bluuebunny/crossref_metadata_2025_split huggingface dataset:
The adaptation front equation explains diversification hotspots and living-fossilization
Authors: Ito Hiroshi C. , Sasaki Akira 
Published: July 2021

AbstractTaxonomic turnovers are common in the evolutionary histories of biological communities. Such turnovers are often associated with the emergence and diversification of groups that have achieved fundamental innovations beneficial in various ecological niches. In the present study, we show that such innovation-driven turnovers could be analyzed using an equation that describes the dynamics of zero-fitness isoclines in a two-dimensional trait space comprising a “fundamental trait” (describing fundamental innovation) and a “niche trait” (describing niche position) or with its higher-dimensional extensions. Our equation allows analytical prediction of evolutionary source–sink dynamics along the niche axis for an arbitrary unimodal (or multimodal with weak separation) carrying capacity distribution. The prediction was confirmed by numerical simulation under different assumptions for resource competition, reproduction, and mutation. In the simulated evolution, biodiversity sources are the central niches having higher carrying capacities than the outer niches, allowing species there the faster evolutionary advancement in fundamental traits and their repeated diversification into outer niches, which outcompete the indigenous less advanced species. The outcompeted species go extinct or evolve directionally toward the far outer niches of the far slower advancement because of the far lower carrying capacities. In consequence of this globally acting process over niches, species occupying peripheral (i.e., the outermost) niches can have significantly primitive fundamental traits and deep divergence times from their closest relatives, and thus, they correspond to living fossils. The extension of this analysis for multiple geographic regions showed that living fossils are also expected in geographically peripheral regions for the focal species group.Significance StatementWe developed a new equation for analyzing the long-term coevolution of many species through their directional evolution, evolutionary branching, and extinction in an arbitrary trait space comprising traits describing niche positions and traits describing fundamental innovations. This equation describes the many coevolving species as a fluid, as in the study of galaxy dynamics in astronomical physics. This equation may be used to explain how innovation-driven taxonomic turnovers generate diversification hotspots and coldspots among niches or geographical regions, accompanied by continuous production of “living fossil” species in peripheries, in a logic equivalent to that deduced by Darwin and Darlington from empirical observations.
Single-dose mRNA vaccine effectiveness against SARS-CoV-2 in healthcare workers extending 16 weeks post-vaccination: a test-negative design from Quebec, Canada
Authors: Carazo Sara , Talbot Denis , Boulianne Nicole , Brisson Marc , Gilca Rodica , Deceuninck Geneviève , Brousseau Nicholas , Drolet Mélanie , Ouakki Manale , Sauvageau Chantal , Barkati Sapha , Fortin Elise , Carignan Alex , De Wals Philippe , Skowronski Danuta M. , De Serres Gaston 
Published: July 2021

ABSTRACTIntroductionIn Canada, first and second doses of mRNA vaccines against SARS-CoV-2 were uniquely spaced 16 weeks apart, but the duration of single-dose protection remains uncertain. We estimated one- and two-dose mRNA vaccine effectiveness (VE) among healthcare workers (HCWs) in Quebec, Canada including protection against varying outcome severity, variants of concern (VOC), and the stability of single-dose protection out to 16 weeks post-vaccination.MethodsA test-negative design compared vaccination among SARS-CoV-2 test-positive and weekly-matched (10:1), randomly-sampled, test-negative HCWs using linked surveillance and immunization databases. Vaccine status was defined by one dose ≥14 days or two doses ≥7 days before illness onset or specimen collection. Adjusted VE was estimated by conditional logistic regression.ResultsPrimary analysis included 5,316 cases and 53,160 controls. Single-dose VE was 70% (95%CI: 68-73) against SARS-CoV-2 infection, 73% (95%CI: 71-75) against COVID-19 illness and 97% (95%CI: 92-99) against associated hospitalization. Two-dose VE was 86% (95%CI: 81-90) and 93% (95%CI: 89-95), respectively, with no associated hospitalizations. VE was higher for non-VOC than VOC (73% Alpha) among single-dose (77%, 95%CI: 73-81 versus 63%, 95%CI: 57-67) but not two-dose recipients (87%, 95%CI: 57-96 versus 94%, 95%CI: 89-96). Across 16 weeks, no decline in single-dose VE was observed with appropriate stratification based upon prioritized vaccination determined by higher versus lower likelihood of direct patient contact.ConclusionOne mRNA vaccine dose provided substantial and sustained protection to HCWs extending at least four months post-vaccination. In circumstances of vaccine shortage, delaying the second dose may be a pertinent public health strategy to consider.
Predicting future ocular Chlamydia trachomatis infection prevalence using serological, clinical, molecular, and geospatial data
Authors: Tedijanto Christine , Aragie Solomon , Tadesse Zerihun , Haile Mahteme , Zeru Taye , Nash Scott D. , Wittberg Dionna M. , Gwyn Sarah , Martin Diana L. , Sturrock Hugh J.W. , Lietman Thomas M. , Keenan Jeremy D. , Arnold Benjamin F. 
Published: July 2021

ABSTRACTTrachoma is an infectious disease characterized by repeated exposures to Chlamydia trachomatis (Ct) that may ultimately lead to blindness. District-level estimates of clinical disease are currently used to guide control programs. However, clinical trachoma is a subjective indicator. Serological markers present an objective, scalable alternative for monitoring and targeting of more intensive control efforts. We hypothesized that IgG seroprevalence in combination with geospatial layers, machine learning, and model-based geostatistics would be able to accurately predict future community-level ocular Ct infections detected by PCR. Among 40 communities in the hyperendemic Amhara region of Ethiopia, median Ct infection prevalence among children 0-5 years old increased from 6% at enrollment to 29% at month 36. Seroprevalence was the strongest concurrent predictor of infection prevalence at month 36 among children 0-5 years old (cross-validated R2 = 0.75, 95% CI: 0.58-0.85), though predictive performance declined substantially with increasing temporal lag between predictor and outcome measurements. Geospatial variables, a spatial Gaussian process, and stacked ensemble machine learning did not meaningfully improve predictions. Serological markers among children 0-5 years old may be a promising programmatic tool for identifying communities with high levels of active ocular Ct infections, but accurate, future prediction in the context of changing transmission remains a challenge.
Re-emergence of respiratory syncytial virus following the COVID-19 pandemic in the United States: a modeling study
Authors: Zheng Zhe , Pitzer Virginia E. , Shapiro Eugene D. , Bont Louis J. , Weinberger Daniel M. 
Published: July 2021

AbstractImportanceRespiratory syncytial virus (RSV) is a leading cause of hospitalizations in young children. RSV largely disappeared in 2020 due to precautions taken because of the COVID-19 pandemic. Projecting the timing and intensity of the re-emergence of RSV and the age groups affected is crucial for planning for the administration of prophylactic antibodies and anticipating hospital capacity.ObjectiveTo project the potential timing and intensity of re-emergent RSV epidemics in different age groups.Design, Setting, ParticipantsMathematical models were used to reproduce the annual RSV epidemics before the COVID-19 pandemic in New York and California. These models were modified to project the trajectory of RSV epidemics in 2020-2025 under different scenarios with varying stringency of mitigation measures for SARS-CoV-2: 1) constant low RSV transmission rate from March 2020 to March 2021; 2) an immediate decrease in RSV transmission in March 2020 followed by a gradual increase in transmission until April 2021; 3) a decrease in non-household contacts from April to July 2020. Simulations also evaluated factors likely to impact the re-emergence of RSV epidemics, including introduction of virus from out-of-state sources and decreased transplacentally-acquired immunity in infants.Main Outcomes and MeasuresThe primary outcome of this study was defined as the predicted number of RSV hospitalizations each month in the entire population. Secondary outcomes included the age distribution of hospitalizations among children <5 years of age, incidence of any RSV infection, and incidence of RSV lower respiratory tract infection (LRI).ResultsIn the 2021-2022 RSV season, we expect that the lifting of mitigation measures and build-up of susceptibility will lead to a larger-than-normal RSV outbreak. We predict an earlier-than-usual onset in the upcoming RSV season if there is substantial external introduction of RSV. Among children 1-4 years of age, the incidence of RSV infections could be twice that of a typical RSV season, with infants <6 months of age having the greatest seasonal increase in the incidence of both severe RSV LRIs and hospitalizations.Conclusions and RelevancePediatric departments, including pediatric intensive care units, should be alert to large RSV outbreaks. Enhanced surveillance is required for both prophylaxis administration and hospital capacity management.
Seroprevalence and Dynamics of anti-SARS-CoV-2 antibody among healthcare workers following ChAdOx1 nCoV-19 vaccination
Authors: Sarkar Soma , Das Shantanab , Choudhury Kabita , Mukherjee Saibal , Chatterjee Raghunath 
Published: July 2021

AbstractBackgroundThe serological evaluations of IgG, IgM, and IgA to the SARS-CoV-2 proteins are widely used for the epidemiological assessment of COVID-19. The Health Care Workers (HCWs) are presumably exposed to a higher risk of acquiring the disease owing to their regular contact with the patients.MethodsCOVID-19 prevalence was investigated by classifying 313 HCWs into four groups based on their degree of exposure and estimating the IgG and total antibody. The serological assessment of the anti-SARS-CoV-2 antibody was conducted 21 days post-vaccination of first or both doses of the ChAdOx1 nCoV-19 vaccine among 174 HCWs. The vaccinated HCWs were followed up for 3 months for SARS-CoV-2 infection.FindingsThe levels of anti-SARS-CoV-2 IgG were comparable among different groups, but the seroprevalence gradually decreased from the most exposed to the less exposed group. The neutralizing antibody was positively correlated with IgG as well as total antibody. IgG was marginally decreased after 2 months followed by a significant drop after 4-6 months post-infection. However, 80% of the HCWs developed a detectable amount of IgG after the first dose of vaccination, the median titer of which was comparable to the seropositive HCWs after natural infection. Almost 100% of the HCWs developed antibodies after the second dose of vaccine with boosting effect among the seropositive HCWs. Although ∼11.5% of the vaccinated HCWs were infected with the SARS-CoV-2, ∼94% of them showed mild symptoms and recovered in home isolation without any O2support.InterpretationsThe varying level of seroprevalence among the four groups suggested stratified spread of the disease. One dose of SARS-CoV-2 vaccination was found to be effective in terms of the antibody titer, while the second dose was required to cover the larger population. The effectiveness of the ChAdOx1 nCoV-19 vaccine was noticeable due to the low rate of post-vaccination infection with moderate or severe symptoms.
Rapamycin microparticles induce autophagy, prevent senescence and are effective in treatment of Osteoarthritis
Authors: Dhanabalan Kaamini M. , Dravid Ameya A. , Agarwal Smriti , Sharath Ramanath K. , Padmanabhan Ashok K. , Agarwal Rachit 
Published: July 2021

AbstractTrauma to the knee joint is associated with significant cartilage degeneration and erosion of subchondral bone, which eventually leads to osteoarthritis (OA), resulting in substantial morbidity and healthcare burden. With no disease-modifying drugs in clinics, the current standard of care focuses on symptomatic relief and viscosupplementation. Modulation of autophagy and targeting senescence pathways are emerging as potential treatment strategies. Rapamycin has shown promise in OA disease amelioration by autophagy upregulation, yet its clinical use is hindered by difficulties in achieving therapeutic concentrations, necessitating multiple weekly injections. Here, we have synthesized rapamycin - loaded poly (lactic-co-glycolic acid) microparticles (RMPs) that induced autophagy, prevented senescence and sustained sulphated glycosaminoglycans(sGAG) production in primary human articular chondrocytes from OA patients. RMPs were potent, nontoxic, and exhibited high retention time (up to 35 days) in mice joints. Intra-articular delivery of RMPs effectively mitigated cartilage damage and inflammation in surgery-induced OA when administered as a prophylactic or therapeutic regimen. Together, our studies demonstrate the feasibility of using RMPs as a potential clinically translatable therapy to prevent and treat post-traumatic osteoarthritis.Graphical Abstract
Mechanism of tissue expansion in the early stage of the migration
Authors: Kiran Abhimanyu , Kumar Navin , Mehandia Vishwajeet 
Published: July 2021

AbstractThe collective cell migration is observed in many biological processes such as wound healing, embryogenesis, and cancer metastasis. Despite extensive theoretical and experimental studies on collective cell motion, there is no unified mechanism to explain it. In this work, we experimentally report the collectively growing cell colonies in the sub-marginal region of a freely expanding cell monolayer. These colonies could be responsible for the highly aligned collective cell migration observed in front cell rows. Our results provide a basic framework to understand the physical mechanism responsible for collective cell migration in the freely expanding monolayer.
A novel PD-L1-targeted shark VNAR single domain-based CAR-T strategy for treating breast cancer and liver cancer
Authors: Li Dan , English Hejiao , Hong Jessica , Liang Tianyuzhou , Merlino Glenn , Day Chi-Ping , Ho Mitchell 
Published: July 2021

AbstractChimeric antigen receptor (CAR)-T cell therapy shows great potency against hematological malignancies, whereas it remains difficult to treat solid tumors mainly due to lack of appropriate antigenic targets and immunosuppressive tumor microenvironment (TME). Checkpoint molecule PD-L1 is widely overexpressed on multiple tumor types, and the PD-1/PD-L1 interaction is a key mediator of immunosuppression in TME. Here, we isolated anti-PD-L1 single domain antibodies from a newly constructed semi-synthetic nurse shark VNAR phage library. We found that one VNAR, B2, showed cross-reactivity to human, mouse, and canine PD-L1 antigens, and it partially blocked the interaction of human PD-1 to PD-L1. Furthermore, CAR (B2) T cells specifically lysed human breast cancer and liver cancer cells by targeting constitutive and inducible expression of PD-L1, and also hindered tumor metastasis. Importantly, the combination of CAR (B2) T cells with CAR-T cells targeting liver cancer-specific antigen GPC3 regress liver tumors in mice. We concluded that PD-L1-targeted shark VNAR single domain-based CAR-T therapy is a novel strategy to treat breast cancer and liver cancer. This provides a rationale for potential use of CAR (B2) T cells as a monotherapy or combination with a tumor-specific therapy in clinical studies.
Mutations in coral soma and sperm imply lifelong stem cell renewal and cell lineage selection
Authors: López-Nandam Elora H. , Albright Rebecca , Hanson Erik A. , Sheets Elizabeth A. , Palumbi Stephen R. 
Published: July 2021

AbstractIn many animals, the germline differentiates early in embryogenesis, so only mutations that accumulate in germ cells are inherited by offspring1. Exceptions to this developmental process may indicate that other mechanisms have evolved to limit the effects of deleterious mutation accumulation2. Stony corals are animals that can live for hundreds of years3 and have long been thought to produce gametes from somatic tissue4. To clarify conflicting evidence about germline-soma distinction in corals, we sequenced high coverage, full genomes with technical replicates for parent coral branches and their sperm pools. We identified post-embryonic single nucleotide variants (SNVs) unique to each parent branch, then checked if each SNV was shared by the respective sperm pool: 26% of post-embryonic SNVs were shared by the sperm but 74% were not. We also identified germline SNVs, those that were present in the sperm but not in the parent. These data suggest that self-renewing stem cells in corals differentiate into germ and soma throughout the adult life of the colony, with SNV rates and patterns differing markedly in stem, soma, and germ lineages. In addition to informing the important place in the evolutionary spectrum from non-Weismannian to Weismmanian animals that corals occupy, these insights inform how corals may generate adaptive diversity necessary in the face of global climate change.
Synergistic regulation of bZIP53 and dimerizing partners results in abnormal seed phenotype in Arabidopsis: Use of a designed dominant negative protein A-ZIP53
Authors: Jain Prateek , Rishi Vikas 
Published: July 2021

ABSTRACTIn Arabidopsis, basic leucine zipper (bZIP) family of transcription factors (TFs) are key proteins to regulate the expression of seed maturation (MAT) genes. bZIPs are functionally redundant and their DNA-binding activity is dependent on dimerization partner. The intervention of loss of function mutation is inadequate to understand and regulate the redundant behavior of TFs and one such example is bZIP53, which is known as a key regulator of seed maturation phenomena. Here, to examine the consequences of hindering the function of bZIP53 and its known and unknown heterodimerizing partners, a transgenic Arabidopsis constitutively expressing a novel dominant negative (DN) protein A-ZIP53 was raised. Transgenic plants demonstrated a delayed growth and retarded seed phenotype. The in vivo inhibition of DNA binding of bZIP53, bZIP10, and bZIP25 to the G-box demonstrated the efficacy of A-ZIP53 protein. In first generation, majority of plants failed to survive beyond four weeks suggesting a pleiotropic nature of bZIP53. Plants expressing A-ZIP53 have small flower, shorter siliques, and small-seeded phenotype. RNA seq analysis of the transgenic lines revealed the reduced expression of target genes of bZIP53 and its heterodimerizing partners. Furthermore, immunoprecipitation followed by mass spectrometry (IP-MS/MS) of transgenic plants helped to identify the additional heterodimerizing partners of the A-ZIP53. The interactions were subsequently confirmed with the transient transfection experiments. Unlike other gene knock out technologies, DN protein can inhibit the function of members of the same group of bZIP TFs.
Two redundant ubiquitin-dependent pathways of BRCA1 localization to DNA damage sites
Authors: Sherker Alana , Chaudhary Natasha , Adam Salomé , Noordermeer Sylvie M. , Fradet-Turcotte Amélie , Durocher Daniel 
Published: July 2021

AbstractThe tumor suppressor BRCA1 accumulates at sites of DNA damage in a ubiquitin-dependent manner. In this work, we revisit the role of the ubiquitin-binding protein RAP80 in BRCA1 recruitment to damaged chromatin. We found that RAP80, or the phosphopeptide-binding residues in the BRCA1 BRCT domains, act redundantly with the BRCA1 RING domain to promote BRCA1 recruitment to DNA double-strand break sites. We show that that RNF8 E3 ubiquitin ligase acts upstream of both the RAP80- and RING-dependent activities whereas RNF168 acts uniquely upstream of the RING domain. The function of the RING domain in BRCA1 recruitment is not solely linked to its role in mediating an interaction with BARD1 since RING mutations that do not impact BARD1 interaction, such as the E2-binding deficient Ile26Ala (I26A) mutation, produce a BRCA1 protein unable to accumulate at DNA damage sites in the absence of RAP80. Cells that combine the BRCA1 I26A mutation and mutations that disable the RAP80-BRCA1 interaction are deficient in RAD51 filament formation and are hypersensitive to poly (ADP-ribose) polymerase inhibition. Our results suggest that in the absence of RAP80, the BRCA1 E3 ligase activity is necessary for the recognition of unmethylated histone H4 Lys20 and histone H2A Lys13/Lys15 ubiquitylation by BARD1 although we cannot rule out the possibility that the RING- E2 complex itself may facilitate ubiquitylated nucleosome recognition in other ways. Finally, given that tumors expressing RING-less BRCA1 isoforms readily acquire resistance to therapy, this work suggests that targeting RAP80, or its interaction with BRCA1, could represent a novel strategy for restoring sensitivity of such tumors to DNA damaging agents.
Gram-positive bacteria secrete RNA aptamers to activate human STING for IL-1β release
Authors: Duduskar Shivalee N. , Ghait Mohamed , Westermann Martin , Guo Huijuan , Ramoji Anuradha , Sponholz Christoph , Göhrig Bianca , Bruns Tony , Neugebauer Ute , Popp Jurgen , Tuchscherr Lorena P N , Löffler Bettina , Ueberschaar Nico , Beemelmanns Christine , Singer Mervyn , Bauer Michael , Deshmukh Sachin D. 
Published: July 2021

ABSTRACTMolecular mechanisms through which Gram-positive bacteria induce the canonical inflammasome are poorly understood. Here, we studied the effects of Group B streptococci (GBS) and Staphylococcus aureus (SA) on inflammasome activation in human macrophages. Dinucleotide binding small RNA aptamers released by SA and GBS were shown to trigger increased IL-1β generation by inflammasomes. The stimulator of interferon genes-STING as a central mediator of innate immune responses has been identified as the key target of pathogenic RNA. Multi-lamellar lipid bodies (MLBs) produced by SA function as vehicles for the RNA aptamers. Notably, expression of RNA aptamers is controlled by an accessory gene regulator quorum sensing system of the bacteria. These findings have been translated to patients with Gram-positive sepsis showing hallmarks of MLB-RNA-mediated inflammasome activation. Together our findings may provide a new perspective for the pathogenicity of Gram-positive bacterial infection in man.