bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular counting enables accurate and precise quantification of methylated ctDNA for tumor-naive cancer therapy response monitoring
Authors: Ye Patrick Peiyong , Viens Robb Andrew , Shelburne Katherine Elise , Langpap Sydne Scot , Bower Xavier Scott , Zhou Wen , Wignall Jan Christian , Zhu Joyce Jiawei , Woodward Brian D , Husain Hatim , Tsao David S , Atay Oguzhan 
Published: June 2023

AbstractPersonalized cancer treatment can significantly extend survival and improve quality of life for many patients, but accurate and real-time therapy response monitoring remains challenging. To overcome logistical and technical challenges associated with using imaging scans or assays that track the variant allele fraction (VAF) of somatic mutations in circulating tumor DNA (ctDNA) for response monitoring, we developed a tumor-naive liquid biopsy assay that leverages quantitative counting template (QCT) technology to accurately and precisely quantify methylated ctDNA (Northstar ResponseTM). Northstar ResponseTMachieves <10% coefficient of variation at 1% tumor fraction, which is 2x lower than VAF-based response monitoring approaches. The assay accurately distinguishes 0.25% absolute changes in contrived tumor fraction (AUC > 0.94) and performs well in 12 solid tumor types. Preliminary clinical results from patients with lung, colorectal, or pancreatic cancer demonstrate that Northstar ResponseTMdetects changes in ctDNA methylation that correlate with clinical outcomes. As a novel tool for therapy response monitoring, the assay’s serial measurements of ctDNA methylation can be precise, reflect clinical outcomes, and have potential to inform clinical decision making for cancer treatment.
Predicting Ventricular Tachycardia Circuits in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy using Genotype-specific Heart Digital Twins
Authors: Zhang Yingnan , Zhang Kelly , Prakosa Adityo , James Cynthia , Zimmerman Stefan L , Carrick Richard , Sung Eric , Gasperetti Alessio , Tichnell Crystal , Murray Brittney , Calkins Hugh , Trayanova Natalia 
Published: June 2023

AbstractArrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease that leads to ventricular tachycardia (VT), a life-threatening heart rhythm disorder. Treating ARVC remains challenging due to the complex underlying arrhythmogenic mechanisms, which involve structural and electrophysiological (EP) remodeling. Here, we developed a novel genotype-specific heart digital twin (Geno-DT) approach to investigate the role of pathophysiological remodeling in sustaining VT reentrant circuits and to predict the VT circuits in ARVC patients of different genotypes. This approach integrates the patient’s disease-induced structural remodeling reconstructed from contrast-enhanced magnetic-resonance imaging and genotype-specific cellular EP properties. In our retrospective study of 16 ARVC patients with two genotypes: plakophilin-2 (PKP2,n= 8) and gene-elusive (GE,n= 8), we found that Geno-DT accurately and non-invasively predicted the VT circuit locations for both genotypes (with 100%, 94%, 96% sensitivity, specificity, and accuracy for GE patient group, and 86%, 90%, 89% sensitivity, specificity, and accuracy forPKP2patient group), when compared to VT circuit locations identified during clinical EP studies. Moreover, our results revealed that the underlying VT mechanisms differ among ARVC genotypes. We determined that in GE patients, fibrotic remodeling is the primary contributor to VT circuits, while inPKP2patients, slowed conduction velocity and altered restitution properties of cardiac tissue, in addition to the structural substrate, are directly responsible for the formation of VT circuits. Our novel Geno-DT approach has the potential to augment therapeutic precision in the clinical setting and lead to more personalized treatment strategies in ARVC.
Protein Vaccine Demonstrates Less Reactogenicity than mRNA – A Real World Study
Authors: Rousculp Matthew , Ziemiecki Ryan , Marchese Anthony M. 
Published: June 2023

AbstractA prospective, observational study investigated the burden and impact of vaccine reactogenicity in adults from the United States and Canada who received an approved/authorized mRNA COVID-19 vaccine or the Novavax COVID vaccine as a booster dose. As part of the real-world study, reactogenic events captured via patient symptom diaries were compared. Results demonstrated that the overall percentage of Novavax COVID booster recipients experiencing any reactogenicity event (77.6%) was lower than that of mRNA doses (95.9%).
Highly Pathogenic Avian Influenza Vaccines: challenges for innovation, technological development and pandemic preparedness
Authors: Possas Cristina , Marques Ernesto TA , Oliveira Alessandra , Schumacher Suzanne , Mendes Flavia , Siqueira Marilda M , Antunes Adelaide , Homma Akira 
Published: June 2023

AbstractIntroductionHighly Pathogenic Avian Influenza (HPAI) pandemic potential is a critical issue. Outbreaks of H5N1 Avian Flu, causing mass die-offs in poultry and other birds, are now affecting mammals from otters to dolphins worldwide. H5N1 and other HPAI viruses have so far caused rare human infections. However, if they evolve to spread between people, they could trigger major outbreaks. The main question is: how to overcome bottlenecks in HPAI vaccine development to accelerate scale-up and implement an effective global Vaccine Preparedness System?MethodsFrom a patent landscape approach, we identified breakthroughs and gaps in HPAI vaccine development for the search period (2010-2021), discussing technological strategies in patent filings, including universal vaccine patent documents.ResultsVery few patent documents for human HPAI vaccines were retrieved: from 49 deposits in the search period, only 18 were in active status (37%), with few breakthroughs and in early stages of development. These results indicate a technological lag in HPAI vaccine development and highlight the constraints for scaling-up these vaccines when they will be needed. Current egg-based processes are laborious and too difficult to scale-up in the case of a pandemic. Concerning mRNA technology, there are still issues on the duration and level of protection mRNA vaccines might induce. Vaccinating farm animals is not sufficient to protect the population: if not properly executed, the virus could continue to circulate at a low level, increasing the chance of mutations and adaptation to humans. Universal Influenza vaccines would be key, but we identified only few (20 in the search period) patents for these vaccines, still in early stages of development. In addition, it is the impact immunological memory would have on the development of protective immunity to a broad-spectrum of viruses, due to original antigenic sin mechanism.DiscussionThis study identified critical barriers to overcome in HPAI vaccine development, improving efficacy and reducing costs. It highlights the urgent need for an effective global Vaccine Preparedness model, supported by Genomic, Antigenic and Epidemiological Surveillance, an Innovation Fund and Public-Private Partnerships. We strongly support WHO in coordinating a Global Initiative for Influenza Pandemic Preparedness.
Meta-Analysis of Breast Cancer Risk for Individuals with PALB2 Pathogenic Variants
Authors: Ruberu Thanthirige Lakshika M. , Braun Danielle , Parmigiani Giovanni , Biswas Swati 
Published: June 2023

AbstractBackgroundPathogenic variants in cancer susceptibility genes can now be tested efficiently and economically with the wide availability of multi-gene panel testing. This has resulted in an unprecedented rate of identifying individuals carrying pathogenic variants. These carriers need to be counselled about their future cancer risk conferred by the specific gene mutation. An important cancer susceptibility gene is PALB2. Several studies reported risk estimates for breast cancer (BC) associated with pathogenic variants in PALB2. Because of the variety of modalities (age specific risk, odds ratio, relative risk, and standardized incidence ratio) and effect sizes of these risk estimates, a meta-analysis of all of these estimates of BC risk is necessary to provide accurate counselling of patients with pathogenic variants in PALB2. The challenge, though, in combining these estimates is the heterogeneity of studies in terms of study design and risk measure.MethodsWe utilized a recently proposed novel Bayesian random-effects meta-analysis method that can synthesize and combine information from such heterogeneous studies. We applied this method to combine estimates from twelve different studies on BC risk for carriers of pathogenic PALB2 mutations, out of which two report age-specific penetrance, one reports relative risk, and nine report odds ratios.ResultsThe estimated overall (meta-analysis based) risk of BC is 12.80% by age 50 (6.11% − 22.59%) and 48.47% by age 80 (36.05% − 61.74%).ConclusionPathogenic mutations in PALB2 makes women more susceptible to BC. Our risk estimates can help clinically manage patients carrying pathogenic variants in PALB2.
Detection of circulating plasma tumour mutations in early stage triple negative breast cancer as an adjunct to pathological complete response assessment
Authors: Zaikova Elena , Cheng Brian Y.C , Cerda Viviana , Kong Esther , Lai Daniel , Lum Amy , Bates Cherie , Brok Wendie den , Kono Takako , Bourque Sylvie , Chan Angela , Feng Xioalan , Fenton David , Gurjal Anagha , Levasseur Nathalie , Lohrisch Caroline , Roberts Sarah , Shenkier Tamara , Simmons Christine , Taylor Sara , Villa Diego , Miller Ruth , Aguirre-Hernandez Rosalia , Aparicio Samuel , Gelmon Karen 
Published: June 2023

AbstractCirculating tumour DNA (ctDNA) detection in liquid biopsy is an emerging alternative to tissue biopsy, but its utility in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) is not yet well understood. In this study, we determined the presence of ctDNA detectable actionable mutations with a clinically validated hotspot treatment indication panel in early stage TNBC patients, without local recurrence or metastatic disease at the time of evaluation. Sequencing of plasma DNA and validation of variants from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at much higher risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in NAT protocols may be identifiable by combining tissue response and sensitive ctDNA detection.
A quantitative evaluation of the impact of vaccine roll-out rate and coverage on reducing deaths from COVID-19: a counterfactual study on the impact of the delayed vaccination programme in Iran
Authors: Ghafari Mahan , Hosseinpour Sepanta , Rezaee-Zavareh Mohammad Saeid , Dascalu Stefan , Rostamian Somayeh , Aramesh Kiarash , Madani Kaveh , Kordasti Shahram 
Published: June 2023

AbstractVaccination has been a crucial factor in the fight against COVID-19 because of its effectiveness in suppressing virus circulation, lowering the risk of severe disease, and ultimately saving lives. Many countries with an early and rapid distribution of COVID-19 vaccines performed much better in reducing their total number of deaths than those with lower coverage and slower roll-out pace. However, we still do not know how many more deaths could have been averted if countries with slower vaccine roll-outs followed the same rate as countries with earlier and faster distribution of vaccines. Here, we investigated counterfactual scenarios for the number of avertable COVID-19 deaths in a given country based on other countries’ vaccine roll-out rates. As a case study, we compared Iran to eight model countries with similar income brackets and dominant COVID-19 vaccine types. Our analysis revealed that faster roll-outs were associated with higher numbers of averted deaths. While Iran’s percentage of fully vaccinated individuals would have been similar to Bangladesh, Nepal, Sri Lanka, and Turkey under counterfactual roll-out rates, adopting Turkey’s rates could have averted up to 50,000 more deaths, whereas following Bangladesh’s rates could have led to up to 52,800 additional losses of lives in Iran. Notably, a counterfactual scenario based on Argentina’s early but slow roll-out rate resulted in a smaller number of averted deaths in Iran, up to 12,600 more individuals. Following Montenegro’s or Bolivia’s model of faster per capita roll-out rates for Iran could have resulted in more averted deaths in older age groups, particularly during the Alpha and Delta waves, despite their lower overall coverage. Also, following Bahrain’s model as an upper bound benchmark, Iran could have averted 75,300 deaths throughout the pandemic, primarily in the >50 age groups. This study provides insights into future decisions on the management of infectious disease epidemics through vaccination strategies by comparing the relative performance of different countries in terms of their timing, pace, and coverage of vaccination in preventing COVID-19 deaths.
An ensemble ofGleditsia sinensis Lam. and gut microbiota against alcoholic liver disease
Authors: Oh Ki-Kwang , Yoon Sang-Jun , Lee Su-Been , Lee Sang Youn , Gupta Haripriya , Ganesan Raja , Sharma Satya Priya , Won Sung-Min , Jeong Jin-Ju , Kim Dong Joon , Suk Ki-Tae 
Published: June 2023

AbstractGleditsia sinensis Lam.(GSL) is a medicinal herb and a noticeable resource of possessing hepatic protective agents such as alcoholic liver disease (ALD). At present, it has been documented that gut microbiota (GM) is related directly to etiology of ALD. Nevertheless, the bioactive molecules in GSL, favorable GM, targets, and key mechanism(s) against ALD are yet to be revealed. Hence, we integrated the significant four components to clarify the nuanced pathogenesis with help of network pharmacology (NP) concept. We retrieved significant metabolites via gutMGene and constructed GSL or GM-Signaling pathways-Targets-Metabolites (GGSTM) networks. Finally, molecular docking test (MDT) was performed to verify the key findings. The gutMGene suggested that 16 GM and 6 metabolites were related to the two signaling pathways through GGSTM networks. Both MDT and frontier molecular orbitals (FMO) theory revealed the most stable conformers: equol fromLactobacillus paracasei JS1on IL6, Bauer-7-en-3-one, and Urs-12-en-3-one from GSL on PPARA, PPARD, and PPARG, respectively. In conclusion, this study sheds light on the combinatorial effects of GM, and GSL in treating ALD via systems biology concept.
Assessment of environmental impacts based on particulate matter, and chlorophyll content of urban trees
Authors: Abriha-Molnár Vanda Éva , Szabó Szilárd , Magura Tibor , Tóthmérész Béla , Abriha Dávid , Sipos Bianka , Simon Edina 
Published: June 2023

AbstractTrees improve air quality, and they have irreplaceable aesthetic value in urban landscapes. The amount of dust deposited on tree leaves is a simple and cost-effective indicator of air quality. Our aim was to explore particle filtering capacity of roadside trees in an urbanized area. We also assessed the impact of meteorological conditions on the amount of deposited dust. We measured the leaf surface deposition, and chlorophyll content of leaves along a road section that started at an intersection and ended in a less disturbed suburban area in Debrecen city, Hungary. Samples were collected in July, and September fromCeltis occidentalis, a frequent species. We found a significant negative correlation between dust deposition on the leaves, and the distance from the intersection in July, meaning that the amount of dust on the leaves decreased as the distance from traffic increased. In September, dust deposition decreased considerably compared to July, caused by the rainfall before the second sampling. Chlorophyll content also had a significant negative correlation with the distance from the traffic intersection in July, as it decreased towards the less disturbed end of the transect. We also found a positive correlation between dust deposition and chlorophyll content in July. Surprisingly, the exposure to moderate amounts of pollutants in the air caused an increase in chlorophyll content. Our findings suggest that dust deposition on leaves serves as a reliable indicator of traffic intensity, because excess dust caused by the proximity of car traffic can be detected on the leaf surface. Although, certain weather conditions like rainfall and wind can disrupt the patterns in dust deposition that have developed over an extended period through wash-off and resuspension. Hence, it is advisable to consider these effects while selecting the sampling time and evaluating the results.HighlightsLeaves of urban trees are used as bioindicators of deposited dust pollution.Dust deposition, and chlorophyll content was measured along a roadside transect.We found that dust and chlorophyll content decreased with distance from traffic emissions.Moderate level of dust pollution resulted in an increase in chlorophyll content.
Germinal centers are permissive to subdominant antibody responses
Authors: Robert Philippe A. , Arulraj Theinmozhi , Meyer-Hermann Michael 
Published: June 2023

AbstractA protective humoral response to pathogens requires the development of high affinity antibodies in germinal centers (GC). The combination of antigens available during immunization has a strong impact on the strength and breadth of the antibody response. Antigens can display various levels of immunogenicity, and a hierarchy of immunodominance arises when the GC response to an antigen dampens the response to other antigens. Immunodominance is a challenge for the development of vaccines to mutating viruses, and for the development of broadly neutralizing antibodies. The extent by which antigens with different levels of immunogenicity compete for the induction of high affinity antibodies and therefore contribute to immunodominance is not known. Here, we performin silicosimulations of the GC response, using a structural representation of antigens with complex surface amino acid composition and topology. We generate antigens with different levels of immunogenicity and perform simulations with combinations of these antigens. We found that GC dynamics were driven by the most immunogenic antigen and immunodominance arose as affinity maturation to less immunogenic antigens was inhibited. However, this inhibition was moderate since the less immunogenic antigen exhibited a weak GC response in the absence of other antigens. Less immunogenic antigens reduced the dominance of GC responses to more immunogenic antigens, albeit at a later time point. The simulations suggest that increased vaccine valence may decrease immunodominance of the GC response to strongly immunogenic antigens and therefore, act as a potential strategy for the natural induction of broadly neutralizing antibodies in GC reactions.
When is sympatric speciation a possible evolutionary outcome?
Authors: Venkataraman Pavithra , Saini Supreet 
Published: June 2023

AbstractThe process of speciation is the source of biodiversity. The most popularly accepted mode of speciation is allopatric speciation, where geography imposes the initial barrier to gene flow, and then biological barriers come up. On the other hand, sympatric speciation, which was not accepted as a possibility for long, requires that the process of speciation happen in the absence of a geographical barrier, in a well-mixed population. Several attempts have been made to theoretically identify the conditions in which speciation can occur in sympatry, but have several problems associated with them. We propose a model for sympatric speciation based on adaptation for resource utilization. We use this genetics- based model to investigate the relative roles of prezygotic and postzygotic barriers, from the context of ecological disruptive selection, sexual selection, and genetic architecture, in causing and maintaining sympatric speciation. We show that sexual selection that acts on secondary sexual traits does not play any role in the process of speciation in sympatry, and that assortative mating based on an ecologically relevant trait forces the population to show an adaptive response. We also demonstrate that understanding the genetic architecture of the trait under ecological selection is very important, and that it is not required for the strength of ecological disruptive selection to be very high in order for speciation to occur in sympatry. With this, we provide an insight into the kind of scenarios in which sympatric speciation can be demonstrated in lab.
Accelerometer-based predictions of behaviour elucidate factors affecting the daily activity patterns of spotted hyenas
Authors: Minasandra Pranav , Jensen Frants H. , Gersick Andrew S , Holekamp Kay E , Strauss Eli D , Strandburg-Peshkin Ariana 
Published: June 2023

AbstractAnimal activity patterns are highly variable and influenced by internal and external factors, including social processes. Quantifying activity patterns in natural settings can be challenging, as it is difficult to monitor animals over long time periods. Here, we developed and validated a machine-learning based classifier to identify behavioural states from accelerometer data of wild spotted hyenas(Crocuta crocuta), social carnivores that live in large fission-fusion societies. By combining this classifier with continuous collar-based accelerometer data from five hyenas, we generated a complete record of activity patterns over more than one month. We used these continuous behavioural sequences to investigate how past activity, individual idiosyncrasies, and social synchronisation influence hyena activity patterns. We found that hyenas exhibit characteristic crepuscular-nocturnal daily activity patterns. Time spent active was independent of activity level on previous days, suggesting that hyenas do not show activity compensation. We also found limited evidence for an effect of individual identity on activity, and showed that pairs of hyenas who spent more time together synchronised their activity patterns. This study sheds light on the patterns and drivers of activity in spotted hyena societies, and also provides a useful tool for quantifying behavioural sequences from accelerometer data.
Growth plate resting zone chondrocytes acquire transient clonal competency upon Hedgehog activation and efficiently transform into trabecular bone osteoblasts
Authors: Orikasa Shion , Matsushita Yuki , Fogge Michael , Mizuhashi Koji , Sakagami Naoko , Ono Wanida , Ono Noriaki 
Published: June 2023

AbstractThe resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP–indian hedgehog (Ihh) feedback regulation is essential for sustaining growth plate activities; however, molecular mechanisms regulating cell fates of PTHrP+resting chondrocytes and their eventual transformation into osteoblasts remain largely undefined. Here, in a mouse model, we utilized a tamoxifen-induciblePTHrP-creERline withPatched-1(Ptch1) floxed and tdTomato reporter alleles to specifically activate Hedgehog signaling in PTHrP+resting chondrocytes and trace the fate of their descendants. Hedgehog-activated PTHrP+chondrocytes formed large concentric clonally expanded cell populations within the resting zone (‘patched roses’) and generated significantly wider columns of chondrocytes, resulting in hyperplasia of the growth plate. Interestingly, Hedgehog-activated PTHrP+cell-descendants migrated away from the growth plate and eventually transformed into trabecular osteoblasts in the diaphyseal marrow space in the long term. Therefore, Hedgehog activation drives resting zone chondrocytes into transit-amplifying states as proliferating chondrocytes and eventually converts these cells into osteoblasts, unraveling a novel Hedgehog-mediated mechanism that facilitates osteogenic cell fates of PTHrP+skeletal stem cells.