bluuebunny/crossref_metadata_2025 huggingface dataset:
Projected resurgence of COVID-19 in the United States in July—December 2021 resulting from the increased transmissibility of the Delta variant and faltering vaccination
Authors: Truelove Shaun , Smith Claire P. , Qin Michelle , Mullany Luke C. , Borchering Rebecca K. , Lessler Justin , Shea Katriona , Howerton Emily , Contamin Lucie , Levander John , Salerno Jessica , Hochheiser Harry , Kinsey Matt , Tallaksen Kate , Wilson Shelby , Shin Lauren , Rainwater-Lovett Kaitlin , Lemaitre Joseph C. , Dent Juan , Kaminsky Joshua , Lee Elizabeth C. , Perez-Saez Javier , Hill Alison , Karlen Dean , Chinazzi Matteo , Davis Jessica T. , Mu Kunpeng , Xiong Xinyue , y Piontti Ana Pastore , Vespignani Alessandro , Srivastava Ajitesh , Porebski Przemyslaw , Venkatramanan Srinivasan , Adiga Aniruddha , Lewis Bryan , Klahn Brian , Outten Joseph , Schlitt James , Corbett Patrick , Telionis Pyrros Alexander , Wang Lijing , Peddireddy Akhil Sai , Hurt Benjamin , Chen Jiangzhuo , Vullikanti Anil , Marathe Madhav , Hoops Stefan , Bhattacharya Parantapa , Machi Dustin , Chen Shi , Paul Rajib , Janies Daniel , Thill Jean-Claude , Galanti Marta , Yamana Teresa , Pei Sen , Shaman Jeffrey , Reich Nicholas G. , Healy Jessica M. , Slayton Rachel B. , Biggerstaff Matthew , Johansson Michael A. , Runge Michael C. , Viboud Cécile
Published: August 2021

What is already known about this topic?

The highly transmissible SARS-CoV-2 Delta variant has begun to cause increases in cases, hospitalizations, and deaths in parts of the United States. With slowed vaccination uptake, this novel variant is expected to increase the risk of pandemic resurgence in the US in July—December 2021.

What is added by this report?

Data from nine mechanistic models project substantial resurgences of COVID-19 across the US resulting from the more transmissible Delta variant. These resurgences, which have now been observed in most states, were projected to occur across most of the US, coinciding with school and business reopening. Reaching higher vaccine coverage in July—December 2021 reduces the size and duration of the projected resurgence substantially. The expected impact of the outbreak is largely concentrated in a subset of states with lower vaccination coverage.

What are the implications for public health practice?

Renewed efforts to increase vaccination uptake are critical to limiting transmission and disease, particularly in states with lower current vaccination coverage. Reaching higher vaccination goals in the coming months can potentially avert 1.5 million cases and 21,000 deaths and improve the ability to safely resume social contacts, and educational and business activities. Continued or renewed non-pharmaceutical interventions, including masking, can also help limit transmission, particularly as schools and businesses reopen.
Melodic Intonation Therapy for aphasia: A multi-level meta-analysis of randomised controlled trials and individual participant data
Authors: Popescu Tudor , Stahl Benjamin , Wiernik Brenton M. , Haiduk Felix , Zemanek Michaela , Helm Hannah , Matzinger Theresa , Beisteiner Roland , Fitch W. Tecumseh
Published: August 2021

Abstract

Melodic Intonation Therapy (MIT) is a prominent rehabilitation programme for individuals with post-stroke aphasia. The present meta-analysis investigated the efficacy of MIT while considering outcome measure quality, experimental design, influence of spontaneous recovery, MIT protocol, and level of generalisation.

An extensive literature search identified 606 studies in major databases and trials registers; of those, 22 studies, overall 129 participants, met all eligibility criteria. Multi-level mixed- and random-effects models served to separately meta-analyse RCT and non-RCT data.

RCT evidence on validated measures revealed a small-to-moderate standardised effect in non-communicative language expression for MIT, with substantial uncertainty. Unvalidated measures attenuated MIT’s effect size compared to validated tests. MIT’s effect size was 5.7 times larger for non-RCT data compared to RCT data. Effect size in non-RCT data decreased with number of months post-stroke, suggesting confound through spontaneous recovery. Variation from the original MIT protocol did not systematically alter benefit from treatment. Progress on validated tests arose mainly from gains in repetition tasks rather than other domains of verbal expression such as everyday communication ability.

The current results confirm the promising role of MIT in improving trained/untrained performance with unvalidated measures, alongside validated repetition tasks; whilst highlighting possible limitations in promoting everyday communication ability.
Definition of a new blood cell count (BCT) score for early survival prediction for non-small cell lung cancer patients treated with atezolizumab: Integrated analysis of 4 multicenter clinical trials
Authors: Zhou Jian-Guo , Wong Ada Hang-Heng , Wang Haitao , Jin Su-Han , Tan Fangya , Chen Yu-Zhong , He Si-Si , Shen Gang , Frey Benjamin , Fietkau Rainer , Hecht Markus , Carr Shamus R. , Wang Ruihong , Shen Bo , Schrump David S , Ma Hu , Gaipl Udo S.
Published: August 2021

Introduction

Immune checkpoint inhibitor (ICI) therapy is a major breakthrough in non-small cell lung cancer (NSCLC) treatment. However, valid predictive biomarkers are lacking. Blood cell count test (BCT) provides a direct quantification of various types of immune cells (ICs) to reveal the immune landscape to predict ICI treatment.

Methods

This study analyzed four international, multi-center clinical trials (OAK, BIRCH, POPLAR and FIR trials) to conduct post-hoc analyses of NSCLC patients undergoing atezolizumab (anti-PD-L1) single-agent treatment (n = 1,479) or docetaxel single-agent treatment (n = 707). BCT was conducted at three timepoints: pre-treatment (T1), the first day of treatment cycle 3 (T2), and first day of treatment cycle 5 (T3). Univariate and multivariate Cox regression analyses were conducted to identify early BCT biomarkers to predict atezolizumab treatment outcomes in NSCLC patients.

Results

The BCT biomarkers of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) at timepoint T3 and neutrophil-to-monocyte ratio (NMR) at timepoint T2 were identified as strong predictive biomarkers for atezolizumab (Ate)-treated NSCLC patients in comparison to docetaxel (Dtx)-treated patients regarding overall survival (OS) (BCTscore low-risk: HR Ate vs Dtx = 1.54 (95% CI: 1.04-2.27), P = 0.036; high-risk: HR Ate vs Dtx = 0.84 (95% CI: 0.62-1.12), P = 0.236). This identified BCTscore model showed better OS AUC in the OAK (AUC12month=0.696), BIRCH (AUC12month=0.672) and POPLAR+FIR studies (AUC12month=0.727) than that of each of the three single BCT biomarkers.

Conclusion

The BCTscore model is a valid predictive and prognostic biomarker for atezolizumab-treated NSCLC patients.
COVID-19 vaccine hesitancy among Algerian medical students: a cross-sectional study in five universities
Authors: Kerdoun Mohamed Amine , Henni Abdellah Hamza , Yamoun Assia , Rahmani Amine , Kerdoun Rym Messaouda , Elouar Nazia
Published: August 2021

Vaccine hesitancy is a limiting factor in global efforts to contain the current pandemic, wreaking havoc on public health. As today’s students are tomorrow’s doctors, it is critical to understand their attitudes toward the COVID-19 vaccine. To our knowledge, this study was the first national one to look into the attitudes of Algerian medical students toward the SARS-CoV-2 vaccine using an electronic convenience survey.

383 medical students from five Algerian universities were included, with a mean age of 21.02. 85.37% (n=327) of respondents had not taken the COVID-19 vaccine yet and were divided into three groups; the vaccine acceptance group (n=175, 53.51%), the vaccine-hesitant group (n=75, 22.93%), and the vaccine refusal group (n=77, 23.54%).

Gender, age, education level, university, and previous experience with COVID-19 were not significant predictors for vaccine acceptance. The confirmed barriers to the COVID-19 vaccine concern available information, effectiveness, safety, and adverse effects.

This work highlights the need for an educational strategy about the safety and effectiveness of the COVID-19 vaccine. Medical students should be educated about the benefits of vaccination for themselves and their families and friends.

The Vaccine acceptant students’ influence should not be neglected with a possible ambassador role to hesitant and resistant students.

Graphical abstract
SIOP Ependymoma I: Final results, long term follow-up and molecular analysis of the trial cohort: A BIOMECA Consortium Study
Authors: Ritzmann Timothy A , Chapman Rebecca J , Kilday John-Paul , Thorp Nicola , Modena Piergiorgio , Dineen Robert A , Macarthur Donald , Mallucci Conor , Jaspan Timothy , Pajtler Kristian W , Giagnacovo Marzia , Jacques Thomas S , Paine Simon ML , Ellison David W , Bouffet Eric , Grundy Richard G
Published: August 2021

Background

SIOP Ependymoma I was a non-randomised trial assessing event free and overall survival (EFS/OS) from non-metastatic intracranial ependymoma in children aged 3 to 21 years, treated with a staged management strategy. Chemotherapy efficacy in ependymoma is debated and therefore the response rate (RR) of subtotally resected (STR) ependymoma to vincristine, etoposide and cyclophosphamide (VEC) was an additional primary outcome. We report final results with 12-year follow-up and post hoc analyses of recently described biomarkers.

Methods

74 participants were eligible. Children with gross total resection (GTR) received radiotherapy, whilst those with STR received VEC before radiotherapy. DNA methylation and 1q status were evaluated, alongside hTERT, ReLA, Tenascin-C, H3K27me3 and pAKT expression.

Results

Five- and ten-year EFS was 49.5% and 46.7%, OS was 69.3% and 60.5%. GTR was achieved in 33/74 (44.6%) and associated with improved EFS (p=0.003, HR=2.6, 95% confidence interval (CI) 1.4-5.1). Grade 3 tumours were associated with worse OS (p=0.005, HR=2.8, 95%CI 1.3-5.8). 1q gain and hTERT expression were associated with poorer EFS (p=0.003, HR=2.70, 95%CI 1.49-6.10 and p=0.014, HR=5.8, 95%CI 1.2-28 respectively) and H3K27me3 loss with worse OS (p=0.003, HR=4.6, 95%CI 1.5-13.2). DNA methylation profiles showed expected patterns. 12 participants with STR did not receive chemotherapy; a protocol violation. However, chemotherapy RR was 65.5% (19/29, 95%CI 45.7-82.1), exceeding a prespecified 45% RR.

Conclusions

RR of STR to VEC exceeded the pre-specified criterion for efficacy. However, cases of inaccurate treatment stratification highlighted the need for rapid central review. Prognostic associations for 1q gain, H3K27me3 and hTERT were confirmed.
WHAT FUELS SUBOPTIMAL CARE OF PERIPHERAL INTRAVENOUS CATHETER-RELATED INFECTIONS IN HOSPITALS? – A QUALITATIVE STUDY OF DECISION-MAKING AMONG SPANISH NURSES
Authors: Blanco-Mavillard Ian , Castro-Sánchez Enrique , Parra-García Gaizka , Rodríguez-Calero Miguel Ángel , Bennasar-Veny Miquel , Fernández-Fernández Ismael , Lorente-Neches Harri , de Pedro-Gómez Joan
Published: August 2021

Background

Peripheral intravenous catheters (PIVC) are commonly used in hospital worldwide. However, PIVC are not exempt from complications. Catheter-related bloodstream infections (CRBSI) increase morbidity and mortality rates, and costs for the healthcare organization. PIVC care is shaped by the complex mix of professional and organizational culture, such as knowledge gaps, low perception of impact of PIVCs on patient safety, or lack of hospital guidelines.

Aim

To explore determinants of decision-making about the prevention of PIVC-BSI among nurses in Spanish hospitals.

Methods

We conducted a descriptive qualitative study with semi-structured interviews in three public hospitals, the Balearic Islands Health Care Service in Spain. We considered hospital ward nurses working routinely with inpatients at any of the three hospitals for enrolment in the study. We approached relevant informants to identify suitable participants who recruited other participants through a ‘snowball’ technique. Fourteen inpatient nurses from the hospital took part in this study between September and November 2018. We employed several triangulation strategies to underpin the methodological rigour of our analysis and conducted the member checking, showing the information and codes applied in the recording of the interviews to identify the coherence and any discrepancies of the discourse by participants. We used the COREQ checklist for this study.

Findings

We identified four major themes in the analysis related to determinants of care: The fog of decision-making in PIVC; The taskification of PIVC care; PIVC care is accepted to be suboptimal, yet irrelevant; and PIVC care gaps may reflect behavioural shortcomings, yet solutions proposed to involve education and training.

Conclusion

The clinical management of PIVCs appear ambiguous, unclear, and fragmented, with no clear professional responsibility and no nurse leadership, causing a gap in preventing infections. Furthermore, the perception of low risk on PIVC care impact can cause a relevant lack of adherence to the best evidence and patient safety. Implementing facilitation strategies could improve the fidelity of the best available evidence regarding PIVC care and raise awareness among nurses of impact that excellence of care.
Correlation between times to SARS-CoV-2 symptom onset and secondary transmission undermines epidemic control efforts
Authors: Linton Natalie M. , Akhmetzhanov Andrei R. , Nishiura Hiroshi
Published: August 2021

Severe acute respiratory coronavirus 2 (SARS-CoV-2) infections have been associated with substantial presymptomatic transmission, which occurs when the generation interval—the time between infection of an individual with a pathogen and transmission of the pathogen to another individual—is shorter than the incubation period—the time between infection and symptom onset. We collected a dataset of 257 SARS-CoV-2 transmission pairs in Japan and jointly estimated the mean generation interval (3.7–5.1 days) and mean incubation period (4.4–5.7 days) as well as measured their dependence (Kendall’s tau of 0.4–0.6), taking into consideration demographic and epidemiological characteristics of the pairs. The positive correlation between the two parameters demonstrates that reliance on isolation of symptomatic COVID-19 cases as a focal point of control efforts is insufficient to address the challenges posed by SARS-CoV-2 transmission dynamics. Accounting for this dependence within SARS-CoV-2 epidemic models can also improve model estimates.
LED transillumination of the chest and abdomen in the diagnosis of neonatal conditions
Authors: Abreu José , Baldacci Michelle , Tarenzi Gladys , Villegas Karla
Published: August 2021

Air leak syndromes, such as pneumothorax and pneumoperitoneum, are commonly diagnosed in Neonatal Intensive Care Units. However, this finding is usually detected with radiographic studies when the neonate is in poor condition. LED transillumination is an alternative method that allows a fast, inexpensive, and non-invasive diagnosis.We aimedto evaluate the clinical utility of LED transillumination in neonates by comparing the results to chest and abdomen radiograph as reference test.

Methodology

diagnostic and prospective study that included 56 neonates. We used a simple and inexpensive handcrafted LED transilluminator to evaluate the chest and abdomen of patients, blind to the final diagnosis. The findings were compared to the radiographs.

Results

the study presented 3 true positive pneumothorax cases (sensibility 100%, 95%CI 29.24-100; specificity 100%, 95%CI 93.28-100), 1 true positive pneumoperitoneum case (sensibility 100%, 95%CI 2.50-100; specificity 100%, 95%CI 93.51-100), 10 true positive and 5 false negatives cases of gastric dilation (sensibility 66.67%, 95%CI 38.38-88.18; specificity 100%, 95%CI 91.19-100; negative likelihood ratio 0.33, 95%CI 0.16-0.68) and 4 true positive cases of dilation of bowel loops (sensibility 100%, 95%CI 39.76-100; specificity 100%, 95%CI 93.02-100).

Discussion

LED transillumination is a safe, inexpensive, and easy-to-use clinical tool that may be employed to promote early intervention during severe cases of air leak syndrome that require immediate action, especially in low-income and rural areas. Further research with larger sample sizes is required to properly define the efficacy and usefulness of LED transillumination in routine use.
Precision MRI Phenotyping Enables Detection of Small Changes in Body Composition for Longitudinal Cohorts
Authors: Whitcher Brandon , Thanaj Marjola , Cule Madeleine , Liu Yi , Basty Nicolas , Sorokin Elena P. , Bell Jimmy D. , Thomas E. Louise
Published: August 2021

Longitudinal studies provide unique insights into the impact of environmental factors and lifespan issues on health and disease. Here we investigate changes in body composition in 3,088 free-living participants, part of the UK Biobank in-depth imaging study. All participants underwent neck-to-knee MRI scans at the first imaging visit and after approximately two years (second imaging visit). Image-derived phenotypes for each participant were extracted using a fully-automated image processing pipeline, including volumes of several tissues and organs: liver, pancreas, spleen, kidneys, total skeletal muscle, iliopsoas muscle, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), as well as fat and iron content in liver, pancreas and spleen. Overall, no significant changes were observed in BMI, body weight, or waist circumference over the scanning interval, despite some large individual changes. A significant decrease in grip strength was observed, coupled to small, but statistically significant, decrease in all skeletal muscle measurements. Significant increases in VAT and intermuscular fat in the thighs were also detected in the absence of changes in BMI, waist circumference and ectopic-fat deposition. Adjusting for disease status at the first imaging visit did not have an additional impact on the changes observed. In summary, we show that even after a relatively short period of time significant changes in body composition can take place, probably reflecting the obesogenic environment currently inhabited by most of the general population in the United Kingdom.
Task-related, intrinsic oscillatory and aperiodic neural activity predict performance in naturalistic team-based training scenarios
Authors: Cross Zachariah R. , Chatburn Alex , Melberzs Lee , Temby Philip , Pomeroy Diane , Schlesewsky Matthias , Bornkessel-Schlesewsky Ina
Published: August 2021

Effective teams are essential for optimally functioning societies. However, little is known regarding the neural basis of two or more individuals engaging cooperatively in real-world tasks, such as in operational training environments. In this exploratory study, we recruited forty individuals paired as twenty dyads and recorded dual-EEG at rest and during realistic training scenarios of increasing complexity using virtual simulation systems. We estimated markers of intrinsic brain activity (i.e., individual alpha frequency and aperiodic activity), as well as task-related theta and alpha oscillations. Using nonlinear modelling and a logistic regression machine learning model, we found that resting-state EEG predicts performance and can also reliably differentiate between members within a dyad. Task-related theta and alpha activity during easy training tasks predicted later performance on complex training to a greater extent than prior behaviour. These findings complement laboratory-based research on both oscillatory and aperiodic activity in higher-order cognition and provide evidence that theta and alpha activity play a critical role in complex task performance in team environments.
Real-Time Brain-Machine Interface Achieves High-Velocity Prosthetic Finger Movements using a Biologically-Inspired Neural Network Decoder
Authors: Willsey Matthew S. , Nason Samuel R. , Ensel Scott R. , Temmar Hisham , Mender Matthew J. , Costello Joseph T. , Patil Parag G. , Chestek Cynthia A.
Published: August 2021

Despite the rapid progress and interest in brain-machine interfaces that restore motor function, the performance of prosthetic fingers and limbs has yet to mimic native function. The algorithm that converts brain signals to a control signal for the prosthetic device is one of the limitations in achieving rapid and realistic finger movements. To achieve more realistic finger movements, we developed a shallow feed-forward neural network, loosely inspired by the biological neural pathway, to decode real-time two-degree-of-freedom finger movements. Using a two-step training method, a recalibrated feedback intention–trained (ReFIT) neural network achieved a higher throughput with higher finger velocities and more natural appearing finger movements than the ReFIT Kalman filter, which represents the current standard. The neural network decoders introduced herein are the first to demonstrate real-time decoding of continuous movements at a level superior to the current state-of-the-art and could provide a starting point to using neural networks for the development of more naturalistic brain-controlled prostheses.
Conservation and divergence of poly(A) tail regulation during the mammalian oocyte-to-embryo transition
Authors: Liu Yusheng , Jin Junxue , Zhang Yiwei , Wang Le-Yun , Zhang Chuanxin , Hou Zhenzhen , Li Wei , Liu Zhonghua , Lu Falong , Wang Jiaqiang
Published: August 2021

Poly(A) tail length and non-A residues are vital for oocyte-to-embryo transition (OET) in mice and humans1–5. However, the role of poly(A) tail length and non-A residues during OET in other commonly used mammalian animal models for human diseases remains unexplored. In addition, the degree of conservation in maternal mRNA poly(A) tail dynamics during OET across different mammal species is unknown. Here, we conduct a comparative analysis of the poly(A) tails during OET across four species: mice, rats, pigs, and humans. Dynamics during OET found to be conserved across all four species include: maternal mRNA deadenylation during oocyte maturation and re-polyadenylation after fertilization; a fall-rise trend in poly(A) tail length distribution; a rise-fall trend in the ratio of poly(A) tails with non-A residues; higher abundance of non-A residues in poly(A) tails of maternal mRNA than in zygotic genome activation (ZGA) mRNA; maternal mRNA with U residues degrades faster than those without U residues at the stage when ZGA takes place. While in mice and rats maternal mRNA deadenylation is impaired in parthenogenetic embryos and ZGA inhibition leads to blocked maternal mRNA deadenylation in mice and humans. In contrast, the length of consecutive U residues and the duration time of U residues in poly(A) tail diverges across the four species. Together, these findings reveal that the poly(A) tail mediated maternal mRNA post-transcriptional regulation is highly conserved in mammals with unique divergences in the length and life-span of U residues, providing new insights for the further understanding of OET across different mammals.
Dynamics of mitochondrial mRNA abundance and poly(A) tail during the mammalian oocyte-to-embryo transition
Authors: Liu Yusheng , Zhang Yiwei , Liu Zhonghua , Lu Falong , Wang Jiaqiang
Published: August 2021

Mitochondria are responsible for producing a cell’s energy and play a central role in many metabolic tasks, as well as signaling transduction and cell death1. Mitochondria dysfunctions cause several human diseases and aging processes2–8. Mammalian oocytes contain far more mitochondria than somatic cells. The nuclear localization of mitochondrial tricarboxylic acid cycle (TCA) cycle enzymes, which normally localize in the mitochondria, is critical for zygotic genome activation (ZGA) and the oocyte-to-embryo transition (OET) in mice9. However, during the mammalian OET, the abundance and post-transcriptional regulation of mitochondrial mRNA (MT-mRNA), particularly the poly(A) tail, has never been studied. Here, we used two independent sequencing methods (PAIso-seq1 and PAIso-seq2) to describe the features of MT-mRNA in mouse cell lines, thirteen mouse tissues and during the OET in mouse, rat, pig, and humans. These features included expression abundance, poly(A) tail length, and non-A residues in poly(A) tails. Unlike nuclear mRNA, we discovered that MT-mRNA has a stable distribution pattern of poly(A) tail length in different cell lines, across tissues, and during mammalian OET. MT-mRNA possesses non-A residues in the poly(A) tail (non-A residues hereafter), which change slightly across tissues and during the OET. We also found that the abundance of MT-mRNA varies substantially across tissues, increases during the OET, and increases along major ZGA in mice, rats, pigs, and humans. These findings provide insights into changes in MT-mRNA abundance and poly(A) tail during the mammalian OET and provide a resource for future studies on the posttranscriptional regulation of mitochondrial transcripts.
Abundant non-A residues in the poly(A) tail orchestrate the mouse oocyte-to-embryo transition
Authors: Liu Yusheng , Nie Hu , Wang Le-Yun , Wu Shuang , Li Wei , Zhou Qi , Wang Jiaqiang , Lu Falong
Published: August 2021

Non-A (U, G, and C) residues can be added to the 5’-end, internal, and 3’-end positions of poly(A) tails of RNA transcripts1–3, and some of these have been shown to regulate mRNA stability4, 5. The mammalian oocyte-to-embryo transition (OET) relies on post-transcriptional regulation of maternal RNA, because transcription is silent during this process until the point of zygotic genome activation (ZGA)6–9. Although the regulation of mRNA translation by poly(A) tail length plays an important role in the mammalian OET, the dynamics and functions of non-A residues in poly(A) tails are completely unknown. In this study, we profiled the genome-wide presence, abundance, and roles of non-A residues during the OET in mice using PAIso-seq1 and PAIso-seq22, 10, two complementary methods of poly(A) tail analysis. We found that non-A residues are highly dynamic in maternal mRNA, following a general pattern of beginning to increase at the MII stage, becoming highly abundant after fertilization with U residues in about half of poly(A) tails in 1-cell embryos, and declining in 2-cell embryos. We revealed that Btg4-mediated global maternal mRNA deadenylation created the substrates for U residue addition by Tut4/7 at their 3’-ends and further re-polyadenylation. In addition, G residues can be added by Tent4a/b. Finally, we demonstrate that G residues stabilize the modified mRNA, while the U residues mark maternal RNA for faster degradation in 2-cell mouse embryos. Taken together, these findings demonstrate that non-A residues are abundant and re-sculpt the maternal transcriptome to initiate zygotic development, which reveals the functional importance of the post-transcriptional regulation mediated by non-A residues in mRNA poly(A) tails.
Cross-frequency slow oscillation–spindle coupling in a biophysically realistic thalamocortical neural mass model
Authors: Jajcay Nikola , Cakan Caglar , Obermayer Klaus
Published: August 2021

Sleep manifests itself by the spontaneous emergence of characteristic oscillatory rhythms, which often timelock and are implicated in the memory formation. Here, we analyze a neural mass model of the thalamocortical loop of which the cortical node can generate slow oscillations (approx. 1 Hz) while its thalamic component can generate fast sleep spindles of σ-band activity (12–15 Hz). We study the dynamics for different coupling strengths between the thalamic and cortical nodes, for different conductance values of the thalamic node’s potassium leak and anomalous rectifying currents, and for different parameter regimes of the cortical node. The latter are: (1) a low activity (DOWN) state with noise-induced, transient excursions into a high activity (UP) state, (2) an adaptation induced slow oscillation limit cycle with alternating UP and DOWN states, and (3) a high activity (UP) state with noise-induced, transient excursions into the low activity (DOWN) state. During UP states, thalamic spindling is abolished or reduced. During DOWN states, the thalamic node generates sleep spindles, which in turn can cause DOWN to UP transitions in the cortical node. Consequently, this leads to spindle-induced UP state transitions in parameter regime (1), thalamic spindles induced in some but not all DOWN states in regime (2), and thalamic spindles following UP to DOWN transitions in regime (3). The spindle-induced σ-band activity in the cortical node, however, is typically strongest during the UP state, which follows a DOWN state “window of opportunity” for spindling. When the cortical node is parametrized in regime (3), the model well explains the interactions between slow oscillations and sleep spindles observed experimentally during Non-Rapid Eye Movement sleep. The model is computationally efficient and can be integrated into large-scale modeling frameworks to study spatial aspects like sleep wave propagation.
The polyglutamine amyloid nucleus in living cells is a monomer with competing dimensions of order
Authors: Kandola Tej , Venkatesan Shriram , Zhang Jiahui , Lerbakken Brooklyn , Blanck Jillian F , Wu Jianzheng , Unruh Jay , Berry Paula , Lange Jeffrey J. , Von Schulze Alex , Box Andrew , Cook Malcolm , Sagui Celeste , Halfmann Randal
Published: August 2021

A long-standing goal of the study of amyloids has been to characterize the structural basis of the rate-determining nucleating event. However, the ephemeral nature of that event has made it inaccessible to classical biochemistry, structural biology, and computational approaches. Here, we addressed that limitation by measuring the dependence of amyloid formation on concentration and conformational templates in living cells, whose volumes are sufficiently small to resolve the outcomes of independent nucleation events. We characterized numerous rationally designed sequence variants of polyglutamine (polyQ), a polypeptide that precipitates Huntington’s and other amyloid-associated neurodegenerative diseases when its length exceeds a characteristic threshold. This effort uncovered a pattern of approximately twelve Qs, only for polypeptides exceeding the clinical length threshold, that allow for amyloid nucleation to occur spontaneously within single polypeptides. Nucleation was inhibited by intermolecular phase separation. Using atomistic molecular dynamics simulations, we found that the pattern encodes a minimal steric zipper of interdigitated side chains. Lateral growth of the steric zipper competed with axial growth to produce “pre-amyloid” oligomers. By illuminating the structural mechanism of polyQ amyloid formation in cells, our findings reveal a potential molecular etiology for polyQ diseases, and may provide a roadmap for the design of new therapies.
Simpler and Faster Development of Tumor Phylogeny Pipelines
Authors: Ali Sarwan , Ciccolella Simone , Lucarella Lorenzo , Vedova Gianluca Della , Patterson Murray
Published: August 2021

In the recent years there has been an increasing amount of single-cell sequencing (SCS) studies, producing a considerable number of new datasets. This has particularly affected the field of cancer analysis, where more and more papers are published using this sequencing technique that allows for capturing more detailed information regarding the specific genetic mutations on each individually sampled cell.

As the amount of information increases, it is necessary to have more sophisticated and rapid tools for analyzing the samples. To this goal we developed plastic, an easy-to-use and quick to adapt pipeline that integrates three different steps: (1) to simplify the input data; (2) to infer tumor phylogenies; and (3) to compare the phylogenies.

We have created a pipeline submodule for each of those steps, and developed new in-memory data structures that allow for easy and transparent sharing of the information across the tools implementing the above steps.

While we use existing open source tools for those steps, we have extended the tool used for simplifying the input data, incorporating two machine learning procedures — which greatly reduce the running time without affecting the quality of the downstream analysis. Moreover, we have introduced the capability of producing some plots to quickly visualize results.
SHED-dependent oncogenic signalling of the PEAK3 pseudo-kinase
Authors: Ounoughene Youcef , Fourgous Elise , Boublik Yvan , Saland Estelle , Guiraud Nathan , Recher Christian , Urbach Serge , Fort Philippe , Sarry Jean-Emmanuel , Fesquet Didier , Roche Serge
Published: August 2021

The PEAK1 and pragmin/PEAK2 pseudo-kinases have emerged as important components of the protein tyrosine kinase pathway implicated in cancer progression. They can signal by a scaffolding mechanism that involves a conserved split helical dimerization (SHED) module. We recently identified PEAK3 as a novel member of this family based on structural homology; however, its signalling mechanism remains unclear. Here, we found that although it can self-associate, PEAK3 shows higher evolutionary divergence than PEAK1/2. Moreover, PEAK3 protein is strongly expressed in human haematopoietic cells, and is upregulated in acute myeloid leukaemia. Functionally, PEAK3 overexpression in U2OS sarcoma cells enhanced their growth and migratory properties, while its silencing in THP1 leukemic cells reduced these effects. Importantly, an intact SHED module was required for these PEAK3 oncogenic activities. Mechanistically, through a phosphokinase survey, we identified PEAK3 as a novel inducer of AKT signalling, independent of growth factor stimulation. Then, proteomic analyses revealed that PEAK3 interacts with the signalling proteins GRB2 and ASAP1/2 and the protein kinase PYK2, and that these interactions require the SHED domain. Moreover, PEAK3 activated PYK2 to promote AKT signalling. Thus, the PEAK1-3 pseudo-kinases may use a conserved SHED-dependent mechanism to activate specific signalling proteins to promote oncogenesis.
Beyond RuBisCO: Convergent molecular evolution of multiple chloroplast genes in C4 plants
Authors: Casola Claudio , Li Jingjia
Published: August 2021

Background

The recurrent evolution of the C4 photosynthetic pathway in angiosperms represents one of the most extraordinary examples of convergent evolution of a complex trait. Comparative genomic analyses have unveiled some of the molecular changes associated with the C4 pathway. For instance, several key enzymes involved in the transition from C3 to C4 photosynthesis have been found to share convergent amino acid replacements along C4 lineages. However, the extent of convergent replacements potentially associated with the emergence of C4 plants remains to be fully assessed. Here, we introduced a robust empirical approach to test molecular convergence along a phylogeny including multiple C3 and C4 taxa. By analyzing proteins encoded by chloroplast genes, we tested if convergent replacements occurred more frequently than expected in C4 lineages compared to C3 lineages. Furthermore, we sought to determine if convergent evolution occurred in multiple chloroplast proteins beside the well-known case of the large RuBisCO subunit encoded by the chloroplast gene rbcL.

Methods

Our study was based on the comparative analysis of 43 C4 and 21 C3 grass species belonging to the PACMAD clade, a focal taxonomic group in many investigations of C4 evolution. We first used protein sequences of 67 orthologous chloroplast genes to build an accurate phylogeny of these species. Then, we inferred amino acid replacements along 13 C4 lineages and 9 C3 lineages using reconstructed protein sequences of their ancestral branches, corresponding to the most recent common ancestor of each lineage. Pairwise comparisons between ancestral branches allowed us to identify both convergent and divergent amino acid replacements between C4-C4, C3-C3 and C3-C4 lineages.

Results

The reconstructed phylogenetic tree of 64 PACMAD grasses was characterized by strong supports in all nodes used for analyses of convergence. We identified 217 convergent replacements and 201 divergent replacements in 45/67 chloroplast proteins in both C4 and C3 ancestral branches. Pairs of C4-C4 ancestral branches showed higher levels of convergent replacements than C3-C3 and C3-C4 pairs. Furthermore, we found that more proteins shared unique convergent replacements in C4 lineages, with both RbcL and RpoC1 (the RNA polymerase beta’ subunit 1) showing a significantly higher convergent/divergent replacements ratio in C4 branches. Notably, significantly more C4-C4 pairs of ancestral branches showed higher numbers of convergent vs. divergent replacements than C3-C3 and C3-C4 pairs. Our results demonstrated that, in the PACMAD clade, C4 grasses experienced higher levels of molecular convergence than C3 species across multiple chloroplast genes. These findings have important implications for both our understanding of the evolution of photosynthesis and the goal of engineering improved crop varieties that integrates components of the C4 pathway.
Predictive coding during action observation - a depth-resolved intersubject functional correlation study at 7T
Authors: Cerliani Leonardo , Bhandari Ritu , De Angelis Lorenzo , van der Zwaag Wietske , Bazin Pierre-Louis , Gazzola Valeria , Keysers Christian
Published: August 2021

While the brain regions involved in action observation are relatively well documented in humans and primates, how these regions communicate to help understand and predict actions remains poorly understood. Traditional views emphasized a feed-forward architecture in which visual features are organized into increasingly complex representations that feed onto motor programs in parietal and then premotor cortices where the matching of observed actions upon the observer’s own motor programs contributes to action understanding. Predictive coding models place less emphasis on feed-forward connections and propose that feed-back connections from premotor regions back to parietal and visual neurons represent predictions about upcoming actions that can supersede visual inputs when actions become predictable, with visual input then merely representing prediction errors. Here we leverage the notion that feed-back connections target specific cortical layers to help adjudicate across these views. Specifically, we test whether observing sequences of hand actions in their natural order, which permits participants to predict upcoming actions, triggers more feed-back input to parietal regions than seeing the same actions in a scrambled sequence that hinders making predictions. Using submillimeter fMRI acquisition at 7T, we find that watching predictable sequences triggers more action-related activity (as measured using intersubject functional correlation) in the parietal cortical area PFt at depths receiving feed-back connections (layers III and V/VI) than watching the exact same actions in scrambled and hence unpredictable sequence. In addition, functional connectivity analysis performed using intersubject functional connectivity confirms that these increased action-related signals in PFt could originate from ventral premotor region BA44. This data showcases the utility of intersubject functional correlation in combination with 7T MRI to explore the architecture of social cognition under more naturalistic conditions, and provides evidence for models that emphasize the importance of feed-back connections in action prediction.
LectinOracle – A Generalizable Deep Learning Model for Lectin-Glycan Binding Prediction
Authors: Lundstrøm Jon , Korhonen Emma , Lisacek Frédérique , Bojar Daniel
Published: August 2021

Ranging from bacterial cell adhesion over viral cell entry to human innate immunity, glycan-binding proteins or lectins abound in nature. Widely used as staining and characterization reagents in cell biology, and crucial for understanding the interactions in biological systems, lectins are a focal point of study in glycobiology. Yet the sheer breadth and depth of specificity for diverse oligosaccharide motifs has made studying lectins a largely piecemeal approach, with few options to generalize. Here, we present LectinOracle, a model combining transformer-based representations for proteins and graph convolutional neural networks for glycans to predict their interaction. Using a curated dataset of 564,647 unique protein-glycan interactions, we show that LectinOracle predictions agree with literature-annotated specificities for a wide range of lectins. We further identify clusters of lectins with related binding specificity that are not clustered based on sequence similarity. Using a range of specialized glycan arrays, we show that LectinOracle predictions generalize to new glycans and lectins, with qualitative and quantitative agreement with experimental data. We further demonstrate that LectinOracle can analyze whole lectomes and their role in host-microbe interactions. We envision that the herein presented platform will advance both the study of lectins and their role in (glyco)biology.
Interannual climate variability data improves niche estimates in species distribution models
Authors: Karger Dirk Nikolaus , Saladin Bianca , Wüest-Karpati Rafael O. , Graham Catherine H. , Zurell Damaris , Mo Lidong , Zimmermann Niklaus E.
Published: August 2021

Aim

Climate is an essential element of species’ niche estimates in many current ecological applications such as species distribution models (SDMs). Climate predictors are often used in the form of long-term mean values. Yet, climate can also be described as spatial or temporal variability for variables like temperature or precipitation. Such variability, spatial or temporal, offers additional insights into niche properties. Here, we test to what degree spatial variability and long-term temporal variability in temperature and precipitation improve SDM predictions globally.

Location

Global.

Time period

1979-2013

Major taxa studies

Mammal, Amphibians, Reptiles

Methods

We use three different SDM algorithms, and a set of 833 amphibian, 779 reptile, and 2211 mammal species to quantify the effect of spatial and temporal climate variability in SDMs. All SDMs were cross-validated and accessed for their performance using the Area under the Curve (AUC) and the True Skill Statistic (TSS).

Results

Mean performance of SDMs with climatic means as predictors was TSS=0.71 and AUC=0.90. The inclusion of spatial variability offers a significant gain in SDM performance (mean TSS=0.74, mean AUC=0.92), as does the inclusion of temporal variability (mean TSS=0.80, mean AUC=0.94). Including both spatial and temporal variability in SDMs shows similarly high TSS and AUC scores.

Main conclusions

Accounting for temporal rather than spatial variability in climate improved the SDM prediction especially in exotherm groups such as amphibians and reptiles, while for endotermic mammals no such improvement was observed. These results indicate that more detailed information about temporal climate variability offers a highly promising avenue for improving niche estimates and calls for a new set of standard bioclimatic predictors in SDM research.
Microstructural Properties of Human Brain Revealed by Fractional Anisotropy can Predict the After-effect of Intermittent Theta Burst Stimulation
Authors: Kimura Ikko , Oishi Hiroki , Hayashi Masamichi J , Amano Kaoru
Published: August 2021

Intermittent theta burst stimulation (iTBS) delivered by transcranial magnetic stimulation (TMS) produces a long term potentiation (LTP)-like after-effect useful for investigations of cortical function and of potential therapeutic value. However, the iTBS-evoked after-effect over the primary motor cortex (M1) as measured by changes in motor evoked potential (MEP) amplitude exhibits a largely unexplained variability across individuals. Here, we present evidence that individual differences in white and grey matter microstructural properties revealed by fractional anisotropy (FA) predict the magnitude of the iTBS-induced after-effect over M1. The MEP amplitude change in the early phase (5–10 min) post-iTBS was associated with FA values in white matter tracts such as right superior longitudinal fasciculus and corpus callosum. In contrast, the MEP amplitude change in the late phase (15–30 min) post-iTBS was associated with FA in grey matter, primarily in right frontal cortex. These results suggest that the microstructural properties of regions connected directly or indirectly to the target region (M1) are crucial determinants of the iTBS after-effect. FA values indicative of these microstructural differences can predict the potential effectiveness of rTMS for both investigational use and clinical application.
Mutationathon: towards standardization in estimates of pedigree-based germline mutation rates
Authors: Bergeron Lucie A. , Besenbacher Søren , Turner Tychele N. , Versoza Cyril J. , Wang Richard J. , Price Alivia Lee , Armstrong Ellie , Riera Meritxell , Carlson Jedidiah , Chen Hwei-yen , Hahn Matthew W. , Harris Kelley , Snøfrid Lo Natalie M Kleppe April , López-Nandam Elora H. , Moorjani Priya , Pfeifer Susanne P. , Tiley George P. , Yoder Anne D. , Zhang Guojie , Schierup Mikkel H.
Published: August 2021

In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various non-human species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and how to appropriately account for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a “Mutationathon”, a competition organized among five research labs to compare germline mutation rate estimates for a single pedigree of rhesus macaques. We report almost a two-fold variation in the final estimated rate among groups using different post-alignment processing, calling, and filtering criteria and provide details into the sources of variation across studies. Though the difference among estimates is not statistically significant, this discrepancy emphasizes the need for standardized methods in mutation rate estimations and the difficulty in comparing rates from different studies. Finally, this work aims to provide guidelines for computational and statistical benchmarks for future studies interested in identifying germline mutations from pedigrees.
Evidence for Free Radical Drug Ligands in class A G-protein Coupled Receptors
Authors: Gehrckens Angela S , Horsfield Andrew P , Skoulakis Efthimios M C , Turin Luca
Published: August 2021

We analyse the conformation of 22 cationic ligands bound to G-protein coupled receptors of known structure and find three ligands that are present inside receptors not in their closed shell cation form, but as neutral radicals, i.e. after addition of an electron to the ligand. The implications of this finding for GPCR function are discussed and a possible experimental test is proposed.