bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of long-term effects in individuals diagnosed with COVID-19: an updated living systematic review
Authors: Domingo Francesca Reyes , Waddell Lisa A , Cheung Angela M. , Cooper Curtis L. , Belcourt Veronica J. , Zuckermann Alexandra M. E. , Corrin Tricia , Ahmad Rukshanda , Boland Laura , Laprise Claudie , Idzerda Leanne , Khan Anam , Morissette Kate , Garcia Alejandra Jaramillo
Published: June 2021

Objective

Post COVID-19 condition refers to persisting or recurring symptoms weeks after acute COVID-19 illness which can significantly impact quality of life and health systems. It is important to understand the manifestation and magnitude of this condition. The objective of this living systematic review is to summarize the prevalence of symptoms and sequelae reported by people ≥4 weeks after COVID-19 diagnosis.

Design

Systematic review, meta-analysis and narrative synthesis.

Data sources

Embase, Medline, PsychInfo, Cochrane Central and select grey literature up to April 14, 2021.

Methods

We adapted a previous search strategy used by the U.K. National Institute for Health and Care Excellence and updated it to search for new literature. Two reviewers screened references independently; one extracted data and assessed risk of bias and certainty of the evidence while another verified them. Prevalence data from laboratory-confirmed populations were meta-analyzed using a random effects model and synthesized separately in the short-term (4-12 weeks) and long-term (>12 weeks) periods after diagnosis. Data from clinically-diagnosed populations were synthesized narratively.

Results

Of the 4444 unique citations, 84 observational studies met our inclusion criteria. Over 100 post COVID-19 symptoms and sequelae were reported. Sixty-one percent (95% CI: 44-76%,low certainty) and 53% (95% CI: 41-65%,low certainty) of laboratory-confirmed individuals reported persistence or presence of one or more symptoms in the short- and long-term periods, respectively. The most prevalent symptoms in both periods included: fatigue, general pain or discomfort, shortness of breath, cognitive impairment and mental health symptoms.

Conclusions

A substantial proportion of individuals reported a variety of symptoms ≥4 weeks after COVID-19 diagnosis. Due to gaps in the research base, and the low certainty of the evidence currently available, further research is needed to determine the true burden of post COVID-19 condition in the general population and in specific subgroups.

PROSPERO registration number

CRD42021231476.
Non-Coding Genetic Analysis Implicates Interleukin 18 Receptor Accessory Protein 3′UTR in Amyotrophic Lateral Sclerosis
Authors: Eitan Chen , Siany Aviad , Barkan Elad , Olender Tsviya , van Eijk Kristel R. , Moisse Matthieu , Farhan Sali M. K. , Danino Yehuda M. , Yanowski Eran , Marmor-Kollet Hagai , Rivkin Natalia , Yacovzada Nancy , Hung Shu-Ting , Cooper-Knock Johnathan , Yu Chien-Hsiung , Louis Cynthia , Masters Seth L. , Kenna Kevin P. , van der Spek Rick A. A. , Sproviero William , Al Khleifat Ahmad , Iacoangeli Alfredo , Shatunov Aleksey , Jones Ashley R. , Elbaz-Alon Yael , Cohen Yahel , Chapnik Elik , Rothschild Daphna , Weissbrod Omer , Beck Gilad , Ainbinder Elena , Ben-Dor Shifra , Werneburg Sebastian , Schafer Dorothy P. , Brown Robert H. , Shaw Pamela J. , Van Damme Philip , van den Berg Leonard H. , Phatnani Hemali P. , Segal Eran , Ichida Justin K. , Al-Chalabi Ammar , Veldink Jan H. ,   Project MinE ALS Sequencing Consortium,   NYGC ALS Consortium, Hornstein Eran
Published: June 2021

The non-coding genome is substantially larger than the protein-coding genome but is largely unexplored by genetic association studies. Here, we performed region-based burden analysis of >25,000 variants in untranslated regions of 6,139 amyotrophic lateral sclerosis (ALS) whole-genomes and 70,403 non-ALS controls. We identified Interleukin-18 Receptor Accessory Protein (IL18RAP) 3′UTR variants significantly enriched in non-ALS genomes, replicated in an independent cohort, and associated with a five-fold reduced risk of developing ALS. Variant IL18RAP 3′UTR reduces mRNA stability and the binding of RNA-binding proteins. Variant IL18RAP 3′UTR further dampens neurotoxicity of human iPSC-derived C9orf72-ALS microglia that depends on NF-κB signaling. Therefore, the variant IL18RAP 3′UTR provides survival advantage for motor neurons co-cultured with C9-ALS microglia. The study reveals direct genetic evidence and therapeutic targets for neuro-inflammation, and emphasizes the importance of non-coding genetic association studies.

One Sentence Summary

Non-coding genetic variants in IL-18 receptor 3’UTR decrease ALS risk by modifying IL-18-NF-κB signaling in microglia.
Depletion of TAX1BP1 amplifies innate immune responses during respiratory syncytial virus infection
Authors: Descamps Delphyne , de Oliveira Andressa Peres , Gonnin Lorène , Madrières Sarah , Fix Jenna , Drajac Carole , Marquant Quentin , Bouguyon Edwige , Pietralunga Vincent , Iha Hidekatsu , Ventura Armando Morais , Tangy Frédéric , Vidalain Pierre-Olivier , Eléouët Jean-François , Galloux Marie
Published: June 2021

Respiratory syncytial virus (RSV) is the main cause of acute respiratory infections in young children, and also has a major impact in the elderly and immunocompromised people. In the absence of vaccine or efficient treatment, a better understanding of RSV interactions with the host antiviral response during infection is needed. Previous studies revealed that cytoplasmic inclusion bodies (IBs) where viral replication and transcription occur could play a major role in the control of innate immunity during infection by recruiting cellular proteins involved in the host antiviral response. We recently showed that the morphogenesis of IBs relies on a liquid-liquid phase separation mechanism depending on the interaction between viral nucleoprotein (N) and phosphoprotein (P). These scaffold proteins are expected to play a central role in the recruitment of cellular proteins to IBs. Here, we performed a yeast two-hybrid screen using RSV N protein as a bait, and identified the cellular protein TAX1BP1 as a potential partner of N. This interaction was validated by pulldown and immunoprecipitation assays. We showed that TAX1BP1 suppression has only a limited impact on RSV infection in cell cultures. On the contrary, in vivo experiments showed that RSV replication is decreased in TAX1BP1KO mice, whereas the production of inflammatory and antiviral cytokines is enhanced. In vitro infection of either wild-type or TAX1BP1KO alveolar macrophages confirmed that the innate immune response to RSV infection is enhanced in the absence of TAX1BP1. Altogether, our results suggest that RSV could hijack TAX1BP1 to restrain the host immune response during infection.

Importance

Respiratory syncytial virus (RSV), which is the leading cause of lower respiratory tract illness in infants, still remains a medical problem in the absence of vaccine or efficient treatment. This virus is also recognized as a main pathogen in the elderly and immunocompromised people, and the occurrence of co-infections (with other respiratory viruses and bacteria) amplifies the risks of developing respiratory distress. In this context, a better understanding of the pathogenesis associated to viral respiratory infections, which depends on both viral replication and the host immune response, is needed. The present study reveals that the cellular protein TAX1BP1, which interacts with the RSV nucleoprotein N, participates in the control of the innate immune response during RSV infection, suggesting that N-TAX1BP1 interaction represents a new target for the development of antivirals.
Screening of Botanical Drugs against SARS-CoV-2 Entry
Authors: Cao Junyuan , Liu Yang , Zhou Minmin , Dong Siqi , Jia Xiaoying , Lan Xiaohao , Zhang Yueli , Guo Jiao , Xiao Gengfu , Wang Wei
Published: June 2021

An escalating pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is impacting global health. Specific treatment options for diseases caused by SARS-CoV-2 are largely lacking. Herein, we used a pseudotype virus (pv) bearing the SARS-CoV-2 S glycoprotein to screen a botanical drug library to identify an agent against SARS-CoV-2 entry. All the four hits, including angeloylgomisin O, schisandrin B, procyanidin, and oleanonic acid, were identified for effective inhibition of SARS-CoV-2 S pv entry in the micromolar range. A mechanistic study revealed that these four agents inhibit SARS-CoV-2 S pv entry by blocking S-mediated membrane fusion. Furthermore, angeloylgomisin O, schisandrin B, and oleanonic acid inhibited authentic SARS-CoV-2 with a high selective index (SI). We also showed that all the four hits could also inhibit the entry of pv of Middle East respiratory syndrome coronavirus (MERS-CoV) and newly emerged SARS-CoV-2 variants (D614G, K417N/E484K/N501Y/D614G). In drug combination studies performed in cellular antiviral assays, angeloylgomisin O and schisandrin B displayed synergistic effects in combination with remdesivir. These results indicated that angeloylgomisin O, schisandrin B, procyanidin, and oleanonic acid can inhibit SARS-CoV-2 and that they are potential therapeutic agents for COVID-19.
Costs and predictors of early readmissions in patients with Infective Endocarditis. Utilizing the Nationwide Readmission Database
Authors: Zaman Jesan , Amritphale Amod , Malozzi Christopher , Amritphale Nupur , Sehgal Mukul , Bassam Omar
Published: June 2021

BACKGROUND

There have been previous studies detailing the variables involved in readmissions in patients with a primary admission diagnosis of infective endocarditis – however those studies were done prior to the 2015 change in AHA guidelines and introduction to ICD-10 codes.

OBJECTIVES

The aim of this study was to describe the frequency, causes, factors, and costs associated with infective endocarditis encounters.

METHODS

Utilizing the 2017 national readmission database (NRD), we identified all patients that were admitted with infective endocarditis. These patients were evaluated for the rates, predictors, and costs of unplanned 30 days readmissions. Weighted analysis was performed to obtain nationally representative data.

RESULTS

56,357 patients were identified to have been admitted with a diagnosis of infective endocarditis of whom 13,004 patients (23%) were readmitted within 30 days of the index discharge. The most common causes of readmission were septicemia (15.1%), endocarditis and endocardial disease (10.5%), heart failure (9.5%), and complication of cardiovascular device, implant or graft, initial encounter (5.6%). Data showed that there were certain comorbidities that resulted in a higher risk of being readmitted, these include chronic kidney disease, COPD, tobacco use, and hepatic failure. Cost of readmissions per patient was approximately $22,059 (IQR $11,630 - $49,964).

CONCLUSIONS

Thirty-day unplanned readmissions remain a significant issue affecting nearly 1 in 6 patients with infective endocarditis. This is associated with significant mortality and financial burden. Multi-disciplinary approach may help decrease readmissions, reduce complications, and improve overall outcomes as well as the overall quality of life of our patients.
Factors influencing plasma galectin-3 concentrations in catheter-bearing hospitalized patients
Authors: Iftimie Simona , Hernández-Aguilera Anna , López-Azcona Ana F. , Castañé Helena , Rodríguez-Tomàs Elisabet , Baiges-Gaya Gerard , Castro Antoni , Camps Jordi , Joven Jorge
Published: June 2021

Introduction

Catheters are an integral part of modern medicine although their use is not without complications. Catheter-related infection triggers a strong inflammatory reaction and has been associated with high morbidity, mortality, and healthcare costs. The clinical diagnosis of catheter-related infection is made difficult by non-specific symptoms. Investigating the alterations in biochemical parameters related to infectious and inflammatory processes in these patients constitute an active line of research. The aim of this study was to investigate factors influencing the plasma concentration of galectin-3 in catheter-bearing patients and to explore its potential usefulness as an index for catheter-related infections.

Methods

Circulating concentrations of galectin-3, chemokine (C-C) motif ligand 2, procalcitonin and C-reactive protein were measured in 110 patients with a central venous catheter, 165 patients with a urinary catheter, and 72 control subjects.

Results

Catheter-bearing patients had significantly higher concentrations of galectin-3 and the other markers than the control group. We identified chronic kidney disease as an independent determinant of plasma galectin-3 concentrations in patients with a central catheter, and serum creatinine concentration, cardiovascular disease and the number of days the catheter was indwelling as determinants in urinary catheter patients. We also found that measuring galectin-3 in urinary catheter patients with a catheter-related infection was more accurate for diagnosis than the other parameters. At galectin-3 = 15 ng/mL, sensitivity was 90%.

Conclusion

We conclude that measurement of galectin-3 concentration may be useful for assessing the inflammatory status of catheter-bearing patients and may contribute to the diagnosis of catheter-related infection in those with a urinary catheter.
SARS-CoV-2 variants of concern dominate in Lahore, Pakistan in April 2021
Authors: Sarwar Muhammad Bilal , Yasir Muhammad , Alikhan Nabil-Fareed , Afzal Nadeem , de Oliveira Martins Leonardo , Viet Thanh Le , Trotter Alexander J , Prosolek Sophie J , Kay Gemma L , Foster-Nyarko Ebenezer , Rudder Steven , Baker David J , Sidra-tul-muntaha  , Roman Muhammad , Webber Mark A , Shafiq Almina , Shabir Balqees , Akram Javed , Page Andrew J , Jahan Shah
Published: June 2021

Background

The SARS-CoV-2 pandemic continues to expand globally, with case numbers rising in many areas of the world, including the Indian sub-continent. Pakistan has one of the world ‘s largest population, of over 200 million people and is experiencing a severe third wave of infections caused by SARS-CoV-2 that begun in March 2021.In Pakistan, during third wave until now only 12 SARS-CoV-2 genomes have been collected and among these 9 are from Islamabad. This highlights the need for more genome sequencing to allow surveillance of variants in circulation. In fact more genomes are available among travellers with a travel history from Pakistan, than from within the country itself.

Methods

For a better understanding of the circulating variants in Lahore and surrounding areas with a combined population of 11.1 million, within a week of April 2021, 102 samples were sequenced. The samples were randomly collected from 2 hospitals with a diagnostic polymerase chain reaction (PCR) cutoff value of less than 25 cycles.

Results

Analysis of the lineages shows that B.1.1.7 (first identified in the UK, Alpha variant) dominates, accounting for 97.9% (97/99) of cases, with B.1.351 (first identified in South Africa, Beta variant) accounting for 2.0% (2/99) of cases. No other lineages were observed.

Discussion

In depth analysis of the B.1.1.7 lineages indicates multiple separate introductions and subsequent establishment within the region. Eight samples were identical to genomes observed in Europe (7 UK, 1 Switzerland), indicating recent transmission. Genomes of other samples show evidence that these have evolved, indicating sustained transmission over a period of time either within Pakistan or other countries with low density genome sequencing. Vaccines remain effective against B.1.1.7, however the low level of B.1.351 against which some vaccines are less effective demonstrates the requirement for continued prospective genomic surveillance.
Law, Criminalisation and HIV in the World: Have countries that criminalise achieved more or less successful AIDS pandemic response?
Authors: Kavanagh Matthew M. , Agbla Schadrac C. , Pillinger Mara , Joy Marissa , Case Alaina , Erondu Ngozi , Aneja Kashish , Erkkola Taavi , Graeden Ellie
Published: June 2021

How does the use of criminal law affect disease-fighting efforts, particularly in a pandemic? This longstanding question for governments around the world is felt acutely in the context of the COVID-19 and HIV pandemics. Many countries have laws and policies that criminalise behaviours, making same-sex relationships, illicit drug use, and sex work illegal. Meanwhile, some countries have enshrined gender- and rights-protective institutions in law. Under the global AIDS strategy of the last five years, national AIDS response efforts in countries have focused on reaching people living with HIV with testing and antiretroviral treatment to suppress the HIV virus, preventing mortality and HIV transmission. At the end of this 5-year push, this article provides an ecological analysis of whether those countries with criminalising legal environments achieved more or less success. In countries where same-sex relationships were fully criminalised, the portion of people living with HIV who knew their status was 11% lower and viral suppression rates were 8% lower. Under sex-work criminalization, the rate of people living with HIV who knew their status was 10% lower and viral suppression 6% lower. Drug use criminalisation was associated with 14% lower knowledge of status and viral. On the other hand in countries with laws advancing non-discrimination, human rights institutions, and gender-based violence response, HIV services indicators were significantly better. This ecological evidence on the relationships between the legal environment and successful HIV response provides support for a strategy that includes a focus on law reform to achieve goals missed in 2020.

Summary Box

Countries around the world, across economic and geographic boundaries, have taken different approaches to the application of criminal law to same-sex sex, sex work, and drug use—with most taking a partially or fully criminalising legal approach in one or more of these areas.

In tackling the AIDS pandemic, globally agreed goals for 2020 focused on ensuring most people living with HIV were aware of their HIV status and had suppressed the HIV virus through effective antiretroviral treatment.

The AIDS response in countries that criminalised was less successful than those that did not—achieving significantly lower levels of HIV status knowledge and HIV viral suppression.

Countries with clear laws advancing non-discrimination, human rights institutions, and gender-based violence response had better knowledge of HIV status and viral suppression rates.

This analysis suggests a new global AIDS strategy that includes a focus on law reform may hold promise in achieving goals that were missed in 2020.
Genetic expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy
Authors: Nguyen Lena H. , Xu Youfen , Mahadeo Travorn , Zhang Longbo , Lin Tiffany V. , Born Heather A. , Anderson Anne E. , Bordey Angélique
Published: June 2021

Hyperactivation of mTOR signaling during fetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development (FMCD) and intractable epilepsy. Recent evidence suggests increased cap-dependent translation downstream of mTOR contributes to FMCD formation and seizures. However, whether reducing overactive translation once the developmental pathologies are established reverses neuronal abnormalities and seizures is unknown. Here, we found that the translational repressor 4E-BP1, which is inactivated by mTOR-mediated phosphorylation, is hyperphosphorylated in patient FMCD tissue and in a mouse model of FMCD. Expressing constitutive active 4E-BP1 to repress aberrant translation in juvenile mice with FMCD reduced neuronal cytomegaly and corrected several electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern, and aberrant HCN4 channel expression. This was accompanied by improved cortical spectral activity and decreased seizures. Although mTOR controls multiple pathways, our study shows that targeting 4E-BP1-mediated translation alone is sufficient to alleviate neuronal dysfunction and ongoing epilepsy.
Multi-omics approach reveals new insights into the gut microbiome of Galleria mellonella (Lepidoptera:Pyralidae) exposed to polyethylene diet
Authors: Latour Samuel , Noël Grégoire , Serteyn Laurent , Sare Abdoul Razack , Massart Sébastien , Delvigne Frank , Francis Frédéric
Published: June 2021

The current plastic pollution throughout the world implies a crucial optimization of its (bio)degradation processes. In order to identify plastic degrading bacteria and associated enzymes, the gut microbiota of insects has raised interest. Some entomological models such as Tenebrio molitor (L. 1758), Plodia interpunctella (Hübner 1813) or Galleria mellonella (L. 1758) have the ability to ingest and degrade polyethylene. Then, it is promising to identify the composition and the role of the gut microbiota in this process. This study takes part in this issue by investigating G. mellonella as a biological model feeding with a polyethylene diet. Gut microbiome samples were processed by high throughput 16S rRNA sequencing, and Enterococcaceae and Oxalobacteraceae were found to be the major bacterial families. At low polyethylene dose, we detect no bacterial community change and no amplicon sequence variant associated with the polyethylene diet suggesting microbiome resilience. The functional analysis of insects gut content was promising for the identification of plastic degrading enzymes such as the phenylacetaldehyde dehydrogenase which participate in styrene degradation. This study allows a better characterization of the gut microbiota of G. mellonella and provides a basis for the further biodegradation study of polyethylene based on the microorganism valorization from insect guts.
Toll-like receptor 2 orchestrates a potent anti-tumor response in non-small cell lung cancer
Authors: Millar Fraser R. , Pennycuick Adam , Muir Morwenna , Quintanella Andrea , Hari Priya , Freyer Elisabeth , Gautier Philippe , Meynert Alison , Teixeira Vitor H. , Connelly John , Wallace William AH , Sims Andrew H , Frame Margaret C. , Boulter Luke , Janes Sam M. , Wilkinson Simon , Acosta Juan Carlos
Published: June 2021

Targeting early-stage lung cancer is vital to improve overall survival. We previously identified Toll-like receptor 2 (TLR2) as a regulator of oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP), both key for tumor suppression. Here, we demonstrate that TLR2 is widely expressed in human lung tumor epithelium where it correlates with improved survival and clinical regression. Using genetically engineered mouse models of lung cancer we have shown that Tlr2 is a tumor suppressor in lung cancer initiation via regulation of proliferation and the SASP. The SASP is integral in the regulation of immune surveillance of premalignant cells, and we observe impaired myeloid derived immune surveillance following Tlr2 loss. Lastly, we show that administration of a synthetic Tlr2 agonist significantly reduces preinvasive lung tumor growth. Our data highlight an unexpected tumor surveillance pathway in early-stage lung cancer with therapeutic potential.

Statement of significance

Lung cancer is a major cancer of unmet need. This study identifies a novel tumor suppressor mechanism in lung cancer. Not only does this highlight a potential therapeutic target for early-stage disease but also multiple secreted candidate biomarkers that could be exploited to augment lung cancer screening approaches.
Spatially heterogeneous microstructural development within subcortical regions from 9-13 years
Authors: Palmer C E , Pecheva D , Iversen J , Hagler DJ , Sugrue L , Nedelec P , Fan C , Thompson W K , Jernigan T L , Dale A M
Published: June 2021

During late childhood behavioral changes, such as increased risk-taking and emotional reactivity, have been associated with the maturation of cortico-subcortical circuits. Understanding microstructural changes in subcortical regions may aid our understanding of how individual differences in these behaviors emerge. Restriction spectrum imaging (RSI) is a framework for modelling diffusion-weighted imaging that decomposes the diffusion signal from a voxel into hindered and restricted compartments. This yields greater specificity than conventional methods of characterizing intracellular diffusion. Using RSI, we modelled voxelwise restricted isotropic, N0, and anisotropic, ND, diffusion across the brain and measured cross-sectional and longitudinal age associations in a large sample (n=8,039) from the Adolescent Brain and Cognitive Development (ABCD) study aged 9-13 years. Older participants had higher N0 and ND across subcortical regions. The largest associations for N0 were within the basal ganglia and for ND within the ventral diencephalon. Importantly, age associations varied with respect to the internal cytoarchitecture within subcortical structures, for example age associations differed across thalamic nuclei. This suggests that developmental effects may map onto specific cell populations or circuits and highlights the utility of voxelwise compared to ROI-wise analyses. Future analyses will aim to understand the relevance of this subcortical microstructural developmental for behavioral outcomes.
Interpersonal comparison of utility by measuring neural activity
Authors: Matsumori Kaosu , Iijima Kazuki , Yomogida Yukihito , Matsumoto Kenji
Published: June 2021

Aggregating well-being across individuals to reach collective decisions is one of the most fundamental problems in our society. Interpersonal comparisons of utility are pivotal and inevitable for well-being aggregation, because if utility is not interpersonally comparable, there is no rational aggregation procedure that simultaneously satisfies even mild conditions for validity (Arrow’s impossibility theorem); however, there are as yet no scientific methods for interpersonal comparison of utility. In this study, we developed a method based on brain signals. We found that the anterior cingulate and its adjacent ventromedial prefrontal activity is correlated with changes in expected utility. The ratio of lower- and higher-income participants’ neural signals coincided with estimates of their psychological pleasure by “impartial spectators.” We confirmed the validity of our interpersonal utility comparison method using an independent large-scale dataset and used the aggregated well-being from our experimental data to derive an optimal decision rule. These findings suggest that our interpersonal comparison method enables scientifically reasonable well-being aggregation by escaping Arrow’s impossibility and has implications for the fair distribution of economic goods. Our method can be used for evidence-based policy-making in nations that use cost-benefit analyses or optimal taxation theory for policy evaluation.
Patterning on the move: the effects of Hh morphogen source movement on signaling dynamics
Authors: Míguez D. G. , Iannini A. , García-Morales D. , Casares F.
Published: June 2021

Morphogens of the Hh-family trigger gene expression changes of receiving cells in a concentration-dependent manner. The outputs of the pathway include regulation of cell identity, proliferation, death or metabolism, depending on the tissue or organ. This variety of responses relies on a conserved signaling pathway. Its internal logic includes a negative feedback loop involving the Hh receptor Ptc. In this paper, we use experiments and computational models to study and compare the different spatial signaling profiles downstream of Hh in several developing Drosophila organs. We show that the spatial distribution of Ptc and the activator form of the Gli transcription factor, CiA, in wing, antenna and ocellus show similar features, but markedly different from that in the compound eye (CE). We show that these two profile types represent two time points along the signaling dynamics, and that the interplay between the spatial displacement of the Hh source in the CE and the negative feedback loop maintains the receiving cells effectively in an earlier stage of signaling. These results indicate that the dynamics of the Hh source strongly influences the signaling profile Hh elicits in receiving cells, and show how the interaction between spatial and temporal dynamics of signaling and differentiation processes can contribute to the informational versatility of the conserved Hh signaling pathway.
Human inhalable antibody fragments neutralizing SARS-CoV-2 variants for COVID-19 therapy
Authors: Minenkova Olga , Santapaola Daniela , Milazzo Ferdinando Maria , Anastasi Anna Maria , Battistuzzi Gianfranco , Chiapparino Caterina , Rosi Antonio , Gritti Giuseppe , Borleri Gianmaria , Rambaldi Alessandro , Dental Clélia , Viollet Cécile , Pagano Bruno , Salvini Laura , Marra Emanuele , Luberto Laura , Rossi Antonio , Riccio Anna , Pich Emilio Merlo , Santoro Maria Gabriella , De Santis Rita
Published: June 2021

As of October 2021, coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global emergency, and novel therapeutics are urgently needed. Here we describe human single chain variable fragment (scFv) antibodies (76clAbs) that block an epitope of the SARS-CoV-2 spike protein essential for ACE2-mediated entry into cells. 76clAbs neutralize the delta variant and other variants being monitored (VBMs) and inhibit spike-mediated pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. In two independent animal models, intranasal administration counteracted the infection. Due to high efficiency, remarkable stability, resilience to nebulization and low production cost, 76clAbs may become a relevant tool for rapid, self-administrable early intervention in SARS-CoV-2-infected subjects independently of their immune status.
Spatio-temporal point processes as meta-models for population dynamics in heterogeneous landscapes
Authors: Zamberletti Patrizia , Papaïx Julien , Gabriel Edith , Opitz Thomas
Published: June 2021

Landscape heterogeneity affects population dynamics, which determine species persistence, diversity and interactions. These relationships can be accurately represented by advanced spatially-explicit models (SEMs) allowing for high levels of detail and precision. However, such approaches are characterised by high computational complexity, high amount of data and memory requirements, and spatio-temporal outputs may be difficult to analyse. A possibility to deal with this complexity is to aggregate outputs over time or space, but then interesting information may be masked and lost, such as local spatio-temporal relationships or patterns. An alternative solution is given by meta-models and meta-analysis, where simplified mathematical relationships are used to structure and summarise the complex transformations from inputs to outputs. Here, we propose an original approach to analyse SEM outputs. By developing a meta-modelling approach based on spatio-temporal point processes (STPPs), we characterise spatio-temporal population dynamics and landscape heterogeneity relationships in agricultural contexts. A landscape generator and a spatially-explicit population model simulate hierarchically the pest-predator dynamics of codling moth and ground beetles in apple orchards over heterogeneous agricultural landscapes. Spatio-temporally explicit outputs are simplified to marked point patterns of key events, such as local proliferation or introduction events. Then, we construct and estimate regression equations for multi-type STPPs composed of event occurrence intensity and magnitudes. Results provide local insights into spatio-temporal dynamics of pest-predator systems. We are able to differentiate the contributions of different driver categories (i.e., spatio-temporal, spatial, population dynamics). We highlight changes in the effects on occurrence intensity and magnitude when considering drivers at global or local scale. This approach leads to novel findings in agroecology where the organisation of cultivated fields and semi-natural elements are known to play a crucial role for pest regulation. It aids to formulate guidelines for biological control strategies at global and local scale.
Targeted High-Resolution Taxonomic Identification of Bifidobacterium longum subsp. infantis Using Human Milk Oligosaccharide Metabolizing Genes
Authors: Tso Lauren , Bonham Kevin S. , Fishbein Alyssa , Rowland Sophie , Klepac-Ceraj Vanja
Published: June 2021

Bifidobacterium longum subsp. infantis (B. infantis) is one of a few microorganisms capable of metabolizing human breast milk and is a pioneer colonizer in the guts of breastfed infants. One current challenge is differentiating B. infantis from its close relatives, B. longum and B. suis. All three organisms are classified in the same species group but only B. infantis can metabolize human milk oligosaccharides (HMOs). We compared HMO-metabolizing genes across different Bifidobacterium genomes and developed B. infantis-specific primers to determine if the genes alone or the primers can be used to quickly characterize B. infantis. We showed that B. infantis is uniquely identified by the presence of five HMO-metabolizing gene clusters, tested for its prevalence in infant gut metagenomes, and validated the results using the B. infantis-specific primers. We observed that only 15 of 203 (7.4%) children under 2 years old from a cohort of US children harbored B. infantis. These results highlight the importance of developing and improving approaches to identify B. infantis. A more accurate characterization may provide insights into regional differences of B. infantis prevalence in infant gut microbiota.
Enviromic assembly increases accuracy and reduces costs of the genomic prediction for yield plasticity
Authors: Costa-Neto Germano , Crossa Jose , Fritsche-Neto Roberto
Published: June 2021

Quantitative genetics states that phenotypic variation is a consequence of genetic and environmental factors and their subsequent interaction. Here, we present an enviromic assembly approach, which includes the use of ecophysiology knowledge in shaping environmental relatedness into whole-genome predictions (GP) for plant breeding (referred to as E-GP). We propose that the quality of an environment is defined by the core of environmental typologies (envirotype) and their frequencies, which describe different zones of plant adaptation. From that, we derive markers of environmental similarity cost-effectively. Combined with the traditional genomic sources (e.g., additive and dominance effects), this approach may better represent the putative phenotypic variation across diverse growing conditions (i.e., phenotypic plasticity). Additionally, we couple a genetic algorithm scheme to design optimized multi-environment field trials (MET), combining enviromic assembly and genomic kinships to provide in-silico realizations of the future genotype-environment combinations that must be phenotyped in the field. As a proof-of-concept, we highlight E-GP applications: (1) managing the lack of phenotypic information in training accurate GP models across diverse environments and (2) guiding an early screening for yield plasticity using optimized phenotyping efforts. Our approach was tested using two non-conventional cross-validation schemes to better visualize the benefits of enviromic assembly in sparse experimental networks. Results on tropical maize show that E-GP outperforms benchmark GP in all scenarios and cases tested. We show that for training accurate GP models, the genotype-environment combinations’ representativeness is more critical than the MET size. Furthermore, we discuss theoretical backgrounds underlying how the intrinsic envirotype-phenotype covariances within the phenotypic records of (MET) can impact the accuracy of GP and limits the potentialities of predictive breeding approaches. The E-GP is an efficient approach to better use environmental databases to deliver climate-smart solutions, reduce field costs, and anticipate future scenarios.
An accurate assignment test for extremely low-coverage whole-genome sequence data
Authors: Ferrari Giada , Atmore Lane M. , Jentoft Sissel , Jakobsen Kjetill S. , Makowiecki Daniel , Barrett James H. , Star Bastiaan
Published: June 2021

Genomic assignment tests can provide important diagnostic biological characteristics, such as population of origin or ecotype. In ancient DNA research, such characters can provide further information on population continuity, evolution, climate change, species migration, or trade, depending on archaeological context. Yet, assignment tests often rely on moderate- to high-coverage sequence data, which can be difficult to obtain for many ancient specimens and in ecological studies, which often use sequencing techniques such as ddRAD to bypass the need for costly whole-genome sequencing. We have developed a novel approach that efficiently assigns biologically relevant information (such as population identity or structural variants) in extremely low-coverage sequence data. First, we generate databases from existing reference data using a subset of diagnostic Single Nucleotide Polymorphisms (SNPs) associated with a biological characteristic. Low coverage alignment files from ancient specimens are subsequently compared to these databases to ascertain allelic state yielding a joint probability for each association. To assess the efficacy of this approach, we assigned inversion haplotypes and population identity in several species including Heliconius butterflies, Atlantic herring, and Atlantic cod. We used both modern and ancient specimens, including the first whole-genome sequence data recovered from ancient herring bones. The method accurately assigns biological characteristics, including population membership, using extremely low-coverage (e.g. 0.0001x fold) based on genome-wide SNPs. This approach will therefore increase the number of ancient samples in ecological and bioarchaeological research for which relevant biological information can be obtained.
Retinoic acid exerts sexually dimorphic effects over muscle energy metabolism and function
Authors: Zhao Yaxin , Vuckovic Marta , Yoo Hong Sik , Fox Nina , Rodriguez Adrienne , McKessy Kyler , Napoli Joseph L.
Published: June 2021

The retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and suppresses adiposity. Relative to WT,Rdh10+/− males experienced reduced fatty-acid oxidation, glucose intolerance and insulin resistance. Running endurance decreased 40%.Rdh10+/− females increased reliance on fatty acid oxidation and did not experience glucose intolerance nor insulin resistance. Running endurance improved 2.2-fold. Estrogen increased, revealed by a 40% increase in uterine weight. Because skeletal muscle energy use restricts adiposity and insulin resistance, we assessed the mixed fiber type gastrocnemius muscle (GM) to determine the effects of endogenous RA on muscle metabolism in vivo. RA inRdh10+/− male GM decreased 38% relative to WT. TAG content increased 1.7-fold.Glut1mRNA and glucose decreased >30%.Rdh10+/− male GM had impaired electron transport chain activity, and a 60% reduction in fasting ATP. The share of oxidative fibers increased, as did expression of the myogenic transcription factorsMyogandMyf5. Centralized nuclei increased 5-fold in fibers—indicating muscle malady or repair. InRdh10+/− female GM, RA decreased only 17%, due to a 1.8-fold increase in the estrogen-induced retinol dehydrogenase, Dhrs9.Rdh10+/− female GM did not amass TAG, increase oxidative fibers, decreaseGlut1mRNA or glucose, nor increase centralized nuclei. Expression ofMyogandMyf5decreased. Electron transport chain activity increased, elevating fasting ATP >3-fold. Thus, small decreases in skeletal muscle RA affect whole body energy use, insulin resistance and adiposity, in part through estrogen-related sexual dimorphic effects on mitochondria function.
Equivalent noise characterization of human lightness constancy
Authors: Singh Vijay , Burge Johannes , Brainard David H.
Published: June 2021

A goal of visual perception is to provide stable representations of task-relevant scene properties (e.g. object reflectance) despite variation in task-irrelevant scene properties (e.g. illumination, reflectance of other nearby objects). To study such stability in the context of the perceptual representation of lightness, we introduce a threshold-based psychophysical paradigm. We measure how thresholds for discriminating the achromatic reflectance of a target object (task-relevant property) in rendered naturalistic scenes are impacted by variation in the reflectance functions of background objects (task-irrelevant property), using a two-alternative forced-choice paradigm in which the reflectance of the background objects is randomized across the two intervals of each trial. We control the amount of background reflectance variation by manipulating a statistical model of naturally-occurring surface reflectances. For low background object reflectance variation, discrimination thresholds were nearly constant, indicating that observers’ internal noise determines threshold in this regime. As background object reflectance variation increases, its effects start to dominate performance. A model based on signal detection theory allows us to express the effects of task-irrelevant variation in terms of the equivalent noise, that is relative to the intrinsic precision of the task-relevant perceptual representation. The results indicate that although naturally-occurring background object reflectance variation does intrude on the perceptual representation of target object lightness, the effect is modest - within a factor of two of the equivalent noise level set by internal noise.
Early epidemiological signatures of novel SARS-CoV-2 variants: establishment of B.1.617.2 in England
Authors: Challen Robert , Dyson Louise , Overton Christopher E. , Guzman-Rincon Laura M. , Hill Edward M. , Stage Helena B. , Brooks-Pollock Ellen , Pellis Lorenzo , Scarabel Francesca , Pascall David J. , Blomquist Paula , Tildesley Michael , Williamson Daniel , Siegert Stefan , Xiong Xiaoyu , Youngman Ben ,   Juniper, Read Jonathan M. , Gog Julia R. , Keeling Matthew J. , Danon Leon
Published: June 2021

The rapid emergence of SARS-CoV-2 mutants with new phenotypic properties is a critical challenge to the control of the ongoing pandemic. B.1.1.7 was monitored in the UK through routine testing and S-gene target failures (SGTF), comprising over 90% of cases by March 2021. Now, the reverse is occurring: SGTF cases are being replaced by an S-gene positive variant, which we associate with B.1.617.2. Evidence from the characteristics of S-gene positive cases demonstrates that, following importation, B.1.617.2 is transmitted locally, growing at a rate higher than B.1.1.7 and a doubling time between 5-14 days. S-gene positive cases should be prioritised for sequencing and aggressive control in any countries in which this variant is newly detected.

One-Sentence Summary

The B.1.617.2 variant of SARS-CoV-2 is replacing B.1.1.7 and emerging as the dominant variant in England, evidenced by sustained local transmission.
Prediction of severe COVID-19 cases requiring intensive care in Osaka, Japan
Authors: Kurita Junko , Sugawara Tamie , Ohkusa Yasushi
Published: June 2021

Background

To avoid exhaustion of medical resources by COVID-19 care, policy-makers must predict care needs, specifically estimating the proportion of severe cases likely to require intensive care. In Osaka prefecture, Japan, the number of these severe cases exceeded the capacity of ICU units prepared for COVID-19 from mid-April, 2021.

Objective

This study used a statistical model to elucidate dynamics of severe cases in Osaka and validated the model through prospective testing.

Methods

The study extended from April 3, 2020 through April 26, 2021 in Osaka prefecture, Japan prefecture. We regressed the number of severe cases on the number of severe cases the day prior and the newly onset patients of more than 21 days prior.

Results

We selected the number of severe cases the day prior and the number of newly onset patients on 21 and 28 days prior as explanatory variables for explaining the number of severe cases based on the adjusted determinant coefficient. The adjusted coefficient of determination was greater than 0.995 and indicated good fit. Prospective out of sample three-week prediction forecast the peak date precisely, but the level was not t.

Discussion and Conclusion

A reason for the gap in the prospective prediction might be the emergence of variant strains.
Statistical Power or More Precise Insights into Neuro-Temporal Dynamics? Assessing the Benefits of Rapid Temporal Sampling in fMRI
Authors: Dowdle Logan T. , Ghose Geoffrey , Chen Clark C. C. , Ugurbil Kamil , Yacoub Essa , Vizioli Luca
Published: June 2021

Functional magnetic resonance imaging (fMRI), a non-invasive and widely used human neuroimaging method, is most known for its spatial precision. However, there is a growing interest in its temporal sensitivity. This is despite the temporal blurring of neuronal events by the blood oxygen level dependent (BOLD) signal, the peak of which lags neuronal firing by 4 to 6 seconds. Given this, the goal of this review is to answer a seemingly simple question – “What are the benefits of increased temporal sampling for fMRI?”. To answer this, we have combined fMRI data collected at multiple temporal scales, from 323 to 1000 milliseconds, with a review of both historical and contemporary temporal literature. After a brief discussion of technological developments that have rekindled interest in temporal research, we next consider the potential statistical and methodological benefits. Most importantly, we explore how fast fMRI can uncover previously unobserved neuro-temporal dynamics – effects that are entirely missed when sampling at conventional 1 to 2 second rates. With the intrinsic link between space and time in fMRI, this temporal renaissance also delivers improvements in spatial precision. Far from producing only statistical gains, the array of benefits suggest that the continued temporal work is worth the effort.
NeTOIF: A Network-based Approach for Time-Series Omics Data Imputation and Forecasting
Authors: Shi Min , Mollah Shamim
Published: June 2021

Motivation

High-throughput studies of biological systems are rapidly generating a wealth of ‘omics’-scale data. Many of these studies are time-series collecting proteomics and genomics data capturing dynamic observations. While time-series omics data are essential to unravel the mechanisms of various diseases, they often include missing (or incomplete) values resulting in data shortage. Data missing and shortage are especially problematic for downstream applications such as omics data integration and computational analyses that need complete and sufficient data representations. Data imputation and forecasting methods have been widely used to mitigate these issues. However, existing imputation and forecasting techniques typically address static omics data representing a single time point and perform forecasting on data with complete values. As a result, these techniques lack the ability to capture the time-ordered nature of data and cannot handle omics data containing missing values at multiple time points.

Results

We propose a network-based method for time-series omics data imputation and forecasting (NeTOIF) that handle omics data containing missing values at multiple time points. NeTOIF takes advantage of topological relationships (e.g., protein-protein and gene-gene interactions) among omics data samples and incorporates a graph convolutional network to first infer the missing values at different time points. Then, we combine these inferred values with the original omics data to perform time-series imputation and forecasting using a long short-term memory network. Evaluating NeTOIF with a proteomic and a genomic dataset demonstrated a distinct advantage of NeTOIF over existing data imputation and forecasting methods. The average mean square error of NeTOIF improved 11.3% for imputation and 6.4% for forcasting compared to the baseline methods.

Contact

smollah@wustl.edu