more than 1,500 CRC patients using bulk transcriptomic data that significantly stratifies overall survival in multiple independent cohorts. We also uncovered two CAF-S1 subpopulations, ecm-myCAF and TGFß-myCAF, known to be associated with primary resistance to immunotherapies. We demonstrate that scRNA analysis of malignant, stromal, and immune cells exhibit a more complex picture than portrayed by bulk transcriptomic-based Consensus Molecular Subtypes (CMS) classification. By demonstrating an abundant degree of heterogeneity amongst these cell types, our work shows that CRC is best represented in a transcriptomic continuum crossing traditional classification systems boundaries. Overall, this CRC cell map provides a framework to re-evaluate CRC tumor biology with implications for clinical trial design and therapeutic development.
Active Inference as a Framework for Brain-Computer Interfaces
Authors: Ather Syed Hussain
Published: February 2021

As Karl Friston explained during the International Symposium on Artificial Intelligence and Brain Science 2020, active inference provides a way of using abstract rule-learning and approximate Bayesian inference to show how minimizing (expected) free energy leads to active sampling of novel contingencies. Friston elaborated how there were ways of making an optimal decision using active inference that can offer perspectives to advances in artificial intelligence. These methods of optimization within the context of active inference can also be used as a framework for improving brain-computer interfaces (BCI). This way, BCIs can give rise to artificial curiosity in the way Friston had described during his session. Using Friston’s free energy principle, we can optimize the criterion a BCI uses to infer the intentions of the user from EEG observations. Under Friston’s criteria for making an optimal decision, BCIs can expand their framework of optimal decision-making using active inference.
Deep Proteome Profiling of Human Mammary Epithelia at Lineage and Age Resolution
Authors: Hinz Stefan , Manousopoulou Antigoni , Miyano Masaru , Sayaman Rosalyn W. , Aguilera Kristina Y. , Todhunter Michael E. , Lopez Jennifer C. , Sohn Lydia L. , Wang Leo D. , LaBarge Mark A.
Published: February 2021

Age is the major risk factor in most carcinomas, yet little is known about how proteomes change with age in any human epithelium. We present comprehensive proteomes comprised of >9,000 total proteins, and >15,000 phosphopeptides, from normal primary human mammary epithelia at lineage resolution from ten women ranging in age from 19 to 68. Data were quality controlled, and results were biologically validated with cell-based assays. Age-dependent protein signatures were identified using differential expression analyses and weighted protein co-expression network analyses. Up-regulation of basal markers in luminal cells, including KRT14 and AXL, were a prominent consequence of aging. PEAK1 was identified as an age-dependent signaling kinase in luminal cells, which revealed a potential age-dependent vulnerability for targeted ablation. Correlation analyses between transcriptome and proteome revealed age-associated loss of proteostasis regulation. Protein expression and phosphorylation changes in the aging breast epithelium identify potential therapeutic targets for reducing breast cancer susceptibility.
Population size mediates the contribution of high-rate and large-benefit mutations to parallel evolution
Authors: Schenk Martijn F. , Zwart Mark P. , Hwang Sungmin , Ruelens Philip , Severing Edouard , Krug Joachim , de Visser J. Arjan G.M.
Published: February 2021

Both mutations with large benefits and mutations occurring at high rates may cause parallel evolution, but their contribution is expected to depend on population size. We show that small and large bacterial populations adapt to a novel antibiotic using similar numbers, but different types of mutations. Small populations repeatedly substitute similar high-rate structural variants, including the deletion of a nonfunctional β-lactamase, and evolve modest resistance levels. Hundred-fold larger populations more frequently use the same low-rate, large-benefit point mutations, including those activating the β-lactamase, and reach 50-fold higher resistance levels. Our results demonstrate a key role of clonal interference in mediating the contribution of high-rate and large-benefit mutations in populations of different size, facilitated by a tradeoff between rates and fitness effects of different mutation classes.
Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors
Authors: Pandey Shubhi , Kumari Punita , Baidya Mithu , Kise Ryoji , Cao Yubo , Dwivedi-Agnihotri Hemlata , Banerjee Ramanuj , Li Xaria X. , Cui Cedric S. , Lee John D. , Kawakami Kouki , Chaturvedi Madhu , Ranjan Ashutosh , Laporte Stéphane A. , Woodruff Trent M. , Inoue Asuka , Shukla Arun K.
Published: February 2021

G protein-coupled receptors (GPCRs) are typically characterized by their seven transmembrane (7TM) architecture, and interaction with two universal signal-transducers namely, the heterotrimeric G-proteins and β-arrestins (βarrs). Synthetic ligands and receptor mutants have been designed to elicit transducer-coupling preferences and distinct downstream signaling outcomes for many GPCRs. This raises the question if some naturally-occurring 7TMRs may selectively engage one of these two signal-transducers, even in response to their endogenous agonists. Although there are scattered hints in the literature that some 7TMRs lack G-protein coupling but interact with βarrs, an in-depth understanding of their transducer-coupling preference, GRK-engagement, downstream signaling and structural mechanism remains elusive. Here, we use an array of cellular, biochemical and structural approaches to comprehensively characterize two non-canonical 7TMRs namely, the human decoy D6 receptor (D6R) and the human complement C5a receptor (C5aR2), in parallel with their canonical GPCR counterparts, CCR2 and C5aR1, respectively. We discover that D6R and C5aR2 couple exclusively to βarrs, exhibit distinct GRK-preference, and activate non-canonical downstream signaling partners. We also observe that βarrs, in complex with these receptors, adopt distinct conformations compared to their canonical GPCR counterparts despite being activated by a common natural agonist. Our study therefore establishes D6R and C5aR2 as bona-fide arrestin-coupled receptors (ACRs), and provides important insights into their regulation by GRKs and downstream signaling with direct implications for biased agonism.
Amplification of the epigenetic (gestational) age acceleration signal
Authors: Lee Yunsung , Bohlin Jon
Published: February 2021

Background

Epigenetic (gestational) age acceleration (E(G)AA) is associated with environmental exposures and health outcomes in humans. However, E(G)AA is the residual term from a regression of epigenetic age (outcome) on chronological (gestational) age (predictor) and therefore strongly obscured by ‘noise’ from multiple sources. Here, we propose a simple procedure, based on regression, principal component analysis (PCA), and the Lasso, that amplifies E(G)AA signals. More specifically, we first regress given (gestational) age against each CpG used for epigenetic (gestational) age prediction. The CpGs are typically taken from one of several epigenetic clocks available. PCA is subsequently performed on the resulting matrix of residual vectors for each CpG as it projects the E(G)AA signal onto perpendicular principal components (PCs), thereby separating ‘signal’ from noise. Finally, we use the Lasso to select PCs associated with an outcome of interest. We apply our method to previous studies: EAA in patients with Down’s syndrome and Werner’s syndrome and EGAA of newborns exposed to prenatal smoking as well as associations with maternal BMI.

Results

The extracted EAA components computed using our proposed procedure revealed a significant association with Down’s syndrome (PB<0.05, Bonferroni adjusted for multiple testing) as well as for Werner’s Syndrome (PB<0.05). For EGAA we find a significant association with maternal prenatal smoking (PB<0.05, also Bonferroni adjusted) and maternal BMI (PB<0.05). Additionally, by examining the loadings of the PCs of interest, and contrary to residual EGAA, our method can identify implicated CpGs.

Conclusions

Our findings suggest that our proposed procedure leads to a remarkable amplification of the E(G)AA signal. Furthermore, our method reveals that E(G)AA is a composite signal that can be driven by multiple independent factors.
Wilms Tumorigenesis in Human Kidney Organoids
Authors: Waehle Verena , Ungricht Rosemarie , Hoppe Philipp S. , Betschinger Joerg
Published: February 2021

The loss or failure of cell differentiation is a hallmark of cancer, yet whether perturbation of differentiation is causal or consequential to malignant transformation is largely unclear. Wilms tumor is the most widespread kidney cancer in children. Here, we establish a model for Wilms tumorigenesis in human kidney organoids. We show that loss of the tumor suppressor WT1 during organoid formation induces overgrowth of kidney progenitor cells at the expense of differentiating tubules. Functional and gene expression analyses demonstrate that absence of WT1 halts progenitor cell progression at a pre-epithelialized cell state and recapitulates the transcriptional changes detected in a subgroup of Wilms tumor patients with ectopic myogenesis. By “transplanting” WT1 mutant cells into wild-type kidney organoids, we find that their propagation requires an untransformed microenvironment. Genetic engineering of cancer lesions in human organoids therefore permits phenotypic modeling of tumor initiation and progression, and complements the current toolbox of pre-clinical Wilms tumor models.
PolyQ expansion does not alter the Huntingtin-HAP40 complex
Authors: Huang Bin , Guo Qiang , Niedermeier Marie L. , Cheng Jingdong , Engler Tatjana , Maurer Melanie , Pautsch Alexander , Baumeister Wolfgang , Stengel Florian , Kochanek Stefan , Fernández-Busnadiego Rubén
Published: February 2021

The abnormal amplification of a CAG repeat in the gene coding for huntingtin (HTT) leads to Huntington disease (HD). At the protein level, this translates into the expansion of a poly-glutamine (polyQ) stretch located at the HTT N-terminus, which renders it aggregation-prone by unknown mechanisms. Here we investigated the effects of polyQ expansion on HTT in a complex with its stabilizing interaction partner huntingtin-associated protein 40 (HAP40). Surprisingly, our comprehensive biophysical, crosslinking mass spectrometry and cryo-EM experiments revealed no major differences in the conformation of HTT-HAP40 complexes of various polyQ length, including 17QHTT-HAP40 (wild type), 46QHTT-HAP40 (typical polyQ length in HD patients) and 128QHTT-HAP40 (extreme polyQ length). Thus, HTT polyQ expansion does not alter the global structure of HTT when associated with HAP40.
MicroPIPE: An end-to-end solution for high-quality complete bacterial genome construction
Authors: Murigneux Valentine , Roberts Leah W. , Forde Brian M. , Phan Minh-Duy , Nhu Nguyen Thi Khanh , Irwin Adam D. , Harris Patrick N. A. , Paterson David L. , Schembri Mark A. , Whiley David M. , Beatson Scott A.
Published: February 2021

Oxford Nanopore Technology (ONT) long-read sequencing has become a popular platform for microbial researchers; however, easy and automated construction of high-quality bacterial genomes remains challenging. Here we present MicroPIPE: a reproducible end-to-end bacterial genome assembly pipeline for ONT and Illumina sequencing. To construct MicroPIPE, we evaluated the performance of several tools for genome reconstruction and assessed overall genome accuracy using ONT both natively and with Illumina. Further validation of MicroPIPE was carried out using 11 sequence type (ST)131 Escherichia coli and eight publicly available Gram-negative and Gram-positive bacterial isolates. MicroPIPE uses Singularity containers and the workflow manager Nextflow and is available at https://github.com/BeatsonLab-MicrobialGenomics/micropipe.
Animal-appropriate housing of ball pythons (Python regius) — Behavior-based evaluation of two types of housing systems
Authors: Hollandt Tina , Baur Markus , Wöhr Caroline
Published: February 2021

Considering animal welfare, animals should be kept in animal-appropriate and stress-free housing conditions in all circumstances. To assure such conditions, not only basic needs must be met, but also possibilities must be provided that allow animals in captive care to express all species-typical behaviors. Rack housing systems for snakes have become increasingly popular and are widely used; however, from an animal welfare perspective, they are no alternative to furnished terrariums. In this study, we therefore evaluated two types of housing systems for ball pythons (Python regius) by considering the welfare aspect animal behavior. In Part 1 of the study, ball pythons (n= 35) were housed individually in a conventional rack system. The pythons were provided with a hiding place and a water bowl, temperature control was automatic, and the lighting in the room served as indirect illumination. In Part 2 of the study, the same ball pythons, after at least 8 weeks, were housed individually in furnished terrariums. The size of each terrarium was correlated with the body length of each python. The terrariums contained substrate, a hiding place, possibilities for climbing, a water basin for bathing, an elevated basking spot, and living plants. The temperature was controlled automatically, and illumination was provided by a fluorescent tube and a UV lamp. The shown behavior spectrum differed significantly between the two housing systems (p< 0.05). The four behaviors basking, climbing, burrowing, and bathing could only be expressed in the terrarium. Abnormal behaviors that could indicate stereotypies were almost exclusively seen in the rack system. The results show that the housing of ball pythons in a rack system leads to a considerable restriction in species-typical behaviors; thus, the rack system does not meet the requirements for animal-appropriate housing.
The Arabidopsis AAC Proteins CIL and CIA2 Are Sub-functionalized Paralogs involved in Chloroplast Development
Authors: Li Mingjiu , Ruwe Hannes , Melzer Michael , Junker Astrid , Hensel Götz , Tschiersch Henning , Schwenkert Serena , Chamas Sindy , Schmitz-Linneweber Christian , Börner Thomas , Stein Nils
Published: February 2021

The Arabidopsis geneChloroplast Import Apparatus 2 (CIA2)encodes a transcription factor that positively affects the activity of nuclear genes for chloroplast ribosomal proteins and chloroplast protein import machineries.CIA2-like (CIL)is the paralogous gene ofCIA2. We generated acilmutant by site-directed mutagenesis and compared it withcia2andcia2cildouble mutant. Phenotype of thecilmutant did not differ from the wild type under our growth conditions, except faster growth and earlier time to flowering. Compared tocia2,thecia2cilmutant showed more impaired chloroplast functions and reduced amounts of plastid ribosomal RNAs.In silicoanalyses predict for CIA2 and CIL a C-terminal CCT domain and an N-terminal chloroplast transit peptide (cTP). Chloroplast (and potentially nuclear) localization was previously shown for HvCMF3 and HvCMF7, the homologs of CIA2 and CIL in barley. We observed nuclear localization of CIL after transient expression in Arabidopsis protoplasts. Surprisingly, transformation ofcia2withHvCMF3, HvCMF7or with a truncatedCIA2lacking the predicted cTP could partially rescue the pale-green phenotype ofcia2. These data are discussed with respect to potentially overlapping functions between CIA2, CIL and their barley homologs and to the function of the putative cTPs of CIA2 and CIL.

HIGHLIGHT

The nucleus-localized CCT domain proteins CIA2 and CIL in Arabidopsis and the homologous chloroplast-localized HvCMF3 and HvCMF7 in barley retained partially overlapping functions in chloroplast development.
Extracellular membrane tubules involved in suberin deposition in plant cell walls
Authors: De Bellis Damien , Kalmbach Lothar , Marhavy Peter , Daraspe Jean , Geldner Niko , Barberon Marie
Published: February 2021

Suberin is a fundamental plant biopolymer, found in protective tissues, such as seed coats, exodermis and endodermis of roots, the outer layers of stems and roots with secondary growth, as well as in wound-induced tissues. Its presence allows organs to resist various environmental stresses, such as pathogen attack, drought or excessive salt concentrations. Suberin is a mostly aliphatic polyester of long-chain fatty acids and alcohols, often co-occurring with lignin-like polymers in the same cells. Most suberizing cells appear to deposit suberin in the form of lamellae just outside of the plasma membrane, below the primary cell wall. The monomeric precursors of suberin are thought to be glycerated fatty acids, synthesized at the endoplasmic reticulum. However, it has remained obscure how these monomers are transported outside of the cell, where they will be polymerized to form suberin lamellae. Here, we demonstrate that extracellular vesicular-tubular structures accumulate specifically in suberizing cells. By employing various, independent mutational and hormonal challenges, known to affect suberization in distinct ways, we demonstrate that their presence correlates perfectly with root suberization. Surprisingly, no endosomal compartment marker showed any conspicuous changes upon induction of suberization, suggesting that this compartment might not derive from endosomal multi-vesicular bodies, but possibly form directly from endoplasmic reticulum subdomains. Consistent with this, we could block formation of both, suberin deposition and vesicle accumulation by a pharmacogenetic manipulation affecting early steps in the secretory pathway. Whereas many previous reports have described extracellular vesicle occurrence in the context of biotic interactions, our results suggest a developmental role for extracellular vesicles in suberin formation.

One Sentence Summary

Suberin lamellae formation is associated with extracellular membrane tubules.
Investigation of USP30 inhibition to enhance Parkin-mediated mitophagy: tools and approaches
Authors: Tsefou Eliona , Walker Alison S. , Clark Emily H. , Hicks Amy R. , Luft Christin , Takeda Kunitoshi , Watanabe Toru , Ramazio Bianca , Staddon James M. , Briston Thomas , Ketteler Robin
Published: February 2021

Mitochondrial dysfunction is implicated in Parkinson disease (PD). Mutations in Parkin, an E3 ubiquitin ligase, can cause juvenile-onset Parkinsonism probably through impairment of mitophagy. Inhibition of the de-ubiquitinating enzyme USP30 may counter this effect to enhance mitophagy. Using different tools and cellular approaches, we wanted to independently confirm this claimed role for USP30. Pharmacological characterization of additional tool compounds that selectively inhibit USP30 are reported. The consequence of USP30 inhibition by these compounds, siRNA knockdown and overexpression of dominant-negative USP30 in the mitophagy pathway in different disease-relevant cellular models was explored. Knockdown and inhibition of USP30 showed increased p-Ser65-ubiquitin levels and mitophagy in neuronal cell models. Furthermore, patient-derived fibroblasts carrying pathogenic mutations in Parkin showed reduced p-Ser65-ubiquitin levels compared to wild-type cells, levels that could be restored using either USP30 inhibitor or dominant-negative USP30 expression. Our data provide additional support for USP30 inhibition as a regulator of the mitophagy pathway.
Evidence for spatiotemporal shift in demersal fisheries management priority areas in the western Mediterranean
Authors: Paradinas Iosu , Giménez Joan , Conesa David , López-Quílez Antonio , Pennino Maria Grazia
Published: February 2021

Marine Protected Areas (MPAs) are a promising management tool for the conservation and recovery of marine ecosystems, as well as fisheries management. MPAs are generally established as permanent closures but marine systems are dynamic, which has generated debate in favour of more dynamic designs. As a consequence, the identification of priority areas should assess their persistence in space and time. Here, we develop a step-by-step approach to assess the spatiotemporal dynamics of fisheries management priority areas using standard fishery-independent survey data. To do so, we fit Bayesian hierarchical spatiotemporal SDM models to different commercially important demersal species and use the resulting maps to fit different spatial prioritisation configurations. We use these results to assess the spatiotemporal dynamics of fisheries priority areas. The proposed method is illustrated through a western Mediterranean case study using fishery-independent trawl survey data on six commercially important species collected over 17 years. We identified two fisheries priority area patterns in the study area, each predominant during a different time-period of the study, asserting the importance of regularly re-assessing MPA designs.
H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis
Authors: Verma Ayushi , Singh Akhilesh , Nengroo Mushtaq Ahmad , Saini Krishan Kumar , Sinha Abhipsa , Singh Anup Kumar , Datta Dipak
Published: February 2021

Triple Negative Breast Cancer (TNBC) is known to have poor prognosis and adverse clinical outcome among all breast cancer subtypes due to the absence of available targeted therapy for it. Emerging literature indicates that epigenetic reprogramming is now appreciated as a driving force for TNBC pathophysiology. High expression of epigenetic modulator EZH2 (Enhancer of zeste homolog 2) has been shown to correlate with TNBC poor prognosis but the contribution of EZH2 catalytic (H3K27me3) versus non-catalytic EZH2 (NC-EZH2) function in TNBC growth and progression remains elusive. In the process of dissecting the impact of H3K27me3 versus NC-EZH2 function in TNBC pathogenesis, we reveal that selective hyperactivation of H3K27me3 over NC-EZH2 not only promotes TNBC metastasis but also alters the metastatic landscape of TNBC. Using extensivein- vivolive animal imaging, we present conclusive evidence that peritoneal metastasis, particularly splenic metastasis of TNBC is governed by H3K27me3. Transcriptome analyses of hyperactive H3K27me3 cells lead us to discover Cytokeratin-14 (KRT14) as a new target of H3K27me3. Unlike classical H3K27me3 mediated suppression of gene expression, here; we observe that H3K27me3 enhances KRT14 transcription by attenuating the binding of transcriptional repressor Sp1 to its promoter. Further, loss of KRT14 significantly reduces TNBC migration, invasion and splenic metastasis. Finally, genetic ablation of EZH2 or pharmacological inhibition of EZH2 catalytic function by FDA approved drug tazemetostat (EPZ6438) robustly inhibits TNBC peritoneal metastasis. Altogether, our preclinical findings posit a rational insight for the clinical development of H3K27me3 inhibitor like tazemetostat as a targeted therapy against TNBC.