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BackgroundMechanisms of sex-based differences in outcomes following cardiac resynchronization therapy (CRT) are poorly understood.ObjectiveTo use cardiac magnetic resonance (CMR) to define mechanisms of sex-based differences in outcomes after CRT and describe distinct CMR-based phenotypes of CRT candidates based on sex and non-ischemic/ischemic cardiomyopathy type.Materials and methodsIn a prospective study, sex-based differences in three short-term CRT response measures [fractional change in left ventricular end-systolic volume index 6 months after CRT (LVESVI-FC), B-type natriuretic peptide (BNP) 6 months after CRT, change in peak VO2 6 months after CRT], and long-term survival were evaluated with respect to 39 baseline parameters from CMR, exercise testing, laboratory testing, electrocardiograms, comorbid conditions, and other sources. CMR was also used to quantify the degree of left-ventricular mechanical dyssynchrony by deriving the circumferential uniformity ratio estimate (CURE-SVD) parameter from displacement encoding with stimulated echoes (DENSE) strain imaging. Statistical methods included multivariable linear regression with evaluation of interaction effects associated with sex and cardiomyopathy type (ischemic and non-ischemic cardiomyopathy) and survival analysis.ResultsAmong 200 patients, the 54 female patients (27%) pre-CRT had a smaller CMR-based LVEDVI (p = 0.04), more mechanical dyssynchrony based on the validated CMR CURE-SVD parameter (p = 0.04), a lower frequency of both late gadolinium enhancement (LGE) and ischemic cardiomyopathy (p < 0.0001), a greater RVEF (p = 0.02), and a greater frequency of LBBB (p = 0.01). After categorization of patients into four groups based on cardiomyopathy type (ischemic/non-ischemic cardiomyopathy) and sex, female patients with non-ischemic cardiomyopathy had the lowest CURE-SVD (p = 0.003), the lowest pre-CRT BNP levels (p = 0.01), the lowest post-CRT BNP levels (p = 0.05), and the most favorable LVESVI-FC (p = 0.001). Overall, female patients had better 3-year survival before adjustment for cardiomyopathy type (p = 0.007, HR = 0.45) and after adjustment for cardiomyopathy type (p = 0.009, HR = 0.67).ConclusionCMR identifies distinct phenotypes of female CRT patients with non-ischemic and ischemic cardiomyopathy relative to male patients stratified by cardiomyopathy type. The more favorable short-term response and long-term survival outcomes in female heart failure patients with CRT were associated with lower indexed CMR-based LV volumes, decreased presence of scar associated with prior myocardial infarction and ICM, and greater CMR-based dyssynchrony with the CURE-SVD.

Background: Vagus nerve stimulation (VNS) has gained great importance as a promising therapy for a myriad of diseases. Of particular interest is the therapy of cardiovascular diseases, such as heart failure or atrial fibrillation using selective cardiac VNS. However, there is still a lack of organ-specific anatomical knowledge about the fascicular anatomy and topography of the cardiac branch (CB), which diminishes the therapeutic possibilities for selective cardiac neuromodulation. Here, we established a topographical and anatomical map of the superior cardiac VN in two animal species to dissect cervical and cardiac VN morphology.Methods: Autonomic nerves including superior CBs were harvested from domestic pigs and New Zeeland rabbits followed by imaging with microcomputed tomography (µCT) and 3D rendering. The data were analyzed in terms of relevant topographical and anatomical parameters.Results: Our data showed that cardiac vagal fascicles remained separated from other VN fascicles up to 22.19 mm (IQR 14.02–41.30 mm) in pigs and 7.68 mm (IQR 4.06–12.77 mm) in rabbits from the CB point and then started merging with other fascicles. Exchanges of nerve fascicles between sympathetic trunk (ST) and VN were observed in 3 out of 11 nerves, which might cause additional unwanted effects in unselective VNS. Our 3D rendered digital model of the cardiac fascicles was generated showing that CB first remained on the medial side where it branched off the VN, as also shown in the µCT data of 11 pig nerves, and then migrated towards the ventromedial site the further it was traced cranially.Conclusion: Our data provided an anatomical map of the cardiac vagal branches including cervical VN and ST for future approaches of selective cardiac neurostimulation, indicating the best position of selective cardiac VNS just above the CB point.

Objectives At the very start of medical residency training, entrustment of clinical tasks may be a major challenge, on which current scientific knowledge is scarce. This study therefore aimed to gain insight into the process of supervisors’ decision making underlying the entrustment of clinical tasks at the start of one-on-one supervisor–trainee working relationships.Setting This study was performed in a general practice (GP) training department in the Netherlands.Participants For this study, we recruited supervisor–trainee pairs who were just about to start the first year of GP residency training. Of 10 eligible supervisor–trainee pairs, 4 participated.Design We used a qualitative, social-constructivist research approach. Data from naturalistic non-participant observations and semistructured interviews with supervisors in four GP practices were triangulated and analysed using a thematic analysis approach.Results Supervisors’ early entrustment decisions were based on generic trainee qualities such as self-reflexivity, knowing one’s limitations and asking for help in time, rather than on task-specific performance. At the start of residency training, supervisors’ primary concern was to create a safe working and learning environment in which trainees could and would ask for timely supervision while being entrusted with challenging tasks. Supervisors used idiosyncratic entrustment strategies that were influenced by their propensity to trust, previous experiences with trainees, and their perspective on learning and teaching.Conclusion Entrustment decisions require high levels of safety for all stakeholders involved. Especially at the beginning of supervisor–trainee relationships, establishing an educational alliance in which entrustment is the subject of ongoing trainee–supervisor conversations is essential to achieve and maintain and optimal balance between trainee learning and patient safety. Additional research may further our understanding of early entrustment decision making and the role of generic trainee qualities in different settings.

Abstract In nature, plants experience rapid changes in light intensity and quality throughout the day. To maximize growth, they have established molecular mechanisms to optimize photosynthetic output while protecting components of the light‐dependent reaction and CO2 fixation pathways. Plant phenotyping of mutant collections has become a powerful tool to unveil the genetic loci involved in environmental acclimation. Here, we describe the phenotyping of the transfer‐DNA (T‐DNA) insertion mutant line SALK_008491, previously known as nhd1‐1. Growth in a fluctuating light regime caused a loss in growth rate accompanied by a spike in photosystem (PS) II damage and increased non‐photochemical quenching (NPQ). Interestingly, an independent nhd1 null allele did not recapitulate the NPQ phenotype. Through bulk sequencing of a backcrossed segregating F2 pool, we identified an ~14‐kb large deletion on chromosome 3 (Chr3) in SALK_008491 affecting five genes upstream of NHD1. Besides NHD1, which encodes for a putative plastid Na+/H+ antiporter, the stromal NAD‐dependent D‐3‐phosphoglycerate dehydrogenase 3 (PGDH3) locus was eradicated. Although some changes in the SALK_008491 mutant's photosynthesis can be assigned to the loss of PGDH3, our follow‐up studies employing respective single mutants and complementation with overlapping transformation‐competent artificial chromosome (TAC) vectors reveal that the exacerbated fluctuating light sensitivity in SALK_008491 mutants result from the simultaneous loss of PGDH3 and NHD1. Altogether, the data obtained from this large deletion‐carrying mutant provide new and unintuitive insights into the molecular mechanisms that function to protect the photosynthetic machinery. Moreover, our study renews calls for caution when setting up reverse genetic studies using T‐DNA lines. Although second‐site insertions, indels, and SNPs have been reported before, large deletion surrounding the insertion site causes yet another problem. Nevertheless, as shown through this research, such unpredictable genetic events following T‐DNA mutagenesis can provide unintuitive insights that allow for understanding complex phenomena such as the plant acclimation to dynamic high light stress.

A city in northern Ontario, which has suffered more than a century of pollution from mining, went from being internationally notorious for its pollution to winning awards for its environmental restoration. The inquiry was into the levers of change that led from an awareness of environmental destruction to taking action. Semi-structured interviews were conducted with 60 people from the community, politicians, industry, miners, and academics. The theory-based analysis led to a community-change model that has helped identify the multiple layers of change required for the re-greening of the environment. With reference to the collective impact literature, this city-level case study found that the city has embraced change based upon agreement on an emerging vision, taking advantage of a confluence of timing and events, adopting evidence-based knowledge, building a sense of pride and place, and having a diffuse yet linked leadership. The Sudbury story is helpful for other industrial communities looking to achieve change.

Abstract Background The educational beliefs of medical educators influence their teaching practices. Insight into these beliefs is important for medical schools to improve the quality of education they provide students and to guide faculty development. Several studies in the field of higher education have explored the educational beliefs of educators, resulting in classifications that provide a structural basis for diverse beliefs. However, few classification studies have been conducted in the field of medical education. We propose a framework that describes faculty beliefs about teaching, learning, and knowledge which is specifically adapted to the medical education context. The proposed framework describes a matrix in which educational beliefs are organised two dimensionally into belief orientations and belief dimensions. The belief orientations range from teaching-centred to learning-centred; the belief dimensions represent qualitatively distinct aspects of beliefs, such as ‘desired learning outcomes’ and ‘students’ motivation’. Methods We conducted in-depth semi-structured interviews with 26 faculty members, all of whom were deeply involved in teaching, from two prominent medical schools. We used the original framework of Samuelowicz and Bain as a starting point for context-specific adaptation. The qualitative analysis consisted of relating relevant interview fragments to the Samuelowicz and Bain framework, while remaining open to potentially new beliefs identified during the interviews. A range of strategies were employed to ensure the quality of the results. Results We identified a new belief dimension and adapted or refined other dimensions to apply in the context of medical education. The belief orientations that have counterparts in the original Samuelowicz and Bain framework are described more precisely in the new framework. The new framework sharpens the boundary between teaching-centred and learning-centred belief orientations. Conclusions Our findings confirm the relevance of the structure of the original Samuelowicz and Bain beliefs framework. However, multiple adaptations and refinements were necessary to align the framework to the context of medical education. The refined belief dimensions and belief orientations enable a comprehensive description of the educational beliefs of medical educators. With these adaptations, the new framework provides a contemporary instrument to improve medical education and potentially assist in faculty development of medical educators.

Background Education is essential to the integration of eHealth into primary care, but eHealth is not yet embedded in medical education. Objectives In this opinion article, we aim to support organisers of Continuing Professional Development (CPD) and teachers delivering medical vocational training by providing recommendations for eHealth education. First, we describe what is required to help primary care professionals and trainees learn about eHealth. Second, we elaborate on how eHealth education might be provided. Discussion We consider four essential topics. First, an understanding of existing evidence-based eHealth applications and conditions for successful development and implementation. Second, required digital competencies of providers and patients. Third, how eHealth changes patient-provider and provider-provider relationships and finally, understanding the handling of digital data. Educational activities to address these topics include eLearning, blended learning, courses, simulation exercises, real-life practice, supervision and reflection, role modelling and community of practice learning. More specifically, a CanMEDS framework aimed at defining curriculum learning goals can support eHealth education by describing roles and required competencies. Alternatively, Kern’s conceptual model can be used to design eHealth training programmes that match the educational needs of the stakeholders using eHealth. Conclusion Vocational and CPD training in General Practice needs to build on eHealth capabilities now. We strongly advise the incorporation of eHealth education into vocational training and CPD activities, rather than providing it as a separate single module. How learning goals and activities take shape and how competencies are evaluated clearly requires further practice, evaluation and study.

Abstract Background It is assumed that portfolios contribute to self-regulated learning (SRL). Presence of these SRL processes within the documentation kept in portfolios is presupposed in common educational practices, such as the assessment of reflective entries. However, questions can be asked considering the presence of SRL within portfolios. The aim of this study was to gain insight into the documentation of SRL processes within the electronic (e)-portfolio content of medical trainees. SRL consists of numerous processes, for this study the focus was on self-assessment via reflection and feedback, goal-setting and planning, and monitoring, as these are the processes that health professions education research mentions to be supported by portfolios. Methods A database containing 1022 anonymous e-portfolios from General Practitioner trainees was used to provide descriptive statistics of the various available e-portfolio forms. This was followed by a quantitative content analysis of 90 e-portfolios, for which, a codebook was constructed to rate the documentation of the included SRL processes. Results The numbers of forms in the e-portfolios varied to a great extent. Content analysis showed a limited documentation of reflective entries, and available entries mainly described events and experiences without explanations and context. Feedback was generally limited to comments on what went well and lacked specificity, context and suggestions for future action. Learning goals and plans were short of specificity, but did contain challenging topics and different goals were compatible with each other. 75% of the e-portfolios showed (limited) signs of monitoring. Conclusions The e-portfolio content showed limited documentation of SRL processes. As documentation of SRL requires time and asks for a high level of introspection and writing skills, one cannot expect documentation of SRL processes to appear in e-portfolio content without efforts.

There have been several genome-wide association study (GWAS) reported for carcass, growth, and meat traits in chickens. Most of these studies have been based on single SNPs GWAS. In contrast, haplotype-based GWAS reports have been limited. In the present study, 2 Northeast Agricultural University broiler lines divergently selected for abdominal fat content (NEAUHLF) and genotyped with the chicken 60K SNP chip were used to perform a haplotype-based GWAS. The lean and fat chicken lines were selected for abdominal fat content for 11 yr. Abdominal fat weight was significantly different between the 2 lines; however, there was no difference for body weight between the lean and fat lines. A total of 132 haplotype windows were significantly associated with abdominal fat weight. These significantly associated haplotype windows were primarily located on chromosomes 2, 4, 8, 10, and 26. Seven candidate genes, including SHH, LMBR1, FGF7, IL16, PLIN1, IGF1R, and SLC16A1, were located within these associated regions. These genes may play important roles in the control of abdominal fat content. Two regions on chromosomes 3 and 10 were significantly associated with testis weight. These 2 regions were previously detected by the single SNP GWAS using this same resource population. TCF21 on chromosome 3 was identified as a potentially important candidate gene for testis growth and development based on gene expression analysis and the reported function of this gene. TCF12, which was previously detected in our SNP by SNP interaction analysis, was located in a region on chromosome 10 that was significantly associated with testis weight. Six candidate genes, including TNFRSF1B, PLOD1, NPPC, MTHFR, EPHB2, and SLC35A3, on chromosome 21 may play important roles in bone development based on the known function of these genes. In addition, several regions were significantly associated with other carcass and growth traits, but no candidate genes were identified. The results of the present study may be helpful in understanding the genetic mechanisms of carcass and growth traits in chickens.

Abstract Background Direct observation of clinical task performance plays a pivotal role in competency-based medical education. Although formal guidelines require supervisors to engage in direct observations, research demonstrates that trainees are infrequently observed. Supervisors may not only experience practical and socio-cultural barriers to direct observations in healthcare settings, they may also question usefulness or have low perceived self-efficacy in performing direct observations. A better understanding of how these multiple factors interact to influence supervisors’ intention to perform direct observations may help us to more effectively implement the aforementioned guidelines and increase the frequency of direct observations. Methods We conducted an exploratory quantitative study, using the Theory of Planned Behaviour (TPB) as our theoretical framework. In applying the TPB, we transfer a psychological theory to medical education to get insight in the influence of cognitive and emotional processes on intentions to use direct observations in workplace based learning and assessment. We developed an instrument to investigate supervisors intention to perform direct observations. The relationships between the TPB measures of our questionnaire were explored by computing bivariate correlations using Pearson’s R tests. Hierarchical regression analysis was performed in order to assess the impact of the respective TPB measures as predictors on the intention to perform direct observations. Results In our study 82 GP supervisors completed our TPB questionnaire. We found that supervisors had a positive attitude towards direct observations. Our TPB model explained 45% of the variance in supervisors’ intentions to perform them. Normative beliefs and past behaviour were significant determinants of this intention. Conclusion Our study suggests that supervisors use their past experiences to form intentions to perform direct observations in a careful, thoughtful manner and, in doing so, also take the preferences of the learner and other stakeholders potentially engaged in direct observations into consideration. These findings have potential implications for research into work-based assessments and the development of training interventions to foster a shared mental model on the use of direct observations.

Abstract Background Aedes aegypti is a potential vector for several arboviruses including dengue and Zika viruses. The species seems to be restricted to subtropical/tropical habitats and has difficulties in establishing permanent populations in southern Europe, probably due to constraints during the winter season. The aim of this study was to systematically analyze the cold tolerance (CT) of Ae. aegypti in its most cold-resistant life stage, the eggs. Methods The CT of Ae. aegypti eggs was compared with that of Ae. albopictus which is well established in large parts of Europe. By systematically studying the literature (meta-analysis), we recognized that CT has been rarely tested in Ae. aegypti eggs, but eggs can survive at zero and sub-zero temperatures for certain exposure periods. To overcome potential bias from experimental differences between studies, we then conducted species comparisons using a harmonized high-resolution CT measuring method. From subtropical populations of the same origin, the survival (hatching in %) and emergence of adults of both species were measured after zero and sub-zero temperature exposures for up to 9 days (3 °C, 0 °C and − 2 °C: ≤ 9 days; − 6 °C: ≤ 2 days). Results Our data show that Ae. aegypti eggs can survive low and sub-zero temperatures for a short time period similar to or even better than those of Ae. albopictus. Moreover, after short sub-zero exposures of eggs of both species, individuals still developed into viable adults (Ae. aegypti: 3 adults emerged after 6 days at − 2 °C, Ae. albopictus: 1 adult emerged after 1 day at − 6 °C). Conclusions Thus, both the literature and the present experimental data indicate that a cold winter may not be the preventing factor for the re-establishment of the dengue vector Ae. aegypti in southern Europe.

Deforestation alters wildlife communities and modifies human–wildlife interactions, often increasing zoonotic spillover potential. When deforested land reverts to forest, species composition differences between primary and regenerating (secondary) forest could alter spillover risk trajectory. We develop a mathematical model of land-use change, where habitats differ in their relative spillover risk, to understand how land reversion influences spillover risk. We apply this framework to scenarios where spillover risk is higher in deforested land than mature forest, reflecting higher relative abundance of highly competent species and/or increased human–wildlife encounters, and where regenerating forest has either very low or high spillover risk. We find the forest regeneration rate, the spillover risk of regenerating forest relative to deforested land, and how rapidly regenerating forest regains attributes of mature forest determine landscape-level spillover risk. When regenerating forest has a much lower spillover risk than deforested land, reversion lowers cumulative spillover risk, but instaneous spillover risk peaks earlier. However, when spillover risk is high in regenerating and cleared habitats, landscape-level spillover risk remains high, especially when cleared land is rapidly abandoned then slowly regenerates to mature forest. These results suggest that proactive wildlife management and awareness of human exposure risk in regenerating forests could be important tools for spillover mitigation.

Matching strategies based on HLA eplets instead of HLA antigens in solid organ transplantation may not only increase the donor pool for highly sensitized patients, but also decrease the incidence of de novo donor-specific antibody formation. However, since not all eplets are equally capable of inducing an immune response, antibody verification is needed to confirm their ability to be bound by antibodies, such that only clinically relevant eplets are considered. The HLA Epitope Registry has documented all theoretically defined HLA eplets along with their antibody verification status and has been the foundation for many clinical studies investigating eplet mismatch in transplantation. The verification methods for eplets in the Registry range from polyclonal sera from multi- and uni-parous women to murine and human monoclonal antibodies (mAbs), and antibodies purified by adsorption and elution from sera of HLA immunized individuals. The classification of antibody verification based on different methods for validation is problematic, since not all approaches represent the same level of evidence. In this study, we introduce a classification system to evaluate the level of evidence for the antibody-verified status of all eplets in the HLA Epitope Registry. We demonstrate that for a considerable number of eplets, the antibody-verified status is solely based on polyclonal serum reactivity of multiparous women or on reactivity of murine mAbs. Furthermore, we noted that a substantial proportion of patient sera analyses and human mAb data presented in the HLA Epitope Registry Database has never been published in a peer-reviewed journal. Therefore, we tested several unpublished human HLA-specific mAbs by luminex single antigen beads assay to analyze their HLA reactivity for eplet antibody verification. Although the majority of analyzed mAbs indeed verified their assigned eplets, this was not the case for a number of eplets. This comprehensive overview of evidence for antibody verification of eplets in the HLA Epitope Registry is instrumental for future investigations towards eplet immunogenicity and clinical studies considering antibody-verified eplet mismatch in transplantation and warrants further standardization of antibody verification using high quality data.

By crafting a dramatic script about struggling high school readers that I then shared with real students in my Reading classes, I applied Arts-based education research (ABER) methods. Through the writing, presentation, collection, and reflection on student feedback, as well as during the script rewriting process, I was allowed to engage in a unique and motivating research experience. This approach allowed me to attend to three challenges with my Dissertation in Practice (DiP). First, instead of being part of this big, scary, abstract world called ‘research’, it allowed me to demonstrate inquiry though a means that I was more familiar and confident with—writing and theatre. My confidence working in these areas allowed me to initiate and remain engaged throughout the dissertation work. Second, it allowed me to take on a problem in my practice—the skepticism of many high school students in Reading classes about being in those classes. This helped me better understand my students, and thus inform and guide in the identification of best practices. Third, it positioned me to work with colleagues and administrators in my building and across our school district to rethink how we offer reading support to the heterogeneous cross-section of students who currently are being identified as needing such support. This account summarizes my DiP and, I hope, positions other classroom teachers who double as EdD students to imagine new and effective ways forward as they engage with problems of practice.

HLA-DQ donor-specific antibodies (DSA) are the most prevalent type of DSA after renal transplantation and have been associated with eplet mismatches between donor and recipient HLA. Eplets are theoretically defined configurations of surface exposed amino acids on HLA molecules that require verification to confirm that they can be recognized by alloantibodies and are therefore clinically relevant. In this study, we isolated HLA-DQ specific memory B cells from immunized individuals by using biotinylated HLA-DQ monomers to generate 15 recombinant human HLA-DQ specific monoclonal antibodies (mAb) with six distinct specificities. Single antigen bead reactivity patterns were analyzed with HLA-EMMA to identify amino acids that were uniquely shared by the reactive HLA alleles to define functional epitopes which were mapped to known eplets. The HLA-DQB1*03:01-specific mAb LB_DQB0301_A and the HLA-DQB1*03-specific mAb LB_DQB0303_C supported the antibody-verification of eplets 45EV and 55PP respectively, while mAbs LB_DQB0402_A and LB_DQB0602_B verified eplet 55R on HLA-DQB1*04/05/06. For three mAbs, multiple uniquely shared amino acid configurations were identified, warranting further studies to define the inducing functional epitope and corresponding eplet. Our unique set of HLA-DQ specific mAbs will be further expanded and will facilitate the in-depth analysis of HLA-DQ epitopes, which is relevant for further studies of HLA-DQ alloantibody pathogenicity in transplantation.

Converting a vaccine into a thermostable dry powder is advantageous as it reduces the resource burden linked with the cold chain and provides flexibility in dosage and administration through different routes. Such a dry powder presentation may be especially useful in the development of a vaccine towards the respiratory infectious disease tuberculosis (TB). This study assesses the immunogenicity and protective efficacy of spray-dried ID93+GLA-SE, a promising TB vaccine candidate, against Mycobacterium tuberculosis (Mtb) in a murine model when administered via different routes. Four administration routes for the spray-dried ID93+GLA-SE were evaluated along with relevant controls—1) reconstitution and intramuscular injection, 2) reconstitution and intranasal delivery, 3) nasal dry powder delivery via inhalation, and 4) pulmonary dry powder delivery via inhalation. Dry powder intranasal and pulmonary delivery was achieved using a custom nose-only inhalation device, and optimization using representative vaccine-free powder demonstrated that approximately 10 and 44% of the maximum possible delivered dose would be delivered for intranasal delivery and pulmonary delivery, respectively. Spray-dried powder was engineered according to the different administration routes including maintaining approximately equivalent delivered doses of ID93 and GLA. Vaccine properties of the different spray-dried lots were assessed for quality control in terms of nanoemulsion droplet diameter, polydispersity index, adjuvant content, and antigen content. Our results using the Mtb mouse challenge model show that both intranasal reconstituted vaccine delivery as well as pulmonary dry powder vaccine delivery resulted in Mtb control in infected mice comparable to traditional intramuscular delivery. Improved protection in these two vaccinated groups over their respective control groups coincided with the presence of cytokine-producing T cell responses. In summary, our results provide novel vaccine formulations and delivery routes that can be harnessed to provide protection against Mtb infection.

We present 294 pulsars found in GeV data from the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope. Another 33 millisecond pulsars (MSPs) discovered in deep radio searches of LAT sources will likely reveal pulsations once phase-connected rotation ephemerides are achieved. A further dozen optical and/or X-ray binary systems colocated with LAT sources also likely harbor gamma-ray MSPs. This catalog thus reports roughly 340 gamma-ray pulsars and candidates, 10% of all known pulsars, compared to ≤11 known before Fermi. Half of the gamma-ray pulsars are young. Of these, the half that are undetected in radio have a broader Galactic latitude distribution than the young radio-loud pulsars. The others are MSPs, with six undetected in radio. Overall, ≥236 are bright enough above 50 MeV to fit the pulse profile, the energy spectrum, or both. For the common two-peaked profiles, the gamma-ray peak closest to the magnetic pole crossing generally has a softer spectrum. The spectral energy distributions tend to narrow as the spindown power $\dot{E}$ decreases to its observed minimum near 10 ^33 erg s ^−1 , approaching the shape for synchrotron radiation from monoenergetic electrons. We calculate gamma-ray luminosities when distances are available. Our all-sky gamma-ray sensitivity map is useful for population syntheses. The electronic catalog version provides gamma-ray pulsar ephemerides, properties, and fit results to guide and be compared with modeling results.

The responses of plant photosynthesis to rapid fluctuations in environmental conditions are critical for efficient conversion of light energy. These responses are not well-seen laboratory conditions and are difficult to probe in field environments. We demonstrate an open science approach to this problem that combines multifaceted measurements of photosynthesis and environmental conditions, and an unsupervised statistical clustering approach. In a selected set of data on mint (Mentha sp.), we show that ‘light potentials’ for linear electron flow and non-photochemical quenching (NPQ) upon rapid light increases are strongly suppressed in leaves previously exposed to low ambient photosynthetically active radiation (PAR) or low leaf temperatures, factors that can act both independently and cooperatively. Further analyses allowed us to test specific mechanisms. With decreasing leaf temperature or PAR, limitations to photosynthesis during high light fluctuations shifted from rapidly induced NPQ to photosynthetic control of electron flow at the cytochrome b6f complex. At low temperatures, high light induced lumen acidification, but did not induce NPQ, leading to accumulation of reduced electron transfer intermediates, probably inducing photodamage, revealing a potential target for improving the efficiency and robustness of photosynthesis. We discuss the implications of the approach for open science efforts to understand and improve crop productivity.

Individuals with bleeding tendencies are more likely to have blood type O than blood types A, B, or AB. Platelet storage pool deficiencies are a lesser-known group of bleeding disorders which often go undiagnosed and may account for a significant number of patients with unexplained bleeding defects. We hypothesized that patients with platelet δ-storage pool deficiency might also have a predominance of type O blood. A retrospective review of medical records of 2,020 patients with unexplained bleeding and evaluated for δ-storage pool deficiency was performed. Correlations between dense granule numbers, blood type, and von Willebrand factor were analyzed for statistical differences. 51.5% of blood samples were blood type O compared to an incidence of 44.0% in the U.S. population. There was a significant association of vWF and blood type O but not with the delta storage pool. There is a preponderance of blood type O in the study population compared to the U.S. population. There is no statistically significant link between blood type O and lower dense granule numbers in this study.

In algae, it is well established that the pyrenoid, a component of the carbon-concentrating mechanism (CCM), is essential for efficient photosynthesis at low CO2. However, the signal that triggers the formation of the pyrenoid has remained elusive. Here, we show that, in Chlamydomonas reinhardtii, the pyrenoid is strongly induced by hyperoxia, even at high CO2 or bicarbonate levels. These results suggest that the pyrenoid can be induced by a common product of photosynthesis specific to low CO2 or hyperoxia. Consistent with this view, the photorespiratory by-product, H2O2, induced the pyrenoid, suggesting that it acts as a signal. Finally, we show evidence for linkages between genetic variations in hyperoxia tolerance, H2O2 signaling, and pyrenoid morphologies.

Sjögren’s Syndrome (SS) is a chronic autoimmune disease of unknown etiology which primarily affects the salivary and lacrimal glands resulting in the loss of secretory function. Treatment options for SS have been hampered due to the lack of a better understanding of the underlying gene regulatory circuitry and the interplay between the myriad pathological cellular states that contribute to salivary gland dysfunction. To better elucidate the molecular nature of SS, we have performed RNA-sequencing analysis of the submandibular glands (SMG) of a well-established primary Sjögren’s Syndrome (pSS) mouse model. Our comprehensive examination of global gene expression and comparative analyses with additional SS mouse models and human datasets, have identified a number of important pathways and regulatory networks that are relevant in SS pathobiology. To complement these studies, we have performed single-cell RNA sequencing to examine and identify the molecular and cellular heterogeneity of the diseased cell populations of the mouse SMG. Interrogation of the single-cell transcriptomes has shed light on the diversity of immune cells that are dysregulated in SS and importantly, revealed an activated state of the salivary gland epithelial cells that contribute to the global immune mediated responses. Overall, our broad studies have not only revealed key pathways, mediators and new biomarkers, but have also uncovered the complex nature of the cellular populations in the SMG that are likely to drive the progression of SS. These newly discovered insights into the underlying molecular mechanisms and cellular states of SS will better inform targeted therapeutic discoveries.

Abstract With mounting data on its accuracy and prognostic value, cardiovascular magnetic resonance (CMR) is becoming an increasingly important diagnostic tool with growing utility in clinical routine. Given its versatility and wide range of quantitative parameters, however, agreement on specific standards for the interpretation and post-processing of CMR studies is required to ensure consistent quality and reproducibility of CMR reports. This document addresses this need by providing consensus recommendations developed by the Task Force for Post-Processing of the Society for Cardiovascular Magnetic Resonance (SCMR). The aim of the Task Force is to recommend requirements and standards for image interpretation and post-processing enabling qualitative and quantitative evaluation of CMR images. Furthermore, pitfalls of CMR image analysis are discussed where appropriate. It is an update of the original recommendations published 2013.

Abstract This document is an update to the 2013 publication of the Society for Cardiovascular Magnetic Resonance (SCMR) Board of Trustees Task Force on Standardized Protocols. Concurrent with this publication, 3 additional task forces will publish documents that should be referred to in conjunction with the present document. The first is a document on the Clinical Indications for CMR, an update of the 2004 document. The second task force will be updating the document on Reporting published by that SCMR Task Force in 2010. The 3rd task force will be updating the 2013 document on Post-Processing. All protocols relative to congenital heart disease are covered in a separate document. The section on general principles and techniques has been expanded as more of the techniques common to CMR have been standardized. A section on imaging in patients with devices has been added as this is increasingly seen in day-to-day clinical practice. The authors hope that this document continues to standardize and simplify the patient-based approach to clinical CMR. It will be updated at regular intervals as the field of CMR advances.

Obstructive bioprosthetic valve thrombosis is associated with hemodynamic compromise, and evidence on management with fibrinolysis is limited. Echocardiography is required to assess thrombus size and its effects on valve gradients, area, and leaflet motion. This case demonstrates use of echocardiography guided slow-infusion low-dose fibrinolytic therapy in a patient with obstructive bioprosthetic valve thrombosis. (Level of Difficulty: Intermediate.)

Hemorrhage associated with anticoagulation therapy is a feared and relatively common complication. Few cases have been documented of spontaneous pancreatic hemorrhage related to anticoagulation, and fewer yet of ruptured pancreatic pseudocyst secondary to anticoagulation-related bleeding. We describe the case of a 74-year-old female with massive intra- and extraperitoneal hemorrhage secondary to an anticoagulation-related ruptured hemorrhagic pancreatic pseudocyst that was treated successfully with coil embolization. An inferior vena cava filter was placed at the same time as the embolization procedure, as she had a contraindication for anticoagulation in the setting of submassive pulmonary emboli and lower extremity deep venous thrombosis. Keywords: Embolization, Anticoagulation, Hemorrhage, Pancreas, Pseudocyst

Abstract Background Petal nectar spurs, which facilitate pollination through animal attraction and pollen placement, represent a key innovation promoting diversification in the genus Aquilegia (Ranunculaceae). Identifying the genetic components that contribute to the development of these three-dimensional structures will inform our understanding of the number and types of genetic changes that are involved in the evolution of novel traits. In a prior study, gene expression between two regions of developing petals, the laminar blade and the spur cup, was compared at two developmental stages in the horticultural variety A. coerulea ‘Origami’. Several hundred genes were differentially expressed (DE) between the blade and spur at both developmental stages. In order to narrow in on a set of genes crucial to early spur formation, the current study uses RNA sequencing (RNAseq) to conduct comparative expression analyses of petals from five developmental stages between four Aquilegia species, three with morphologically variable nectar spurs, A. sibirica, A. formosa, and A. chrysantha, and one that lacks nectar spurs, A. ecalcarata. Results Petal morphology differed increasingly between taxa across the developmental stages assessed, with petals from all four taxa being indistinguishable pre-spur formation at developmental stage 1 (DS1) and highly differentiated by developmental stage 5 (DS5). In all four taxa, genes involved in mitosis were down-regulated over the course of the assessed developmental stages, however, many genes involved in mitotic processes remained expressed at higher levels later in development in the spurred taxa. A total of 690 genes were identified that were consistently DE between the spurred taxa and A. ecalcarata at all five developmental stages. By comparing these genes with those identified as DE between spur and blade tissue in A. coerulea ‘Origami’, a set of only 35 genes was identified that shows consistent DE between petal samples containing spur tissue versus those without spur tissue. Conclusions The results of this study suggest that expression differences in very few loci are associated with the presence and absence of spurs. In general, it appears that the spurless petals of A. ecalcarata cease cell divisions and enter the cell differentiation phase at an earlier developmental time point than those that produce spurs. This much more tractable list of 35 candidates genes will greatly facilitate targeted functional studies to assess the genetic control and evolution of petal spurs in Aquilegia.

Abstract The introduced fungal pathogen Pseudogymnoascus destructans is causing decline of several species of bats in North America, with some even at risk of extinction or extirpation. The severity of the epidemic of white‐nose syndrome caused by P. destructans has prompted investigation of the transmission and virulence of infection at multiple scales, but linking these scales is necessary to quantify the mechanisms of transmission and assess population‐scale declines. We built a model connecting within‐hibernaculum disease dynamics of little brown bats to regional‐scale dispersal, reproduction, and disease spread, including multiple plausible mechanisms of transmission. We parameterized the model using the approach of plausible parameter sets, by comparing stochastic simulation results to statistical probes from empirical data on within‐hibernaculum prevalence and survival, as well as among‐hibernacula spread across a region. Our results are consistent with frequency‐dependent transmission between bats, support an important role of environmental transmission, and show very little effect of dispersal among colonies on metapopulation survival. The results help identify the influential parameters and largest sources of uncertainty. The model also offers a generalizable method to assess hypotheses about hibernaculum‐to‐hibernaculum transmission and to identify gaps in knowledge about key processes, and could be expanded to include additional mechanisms or bat species.

Abstract Objectives Whole body [18F]-fluorodihydrotestosterone positron emission tomography ([18F]FDHT PET) imaging directly targets the androgen receptor and is a promising prognostic and predictive biomarker in metastatic castration-resistant cancer (mCRPC). To optimize [18F]FDHT PET-CT for diagnostic and response assessment purposes, we assessed how count statistics and reconstruction protocol affect its accuracy, repeatability, and lesion detectability. Methods Whole body [18F]FDHT PET-CT scans were acquired on an analogue PET-CT on two consecutive days in 14 mCRPC patients harbouring a total of 336 FDHT-avid lesions. Images were acquired at 45 min post-injection of 200 MBq [18F]FDHT at 3 min per bed position. List-mode PET data were split on a count-wise basis, yielding two statistically independent scans with each 50% of counts. Images were reconstructed according to current EANM Research Ltd. (EARL1, 4 mm voxel) and novel EARL2 guidelines (4 mm voxel + PSF). Per lesion, we measured SUVpeak, SUVmax, SUVmean, and contrast-to-noise ratio (CNR). SUV was normalized to dose per bodyweight as well as to the parent plasma input curve integral. Variability was assessed with repeatability coefficients (RCs). Results Count reduction increased liver coefficient of variation from 9.0 to 12.5% and from 10.8 to 13.2% for EARL1 and EARL2, respectively. SUVs of EARL2 images were 12.0–21.7% higher than EARL1. SUVs of 100% and 50% count data were highly correlated (R 2 > 0.98; slope = 0.97–1.01; ICC = 0.99–1.00). Intrascan variability was volume-dependent, and count reduction resulted in higher intrascan variability for EARL2 than EARL1 images. Intrascan RCs were lowest for SUVmean (8.5–10.6%), intermediate for SUVpeak (12.0–16.0%), and highest for SUVmax (17.8–22.2%). Count reduction increased test-retest variance non-significantly (p > 0.05) for all SUV types and normalizations. For SUVpeak at 50% of counts, RCs remained

Abstract Background The educational beliefs of medical academics influence how they act in class and thus influence student learning. One component of these are beliefs academics hold about the qualities of teachers themselves. These teacher qualities range from behaviours and competencies to more personal attributes such as the teacher’s identity and mission. However, it is unclear what medical academics believe to be key teacher qualities. Therefore, this study explored the variety of medical academics’ beliefs about ‘teacher qualities’, aiming to identify and characterise profiles of academics with similar beliefs. Methods We interviewed 26 expert academics from two medical schools to explore their beliefs about teacher qualities. A concentric onion-model focusing on teacher qualities was used to analyse and categorise the data deductively. Within each theme we developed subthemes inductively. To gain insight into the variety of beliefs we then clustered the participants into teacher profiles according to the themes. To better understand each of the profiles we carried out a quantitative study of the differences between profiles regarding subthemes, contextual and personal factors, and analysed statistical significance using Fisher’s exact- and Student’s t-tests for categorical and continuous data, respectively. Results Four profiles of medical academics were identified, corresponding to the most central theme that each participant had reflected on: the ‘Inspirer’, ‘Role-model’, ‘Practitioner’, and ‘Critic’. The focus of the profiles varied from external constraining factors within the ‘Critic’ profile to affective personal qualities within the ‘Role-model’ and ‘Inspirer’ profiles. The profiles could be regarded as hierarchically ordered by inclusiveness. Educational institute was the only significant factor related to the profiles. Conclusions Besides the relevance of affective teacher qualities, the ‘Inspirer’ profile demonstrates the importance of developing a clear mission as a teaching academic, centred around student learning and professional development. In our view, academics who inspire their students continue to be inspired themselves. The practical implications are described for faculty development programmes, and for the potential value of using these profiles within medical schools. In the discourse on educational beliefs, the authors argue that more attention should be paid to affective qualities, in particular to explicating the educational mission of academics.

Abstract Background In our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRGSTIM), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways. Methods Blood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3 months L4-DRGSTIM using PANTHER™ pathway enrichment analysis tool. Results Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRGSTIM. Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated. Conclusions In our sub-group analysis of L4-DRGSTIM treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267

The concept of invasion is useful across a broad range of contexts, spanning from the fine scale landscape of cancer tumors up to the broader landscape of ecosystems. Invasion biology provides extraordinary opportunities for studying the mechanistic basis of contemporary evolution at the molecular level. Although the field of invasion genetics was established in ecology and evolution more than 50 years ago, there is still a limited understanding of how genomic level processes translate into invasive phenotypes across different taxa in response to complex environmental conditions. This is largely because the study of most invasive species is limited by information about complex genome level processes. We lack good reference genomes for most species. Rigorous studies to examine genomic processes are generally too costly. On the contrary, cancer studies are fortified with extensive resources for studying genome level dynamics and the interactions among genetic and non-genetic mechanisms. Extensive analysis of primary tumors and metastatic samples have revealed the importance of several genomic mechanisms including higher mutation rates, specific types of mutations, aneuploidy or whole genome doubling and non-genetic effects. Metastatic sites can be directly compared to primary tumor cell counterparts. At the same time, clonal dynamics shape the genomics and evolution of metastatic cancers. Clonal diversity varies by cancer type, and the tumors’ donor and recipient tissues. Still, the cancer research community has been unable to identify any common events that provide a universal predictor of “metastatic potential” which parallels findings in evolutionary ecology. Instead, invasion in cancer studies depends strongly on context, including order of events and clonal composition. The detailed studies of the behavior of a variety of human cancers promises to inform our understanding of genome level dynamics in the diversity of invasive species and provide novel insights for management.

Introduction Preterm birth is one of the main problems in obstetrics, and the most important cause of neonatal mortality, morbidity and neurodevelopmental impairment. Multiple gestation is an important risk factor for preterm birth, with up to 50% delivering before 37 weeks. Progesterone has a role in maintaining pregnancy and is frequently prescribed to prevent (recurrent) preterm birth and improve pregnancy outcomes in high-risk patients. However, little is known about its long-term effects in multiple gestations. The objective of this follow-up study is to assess long-term benefits and harms of prenatal exposure to progesterone treatment in multiple gestations on child development.Methods and analysis This is a follow-up study of a multicentre, double-blind, placebo-controlled randomised trial (AMPHIA trial, ISRCTN40512715). Between 2006 and 2009 women with a multiple gestation were randomised at 16–20 weeks of gestation to weekly injections 250 mg 17α-hydroxyprogesterone caproate or placebo, until 36 weeks of gestation or delivery. The current long-term follow-up will assess all children (n=1355) born to mothers who participated in the AMPHIA trial, at 11–14 years of age, with internationally validated questionnaires, completed by themselves, their parents and their teachers.Main outcomes are child cognition and behaviour Additional outcomes are death (perinatal and up to age 14), gender identity, educational performance and health-related problems. We will use intention-to-treat analyses comparing experimental and placebo group. To adjust for the correlation between twins, general linear mixed-effects models will be used.Ethics and dissemination Amsterdam UMC MEC provided a waiver for the Medical Research Involving Human Subjects Act (W20_234#20.268). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders, patients and participants. This protocol is published before analysis of the results.Trial registration number NL8933.

Antibody response to porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) infection, measured as sample-to-positive (S/P) ratio, has been proposed as an indicator trait for improved reproductive performance during a PRRS outbreak in Landrace sows. However, this result has not yet been validated in Landrace sows or evaluated in terminal sire lines. The main objectives of this work were to validate the use of S/P ratio as an indicator trait to select pigs during a PRRS outbreak and to explore the genetic basis of antibody response to PRRSV. Farrowing data included 2,546 and 2,522 litters from 894 Duroc and 813 Landrace sows, respectively, split into pre-PRRS, PRRS, and post-PRRS phases. Blood samples were taken from 1,231 purebred sows (541 Landrace and 690 Duroc) following a PRRS outbreak for subsequent PRRSV ELISA analysis for S/P ratio measurement. All animals had high-density genotype data available (29,799 single nucleotide polymorphisms; SNPs). Genetic parameters and genome-wide association studies (GWAS) for S/P ratio were performed for each breed separately. Heritability estimates (± standard error) of S/P ratio during the PRRS outbreak were moderate, with 0.35 ± 0.08 for Duroc and 0.34 ± 0.09 for Landrace. During the PRRS outbreak, favorable genetic correlations of S/P ratio with the number of piglets born alive (0.61 ± 0.34), number of piglets born dead (−0.33 ± 0.32), and number of stillborn piglets (−0.27 ± 0.31) were observed for Landrace sows. For Duroc, the GWAS identified a major quantitative trait locus (QTL) on chromosome (Chr) 7 (24-15 megabases; Mb) explaining 15% of the total genetic variance accounted for by markers (TGVM), and another one on Chr 8 (25 Mb) explaining 2.4% of TGVM. For Landrace, QTL on Chr 7 (24–25 Mb) and Chr 7 (108–109 Mb), explaining 31% and 2.2% of TGVM, respectively, were identified. Some of the SNPs identified in these regions for S/P ratio were associated with reproductive performance but not during the PRRS outbreak. Genomic prediction accuracies for S/P ratio were moderate to high for the within-breed analysis. For the between-breed analysis, these were overall low. These results further support the use of S/P ratio as an indicator trait for improved reproductive performance during a PRRS outbreak in Landrace sows.

Porcine Reproductive and Respiratory Syndrome (PRRS) is historically the most economically important swine disease worldwide that severely affects the reproductive performance of sows. However, little is still known about the genetic basis of reproductive performance in purebred herds during a PRRS outbreak through the comparison of maternal and terminal breeds. Thus, the objective of this work was to explore the host genetics of response to PRRS in purebred sows from two breeds. Reproductive data included 2546 Duroc and 2522 Landrace litters from 894 and 813 purebred sows, respectively, which had high-density genotype data available (29,799 single nucleotide polymorphisms; SNPs). The data were split into pre-PRRS, PRRS, and post-PRRS phases based on standardized farrow-year-week estimates. Heritability estimates for reproductive traits were low to moderate (≤0.20) for Duroc and Landrace across PRRS phases. On the other hand, genetic correlations of reproductive traits between PRRS phases were overall moderate to high for both breeds. Several associations between MARC0034894, a candidate SNP for response to PRRS, with reproductive performance were identified (P-value < 0.05). Genomic analyses detected few QTL for reproductive performance across all phases, most explaining a small percentage of the additive genetic variance (≤8.2%, averaging 2.1%), indicating that these traits are highly polygenic. None of the identified QTL within a breed and trait overlapped between PRRS phases. Overall, our results indicate that Duroc sows are phenotypically more resilient to PRRS than Landrace sows, with a similar return to PRRS-free performance between breeds for most reproductive traits. Genomic prediction results indicate that genomic selection for improved reproductive performance under a PRRS outbreak is possible, especially in Landrace sows, by training markers using data from PRRS-challenged sows. On the other hand, the high genetic correlations with reproductive traits between PRRS phases suggest that selection for improved reproductive performance in a clean environment could improve performance during PRRS, but with limited efficiency due to their low heritability estimates. Thus, we hypothesize that an indicator trait that could be indirectly selected to increase the response to selection for these traits would be desirable and would also improve the reproductive performance of sows during a PRRS outbreak.

Primary Sjögren’s syndrome is an autoimmune disease that is predominantly seen in women. The disease is characterized by exocrine gland dysfunction in combination with serious systemic manifestations. At present, the causes of pSS are poorly understood. Pulmonary and renal inflammation are observed in pSS mice, reminiscent of a subset of pSS patients. A growing body of evidence indicates that inflammation mediated by Damage-Associated Molecular Patterns (DAMPs) contributes to autoimmunity, although this is not well-studied in pSS. Degraded extracellular matrix (ECM) constituents can serve as DAMPs by binding pattern-recognition receptors and activating Myd88-dependent signaling cascades, thereby exacerbating and perpetuating inflammatory cascades. The ECM components biglycan (Bgn) and decorin (Dcn) mediate sterile inflammation and both are implicated in autoimmunity. The objective of this study was to determine whether these ECM components and anti-ECM antibodies are altered in a pSS mouse model, and whether this is dependent on Myd88 activation in immune cells. Circulating levels of Bgn and Dcn were similar among pSS mice and controls and tissue expression studies revealed pSS mice had robust expression of both Bgn and Dcn in the salivary tissue, saliva, lung and kidney. Sera from pSS mice displayed increased levels of autoantibodies directed against ECM components when compared to healthy controls. Further studies using sera derived from conditional knockout pSS mice demonstrated that generation of these autoantibodies relies, at least in part, on Myd88 expression in the hematopoietic compartment. Thus, this study demonstrates that ECM degradation may represent a novel source of chronic B cell activation in the context of pSS.

During mitosis in higher eukaryotes, each chromosome condenses into a pair of rod-shaped chromatids. This process is co-regulated by the activity of several gene families, and the underlying biophysics remains poorly understood. To better understand the factors regulating chromosome condensation, we compiled a database of mitotic chromosome size and DNA content from the tables and figures of >200 published papers. A comparison across vertebrate species shows that chromosome width, length and volume scale with DNA content to the powers ∼1/4, ∼1/2, and ∼1, respectively. Angiosperms (flowering plants) show a similar length scaling, so this result is not specific to vertebrates. Chromosome shape and size thus satisfy two conditions: (1) DNA content per unit volume is approximately constant and (2) the cross-sectional area increases proportionately with chromosome length. Since viscous drag forces during chromosome movement are expected to scale with length, we hypothesize that the cross-section increase is necessary to limit the occurrence of large chromosome elongations that could slow or stall mitosis. Lastly, we note that individual vertebrate karyotypes typically exhibit a wider range of chromosome lengths as compared with angiosperms.

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized primarily by immune-mediated destruction of exocrine tissues, such as those of the salivary and lacrimal glands, resulting in the loss of saliva and tear production, respectively. This disease predominantly affects middle-aged women, often in an insidious manner with the accumulation of subtle changes in glandular function occurring over many years. Patients commonly suffer from pSS symptoms for years before receiving a diagnosis. Currently, there is no effective cure for pSS and treatment options and targeted therapy approaches are limited due to a lack of our overall understanding of the disease etiology and its underlying pathology. To better elucidate the underlying molecular nature of this disease, we have performed RNA-sequencing to generate a comprehensive global gene expression profile of minor salivary glands from an ethnically diverse cohort of patients with pSS. Gene expression analysis has identified a number of pathways and networks that are relevant in pSS pathogenesis. Moreover, our detailed integrative analysis has revealed a primary Sjögren’s syndrome molecular signature that may represent important players acting as potential drivers of this disease. Finally, we have established that the global transcriptomic changes in pSS are likely to be attributed not only to various immune cell types within the salivary gland but also epithelial cells which are likely playing a contributing role. Overall, our comprehensive studies provide a database-enriched framework and resource for the identification and examination of key pathways, mediators, and new biomarkers important in the pathogenesis of this disease with the long-term goals of facilitating earlier diagnosis of pSS and to mitigate or abrogate the progression of this debilitating disease.

Tenderness is a major quality attribute for fresh beef steaks in the United States, and meat quality traits in general are suitable candidates for genomic research. The objectives of the present analysis were to (1) perform genome-wide association (GWA) analysis for marbling, Warner-Bratzler shear force (WBSF), tenderness, and connective tissue using whole-genome data in an Angus population, (2) identify enriched pathways in each GWA analysis; (3) construct a protein–protein interaction network using the associated genes and (4) perform a μ-calpain proteolysis assessment for associated structural proteins. An Angus-sired population of 2,285 individuals was assessed. Animals were transported to a commercial packing plant and harvested at an average age of 457 ± 46 days. After 48 h postmortem, marbling was recorded by graders’ visual appraisal. Two 2.54-cm steaks were sampled from each muscle for recording of WBSF, and tenderness, and connective tissue by a sensory panel. The relevance of additive effects on marbling, WBSF, tenderness, and connective tissue was evaluated on a genome-wide scale using a two-step mixed model-based approach in single-trait analysis. A tissue-restricted gene enrichment was performed for each GWA where all polymorphisms with an association p-value lower than 1 × 10–3 were included. The genes identified as associated were included in a protein–protein interaction network and a candidate structural protein assessment of proteolysis analyses. A total of 1,867, 3,181, 3,926, and 3,678 polymorphisms were significantly associated with marbling, WBSF, tenderness, and connective tissue, respectively. The associate region on BTA29 (36,432,655–44,313,046 bp) harbors 13 highly significant markers for meat quality traits. Enrichment for the GO term GO:0005634 (Nucleus), which includes transcription factors, was evident. The final protein–protein network included 431 interations between 349 genes. The 42 most important genes based on significance that encode structural proteins were included in a proteolysis analysis, and 81% of these proteins were potential μ-Calpain substrates. Overall, this comprehensive study unraveled genetic variants, genes and mechanisms of action responsible for the variation in meat quality traits. Our findings can provide opportunities for improving meat quality in beef cattle via marker-assisted selection.

The objectives of this study were to explore the usefulness of blood-based traits as indicators of health and performance in beef cattle at weaning and identify the genetic basis underlying the different blood parameters obtained from complete blood counts (CBCs). Disease costs represent one of the main factors determining profitability in animal production. Previous research has observed associations between blood cell counts and an animal’s health status in some species. CBC were recorded from approximately 570 Angus based, crossbred beef calves at weaning born between 2015 and 2016 and raised on toxic or novel tall fescue. The calves (N = ∼600) were genotyped at a density of 50k SNPs and the genotypes (N = 1160) were imputed to a density of 270k SNPs. Genetic parameters were estimated for 15 blood and 4 production. Finally, with the objective of identifying the genetic basis underlying the different blood-based traits, genome-wide association studies (GWAS) were performed for all traits. Heritability estimates ranged from 0.11 to 0.60, and generally weak phenotypic correlations and strong genetic correlations were observed among blood-based traits only. Genome-wide association study identified ninety-one 1-Mb windows that accounted for 0.5% or more of the estimated genetic variance for at least 1 trait with 21 windows overlapping across two or more traits (explaining more than 0.5% of estimated genetic variance for two or more traits). Five candidate genes have been identified in the most interesting overlapping regions related to blood-based traits. Overall, this study represents one of the first efforts represented in scientific literature to identify the genetic basis of blood cell traits in beef cattle. The results presented in this study allow us to conclude that: (1) blood-based traits have weak phenotypic correlations but strong genetic correlations among themselves. (2) Blood-based traits have moderate to high heritability. (3) There is evidence of an important overlap of genetic control among similar blood-based traits which will allow for their use in improvement programs in beef cattle.

Abstract The axion emerges in extensions of the Standard Model that explain the absence of CP violation in the strong interactions. Simultaneously, it can provide naturally the cold dark matter in our universe. Several searches for axions and axion-like particles (ALPs) have constrained the corresponding parameter space over the last decades but no unambiguous hints of their existence have been found. The axion mass range below 1 meV remains highly attractive and a well motivated region for dark matter axions. In this White Paper we present a description of a new experiment based on the concept of a dielectric haloscope for the direct search of dark matter axions in the mass range of 40 to 400 $$\upmu \hbox {eV}$$ μeV . This MAgnetized Disk and Mirror Axion eXperiment (MADMAX) will consist of several parallel dielectric disks, which are placed in a strong magnetic field and with adjustable separations. This setting is expected to allow for an observable emission of axion induced electromagnetic waves at a frequency between 10 to 100 GHz corresponding to the axion mass.