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ADP-heptose (ADP-Hep), a metabolite produced by gram-negative bacteria, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. However, the function of ALPK1-TIFA signaling in primary cells and in physiological settings remains poorly understood. Here, we showed that, in the intestinal epithelium, ALPK1 and TIFA were mainly expressed by the intestinal stem cell (ISC) pool, where they controlled the replacement of homeostatic ISCs by new revival...

Background/Objectives: An accurate evaluation of variant actionability is essential in cancer management. In Von Hippel-Lindau Syndrome (VHL), the interpretation of the germline variants is confounded by the presence of non-syndromic component tumors, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma, pheochromocytoma, and neuroendocrine tumors. These tumors frequently occur sporadically, without any association with VHL syndrome. The presence of these tumors in a patient with a...

The controlled migration of ions in biological systems has inspired the development of ion-based electronics. Ionic diodes, leveraging ions as charge carriers, offer selective control over ion flux, mimicking ion-selective behavior observed in biological systems. Conventional ionic diodes containing fluids encounter challenges in adapting to biological systems due to their limited stretchability and stability. Recent advancements in solid-state ionic diodes based on stretchable gels enable...

In this 5th version of the European LeukemiaNet guidance for adult patients, there are important changes in several areas of management based on evidence available since 2020, including the World Health Organisation's reclassification of CML as a biphasic disease. Previous advice to switch the tyrosine kinase inhibitor (TKI) on failure of molecular milestones, is modified to better account for individual patient circumstances. Our recommendations are summarized in tables designed to be read in...

Proximity-dependent biotinylation (BioID) is a powerful means of exploring the cellular environments in which proteins reside. Expressing a protein of interest (bait) fused to a biotin ligase and adding biotin induces the covalent biotinylation of proximal partners (preys), which are recovered on streptavidin beads and identified by MS. However, a major technical limitation of BioID is peptide carryover into subsequent MS runs. This is typically mitigated via lengthy intersample wash cycles,...

Many phages encode recombination-mediating enzymes, but characterization of their roles in phage lifecycles is limited, and their impact on phage replication is controversial. To address these issues, we have searched for phages whose growth is impacted by the major recombination-promoting helicase-nuclease of Escherichia coli, the RecBCD enzyme. Although no phages inhibited by RecBCD are identified, growth of a newly isolated phage, named LLS, is enhanced by RecBCD. LLS's genome sequence...

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The subgenual anterior cingulate cortex (sgACC) plays a central role in the pathophysiology of major depressive disorder (MDD). Its functional interactive profile with the left dorsal lateral prefrontal cortex (DLPFC) is associated with transcranial magnetic stimulation (TMS) treatment outcomes. Previous research on sgACC functional connectivity (FC) in MDD has yielded inconsistent results, partly due to small sample sizes and limited statistical power. Furthermore, calculating sgACC-FC to...

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CONCLUSION: Preoperative zonulin levels were lowest in the TCA group. The change in zonulin levels on the first day after surgery can serve as a useful indicator for predicting the risk of postoperative HAEC occurrence.

CONCLUSIONS: The qualitative results indicate that the curriculum had a broadly positive impact on residents, with specific suggestions for both scaling the curriculum as well as improving it. While no conclusions can be drawn about the specific quantitative impact of this implementation of the curriculum, these findings demonstrate an acute need for greater cancer survivorship care education for FM residents. Future initiatives iterating on expansion to multiple academic sites would be an...

Ultrasoft conductors have advanced the field of electronics by achieving a level of softness comparable to that of biological tissues. However, the inherent difference in charge carriers between conventional ultrasoft electronics (utilizing electrons) and tissues (utilizing ions) could lead to high contact impedance, hindering electronic performance for physiological signal recordings. Although ultrasoft hydrogels exhibit ionic conductivity, their high water content could limit their practical...

Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally. In murine medulloblastoma model systems, provision of a single dose of radiation to the tumor drives...

Pancreatic ductal adenocarcinoma (PDAC) is a high-mortality cancer characterized by its aggressive, treatment-resistant phenotype and a complex tumour microenvironment (TME) featuring significant hypoxia. Bulk transcriptomic analysis has identified the "classical" and "basal-like" transcriptional subtypes which have prognostic value; however, it is not well-established how microenvironmental heterogeneity contributes to these transcriptional signatures. Here, we exploited the TRACER platform to...

CONCLUSION: These findings offer important insights into the durability and breadth of immunity following natural infection in immunocompromised transplant recipients. While heterologous neutralizing antibodies were limited, sustained CD4^(+) T-cell responses may help mitigate severe disease following exposure to JN.1-derived variants, which continue to dominate the SARS-CoV-2 landscape.

Understanding SARS-CoV-2 human protein-protein interactions (PPIs) and the host response to infection is essential for developing effective COVID-19 antivirals. However, how the ancestral virus and its variants remodel virus-host protein assemblies in various organ-specific cells and bodily fluids remains unclear. Here, we conduct 639 affinity-purifications by tagging and expressing 28 SARS-CoV-2 and spike proteins from the ancestral virus and four variants in eight cell lines representing five...

Despite advances in genome sequencing, many individuals with rare genetic disorders remain undiagnosed. Transcriptional profiling via RNA-seq can reveal functional impacts of DNA variants and improve diagnosis. We assessed blood-derived RNA-seq in the largely undiagnosed SickKids Genome Clinic cohort (n = 134), which has been subjected to multiple analyses benchmarking the utility of genome sequencing. Our RNA-centric analysis identifies gene expression outliers, aberrant splicing, and...

Characterization of DNA binding sites for specific proteins is of fundamental importance in molecular biology. It is commonly addressed experimentally by chromatin immunoprecipitation and sequencing (ChIP-seq) of bulk samples (10³-10⁷ cells). We have developed an alternative method that uses a Chromatin Antibody-mediated Methylating Protein (ChAMP) composed of a GpC methyltransferase fused to protein G. By tethering ChAMP to a primary antibody directed against the DNA-binding protein of...

Fungal infections cause more than 2.5 million deaths a year. Due to emerging antifungal drug resistance, novel strategies are urgently needed to combat life-threatening fungal diseases. Here, by screening a collection of 5297 compounds derived from three chemical libraries, we demonstrate that the antibacterial agent colistin (COL) can potentiate the fungistatic echinocandins caspofungin (CAS) and anidulafungin, as well as the structurally distinct cell wall targeting antifungal ibrexafungerp...

Recurrent mutations in the third base of U1 spliceosomal RNA responsible for marked splicing and expression abnormalities have been described in chronic lymphocytic leukemia (CLL) and some solid tumors. However, the clinical significance of these mutations in large and independent CLL cohorts as well as their presence in other B-cell neoplasms is unknown. Here we characterized U1 mutations in 1670 CLL and 363 mature B-cell lymphomas. We confirmed that the g.3A>C U1 mutation is found in 3.5% of...