51886 research outputs found
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Peripheral extremity gangrene following infant oral mutilation (Ebinyo): a case report from Northern Uganda
No full textBackground: "Ebinyo" is a form of infant oral mutilation (IOM) practiced by some traditional healers in parts of sub-Saharan Africa, and often results in severe health complications. We present a novel case of ebinyo in a child from northern Uganda which resulted in sepsis and disseminated intravascular coagulation (DIC) with peripheral extremity gangrene.
Case presentation: A 3-year-old male presented with two weeks of epistaxis, oralbleeding, and cough to a large referral hospital in northern Uganda. At home, the child had undergone ebinyo, performed by a traditional healer, and was receiving treatment for malaria. On arrival, the child presented with fever, jaundice, and malaise. Labs revealed pancytopenia and an elevated D-dimer, diagnosed as DIC. On day four, physical exam revealed demarcated darkening of the fourth digit on the right foot and third and fourth digits on the left foot, diagnosed as dry gangrene. A doppler ultrasound revealed lower extremity arterial insufficiency. On day seven, the patient started improving with vancomycin. On day eleven, the patient was discharged.
Conclusion: This case describes an uncommon sequela of sepsis and DIC with peripheral extremity gangrene after undergoing ebinyo. Prompt identification of ebinyo is critical for diagnosis and management of its complications
Hepatoprotective action of Sonchus oleraceus against paracetamol-induced toxicity via Nrf2/KEAP-1/HO-1 pathway in relation to its metabolite fingerprint and in silico studies
No full textBackground: Paracetamol overdose causes severe hepatotoxicity. Sonchus oleraceus is traditionally used to treat liver disorders, but its potential against paracetamol-induced liver injury is unexplored. This work aimed to investigate the protective mechanisms of an S. oleraceus extract (SOEtOH) using in vivo, histological and biochemical assessments along with metabolomics profiling and in silico studies, including molecular docking and dynamic simulations (MD).
Methods and findings: SOEtOH was administered to rats with paracetamol-induced hepatotoxicity at 50, 100, and 200 mg/kg doses. Serum enzymes, hepatic antioxidants, and histopathology were evaluated. UPLC-MS characterized bioactive metabolites and molecular docking and assessed their anti-inflammatory potential. SOEtOH significantly restored serum ALT and AST toward normal levels in a dose-dependent manner. It also replenished depleted hepatic glutathione (up to 3.9-fold) and superoxide dismutase (up to 4.7-fold). Immunohistochemistry revealed SOEtOH progressively attenuated caspase-3 expression related to apoptosis. It also ameliorated characteristic histopathological alterations like necrosis, inflammation, and sinusoidal congestion. Thirty-two bioactive metabolites, including flavonoids, phenolic acids, and terpenes, were identified. Molecular docking revealed potent anti-inflammatory effects via JNK inhibition, with luteolin-O-dihexoside, isorhamnetin-O-hexoside, di-O-caffeoylquinic, and kaempferol-O-hexoside having the strongest binding affinities. MD simulations demonstrated that these compounds' complexes significantly contribute to JNK1 and JNK2's catalytic binding site.
Conclusion: This integrated study demonstrates that SOEtOH protects against paracetamol hepatotoxicity by mitigating oxidative stress and inhibiting pro-inflammatory/apoptotic signaling. Our results reveal therapeutic lead compounds that may be further explored for clinical applications
The Landscape of Shared and Divergent Genetic Influences across 14 Psychiatric Disorders
No full textPsychiatric disorders display high levels of comorbidity and genetic overlap 1,2. Genomic methods have shown that even for schizophrenia and bipolar disorder, two disorders long-thought to be etiologically distinct 3, the majority of genetic signal is shared 4. Furthermore, recent cross-disorder analyses have uncovered over a hundred pleiotropic loci shared across eight disorders 5. However, the full scope of shared and disorder-specific genetic basis of psychopathology remains largely uncharted. Here, we address this gap by triangulating across a suite of cutting-edge statistical genetic and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Our analyses identify and characterize five underlying genomic factors 6 that explain the majority of the genetic variance of the individual disorders (~66% on average) and are associated with 268 pleiotropic loci. We observed particularly high levels of polygenic overlap 7 and local genetic correlation 8 and very few disorder-specific loci 9 for two factors defined by: (i) schizophrenia and bipolar disorder ("SB factor"), and by (ii) major depression, PTSD, and anxiety ("internalizing factor"). At the functional level, we applied multiple methods 10-12 which demonstrated that the shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the internalizing factor was associated with oligodendrocyte biology. By comparison, the genetic signal shared across all 14 disorders was enriched for broad biological processes (e.g., transcriptional regulation). These results indicate increasing differentiation of biological function at different levels of shared cross-disorder risk, from quite general vulnerability to more specific pathways associated with subsets of disorders. These observations may inform a more neurobiologically valid psychiatric nosology and implicate novel targets for therapeutic developments designed to treat commonly occurring comorbid presentations
Dual targeting of tumoral cells and immune microenvironment by blocking the IL-33/IL1RL1 pathway
No full textLeukemia stem cells (LSCs) are a small yet powerful subset of leukemic cells that possess the ability to self-renew and have a long-term tumorigenic capacity, playing a crucial role in both leukemia development and therapy resistance. These LSCs are influenced by external and internal factors within the bone marrow niche. By delving into the intricate interplay between LSCs and their immune environment, we can pave the way for innovative immunotherapies that target both the malignant stem cells and the suppressive immune microenvironment, addressing both the "seed" and the "soil" simultaneously. Through the analysis of public datasets and patient samples, we show that elevated IL1RL1 expression correlates with poor prognosis and therapy resistance in acute myeloid leukemia (AML). At the core of this process, stem cell leukemogenesis initiation and maintenance signals are driven by a stress-induced IL-33/IL1RL1 autocrine loop. This LSC-induced IL-33/IL1RL1 signaling fosters an immune regulatory microenvironment. Therefore, IL1RL1 emerges as a promising therapeutic target, with IL1RL1-specific T cell-engaging bispecific antibodies holding great potential as cutting-edge immunotherapeutics for AML
Indiana's Jake Laird Law: Stakeholder Perspectives and Policy Recommendations
No full textBackground: Indiana’s Extreme Risk Protection Order (ERPO) law—commonly known as Indiana’s “Red Flag” or “Jake Laird” law —allows law enforcement to temporarily remove firearms from individuals deemed dangerous. This report summarizes findings from a stakeholder survey examining knowledge, implementation practices, challenges, and perspectives on ERPO-related firearm seizures.
Methods: Participants completed a structured questionnaire on experiences, training, challenges, and perceptions of Indiana’s ERPO law. The survey was sent to Indiana State Police, the Indiana Association of Chiefs of Police (IACP) President, and the Executive Director of the Indiana Sheriffs Association (ISA), who forwarded it to all 92 sheriffs. In total, 129 named recipients were invited; 18 responded. Recipient distribution was heavily concentrated in Marion County (77) and Boone County (33), with far fewer in other counties (Clinton 1, Hamilton 2, Morgan 13, Union 2, Vanderburgh 1), revealing geographic disparities that may have influenced the findings. All responses were collected anonymously.
Findings: Stakeholders generally support the ERPO law as a harm-prevention tool but report challenges, including tight filing deadlines, limited mental health access in rural areas, and inconsistent training.
Conclusion: While widely valued, Indiana’s ERPO law could be strengthened through expanded petition authority, enhanced training, greater mental health collaboration, public awareness, and improved transparency
The Consortium for Clarity in ADRD Research Through Imaging (CLARiTI): Overview of consortium sites and anticipated enrollment
No full textIntroduction: The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI.
Methods: We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts.
Results: Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site-level strategies in enrollment into CLARiTI versus other imaging efforts.
Discussion: We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network.
Highlights: The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi-etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs)
Leveraging transcription factor physical proximity for enhancing gene regulation inference
No full textMotivation: Gene regulation inference, a key challenge in systems biology, is crucial for understanding cell function, as it governs processes such as differentiation, cell state maintenance, signal transduction, and stress response. Leading methods utilize gene expression, chromatin accessibility, transcription factor (TF) DNA binding motifs, and prior knowledge. However, they overlook the fact that TFs must be in physical proximity to facilitate transcriptional gene regulation.
Results: To fill the gap, we develop GRIP-Gene Regulation Inference by considering TF Proximity-a gene regulation inference method that directly considers the physical proximity between regulating TFs. Specifically, we use the distance in a protein-protein interaction (PPI) network to estimate the physical proximity between TFs. We design a novel Boolean convex program, which can identify TFs that not only can explain the gene expression of target genes (TGs) but also stay close in the PPI network. We propose an efficient algorithm to solve the Boolean relaxation of the proposed model with a theoretical tightness guarantee. We compare our GRIP with state-of-the-art methods (SCENIC+, DirectNet, Pando, and CellOracle) on inferring cell-type-specific (CD4, CD8, and CD 14) gene regulation using the PBMC 3k scMultiome-seq data and demonstrate its out-performance in terms of the predictive power of the inferred TFs, the physical distance between the inferred TFs, and the agreement between the inferred gene regulation and PCHiC data.
Availability and implementation: https://github.com/EJIUB/GRIP
Spt6-Spn1 interaction is required for RNA polymerase II association and precise nucleosome positioning along transcribed genes
No full textSpt6-Spn1 is an essential histone chaperone complex that associates with RNA Polymerase II (RNAPII) and reassembles nucleosomes during gene transcription. While the interaction between Spt6 and Spn1 is important for its histone deposition and transcription functions, a precise mechanistic understanding is still limited. Here, using temperature-sensitive alleles of spt6 and spn1 that disrupt their interaction in yeast, we show that the Spt6-Spn1 association is important for its stable interaction with the elongating RNAPII complex and nucleosomes. Using micrococcal nuclease (MNase)-based chromatin occupancy profiling, we further find that Spt6-Spn1 interaction is required to maintain a preferred nucleosome positioning at actively transcribed genes; in the absence of Spt6-Spn1 interaction, we observe a return to replication-dependent phasing. In addition to positioning defects, Spt6-Spn1 disrupting mutants also resulted in an overall shift of nucleosomes toward the 5' end of genes that were correlated with decreased RNAPII levels. As loss of Spt6-Spn1 association results in cryptic transcription at a subset of genes, we examined these genes for their nucleosome profiles. These findings revealed that the chromatin organization at these loci is similar to other active genes, thus underscoring the critical role of DNA sequence in mediating cryptic transcription when nucleosome positioning is altered. Taken together, these findings reveal that Spt6-Spn1 interaction is key to its association with elongating RNAPII and to its ability to precisely organize nucleosomes across transcription units
ManyClasses 2: The Effects of Prequestions on Media Interactions and Learning
No full textWe conducted a ManyClasses study in 30 different classes, where student participants (n = 1,571) were assigned to watch two online lecture videos, and one of these videos (order randomized) was immediately preceded by ungraded multiple-choice prequestions, with no feedback or answers shown. In the laboratory, decades of research have observed that prequestions reliably improve learning from subsequent instruction when compared to instruction not preceded by prequestions, but evidence in authentic education settings has been elusive. The current experiment, embedded in authentic classes ranging from sixth grade through senior-level college, with class-specific videos and questions created by teachers, confirmed that prequestions improve average student learning performance, measured by delayed classroom assessments that included the prequestions. Furthermore, we examined how prequestions affected students’ interactions with the online videos. Despite the generalizable average benefit of prequestions for student learning, we found that prequestions also caused some students to disengage, skipping the assigned video entirely. Among students who did watch the videos, there was no increase in the amount viewed after answering prequestions compared to videos with no prequestions. These findings lead us to suggest that prequestions do not increase attention to the subsequent learning materials, but rather, prequestions cause learners to activate a relevant mental model in advance of instruction. This account is corroborated by the finding that answering prequestions correctly was a significant moderator of the benefits of prequestions, suggesting that the prequestions, while beneficial on average, may cause a rich-get-richer scenario when implemented in authentic education settings.
Educational Impact and Implications Statement:
People look to psychological science for instructional strategies that may help improve education outcomes in practice. One promising strategy is to present prequestions, questions prior to instruction, which has yielded promising results across many laboratory studies but has limited evidence from authentic education settings. Here we ran a large-scale prequestion experiment across many classrooms, and observed that prequestions tend to improve student learning on average. However, we also found that these benefits depend on learners having relevant prior knowledge, and that prequestions may also cause some students with less prior knowledge to disengage. These results lead us to reconsider our understanding of the prequestion effect, demonstrating how a practical, real-world test can also inform psychological science