bluuebunny/crossref_metadata_2025 huggingface dataset:
The Dearth of the Author: Philip Massinger and the Beaumont and Fletcher Folio
Authors: Price Eoin
Published: December 2022

In 1647, Humphrey Moseley and Humphrey Robinson published a folio collection of unpublished works which they attributed to Francis Beaumont and John Fletcher, two writers famous for their collaborations from 1606 to 1613. But in affording Beaumont a place on the title page, the publishers misattributed the volume. Scholars now accept that Beaumont had very little direct input in the collection whereas Philip Massinger, who began collaborating with Fletcher soon after Beaumont’s retirement, had a very significant, unacknowledged role in the collected plays. This essay offers the first extended discussion of why it was that Massinger was written out of this canon-defining volume. I argue first that Massinger was by many accounts a popular and vendible dramatist, whose omission from the folio had little to do with him having a poor reputation. Instead, I suggest that the reputation of the names Beaumont and Fletcher, established in the preceding decades, proved irresistible to the publishers. Furthermore, I argue that Massinger’s reputation as a distinctive solo playwright also counted against him, making it harder to apprehend him as a prolific collaborator. Next, I demonstrate how the 1647 folio participated in a process of canonization which elided Massinger’s significant collaborative contribution and discuss the distorting effect this has had on our understanding of Beaumont, Fletcher, Massinger, and playwrighting practice more broadly. I end by pointing towards some ways of rectifying the historical elision of Massinger’s collaboration with Fletcher.
RADIOLOGICAL ASSESSMENT OF NATURAL RADIOACTIVITY IN A URANIUM DEPOSIT AREA: KÖPRÜBAŞI, TÜRKIYE
Authors: Bıyık Recep , Bingöldağ Nesli , Ataksor Berna , Duhan Fatma
Published: December 2022

In this study, the results of environmental radioactivity studies conducted in Köprübaşı, Manisa district, where Türkiye’s uranium mineral exploration and processing studies were carried out, are shared. Because this is a populated area, there is a need for radio ecological dosimetry assessment to investigate the possible risk to the population. The region where radiological monitoring is carried out is discussed in two parts as the areas where uranium mineral exploration is performed and the settlements close to these areas. It was observed that 714–4714 nGy/h values were obtained in the outdoor absorbed dose rate in air measurements taken in the areas where mineral exploration was performed and this value reached up to 22 857 nGy/h in open field mining areas. In the residential areas, it was recorded that the outdoor absorbed dose rate in air values ranged between 142 and 242 nGy/h and the indoor values ranged between 171 and 400 nGy/h. The world absorbed dose rate in air average values is 57 nGy/h (outdoor) and 75 nGy/h (indoor). The high 226Ra values in the radioactivity analyses of the soil samples draw attention. The mean values of the activity concentrations of the radionuclides 226Ra, 232Th and 40K in the soil samples are 3169, 55 and 802 Bq/kg and the world averages of these values are 35, 30 and 400 Bq/kg, respectively. It was determined that high 226Ra value in the soil in the areas close to the open field uranium mining area was passed on to the agricultural products. Radioactivity measurement results of drinking water samples did not exceed World Health Organization guidelines. According to the radon gas measurement results of 44 houses in Köprübaşı villages, the average radon concentrations in winter, spring, summer and autumn seasons were 72, 61, 50 and 55 Bq/m3, and the annual average value was 60 Bq/m3, respectively. Although these values are greater than the world average of 46 Bq/m3, they are below the recommended limit value (100 Bq/m3). By evaluating the data obtained, the total annual effective equivalent dose values (originating from outdoor–indoor absorbed dose in air, drinking water and indoor radon gas concentration) to which the people in the region are exposed were calculated as a 3.12 mSv.
When is caring sharing? Primary care provider interdependence and continuity of care
Authors: Everett Christine M. , Christy Jacob , Morgan Perri A. , Docherty Sharron L. , Smith Valerie A. , Anderson John B. , Viera Anthony , Jackson George L.
Published: December 2022

Efforts to improve access to high-quality, efficient primary care have highlighted the need for team-based care. Most primary care teams are designed to maintain continuity of care between patients and primary care providers (PCPs), because continuity of care can improve some patient outcomes. However, PCPs are interdependent because they care for, or share, patients. PCP interdependence, and its association with continuity of care, is not well described. This study describes a measure of PCP interdependence. We also evaluate the association between patient and panel characteristics, including PCP interdependence. Our results found that the extent of interdependence between PCPs in the same clinic varies widely. A range of patient and panel characteristics affect continuity of care, including patient complexity and PCP interdependence. These results suggest that continuity of care for complex patients is sensitive to panel characteristics, including PCP interdependence and panel size. This information can be used by primary care organizations for evidence-based team design.
Identifying Meaningful Patterns of Internal Medicine Clerkship Grading Distributions: Application of Data Science Techniques Across 135 U.S. Medical Schools
Authors: Burk-Rafel Jesse , Reinstein Ilan , Park Yoon Soo
Published: December 2022

Problem

Residency program directors use clerkship grades for high-stakes selection decisions despite substantial variability in grading systems and distributions. The authors apply clustering techniques from data science to identify groups of schools for which grading distributions were statistically similar in the internal medicine clerkship.

Approach

Grading systems (e.g., honors/pass/fail) and distributions (i.e., percent of students in each grade tier) were tabulated for the internal medicine clerkship at U.S. MD-granting medical schools by manually reviewing Medical Student Performance Evaluations (MSPEs) in the 2019 and 2020 residency application cycles. Grading distributions were analyzed using k-means cluster analysis, with the optimal number of clusters selected using model fit indices.

Outcomes

Among the 145 medical schools with available MSPE data, 64 distinct grading systems were reported. Among the 135 schools reporting a grading distribution, the median percent of students receiving the highest and lowest tier grade was 32% (range: 2%–66%) and 2% (range: 0%–91%), respectively. Four clusters was the most optimal solution (η2 = 0.8): cluster 1 (45% [highest grade tier]–45% [middle tier]–10% [lowest tier], n = 64 [47%] schools), cluster 2 (25%–30%–45%, n = 40 [30%] schools), cluster 3 (20%–75%–5%, n = 25 [19%] schools), and cluster 4 (15%–25%–25%–25%–10%, n = 6 [4%] schools). The findings suggest internal medicine clerkship grading systems may be more comparable across institutions than previously thought.

Next Steps

The authors will prospectively review reported clerkship grading approaches across additional specialties and are conducting a mixed-methods analysis, incorporating a sequential explanatory model, to interview stakeholder groups on the use of the patterns identified.
Advances in antibody-drug conjugates for gynecologic malignancies
Authors: Tymon-Rosario Joan , Gorman Megan , Richardson Debra L. , Washington Christina , Santin Alessandro D.
Published: December 2022

Purpose of review

Antibody-drug conjugates (ADCs) represent a new class of drugs that combine a surface receptor-targeting antibody linked to a cytotoxic molecule delivering the potent cytotoxic payload directly to tumor cells. This review summarizes the current literature demonstrating their use in the treatment of gynecologic malignancies.

Recent findings

Tisotumab vedotin is the first U.S. Food and Drug Administration (FDA) approved ADC for the treatment of gynecologic cancers. While in the phase 3 randomized controlled trial in platinum resistant ovarian cancer patients, FORWARD 1, mirvetuximab did not meet its primary endpoint of progression-free survival. But we await more recent data from the two ongoing phase 3 trials of mirvetuximab in recurrent ovarian cancer patients. HER2/neu, Napi2b, mesothelin, and human trophoblast cell-surface marker (Trop-2) overexpression have also been exploited as excellent targets by novel ADCs in multiple tumors including ovarian, endometrial, and cervical cancers.

Current evidence strongly supports the use of ADCs and ongoing clinical trials will provide further information into the potential of making these drugs part of current standard practice allowing patients to be treated with a higher level of personalized cancer care.
Cataract surgery and the risk of progression of macular degeneration
Authors: Bhandari Sanjeeb , Chew Emily Y.
Published: December 2022

Purpose of review

Cataract surgery improves vision loss due to cataracts in eyes with co-existing age-related macular degeneration (AMD), but whether surgery itself pose an increased risk for the progression of AMD has been of concern to both physicians and their patients. This review describes evidence on cataract surgery and its impact on the progression of AMD.

Recent findings

Recent evidence suggests that cataract surgery does not increase the risk for progression of AMD.

Cataract surgery should be discussed in patients with both AMD and visually significant cataract. Patients should be reassured that the cataract surgery will not increase the risk of AMD progression. In patients with AMD, especially those with the more severe intermediate stage and those with advanced AMD in the fellow eye, the natural course of progression to late AMD is high. The importance of vigilant follow-up needs to be emphasized for the detection of natural progression of the disease and early initiation of treatment should signs of neovascularization develop.
Epicardial atherosclerosis and coronary tortuosity in patients with acetylcholine-induced coronary spasm
Authors: McChord Johanna , Gollwitzer Robert , Seitz Andreas , Sechtem Udo , Bekeredjian Raffi , Ong Peter
Published: December 2022

Background

Angina pectoris in the absence of relevant epicardial stenoses is frequently caused by coronary spasm. This mechanism of angina is common yet underdiagnosed in daily clinical practice. The pathophysiology of coronary spasm is complex, multifactorial, and not completely understood. The purpose of this study was to analyze the relationship between macroscopic coronary morphologies and coronary spasm.

Methods

Epicardial atherosclerosis, coronary vessel tortuosity, coronary aneurysms, and myocardial bridges were analyzed angiographically in 610 patients and a potential association with the result of an intracoronary acetylcholine (ACh) provocation test was investigated.

Results

The comparison showed that angiographic morphologic variations in the coronary arteries are related to the occurrence of coronary spasm. We observed a strong association between the presence of epicardial atherosclerosis and epicardial spasm [87 patients of 179 with epicardial spasm had epicardial atherosclerosis (49%) vs. 45 patients of 172 with microvascular spasm (26%) vs. 89 patients of 259 with negative/inconclusive ACh test (36%); P < 0.005]. Moreover, we found a higher frequency of coronary tortuosity in patients with microvascular spasm [99 patients of 172 with microvascular spasm had at least moderate coronary tortuosity (58%) vs. 76 patients of 179 with epicardial spasm (43%) vs. 126 patients of 259 with negative/inconclusive ACh test (49%); P = 0.017]. Multivariable analysis revealed epicardial atherosclerosis (<50% stenosis) on coronary angiography as a predictor for epicardial spasm (OR, 2.096; 95% CI, 1.467–2.995; P < 0.0005). Female sex (OR, 5.469; 95% CI, 3.433–8.713; P < 0.0005), and exertional angina (OR, 2.411; 95% CI, 1.597–3.639; P < 0.0005) were predictors of microvascular spasm in multivariable analysis.

Conclusion

In angina patients with no obstructive coronary artery disease, epicardial atherosclerosis is associated with ACh-induced epicardial coronary spasm. Moreover, coronary microvascular spasm is more prevalent in female patients and those with exertional angina. Our results provide insights into the relationship between coronary morphology and coronary vasomotor function.
Everolimus-eluting bioresorbable scaffold versus everolimus-eluting metallic stent in primary percutaneous coronary intervention of ST-segment elevation myocardial infarction: a randomized controlled trial
Authors: Eriksen Erlend , Neghabat Omeed , Saeed Sahrai , Herstad Jon , Nordrehaug Jan Erik , Tuseth Vegard , Holm Niels Ramsing , Holck Emil Nielsen , Sejr-Hansen Martin , Maule Camilla Fox , Barkholt Trine Ørhøj , Andreasen Lene Nyhus , Christiansen Evald Høj , Bleie Øyvind
Published: December 2022

Background

Primary percutaneous coronary intervention with implantation of a metallic drug-eluting stent (DES) is the standard treatment for patients presenting with ST-elevation myocardial infarction (STEMI). Implantation of a bioresorbable scaffold (BRS) during STEMI represents a novel strategy without intravascular metal.

Objective

The aim of the study was to investigate 12-month healing response in an STEMI population after implantation of either the Absorb BRS or Xience DES (Abbott Vascular, USA).

Methods

The present trial was a prospective, randomized, controlled, nonblinded, noninferiority study with planned inclusion of 120 patients with STEMI. Patients were randomly assigned 1:1 to treatment with Absorb BRS or Xience DES. Implantation result and healing response were evaluated by angiography and optical coherence tomography (OCT) at baseline and 12-month follow-up. The primary endpoint was minimum flow area (MFA) assessed at 12 months. Coronary stent healing index (CSHI) was calculated from OCT images.

Results

Out of 66 included patients, 58 had follow-up OCT after 12 months, and 49 entered matched analysis. One death occurred in each group; none were stent-related. MFA was 5.13 ± 1.70 mm2 (95% CI, 4.44–5.82) in the BRS group compared with 6.30 ± 2.49 mm2 (95% CI, 5.22–7.37) (P = 0.06) in the DES group. Noninferiority could not be evaluated. CSHI for both groups had a median score of 3.

Conclusion

The DES group performed numerically better in primary and secondary endpoints, but the CSHI showed good stent healing in both groups.
Validity and feasibility of the global leadership initiative on malnutrition diagnostic concept in older people: a literature review from August 2021 to August 2022
Authors: Cederholm Tommy , Barazzoni Rocco
Published: December 2022

Purpose of review

Early 2019, the Global Leadership Initiative on Malnutrition (GLIM) concept offered a clinically applicable and objective procedure for diagnosing malnutrition. This review summarizes 40 publications from August 2021 to August 2022 that applied the GLIM criteria in older populations from various clinical settings for criterion and predictive validation.

Recent findings

Criterion validity studies, by comparing the GLIM construct with various semi-gold standards such as SGA, PG-SGA, MNA-FF/SF and ESPEN criteria, indicate by sensitivity, specificity and agreement that GLIM performs at least as well as the other tools to capture malnutrition. One meta-analysis of 20 studies with various comparators reports high accuracy for distinguishing malnutrition. GLIM-malnutrition prevalence figures vary with screening tool. Predictive validity of GLIM for mortality, and other outcomes, is good in all settings reported. Sarcopenia and GLIM show some expected overlapping.

In populations more than 60 years old, the GLIM construct appears to have well acceptable criterion validity as well as predictive validity. The continuous implementation of the GLIM concept is justified.
Scientific Advances and Technical Innovations in Musculoskeletal Radiology
Authors: Fritz Jan , Runge Val M.
Published: December 2022

Decades of technical innovations have propelled musculoskeletal radiology through an astonishing evolution. New artificial intelligence and deep learning methods capitalize on many past innovations in magnetic resonance imaging (MRI) to reach unprecedented speed, image quality, and new contrasts. Similarly exciting developments in computed tomography (CT) include clinically applicable molecular specificity and substantially improved spatial resolution of musculoskeletal structures and diseases. This special issue of Investigative Radiology comprises a collection of expert summaries and reviews on the most impactful innovations and cutting-edge topics in musculoskeletal radiology, including radiomics and deep learning methods for musculoskeletal disease detection, high-resolution MR neurography, deep learning–driven ultra-fast musculoskeletal MRI, MRI-based synthetic CT, quantitative MRI, modern low-field MRI, 7.0 T MRI, dual-energy CT, cone beam CT, kinematic CT, and synthetic contrast generation in musculoskeletal MRI.
Deriving calibrations for Arawakan using archaeological evidence
Authors: Michael Lev , de Carvalho Fernando , Chacon Thiago , Rybka Konrad , Sabogal Andrés , Chousou-Polydouri Natalia , Kaiping Gereon
Published: December 2022

This paper identifies time calibration points for accurately rooting and dating the phylogeny of Arawakan, the largest Indigenous linguistic family of the Americas. We present and model a methodology for extracting calibration points from the archaeological record, based on principles of geographical overlap between archaeological sites and Arawakan peoples, and on continuity in material culture between archaeological finds and modern Arawakan practices. Based on a consensus model of the expansion of the Arawakan family from Central Amazonia, we focus on archaeological finds in Arawakan expansion zones, where Arawakan material culture abruptly appears in a given region, and where only a single major Arawakan subgroup/clade is present. We find 12 calibration points from archaeological sites in Arawakan expansion zones and also identify more recent calibration points from the historical record based on first mentions of ethnonyms and early sources of lexical data.
Student-led Public Engagement Event: Increasing Audience Diversity and Impact in a Non-Science Space
Authors: Lacey Melissa , Capper-Parkin Kelly , Schwartz-Narbonne Rachel , Hargreaves Kate , Higham Catherine , Duckett Catherine , Forbes Sarah , Rawlinson Katherine
Published: December 2022

There is a wealth of innovation in microbiology outreach events globally, including in the setting where the public engagement is hosted. Previous data indicates underrepresentation of marginalised ethnic groups attending UK science-based public engagement events. This project engaged our student cohort, encompassing a diverse range of ethnic groups, to create an integrated art and science event within an existing series of adult education evenings. The study’s objectives were to increase the proportion of visitors from marginalised ethnic groups and to gain a greater understanding of the impact of the event on the visitors’ reported science capital. The participants' demographics, links to our students and University, and detailed impact on participants' science capital of the event were determined through analysis of exit questionnaires. There was an increase in the proportion of marginalised ethnic group visitors compared to similar previous events. A higher proportion of visitors from marginalised ethnic groups had links with our students and University compared to white/white British visitors. Elements of the exit-questionnaire were mapped to the science capital framework and participants' science capital determined. Both ethnically marginalised participants and white/white British visitors showed an increase in science capital, specifically dimensions of science-related social capital and science-related cultural capital, after the event. In conclusion, our study suggests that a student-led blended art and science public engagement can increase the ethnic diversity of those attending and can contribute towards creating more inclusive public engagement events.
Large-scale changes of molecular network states explain complex traits
Authors: Weith Matthias , Großbach Jan , Clement-Ziza Mathieu , Gillet Ludovic , Rodríguez-López María , Marguerat Samuel , Workman Christopher T. , Picotti Paola , Bähler Jürg , Aebersold Ruedi , Beyer Andreas
Published: December 2022

The complexity of many cellular and organismal traits results from poorly understood mechanisms integrating genetic and environmental factorsviamolecular networks. Here, we show when and how genetic perturbations lead to molecular changes that are confined to small parts of a networkversuswhen they lead to large-scale adaptations of global network states. Integrating multi-omics profiling of genetically heterogeneous budding and fission yeast strains with an array of cellular traits identified a central state transition of the yeast molecular network that is related to PKA and TOR (PT) signaling. Genetic variants affecting this PT state globally shifted the molecular network along a single-dimensional axis, thereby modulating processes including energy- and amino acid metabolism, transcription, translation, cell cycle control and cellular stress response. We propose that genetic effects can propagate through large parts of molecular networks because of the functional requirement to centrally coordinate the activity of fundamental cellular processes.

Graphical abstract

Graphical abstract:

Genetic variants directly or indirectly affecting the activity of PKA and/or TOR signaling cause global changes of transcriptomic and proteomic network states by modulating the activity of diverse cellular functions and network modules. Using marker genes acting downstream of PKA and TOR signaling we are able to quantify the activity status of combined PKA and TOR signaling (‘PT Score’). This PT Score correlates with major transcriptomic and proteomic changes in response to genetic variability. Those large-scale molecular adaptations correlate with and explain phenotypic consequences for multiple cellular traits. Variants affecting the stoichiometry of proteins within a specific module have regional effects that remain confined to smaller parts of the molecular network. Variants affecting only one or very few proteins change molecular networks only locally. The global reorganization of network states caused by variants of the first type result in consequences for many cellular traits (i.e. pleiotropic effects), such as growth on different carbon sources, stress response, energy metabolism and replicative lifespan. (Created withBioRender.com)
BCLncRDB: A comprehensive database of LncRNAs associated with breast cancer
Authors: Kumar Swapnil , Agarwal Avantika , Vindal Vaibhav
Published: December 2022

Motivation

Breast cancer, the most common cancer in women, is characterized by high morbidity and mortality worldwide. Recent evidence has shown that long non-coding RNAs (lncRNAs) play a crucial role in the development and progression of breast cancer. Despite this, no database exists primarily for lncRNAs associated with only breast cancer.

Results

We developed BCLncRDB, a manually curated, comprehensive database of lncRNAs associated with breast cancer. For this, we collected, processed, and analyzed data on breast cancer-associated lncRNAs from different sources, including published literature and TCGA. Currently, our database contains 5,279 unique breast cancer-lncRNA associations. It has the following features: (I) Differentially expressed and methylated lncRNAs, (II) Stage and subtype-specific lncRNAs, and (III) Drugs, Subcellular localization, Sequence, and Chromosome information. Thus, the BCLncRDB provides a dedicated platform for exploring breast cancer-related lncRNAs to advance and support the ongoing research on this disease.

Availability and implementation

The database BCLncRDB is publicly available for use athttp://sls.uohyd.ac.in/new/bclncrdb.

Contact

vaibhav@uohyd.ac.in
Fungal traits help to understand the decomposition of simple and complex plant litter
Authors: Leifheit Eva F. , Camenzind Tessa , Lehmann Anika , Andrade-Linares Diana R. , Fussan Max , Westhusen Sophia , Wineberger Till M. , Rillig Matthias C.
Published: December 2022

Litter decomposition is a key ecosystem process, responsible for the release and storage of nutrients and carbon. Soil fungi are one of the dominant drivers of organic matter decomposition, but fungal taxa differ substantially in their functional ability to decompose plant litter. We used a trait-based approach to better understand functional differences among saprotrophic soil fungi (originating from a natural grassland ecosystem) in decomposing leaf and wood litter. Decomposition strongly varied among phyla and isolates, with Ascomycota decomposing the most and Mucoromycota decomposing the least. In this study, the phylogeny of the fungi in our dataset, but also the ability of fungi to use more complex carbon were important predictors for decomposition. While some enzymes (e.g. laccase and cellulase) influenced decomposition, the majority of enzyme activities was not correlated with decomposition. Thus, we suggest using more directly assessed traits as predictors for decomposition, such as the ability to use carbon substrates, rather than a single enzyme activity, which could misrepresent the degradation potential of certain isolates. The findings of our study offer important new insights for the trait-based prediction of fungal litter decomposition in grassland soils.
Structural diversity and stress regulation of the plant immunity-associated CALMODULIN-BINDING PROTEIN 60 (CBP60) family of transcription factors inSolanum lycopersicum(tomato)
Authors: Shivnauth Vanessa , Pretheepkumar Sonya , Marchetta Eric , Amani Keaun , Castroverde Christian Danve M.
Published: December 2022

Cellular signalling generates calcium (Ca2+) ions, which are ubiquitous secondary messengers decoded by calcium-dependent protein kinases, calcineurins, calreticulin, calmodulins (CAMs) and CAM-binding proteins. Previous studies in the model plantArabidopsis thalianahave shown the critical roles of the CAM-BINDING PROTEIN 60 (CBP60) protein family in plant growth, stress responses and immunity. Certain CBP60 factors can regulate plant immune responses, like pattern-triggered immunity, effector-triggered immunity, and synthesis of major plant immune-activating metabolites salicylic acid (SA) and N-hydroxypipecolic acid (NHP). Although homologous CBP60 sequences have been identified in the plant kingdom, their function and regulation in most species remain unclear. In this paper, we specifically characterized 11 members of the CBP60 family in the agriculturally important crop tomato (Solanum lycopersicum). Protein sequence analyses revealed that three CBP60 homologs have the closest amino acid identity toArabidopsisCBP60g and SARD1, master transcription factors involved in plant immunity. Strikingly, AlphaFold deep learning-assisted prediction of protein structures highlighted close structural similarity between these tomato andArabidopsisCBP60 homologs. Conserved domain analyses revealed that they possess CAM-binding domains and DNA-binding domains, reflecting their potential involvement in linking Ca2+signalling and transcriptional regulation in tomato plants. In terms of their gene expression profiles under biotic (Pseudomonas syringaepv.tomatoDC3000 pathogen infection) and/or abiotic stress (warming temperatures), five tomatoCBP60genes were pathogen-responsive and temperature-sensitive, reminiscent ofArabidopsis CBP60gandSARD1. Overall, we present a genome-wide identification of the CBP60 gene/protein family in tomato plants, and we provide evidence on their regulation and potential function as Ca2+-sensing transcriptional regulators.
Structural pre-training improves physical accuracy of antibody structure prediction using deep learning
Authors: Kończak Jarosław , Janusz Bartosz , Młokosiewicz Jakub , Satława Tadeusz , Wróbel Sonia , Dudzic Paweł , Krawczyk Konrad
Published: December 2022

Protein folding problem obtained a practical solution recently, owing to advances in deep learning. There are classes of proteins though, such as antibodies, that are structurally unique, where the general solution still lacks. In particular, the prediction of the CDR-H3 loop, which is an instrumental part of an antibody in its antigen recognition abilities, remains a challenge. Antibody-specific deep learning frameworks were proposed to tackle this problem noting great progress, both on accuracy and speed fronts. Oftentimes though, the original networks produce physically implausible bond geometries that then need to undergo a time-consuming energy minimization process. Here we hypothesized that pre-training the network on a large, augmented set of models with correct physical geometries, rather than a small set of real antibody X-ray structures, would allow the network to learn better bond geometries. We show that fine-tuning such a pre-trained network on a task of shape prediction on real X-ray structures improves the number of correct peptide bond distances. We further demonstrate that pre-training allows the network to produce physically plausible shapes on an artificial set of CDR-H3s, showing the ability to generalize to the vast antibody sequence space. We hope that our strategy will benefit the development of deep learning antibody models that rapidly generate physically plausible geometries, without the burden of time-consuming energy minimization.
Differentiation and admixture ofFagus sylvaticaL. andFagus orientalisLipsky in a northern German forest — learning from pioneer forest work
Authors: Budde Katharina Birgit , Hötzel Sophie , Müller Markus , Samsonidze Natia , Papageorgiou Aristotelis C. , Gailing Oliver
Published: December 2022

Tree species are suffering from changing and stressful environmental conditions worldwide.Fagus sylvaticaL., one of the most common Central European deciduous tree species showed symptoms of crown damage, a reduction in growth and increased mortality following the severe recent drought years. For GermanyFagus orientalisLipsky, a closely related species with higher drought tolerance, originating from south-eastern Europe, Turkey, the Greater Caucasus region and the Hyrcanian forest, has been proposed as an alternative with high future potential. The translocation of pre-adapted planting material has been proposed as a tool to mitigate negative effects of climate change. This approach can be beneficial but might also harbor risks. Taking advantage ofF. orientalistrees planted over 100 years ago in the forest district of Memsen, Germany, we set out to study admixture between the two beech species and the direction of gene flow. Furthermore, we used a range-wide dataset ofF. sylvaticaandF. orientalisprovenances to determine the origin of the introduced trees. Using a combination of nuclear EST-SSRs and one chloroplast SSR marker with species-specific variants, we could show that interspecific gene flow was going in both directions. In most cases,F. sylvaticawas the pollen donor which is likely explained by the higher abundance of this species producing vast amounts of pollen. The planted trees originated from the Greater Caucasus region and showed strong genetic divergence from GermanF. sylvaticapopulations. In the future, gene flow patterns as well as hybrid performance from different provenances should be tested in additional stands and in comparison toF. sylvaticaprovenances from southern Europe to assess the suitability of Oriental beech for the mitigation of climate change impacts.
Heating tolerance of ectotherms is explained by temperature’s non-linear influence on biological rates
Authors: Kong Jacinta D. , Arnoldi Jean-Francois , Jackson Andrew L. , Bates Amanda E. , Morley Simon A. , Smith James A. , Payne Nicholas L.
Published: December 2022

The capacity of ectotherms to adjust their thermal tolerance limits through evolution or acclimation seems relatively modest and highly variable, and we lack satisfying explanations for both findings given a limited understanding of what ultimately determines an organism’s thermal tolerance. Here, we test if the amount of heating an ectotherm tolerates throughout a heating event until organismal failure scales with temperature’s non-linear influence on biological rates. To account for the non-linear influence of temperature on biological rates on heating tolerance, we rescaled the duration of heating events of 316 ectothermic taxa acclimated to different temperatures and describe the biological rate-corrected heating duration. This rescaling reveals that the capacity of an organism to resist a heating event is in fact remarkably constant across any acclimation temperature, enabling high-precision estimates of how organismal thermal tolerance limits vary under different thermal regimes. We also find that faster heating consistently reduces biological rate-corrected heating durations, which helps further explain why thermal tolerance limits seem so variable on absolute temperature scales. Existing paradigms are that heating tolerances and thermal tolerance limits reflect incomplete metabolic compensatory responses, are constrained by evolutionary conservatism, or index failure of systems such as membrane function; our data provide a different perspective and show that an organism’s thermal tolerance emerges from the interaction between the non-linear thermal dependence of biological rates and heating durations, which is an approximately-fixed property of a species.
Towards the integrative theory of Alzheimer’s disease: linking molecular mechanisms of neurotoxicity, beta-amyloid biomarkers, and the diagnosis
Authors: Molkov Yaroslav I. , Zaretskaia Maria V. , Zaretsky Dmitry V. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2022

A major gap in amyloid-centric theories of Alzheimer’s disease (AD) is that even though amyloid fibrilsper seare not toxicin vitro, the diagnosis of AD clearly correlates with the density of beta-amyloid (Aβ) deposits. Based on our proposed amyloid degradation toxicity hypothesis, we developed a mathematical model explaining this discrepancy. It suggests that cytotoxicity depends on the cellular uptake of soluble Aβ rather than on the presence of amyloid aggregates. The dynamics of soluble Aβ in the cerebrospinal fluid (CSF) and the density of Aβ deposits is described using a system of differential equations. In the model, cytotoxic damage is proportional to the cellular uptake of Aβ, while the probability of an AD diagnosis is defined by the Aβ cytotoxicity accumulated over the duration of the disease. After uptake, Aβ is concentrated intralysosomally, promoting the formation of fibrillation seeds inside cells. These seeds cannot be digested and are either accumulated intracellularly or exocytosed. Aβ starts aggregating on the extracellular seeds and, therefore, its concentration decreases in the interstitial fluid. The dependence of both Aβ toxicity and aggregation on the same process – cellular uptake of Aβ – explains the correlation between AD diagnosis and the density of amyloid aggregates in the brain.

We tested the model using clinical data obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which included records of beta-amyloid concentration in the cerebrospinal fluid (CSF-Aβ42) and the density of beta-amyloid deposits measured using positron emission tomography (PET). The model predicts the probability of AD diagnosis as a function of CSF-Aβ42 and PET and fits the experimental data at the 95% confidence level.

Our study shows that existing clinical data allows for the inference of kinetic parameters describing beta-amyloid turnover and disease progression. Each combination of CSF-Aβ42 and PET values can be used to calculate the individual’s cellular uptake rate, the effective disease duration, and the accumulated toxicity. We show that natural limitations on these parameters explain the characteristic distribution of the clinical dataset for these two biomarkers in the population.

The resulting mathematical model interprets the positive correlation between the density of Aβ deposits and the probability of an AD diagnosis without assuming any cytotoxicity of the aggregated beta-amyloid. Finally, to the best of our knowledge, this model is the first to mechanistically explain the negative correlation between the concentration of Aβ42 in the CSF and the probability of an AD diagnosis.
NAPS: Integrating pose estimation and tag-based tracking
Authors: Wolf Scott W. , Ruttenberg Dee M. , Knapp Daniel Y. , Webb Andrew E. , Traniello Ian M. , McKenzie-Smith Grace C. , Leheny Sophie A. , Shaevitz Joshua W. , Kocher Sarah D.
Published: December 2022

Significant advances in computational ethology have allowed the quantification of behavior in unprecedented detail. Tracking animals in social groups, however, remains challenging as most existing methods can either capture pose or robustly retain individual identity over time but not both. To capture finely resolved behaviors while maintaining individual identity, we built NAPS (NAPS is ArUco Plus SLEAP), a hybrid tracking framework that combines state-of-the-art, deep learning-based methods for pose estimation (SLEAP) with unique markers for identity persistence (ArUco). We show that this framework allows the exploration of the social dynamics of the common eastern bumblebee (Bombus impatiens). We provide a stand-alone Python package for implementing this framework along with detailed documentation to allow for easy utilization and expansion. We show that NAPS can scale to long timescale experiments at a high frame rate and that it enables the investigation of detailed behavioral variation within individuals in a group. Expanding the toolkit for capturing the constituent behaviors of social groups is essential for understanding the structure and dynamics of social networks. NAPS provides a key tool for capturing these behaviors and can provide critical data for understanding how individual variation influences collective dynamics.
Functional characterization of cytochrome P450s associated with pyrethroid resistance in the olive fruit flyBactrocera oleae
Authors: Kampouraki Anastasia , Tsakireli Dimitra , Koidou Venetia , Stavrakaki Marianna , Kaili Stavroula , Livadaras Yannis , Grigoraki Linda , Ioannidis Panagiotis , Roditakis Emmanouil , Vontas John
Published: December 2022

Resistance to pyrethroid insecticides has evolved inBactrocera oleaepopulations in Greece, threatening the efficacy of control interventions based on this insecticide class. Here we report the collection of populations from Crete with resistance levels reaching up to 331-folds, compared to susceptible laboratory strains and show that pyrethroid resistance is substantially suppressed by the PBO synergist, suggesting the involvement of detoxification enzymes. To identify specific candidate genes implicated in resistance, we performed comparative transcriptomic analysis, between the pyrethroid resistant populations from Crete and the susceptible laboratory strains, using both whole bodies and Malpighian tubules. Several genes were found differentially transcribed between resistant and susceptible flies in each comparison, with P450s being among the most highly over-expressed detoxification genes in pyrethroid resistant populations. Four of the over-expressed P450s (Cyp6A61, Cyp6G6, Cyp4P6andCyp6G28) were recombinantly expressed inEscherichia coliandin vitrometabolism assays revealed that CYP6A61 is capable of metabolizing alpha-cypermethrin, while CYP6G6, CYP4P6 and CYP6G28 are capable of metabolizing deltamethrin. No metabolism of neonicotinoid insecticides was recorded. We further silencedCYP6G6 in vivo, via RNAi, which led to a small, but significant increase in deltamethrin toxicity. The study provides valuable information towards the development of molecular diagnostics and evidence-based insecticide resistance management strategies.
Telomerase Reverse Transcriptase Enzyme (hTERT) expression in bronchial mucosa inversely correlates with the severity of airway obstruction in patients with chronic airway obstructive diseases
Authors: Moermans C. , Medard L. , Graff S. , Njock MS. , Bougard N. , Schleich F. , Guiot J. , Corhay J-L. , Louis R.
Published: December 2022

Rationale

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are the two main chronic airway inflammatory diseases related to aging. Cellular aging is prevented by telomeres and their shortening induces cellular senescence. Human Telomerase Reverse Transcriptase Enzyme (hTERT) can act directly on DNA and prevent telomere shortening. The goal of this study was to assess hTERT expression in the bronchial mucosa of patients suffering from chronic airway obstructive diseases and to relate the hTERT expression to demographics and lung function characteristics.

Methods

We collected bronchial biopsies from 38 patients suffering from chronic airway diseases including 21 severe asthmatics and 17 COPD who underwent bronchoscopy in routine practice. hTERT expression was assessed by immunochemistry and co-immunostaining was performed to identify hTERT positive cells within the different immune cell populations.

Results

hTERT expression in airway mucosa was essentially found in structural cells. Among leukocytes, lymphocytes were the principal cells expressing hTERT. On the whole cohort, hTERT expression score was not different between men and women and not influenced by the age nor by the smoking history as reflected by the pack years. Total airway hTERT positive staining score positively correlated with post-bronchodilation (post-BD) FEV1% predicted and FEV1/FVC. (r=0.38, p<0.05 for both). hTERT+ lymphocytes were also positively correlated to post-BD FEV1/FVC (r=0.37, p<0.05). Consequently, hTERT expression was lower in those patients with fixed airway obstruction (post-BD FEV1/FVC < 70%). There was no difference between asthmatics and COPD.

Conclusions

In patients with chronic airway diseases, total and lymphocyte hTERT expressions inversely correlate with the degree of airway obstruction and are reduced in patients with fixed airway obstruction, which supports a role of hTERT in airway remodeling.
Selection bias as an explanation for the observed protective association of childhood adiposity with breast cancer
Authors: Schooling C M , Fei K , Zhao J V
Published: December 2022

Objective

Recalled childhood adiposity is inversely associated with breast cancer observationally, including in Mendelian randomization (MR) studies, questioning its role. Breast cancer studies recruited in adulthood only include survivors of childhood adiposity and breast cancer. We assessed recalled childhood adiposity on participant reported sibling and maternal breast cancer to ensure ascertainment of non-survivors using MR.

Study Design and Setting

We obtained independent strong genetic predictors of recalled childhood adiposity for women and their associations with participant reported own, sibling and maternal breast cancer from UK Biobank genome wide association studies (GWAS). We obtained MR inverse variance weighting estimates.

Results

Childhood adiposity in women was inversely associated with own breast cancer (odds ratio (OR) 0.66, 95% confidence interval (CI) 0.52 to 0.84) but unrelated to participant reported sibling (OR 0.85, 95% CI 0.60 to 1.20) or maternal breast cancer (OR 0.84, 95% CI 0.67 to 1.05 respectively).

Conclusion

Weaker inverse associations of recalled childhood adiposity with breast cancer with more comprehensive ascertainment of cases before recruitment suggests the inverse association of recalled childhood adiposity with breast cancer is due to selection bias arising from preferential selection of survivors. Greater consideration of left truncation in public health relevant causal inferences is warranted.

Highlights

Recalled childhood adiposity is inversely associated with breast cancer.

Studies of childhood exposures recruited in adulthood are open to left truncation.

Participant reports about family members include deaths before recruitment.

We tested childhood adiposity on sibling breast cancer using Mendelian randomization.

Childhood adiposity with sibling breast cancer was null, suggesting left truncation.
Therapeutic administration of mouse mast cell protease 6 improves functional recovery after traumatic spinal cord injury in mice by promoting remyelination and reducing glial scar formation
Authors: Vangansewinkel Tim , Lemmens Stefanie , Tiane Assia , Geurts Nathalie , Dooley Dearbhaile , Vanmierlo Tim , Pejler Gunnar , Hendrix Sven
Published: December 2022

Traumatic spinal cord injury (SCI) most often leads to permanent paralysis due to the inability of axons to regenerate in the adult mammalian central nervous system (CNS). In the past, we have shown that mast cells (MCs) improve the functional outcome after SCI by suppressing scar tissue formation at the lesion site via mouse mast cell protease 6 (mMCP6). In this study, we investigated whether recombinant mMCP6 can be used therapeutically to improve the functional outcome after SCI. Therefore, we applied mMCP6 locally via an intrathecal catheter in the subacute phase after a spinal cord hemisection injury in mice. Our findings showed that hind limb motor function was significantly improved in mice that received recombinant mMCP6 compared to the vehicle-treated group. In contrast to our previous findings in mMCP6 knockout mice, the lesion size and expression levels of the scar components fibronectin, laminin, and axon-growth-inhibitory chondroitin sulfate proteoglycans were not affected by the treatment with recombinant mMCP6. Surprisingly, no difference in infiltration of CD4+ T cells and reactivity of Iba-1+ microglia/macrophages at the lesion site was observed between the mMCP6-treated mice and control mice. Additionally, local protein levels of the pro- and anti-inflammatory mediators IL-1β, IL-2, IL-4, IL-6, IL-10, TNF-α, IFNγ, and MCP-1 were comparable between the two treatment groups, indicating that locally applied mMCP6 did not affect inflammatory processes after injury. However, the increase in locomotor performance in mMCP6-treated mice was accompanied by reduced demyelination and astrogliosis in the perilesional area after SCI. Consistently, we found that TNF-a/IL-1B-astrocyte activation was decreased, and that oligodendrocyte precursor cell (OPC) differentiation was increased after recombinant mMCP6 treatmentin vitro. Mechanistically, this suggests effects of mMCP6 on reducing astrogliosis and improving (re)myelination in the spinal cord after injury. In conclusion, these data show for the first time that recombinant mMCP6 is therapeutically active in enhancing recovery after SCI.