During epithelial morphogenesis, the apical junctions connecting cells must remodel as cells change shape and make new connections with their neighbors. In the C. elegans embryo, new apical junctions ...form when epidermal cells migrate and seal with one another to encase the embryo in skin (‘ventral enclosure’), and junctions remodel when epidermal cells change shape to squeeze the embryo into a worm shape (‘elongation’). The junctional cadherin-catenin complex (CCC), which links epithelial cells to each other and to cortical actomyosin, is essential for C. elegans epidermal morphogenesis. RNAi genetic enhancement screens have identified several genes encoding proteins that interact with the CCC to promote epidermal morphogenesis, including the scaffolding protein Afadin (AFD-1), whose depletion alone results in only minor morphogenesis defects. Here, by creating a null mutation in afd-1, we show that afd-1 provides a significant contribution to ventral enclosure and elongation on its own. Unexpectedly, we find that afd-1 mutant phenotypes are strongly modified by diet, revealing a previously unappreciated parental nutritional input to morphogenesis. We identify functional interactions between AFD-1 and the CCC by demonstrating that E-cadherin is required for the polarized distribution of AFD-1 to cell contact sites in early embryos. Finally, we show that afd-1 promotes the enrichment of polarity regulator, and CCC-interacting protein, PAC-1/ARHGAP21 to cell contact sites, and we identify genetic interactions suggesting that afd-1 and pac-1 regulate epidermal morphogenesis at least in part through parallel mechanisms. Our findings reveal that C. elegans AFD-1 makes a significant contribution to epidermal morphogenesis and functionally interfaces with core and associated CCC proteins.
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•afd-1 null mutant reveals diet-influenced roles for Afadin in C. elegans epidermal morphogenesis.•afd-1 genetically interacts with RhoGAP pac-1 to regulate epidermal morphogenesis.•E-cadherin enriches AFD-1 at cell contacts.•AFD-1 promotes PAC-1 cell localization.
Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive cancer, and its detection, diagnosis, and management are controversial. DCIS incidence grew with the expansion of screening ...mammography programs in the 1980s and 1990s, and DCIS is viewed as a major driver of overdiagnosis and overtreatment. For pathologists, the diagnosis and classification of DCIS is challenging due to undersampling and interobserver variability. Understanding the progression from normal breast tissue to DCIS and, ultimately, to invasive cancer is limited by a paucity of natural history data with multiple proposed evolutionary models of DCIS initiation and progression. Although radiologists are familiar with the classic presentation of DCIS as asymptomatic calcifications at mammography, the expanded pool of modalities, advanced imaging techniques, and image analytics have identified multiple potential biomarkers of histopathologic characteristics and prognosis. Finally, there is growing interest in the nonsurgical management of DCIS, including active surveillance, to reduce overtreatment and provide patients with more personalized management options. However, current biomarkers are not adept at enabling identification of occult invasive disease at biopsy or accurately predicting the risk of progression to invasive disease. Several active surveillance trials are ongoing and are expected to better identify women with low-risk DCIS who may avoid surgery.
Some cells discard undesired inherited components in bulk by forming large compartments that are subsequently eliminated. Caenorhabditis elegans primordial germ cells (PGCs) jettison mitochondria and ...cytoplasm by forming a large lobe that is cannibalized by intestinal cells. Although PGCs are nonmitotic, we find that lobe formation is driven by constriction of a contractile ring and requires the RhoGEF ECT-2, a RhoA activator also essential for cytokinesis. Whereas centralspindlin activates ECT-2 to promote cytokinetic contractile ring formation, we show that the ECT-2 regulator NOP-1, but not centralspindlin, is essential for PGC lobe formation. We propose that lobe contractile ring formation is locally inhibited by the PGC nucleus, which migrates to one side of the cell before the cytokinetic ring assembles on the opposite cortex. Our findings reveal how components of the cytokinetic contractile ring are reemployed during interphase to create compartments used for cellular remodeling, and they reveal differences in the spatial cues that dictate where the contractile ring will form.
In RNA interference (RNAi), short double-stranded RNA (known as siRNA) inhibits expression from homologous genes. Clinical or pre-clinical use of siRNAs is likely to require stabilizing modifications ...because of the prevalence of intracellular and extracellular nucleases. In order to examine the effect of modification on siRNA efficacy and stability, we developed a new method for synthesizing stereoregular boranophosphate siRNAs. This work demonstrates that boranophosphate siRNAs are consistently more effective than siRNAs with the widely used phosphorothioate modification. Furthermore, boranophosphate siRNAs are frequently more active than native siRNA if the center of the antisense strand is not modified. Boranophosphate modification also increases siRNA potency. The finding that boranophosphate siRNAs are at least ten times more nuclease resistant than unmodified siRNAs may explain some of the positive effects of boranophosphate modification. The biochemical properties of boranophosphate siRNAs make them promising candidates for an RNAi-based therapeutic.
Elucidation of maternal immune correlates of protection against congenital cytomegalovirus (CMV) is necessary to inform future vaccine design. Here, we present a novel rhesus macaque model of ...placental rhesus CMV (rhCMV) transmission and use it to dissect determinants of protection against congenital transmission following primary maternal rhCMV infection. In this model, asymptomatic intrauterine infection was observed following i.v. rhCMV inoculation during the early second trimester in two of three rhCMV-seronegative pregnant females. In contrast, fetal loss or infant CMV-associated sequelae occurred in four rhCMV-seronegative pregnant macaques that were CD4⁺ T-cell depleted at the time of inoculation. Animals that received the CD4⁺ T-cell–depleting antibody also exhibited higher plasma and amniotic fluid viral loads, dampened virus-specific CD8⁺ T-cell responses, and delayed production of autologous neutralizing antibodies compared with immunocompetent monkeys. Thus, maternal CD4⁺ T-cell immunity during primary rhCMV infection is important for controlling maternal viremia and inducing protective immune responses that prevent severe CMV-associated fetal disease.
Abstract
Neutrinos are particles that interact rarely, so identifying them requires large detectors which produce lots of data. Processing this data with the computing power available is becoming ...even more difficult as the detectors increase in size to reach their physics goals.
Liquid argon time projection chamber (LArTPC) neutrino experiments are expected to grow in the next decade to have 100 times more wires than in currently operating experiments, and modernization of LArTPC reconstruction code, including parallelization both at data- and instruction-level, will help to mitigate this challenge.
The LArTPC hit finding algorithm is used across multiple experiments through a common software framework. In this paper we discuss a parallel implementation of this algorithm. Using a standalone setup we find speedup factors of two times from vectorization and 30–100 times from multi-threading on Intel architectures. The new version has been incorporated back into the framework so that it can be used by experiments. On a serial execution, the integrated version is about 10 times faster than the previous one and, once parallelization is enabled, further speedups comparable to the standalone program are achieved.
Purpose of Reveiw
To compile knowledge of expected intravascular imaging findings in coronary venous and arterial bypass grafts, both at baseline and in diseased states in order to improve ...understanding of the pathology demonstrated in failing grafts. Also, to learn how intravascular imaging could be used to guide necessary graft interventions and to consider whether imaging practices in grafts could become formalized or potentially influence outcomes of graft interventions, which are notoriously poor.
Recent Findings
Disease in saphenous vein grafts has features overlapping with pathology in native vessels, but can also involve unique findings which have been described in studies and can be delineated well with intravascular imaging. The latter has also been used successfully to examine findings in internal mammary as well as radial artery grafts, particularly in the peri-operative period. Previously reported cases, as well as a case example here, show the feasibility and potential utility of these imaging modalities within grafts to guide coronary intervention.
Summary
Intravascular imaging within bypass grafts is feasible and expected findings can be recognized and understood with review of existing data and with clinical experience gained in individual operator practice. Future directions could explore guidelines for imaging-guided intervention within bypass grafts and could examine whether outcomes could be improved with intravascular imaging guidance.
This study investigated a 3-year implementation of accredited massive online open courses (MOOCs) in a conventional university in China. Fifteen students and two staff were interviewed, and relevant ...policy documents were examined. Thematic analysis was utilised to analyse the data. The study found that students mostly took a wary stance towards accredited MOOCs, while the university supported them. Reasons for students' favour and disfavour were explored. There was widespread online absenteeism, which was unique to accredited MOOCs. Moreover, accredited MOOCs were found to be completely independent of traditional onsite courses, making them difficult to form a synergy with the latter. Also, a distinct mismatch was identified between the course assessment system and the new course format. Furthermore, there were insufficient regulation, support, and incentives from the university in facilitating the implementation of accredited MOOCs, indicating a discrepancy between university policies and practice. Solutions for future improvement of accredited MOOCs were explored. This study will aid educational practitioners and policymakers in widening access to quality education by exploring effective solutions regarding integrating accredited MOOCs into conventional higher education.
During mating, Saccharomyces cerevisiae cells must degrade the intervening cell wall to allow fusion of the partners. Because improper timing or location of cell wall degradation would cause lysis, ...the initiation of cell fusion must be highly regulated. Here, we find that yeast cell fusion is negatively regulated by components of the cell wall integrity (CWI) pathway. Loss of the cell wall sensor, MID2, specifically causes "mating-induced death" after pheromone exposure. Mating-induced death is suppressed by mutations in cell fusion genes ( FUS1, FUS2, RVS161, CDC42), implying that mid2Δ cells die from premature fusion without a partner. Consistent with premature fusion, mid2Δ shmoos had thinner cell walls and lysed at the shmoo tip. Normally, Cdc42p colocalizes with Fus2p to form a focus only when mating cells are in contact (prezygotes) and colocalization is required for cell fusion. However, Cdc42p was aberrantly colocalized with Fus2p to form a focus in mid2Δ shmoos. A hyperactive allele of the CWI kinase Pkc1p ( PKC1*) caused decreased cell fusion and Cdc42p localization in prezygotes. In shmoos, PKC1* increased Cdc42p localization; however, it was not colocalized with Fus2p or associated with cell death. We conclude that Mid2p and Pkc1p negatively regulate cell fusion via Cdc42p and Fus2p.
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