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The concept of precision oncology, the application of targeted drugs based on comprehensive molecular profiling, has revolutionized treatment strategies in oncology. This review summarizes the current status of precision oncology in glioblastoma (GBM), the most common and aggressive primary brain tumor in adults with a median survival below 2 years. Targeted treatments without prior target verification have consistently failed. Patients with BRAF V600E‐mutated GBM benefit from BRAF/MEK‐inhibition, whereas targeting EGFR alterations was unsuccessful due to poor tumor penetration, tumor cell heterogeneity, and pathway redundancies. Systematic screening for actionable molecular alterations resulted in low rates (

We found Mycobacterium leprae, the most common etiologic agent of Hansen disease or leprosy, in tissues from 9 (18.75%) of 48 nine-banded armadillos (Dasypus novemcinctus) collected across continental Ecuador. Finding evidence of a wildlife reservoir is the first step to recognizing leprosy zoonotic transmission pathway in Ecuador or elsewhere.

Abstract Understanding the concurrent responses of aboveground and belowground biota compartments to global changes is crucial for the maintenance of ecosystem functions and biodiversity conservation. We conduct a comprehensive analysis synthesizing data from 13,209 single observations and 3223 pairwise observations from 1166 publications across the world terrestrial ecosystems to examine the responses of plants and soil organisms and their synchronization. We find that global change factors (GCFs) generally promote plant biomass but decreased plant species diversity. In comparison, the responses of belowground soil biota to GCFs are more variable and harder to predict. The analysis of the paired aboveground and belowground observations demonstrate that responses of plants and soil organisms to GCFs are decoupled among diverse groups of soil organisms for different biomes. Our study highlights the importance of integrative research on the aboveground-belowground system for improving predictions regarding the consequences of global environmental change.

Abstract The evaluation of compound-target interactions (CTIs) is at the heart of drug discovery efforts. Given the substantial time and monetary costs of classical experimental screening, significant efforts have been dedicated to develop deep learning-based models that can accurately predict CTIs. A comprehensive comparison of these models on a large, curated CTI dataset is, however, still lacking. Here, we perform an in-depth comparison of 12 state-of-the-art deep learning architectures that use different protein and compound representations. The models were selected for their reported performance and architectures. To reliably compare model performance, we curated over 300 thousand binding and non-binding CTIs and established several gold-standard datasets of varying size and information. Based on our findings, DeepConv-DTI consistently outperforms other models in CTI prediction performance across the majority of datasets. It achieves an MCC of 0.6 or higher for most of the datasets and is one of the fastest models in training and inference. These results indicate that utilizing convolutional-based windows as in DeepConv-DTI to traverse trainable embeddings is a highly effective approach for capturing informative protein features. We also observed that physicochemical embeddings of targets increased model performance. We therefore modified DeepConv-DTI to include normalized physicochemical properties, which resulted in the overall best performing model Phys-DeepConv-DTI. This work highlights how the systematic evaluation of input features of compounds and targets, as well as their corresponding neural network architectures, can serve as a roadmap for the future development of improved CTI models. Scientific contribution This work features comprehensive CTI datasets to allow for the objective comparison and benchmarking of CTI prediction algorithms. Based on this dataset, we gained insights into which embeddings of compounds and targets and which deep learning-based algorithms perform best, providing a blueprint for the future development of CTI algorithms. Using the insights gained from this screen, we provide a novel CTI algorithm with state-of-the-art performance.

Children from disadvantaged families are at greater risk of developing regulation difficulties. Research suggests that family-level resources such as parental education or income are related to self-regulation development. However, most studies looking at the role of family resources have used single estimators of socioeconomic status or applied a composite score, neglecting that an interplay of resources may affect self-regulation outcomes. In N = 248 at-risk children (M[subscript age]: 65.7 months, 51% female), we examined the effect of economic, cultural, and social family resources on behavioral self-regulation in kindergarten. Results showed that family income, maternal education, and available help in child-rearing predicted the Head-Toes-Knees-Shoulders task performance. The results indicate that behavioral self-regulation is associated with different family resources beyond socioeconomic status.

Educators' preparedness to include children with disability in day-care is key to the success of early childhood inclusion. This study examines the relationship between attitudes and self-efficacy as key predictors of preparedness for inclusion. The study was conducted in Switzerland, a country with a young tradition of inclusive early childhood care and education, (ECEC) but with increasing numbers of children with disability in public day-care facilities. Early childhood educators (N = 214) completed a questionnaire on their feelings, beliefs, self-efficacy, and behavioural intentions. Structural equation modelling (SEM) was used to analyse paths of effects of participants' background on behavioural intentions. Results show that inclusive ECEC experience, private interactions and training on disability were associated with higher behavioural intentions. This effect was mediated by participants' self-efficacy and their beliefs. General ECEC experience was directly associated with lower behavioural intentions. Implications for research and practice are discussed.

To ensure all children can be successful in school and beyond, states have increasingly supported and expanded pre-kindergarten (pre-k) programs aimed and improving student outcomes and reducing disparities. While research has shown generally positive short-term outcomes for specific programs, state design and support for pre-k programs varies widely across the US, making cross-state comparisons difficult. As a means to better inform state policy decisions, this study assesses the relation between structural aspects of pre-k programs on fourth-grade student achievement and gaps across all 50 states. In assessing the relation of ELA achievement with state funding, standards of quality, and scope of access, we find that (1) state funding is associated with both increases in student achievement and reduced gaps, (2) the effect of funding is stronger in states that provide targeted pre-k access to low-income/at-risk students, and (3) legislated quality standards only improve overall achievement in states that provide universal access to pre-k. These results help identify how state policy structure may best be used to leverage achievement benefits for pre-k programs and reduce disparities.

Abstract Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (GN). To date, treatment of most patients with ANCA-GN relies on non-specific immunosuppressive agents, which may have serious adverse effects and be only partially effective. Here, using spatial and single-cell transcriptome analysis, we characterize inflammatory niches in kidney samples from 34 patients with ANCA-GN and identify proinflammatory, cytokine-producing CD4+ and CD8+ T cells as a pathogenic signature. We then utilize these transcriptomic profiles for digital pharmacology and identify ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, as the strongest therapeutic drug to use. Moreover, four patients with relapsing ANCA-GN are treated with ustekinumab in combination with low-dose cyclophosphamide and steroids, with ustekinumab given subcutaneously (90 mg) at weeks 0, 4, 12, and 24. Patients are followed up for 26 weeks to find this treatment well-tolerated and inducing clinical responses, including improved kidney function and Birmingham Vasculitis Activity Score, in all ANCA-GN patients. Our findings thus suggest that targeting of pathogenic T cells in ANCA-GN patients with ustekinumab might represent a potential approach and warrants further investigation in clinical trials.

Abstract Background Large language models (LLMs) such as ChatGPT-4 and Google Gemini show potential for patient health education, but concerns about their accuracy require careful evaluation. This study evaluates the readability and accuracy of ChatGPT-4 and Google Gemini in answering questions about retinal detachment. Methods Comparative study analyzing responses from ChatGPT-4 and Google Gemini to 13 retinal detachment questions, categorized by difficulty levels (D1, D2, D3). Masked responses were reviewed by ten vitreoretinal specialists and rated on correctness, errors, thematic accuracy, coherence, and overall quality grading. Analysis included Flesch Readability Ease Score, word and sentence counts. Results Both Artificial Intelligence tools required college-level understanding for all difficulty levels. Google Gemini was easier to understand (p = 0.03), while ChatGPT-4 provided more correct answers for the more difficult questions (p = 0.0005) with fewer serious errors. ChatGPT-4 scored highest on most challenging questions, showing superior thematic accuracy (p = 0.003). ChatGPT-4 outperformed Google Gemini in 8 of 13 questions, with higher overall quality grades in the easiest (p = 0.03) and hardest levels (p = 0.0002), showing a lower grade as question difficulty increased. Conclusions ChatGPT-4 and Google Gemini effectively address queries about retinal detachment, offering mostly accurate answers with few critical errors, though patients require higher education for comprehension. The implementation of AI tools may contribute to improving medical care by providing accurate and relevant healthcare information quickly.

How does prosocial behavior extend beyond in-group boundaries in multiethnic societies? The differentiation of Western societies presents an opportunity to understand the tension between societal pressures that push people outside the comfort zones of their familiar networks to constructively interact with unknown diverse others and the tendency toward homophily and in-group favoritism. We introduce a three-step model of out-group exposure that includes macrostructural conditions for intergroup encounters and microlevel dynamics of intergroup selection and interaction. Using lab-in-the-field experiments with a large representative sample of Italian natives and immigrants from the multiethnic city of Milan, we find that, when pushed to interact with non-coethnics, Italians generally treat them similarly to how they treat coethnics and value signs of social and market integration. However, when given the opportunity to select their interaction partners, Italians favor coethnics over immigrants. Taken together, these results help reconcile classical findings concerning the positive effects of intergroup contact with evidence documenting the persistence of out-group discrimination in selection processes.

Abstract Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations of SATB2 cause SATB2 Associated Syndrome (SAS), a multisymptomatic syndrome involving epilepsy, intellectual disability, speech delay, and craniofacial defects. Here we show that Satb2 controls neuronal migration and callosal axonal outgrowth during murine neocortical development by inducing the expression of the GPI-anchored protein, Semaphorin 7A (Sema7A). We find that Sema7A exerts this biological activity by heterodimerizing in cis with the transmembrane semaphorin, Sema4D. We could also observe that heterodimerization with Sema7A promotes targeting of Sema4D to the plasma membrane in vitro. Finally, we report an epilepsy-associated de novo mutation in Sema4D (Q497P) that inhibits normal glycosylation and plasma membrane localization of Sema4D-associated complexes. These results suggest that neuronal use of semaphorins during neocortical development is heteromeric, and a greater signaling complexity exists than was previously thought.

Abstract We recently indicated that four-week probiotic supplementation significantly reduced depression along with microbial and neural changes in people with depression. Here we further elucidated the biological modes of action underlying the beneficial clinical effects of probiotics by focusing on immune-inflammatory processes. The analysis included a total of N = 43 participants with depression, from which N = 19 received the probiotic supplement and N = 24 received a placebo over four weeks, in addition to treatment as usual. Blood and saliva were collected at baseline, at post-intervention (week 4) and follow-up (week 8) to assess immune-inflammatory markers (IL-1β, IL-6, CRP, MIF), gut-related hormones (ghrelin, leptin), and a stress marker (cortisol). Furthermore, transcriptomic analyses were conducted to identify differentially expressed genes. Finally, we analyzed the associations between probiotic-induced clinical and immune-inflammatory changes. We observed a significant group x time interaction for the gut hormone ghrelin, indicative of an increase in the probiotics group. Additionally, the increase in ghrelin was correlated with the decrease in depressive symptoms in the probiotics group. Transcriptomic analyses identified 51 up- and 57 down-regulated genes, which were involved in functional pathways related to enhanced immune activity. We identified a probiotic-dependent upregulation of the genes ELANE, DEFA4 and OLFM4 associated to immune activation and ghrelin concentration. These results underscore the potential of probiotic supplementation to produce biological meaningful changes in immune activation in patients with depression. Further large-scale mechanistic trials are warranted to validate and extend our understanding of immune-inflammatory measures as potential biomarkers for stratification and treatment response in depression. Trial Registration: www.clinicaltrials.gov , identifier: NCT02957591.

Broadly neutralizing antibodies have been proposed as templates for HIV-1 vaccine design, but it has been unclear how similar vaccine-elicited antibodies are to their naturally elicited templates. To provide insight, here we compare the recognition of naturally elicited and vaccine-elicited antibodies targeting the HIV-1 fusion peptide, which comprises envelope (Env) residues 512–526, with the most common sequence being AVGIGAVFLGFLGAA. Naturally elicited antibodies bound peptides with substitutions to negatively charged amino acids at residue positions 517–520 substantially better than the most common sequence, despite these substitutions rarely appearing in HIV-1; by contrast, vaccine-elicited antibodies were less tolerant of sequence variation, with no substitution of residues 512–516 showing increased binding. Molecular dynamics analysis and cryo-EM structural analysis of the naturally elicited ACS202 antibody in complex with the HIV-1 Env trimer with an alanine 517 to glutamine substitution suggested enhanced binding to result from electrostatic interactions with positively charged antibody residues. Overall, vaccine-elicited antibodies appeared to be more fully optimized to bind the most common fusion peptide sequence, perhaps reflecting the immunization with fusion peptide of the vaccine-elicited antibodies.

BackgroundBrachycephalic dogs are overrepresented with ventricular enlargement. Cerebrospinal fluid (CSF) flow dynamics are not completely understood. MRI techniques have been used for the visualization of CSF dynamics including phase-contrast imaging.ObjectivesThis study aimed to determine a causality between CSF flow and ventriculomegaly or hydrocephalus and to compare CSF flow dynamics among dogs with ventriculomegaly, internal hydrocephalus, and physiologic ventricles.AnimalsA total of 51 client-owned dogs were included in the study.MethodsMagnetic resonance imaging (MRI)-based FLASH sequences and phase-contrast images of the brain were obtained, and the ROI was placed at the level of the mesencephalic aqueduct. ECG monitoring was performed parallel to MRI acquisition. Evaluation of flow diagrams and processing of phase-contrast images were performed using commercially available software (Argus VA80A, Siemens AG Healthcare Sector, Erlangen, Germany). Dogs were divided into three groups: Group 1 consisted of brachycephalic dogs with ventriculomegaly (group 1A) or internal hydrocephalus (group 1B), group 2 consisted of brachycephalic dogs with normal ventricles, and group 3 consisted of meso- to dolichocephalic dogs with normal ventricles.ResultsGroup 1 had a higher median Vrost (4.32 cm/s; CI: 2.94–6.33 cm/s) and Vcaud (−6.1 cm/s, CI: 3.99–9.33 cm/s) than group 2 (Vrost: 1.99 cm/s; CI 1.43–2.78 cm/s; Vcaud: 2.91 cm/s, CI: 2.01–4.21 cm/s; p = 0.008; p = 0.03) and group 3 (Vrost:1.85 cm/s, CI: 1.31–2.60 cm/s; Vcaud − 2.46 cm/s, CI 1.68–3.58 cm/s; p = 0.01; p = 0.02). The median Volcaud of group 1 (−0.23 mL/min, CI: 0.13–0.42 mL/min) was higher than that of group 2 (−0.09 mL/min, CI: 0.05 mL/min and 0.15 mL/min) (p = 0.03). Groups 1A and 1B did not differ in Vcaud, Vrost, Volcaud, and Volrost. Group 1A and 1B showed a higher median Vrost (4.01 cm/s, CI: 2.30–7.05 cm/s; 5.94 cm/s, CI: 2.16–7.88 cm/s) than group 2 (1.85 cm/s, CI: 1.24–2.80 cm/s.) (p = 0.03; p = 0.004).Conclusion and clinical importanceIncreased CSF flow velocities in rostral and caudal directions are present in dogs with ventriculomegaly and internal hydrocephalus compared to normal controls.

We describe a novel biosafety aerosol chamber equipped with state-of-the-art instrumentation for bubble-bursting aerosol generation, size distribution measurement, and condensation-growth collection to minimize sampling artifacts when measuring virus infectivity in aerosol particles. Using this facility, we investigated the effect of relative humidity (RH) in very clean air without trace gases (except ∼400 ppm CO2) on the preservation of influenza A virus (IAV) infectivity in saline aerosol particles. We characterized infectivity in terms of 99%-inactivation time, t99, a metric we consider most relevant to airborne virus transmission. The viruses remained infectious for a long time, namely t99 > 5 h, if RH < 30% and the particles effloresced. Under intermediate conditions of humidity (40% < RH < 70%), the loss of infectivity was the most rapid (t99 ≈ 15–20 min, and up to t99 ≈ 35 min at 95% RH). This is more than an order of magnitude faster than suggested by many previous studies of aerosol-borne IAV, possibly due to the use of matrices containing organic molecules, such as proteins, with protective effects for the virus. We tested this hypothesis by adding sucrose to our aerosolization medium and, indeed, observed protection of IAV at intermediate RH (55%). Interestingly, the t99 of our measurements are also systematically lower than those in 1-μL droplet measurements of organic-free saline solutions, which cannot be explained by particle size effects alone.

Background: Recent reports have indicated that symptom exacerbation after a period of improvement, referred to as relapse, in early-stage psychosis could result in brain changes and poor disease outcomes. We hypothesized that substantial neuroimaging alterations may exist among patients who experience relapse in early-stage psychosis. Methods: We studied patients with psychosis within 2 years after the first psychotic event and healthy controls. We divided patients into 2 groups, namely those who did not experience relapse between disease onset and the magnetic resonance imaging (MRI) scan (no-relapse group) and those who did experience relapse between these 2 timings (relapse group). We analyzed 3003 functional connectivity estimates between 78 regions of interest (ROIs) derived from resting-state functional MRI data by adjusting for demographic and clinical confounding factors. Results: We studied 85 patients, including 54 in the relapse group and 31 in the no-relapse group, along with 94 healthy controls. We observed significant differences in 47 functional connectivity estimates between the relapse and control groups after multiple comparison corrections, whereas no differences were found between the no-relapse and control groups. Most of these pathological signatures (64%) involved the thalamus. The Jonckheere-Terpstra test indicated that all 47 functional connectivity changes had a significant cross-group progression from controls to patients in the no-relapse group to patients in the relapse group. Limitations: Longitudinal studies are needed to further validate the involvement and pathological importance of the thalamus in relapse. Conclusion: We observed pathological differences in neuronal connectivity associated with relapse in early-stage psychosis, which are more specifically associated with the thalamus. Our study implies the importance of considering neurobiological mechanisms associated with relapse in the trajectory of psychotic disorders., Introduction The trajectory of psychotic disorders after onset is heterogeneous and many patients show deteriorating courses. (1,2) One of the major determinants of poor prognosis is the occurrence of relapse, [...]

In an action almost as momentous as his original escape from enslavement, Frederick Douglass adopted an anti-slavery interpretation of the U.S. Constitution. That 1851 decision took Douglass from a platform [...]