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This mini-review examines the emerging role of the gut microbiome in influencing food allergen cross-reactivity. It specifically focuses on how microbial diversity, antigens, and metabolites impact IgE-mediated allergic responses. Cross-reactivity occurs when structurally similar food and microbial antigens trigger hypersensitivities, affecting millions of people worldwide. Recent research underscores the significance of microbial diversity in early life for developing immune tolerance. Beneficial strains, such as Lactobacillus and Bifidobacterium, play a crucial role in supporting the functions of T regulatory cells (Tregs) and immunoglobulin A (IgA). Additionally, we discuss microbial metabolites, particularly short-chain fatty acids (SCFAs), which enhance immune tolerance by promoting Treg differentiation and maintaining gut barrier integrity, thereby reducing allergen entry. However, it is important to note that SCFAs can provoke inflammatory responses under certain conditions, highlighting the necessity for targeted research on their dual effects. Dysbiosis-related intestinal permeability, often referred to as “leaky gut,” can further worsen cross-reactivity. Microbial antigens like lipopolysaccharides (LPS) are known to influence Th2-dominant responses.

Patient derived xenograft (PDX) models are regarded as gold standard preclinical models in leukaemia research, especially in testing new drug combinations where typically 45-50 mice are used per assay. 9000 animal experiments are performed annually in the UK in leukaemia research with these expensive procedures being classed as moderate severity, meaning they cause significant pain, suffering and visible distress to animal’s state. Furthermore, not all clinical leukaemia samples engraft and when they do data turnaround time can be between 6-12 months. Heavy dependence on animal models is because clinical leukaemia samples do not proliferate in vitro. Alternative cell line models though popular for drug testing are not biomimetic – they are not dependent on the microenvironment for survival, growth and treatment response and being derived from relapse samples they do not capture the molecular complexity observed at disease presentation. Here we have developed an in vitro platform to rapidly establish co-cultures of patient-derived leukaemia cells with 3D bone marrow mesenchyme spheroids, BM-MSC-spheroids. We optimise protocols for developing MSC-spheroid leukaemia co-culture using clinical samples and deliver drug response data within a week. Using three patient samples representing distinct cytogenetics we show that patient-derived-leukaemia cells show enhanced proliferation when co-cultured with MSC-spheroids. In addition, MSC-spheroids provided improved protection against treatment. This makes our spheroids suitable to model treatment resistance – a major hurdle in current day cancer management Given this 3Rs approach is 12 months faster (in delivering clinical data), is a human cell-based biomimetic model and uses 45-50 fewer animals/drug-response assay the anticipated target end-users would include academia and pharmaceutical industry. This animal replacement prototype would facilitate clinically translatable research to be performed with greater ethical, social and financial sustainability.

We are all familiar with how computers and smartphones have transformed work and productivity. We now stand at a new threshold with another technology that is predicted to further transform the way we work: Artificial Intelligence (AI). In this article, we hope to take a sober and practical look at AI from the perspective of professional evaluators. We examine how we might use it, how it might transform the nature of our tasks, what threats it might pose to our field, and what evaluators might do to protect themselves and our society from potential adverse effects of this emerging technology.

Despite the salience of monitoring in self-regulated learning (SRL) and foreign and/or second language (L2) speech production in non-testing conditions, little is known about the metacognitive construct in testing contexts and its effects on learner performance. Given the reciprocal effects between L2 testing and L2 learning, a research effort in monitoring working in speaking tests, in particular computer-delivered integrated speaking tests, a testing format that has been advocated as an internal part of L2 classroom instruction and represents the future direction of L2 testing, is warranted. This study, therefore, serves as such an effort through investigating the use of monitoring by 95 Chinese English as foreign language (EFL) learners on a self-reported questionnaire after they performed three computer-delivered integrated speaking test tasks. Descriptive analysis followed by Hierarchical Linear Modelling (HLM) testing reveals that monitoring was used in a high-frequency manner, but it exerted no substantial effects on learner performance. Primarily, the results are expected to provide pedagogical implications for SRL: while fostering self-regulating learners, especially self-monitoring L2 speakers, it is necessary for L2 teachers to purposefully reduplicate testing conditions in their classroom instructions for helping the self-regulating learners be equally self-regulating test-takers. Moreover, the results are hoped to offer some insights into L2 testing through the perspective of self-monitoring, one proposed component of strategic competence, a construct that has been extensively acknowledged to reflect the essence of L2 testing.

Background: Patients receiving warfarin who spend a lower proportion of time in therapeutic international normalized ratio (INR) range (TTR) have a higher risk of both bleeding complications and thromboembolic events. Using warfarin dosing algorithms is one intervention associated with improved INR stability. Objective: To determine the feasibility of an individualized warfarin dosing algorithm (Fearon Algorithm) under anticoagulation management service (AMS) care and compare measures of INR control using the algorithm with standard care. Methods: A pre/post intervention feasibility study consisting of the 12 months prior to patient enrollment (pre-study phase) and 6 months in which patients used the Fearon Algorithm under the supervision of an AMS pharmacist (AMS phase). The primary study outcome was the change in individual TTR. Results: A total of 30 patients were enrolled in the study, 26 (87%) of whom successfully completed the AMS study phase using the Fearon Algorithm. Median corrected individual TTR increased significantly from 53% (IQR: 39%, 64%) during the year prior to enrollment to 63% (IQR: 57%, 73%) during the AMS phase (p

Integration of distributed energy sources, advanced meshed operation, sensors, automation, and communication networks all contribute to autonomous operations and decision-making processes utilized in the grid. Therefore, smart grid systems require sophisticated supporting structures. Furthermore, rapid detection and identification of disturbances and transients are a necessary first step towards situationally aware smart grid systems. This way, high-level monitoring is achieved and the entire system kept operational. Even though smart grid systems are unavoidably sophisticated, low-complexity algorithms need to be developed for real-time sensing on the edge and online applications to alert stakeholders in the event of an anomaly. In this study, the simplest form of anomaly detection mechanism in the absence of any a priori knowledge, namely, the energy detector (also known as radiometer in the field of wireless communications and signal processing), is investigated as a triggering mechanism, which may include automated alerts and notifications for grid anomalies. In contrast to the mainstream literature, it does not rely on transform domain tools; therefore, utmost design and implementation simplicity are attained. Performance results of the proposed energy detector algorithm are validated by real power system data obtained from the DOE/EPRI National Database of power system events and the Grid Signature Library.

Vaccines are needed to disrupt or prevent continued outbreaks of filoviruses in humans across Western and Central Africa, including outbreaks of Marburg virus (MARV). As part of a filovirus vaccine product development plan, it is important to investigate dose response early in preclinical development to identify the dose range that may be optimal for safety, immunogenicity, and efficacy, and perhaps demonstrate that using lower doses is feasible, which will improve product access. To determine the efficacious dose range for a manufacturing-ready live recombinant vesicular stomatitis virus vaccine vector (rVSV∆G-MARV-GP) encoding the MARV glycoprotein (GP), a dose-range study was conducted in cynomolgus macaques. Results showed that a single intramuscular injection with as little as 200 plaque-forming units (PFUs) was 100% efficacious against lethality and prevented development of viremia and clinical pathologies associated with MARV Angola infection. Across the vaccine doses tested, there was nearly a 2000-fold range of anti-MARV glycoprotein (GP) serum IgG titers with seroconversion detectable even at the lowest doses. Virus-neutralizing serum antibodies also were detected in animals vaccinated with the higher vaccine doses indicating that vaccination induced functional antibodies, but that the assay was a less sensitive indicator of seroconversion. Collectively, the data indicates that a relatively wide range of anti-GP serum IgG titers are observed in animals that are protected from disease implying that seroconversion is positively associated with efficacy, but that more extensive immunologic analyses on samples collected from our study as well as future preclinical studies will be valuable in identifying additional immune responses correlated with protection that can serve as markers to monitor in human trials needed to generate data that can support vaccine licensure in the future.

The study was a pilot intervention to develop Year 5-8 students' close reading and writing of literary texts using the T-Shape Literacy Model (Wilson and Jesson in Set Res Inf Teach 1:15-22, 2019). Students analysed text sets to explore how different authors use language to engender mood and atmosphere. The study used a single-subject design logic for repeated researcher-designed and a quasi-experimental, matched control group design for repeated standardised measures of reading and writing. Nine teachers and their classes participated. The schools were part of a large school improvement programme using digital tools and pedagogy to accelerate students' learning participated that the authors were research-practice partners in. The schools all served low socio-economic status communities and the majority of students were Maori (51%) and Pacific (28%). There was a large effect size on the overall score for the researcher-designed measure (effect size = 1.00) and for the close reading of single texts sub-score (effect size = 0.90). There was a moderate-to-high effect for students' identification of language features (effect size = 0.75) but no significant effect on their synthesis scores. Students in the intervention significantly outperformed matched control group students in the standardised writing post-test (effect size = 0.65) but differences for the standardized reading comprehension test were not significant (effect size = 0.15). Results overall suggest the approach has promise for improving the metalinguistic knowledge, literary analysis and creative writing of younger and historically underserved groups of students.

Recently, clinical development of PARP inhibitors (PARPi) expanded from using them as a single agent to combining them with DNA-damaging therapy to derive additional therapeutic benefit from stimulated DNA damage. Furthermore, inhibiting PARP in cancers with BRCA1/2 mutations has been shown to be an effective synthetic lethality approach either as a single agent or in combination with the different DNA damaging agents: chemotherapy or ionizing radiation (IR). However, inherited BRCA1/2 mutations account only for 5–10% of breast cancers, 10–15% of ovarian cancers, and lesser for the other cancers. Hence, for most of the cancer patients with BRCA1/2-proficient tumors, sensitization to DNA-damaging agents with PARPi is significantly less effective. We recently demonstrated that moderate, non-toxic concentrations of NO-donors inhibited BRCA1 expression, with subsequent inhibition of error-free HRR and increase of error-prone non-homologous end joining (NHEJ). We also demonstrated that the effect of NO-dependent block of BRCA1 expression can only be achieved in the presence of oxidative stress, a condition that characterizes the tumor microenvironment and is also a potential effect of IR. Hence, NO-donors in combination with PARPi, with effects limited by tumor microenvironment and irradiated area, suggest a precise tumor-targeted approach for radio-sensitization of BRCA1/2-proficient tumors. The combination with NO-donors allows PARPi to be successfully applied to a wider variety of tumors. The present work demonstrates a new drug combination (NO-donors and PARP-inhibitors) which demonstrated a high potency in sensitization of wide variety of tumors to ionizing radiation treatment. Keywords: Nitric oxide donors, PARP inhibitors, Synthetic lethality, Ionizing radiation, Homologous recombination repair

Satellite-based hot-spot analysis for the Pan-Arctic, shows that Asia experiences a greater number of fires compared to North America and Europe. While hot spots are prevalent through the year in Asia, Europe (North America) exhibits marked annual (semi-annual) variability. The Potential Fire Danger index (PFIv2) demonstrates increased fire incidence vulnerability across the Arctic and extra-tropics. Though not significant in northwestern North America and eastern Asia, significant-positive trends across the mid-latitudes of Eurasia and Siberia are clear. PFIv2 accurately matches the regional distribution of observed fires, while the worldwide used Fire Weather Index does not. Fire danger has evolved as distributions of short-interval precipitation events and background vegetation characteristics change. In conjunction with increased population and expanded infrastructure, frequent extreme events may increase pressure for new settlements that lead to greater fire exposure across the Pan-Arctic. Thus, PFIv2 may be useful for decision planners and danger managers to anticipate and minimize the adverse effects of indiscriminate fire use.

The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia in vitro and in vivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases.

Background: This study set out to measure the extent and perceived impact of service user involvement (SUI) in mental health services and to explore different forms of SUI, both collective and individual. The focus was on service users’ (SUs’) interactions with managers and other key decision-makers in the UK NHS and social care. The theoretical frameworks used were organisational theory and new social movement theory. Objectives: To explore the impact of service user involvement in mental health on shaping policy agendas and delivery specifically in terms of their impact on key decision-makers. Design: A mixed-methods design was used. Setting: The study took place in three NHS foundation trusts (FTs): two metropolitan and one rural. Methods: The methods included surveys, interviews, ethnographies, case studies and focus groups. Results: In the first phase of the study, which took the form of surveys, it was found that ‘ordinary’ SUs had a relatively high level of involvement in at least one service domain and that where they were involved they believed this had produced a positive impact on service development and delivery. Likewise a majority of front-line staff encouraged SUI and thought this had a positive impact although social workers were more likely to have directly participated in SUI initiatives than nurses. In the second phase of the study, which used qualitative methods, an ethnography of user-led organisations (ULOs) was conducted, which showed that ULOs were being forced to adapt in an organisational climate of change and complexity, and that decision-makers no longer claimed the high moral ground for working with ULOs, but expected them to work within a system of institutional behavioural norms. This posed many challenges for the ULOs. In phase 2 of the research we also examined the role of SU governors in NHS FTs. We posed the question of whether or not SU governors represented a shift away from more collective forms of organisation to a more individual form. It was found that SU governors, too, had to work within a system of norms deriving from the organisational structure and culture of the NHS, and this impacted on how far they were able to exercise influence. There was also evidence that user governors were beginning to organise collectively. In respect of individual forms of involvement we also attempted to run focus groups of people in receipt of personal budgets but concluded that, as yet, they are not embedded in mental health services. Conclusions: It was concluded that SUs and managers are working in a climate of dynamic and complex organisational change, of which user involvement is an integral part, and that this has impacted on the nature of SUI as a new social movement. Managers need to attend to this in their interactions with SUs and their organisations. Funding: The National Institute for Health Research Health Services and Delivery Research programme.

Though vaccination with live-attenuated SIV provides the greatest protection from progressive disease caused by SIV challenge in rhesus macaques, attenuated HIV presents safety concerns as a vaccine; therefore, live viral vectors carrying HIV immunogens must be considered. We have designed a replication-competent vesicular stomatitis virus (VSV) displaying immunogenic HIV-1 Env trimers and attenuating quantities of the native surface glycoprotein (G). The clade B Env immunogen is an Env-VSV G hybrid (EnvG) in which the transmembrane and cytoplasmic tail regions are derived from G. Relocation of the G gene to the 5'terminus of the genome and insertion of EnvG into the natural G position induced a ∼1 log reduction in surface G, significant growth attenuation compared to wild-type, and incorporation of abundant EnvG. Western blot analysis indicated that ∼75% of incorporated EnvG was a mature proteolytically processed form. Flow cytometry showed that surface EnvG bound various conformationally- and trimer-specific antibodies (Abs), and in-vitro growth assays on CD4+CCR5+ cells demonstrated EnvG functionality. Neither intranasal (IN) or intramuscular (IM) administration in mice induced any observable pathology and all regimens tested generated potent Env-specific ELISA titers of 10(4)-10(5), with an IM VSV prime/IN VSV boost regimen eliciting the highest binding and neutralizing Ab titers. Significant quantities of Env-specific CD4+ T cells were also detected, which were augmented as much as 70-fold by priming with IM electroporated plasmids encoding EnvG and IL-12. These data suggest that our novel vector can achieve balanced safety and immunogenicity and should be considered as an HIV vaccine platform.

In order to understand the rising number of flash floods and landslides in the densely populated region of southeastern Brazil, this study analyzes the spatial and temporal changes in precipitation from 1978 to 2014. We focus on the sensitivity of mountainous regions, specifically the Rio de Janeiro (RJMR) and Santa Catarina (SCMR) regions. Daily rainfall observations are aggregated into annual and seasonal indexes, and RClimdex is used to evaluate a suite of precipitation and extreme event indexes. Results show positive annual and seasonal precipitation trends during all seasons except for the winter season in the RJMR. Diverse change points in their time series, spatial differences in the trends at individual stations, and trends associated with elevation suggest that despite the close proximity of these two regions, climate impacts are not uniform across all of southeastern Brazil. The majority of precipitation-related indexes present positive trends, especially in the extreme precipitation indexes (PRCPTOT, RX1day, Rx5day and R30 mm). Statistically significant positive correlations are discovered between landslides/flash floods events and annual maximum 1-day and 5-day consecutive precipitation, and these indexes may be useful indicators of natural hazard events for this region.

Patient derived xenograft (PDX) models are regarded as gold standard preclinical models in leukaemia research, especially in testing new drug combinations where typically 45-50 mice are used per assay. 9000 animal experiments are performed annually in the UK in leukaemia research with these expensive procedures being classed as moderate severity, meaning they cause significant pain, suffering and visible distress to animal’s state. Furthermore, not all clinical leukaemia samples engraft and when they do data turnaround time can be between 6-12 months. Heavy dependence on animal models is because clinical leukaemia samples do not proliferate in vitro. Alternative cell line models though popular for drug testing are not biomimetic – they are not dependent on the microenvironment for survival, growth and treatment response and being derived from relapse samples they do not capture the molecular complexity observed at disease presentation. Here we have developed an in vitro platform to rapidly establish co-cultures of patient-derived leukaemia cells with 3D bone marrow mesenchyme spheroids, BM-MSC-spheroids. We optimise protocols for developing MSC-spheroid leukaemia co-culture using clinical samples and deliver drug response data within a week. Using three patient samples representing distinct cytogenetics we show that patient-derived-leukaemia cells show enhanced proliferation when co-cultured with MSC-spheroids. In addition, MSC-spheroids provided improved protection against treatment. This makes our spheroids suitable to model treatment resistance – a major hurdle in current day cancer management Given this 3Rs approach is 12 months faster (in delivering clinical data), is a human cell-based biomimetic model and uses 45-50 fewer animals/drug-response assay the anticipated target end-users would include academia and pharmaceutical industry. This animal replacement prototype would facilitate clinically translatable research to be performed with greater ethical, social and financial sustainability.

Patient derived xenograft (PDX) models are regarded as gold standard preclinical models in leukaemia research, especially in testing new drug combinations where typically 45-50 mice are used per assay. 9000 animal experiments are performed annually in the UK in leukaemia research with these expensive procedures being classed as moderate severity, meaning they cause significant pain, suffering and visible distress to animal’s state. Furthermore, not all clinical leukaemia samples engraft and when they do data turnaround time can be between 6-12 months. Heavy dependence on animal models is because clinical leukaemia samples do not proliferate in vitro. Alternative cell line models though popular for drug testing are not biomimetic – they are not dependent on the microenvironment for survival, growth and treatment response and being derived from relapse samples they do not capture the molecular complexity observed at disease presentation. Here we have developed an in vitro platform to rapidly establish co-cultures of patient-derived leukaemia cells with 3D bone marrow mesenchyme spheroids, BM-MSC-spheroids. We optimise protocols for developing MSC-spheroid leukaemia co-culture using clinical samples and deliver drug response data within a week. Using three patient samples representing distinct cytogenetics we show that patient-derived-leukaemia cells show enhanced proliferation when co-cultured with MSC-spheroids. In addition, MSC-spheroids provided improved protection against treatment. This makes our spheroids suitable to model treatment resistance – a major hurdle in current day cancer management Given this 3Rs approach is 12 months faster (in delivering clinical data), is a human cell-based biomimetic model and uses 45-50 fewer animals/drug-response assay the anticipated target end-users would include academia and pharmaceutical industry. This animal replacement prototype would facilitate clinically translatable research to be performed with greater ethical, social and financial sustainability.