Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma.

In patients with pancreatic ductal adenocarcinoma (PDAC), intratumoural and intertumoural heterogeneity increases chemoresistance and mortality rates. However, such morphological and phenotypic diversities are not typically captured by organoid models of PDAC. Here we show that branched organoids embedded in collagen gels can recapitulate the phenotypic landscape seen in murine and human PDAC, that the pronounced molecular and morphological intratumoural and intertumoural heterogeneity of organoids is governed by defined transcriptional programmes (notably, epithelial-to-mesenchymal plasticity), and that different organoid phenotypes represent distinct tumour-cell states with unique biological features in vivo.

A quantitative approach to ranking management actions for an endangered pool-breeding amphibian.

Management of vulnerable amphibian populations requires a better understanding of the habitat factors that will make the greatest difference in their preservation. We set out to develop a predictive model of amphibian abundance based on habitat characteristics that may influence their survival and persistence. Our study system was the Sonoma County California tiger salamander (Ambystoma californiense; SCTS), an amphibian threatened by habitat loss and fragmentation.

Valorisation of hop leaves for their bioactive compounds: Identification and quantification of phenolics across different varieties, crop years and stages of development.

Hop leaves, a by-product from hop cone harvesting, contain phenolic compounds of potential value for food or beverage applications. However, the abundant phenolics in hop leaves remain largely unquantified. This study quantified phenolics in hop leaves over two crop years, for three commercially significant varieties, at different developmental stages post-flowering.

Faculty Reflections on What Makes a Good Surgeon: "The operating Room is Often the Smallest Part of the Puzzle".

Objective: Little research has inductively investigated the unique nontechnical qualities required of a surgeon holistic to their practice. This is problematic because there may be additional nuances, or entirely new attributes, that can only be identified in the authentic context of surgical practice. The aim of this study was to investigate the unique nontechnical qualities required of surgeons holistic to their practice.

Chromatin remodelling in damaged intestinal crypts orchestrates redundant TGFβ and Hippo signalling to drive regeneration.

Cell state dynamics underlying successful tissue regeneration are undercharacterized. In the intestine, damage prompts epithelial reprogramming into revival stem cells (revSCs) that reconstitute Lgr5 intestinal stem cells (ISCs). Here single-nuclear multi-omics of mouse crypts regenerating from irradiation shows revSC chromatin accessibility overlaps with ISCs and differentiated lineages.

The Drosophila adult midgut progenitor cells arise from asymmetric divisions of neuroblast-like cells.

The Drosophila adult midgut progenitor cells (AMPs) give rise to all cells in the adult midgut epithelium, including the intestinal stem cells (ISCs). While they share many characteristics with the ISCs, it remains unclear how they are generated in the early embryo. Here, we show that they arise from a population of endoderm cells, which exhibit multiple similarities with Drosophila neuroblasts.

Phase I First-in-Human Dose Escalation Study of the oral Casein Kinase 1α and Cyclin Dependent Kinase 7/9 inhibitor BTX-A51 in advanced MDS and AML.

BTX-A51, a first-in-class oral small molecule inhibitor of casein kinase 1α (CK1α) and cyclin dependent kinase (CDK) 7 and 9, induces apoptosis of leukemic cells by activating p53 and inhibiting expression of . Here, we report on the results of the phase 1 clinical trial of BTX-A51 in patients with relapsed or refractory AML and MDS. Thirty-one patients were enrolled into 8 dose-escalation cohorts at BTX-A51 doses ranging from 1mg to 42mg dosed three days/week for 21 or 28 days out a 28-day cycle.

LINE1 and PRC2 control nucleolar organization and repression of the 8C state in human ESCs.

The mechanisms that ensure developmental progression in the early human embryo remain largely unknown. Here, we show that the family of long interspersed nuclear element 1 (LINE1) transposons prevents the reversion of naive human embryonic stem cells (hESCs) to 8-cell-like cells (8CLCs). LINE1 RNA contributes to maintenance of H3K27me3 levels, particularly at chromosome 19 (Chr19).

Significance of honeybee pollination in increasing seed yield of Trifolium alexandrinum (Fabales: Fabaceae) and its impact on economic sustainability of smallholder farmers.

A major limitation to producing high seed yields in berseem clover (Trifolium alexandrinum L.) is failure to set seed, predominantly due to lack of pollination. Despite the importance of berseem clover as a leading forage legume, the contribution of pollinators to seed set is scarce.

PTEN Loss Shapes Macrophage Dynamics in High-Grade Serous Ovarian Carcinoma.

High-grade serous ovarian carcinoma (HGSC) remains a disease with poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity.

Using recurrent neural networks to detect supernumerary chromosomes in fungal strains causing blast diseases.

The genomes of the fungus that causes blast diseases on diverse grass species, including major crops, have indispensable core-chromosomes and may contain supernumerary chromosomes, also known as mini-chromosomes. These mini-chromosomes are speculated to provide effector gene mobility, and may transfer between strains. To understand the biology of mini-chromosomes, it is valuable to be able to detect whether a strain possesses a mini-chromosome.

Peripheral liver metastases are more frequently missed than central metastases in contrast-enhanced CT: insights from a 25-reader performance study.

Purpose: Subtle liver metastases may be missed in contrast enhanced CT imaging. We determined the impact of lesion location and conspicuity on metastasis detection using data from a prior reader study.

Methods: In the prior reader study, 25 radiologists examined 40 CT exams each and circumscribed all suspected hepatic metastases.

Transcriptional regulation of the postnatal cardiac conduction system heterogeneity.

The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information.

Can the Necrophagous Blow Fly (Diptera: Calliphoridae) Be Reared on Plant-Based Meal?

The use of the blow fly as a potential pollination species to augment the current reliance on honeybees () in Australian horticulture requires knowledge of how best to mass-rear this fly species. lays eggs onto carrion soon after death, and the resultant larvae that hatch are necrophagous and feed on the decomposing tissues of the dead animal. Newly hatched larvae of this fly were provided with plant-based meals (soya bean and canola) and compared with larvae provided with livestock-derived meatmeal to determine if plant-based meal could be used to mass-rear this blow fly species.

Prioritising deteriorating patients using time-to-event analysis: prediction model development and internal-external validation.

Background: Binary classification models are frequently used to predict clinical deterioration, however they ignore information on the timing of events. An alternative is to apply time-to-event models, augmenting clinical workflows by ranking patients by predicted risks. This study examines how and why time-to-event modelling of vital signs data can help prioritise deterioration assessments using lift curves, and develops a prediction model to stratify acute care inpatients by risk of clinical deterioration.

Creating virtual patients using large language models: scalable, global, and low cost.

Virtual patients (VPs) have long been used to teach and assess clinical reasoning. VPs can be programmed to simulate authentic patient-clinician interactions and to reflect a variety of contextual permutations. However, their use has historically been limited by the high cost and logistical challenges of large-scale implementation.

PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.

While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo.

Diazepam nasal spray administration is effective to control seizure clusters irrespective of time of day.

Introduction: Neurologic circadian influences, including sleep/wake transitions, processes (e.g., hormonal variation), and behavioral patterns (e.

Phase-changing citrate macromolecule combats oxidative pancreatic islet damage, enables islet engraftment and function in the omentum.

Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) are suboptimal due to pancreas inflammation, oxidative stress during islet isolation, and harsh engraftment conditions in the liver's vasculature. We describe a thermoresponsive, antioxidant macromolecule poly(polyethylene glycol citrate---isopropylacrylamide) (PPCN) to protect islet redox status and function and to enable extrahepatic omentum islet engraftment. PPCN solution transitions from a liquid to a hydrogel at body temperature.

Validation of the motivated strategies for learning questionnaire and instructional materials motivation survey.

Purpose: To validate the Motivated Strategies for Learning Questionnaire (MSLQ), which measures learner motivations; and the Instructional Materials Motivation Survey (IMMS), which measures the motivational properties of educational activities.

Methods: Participants (333 pharmacists, physicians, and advanced practice providers) completed the MSLQ, IMMS, Congruence-Personalization Questionnaire (CPQ), and a knowledge test immediately following an online learning module (April 2021). We randomly divided data for split-sample analysis using confirmatory factor analysis (CFA), exploratory factor analysis (EFA), and the multitrait-multimethod matrix.