The RING Finger E3 Ligase RNF25 Protects DNA Replication Forks Independently of its Canonical Roles in Ubiquitin Signaling.

The DNA damage response (DDR) mechanisms that allow cells to tolerate DNA replication stress are critically important for genome stability and cell viability. Using an unbiased genetic screen we identify a role for the RING finger E3 ubiquitin ligase RNF25 in promoting DNA replication stress tolerance. In response to DNA replication stress, RNF25-deficient cells generate aberrantly high levels of single-stranded DNA (ssDNA), accumulate in S-phase and show reduced mitotic entry.

Therapeutic plasma exchange for fibrinogen-associated hyperviscosity: results of the COVID-19 PLasma EXchange (COPLEX) randomized controlled trial.

Background: Therapeutic plasma exchange (TPE) is the primary intervention for treating symptomatic hyperviscosity from hypergammaglobulinemia, yet its efficacy for treating hyperviscosity related to hyperfibrinogenemia is unclear.

Objectives: Define the safety and efficacy of TPE for critically ill COVID-19 patients with elevated blood viscosity from hyperfibrinogenemia.

Methods: We performed a prospective randomized controlled trial in critically ill COVID-19 patients in a single US healthcare system.

Self-maintenance of zonal hepatocytes during adult homeostasis and their complex plasticity upon distinct liver injuries.

Hepatocytes are organized into distinct zonal subsets across the liver lobule, yet their contributions to liver homeostasis and regeneration remain controversial. Here, we developed multiple genetic lineage-tracing mouse models to systematically address this. We found that the liver lobule can be divided into two major zonal and molecular hepatocyte populations marked by Cyp2e1 or Gls2.

Hybrid performances in sport: Cybathlon spectatorship for critically imagining technologies for disability futures.

Disabled bodies have been historically marginalised in sporting arenas and spectacles. Assistive technologies have been increasingly featuring in, and changing, sporting landscapes. In some ways recent shifts have made disability more present and visible across many (para) sporting cultures, and yet sport continues to operate on a tiered system that assumes a normative able body.

Maternal gut microbiota influence stem cell function in offspring.

The maternal microbiome influences child health. However, its impact on a given offspring's stem cells, which regulate development, remains poorly understood. To investigate the role of the maternal microbiome in conditioning the offspring's stem cells, we manipulated maternal microbiota using Akkermansia muciniphila.

Lgr5 + intestinal stem cells are required for organoid survival after genotoxic injury.

Progenitors and mature cells can maintain the intestinal epithelium by dedifferentiation and facultative intestinal stem cell (fISC) function when active ISCs (aISCs) are lost to damage. Here, we modeled fISC activation in mouse intestinal organoids with doxorubicin (DXR) treatment, a chemotherapeutic known to ablate Lgr5+ aISCs in vivo. Similar fISC gene activation was observed between organoids treated with low versus high DXR, despite significantly decreased survival at the higher dose.

Developing forebrain synapses are uniquely vulnerable to sleep loss.

Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood.

Ionic current blockade in a nanopore due to an ellipsoidal particle.

Nanopores in solid-state membranes have been used to detect, identify, filter, and characterize nanoparticles and biological molecules. In this work, we simulate an ionic flow through a nanopore while an ellipsoidal nanoparticle translocates through a pore. We numerically solve the Poisson-Nernst-Planck equations to obtain the ionic current values for different aspect ratios, sizes, and orientations of a translocating particle.

Simple Climate Models That Can Be Used in Primary, Secondary, and Tertiary Education.

Climate change is of great concern to all age groups but in particular to children. "Simple" climate models have been in place for a long time and can be used effectively with post-16 students. For younger children, modifications are required, and we describe in this paper the development and use of two such models.

Redox properties of [Cp*Rh] complexes supported by mono-substituted 2,2'-bipyridyl ligands.

The redox properties of half-sandwich rhodium complexes supported by 2,2'-bipyridyl (bpy) ligands can be readily tuned by selection of an appropriately substituted derivative of bpy, but the influences of single substituents on the properties of such complexes are not well documented, as disubstituted bpy variants are much more common. Here, the synthesis, characterization, and redox properties of two new [Cp*Rh] complexes (where Cp* is η-1,2,3,4,5-pentamethylcyclopentadienyl) supported by the uncommon mono-substituted ligands 4-chloro-2,2'-bipyridyl (mcbpy) and 4-nitro-2,2'-bipyridyl (mnbpy) are reported. Single-crystal X-ray diffraction studies and related spectroscopic experiments confirm installation of the single substituents (-Cl and -NO, respectively) on the bipyridyl ligands; the precursor monosubstituted ligands were prepared a divergent route from unsubstituted bpy.

Advanced piperazine-containing inhibitors target microbial β-glucuronidases linked to gut toxicity.

The gut microbiome plays critical roles in human homeostasis, disease progression, and pharmacological efficacy through diverse metabolic pathways. Gut bacterial β-glucuronidase (GUS) enzymes reverse host phase 2 metabolism, in turn releasing active hormones and drugs that can be reabsorbed into systemic circulation to affect homeostasis and promote toxic side effects. The FMN-binding and loop 1 gut microbial GUS proteins have been shown to drive drug and toxin reactivation.

Lgr5 marks stem/progenitor cells contributing to epithelial and muscle development in the mouse esophagus.

The existence and function of Lgr5 cells within the developing esophagus remains unknown. Here, we document multiple discrete Lgr5 populations in the developing mouse esophagus, predominantly within nascent epithelial and external muscle layers. Lgr5 expression initially emerges in the developing proximal embryonic epithelium, but progressively extends distally and persists within the distal epithelium of neonates.

Impact of preoperative haemoglobin A levels on postoperative outcomes in adults undergoing major noncardiac surgery: A systematic review.

Aims: Diabetes is known to increase morbidity and mortality after major surgery. However, literature is conflicting on whether elevated preoperative haemoglobin A (HbA) levels are associated with worse outcomes following major noncardiac surgery. We aimed to investigate the effect of incremental preoperative HbA levels on postoperative outcomes in adults who had undergone major noncardiac surgery.

Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers.

How the oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients.

Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer.

To delineate the mechanisms by which the ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS-driven cancer growth, we determined the ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We determined that ERK1 and ERK2 share near-identical signaling and transforming outputs and that the KRAS-regulated phosphoproteome is driven nearly completely by ERK. We identified 4666 ERK-dependent phosphosites on 2123 proteins, of which 79 and 66%, respectively, were not previously associated with ERK, substantially expanding the depth and breadth of ERK-dependent phosphorylation events and revealing a considerably more complex function for ERK in cancer.

Making Information About Cladribine Tablets Accessible to People with Multiple Sclerosis: A Patient-Survey-Led Narrative Review for Healthcare Professionals.

Cladribine tablets have been granted marketing authorization in Europe and approved by the Food and Drug Administration (FDA) in the USA to treat relapsing forms of multiple sclerosis (MS). However, people with MS (PwMS) may be more familiar, and therefore more confident, with treatments requiring long-term and frequent dosing. Differences in such treatment strategies can lead to questions relating to how short-course non-continuous treatments, such as cladribine tablets, can work and how well they are tolerated.

Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis.

The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis.

+ intestinal stem cells are required for organoid survival after genotoxic injury.

Progenitors and mature cells can maintain the intestinal epithelium by dedifferentiation and facultative intestinal stem cell (fISC) function when active ISCs (aISCs) are lost to damage. Here, we sought to model fISC activation in intestinal organoids with doxorubicin (DXR), a chemotherapeutic known to ablate + aISCs . We identified low and high doses of DXR compatible with long-term organoid survival.

Tenofovir-Diphosphate and Emtricitabine-Triphosphate Adherence Benchmarks in Dried Blood Spots for Persons With HIV Receiving Tenofovir Alafenamide and Emtricitabine-Based Antiretroviral Therapy (QUANTI-TAF).

Background: QUANTI-TAF aimed to establish tenofovir-diphosphate (TFV-DP)/emtricitabine-triphosphate (FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with human immunodeficiency virus (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART).

Methods: For 16 weeks, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TFV-DP and FTC-TP in DBS were quantified and summarized at steady-state (week 12 or 16) as median (interquartile range).