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Mononuclear phagocytes facilitate the dissemination of the obligate intracellular parasite Toxoplasma gondii. Here, we report how a set of secreted parasite effector proteins from dense granule organelles (GRA) orchestrates dendritic cell-like chemotactic and pro-inflammatory activation of parasitized macrophages. These effects enabled efficient dissemination of the type II T. gondii lineage, a highly prevalent genotype in humans. We identify novel functions for effectors GRA15 and GRA24 in promoting CCR7-mediated macrophage chemotaxis by acting on NF-κB and p38 mitogen-activated protein kinase signaling pathways, respectively, with contributions by GRA16/18 and counter-regulation by effector TEEGR. Furthermore, GRA28 boosted chromatin accessibility and GRA15/24/NF-κB-dependent transcription at the Ccr7 gene locus in primary macrophages. In vivo, adoptively transferred macrophages infected with wild-type T. gondii outcompeted macrophages infected with a GRA15/24 double mutant in migrating to secondary organs in mice. The data show that T. gondii, rather than being passively shuttled, actively promotes its dissemination by inducing a finely regulated pro-migratory state in parasitized human and murine phagocytes via co-operating polymorphic GRA effectors.ImportanceIntracellular pathogens can hijack the cellular functions of infected host cells to their advantage, for example, for intracellular survival and dissemination. However, how microbes orchestrate the hijacking of complex cellular processes, such as host cell migration, remains poorly understood. As such, the common parasite Toxoplasma gondii actively invades the immune cells of humans and other vertebrates and modifies their migratory properties. Here, we show that the concerted action of a number of secreted effector proteins from the parasite, principally GRA15 and GRA24, acts on host cell signaling pathways to activate chemotaxis. Furthermore, the protein effector GRA28 selectively acted on chromatin accessibility in the host cell nucleus to selectively boost host gene expression. The joint activities of GRA effectors culminated in pro-migratory signaling within the infected phagocyte. We provide a molecular framework delineating how T. gondii can orchestrate a complex biological phenotype, such as the migratory activation of phagocytes to boost dissemination.

Our ability to predict, control, or design biological function is fundamentally limited by poorly annotated gene function. This can be particularly challenging in non-model systems. Accordingly, there is motivation for new high-throughput methods for accurate functional annotation. Here, we used complementation of auxotrophs and DNA barcode sequencing (Coaux-Seq) to enable high-throughput characterization of protein function. Fragment libraries from eleven genetically diverse bacteria were tested in twenty different auxotrophic strains of Escherichia coli to identify genes that complement missing biochemical activity. We recovered 41% of expected hits, with effectiveness ranging per source genome, and observed success even with distant E. coli relatives like Bacillus subtilis and Bacteroides thetaiotaomicron. Coaux-Seq provided the first experimental validation for 53 proteins, of which 11 are less than 40% identical to an experimentally characterized protein. Among the unexpected function identified was a sulfate uptake transporter, an O-succinylhomoserine sulfhydrylase for methionine synthesis, and an aminotransferase. We also identified instances of cross-feeding wherein protein overexpression and nearby non-auxotrophic strains enabled growth. Altogether, Coaux-Seq's utility is demonstrated, with future applications in ecology, health, and engineering.

UNLABELLED: Identifying improved treatments for severe and refractory coccidioidomycosis (Valley fever) is needed. This endemic fungal disease is common in North and South America, and cases have increased substantially over the last 30 years. The current standard of care, oral daily fluconazole, often fails to completely eradicate Coccidioides infection; however, the high cost of identifying new compounds effective in treating Valley fever is a barrier to improving treatment. Therefore, repurposing existing pharmaceutical agents in combination with fluconazole therapy is an attractive option. We screened the Library of Pharmacologically Active Compounds (LOPAC) small molecule library for compounds that inhibited fungal growth in vitro and determined IC50 values for a subset of compounds. Based on these findings, we tested a small subset of these agents to validate the screen, as well as to test the performance of fluconazole in a combination therapy approach, as compared with fluconazole alone, in a murine model. We observed that combination therapy of tamoxifen:fluconazole and sertraline:fluconazole significantly reduced the burden of live fungus in the lung compared with fluconazole alone, and we observed reduced or nonexistent dissemination. These results suggest that tamoxifen and sertraline may be repurposed as adjunctive agents in the treatment of this important fungal disease. IMPORTANCE: Developing new drugs, especially for regional orphan diseases, such as Valley Fever, is a slow and costly endeavor. However, there is a wealth of FDA-approved drugs available for repurposing, offering a more economical and expedited approach to improve treatment. Those existing compounds with antifungal properties can become novel therapies with relative ease: a considerable advantage for patients in need of alternative treatment. Despite the scope of remaining tasks, our comprehensive screening of potential candidates has revealed promising combinations for further exploration. This effort outlines a practical pipeline for Valley fever drug screening and identifies viable drug combinations that could impact patients more rapidly than single drug development pathways.

Introduction: Effective medical education must balance clinical service demands for institutions and learning needs of trainees. The question of whether these are competing demands or can serve complementary roles has profound impacts on graduate medical education, ranging from funding decisions to the willingness of community-based hospitals and physicians to include learners at their clinical sites. Our objective in this article was to systematically review the evidence on the impact of medical trainees on productivity and efficiency in the emergency department (ED).Methods: We queried PubMed, Embase, Scopus, and Web of Science from earliest available dates to March 2023. We identified all studies evaluating the impact of medical students and/or residents in the ED on commonly used productivity and efficiency metrics. Only studies in EDs in the United States were included. No additional filters were used. We assessed the risk of bias of included studies using the Risk of Bias in Non-randomized Studies – of Interventions (ROBINS-I) tool. Certainty of evidence was rated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Study findings were combined in a narrative synthesis and reported according to PRISMA guidelines.Results: The literature search yielded 3,390 unique articles for abstract screening. Eighty-one abstracts were identified as relevant to our PICO question (population, intervention, control, and outcomes), 76 of which had retrievable full-text articles and the themes of which were discussed in a narrative synthesis. We selected 13 of the full-text articles for final inclusion in a systematic review. Studies were roughly split between observational (6) and quasi-experimental (7) designs. The majority of studies (11) were single-site studies. Only two studies could be graded as low risk of bias per the ROBINS-I tool.Conclusion: Low-GRADE evidence suggests that students and residents decrease ED efficiency by a statistically small effect size of debatable clinical importance. Residents provide a moderate boost to ED productivity. Students do not produce a statistically or clinically significant impact on ED productivity. Residents increase emergency department relative value units revenue by $26.30 an hour, while students have no impact. Both types of learners decrease efficiency.

The word avionics is a blend of aviation and electronics and represents the electronic systems used on aircraft. This article identifies which factors might affect production box recurring costs for [...]

How does militarism affect women's presence in the political process? Through a focus on the Republic of Armenia during the period 1990-2020, we examine the puzzle of women's political representation. The country's legacy of communist-era ideology of women's equality, its democratic transition, women's high levels of educational attainment and labor force participation, and the 2007 gender quota adoption should have served to place Armenia in the top 50 countries in women's political representation. Yet for two decades, the country appeared low on international rankings of women's political empowerment. To unpack this puzzle, we revisit two strands of the women-and-war literature--one that ties militarism to the dominance of men, and one that finds increases in women's parliamentary representation in the aftermath of conflict. We find that both have merit. Armenia's long history of conflict with Azerbaijan and high military spending have reproduced traditional gender roles, including a militarized masculinity which favors men in positions of political power. The devastating 2020 war, however, may have helped turn the tide that began earlier with constitutional reforms in 2015, elections in 2017, and anti-government protests in 2018. A new gender quota dramatically enhanced women's political representation. Drawing on socio-economic and political indicators as well as documentary and interview data, our paper contributes to literatures on women, gender, and conflict; on patterns and variations in women's political representation; and on women in Armenia. Future research could examine the direction of gendered political change following the loss of Nagorno-Karabakh after Azerbaijan's unilateral military action in September 2023. Keywords: Armenia, Political representation, Militarization, War, Gender equality, Gender quotas, Women in politics, Introduction In April 2020, during the global COVID-19 pandemic, war broke out between the forces of two former Soviet republics, Armenia and Azerbaijan, over the disputed territory of Nagorno-Karabakh, an [...]

BackgroundIn response to COVID-19, there has been increasing momentum in telehealth development and delivery. To assess the anticipated exponential growth in telehealth, it is important to accurately capture how telehealth has been used in specific mental health fields prior to the pandemic. ObjectiveThis systematic review aimed to highlight how telehealth has been used with clinical samples in the neurodevelopmental field, including patients with neurodevelopmental disorders (NDDs), their families, and health care professionals. To identify which technologies show the greatest potential for implementation into health services, we evaluated technologies for effectiveness, economic impact, and readiness for clinical adoption. MethodsA systematic search of literature was undertaken in April 2018 and updated until December 2019, by using the Medline, Web of Science, Scopus, CINAHL Plus, EMBASE, and PsycInfo databases. Extracted data included the type of technology, how the technology was used (ie, assessment, treatment, and monitoring), participant characteristics, reported outcomes and authors’ views on clinical effectiveness, user impact (ie, feasibility and acceptability), economic impact, and readiness for clinic adoption. A quality review of the research was performed in accordance with the Oxford Centre for Evidence-Based Medicine Levels of Evidence. ResultsA total of 42 studies met the inclusion criteria. These studies included participants and family members with autism spectrum disorders (21/42, 50%), attention deficit hyperactivity disorders (8/42, 19%), attention deficit hyperactivity or autism spectrum disorders (3/42, 7%), communication disorders (7/42, 17%), and tic disorders (2/42, 5%). The focus of most studies (33/42, 79%) was on treatment, rather than assessment (4/42, 10%) or monitoring (5/42, 12%). Telehealth services demonstrated promise for being clinically effective, predominantly in relation to diagnosing and monitoring NDDs. In terms of NDD treatment, telehealth services were usually equivalent to control groups. There was some evidence of positive user and economic impacts, including increased service delivery efficiency (eg, increased treatment availability and decreased waiting times). However, these factors were not widely recorded across the studies. Telehealth was demonstrated to be cost-effective in the few studies that considered cost-effectiveness. Study quality varied, as many studies had small sample sizes and inadequate control groups. Of the 42 studies, only 11 (26%) were randomized controlled trials, 12 (29%) were case studies or case series, 6 (14%) were qualitative studies, and 5 (12%) were noncomparative trials. ConclusionsTelehealth has the potential to increase treatment availability, decrease diagnosis waiting times, and aid in NDD monitoring. Further research with more robust and adequately powered study designs that consider cost-effectiveness and increased efficiency is needed. This systematic review highlights the extent of telehealth technology use prior to the COVID-19 pandemic and the movement for investing in remote access to treatments. Trial RegistrationPROSPERO International Prospective Register of Systematic Reviews CRD42018091156; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018091156

Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.

Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mitochondrial genome in different tissues throughout ageing. We used ultrasensitive duplex sequencing to profile ~2.5 million mitochondrial genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloguing ~1.2 million mitochondrial somatic and ultralow-frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the light strand origin of replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared with primates with a surfeit of reactive oxygen species-associated G > T/C > A mutations, and that somatic mutations in protein-coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that re-align mito-nuclear ancestry within an organisms lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.

Performing conventional mechanical characterization techniques on soft materials can be challenging due to issues such as limited sample volumes and clamping difficulties. Deep indentation and puncture is a promising alternative as it is an information-rich measurement with the potential to be performed in a high-throughput manner. Despite its promise, the method lacks standardized protocols, and open questions remain about its possible limitations. Addressing these shortcomings is vital to ensure consistent methodology, measurements, and interpretation across samples and labs. To fill this gap, we examine the role of finite sample dimensions (and by extension, volume) on measured forces to determine the sample geometry needed to perform and unambiguously interpret puncture tests. Through measurements of puncture on a well-characterized elastomer using systematically varied sample dimensions, we show that the apparent mechanical response of a material is in fact sensitive to near-wall effects, and that additional properties, such as the sliding friction coefficient, can only be extracted in the larger dimension case where such effects are negligible.

Ocean disposal of industrial waste from technical DDT [mainly 1,1-(2,2,2-trichloroethane-1,1-diyl)bis(4-chlorobenzene), or 4,4-DDT] manufacture occurred historically in the Southern California Bight. However, the paucity of historical records highlights uncertainties as to the mode, location, and timing of disposal or ongoing ecological effects of these wastes. This study combines sampling, chemical analysis, and numerical modeling of deep San Pedro Basin sediments revealing substantial DDT contamination that extends at least 25 km from the mainland. These findings narrate bulk DDT waste disposal to the offshore that peaked in the 1950s, prior to the onset of formal regulations; was agnostic to later-designated disposal sites; and has experienced sluggish transformation. Our findings further indicate an attenuating secondary source for the DDT daughter product, 1-chloro-4-[2,2-dichloro-1-(4-chlorophenyl)ethenyl]benzene (4,4-DDE), which still deposits into deep San Pedro Basin sediments. While demonstrating the severity of DDT contamination to the region, these findings further define the burial potential of DDT wastes and inform the past, present, and future contamination potential that is needed to understand and predict ecological consequences. This work also points firmly to bulk, not containerized, disposal of DDT waste and to potential alternative contents of collocated waste.

INTRODUCTION AND OBJECTIVE: The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. METHODS: Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. RESULTS: The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs). CONCLUSIONS: Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible.

Previous research has extensively analysed teachers' and students' Facebook use for instructional engagement, writing, research dissemination and e-learning. However, Facebook as a data collection mechanism for research has scarcely been the subject of previous studies. The current study addressed these gaps by analysing students' awareness, willingness, and utilisation of Facebook for research data collection [RDC]. This study aimed to predict students' Facebook use for research data collection based on their awareness and willingness and to determine age and gender differences in such predictions. A sample of 11,562 students of tertiary institutions participated in an online survey. The researchers designed and validated the online survey. Exploratory Factor Analysis was used for dimensionality. Average Variance Extracted [AVE] was used for convergent validity, whilst the Fornel-Larcker criterion and Heterotrait-Monotrait ratio were used for discriminant validity. Composite reliability indices of 0.97, 0.94 and 0.90 proved the instrument's three sub-scales usable. One sample t-test and multigroup analysis were conducted using SPSS 27 and Smart PLS 3. The study found high awareness but low usage of Facebook for RDC among Nigerian university students. Younger and male students showed higher willingness and actual use of Facebook for RDC. Awareness directly impacted by awareness, and acted as Facebook usage for RDC, with stronger impacts for males and students aged 19 to 28. Willingness was positively impacted and acted as a negative mediator between awareness and usage for some age groups and genders. These findings provide important insights into using Facebook for RDC among students in Nigerian universities and highlight the need to consider the impact of demographic factors such as age and gender when promoting social media platforms for academic purposes.

This study examined the degree to which students indulge in six prominent misconducts in Distance Education Institutions (DEIs). The study also quantified how class size, instructional delivery and institutional policies predict students' indulgence in sharp practices using a general linear modelling approach. A sample of 871 participants was drawn from 1,742 final-year students across two DEIs in Nigeria. A structured questionnaire was used for data collection. The questionnaire had acceptable psychometric estimates of dimensionality, content and construct validity, as well as reliability. Sharp practices such as cheating, plagiarism, falsification, impersonation, and arm-twisting were more prevalent in large classes, whereas only inducement was higher in small classes. Class size influenced students' indulgence in sharp practices in DEIs. Instructional delivery and institutional policies negatively predicted students' indulgence in the six sharp practices. Almost all the six sharp practices correlated positively and significantly, except for impersonation and inducement. Therefore, distance education students who cheat, plagiarize, arm-twist, falsify records, induce lecturers, and promote impersonation are more likely to indulge in other forms of sharp practices. It was concluded that large class sizes, poor instructional delivery, and poorly implemented institutional policies promote sharp practices among distance education students. Based on this conclusion, key policy and research implications are discussed.

An assessment of the possible effect of mathematics symbol instruction on achievement in word problems was the main thrust of the study. Two null hypotheses were tested in the study. The non-equivalent group pre-testpost-test quasi-experimentalresearch design was adopted. The multistage sampling technique was used to select a sample of 387 participants from 6,740 senior secondary class one students in the 81 government-owned coeducational secondary schools in Calabar education zone of Cross River State. The treatment class was exposed to mathematics symbol instructional strategy for solving word problems while the control class was exposed to regular word problem teaching, otherwise called the conventional method. "Students mathematics achievement test" was the instrument used for data collection after validation by experts. The reliability coefficient of 0.90 was determined using the Kuder-Richarson 20 formula. Primary data were obtained after informed consent from the participants. The null hypotheses were all tested at the 0.05 alpha level using the analysis of covariance. Findings revealed a significant effect of the mathematics symbol instructional strategy on students' word problem achievement in secondary schools. Male students perform significantly better in word problems than their female counterparts when taught using the mathematics symbol instruction. These findings discussed fundamental theoretical, practical, and research implications. It was recommended, among other things, that mathematics teachers concentrate on demystifying the abstraction in mathematics by deliberately adopting mathematics symbol instructional strategy in interpreting mathematical statements and sentences into their symbolic notations before engaging in their computation.

There are contradictory results regarding how students' learning outcomes can be predicted by various family and community inputs among previous studies, creating an evidence gap. Furthermore, previous studies have mostly concentrated on the cognitive aspect of students' learning outcomes, ignoring the affective and psychomotor dimensions, creating key knowledge gaps. Bridging these gaps, this predictive correlational study was conducted to understand how cultural capital, parental involvement (family inputs), support for schools, security network and school reforms (community inputs) jointly and partially predict students' overall, cognitive, affective and psychomotor learning outcomes in the context of Calabar Education Zone, Nigeria. A random sample of principals (n = 78) and students (n = 915) recruited through a multistage approach, participated in the study. Data were collected through the physical administration of three sets of questionnaires designed by the researchers. The psychometric properties of the questionnaires (such as validity, dimensionality, reliability and goodness of fit) were all analysed and found acceptable based on pilot data. Data analysis was performed using SPSS version 27 and AMOS version 26 software. Results from the main study proved, among others, that family inputs (family social capital and parental involvement) jointly and individually had a significant contribution to students' overall, cognitive, affective and psychomotor learning outcomes. Similarly, community inputs (support for school, security network and school reforms) have significant composite and partial contributions to students' overall, cognitive, affective and psychomotor learning outcomes in public secondary schools. This result implies that parents and host community leaders must strengthen their partnerships with secondary schools and contribute their quota to institutions' curricular and co-curricular activities.