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This article contributes to growing efforts to explain when nonviolent resistance campaigns emerge in autocratic regimes. Building from a novel framework for distinguishing civil-military relations in autocracies, it contends that regimes in which military and political leaders engage in a 'grand bargain' generate opportunity structures that are especially amenable to nonviolent resistance. Militaries in these regimes exhibit distinctive characteristics – they are corporate, cohesive institutions as opposed to fragmented in structure and also wield political influence in regime institutions. Consequently, these militaries are especially inclined to care about their societal reputations and to retain their institutional independence from the regime's political leaders. These factors together can lessen expectations among activists that the military will repress protests and increase the odds of elite splits in the face of mass movements. They also render the military more receptive to nonviolent protest tactics. We operationalize the concept of grand bargains with indicators from three datasets on civil-military relations and autocratic regimes. We then test the argument quantitatively using data on the onset of nonviolent resistance campaigns, as well as events-level data on nonviolent resistance campaigns. The findings support claims that civil-military grand bargains make nonviolent resistance in autocracies more likely, contributing to scholarship on this vital topic. [ABSTRACT FROM AUTHOR]

Simple Summary: Entomologists, like many other types of scientists, will often share their scientific findings with the public. This is especially true for entomologists, who engage specific audiences, such as extension programs that target farmers, for example. But those focusing on K-12 classrooms are less well studied. Here, we conducted a scoping review to search for all relevant publications, and from those determine (1) the characteristics of K-12 entomology outreach efforts and (2) opportunities for improvement based on identified characteristics. The search of five databases yielded 42 relevant publications. Analysis of those publications identified the following characteristics of K-12 outreach efforts: These publications are most often published in educational journals, they are most often reflective, and they rarely evaluate the interventions employed. We suggest that the practice of K-12 entomology outreach benefits from (i) publishing in entomology-focused journals, (ii) including non-academic authors, (iii) evaluating interventions, (iv) including student data, and (v) considering elements of diversity and inclusion. Engaging the public is a common practice in science disciplines and is deeply rooted in the discipline of entomology. These efforts to engage specific target groups within the general public are well studied, especially extension efforts to engage farmers and agricultural stakeholders, but this is not the case for K-12 educational spaces. Here, we conducted a scoping review to (1) determine the characteristics of entomology outreach efforts engaging K-12 populations and (2) identify opportunities for improvement based on the synthesis of those characteristics. We systematically searched five databases to identify 42 publications relevant to the parameters of this project. Analysis of characteristics indicated that entomology outreach efforts in K-12 classrooms tend to be reflective, are more often published in educationally focused journals, and rarely evaluate the interventions employed. Opportunities for improvement were identified from these trends, and from them we suggest that the practice of K-12 outreach benefits from (i) publishing in entomology-focused journals, (ii) including non-academic authors, (iii) evaluating interventions, (iv) including student data, and (v) considering axes of diversity and inclusion. [ABSTRACT FROM AUTHOR]

The precise classification of copy number variants (CNVs) presents a significant challenge in genomic medicine, primarily due to the complex nature of CNVs and their diverse impact on rare genetic diseases (RGDs). This complexity is compounded by the limitations of existing methods in accurately distinguishing between benign, uncertain, and pathogenic CNVs. Addressing this gap, we introduce CNVoyant, a machine learning-based multi-class framework designed to enhance the clinical significance classification of CNVs. Trained on a comprehensive dataset of 52,176 ClinVar entries across pathogenic, uncertain, and benign classifications, CNVoyant incorporates a broad spectrum of genomic features, including genome position, disease-gene annotations, dosage sensitivity, and conservation scores. Models to predict the clinical significance of copy number gains and losses were trained independently. Final models were selected after testing 29 machine learning architectures and 10,000 hyperparameter combinations each for deletions and duplications via fivefold cross-validation. We validate the performance of CNVoyant by leveraging a comprehensive set of 21,574 CNVs from the DECIPHER database, a highly regarded resource known for its extensive catalog of chromosomal imbalances linked to clinical outcomes. Compared to alternative approaches, CNVoyant shows marked improvements in precision-recall and ROC AUC metrics for binary pathogenic classifications while going one step further, offering multi-classification of clinical significance and corresponding SHAP explainability plots. Additionally, when provided germline CNV calls from real-world RGD cases with diagnostic CNV(s), CNVoyant correctly classified all diagnostic CNVs as having pathogenic significance with high confidence. This large-scale validation demonstrates CNVoyant's superior accuracy and underscores its potential to aid genomic researchers and clinical geneticists in interpreting the clinical implications of real CNVs. [ABSTRACT FROM AUTHOR]

Norovirus infection is characterised by a rapid onset of disease and the development of debilitating symptoms including projectile vomiting and diffuse diarrhoea. Vaccines and antivirals are sorely lacking and developments in these areas are hampered by the lack of an adequate cell culture system to investigate human norovirus replication and pathogenesis. Herein, we describe how the model norovirus, Mouse norovirus (MNV), produces a viral protein, NS3, with the functional capacity to attenuate host protein translation which invokes the activation of cell death via apoptosis. We show that this function of NS3 is conserved between human and mouse viruses and map the protein domain attributable to this function. Our study highlights a critical viral protein that mediates crucial activities during replication, potentially identifying NS3 as a worthy target for antiviral drug development. Author summary: Norovirus infection is a global health problem and is it estimated that ~10% of the world population suffer an infection each year. The infection is characterized by projectile vomiting and profuse diarrhoea, yet surprisingly there are no available preventative or treatment options currently available. This is primarily due to the lack of efficient in vitro virus cultivation system. Within this report we have used the model norovirus, mouse norovirus or MNV, and investigated the role of the virus encoded protein NS3 in potentiating cell death within infected cells. We show that the initiation of cell death is promoted due to the depletion of the cell pro-survival protein induced by both virus infection and expression of the NS3 protein alone. We have showed that this biochemical characteristic is conserved between mouse and human viruses and mapped the functional domain within the NS3 protein. This research has identified a mechanistic role for the NS3 protein during the norovirus replication cycle. [ABSTRACT FROM AUTHOR]

This study evaluates the utilization of in vitro embryo production (IVEP) technology for the conservation and breeding of the Auliekol cattle breed, a primary beef breed in Kazakhstan facing population decline due to the cessation of breeding programs and the incursion of transboundary diseases. We assessed the effect of consecutive ovum pick-up (OPU) procedures on oocyte yield and embryo production in Auliekol and Aberdeen Angus cows. A total of 2232 and 3659 oocytes were aspirated from Auliekol and Aberdeen Angus donors, respectively, with significantly higher yields and embryo production observed in Aberdeen Angus cows. The application of a meiotic block using Butyrolactone I (BLI) and subsequent in vitro fertilization (IVF) protocols was employed, with embryo development monitored up to the morula/blastocyst stage. Results indicated that Auliekol cows exhibited lower oocyte recovery, cleavage, and blastocyst rates compared to Aberdeen Angus cows, likely due to genetic characteristics. Despite the challenges, IVEP presents a valuable tool for the preservation and future propagation of the Auliekol breed, highlighting the need for further research to enhance reproductive outcomes and conservation strategies. [ABSTRACT FROM AUTHOR]

Retroviruses are an ancient viral family that have globally coevolved with vertebrates and impacted their evolution. In Australia, a continent that has been geographically isolated for millions of years, little is known about retroviruses in wildlife, despite the devastating impacts of a retrovirus on endangered koala populations. We therefore sought to identify and characterize Australian retroviruses through reconstruction of endogenous retroviruses from marsupial genomes, in particular the Tasmanian devil due to its high cancer incidence. We screened 19 marsupial genomes and identified over 80,000 endogenous retrovirus fragments which we classified into eight retrovirus clades. The retroviruses were similar to either Betaretrovirus (5/8) or Gammaretrovirus (3/8) retroviruses, but formed distinct phylogenetic clades compared to extant retroviruses. One of the clades (MEBrv 3) lost an envelope but retained retrotranspositional activity, subsequently amplifying throughout all Dasyuridae genomes. Overall, we provide insights into Australian retrovirus evolution and identify a highly active endogenous retrovirus within Dasyuridae genomes. [ABSTRACT FROM AUTHOR]

Background: Systemic thrombolysis (ST) may not be ideal for many patients with acute pulmonary embolism (PE) due to bleeding risk. In this analysis, we evaluated the safety and effectiveness of mechanical thrombectomy (MT) as an alternative to ST for acute PE. Methods: Patients aged ≥18 years who underwent MT and/or ST for PE were identified from the National Inpatient Sample database from 2016 to 2017. Patients who underwent catheter-directed thrombolysis were excluded. We compared in-hospital outcomes of both groups in this retrospective study. Results: Of 16 890 patients who received an intervention for acute PE, 1380 (8.2%) received MT and 15 510 (91.8%) received ST. There was no difference in age between both groups. In-hospital mortality was significantly lower in patients who received MT than that in those who received ST (11.9% vs 20.6%, odds ratio [OR]: 0.52, 95% confidence interval [CI]: 0.29–0.93, p=0.028). There was no statistically significant difference in terms of periprocedural bleeding, intracranial hemorrhage, and acute kidney injury between the 2 groups (p≥0.608 for all). Patients who received MT had a higher rate of respiratory complications (19.0% vs 11.6%, OR: 1.79, 95% CI: 1.06–3.03, p=0.030) and discharge to an outside facility (34.1% vs 19.2%, OR: 2.18, 95% CI: 1.41–3.37, p<0.001) than those who received ST. Conclusion: Mortality was significantly lower with MT than that with ST, but larger randomized studies are needed to validate this. The use of MT should be individualized on the basis of the patients' clinical presentation, risk profile, and local resources. Clinical Impact: In this study, we utilized the National Inpatient Sample database to study the in-hospital outcomes of pulmonary embolism patients who underwent mechanical thrombectomy compared to those who underwent systemic thrombolysis. We found that the patients who were diagnosed with pulmonary embolism and underwent mechanical thrombectomy had significantly lower mortality compared to those who were treated using systemic thrombolysis. This study was the first of its kind, utilizing the national inpatient sample database for evaluation of mechanical thrombectomy in comparison with the standard of care. These result would direct further randomized controlled trials for better evaluation of the utilization of mechanical thrombectomy in the correct clinical context. Furthermore, our study demonstrated comparable peri-operative complications between the mechanical thrombectomy group and the systemic thrombolysis group. These results would direct clinicians to consider mechanical thrombectomy if clinically indicated given the promising results. [ABSTRACT FROM AUTHOR]

Studying moths is an excellent way to include students in science practices by introducing them to a ubiquitous but under-appreciated animal group that can be found in their local places, including urban, suburban, agricultural, forested, and other habitats. In this paper, we share a simple, low-cost method that can allow individual students or groups to collect moth specimens and begin to ask and answer questions about moth diversity and abundance in their local community. [ABSTRACT FROM AUTHOR]

Background: Prior to September 2021, 55,000–90,000 hospital inpatients in England were identified as having a potentially nosocomial SARS-CoV-2 infection. This includes cases that were likely missed due to pauci- or asymptomatic infection. Further, high numbers of healthcare workers (HCWs) are thought to have been infected, and there is evidence that some of these cases may also have been nosocomially linked, with both HCW to HCW and patient to HCW transmission being reported. From the start of the SARS-CoV-2 pandemic interventions in hospitals such as testing patients on admission and universal mask wearing were introduced to stop spread within and between patient and HCW populations, the effectiveness of which are largely unknown. Materials/methods: Using an individual-based model of within-hospital transmission, we estimated the contribution of individual interventions (together and in combination) to the effectiveness of the overall package of interventions implemented in English hospitals during the COVID-19 pandemic. A panel of experts in infection prevention and control informed intervention choice and helped ensure the model reflected implementation in practice. Model parameters and associated uncertainty were derived using national and local data, literature review and formal elicitation of expert opinion. We simulated scenarios to explore how many nosocomial infections might have been seen in patients and HCWs if interventions had not been implemented. We simulated the time period from March-2020 to July-2022 encompassing different strains and multiple doses of vaccination. Results: Modelling results suggest that in a scenario without inpatient testing, infection prevention and control measures, and reductions in occupancy and visitors, the number of patients developing a nosocomial SARS-CoV-2 infection could have been twice as high over the course of the pandemic, and over 600,000 HCWs could have been infected in the first wave alone. Isolation of symptomatic HCWs and universal masking by HCWs were the most effective interventions for preventing infections in both patient and HCW populations. Model findings suggest that collectively the interventions introduced over the SARS-CoV-2 pandemic in England averted 400,000 (240,000 – 500,000) infections in inpatients and 410,000 (370,000 – 450,000) HCW infections. Conclusions: Interventions to reduce the spread of nosocomial infections have varying impact, but the package of interventions implemented in England significantly reduced nosocomial transmission to both patients and HCWs over the SARS-CoV-2 pandemic. [ABSTRACT FROM AUTHOR]

Copyright of Mission Studies: Journal of the International Association for Mission Studies is the property of Brill Academic Publishers and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A critical element in civil wars is military fragmentation. Yet, we have a limited understanding of why military elites fight in civil wars and on what side. In this article I develop a theory of the economic and professional motivations of military elites. I test this theory using the case of West Point graduates in the American Civil War. I argue that in addition to home state, economic and professional interests were a major influence on West Pointers. Graduates with connections to Southern cash crops were less likely to fight for the Union and more likely to fight for the Confederacy. Higher ranking graduates were more likely to fight for both sides, as they were better positioned to compete for promotion. I test this argument using a new dataset of more than 1000 West Point graduates' wartime allegiances and antebellum careers and find strong evidence in support of my expectations. [ABSTRACT FROM AUTHOR]

Clinical exome and genome sequencing (ES/GS) have become indispensable diagnostic tools for rare genetic diseases (RGD). However, the interpretation of ES/GS presents a substantial operational challenge in clinical settings. Test interpretation requires the review of hundreds of genetic variants, a task that has become increasingly challenging given the rising use of ES/ GS. In response, we present Clinical Assessment of Variants by Likelihood Ratios (CAVaLRi), which employ a modified likelihood ratio (LR) framework to assign diagnostic probabilities to candidate germline disease genes. CAVaLRi models aspects of the clinical variant assessment process, taking into consideration the predicted impact of the variant, the proband and parental genotypes, and the proband's clinical characteristics. It also factors in computational phenotype noise and weighs the relative significance of genotype, phenotype, and variant segregation information. We trained and tested CAVaLRi on variant and phenotype data from an internal cohort of 655 clinical ES cases. For validation, CAVaLRi's performance was benchmarked against four leading gene prioritization algorithms (Exomiser's hiPHIVE and PhenIX prioritizers, LIRICAL, and XRare) using a distinct cohort of 12,832 ES cases. Our findings reveal that CAVaLRi significantly outperforms its counterparts when clinician-curated phenotype sets are used, as evidenced by its superior precision-recall curve (PR AUC: 0.701) and average diagnostic gene rank (1.59). Notably, even when substituting highly focused clinician-curated phenotype sets with large and potentially nonspecific computationally derived phenotypes, CAVaLRi retains its precision (PR AUC: 0.658; diagnostic gene average rank: 1.68) and markedly outperforms other tools. In a large, heterogeneous validation cohort, CAVaLRi stood out as the most precise prioritization algorithm (PR AUC: 0.335; average diagnostic rank: 1.91). In conclusion, CAVaLRi presents a robust solution for prioritizing diagnostic genes, surpassing current methods. It demonstrates resilience to noisy, computationally-derived phenotypes, providing a scalable strategy to help labs focus on the most diagnostically relevant variants, thus addressing the growing demand for ES/GS interpretation. [ABSTRACT FROM AUTHOR]

Buonomano and Rovelli (unpubl. manuscript, 2021) and Gruber, Block, and Montemayor (Front. Psychol. , 2022 , 13, art. 718505) grapple with the problem that we experience both a present moment and a flow of time, yet neither of those things seems to be recognised in physics. This paper makes three points about that. The present moment in perception is not the same as the present moment in physics because they occupy radically different time scales, 10–44 s in physics and something in the millisecond range in perception. The information about what is currently being perceived is experienced as in the present not because it is but because it is all labelled with time markers saying that it is the present; there are similar time markers identifying still active historical information as in the past. The flow of time is not generated by actual change over time but by an information structure existing at a single moment of time that represents change over connected time markers. Whether there is an actual present and an actual flow of time in the universe or not, the experienced present and experienced flow of time are perceptual constructs and nothing more. [ABSTRACT FROM AUTHOR]

Background: Two million people in the UK are living with or beyond cancer and a third of them report poor quality of life (QoL) due to problems such as fatigue, fear of cancer recurrence, and concerns about returning to work. We aimed to develop and evaluate an intervention based on acceptance and commitment therapy (ACT), suited to address the concerns of cancer survivors and in improving their QoL. We also recognise the importance of exercise and vocational activity on QoL and therefore will integrate options for physical activity and return to work/vocational support, thus ACT Plus (+). Methods: We will conduct a multi-centre, pragmatic, theory driven, randomised controlled trial. We will assess whether ACT+ including usual aftercare (intervention) is more effective and cost-effective than usual aftercare alone (control). The primary outcome is QoL of participants living with or beyond cancer measured using the Functional Assessment of Cancer Therapy: General scale (FACT-G) at 52 weeks. We will recruit 344 participants identified from secondary care sites who have completed hospital-based treatment for cancer with curative intent, with low QoL (determined by the FACT-G) and randomise with an allocation ratio of 1:1 to the intervention or control. The intervention (ACT+) will be delivered by NHS Talking Therapies, specialist services, and cancer charities. The intervention consists of up to eight sessions at weekly or fortnightly intervals using different modalities of delivery to suit individual needs, i.e. face-to-face sessions, over the phone or skype. Discussion: To date, there have been no robust trials reporting both clinical and cost-effectiveness of an ACT based intervention for people with low QoL after curative cancer treatment in the UK. We will provide high quality evidence of the effectiveness and cost-effectiveness of adding ACT+ to usual aftercare provided by the NHS. If shown to be effective and cost-effective then commissioners, providers and cancer charities will know how to improve QoL in cancer survivors and their families. Trial registration: ISRCTN: ISRCTN67900293. Registered on 09 December 2019. All items from the World Health Organization Trial Registration Data Set for this protocol can be found in Additional file 2 Table S1. [ABSTRACT FROM AUTHOR]

The article focuses on the importance of informed consent in orthopaedic surgery. Topics include the legal and ethical aspects of informed consent, challenges in ensuring patient comprehension and communication, and strategies to overcome barriers for effective shared decision-making between patients and physicians.

Background: Genetic ancestry, inferred from genomic data, is a quantifiable biological parameter. While much of the human genome is identical across populations, it is estimated that as much as 0.4% of the genome can differ due to ancestry. This variation is primarily characterized by single nucleotide variants (SNVs), which are often unique to specific genetic populations. Knowledge of a patient's genetic ancestry can inform clinical decisions, from genetic testing and health screenings to medication dosages, based on ancestral disease predispositions. Nevertheless, the current reliance on self-reported ancestry can introduce subjectivity and exacerbate health disparities. While genomic sequencing data enables objective determination of a patient's genetic ancestry, existing approaches are limited to ancestry inference at the continental level. Results: To address this challenge, and create an objective, measurable metric of genetic ancestry we present SNVstory, a method built upon three independent machine learning models for accurately inferring the sub-continental ancestry of individuals. We also introduce a novel method for simulating individual samples from aggregate allele frequencies from known populations. SNVstory includes a feature-importance scheme, unique among open-source ancestral tools, which allows the user to track the ancestral signal broadcast by a given gene or locus. We successfully evaluated SNVstory using a clinical exome sequencing dataset, comparing self-reported ethnicity and race to our inferred genetic ancestry, and demonstrate the capability of the algorithm to estimate ancestry from 36 different populations with high accuracy. Conclusions: SNVstory represents a significant advance in methods to assign genetic ancestry, opening the door to ancestry-informed care. SNVstory, an open-source model, is packaged as a Docker container for enhanced reliability and interoperability. It can be accessed from https://github.com/nch-igm/snvstory. [ABSTRACT FROM AUTHOR]

Background: Leigh syndrome is a rare, genetic, and severe mitochondrial disorder characterized by neuromuscular issues (ataxia, seizure, hypotonia, developmental delay, dystonia) and ocular abnormalities (nystagmus, atrophy, strabismus, ptosis). It is caused by pathogenic variants in either mitochondrial or nuclear DNA genes, with an estimated incidence rate of 1 per 40,000 live births. Case presentation: Herein, we present an infant male with nystagmus, hypotonia, and developmental delay who carried a clinical diagnosis of Leigh-like syndrome. Cerebral magnetic resonance imaging changes further supported the clinical evidence of an underlying mitochondrial disorder, but extensive diagnostic testing was negative. Trio exome sequencing under a research protocol uncovered compound-heterozygous missense variants in the HTRA2 gene (MIM: #606441): NM_013247.5:c.1037A>T:(p.Glu346Val) (maternal) and NM_ 013247.5:c.1172T>A:(p.Val391Glu) (paternal). Both variants are absent from public databases, making them extremely rare in the population. The maternal variant is adjacent to an exon-intron boundary and predicted to disrupt splicing, while the paternal variant alters a highly conserved amino acid and is predicted to be damaging by nearly all in silico tools. Biallelic variants in HTRA2 cause 3-methylglutaconic aciduria, type VIII (MGCA8), an extremely rare autosomal recessive disorder with fewer than ten families reported to date. Variant interpretation is challenging given the paucity of known disease-causing variants, and indeed we assess both paternal and maternal variants as Variants of Uncertain Significance under current American College of Medical Genetics guidelines. However, based on the inheritance pattern, suggestive evidence of pathogenicity, and significant clinical correlation with other reported MGCA8 patients, the clinical care team considers this a diagnostic result. Conclusion: Our findings ended the diagnostic odyssey for this family and provide further insights into the genetic and clinical spectrum of this critically understudied disorder. [ABSTRACT FROM AUTHOR]

Background: Cancers exhibit complex transcriptomes with aberrant splicing that induces isoform-level differential expression compared to non-diseased tissues. Transcriptomic profiling using short-read sequencing has utility in providing a cost-effective approach for evaluating isoform expression, although short-read assembly displays limitations in the accurate inference of full-length transcripts. Long-read RNA sequencing (Iso-Seq), using the Pacific Biosciences (PacBio) platform, can overcome such limitations by providing full-length isoform sequence resolution which requires no read assembly and represents native expressed transcripts. A constraint of the Iso-Seq protocol is due to fewer reads output per instrument run, which, as an example, can consequently affect the detection of lowly expressed transcripts. To address these deficiencies, we developed a concatenation workflow, PacBio Full-Length Isoform Concatemer Sequencing (PB_FLIC-Seq), designed to increase the number of unique, sequenced PacBio long-reads thereby improving overall detection of unique isoforms. In addition, we anticipate that the increase in read depth will help improve the detection of moderate to low-level expressed isoforms. Results: In sequencing a commercial reference (Spike-In RNA Variants; SIRV) with known isoform complexity we demonstrated a 3.4-fold increase in read output per run and improved SIRV recall when using the PB_FLIC-Seq method compared to the same samples processed with the Iso-Seq protocol. We applied this protocol to a translational cancer case, also demonstrating the utility of the PB_FLIC-Seq method for identifying differential full-length isoform expression in a pediatric diffuse midline glioma compared to its adjacent non-malignant tissue. Our data analysis revealed increased expression of extracellular matrix (ECM) genes within the tumor sample, including an isoform of the Secreted Protein Acidic and Cysteine Rich (SPARC) gene that was expressed 11,676-fold higher than in the adjacent non-malignant tissue. Finally, by using the PB_FLIC-Seq method, we detected several cancer-specific novel isoforms. Conclusion: This work describes a concatenation-based methodology for increasing the number of sequenced full-length isoform reads on the PacBio platform, yielding improved discovery of expressed isoforms. We applied this workflow to profile the transcriptome of a pediatric diffuse midline glioma and adjacent non-malignant tissue. Our findings of cancer-specific novel isoform expression further highlight the importance of long-read sequencing for characterization of complex tumor transcriptomes. [ABSTRACT FROM AUTHOR]

Assumptions about the tirocinium fori are based on claims by Joachim Marquardt that it was a form of training for young elite Romans at about the age of 16, that it lasted for one year, and that it consisted of mentorship by a distinguished elder. Though there is little evidence to support these claims, the theory of a tirocinium fori continues to influence discussions of oratory in the age of Cicero, where it gives a false picture of the process by which aspiring young orators made the transition from the school of rhetoric to practice in the courts. [ABSTRACT FROM AUTHOR]

Background: In introductory biology classrooms, cell and molecular concepts are often taught separate from those related to evolution and ecology, and usually in completely different courses. Furthermore, many examples used to teach introductory concepts are difficult for students to relate to. To address these issues, we developed curricular materials focused on the topic of breast cancer that: (1) aim to teach students how to integrate the various sub-disciplines of biology, with evolution as the unifying theme, and (2) aim to present course materials using relatable examples such as human health and disease. To assess the potential value of these materials, we asked students to complete a pre-unit and post-unit assessment before and after completing the interactive course unit on breast cancer. Results: We found that after learning about breast cancer, students reported that learning about biology in the context of human health made their learning experience easier, more interesting, and more relatable. After the unit, students also rated evolutionary concepts as being more important for understanding human health and disease. Conclusions: These results have important implications for developing introductory biology curricula that have more personal appeal to students and may thus translate to better learning outcomes, as well as help students better understand the process of evolution as it occurs in humans. [ABSTRACT FROM AUTHOR]

Evolution is often challenging for high school students to understand because it encompasses an array of interlinked processes that occur across a broad swath of biological scales. To help address this, we have developed a set of freely accessible, online, and interactive lessons that focus on the evolution of sweet garden peas from their starchy tasting ancestors. Gregor Mendel first explored the genetics of garden peas in the mid-1800s; our materials help students explore the basis of the R and r alleles from genetic, protein, cell function, artificial selection, and population genetics perspectives. These Next Generation Science Standards (NGSS)–linked lessons integrate concepts across scales and are designed to be used in a flexible order, with support provided to teachers on how to choose a sequence that meets their students’ needs. Throughout, students act as scientists as they uncover how multiple processes at disparate scales all worked together in the evolution of sweet and wrinkled peas from ancestors that were starchy and round. [ABSTRACT FROM AUTHOR]

Variants in the AUTS2 gene are associated with a broad spectrum of neurological conditions characterized by intellectual disability, microcephaly, and congenital brain malformations. Here, we use a human cerebral organoid model to investigate the pathophysiology of a heterozygous de novo missense AUTS2 variant identified in a patient with multiple neurological impairments including primary microcephaly and profound intellectual disability. Proband cerebral organoids exhibit reduced growth, deficits in neural progenitor cell (NPC) proliferation and disrupted NPC polarity within ventricular zone-like regions compared to control cerebral organoids. We used CRISPR-Cas9-mediated gene editing to correct this variant and demonstrate rescue of impaired organoid growth and NPC proliferative deficits. Single-cell RNA sequencing revealed a marked reduction of G1/S transition gene expression and alterations in WNT-β-catenin signalling within proband NPCs, uncovering a novel role for AUTS2 in NPCs during human cortical development. Collectively, these results underscore the value of cerebral organoids to investigate molecular mechanisms underlying AUTS2 syndrome. [ABSTRACT FROM AUTHOR]

Why do coups happen and how can state leaders affect their likelihood? Existing research focuses on structural factors as well as "coup-proofing" as drivers of coup risk. I argue that the literature misses an important alternative avenue by which leaders affect the likelihood that their militaries remove them from office: adding or removing military officers from the government. When leaders bring military officers into the government, they signal to the military that there is a peaceful path to sharing power and provide an alternative to coups. In contrast, removing military officers from government dramatically increases the risk of a coup attempt as the military retaliates against the leader's power grab. I test this theory using cross-national data that captures changes in military representation in national cabinets and state councils from 1969 to 2008 and find mixed support. In line with the theory, there is strong evidence that large reductions in the military's government positions lead to coup attempts, and more modest evidence that large increases reduce coup attempts. However, contrary to expectations, the results also suggest that small increases in military government positions increase the risk of a coup. [ABSTRACT FROM AUTHOR]

The article focuses on the experience of a Pentecostal theologian engaging in dialogue with other faiths, advocating for religious tolerance and the use of dialogue and spiritual discernment as tools for interfaith encounters. It discusses the importance of studying other religions without losing one's own faith, the challenges of managing encounters with people of other faiths and the promotion of inclusivity and just relationships in interreligious dialogue.

The great commission, as traditionally understood in Christendom, has been the core basis for church growth. Passion for the lost, evangelism outreach, conversions, and baptism followed by congregating, have culminated in church establishments. Pentecostals, especially the Neo-Pentecostal and Neo-Prophetic Churches have attracted huge crowds. The thrust towards fulling the Missio Dei has seen micro–Neo-Pentecostal Churches and Neo-Prophetic Churches in Africa becoming enormous ministries over a short period of time. However, growth within Neo-Pentecostalism and Neo-Prophetism in the African setting has been associated with all kinds of challenges: leadership crisis, fund misuse, and a lack of accountability. Furthermore, controversy with regard to some of the Neo-Pentecostal and Neo-Prophetic leaders running these 'churches', has made headlines on several accounts within the social media space. It seems that there is a lack of leadership mentorship as many of them do not belong to a denominational body or lack the idea of 'belonging'. In view of the aforementioned reasons and other related challenges, this article proposes an innovative missional model of franchising. The thrust of this article is to explore the possibility of church-franchising and how the Nnoboa mission concept proposed by White (2019) offers an alternative framework within which to engage the Neo-Pentecostal and Neo-Prophetic Churches for church planting and leadership mentorship. [ABSTRACT FROM AUTHOR]

Objective: Epilepsy‐associated developmental lesions, including malformations of cortical development and low‐grade developmental tumors, represent a major cause of drug‐resistant seizures requiring surgical intervention in children. Brain‐restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified. Methods: We enrolled 50 children who were undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA sequencing to identify somatic variation and we confirmed our findings using high‐depth targeted DNA sequencing. Results: We uncovered candidate disease‐causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting solute carrier family 35 member A2 (SLC35A2) and mechanistic target of rapamycin kinase (MTOR) pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) of patients with Type I focal cortical dysplasia (FCD)s. Somatic variation in mitogen‐activated protein kinase (MAPK) pathway genes (i.e., fibroblast growth factor receptor 1 [FGFR1], FGFR2, B‐raf proto‐oncogene, serine/threonine kinase [BRAF], and KRAS proto‐oncogene, GTPase [KRAS]) was associated with low‐grade epilepsy‐associated developmental tumors. RNA sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for more than one‐half of epilepsy‐associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease‐causing variants in genes not yet associated with focal cortical dysplasia. Significance: These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes. [ABSTRACT FROM AUTHOR]

Rhabdoid tumors (RTs) of the brain (atypical teratoid/rhabdoid tumor; AT/RT) and extracranial sites (most often the kidney; RTK) are malignant tumors predominantly occurring in children, frequently those with SMARCB1 germline alterations. Here we present data from seven RTs from three pediatric patients who all had multi-organ involvement. The tumors were analyzed using a multimodal molecular approach, which included exome sequencing of tumor and germline comparator and RNA sequencing and DNA array-based methylation profiling of tumors. SMARCB1 germline alterations were identified in all patients and in all tumors. We observed a second hit in SMARCB1 via chr22 loss of heterozygosity. By methylation profiling, all tumors were classified as rhabdoid tumors with a corresponding subclassification within the MYC, TYR, or SHH AT/RT subgroups. Using RNA-seq gene expression clustering, we recapitulated the classification of known AT/RT subgroups. Synchronous brain and kidney tumors from the same patient showed different patterns of either copy number variants, singlenucleotide variants, and/or genome-wide DNA methylation, suggestive of non-clonal origin. Furthermore, we demonstrated that a lung and abdominal metastasis from two patients shared overlapping molecular features with the patient's primary kidney tumor, indicating the likely origin of the metastasis. In addition to the SMARCB1 events, we identified other whole-chromosome events and single-nucleotide variants in tumors, but none were found to be prognostic, diagnostic, or offer therapeutic potential for rhabdoid tumors. While our findings are of biological interest, there may also be clinical value in comprehensive molecular profiling in patients with multiple rhabdoid tumors, particularly given the potential prognostic and therapeutic implications for different rhabdoid tumor subgroups demonstrated in recent clinical trials and other large cohort studies. [ABSTRACT FROM AUTHOR]

Background: The Orthopaedic In-Training Examination (OITE) is a standardized examination administered annually to orthopaedic surgery residents. The examination is designed to evaluate resident knowledge and academic performance of residency programs. Methods: All OITE foot and ankle questions from 2009 through 2012 and 2017 through 2020 were analyzed. Subtopics, taxonomy, references, and use of imaging modalities were recorded. Results: There were a total of 167 foot and ankle (F&A)–related questions across 8 years of OITE examinations. Trauma remained the most commonly tested subtopic of F&A across both subsets, followed by rehabilitation, tendon disorders, and arthritis. We found an increase in questions related to arthritis (P =.05) and a decrease of questions related to the diabetic foot (P =.02). Taxonomy 3 questions constituted 49.5% of F&A questions from 2009 through 2012 compared with 44.7% of questions from 2017 to 2020 (P =.54). Radiography was the most commonly used imaging modality in both subsets. From 2009 to 2012, 63.6% of questions included a radiograph compared with 76.5% in 2017 through 2020 (P =.13). FAI (Foot & Ankle International), JAAOS (Journal of the American Academy of Orthopaedic Surgeons), and JBJS (The Journal of Bone and Joint Surgery) were the most commonly cited journals, making up more than 50% of total citations. Citations per question increased from 2.20 to 2.42 from 2009-2012 to 2017-2020 (P =.01). The average lag time in the early subset was 8.2 years and 8.9 years in the later subset. Conclusion: This study provides a detailed analysis of the F&A section of the OITE. Use of this analysis can provide residents with a guide on how to better prepare for the OITE examination. Level of Evidence: Level IV, cross-sectional review of Orthopaedic In-Training Examination questions [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is a common group of birth defects with a strong genetic contribution to their etiology, but historically the diagnostic yield from exome studies of isolated CHD has been low. Pleiotropy, variable expressivity, and the difficulty of accurately phenotyping newborns contribute to this problem. We hypothesized that performing exome sequencing on selected individuals in families with multiple members affected by left-sided CHD, then filtering variants by population frequency, in silico predictive algorithms, and phenotypic annotations from publicly available databases would increase this yield and generate a list of candidate disease-causing variants that would show a high validation rate. In eight of the nineteen families in our study (42%), we established a well-known gene/phenotype link for a candidate variant or performed confirmation of a candidate variant's effect on protein function, including variants in genes not previously described or firmly established as disease genes in the body of CHD literature: BMP10, CASZ1, ROCK1 and SMYD1. Two plausible variants in different genes were found to segregate in the same family in two instances suggesting oligogenic inheritance. These results highlight the need for functional validation and demonstrate that in the era of next-generation sequencing, multiplex families with isolated CHD can still bring high yield to the discovery of novel disease genes. Author summary: Congenital heart disease is a common group of birth defects that are a leading cause of death in children under one year of age. There is strong evidence that genetics plays a role in causing congenital heart disease. While studies using individual cases have identified causative genes for those with a heart defect when accompanied by other birth defects or intellectual disabilities, for individuals who have only a heart defect without other problems, a genetic cause can be found in fewer than 10%. In this study, we enrolled families where there was more than one individual with a heart defect. This allowed us to take advantage of inheritance by searching for potential disease-causing genetic variants in common among all affected individuals in the family. Among 19 families studied, we were able to find a plausible disease-causing variant in eight of them and identified new genes that may cause or contribute to the presence of a heart defect. Two families had potential disease-causing variants in two different genes. We designed assays to test if the variants led to altered function of the protein coded by the gene, demonstrating a functional consequence that support the gene and variant as contributing to the heart defect. These findings show that studying families may be more effective than using individuals to find causes of heart defects. In addition, this family-based method suggests that changes in more than one gene may be required for a heart defect to occur. [ABSTRACT FROM AUTHOR]

Keywords: calicivirus; emerging diseases; nidovirus; RNA sequencing; transcriptomics; viral discovery EN calicivirus emerging diseases nidovirus RNA sequencing transcriptomics viral discovery 931 938 8 05/13/22 20220601 NES 220601 INTRODUCTION Agnatha is an ancient superclass of jawless fish that gave rise to all other vertebrates after diverging from chordates ~535 million years ago (mya) (Janvier, 1981). Lamprey and hagfish viruses range from simpler viruses such as caliciviruses, to complex viruses such as bafiniviruses. As a subset of fish viruses, agnathan viruses are even more underexplored than teleost viruses. [Extracted from the article]

De novo variants are increasingly recognized as a common cause of early infantile epileptic encephalopathies. We present a 4-yr-old male with epileptic encephalopathy characterized by seizures, autism spectrum disorder, and global developmental delay. Whole-genome sequencing of the proband and his unaffected parents revealed a novel de novo missense variant in GRIA2 (c.1589A >T; p.Lys530Met; ENST00000264426.14). Variants in the GRIA2 gene were recently reported to cause an autosomal dominant neurodevelopmental disorder with language impairments and behavioral abnormalities (OMIM; MIM #618917), a condition characterized by intellectual disability and developmental delay in which seizures are a common feature. The de novo variant identified in our patient maps to the edge of a key ligand binding domain of the AMPA receptor and has not been previously reported in gnomAD or other public databases, making it novel. Our findings provided a long-sought diagnosis for this patient and support the link between GRIA2 and a dominant neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

Inquiry-driven teaching methods allow students to take on an active role in their own education. Through thisframework, students are able to cultivate meman understanding of scientific concepts and their connections while experi-menting iii the classroom. Our pi-Oject centered around teaching students about habitats of urban moths, which are abundant in most environments. Based on the students' hypotheses on where moths might be, homemade moth traps were placed either in a local nature preserve or in the school playgi-ound over the course of two nights. Overall. 27 moths were captured. Students then learned how to pin moth specimens and assessed what they could infer from how many moths were captured in each of the collection areas. This p#Rject cirated an elivitonment jor students to approach Next Generation Science Standards perfonnance expectations about the diversity ecologiof life and how organisms interact with their envinmments. [ABSTRACT FROM AUTHOR]

Nonnative European earthworms are invading hardwood forests of the Chippewa National Forest, MN. While effects on plant communities at the leading edge of invasion have been studied, little is known about longer‐term effects of invasive earthworms. We applied a model using historic O‐horizon soil thickness and a chronosequence approach to classify 41 hardwood sites in the Chippewa National Forest as "long‐term wormed" (wormed >2 decades), "short‐term wormed" or "unwormed/lightly wormed." Graminoids, especially Carex pensylvanica, had the greatest mean percent cover in sites that had been wormed for over two decades. The families with the greatest negative change in mean percent cover after over two decades of earthworm invasion were Asteraceae, Violaceae, and Sapindaceae (specifically Acer species). Across all diversity metrics measured, long‐term wormed sites had the lowest understory plant species diversity, short‐term wormed sites had intermediate diversity, and unwormed/lightly wormed sites exhibited the highest diversity. Long‐term wormed sites had the lowest mean species richness across all sample scales (1–1024 m2). The greatest within‐group compositional dissimilarity occurred at sites that had been wormed for over two decades, suggesting that sites that had been wormed for over two decades have not reached a compositionally similar end‐state "wormed" community type. Our study suggests that understory diversity will decrease as hardwood forest stands become wormed over time. While our results support other findings that exotic earthworm invasion is associated with lower understory plant diversity in hardwood forests, our study was the first to use space‐for‐time substitution to document the effects after multiple decades of earthworm invasion. [ABSTRACT FROM AUTHOR]

Background: Despite evidence of the nosocomial transmission of novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in hospitals worldwide, the contributions of the pathways of transmission are poorly quantified.Methods: We analysed national records of hospital admissions and discharges, linked to data on SARS-CoV-2 testing, using an individual-based model that considers patient-to-patient, patient-to-healthcare worker (HCW), HCW-to-patient and HCW-to-HCW transmission.Results: Between 1 March 2020 and 31 December 2020, SARS-CoV-2 infections that were classified as nosocomial were identified in 0.5% (0.34-0.74) of patients admitted to an acute National Health Service trust. We found that the most likely route of nosocomial transmission to patients was indirect transmission from other infected patients, e.g. through HCWs acting as vectors or contaminated fomites, followed by direct transmission between patients in the same bay. The risk of transmission to patients from HCWs over this time period is low, but can contribute significantly when the number of infected inpatients is low. Further, the risk of a HCW acquiring SARS-CoV-2 in hospital is approximately equal to that in the community, thereby doubling their overall risk of infection. The most likely route of transmission to HCWs is transmission from other infected HCWs.Conclusions: Current control strategies have successfully reduced the transmission of SARS-CoV-2 between patients and HCWs. In order to reduce the burden of nosocomial COVID-19 infections on health services, stricter measures should be enforced that would inhibit the spread of the virus between bays or wards in the hospital. There should also be a focus on inhibiting the spread of SARS-CoV-2 between HCWs. The findings have important implications for infection-control procedures in hospitals. [ABSTRACT FROM AUTHOR]

Synpolydactyly 1, also called syndactyly type II (SDTY2), is a genetic limb malformation characterized by polydactyly with syndactyly involving the webbing of the third and fourth fingers, and the fourth and fifth toes. It is caused by heterozygous alterations in HOXD13 with incomplete penetrance and phenotypic variability. In our study, a five‐generation family with an SPD phenotype was enrolled in our Rare Disease Genomics Protocol. A comprehensive examination of three generations using Illumina short‐read whole‐genome sequencing (WGS) did not identify any causative variants. Subsequent WGS using Pacific Biosciences (PacBio) long‐read HiFi Circular Consensus Sequencing (CCS) revealed a heterozygous 27‐bp duplication in the polyalanine tract of HOXD13. Sanger sequencing of all available family members confirmed that the variant segregates with affected individuals. Reanalysis of an unrelated family with a similar SPD phenotype uncovered a 21‐bp (7‐alanine) duplication in the same region of HOXD13. Although ExpansionHunter identified these events in most individuals in a retrospective analysis, low sequence coverage due to high GC content in the HOXD13 polyalanine tract makes detection of these events challenging. Our findings highlight the value of long‐read WGS in elucidating the molecular etiology of congenital limb malformation disorders. [ABSTRACT FROM AUTHOR]

Chronic fatigue syndrome (CFS), sometimes referred to as myalgic encephalomyelitis (ME) and often as CFS/ME, is an illness characterized by disabling fatigue and other symptoms, typically worsened by activity. The main evidence-based treatments are rehabilitative in nature and include specific types of cognitive behavior therapy (CBT) and graded exercise therapy (GET). In this article, we briefly review the evidence for their safety and effectiveness and propose that much of the controversy about them arises from misunderstandings about their nature and delivery. In particular, we emphasize that successful rehabilitation from CFS/ME does not indicate that the illness is not real. We recommend that rehabilitative treatment always be preceded by a thorough clinical assessment and delivered by appropriately trained therapists working in close collaboration with the patient. We conclude that properly applied rehabilitative treatments offer the best hope of safely improving fatigue and function for patients with CFS/ME. However, we also recognize the need for more research into the treatment of this neglected condition, especially for those most severely disabled by it. [ABSTRACT FROM AUTHOR]

Noncoding and synonymous coding variants that exert their effects via alternative splicing are increasingly recognized as an important category of disease-causing variants. In this report, we describe two siblings who presented with hypotonia, profound developmental delays, and seizures. Brain magnetic resonance imaging (MRI) in the proband at 5 yr showed diffuse cerebral and cerebellar white matter volume loss. Both siblings later developed ventilator-dependent respiratory insufficiency and scoliosis and are currently nonverbal and nonambulatory. Extensive molecular testing including oligo array and clinical exome sequencing was nondiagnostic. Research genome sequencing under an institutional review board (IRB)-approved study protocol revealed that both affected children were compound-heterozygous for variants in the SEPSECS gene. One variant was an initiator codon change (c.1A >T) that disrupted protein translation, consistent with the observation that most disease-causing variants are loss-of-function changes. The other variant was a coding change (c.846G >A) that was predicted to be synonymous but had been demonstrated to disrupt mRNA splicing in a minigene assay. The SEPSECS gene encodes O-phosphoseryl-tRNA(Sec) selenium transferase, an enzyme that participates in the biosynthesis and transport of selenoproteins in the body. Variations in SEPSECS cause autosomal recessive pontocerebellar hypoplasia type 2D (PCHT 2D; OMIM #613811), a neurodegenerative condition characterized by progressive cerebrocerebellar atrophy, microcephaly, and epileptic encephalopathy. The identification of biallelic pathogenic variants in this family--one of which was a synonymous change not identified by prior clinical testing--not only ended the diagnostic odyssey for this family but also highlights the contribution of occult pathogenic variants that may not be recognized by standard genetic testing methodologies. [ABSTRACT FROM AUTHOR]