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To code-switch or not to code-switch? This is a dilemma for many bilingual language teachers. In this study, the influence of teachers’ CS on bilingual children's language and cognitive development is explored within heritage language (HL) classes in Singapore. Specifically, the relationship between children's language output, vocabulary development, and cognitive flexibility to teachers’ classroom CS behavior, is examined within 20 preschool HL classrooms (10 Mandarin, 6 Malay, and 4 Tamil). Teachers’ and children's utterances were recorded, transcribed, and analyzed for CS frequency and type (i.e., inter-sentential, intra-sentential). 173 students were assessed with receptive vocabulary and dimensional card sort tasks, and their vocabulary and cognitive switching scores assessed using correlational and mixed effects analyses. Results show that inter-sentential and intra-sentential CS frequency is positively and significantly related to children's intra-sentential CS frequency. Overall, findings revealed that teachers code-switched habitually more often than for instructional purposes. Neither inter-sentential nor intra-sentential CS was significantly related to children's development in HL vocabulary, and intra-sentential CS was found to positively and significantly relate to children's growth in cognitive flexibility. These findings reveal the multi-faceted impact of teacher's CS on children's early development.

To code-switch or not to code-switch? This is a dilemma for many bilingual language teachers. In this study, the influence of teachers' CS on bilingual children's language and cognitive development is explored within heritage language (HL) classes in Singapore. Specifically, the relationship between children's language output, vocabulary development, and cognitive flexibility to teachers' classroom CS behavior, is examined within 20 preschool HL classrooms (10 Mandarin, 6 Malay, and 4 Tamil). Teachers' and children's utterances were recorded, transcribed, and analyzed for CS frequency and type (i.e., inter-sentential, intra-sentential). 173 students were assessed with receptive vocabulary and dimensional card sort tasks, and their vocabulary and cognitive switching scores assessed using correlational and mixed effects analyses. Results show that inter-sentential and intra-sentential CS frequency is positively and significantly related to children's intra-sentential CS frequency. Overall, findings revealed that teachers code-switched habitually more often than for instructional purposes. Neither inter-sentential nor intra-sentential CS was significantly related to children's development in HL vocabulary, and intra-sentential CS was found to positively and significantly relate to children's growth in cognitive flexibility. These findings reveal the multi-faceted impact of teacher's CS on children's early development.

Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1 HIGH and MAFA HIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1 HIGH and MAFA HIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca 2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function. Beta cell subpopulations with low expression in PDX1, MAFA, and insulin might contribute to islet function and insulin release. Here the authors show that altering the proportion of PDX1 LOW MAFA LOW to PDX1 HIGH MAFA HIGH cells impairs islet function.

Few studies are available to inform duration of intravenous antibiotics for children and when it is safe and appropriate to switch to oral antibiotics. We have systematically reviewed antibiotic duration and timing of intravenous to oral switch for 36 paediatric infectious diseases and developed evidence-graded recommendations on the basis of the review, guidelines, and expert consensus. We searched databases and obtained information from references identified and relevant guidelines. All eligible studies were assessed for quality. 4090 articles were identified and 170 studies were included. Evidence relating antibiotic duration to outcomes in children for some infections was supported by meta-analyses or randomised controlled trials; in other infections data were from retrospective series only. Criteria for intravenous to oral switch commonly included defervescence and clinical improvement with or without improvement in laboratory markers. Evidence suggests that intravenous to oral switch can occur earlier than previously recommended for some infections. We have synthesised recommendations for antibiotic duration and intravenous to oral switch to support clinical decision making and prospective research.

Interactions between immune and tumor cells in the tumor microenvironment (TME) often impact patient outcome, yet remain poorly understood. In addition, the effects of biophysical features such as hypoxia [low oxygen (O )] on cells within the TME may lead to tumor evasion. Gamma delta T cells (γδTcs) naturally kill transformed cells and are therefore under development as immunotherapy for various cancers. Clinical trials have proven the safety of γδTc immunotherapy and increased circulating γδTc levels correlate with improved patient outcome. Yet, the function of γδTc tumor infiltrating lymphocytes in human breast cancer remains controversial. Breast tumors can be highly hypoxic, thus therapy must be effective under low O conditions. We have found increased infiltration of γδTc in areas of hypoxia in a small cohort of breast tumors; considering their inherent plasticity, it is important to understand how hypoxia influences γδTc function. , the cell density of expanded primary healthy donor blood-derived human γδTc decreased in response to hypoxia (2% O ) compared to normoxia (20% O ). However, the secretion of macrophage inflammatory protein 1α (MIP1α)/MIP1β, regulated on activation, normal T cell expressed and secreted (RANTES), and CD40L by γδTc were increased after 40 h in hypoxia compared to normoxia concomitant with the stabilization of hypoxia inducible factor 1-alpha protein. Mechanistically, we determined that natural killer group 2, member D (NKG2D) on γδTc and the NKG2D ligand MHC class I polypeptide-related sequence A (MICA)/B on MCF-7 and T47D breast cancer cell lines are important for γδTc cytotoxicity, but that MIP1α, RANTES, and CD40L do not play a direct role in cytotoxicity. Hypoxia appeared to enhance the cytotoxicity of γδTc such that exposure for 48 h increased cytotoxicity of γδTc against breast cancer cells that were maintained in normoxia; conversely, breast cancer lines incubated in hypoxia for 48 h prior to the assay were largely resistant to γδTc cytotoxicity. MICA/B surface expression on both MCF-7 and T47D remained unchanged upon exposure to hypoxia; however, ELISAs revealed increased MICA shedding by MCF-7 under hypoxia, potentially explaining resistance to γδTc cytotoxicity. Despite enhanced γδTc cytotoxicity upon pre-incubation in hypoxia, these cells were unable to overcome hypoxia-induced resistance of MCF-7. Thus, such resistance mechanisms employed by breast cancer targets must be overcome to develop more effective γδTc immunotherapies.

Non-targeted analysis (NTA) using high-resolution mass spectrometry allows scientists to detect and identify a broad range of compounds in diverse matrices for monitoring exposure and toxicological evaluation without a priori chemical knowledge. NTA methods present an opportunity to describe the constituents of a sample across a multidimensional swath of chemical properties, referred to as “chemical space.” Understanding and communicating which region of chemical space is extractable and detectable by an NTA workflow, however, remains challenging and non-standardized. For example, many sample processing and data analysis steps influence the types of chemicals that can be detected and identified. Accordingly, it is challenging to assess whether analyte non-detection in an NTA study indicates true absence in a sample (above a detection limit) or is a false negative driven by workflow limitations. Here, we describe the need for accessible approaches that enable chemical space mapping in NTA studies, propose a tool to address this need, and highlight the different ways in which it could be implemented in NTA workflows. We identify a suite of existing predictive and analytical tools that can be used in combination to generate scores that describe the likelihood a compound will be detected and identified by a given NTA workflow based on the predicted chemical space of that workflow. Higher scores correspond to a higher likelihood of compound detection and identification in a given workflow (based on sample extraction, data acquisition, and data analysis parameters). Lower scores indicate a lower probability of detection, even if the compound is truly present in the samples of interest. Understanding the constraints of NTA workflows can be useful for stakeholders when results from NTA studies are used in real-world applications and for NTA researchers working to improve their workflow performance. The hypothetical ChemSpaceTool suggested herein could be used in both a prospective and retrospective sense. Prospectively, the tool can be used to further curate screening libraries and set identification thresholds. Retrospectively, false detections can be filtered by the plausibility of the compound identification by the selected NTA method, increasing the confidence of unknown identifications. Lastly, this work highlights the chemometric needs to make such a tool robust and usable across a wide range of NTA disciplines and invites others who are working on various models to participate in the development of the ChemSpaceTool. Ultimately, the development of a chemical space mapping tool strives to enable further standardization of NTA by improving method transparency and communication around false detection rates, thus allowing for more direct method comparisons between studies and improved reproducibility. This, in turn, is expected to promote further widespread applications of NTA beyond research-oriented settings.

Purpose Immune checkpoint inhibitors (ICIs) are associated with a unique set of immune-related adverse events (irAEs). Few studies have evaluated the risk factors and outcomes of patients who develop ICI-induced hepatitis (ICIH). Methods We utilized an institutional database of patients with advanced cancers treated with ICI to identify patients with ICIH. irAEs were graded using the Common Terminology Criteria for Adverse Events v4. Overall survival (OS) was calculated from the date of ICI to death from any cause or the date of the last follow-up. OS with 95% confidence intervals were estimated using the Kaplan–Meier method and stratified by the occurrence of ICIH. Results We identified 1096 patients treated with ICI. The most common ICIs were PD1/L1 ( n  = 774) and CTLA-4 inhibitors ( n  = 195). ICIH occurred among 64 (6%) patients: severity was < grade 3 in 30 and ≥ grade 3 in 24 patients (3.1% overall). Median time to ICIH was 63 days. ICIH was more frequent in women ( p  = 0.038), in patients treated with combination ICIs ( p  < 0.001), and when given as first-line therapy ( p  = 0.018). Occurrence of ICIH was associated with significantly longer OS, median 37.0 months (95% CI 21.4, NR) compared to 11.3 months (95% CI 10, 13, p  < 0.001); there was no difference in OS between patients with ≥ grade 3 ICIH vs grade 1–2. Conclusions Female sex, combination immunotherapy, and the first line of immunotherapy were associated with ICIH. Patients with ICIH had improved clinical survival compared to those that did not develop ICIH. There is a need for prospective further studies to confirm our findings.

PurposeThis paper presents a case study of a school district–university partnership to co-design a Children’s Cabinet, a cross-sector initiative bringing together institutional and community leaders to address youth well-being in the aftermath of the COVID-19 pandemic. In a vibrant, immigrant-serving community in the Northeast United States, the partnership was initiated by district leaders in Spring 2021 after pandemic disruptions led to a youth mental health crisis.Design/methodology/approachOur descriptive, qualitative case study focuses on the structure and emerging design principles of the research–practice partnership, which established a Children’s Cabinet comprised of educational, government and community leaders along with researchers. From Spring 2021 through Spring 2024, we collected and analyzed member and youth interviews, ethnographic observations and artifacts from all meetings and process interviews with key partners.FindingsWe describe the structure of the partnership, including how researchers and district leaders collaborated on meeting facilitation and how researchers conducted and shared applied research. We then discuss three design principles that guided the work, including centering relationships, sustaining focus on key goals and embedding applied research.Originality/valueAs embedded research partners, our team is uniquely situated to narrate the nature and structure of the partnership and reflect on the design of our cross-sector initiative. Increasingly, universities are partnering directly with districts on school improvement initiatives. Our work shows how engaging in RPPs to bring together school, community and research partners can facilitate local leadership and collaboration to address complex, cross-sector goals such as increasing youth well-being.

The tobacco thrips, Frankliniella fusca Hinds, is a phytophagous pest and vector of orthotospoviruses in many crops around the world. F. fusca causes direct feeding injury to peanut plants, resulting in leaf chlorosis and curling, and yield loss. Adults and larvae also transmit the economically important tomato spotted wilt orthotospovirus (TSWV) in all peanut market types grown in the U.S. TSWV infection causes spotted wilt disease, a plant disease characterized by chlorosis, stunting, and death. From 1996 to 2006, spotted wilt disease resulted in an estimated U.S.$140 million in annual peanut production losses in the U.S. At present, a thorough documentation of F. fusca’s impacts on the U.S. peanut production system is not available. Here, we describe the morphology, life cycle, and biology of F. fusca and provide images of immature life stages. Feeding injury characteristics and TSWV transmission in peanuts are also discussed. Currently, F. fusca and TSWV are managed in peanut with a combination of tactics, including prophylactic insecticide applications and TSWV-resistant cultivars. However, standardized scouting protocols and economic thresholds for F. fusca are not yet available. Very few biological control agents have been evaluated for use against F. fusca, and few studies have quantified the contributions of native natural enemies. More research into natural enemies’ contributions to F. fusca management and the mechanisms underlying TSWV-resistance in peanut could help inform and diversify integrated pest management programs.

Immunodeficient mice, like the NOD-SCID-Gamma (NSG) strain, are important for the study of xenogeneic cells because of their lack of lymphocytes, dysfunctional hemolytic complement factor 5 (C5), and macrophage defects making them permissive hosts. Nonetheless, cellular barriers remain that limit engraftment of foreign cells such as monocytic phagocytes. Accordingly, we created a line of mice that allows for depletion of monocytic cells by breeding NSG mice with macrophage Fas-induced apoptosis (MaFIA) mice resulting in a stable line of NSG-MaFIA mice. NSG-MaFIA mice were generated by crossing NSG and MaFIA mice, with the hybrids backcrossed for nine generations to NSG mice. Flow cytometry was used to detect the expression of the MaFIA gene construct among blood leukocytes. Functional and confirmatory studies evaluated the successful transfer of the MaFIA transgene into the NSG genetic background. Apoptosis of monocytic cells was achieved through administration of a homodimerizer drug. The phenotypic characteristics of NSG mice were confirmed in NSG-MaFIA mice by flow cytometry, CBC analysis, testing of radiation sensitivity, and sequencing of the C5 gene. The permissiveness of NSG-MaFIA mice for xenogeneic engraftment was tested by transfusion of human red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs). The MaFIA transgene was hybridized into NSG mice as exhibited by expression of a fluorescent marker. Functional expression of the MaFIA transgene was evidenced by weight loss and decreased fluorescence after homodimerizer treatment. NSG-MaFIA mice are lymphopenic, are sensitive to X-ray irradiation, and carry a mutated C5 gene. Transfusion of human RBCs resulted in similar clearance in NSG and NSG-MaFIA mice, without homodimerizer treatment, indicating a similar innate immune response. Moreover, transfusion of human RBCs or PBMCs after depletion of monocytic cells led to prolonged circulation of RBCs and rapid engraftment of leukocytes. A novel NSG-MaFIA mouse line was developed that has use in the study of monocytic cells and in the development of better humanized mouse models. Transfusion of human blood cells into cell-depleted NSG-MaFIA mice increased the persistence of the human cells in the circulation, indicating a role for monocytic cells in the removal of xenogeneic cells from immunodeficient mice.