bluuebunny/crossref_metadata_2025 huggingface dataset:
The Need to Update Endpoints and Outcome Analysis in the Rapidly Changing Field of Liver Transplantation
Authors: Fodor Margot , Zoller Heinz , Oberhuber Rupert , Sucher Robert , Seehofer Daniel , Cillo Umberto , Line Pal Dag , Tilg Herbert , Schneeberger Stefan
Published: November 2021

Liver transplantation (LT) survival rates have continued to improve over the last decades, mostly due to the reduction of mortality early after transplantation. The advancement is facilitating a liberalization of access to LT, with more patients with higher risk profiles being added to the waiting list. At the same time, the persisting organ shortage fosters strategies to rescue organs of high-risk donors. This is facilitated by novel technologies such as machine perfusion. Owing to these developments, reconsideration of the current and emerging endpoints for the assessment of the efficacy of existing and new therapies is warranted. While conventional early endpoints in LT have focused on the damage induced to the parenchyma, the fate of the bile duct and the recurrence of the underlying disease have a stronger impact on the long-term outcome. In light of this evolving landscape, we here attempt to reflect on the appropriateness of the currently used endpoints in the field of LT trials.
The RECOVAC Immune-response Study: The Immunogenicity, Tolerability, and Safety of COVID-19 Vaccination in Patients With Chronic Kidney Disease, on Dialysis, or Living With a Kidney Transplant
Authors: Sanders Jan-Stephan F. , Bemelman Frederike J. , Messchendorp A. Lianne , Baan Carla C. , van Baarle Debbie , van Binnendijk Rob , Diavatopoulos Dimitri A. , Frölke Sophie C. , Geers Daryl , GeurtsvanKessel Corine H. , den Hartog Gerco , van der Heiden Marieke , Imhof Celine , Kho Marcia M.L. , Koopmans Marion P.G. , Malahe S. Reshwan K. , Mattheussens Wouter B. , van der Molen Renate , van Mourik Djenolan , Remmerswaal Ester B.M. , Rots Nynke , Vart Priya , de Vries Rory D. , Gansevoort Ron T. , Hilbrands Luuk B. , Reinders Marlies E.J. ,   RECOVAC Collaborators
Published: November 2021

Background.

In kidney patients COVID-19 is associated with severely increased morbidity and mortality. A comprehensive comparison of the immunogenicity, tolerability, and safety of COVID-19 vaccination in different cohorts of kidney patients and a control cohort is lacking.

Methods.

This investigator driven, prospective, controlled multicenter study included 162 participants with chronic kidney disease (CKD) stages G4/5 (eGFR < 30 mL/min/1.73m2), 159 participants on dialysis, 288 kidney transplant recipients, and 191 controls. Participants received 2 doses of the mRNA-1273 COVID-19 vaccine (Moderna). The primary endpoint was seroconversion.

Results.

Transplant recipients had a significantly lower seroconversion rate when compared with controls (56.9% versus 100%, P < 0.001), with especially mycophenolic acid, but also, higher age, lower lymphocyte concentration, lower eGFR, and shorter time after transplantation being associated with nonresponder state. Transplant recipients also showed significantly lower titers of neutralizing antibodies and T-cell responses when compared with controls. Although a high seroconversion rate was observed for participants with CKD G4/5 (100%) and on dialysis (99.4%), mean antibody concentrations in the CKD G4/5 cohort and dialysis cohort were lower than in controls (2405 [interquartile interval 1287–4524] and 1650 [698–3024] versus 3186 [1896–4911] BAU/mL, P = 0.06 and P < 0.001, respectively). Dialysis patients and especially kidney transplant recipients experienced less systemic vaccination related adverse events. No specific safety issues were noted.

Conclusions.

The immune response following vaccination in patients with CKD G4/5 and on dialysis is almost comparable to controls. In contrast, kidney transplant recipients have a poor response. In this latter, patient group development of alternative vaccination strategies are warranted.
Discovery of I-WP minimal-surface-based photonic crystal in the scale of a longhorn beetle
Authors: Kobayashi Yuka , Ohnuki Ryosuke , Yoshioka Shinya
Published: November 2021

The structural colours of certain insects are produced by three-dimensional periodic cuticle networks. The topology of the cuticle network is known to be based on the mathematically well-defined triply periodic minimal surface. In this paper, we report the discovery of an I-WP minimal-surface-based photonic crystal on the scale of a longhorn beetle. In contrast to gyroid or diamond surfaces, which are found in butterfly and weevil scales, respectively, the I-WP surface is an unbalanced minimal surface, wherein two subspaces separated by the surface are different in terms of shape and volume fraction. Furthermore, adjacent photonic crystal domains were observed to share a particular crystal plane as their domain boundary, indicating that they were developed as twin crystals. These structural features pose certain new questions regarding the development of biological photonic crystals. We also performed an optical analysis of the structural colour of the longhorn beetle and successfully explained the wavelength of reflection by the photonic bandgap of the I-WP photonic crystal.
Development of a mesoscopic framework spanning nanoscale protofibril dynamics to macro-scale fibrin clot formation
Authors: Takeishi Naoki , Shigematsu Taiki , Enosaki Ryogo , Ishida Shunichi , Ii Satoshi , Wada Shigeo
Published: November 2021

Thrombi form a micro-scale fibrin network consisting of an interlinked structure of nanoscale protofibrils, resulting in haemostasis. It is theorized that the mechanical effect of the fibrin clot is caused by the polymeric protofibrils between crosslinks, or to their dynamics on a nanoscale order. Despite a number of studies, however, it is still unknown, how the nanoscale protofibril dynamics affect the formation of the macro-scale fibrin clot and thus its mechanical properties. A mesoscopic framework would be useful to tackle this multi-scale problem, but it has not yet been established. We thus propose a minimal mesoscopic model for protofibrils based on Brownian dynamics, and performed numerical simulations of protofibril aggregation. We also performed stretch tests of polymeric protofibrils to quantify the elasticity of fibrin clots. Our model results successfully captured the conformational properties of aggregated protofibrils, e.g., strain-hardening response. Furthermore, the results suggest that the bending stiffness of individual protofibrils increases to resist extension.
Diverse stem-chondrichthyan oral structures and evidence for an independently acquired acanthodid dentition
Authors: Dearden Richard P. , Giles Sam
Published: November 2021

The teeth of sharks famously form a series of transversely organized files with a conveyor-belt replacement that are borne directly on the jaw cartilages, in contrast to the dermal plate-borne dentition of bony fishes that undergoes site-specific replacement. A major obstacle in understanding how this system evolved is the poorly understood relationships of the earliest chondrichthyans and the profusion of morphologically and terminologically diverse bones, cartilages, splints and whorls that they possess. Here, we use tomographic methods to investigate mandibular structures in several early branching ‘acanthodian’-grade stem-chondrichthyans. We show that the dentigerous jaw bones of disparate genera of ischnacanthids are united by a common construction, being growing bones with non-shedding dentition. Mandibular splints, which support the ventro-lateral edge of the Meckel's cartilage in some taxa, are formed from dermal bone and may be an acanthodid synapomorphy. We demonstrate that the teeth ofAcanthodopsisare borne directly on the mandibular cartilage and that this taxon is deeply nested within an edentulous radiation, representing an unexpected independent origin of teeth. Many or even all of the range of unusual oral structures may be apomorphic, but they should nonetheless be considered when building hypotheses of tooth and jaw evolution, both in chondrichthyans and more broadly.
Personality captures dissociations of subjective versus objective hearing in noise
Authors: Wöstmann Malte , Erb Julia , Kreitewolf Jens , Obleser Jonas
Published: November 2021

Acoustic noise is pervasive in human environments. Some individuals are more tolerant to noise than others. We demonstrate the explanatory potential of Big-5 personality traits neuroticism (being emotionally unstable) and extraversion (being enthusiastic, outgoing) on subjective self-report and objective psycho-acoustic metrics of hearing in noise in two samples (total
N
= 1103). Under statistical control for demographics and in agreement with pre-registered hypotheses, lower neuroticism and higher extraversion independently explained superior self-reported noise resistance, speech-hearing ability and acceptable background noise levels. Surprisingly, objective speech-in-noise recognition instead increased with higher levels of neuroticism. In turn, the bias in subjectively overrating one's own hearing in noise decreases with higher neuroticism but increases with higher extraversion. Of benefit to currently underspecified frameworks of hearing in noise and tailored audiological treatments, these results show that personality explains inter-individual differences in coping with acoustic noise, which is a ubiquitous source of distraction and a health hazard.
Effects of symbiotic population impairment on microbiome composition and longevity of
Bactrocera dorsalis
Authors: Akami Mazarin , Tamgue Ousman , Ren Xueming , Wang Yaohui , Qi Xuewei , Martin Luther Koanga Mogtomo , Ngono Ngane Rosalie Annie , Niu Chang-Ying
Published: November 2021

In order to understand the role of symbionts for their insect hosts, it is customary to treat them with antibiotics or to sterilize eggs (treatments), resulting in aposymbiotic and axenic insects, respectively. Such axenic insects can then be compared with untreated controls. Fruit flies often bear complex communities which are greatly reduced by such treatments. However, the bacterial community is not completely eliminated. Here, we examine the effect of these procedures on the structure of the remaining bacterial communities in
Bactrocera dorsalis
(Diptera: Tephritidae) and on the insect longevity. The antibiotics (Norfloxacin and Ceftazedime) were administered to 1-day-old adult flies through sugar meal for 7 days, and eggs were surface sterilized and dechorionated to produce axenic lines. The flies were starved of protein before they were offered full diets or diets containing non-essential amino acids only. Antibiotic and egg disinfection treatments resulted in a significant reduction of the vast majority of gut bacterial populations, especially Proteobacteria, Firmicutes and Bacteroidetes. On the other hand, antibiotic allowed the persistence of Actinobacteria, Cyanobacteria and Acidobacteria populations. In untreated control flies, longevity was extended irrespective of diet quality in comparison to treated flies. Conversely, when gut bacteria were largely reduced (aposymbiotic and axenic flies), longevity was reduced in the non-essential amino acids diet treatment versus slightly improved in the presence of a protein diet. We discuss these results in an ecological–life-history perspective.
Aneurysm risk metrics and hemodynamics are associated with greater vessel wall enhancement in intracranial aneurysms
Authors: Veeturi Sricharan S. , Rajabzadeh-Oghaz Hamidreza , Pintér Nándor K. , Waqas Muhammad , Hasan David M. , Snyder Kenneth V. , Siddiqui Adnan H. , Tutino Vincent M.
Published: November 2021

Vessel wall enhancement (VWE) in contrast-enhanced magnetic resonance imaging (MRI) is a potential biomarker for intracranial aneurysm (IA) risk stratification. In this study, we investigated the relationship between VWE features, risk metrics, morphology and hemodynamics in 41 unruptured aneurysms. We reconstructed the IA geometries from MR angiography and mapped pituitary stalk-normalized MRI intensity on the aneurysm surface using an in-house tool. For each case, we calculated the maximum intensity (CRstalk) and IA risk (via size and the rupture resemblance score (RRS)). We performed correlation analysis to assess relationships between CRstalkand IA risk metrics (size and RRS), as well as each parameter encompassed in RRS, i.e. aneurysmal size ratio (SR), normalized wall shear stress (WSS) and oscillatory shear index. We found that CRstalkhad a strong correlation (Pearson correlation coefficient, PCC = 0.630) with size and a moderate correlation (PCC = 0.472) with RRS, indicating an association between VWE and IA risk. Furthermore, CRstalkhad a weak negative correlation with normalized WSS (PCC = −0.320) and a weak positive correlation with SR (PCC = 0.390). Local voxel-based analysis showed only a weak negative correlation between normalized WSS and contrast-enhanced MRI signal intensity (PCC = −0.240), suggesting that if low-normalized WSS induces enhancement-associated pathobiology, the effect is not localized.
New multipodomerous appendages of stem-group euarthropods from the Cambrian (Stage 4) Guanshan Konservat-Lagerstätte
Authors: Jiao De-guang , Pates Stephen , Lerosey-Aubril Rudy , Ortega-Hernández Javier , Yang Jie , Lan Tian , Zhang Xi-guang
Published: November 2021

Stem-group euarthropods are important for understanding the early evolutionary and ecological history of the most species-rich animal phylum on Earth. Of particular interest are fossil taxa that occupy a phylogenetic position immediately crownwards of radiodonts, for this part of the euarthropod tree is associated with the appearance of several morphological features that characterize extant members of the group. Here, we report two new euarthropods from the Cambrian Stage 4 Guanshan Biota of South China. The fuxianhuiidAlacaris? sp. is represented by isolated appendages composed of a gnathobasic protopodite and an endite-bearing endopod of at least 20 podomeres. This material represents the youngest occurrence of the family Chengjiangocarididae, and its first record outside the Chengjiang and Xiaoshiba biotas. We also describeLihuacaris feroxgen. et sp. nov. based on well-preserved and robust isolated appendages.Lihuacaris feroxexhibits an atypical combination of characters including an enlarged rectangular base, 11 endite-bearing podomeres and a hypertrophied distal element bearing 8–10 curved spines.Alacaris? sp. appendages display adaptations for macrophagy.Lihuacaris feroxappendages resemble the frontal appendages of radiodonts, as well as the post-oral endopods of chengjiangocaridid fuxianhuids and other deuteropods with well-documented raptorial/predatory habits.Lihuacaris feroxcontributes towards the record of endemic biodiversity in the Guanshan Biota.
Giant hornet (Vespa soror) attacks trigger frenetic antipredator signalling in honeybee (Apis cerana) colonies
Authors: Mattila Heather R. , Kernen Hannah G. , Otis Gard W. , Nguyen Lien T. P. , Pham Hanh D. , Knight Olivia M. , Phan Ngoc T.
Published: November 2021

Asian honeybees use an impressive array of strategies to protect nests from hornet attacks, although little is understood about how antipredator signals coordinate defences. We compared vibroacoustic signalling and defensive responses ofApis ceranacolonies that were attacked by either the group-hunting giant hornetVespa sororor the smaller, solitary-hunting hornetVespa velutina.Apis ceranacolonies produced hisses, brief stop signals and longer pipes under hornet-free conditions. However, hornet-attack stimuli—andV. sororworkers in particular—triggered dramatic increases in signalling rates within colonies. Soundscapes were cacophonous whenV. sororpredators were directly outside of nests, in part because of frenetic production of antipredator pipes, a previously undescribed signal. Antipredator pipes share acoustic traits with alarm shrieks, fear screams and panic calls of primates, birds and meerkats. Workers making antipredator pipes exposed their Nasonov gland, suggesting the potential for multimodal alarm signalling that warns nestmates about the presence of dangerous hornets and assembles workers for defence. Concurrent observations of nest entrances showed an increase in worker activities that support effective defences against giant hornets.Apis ceranaworkers flexibly employ a diverse alarm repertoire in response to attack attributes, mirroring features of sophisticated alarm calling in socially complex vertebrates.
Exercise-induced changes in climbing performance
Authors: Watanabe Louis P. , Riddle Nicole C.
Published: November 2021

Exercise is recommended to promote health and prevent a range of diseases. However, how exercise precipitates these benefits is unclear, nor do we understand why exercise responses differ so widely between individuals. We investigate how climbing ability inDrosophila melanogasterchanges in response to an exercise treatment. We find extensive variation in baseline climbing ability and exercise-induced changes ranging from −13% to +20% in climbing ability. Climbing ability, and its exercise-induced change, is sex- and genotype-dependent. GWASs implicate ‘cell–cell signalling’ genes in the control of climbing ability. We also find that animal activity does not predict climbing ability and that the exercise-induced climbing ability change cannot be predicted from the activity level induced by the exercise treatment. These results provide promising new avenues for further research into the molecular pathways controlling climbing activity and illustrate the complexities involved in trying to predict individual responses to exercise.
Inferring temporal dynamics from cross-sectional data using Langevin dynamics
Authors: Dutta Pritha , Quax Rick , Crielaard Loes , Badiali Luca , Sloot Peter M. A.
Published: November 2021

Cross-sectional studies are widely prevalent since they are more feasible to conduct compared with longitudinal studies. However, cross-sectional data lack the temporal information required to study the evolution of the underlying dynamics. This temporal information is essential to develop predictive computational models, which is the first step towards causal modelling. We propose a method for inferring computational models from cross-sectional data using Langevin dynamics. This method can be applied to any system where the data-points are influenced by equal forces and are in (local) equilibrium. The inferred model will be valid for the time span during which this set of forces remains unchanged. The result is a set of stochastic differential equations that capture the temporal dynamics, by assuming that groups of data-points are subject to the same free energy landscape and amount of noise. This is a ‘baseline’ method that initiates the development of computational models and can be iteratively enhanced through the inclusion of domain expert knowledge as demonstrated in our results. Our method shows significant predictive power when compared against two population-based longitudinal datasets. The proposed method can facilitate the use of cross-sectional datasets to obtain an initial estimate of the underlying dynamics of the respective systems.
A vegetation classification and description of white-winged flufftail (
Sarothrura ayresi
) habitat at selected high-altitude peatlands in South Africa
Authors: Marais A. J. , Lloyd K. , Smit-Robinson H. A. , Brown L. R.
Published: November 2021

The white-winged flufftail is listed as critically endangered, and limited knowledge about the species' ecology has been identified as a limiting factor to effectively conserving the bird. Little is known about the vegetation inhabited by the white-winged flufftail, which hampers the identification and management of its habitat. This study presents a fine-scale classification and description of the vegetation of wetland sites where the bird is known to be present. A plant phytosociological study was conducted to describe the plant communities and vegetation structure of the habitat. Three sites were selected at Verloren Valei Nature Reserve and two at Middelpunt Wetland, Mpumalanga, South Africa, shortly after the white-winged flufftail breeding season. A total of 60 sample plots were placed within the study sites, where all plant species present were recorded and identified. Other aspects such as plant height, water depth and anthropogenic influences were also documented. A modified TWINSPAN analysis resulted in the identification of three sub-communities that can be grouped into one major community. The Cyperaceae, Asteraceae and Poaceae families dominate the vegetation, with the sedges
Carex austro-africana
and
Cyperus denudatus
being dominant, and the grasses
Leersia hexandra
and
Arundinella nepalensis
co-dominant. The broad habitat structure consisted of medium to tall herbaceous plants (0.5–0.7 m) with shallow slow-flowing water.
High heart rates in hunting harbour porpoises
Authors: McDonald Birgitte I. , Elmegaard Siri L. , Johnson Mark , Wisniewska Danuta M. , Rojano-Doñate Laia , Galatius Anders , Siebert Ursula , Teilmann Jonas , Madsen Peter T.
Published: November 2021

The impressive breath-hold capabilities of marine mammals are facilitated by both enhanced O
2
stores and reductions in the rate of O
2
consumption via peripheral vasoconstriction and bradycardia, called the dive response. Many studies have focused on the extreme role of the dive response in maximizing dive duration in marine mammals, but few have addressed how these adjustments may compromise the capability to hunt, digest and thermoregulate during routine dives. Here, we use DTAGs, which record heart rate together with foraging and movement behaviour, to investigate how O
2
management is balanced between the need to dive and forage in five wild harbour porpoises that hunt thousands of small prey daily during continuous shallow diving. Dive heart rates were moderate (median minimum 47–69 bpm) and relatively stable across dive types, dive duration (0.5–3.3 min) and activity. A moderate dive response, allowing for some perfusion of peripheral tissues, may be essential for fuelling the high field metabolic rates required to maintain body temperature and support digestion during diving in these small, continuously feeding cetaceans. Thus, despite having the capacity to prolong dives via a strong dive response, for these shallow-diving cetaceans, it appears to be more efficient to maintain circulation while diving: extreme heart rate gymnastics are for deep dives and emergencies, not everyday use.
Detection of live breast cancer cells in brightfield microscopy images containing white blood cells by image analysis and deep learning
Authors: Moallem Golnaz , Pore Adity A. , Gangadhar Anirudh , Sari-Sarraf Hamed , Vanapalli Siva A.
Published: November 2021

Significance

Circulating tumor cells (CTCs) are important biomarkers for cancer management. Isolated CTCs from blood are stained to detect and enumerate CTCs. However, the staining process is laborious and moreover makes CTCs unsuitable for drug testing and molecular characterization.

Aim

The goal is to develop and test deep learning (DL) approaches to detect unstained breast cancer cells in bright field microscopy images that contain white blood cells (WBCs).

Approach

We tested two convolutional neural network (CNN) approaches. The first approach allows investigation of the prominent features extracted by CNN to discriminate cancer cells from WBCs. The second approach is based on Faster Region-based Convolutional Neural Network (Faster R-CNN).

Results

Both approaches detected cancer cells with high sensitivity and specificity with the Faster R-CNN being more efficient and suitable for deployment. The distinctive feature used by the CNN used to discriminate is cell size, however in the absence of size difference, the CNN was found to be capable of learning other features. The Faster R-CNN was found to be robust with respect to intensity and contrast image transformations.

Conclusions

CNN-based deep learning approaches could be potentially applied to detect patient-derived CTCs from images of blood samples.
Simultaneous identification of viruses and viral variants with programmable DNA nanobait
Authors: Bošković Filip , Zhu Jinbo , Tivony Ran , Ohmann Alexander , Chen Kaikai , Alawami Mohammed F. , Đorđević Milan , Ermann Niklas , Dias Joana Pereira , Fairhead Michael , Howarth Mark , Baker Stephen , Keyser Ulrich F.
Published: November 2021

Respiratory infections are the major cause of death from infectious disease worldwide. Multiplexed diagnostic approaches are essential as many respiratory viruses have indistinguishable symptoms. We created self-assembled DNA nanobait that can simultaneously identify multiple short RNA targets. The nanobait approach relies on specific target selection via toehold-mediated strand displacement and rapid read-out via nanopore sensing. Here, we show this platform can concurrently identify several common respiratory viruses, detecting a panel of short targets of viral nucleic acids from multiple viruses. Our nanobait can be easily reprogrammed to discriminate viral variants, as we demonstrated for several key SARS-CoV-2 variants with single-nucleotide resolution. Lastly, we show that nanobait discriminates between samples extracted from oropharyngeal swabs from negative and positive SARS-CoV-2 patients without pre-amplification. Our system allows for multiplexed identification of native RNA molecules, providing a new scalable approach for diagnostics of multiple respiratory viruses in a single assay.
ColocQuiaL: A QTL-GWAS colocalization pipeline
Authors: Chen Brian Y. , Bone William P. , Lorenz Kimberly , Levin Michael , Ritchie Marylyn D. , Voight Benjamin F.
Published: November 2021

Identifying genomic features responsible for genome-wide association study (GWAS) signals has proven to be a difficult challenge; many researchers have turned to colocalization analysis of GWAS signals with expression quantitative trait loci (eQTL) and splicing quantitative trait loci (sQTL) to connect GWAS signals to candidate causal genes. The ColocQuiaL pipeline provides a framework to perform these colocalization analyses at scale across the genome and returns summary files and locus visualization plots to allow for detailed review of the results. As an example, we used ColocQuiaL to perform colocalization between the latest type 2 diabetes GWAS data and Genotype-Tissue Expression (GTEx) v8 single-tissue eQTL and sQTL data.

Availability and Implementation

ColocQuiaL is primarily written in R and is freely available at github: https://github.com/bychen9/eQTL_colocalizer.

Contact

bvoight@pennmedicine.upenn.edu
Cohort Profile: Genetic data in the German Socio-Economic Panel Innovation Sample (Gene-SOEP)
Authors: Koellinger Philipp D. , Okbay Aysu , Kweon Hyeokmoon , Schweinert Annemarie , Karlsson Linnér Richard , Goebel Jan , Richter David , Reiber Lisa , Zweck Bettina Maria , Belsky Daniel W. , Biroli Pietro , Mata Rui , Tucker-Drob Elliot M. , Harden K. Paige , Wagner Gert , Hertwig Ralph
Published: November 2021

The German Socio-Economic Panel (SOEP) serves a global research community by providing representative annual longitudinal data of private households in Germany. The sample provides a detailed life course perspective based on a rich collection of information about living conditions, socio-economic status, family relationships, personality, values, preferences, and health. We collected genetic data from 2,598 individuals in the SOEP Innovation Sample, yielding the first genotyped sample that is representative of the entire German population (Gene-SOEP). The Gene-SOEP sample is a longitudinal study that includes 107 full-sibling pairs, 501 parent-offspring pairs, and 152 parent-offspring trios that are overlapping with the parent-offspring pairs. We constructed a repository of 66 polygenic indices in the Gene-SOEP sample based on results from well-powered genome-wide association studies. The Gene-SOEP data provides a valuable resource to study individual differences, inequalities, life-course development, health, and interactions between genetic predispositions and environment.
How and why do Quality Circles work for General Practitioners - a realist approach
Authors: Rohrbasser Adrian , Wong Geoff , Mickan Sharon , Harris Janet
Published: November 2021

Objectives

To understand how and why general practitioners in quality circles (QC) reflect on and improve routine practice over time. To provide practical guidance for participants and facilitators to implement and for policy makers to organise this complex social intervention.

Design

A theory-driven mixed method

Setting

Primary health care

Method

We collected data in four stages to develop and refine the programme theory of QCs: 1) co-inquiry with Swiss and European stakeholders to develop a preliminary programme theory; 2) realist review with systematic searches in MEDLINE, Embase, PsycINFO, and CINHAL (1980-2020) to extend the preliminary programme theory; 3) programme refinement through interviews with participants, facilitators, tutors and managers of quality circles; 4) consolidation through interviews and iterative searches for theories enabling us to strengthen the programme theory.

Sources of data

The co-inquiry comprised 3 interviews and 3 focus groups with 50 European experts. From the literature search we included 108 papers to develop the literature-based programme theory. In stage 3, we used data from 40 participants gathered in 6 interviews and 2 focus groups to refine the programme theory. In stage 4, five interviewees from different health care systems consolidated our programme theory.

Result

Requirements for successful QCs are governmental trust in GPs’ abilities to deliver quality improvement, training, access to educational material and performance data, protected time, and financial resources. Group dynamics strongly influence success; facilitators should ensure participants exchange knowledge and generate new concepts in a safe environment. Peer interaction promotes professional development and psychological well-being. With repetition, participants gain confidence to put their new concepts into practice.

Conclusion

QCs can improve practice, promote professional development, and psychological well-being given adequate professional and administrative support.

Strengths and limitations of this study

To our knowledge, this is the first published research that explains how and why general practitioners participating in quality circles may improve standard practice and their psychological well-being over time.

The findings can be used to inform practice and policy decisions.

The resulting theory relies on the detail and depth of the reports in the literature and the veracity and adequacy of the information participants revealed in interviews and focus groups.

To mitigate the risk of selection bias if researchers choose underlying theories and synthesise them ad hoc, we used stakeholders’ mental model and programme documentation as our framework for analysis.
Calcium and strontium contractile activation properties of single skinned skeletal muscle fibres from elderly women 66-90 years of age
Authors: Ronaldson Susan M. , Stephenson D. George , Head Stewart I.
Published: November 2021

The single skinned muscle fibre technique was used to investigate Ca2+- and Sr2+- activation properties of skeletal muscle fibres from elderly women (66-90 years). Muscle biopsies were obtained from the vastus lateralis muscle. Three populations of muscle fibres were identified according to their specific Sr2+- activation properties: slow-twitch (type I), fast-twitch (type II) and hybrid (type I/II) fibres. All three fibre types were sampled from the biopsies of 66 to 72 years old women, but the muscle biopsies of women older than 80 years yielded only slow-twitch (type I) fibres. The proportion of hybrid fibres in the vastus lateralis muscle of women of circa 70 years of age (24%) was several-fold greater than in the same muscle of adults (<10%), suggesting that muscle remodelling occurs around this age. There were no differences between the Ca2+- and Sr2+- activation properties of slow-twitch fibres from the two groups of elderly women, but there were differences compared with muscle fibres from adults with respect to sensitivity to Ca2+, steepness of the activation curves, and characteristics of the fibre-type dependent phenomenon of spontaneous force oscillations (SOMO) occurring at submaximal levels of activation. The maximal Ca2+ activated specific force from all the fibres collected from the seven old women use in the present study was significantly lower by 20% than in the same muscle of adults. Taken together these results show there are qualitative and quantitative changes in the activation properties of the contractile apparatus of muscle fibres from the vastus lateralis muscle of women with advancing age, and that these changes need to be considered when explaining observed changes in women’s mobility with aging.
The Open Perimetry Initiative: a framework for cross-platform development for the new generation of portable perimeters
Authors: Marín-Franch Iván , Turpin Andrew , Artes Paul H , Chong Luke X , McKendrick Allison M , Alawa Karam A , Wall Michael
Published: November 2021

The Open Perimetry Initiative is fully open source and consists of the Open Perimetry Interface (OPI) and an accompanying package (visualFields) with analytical tools. The OPI package contains an ever-growing number of drivers for commercially available perimeters, head-mounted devices, and virtual reality headsets. The visualFields package contains tools for the analysis and visualization of visual field data, including methods to compute deviation values and probability maps. The use of the OPI and visualFields is shown through a custom static automated perimetry test for the full visual field (up to 50° nasally and 80° temporally) developed with the OPI driver for the Octopus 900 and using visualFields for statistical analysis. Its potential for the development of cross-platform apps for driving and testing portable devices is demonstrated with an OPI driver for an Android-based headset. With more than 55 citations in clinical and translational science as listed in Scopus, this initiative has contributed significantly to expanding the knowledge base in perimetry and clinical vision research at large, and with clinical translation. The continued support of researchers, clinicians, industry, and public institutions are key in transforming perimetry research from closed to open science. The Open Perimetry Initiative provides framework to achieve this.
CX3CL1 action on microglia protects from diet-induced obesity by restoring POMC neuronal excitability and melanocortin system activity impaired by high-fat diet feeding
Authors: Banerjee Jineta , Dorfman Mauricio D. , Fasnacht Rachael , Douglass John D. , Wyse-Jackson Alice C. , Barria Andres , Thaler Joshua P.
Published: November 2021

Objective

Diet-induced obesity (DIO) is associated with hypothalamic microglial activation and dysfunction of the melanocortin pathway, but the molecular mechanisms linking the two remain unclear. Previous studies have hypothesized that microglial inflammatory signaling is linked with impaired pro-opiomelanocortin (POMC) neuron function, but this mechanism has never been directly tested in vivo. We addressed this hypothesis using the specific microglial silencing molecule, CX3CL1 (fractalkine), to determine whether reducing hypothalamic microglial activation can restore POMC/melanocortin signaling in the brain to protect against DIO.

Methods

We performed metabolic analyses in mice with targeted viral overexpression of CX3CL1 in the hypothalamus exposed to high fat diet (HFD). Electrophysiologic recording in hypothalamic slices from POMC-MAPT-GFP mice was used to determine the effects of HFD feeding and microglial silencing via minocycline or CX3CL1 on GFP-labeled POMC neurons. Finally, mice with hypothalamic overexpression of CX3CL1 received central treatment with the melanocortin receptor antagonist SHU-9119 to determine whether melanocortin signaling is required for the metabolic benefits of CX3CL1.

Results

We found that targeted expression of both soluble and membrane-bound forms of CX3CL1 in the mediobasal hypothalamus potently reduced weight gain and increased leptin sensitivity in animals exposed to high fat diet. The protective effect of CX3CL1 rescued diet-induced changes in POMC neuron excitability and required intact melanocortin receptor signaling in vivo.

Conclusion

Our results provide the first evidence that HFD-induced POMC neuron dysfunction involves microglial activation. Furthermore, our study suggests that the anti-obesity action of CX3CL1 is mediated through the restoration of POMC neuron excitability and melanocortin signaling.
WATLAS: high throughput and real-time tracking of many small birds in the Dutch Wadden Sea
Authors: Bijleveld Allert I. , van Maarseveen Frank , Denissen Bas , Dekinga Anne , Penning Emma , Ersoy Selin , Gupte Pratik , de Monte Luc , Horn Job ten , Bom Roeland A. , Toledo Sivan , Nathan Ran , Beardsworth Christine E.
Published: November 2021

Background

Tracking animal movement is important for understanding how animals interact with their (changing) environment, and crucial for predicting and explaining how animals are affected by anthropogenic effects. The Wadden Sea is a UNESCO World Heritage Site and a region of global importance for millions of small shorebirds. Due to climate change and anthropogenic activity, understanding and predicting movement and space-use in areas like the Wadden Sea is increasingly important. Monitoring and predicting animal movement, however, requires high-resolution tracking of many individuals. While high-resolution tracking has been made possible through GPS, trade-offs between tag weight and battery life limit its use to larger species.

Methods

Here, we introduce WATLAS (the Wadden Sea deployment of the ATLAS tracking system) capable of monitoring the movements of hundreds of (small) birds simultaneously in the Dutch Wadden Sea. WATLAS employs an array of receiver stations that can detect and localise small, low-cost tags at fine spatial (meters) and temporal resolution (seconds). From 2017-2021, we tracked red knots, sanderlings, bar-tailed godwits, and common terns. We use parts of these data to give four examples on its performance and how WATLAS can be used to study numerous aspects of animal behaviour, such as, space-use (both intra- and inter-specific), among-individual variation, and social networks.

Results

After describing the WATLAS system, we first illustrate space-use of red knots across the study area and how the tidal environment affects their movement. Secondly, we show large among-individual differences in distances travelled per day, and thirdly illustrate how high-throughput WATLAS data allows calculating a proximity-based social network. Finally, we demonstrate that using WATLAS to monitor multiple species can reveal differential space use. For example, despite sanderlings and red knots roosting together, they foraged in different areas of the mudflats.

Conclusions

The high-resolution tracking data collected by WATLAS offers many possibilities for research into the drivers of bird movement in the Wadden Sea. WATLAS could provide a tool for impact assessment, and thus aid nature conservation and management of the globally important Wadden Sea ecosystem.
ICOR: Improving codon optimization with recurrent neural networks
Authors: Jain Rishab , Jain Aditya , Mauro Elizabeth , LeShane Kevin , Densmore Douglas
Published: November 2021

Background

In protein sequences—as there are 61 sense codons but only 20 standard amino acids— most amino acids are encoded by more than one codon. Although such synonymous codons do not alter the encoded amino acid sequence, their selection can dramatically affect the expression of the resulting protein. Codon optimization of synthetic DNA sequences is important for heterologous expression. However, existing solutions are primarily based on choosing high-frequency codons only, neglecting the important effects of rare codons. In this paper, we propose a novel recurrent-neural-network based codon optimization tool, ICOR, that aims to learn codon usage bias on a genomic dataset ofEscherichia coli. We compile a dataset of over 7,000 non-redundant, high-expression, robust genes which are used for deep learning. The model uses a bidirectional long short-term memory-based architecture, allowing for the sequential context of codon usage in genes to be learned. Our tool can predict synonymous codons for synthetic genes toward optimal expression inEscherichia coli.

Results

We demonstrate that sequential context achieved via RNN may yield codon selection that is more similar to the host genome. Based on computational metrics that predict protein expression, ICOR theoretically optimizes protein expression more than frequency-based approaches. ICOR is evaluated on 1,481Escherichia coligenes as well as a benchmark set of 40 select DNA sequences whose heterologous expression has been previously characterized. ICOR’s performance is measured across five metrics: the Codon Adaptation Index, GC-content, negative repeat elements, negative cis-regulatory elements, and codon frequency distribution.

Conclusions

The results, based on in silico metrics, indicate that ICOR codon optimization is theoretically more effective in enhancing recombinant expression of proteins over other established codon optimization techniques. Our tool is provided as an open-source software package that includes the benchmark set of sequences used in this study.
Two different adaptive speciation mechanisms operate during adaptation to a novel hot environment
Authors: Hsu Sheng-Kai , Lai Wei-Yun , Novak Johannes , Lehner Felix , Jakšić Ana Marija , Versace Elisabetta , Schlötterer Christian
Published: November 2021

Background

Ecological speciation and mutation-order speciation are two different mechanisms of adaptation-driven speciation. Both mechanisms predict different patterns of reproductive isolation for replicate populations adapting to the same environment. With ecological speciation, barriers to gene flow emerge between populations from different environments, but not among replicate populations from the same environment. Mutation-order speciation predicts reproductive isolation among populations adapted to the same environment.

Results

We demonstrate that both speciation processes occurred within about 100 generations when replicateDrosophila simulanspopulations adapted to a novel, hot environment. Gene expression analysis identified the underlying molecular mechanisms. Premating ecological speciation is the byproduct of an altered lipid metabolism, which also changed the cuticular hydrocarbon (CHC) composition in hot-evolved flies. Postmating reproductive isolation supports mutation-order speciation most likely driven by co-evolution of reproduction-associated genes.

Conclusion

Adaptation processes can rapidly induce incipient speciation and different speciation mechanisms affect pre- and postmating reproductive isolation. We propose that the definition of mutation-order speciation should be expanded to account for polygenic processes from standing genetic variation.
TreeSearch: morphological phylogenetic analysis in R
Authors: Smith Martin R.
Published: November 2021

TreeSearch is an R package for phylogenetic analysis, optimized for morphological datasets. Tree search may be conducted using equal or implied step weights with an explicit (albeit inexact) allowance for inapplicable character entries, avoiding some of the pitfalls inherent in standard parsimony methods. Profile parsimony and user-specified optimality criteria are supported.

A graphical interface, which requires no familiarity with R, is designed to help a user to improve the quality of datasets through critical review of underpinning character codings; and to obtain additional information from results by identifying and summarizing clusters of similar trees, mapping the distribution of trees, and removing ‘rogue’ taxa that obscure underlying relationships.

Taken together, the package aims to support methodological rigour at each step of data collection, analysis, and the exploration of phylogenetic results.
scGate: marker-based purification of cell types from heterogeneous single-cell RNA-seq datasets
Authors: Andreatta Massimo , Berenstein Ariel J. , Carmona Santiago J.
Published: November 2021

Abstract

A common bioinformatics task in single-cell data analysis is to purify a cell type or cell population of interest from heterogeneous datasets. Here we present scGate, an algorithm that automatizes marker-based purification of specific cell populations, without requiring training data or reference gene expression profiles. scGate purifies a cell population of interest using a set of markers organized in a hierarchical structure, akin to gating strategies employed in flow cytometry. In our benchmark for blood-derived and tumor-infiltrating immune cells, scGate outperforms SingleR, a state-of-the-art classifier for single-cell data. scGate is implemented as an R package and integrated with the Seurat framework, providing an intuitive tool to isolate cell populations of interest from complex scRNA-seq datasets.

Availability

R package source code and reproducible tutorials are available at https://github.com/carmonalab/scGate
Large-scale identification of RBP-RNA interactions by RAPseq refines essentials of post-transcriptional gene regulation
Authors: Atanasoai Ionut , Papavasileiou Sofia , Preiß Natalie , Kutter Claudia
Published: November 2021

Over the past decade, thousands of putative human RNA binding proteins (RBPs) have been identified and increased the demand for specifying RNA binding capacities. Here, we developed RNA affinity purification followed by sequencing (RAPseq) that enablesin vitrolarge-scale profiling of RBP binding to native RNAs. First, by employing RAPseq, we found that vertebrate HURs recognize a conserved RNA binding motif and bind predominantly to introns in zebrafish compared to 3’UTRs in human RNAs. Second, our dual RBP assays (co-RAPseq) uncovered cooperative RNA binding of HUR and PTBP1 within an optimal distance of 27 nucleotides. Third, we developed T7-RAPseq to discern m6A-dependent and - independent RNA binding sites of YTHDF1. Fourth, RAPseq of 26 novel non-canonical RBPs revealed specialized moonlighting interactions. Last, five pathological IGF2BP family variants exhibited different RNA binding patterns. Overall, our simple, scalable and versatile method enables to fast-forward RBP-related questions.

Graphical Abstract

HIGHLIGHTS

RAPseq revealsin vitro-derived RBP-RNA interactomes

the vertebrate-conserved HUR binding motif adapted to species-unique RNA features

co-RAPseq and T7-RAPseq uncover binding cooperativity and modification dependencies

non-canonical RBPs have specialized RNA interactomes
Closely Related Tree Species with Overlapping Ranges Exhibit Divergent Adaptation to Climate
Authors: Whale John W. , Ahrens Collin W. , Tissue David T. , Rymer Paul D.
Published: November 2021

With global climate change shifting and altering temperature and precipitation regimes, the ability of natural forest stands to persist in their local environments are being challenged. For many taxa, particularly among long lived tree species, the potential to respond is underpinned by genetic and trait diversity and may be limited. We sampled 326 and 366 individuals of two widely distributed and closely-related red gum Eucalyptus species (E. blakelyi and E. tereticornis) from across their entire Australian range. We identified putatively adaptive variants associated within genes of key biological processes for both species. We mapped the change of allele frequencies of two hierarchical gene ontology groups shared by both species across geography and climate and predict genomically vulnerable regions under a projected 2070 climate scenario. Regions of potential vulnerability to decline under future climate differed between species and may be applied to guide conservation and restoration strategies. Our study indicated that some populations may contain the adaptive genomic variation necessary for these species to persist through climate change, while others may benefit from the adaptive variation of those populations to enhance resilience.