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Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems-level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provides information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights and, when coupled with in vivo models, can be used to unravel pathogenic mechanisms.

Patients with small cell lung cancer (SCLC) generally have a poor prognosis and a median overall survival of only about 13 months, indicating the urgent need for novel therapies. Delta-like protein 3 (DLL3) has been identified as a tumor-specific cell surface marker on neuroendocrine cancers, including SCLC. In this study, we developed a chimeric antigen receptor (CAR) against DLL3 that displays antitumor efficacy in xenograft and murine SCLC models. CAR T cell expression of the proinflammatory cytokine IL-18 greatly enhanced the potency of DLL3-targeting CAR T cell therapy. In a murine metastatic SCLC model, IL-18 production increased the activation of both CAR T cells and endogenous tumor-infiltrating lymphocytes. We also observed an increased infiltration, repolarization, and activation of antigen-presenting cells. Additionally, human IL-18–secreting anti-DLL3 CAR T cells showed an increased memory phenotype, less exhaustion, and induced durable responses in multiple SCLC models, an effect that could be further enhanced with anti–PD-1 blockade. All together, these results define DLL3-targeting CAR T cells that produce IL-18 as a potentially promising novel strategy against DLL3-expressing solid tumors.

Background To promote ideal cardiovascular health, the American Heart Association recommends adhering to Life's Simple 7 (LS7)—achieving healthy targets for body mass index, physical activity, dietary intake, blood pressure, fasting plasma glucose, and cholesterol, along with smoking abstinence. Poorer achievement of LS7 (lower score) has been associated with the development of hypertension and cardiovascular disease. However, less is known about the associations between LS7 and specific biomarkers linked to cardiovascular health: aldosterone, CRP (C‐reactive protein), and IL‐6 (interleukin‐6). Methods and Results We analyzed 379 individuals (age 18–66 years) from the HyperPATH (International Hypertensive Pathotype), who were maintained on ≥200 mEq of sodium daily for 1 week. We calculated a 14‐point summative LS7 score according to participants' baseline data. Based on the range of LS7 score in this population (3–14), we classified participants as “inadequate” (3–6), “average” (7–10), and “optimal” (11–14). Regression analyses found that a higher LS7 score group was associated with lower levels of serum and urinary aldosterone (Ptrend

To reduce the prevalence of youth injuries and fatalities in agricultural settings, safety professionals considered developing a guideline-focused intervention for how and when youth should conduct farm chores. In 1996, the process to create guidelines started, which then expanded to include professionals from the United States, Canada, and Mexico. This team used a consensus driven approach to develop the guidelines and launch the North American Guidelines for Children’s Agricultural Tasks. By 2015, research related to the published guidelines indicated a need to incorporate new empirical evidence and develop dissemination plans based on new technologies. The process for updating the guidelines was supported by a 16-person steering committee and used content experts and technical advisors. The process yielded updated and new guidelines, now called Agricultural Youth Work Guidelines. This report responds to request for further details on the development and update of the guidelines and describes the genesis of the guidelines as an intervention, the process for creating guidelines, recognition of the need to update guidelines based on research, and the process for updating guidelines to assist in others engaged in similar types of interventions.

Background: Culturally and linguistically diverse (CALD) refugees and immigrants in the United States (U.S.) face barriers to accessing health care, and are more likely to have worse health outcomes as it relates to chronic disease. Better understanding health literacy for this population can identify gaps in knowledge, facilitate health education, and improve health outcomes. Purpose: The Refugee Health Literacy Assessment Tool (RHLAT) was developed to improve patient-centered chronic disease management by identifying aspects of health literacy for which individual refugees require additional support. Methods: RHLAT development involved domain identification, item development, expert reviews, and cognitive interviews. Refugee and immigrant patients with uncontrolled diabetes and cardiovascular risk factors were engaged for RHLAT implementation. Results: The tool was valid across different types of interpretation, such as in-person interpreter or over the phone, and revealed a wide range of health literacy in this population. Discussion: The RHLAT was developed and tested with a CALD refugee population. The tool revealed gaps in health literacy that could be addressed by the care team. Translation to Health Education Practice: This study provides a tool that can be used in practice to identify areas for additional health education to assist CALD patients in navigating the U.S. healthcare system.

Objective: The objective of this study was to explore clinician perceptions of how racism affects Black women's pregnancy experiences, perinatal care, and birth outcomes. Materials and Methods: We conducted 25 semi-structured interviews with perinatal care clinicians practicing in the San Francisco Bay Area (January to March 2019) who serve racially diverse women. Participants were primarily recruited through ?Dear Perinatal Care Provider? email correspondences sent through department listservs. Culturally concordant, qualitatively trained research assistants conducted all interviews in person. The interviews ranged from 30 to 60 minutes and were audio-recorded and professionally transcribed verbatim. We used the constant comparative method consistent with grounded theory to analyze data. Results: Most participants were obstetrician/gynecologists (n?=?11, 44%) or certified nurse midwives (n?=?8, 32%), had worked in their current role for 1 to 5 years (n?=?10, 40%), and identified as white (n?=?16, 64%). Three themes emerged from the interviews: provision of inequitable care (e.g., I had a woman who had a massive complication during her labor course and felt like she wasn't being treated seriously); surveillance of Black women and families (e.g., A urine tox screen on the Black baby even though it was not indicated, and they didn't do it on the white baby when, in fact, it was indicated); and structural care issues (e.g., the history of medical racial experimentation). Conclusion: Clinicians' views about how racism is currently operating and negatively impacting Black women's care experiences, health outcomes, and well-being in medical institutions will be used to develop a racial equity training for perinatal care clinicians in collaboration with Black women and clinicians.

Abstract The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients’ selection.

We present the High- z Evolution of Large and Luminous Objects (HELLO) project, a set of |$\sim \!30$| high-resolution cosmological simulations aimed to study Milky Way analogues (⁠|$M_\star \sim 10^{10-11}$|   |${\mathrm{M}}_{\odot }$|⁠) at high redshift (⁠|$z\sim [2-4]$|⁠). Based on the numerical investigation of a hundred astrophysical objects, HELLO features an updated scheme for chemical enrichment and the addition of local photoionization feedback. Independently of redshift and mass, our galaxies exhibit a smooth progression along the star formation main sequence until |$M_\star \sim \!10^{10.5}$|⁠ , around which our sample at |$z \sim 4$| remains mostly unperturbed while the most massive galaxies at |$z \sim 2$| reach their peak star formation rate (SFR) and its subsequent decline, due to a mix of gas consumption and stellar feedback. While active galactic nucleus feedback remains subdominant with respect to stellar feedback for energy deposition, its localized nature likely adds to the physical processes leading to declining SFRs. The phase in which a galaxy in our mass range can be found at a given redshift is set by its gas reservoir and assembly history. Finally, our galaxies are in excellent agreement with various scaling relations observed with the Hubble Space Telescope and the JWST , and hence can be used to provide the theoretical framework to interpret current and future observations from these facilities and shed light on the transition from star-forming to quiescent galaxies. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic highlighted testing inequities in developing countries. Lack of lateral flow test (LFT) manufacturing capacity was a major COVID-19 response bottleneck in low- and middle-income regions. Here we report the development of an open-access LFT for SARS-CoV-2 detection comparable to commercial tests that requires only locally available supplies. The main critical resource is a locally developed horse polyclonal antibody (pAb) whose sensitivity and selectivity are greatly enhanced by affinity purification. We demonstrate that these Abs can perform similarly to commercial monoclonal antibodies (mAbs), as well as mAbs and other pAbs developed against the same antigen. We report a workflow for test optimization using nasopharyngeal swabs collected for RT-qPCR, spiked with the inactivated virus to determine analytical performance characteristics as the limit of detection, among others. Our final prototype showed a performance similar to available tests (sensitivity of 83.3% compared to RT-qPCR, and 90.9% compared to commercial antigen tests). Finally, we discuss the possibility and the challenges of utilizing affinity-purified pAbs as an alternative for the local development of antigen tests in an outbreak context and as a tool to address inequalities in access to rapid tests. [ABSTRACT FROM AUTHOR]

This is an executive summary of the most recent American Society for Radiation Oncology (ASTRO) guidelines on use of partial breast irradiation in early-stage breast cancer. In the conscientious pursuit of "right-sizing" the management of patients with early-stage breast cancer, there has been an emphasis on judicious de-escalation of therapy. A component of this paradigm shift is partial breast irradiation (PBI), an approach characterized by targeted radiation therapy (RT) to lumpectomy cavity margins rather than to the whole breast (i.e., whole breast irradiation [WBI]) after breast conservation surgery (BCS). The American Society for Radiation Oncology (ASTRO) recently completed a revision of its evidence-based guidelines for the application of PBI.1 To accomplish this, recent PBI data were reviewed by panel members, including representatives of the American Society for Radiation Oncology (ASTRO), in collaboration with the American Society of Clinical Oncology (ASCO), and the Society of Surgical Oncology (SSO), which provided representatives and peer reviewers. The guideline was approved by the ASTRO Board of Directors and endorsed by the Canadian Association of Radiation Oncology, European Society for Radiotherapy and Oncology, Royal Australian and New Zealand College of Radiologists, and the Society of Surgical Oncology. The recommendations focused on indications for PBI as an alternative to WBI and technical considerations specific to PBI. This editorial provides a summary and comments on the updated ASTRO PBI guidelines, offering insights into the implications of these findings for clinical practice and multidisciplinary decision-making while underscoring technical considerations for optimal incorporation of PBI into patient care. [ABSTRACT FROM AUTHOR]

This paper reports about professional learning related to mathematics instruction in student-teaching triads. The study focuses on how the joint work of triads offers opportunities for the professional learning of student teachers (interns), mentor teachers, and supervisors. Two elementary student-teaching triads reported different areas of and opportunities for professional learning related to mathematics instruction, with more areas and richer opportunities reported by the triad with more extensive collaboration among its members. Findings suggest the need for professional development activities in which mentors and supervisors can examine their stances toward joint work and professional learning in triads.

Abstract Objective To determine if native Colombian Piper marginatum Jacq. and Ilex guayusa Loes plant extracts have a remineralizing effect on teeth with Amelogenesis imperfecta in comparison with the commercial products Clinpro‐3M and Recaldent™. Material and Methods An in vitro study was carried out with 128 human teeth slices (64 healthy and 64 with Amelogenesis imperfecta) on which an initial Raman spectroscopy was performed followed by Raman spectroscopies at 0, 24, 48, and 72 h to determine possible remineralization by observing mineral increase or decrease as a result of P. marginatum Jacq. and I. guayusa Loes extract application in comparison to control substance (Clinpro and Recaldent™) application. Obtained data were analyzed using a bivariate method with a t unidirectional test. Significant differences among groups were determined by an ANOVA with Dunnett post hoc tests. Results Native I. guayusa Loes and P. marginatum Jacq. Colombian plants extracts exhibited phosphate and orthophosphate mineral apposition, where P. marginatum Jacq. presented better results. Conclusions Native Colombian I. guayusa Loes and P. marginatum Jacq plant extract might in the future be useful for dental tissue remineralization, as they induced phosphate and orthophosphate mineral apposition, main components of tooth enamel. These types of natural compounds can become an alternative to fluorine, whose ingestion is harmful to the human body.

Increased risk of intestinal dysfunction has been reported in patients after Clostridioides difficile infection (CDI). Enteric glial cells (EGCs), a component of the enteric nervous system (ENS), contribute to gut homeostasis. Previous studies showed that adenosine receptors, A2A and A2B, modulate inflammation during CDI. However, it is unknown how these receptors can modulate the EGC response to the C. difficile toxins (TcdA and TcdB). We investigated the effects of these toxins on the expression of adenosine receptors in EGCs and the role of these receptors on toxin-induced EGC death. Rat EGCs line were incubated with TcdA or TcdB alone or in combination with adenosine analogues 1h prior to toxins challenge. After incubation, EGCs were collected to evaluate gene expression (adenosine receptors and proinflammatory markers) and cell death. In vivo, WT, A2A, and A2B KO mice were infected with C. difficile, euthanized on day 3 post-infection, and cecum tissue was processed. TcdA and TcdB increased A2A and A3 transcripts, as well as decreased A2B. A2A agonist, but not A2A antagonist, decreased apoptosis induced by TcdA and TcdB in EGCs. A2B blocker, but not A2B agonist, diminished apoptosis in EGCs challenged with both toxins. A3 agonist, but not A3 blocker, reduced apoptosis in EGCs challenged with TcdA and TcdB. Inhibition of protein kinase A (PKA) and CREB, both involved in the main signaling pathway driven by activation of adenosine receptors, decreased EGC apoptosis induced by both toxins. A2A agonist and A2B antagonist decreased S100B upregulation induced by C. difficile toxins in EGCs. In vivo, infected A2B KO mice, but not A2A, exhibited a decrease in cell death, including EGCs and enteric neuron loss, compared to infected WT mice, reduced intestinal damage and decreased IL-6 and S100B levels in cecum. Our findings indicate that upregulation of A2A and A3 and downregulation of A2B in EGCs and downregulation of A2B in intestinal tissues elicit a protective response against C. difficile toxins. Adenosine receptors appear to play a regulatory role in EGCs death and proinflammatory response induced by TcdA and TcdB, and thus may be potential targets of intervention to prevent post-CDI intestinal dysmotility.

The Gerda collaboration is performing a sensitive search for neutrinoless double beta decay of 76Ge at the INFN Laboratori Nazionali del Gran Sasso, Italy. The upgrade of the Gerda experiment from Phase I to Phase II has been concluded in December 2015. The first Phase II data release shows that the goal to suppress the background by one order of magnitude compared to Phase I has been achieved. Gerda is thus the first experiment that will remain “background-free” up to its design exposure (100 kgyear). It will reach thereby a half-life sensitivity of more than 10 26 year within 3 years of data collection. This paper describes in detail the modifications and improvements of the experimental setup for Phase II and discusses the performance of individual detector components.

The Gerda collaboration is performing a sensitive search for neutrinoless double beta decay of 76Ge at the INFN Laboratori Nazionali del Gran Sasso, Italy. The upgrade of the Gerda experiment from Phase I to Phase II has been concluded in December 2015. The first Phase II data release shows that the goal to suppress the background by one order of magnitude compared to Phase I has been achieved. Gerda is thus the first experiment that will remain “background-free” up to its design exposure (100 kgyear). It will reach thereby a half-life sensitivity of more than 10 26 year within 3 years of data collection. This paper describes in detail the modifications and improvements of the experimental setup for Phase II and discusses the performance of individual detector components.

Abstract Flaviviruses are major human disease-causing pathogens, including dengue virus (DENV), Zika virus, yellow fever virus and others. DENV infects hundreds of millions of people per year around the world, causing a tremendous social and economic burden. DENV capsid (C) protein plays an essential role during genome encapsidation and viral particle formation. It has been previously shown that DENV C enters the nucleus in infected cells. However, whether DENV C protein exhibits nuclear export remains unclear. By spatially cross-correlating different regions of the cell, we investigated DENV C movement across the nuclear envelope during the infection cycle. We observed that transport takes place in both directions and with similar translocation times (in the ms time scale) suggesting a bidirectional movement of both C protein import and export. Furthermore, from the pair cross-correlation functions in cytoplasmic or nuclear regions we found two populations of C molecules in each compartment with fast and slow mobilities. While in the cytoplasm the correlation times were in the 2–6 and 40–110 ms range for the fast and slow mobility populations respectively, in the cell nucleus they were 1–10 and 25–140 ms range, respectively. The fast mobility of DENV C in cytoplasmic and nuclear regions agreed with the diffusion coefficients from Brownian motion previously reported from correlation analysis. These studies provide the first evidence of DENV C shuttling from and to the nucleus in infected cells, opening new venues for antiviral interventions.

Dielectric metasurfaces supporting quasibound states in the continuum (quasi‐BICs) exhibit very high‐quality factor resonances and electric field confinement. However, accessing the high‐Q end of the quasi‐BIC regime usually requires marginally distorting the metasurface design from a BIC condition, pushing the needed nanoscale fabrication precision to the limit. This work introduces a novel concept for generating high‐Q quasi‐BICs, which strongly relaxes this requirement by incorporating a relatively large perturbative element close to high‐symmetry points of an undistorted BIC metasurface, acting as a coupler to the radiation continuum. This approach is validated by adding a ≈100 nm diameter cylinder between two reflection‐symmetry points separated by a 300 nm gap in an elliptical disk metasurface unit cell, using gallium phosphide as the dielectric. It is found that high‐Q resonances emerge when the cylindrical coupler is placed at any position between such symmetry points. This metasurface's second harmonic generation capability in the optical range is further explored. Displacing the coupler as much as a full diameter from a BIC condition produces record‐breaking normalized conversion efficiencies >102 W−1. The strategy of enclosing a disruptive element between multiple high‐symmetry points in a BIC metasurface can be applied to construct robust high‐Q quasi‐BICs in many geometrical designs.