The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate.

Heterochromatic loci marked by histone H3 lysine 9 dimethylation (H3K9me2) are enriched at the nuclear periphery in metazoans, but the effect of spatial position on heterochromatin function has not been defined. Here, we remove three nuclear lamins and lamin B receptor (LBR) in mouse embryonic stem cells (mESCs) and show that heterochromatin detaches from the nuclear periphery. Mutant mESCs sustain naïve pluripotency and maintain H3K9me2 across the genome but cannot repress H3K9me2-marked genes or transposons.

Ultrabroadband two-dimensional electronic spectroscopy in the pump-probe geometry using conventional optics.

We report ultrabroadband two-dimensional electronic spectroscopy (2D ES) measurements obtained in the pump-probe geometry using conventional optics. A phase-stabilized Michelson interferometer provides the pump-pulse delay interval, τ, necessary to obtain the excitation-frequency dimension. Spectral resolution of the probe beam provides the detection-frequency dimension, ω.

Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derived -associated ALS/FTD motor neurons.

A hexanucleotide repeat expansion (HRE) in is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, patients with the HRE exhibit a wide disparity in clinical presentation and age of symptom onset suggesting an interplay between genetic background and environmental stressors. Neurotrauma as a result of traumatic brain or spinal cord injury has been shown to increase the risk of ALS/FTD in epidemiological studies.

Enhancing the Small-Scale Screenable Biological Space beyond Known Chemogenomics Libraries with Gray Chemical Matter─Compounds with Novel Mechanisms from High-Throughput Screening Profiles.

Phenotypic assays have become an established approach to drug discovery. Greater disease relevance is often achieved through cellular models with increased complexity and more detailed readouts, such as gene expression or advanced imaging. However, the intricate nature and cost of these assays impose limitations on their screening capacity, often restricting screens to well-characterized small compound sets such as chemogenomics libraries.

Discovery of KIN-3248, An Irreversible, Next Generation FGFR Inhibitor for the Treatment of Advanced Tumors Harboring FGFR2 and/or FGFR3 Gene Alterations.

Fibroblast growth factor receptor (FGFR) alterations are present as oncogenic drivers and bypass mechanisms in many forms of cancer. These alterations can include fusions, amplifications, rearrangements, and mutations. Acquired drug resistance to current FGFR inhibitors often results in disease progression and unfavorable outcomes for patients.

The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition.

RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAF mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues.

Polyurethane Culture Substrates Enable Long-Term Neuron Monoculture in a Human Model of Neurotrauma.

Human induced pluripotent stem cell (hiPSC)-derived cells can reproduce human-specific pathophysiology, patient-specific vulnerability, and gene-environment interactions in neurological disease. Human models of neurotrauma therefore have great potential to advance the field. However, this potential cannot be realized until important biomaterials challenges are addressed.

Patient randomised controlled trial of technology enabled strategies to promote treatment adherence in liver transplantation: rationale and design of the TEST trial.

Background And Aims: Liver transplantation is a life-saving procedure for end-stage liver disease. However, post-transplant medication regimens are complex and non-adherence is common. Post-transplant medication non-adherence is associated with graft rejection, which can have long-term adverse consequences.

Abyssal hydrothermal springs-Cryptic incubators for brooding octopus.

Does warmth from hydrothermal springs play a vital role in the biology and ecology of abyssal animals? Deep off central California, thousands of octopus () migrate through cold dark waters to hydrothermal springs near an extinct volcano to mate, nest, and die, forming the largest known aggregation of octopus on Earth. Warmth from the springs plays a key role by raising metabolic rates, speeding embryonic development, and presumably increasing reproductive success; we show that brood times for females are ~1.8 years, far faster than expected for abyssal octopods.

Mesenchymal Stem Cells and Regenerative Therapy with Bilateral Gracilis Flaps for Perineal Reconstruction of a Wound Infection in the Setting of Anal Squamous Cell Carcinoma.

Many patients are affected by HIV/AIDS, and these conditions are highly prevalent worldwide. Patients with HIV/AIDS can experience debilitating wound infections that often require flap reconstruction and become challenging for surgeons to treat. In the past 5 years, mesenchymal stem cells have been tested and used as regenerative therapy to promote the growth of tissues throughout the body because of their ability to successfully promote cellular mitogenesis.

The Influence of Athletic Identity, Passion, and Perceptions of Severity of Concussions on Athletes' Willingness to Report Concussion Symptoms.

Context: The influence of several psychological characteristics on the willingness of athletes to report concussion behaviors has not been well explored. Therefore, the purpose of this study was to understand how athletic identity and sport passion predicted participants' willingness to report symptoms above what was explained by athlete demographics, concussion knowledge, and perceived seriousness of concussions.

Design: The study was cross-sectional.

Clinical characteristics and outcomes in CMV infection in intestinal transplant recipients: A single-center experience.

Background: Cytomegalovirus (CMV) infection is one of the most common posttransplantation infections and has been associated with increased rejection and mortality. Data in intestinal transplants recipients are limited.

Methods: This is a single-center, retrospective cohort study of all intestinal transplants performed between January 1, 2009, and August 31, 2020.

A Pilot Single-Blinded, Randomized, Controlled Trial Comparing BNT162b2 vs. JNJ-78436735 Vaccine as the Third Dose After Two Doses of BNT162b2 Vaccine in Solid Organ Transplant Recipients.

Solid Organ Transplant (SOT) recipients are at significant higher risk for COVID-19 and due to immunosuppressive medication, the immunogenicity after vaccination is suboptimal. In the previous studies, booster method showed significant benefit in this population. In the current study, we compared using a mix-and-match method vs.

Dynamics of Chromatin Accessibility During Hematopoietic Stem Cell Differentiation Into Progressively Lineage-Committed Progeny.

Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Mapping the chromatin dynamics of functionally defined cell populations will shed mechanistic insight into 2 major, unanswered questions in stem cell biology: how does epigenetic identity contribute to a cell type's lineage potential, and how do cascades of chromatin remodeling dictate ensuing fate decisions? Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors. Oligopotent progenitor populations operating between the HSCs and unipotent cells play essential roles in effecting hematopoietic homeostasis.

Temporal changes in the utilization of kidneys from hepatitis C virus-infected donors in the United States.

Despite data demonstrating increased utilization of kidneys from hepatitis C virus (HCV)-infected donors, it is unknown whether this is due to an increase in the donor pool or improved organ utilization and whether data from early pilot trials were temporally associated with changes in organ utilization. We used data from the Organ Procurement and Transplantation Network on all kidney donors and recipients of kidney transplants from January 1, 2015, to March 31, 2022 to evaluate temporal changes using joinpoint regression. Our primary analyses compared donors on the basis of their HCV viremic status (HCV-infected vs HCV-negative).

Rapid multiplex ultrafast nonlinear microscopy for material characterization.

We demonstrate rapid imaging based on four-wave mixing (FWM) by assessing the quality of advanced materials through measurement of their nonlinear response, exciton dephasing, and exciton lifetimes. We use a WSe monolayer grown by chemical vapor deposition as a canonical example to demonstrate these capabilities. By comparison, we show that extracting material parameters such as FWM intensity, dephasing times, excited state lifetimes, and distribution of dark/localized states allows for a more accurate assessment of the quality of a sample than current prevalent techniques, including white light microscopy and linear micro-reflectance spectroscopy.

Liver Transplantation for Primary Biliary Cholangitis.

Despite a significant increase in the total number of liver transplants (LTs) performed over the last 3 decades, primary biliary cholangitis (PBC) has become an uncommon indication for LT, which likely reflects the benefits of earlier diagnosis and available treatment, such as ursodeoxycholic acid (UDCA). Nonetheless, LT remains the only cure for patients with progressive PBC despite medical therapy with survival rates that are among the highest of all indications for LT. Post-LT PBC patients, however, are at increased risk of rejection and disease recurrence.

On the Choice of Active Site Sequences for Kinase-Ligand Affinity Prediction.

Recent work showed that active site rather than full-protein-sequence information improves predictive performance in kinase-ligand binding affinity prediction. To refine the notion of an "active site", we here propose and compare multiple definitions. We report significant evidence that our novel definition is superior to previous definitions and better models of ATP-noncompetitive inhibitors.

Imaging dynamic exciton interactions and coupling in transition metal dichalcogenides.

Transition metal dichalcogenides (TMDs) are regarded as a possible material platform for quantum information science and related device applications. In TMD monolayers, the dephasing time and inhomogeneity are crucial parameters for any quantum information application. In TMD heterostructures, coupling strength and interlayer exciton lifetimes are also parameters of interest.

Oxidation of 5-hydroxymethylfurfural with a novel aryl alcohol oxidase from Mycobacterium sp. MS1601.

Bio-based 5-hydroxymethylfurfural (HMF) serves as an important platform for several chemicals, among which 2,5-furan dicarboxylic acid (FDCA) has attracted considerable interest as a monomer for the production of polyethylene furanoate (PEF), a potential alternative for fossil-based polyethylene terephthalate (PET). This study is based on the HMF oxidizing activity shown by Mycobacterium sp. MS 1601 cells and investigation of the enzyme catalysing the oxidation.

In situ tomographic study of a 3D-woven SiC/SiC composite part subjected to severe thermo-mechanical loads.

A high-temperature multi-axial test is carried out to characterize the thermo-mechanical behaviour of a 3D-woven SiC/SiC composite aeronautical part under loads representative of operating conditions. The sample is L-shaped and cut out from the part. It is subjected to severe thermal gradients and a superimposed mechanical load that progressively increases up to the first damage.

Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation.

Background & Aims: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival.

Methods: We included 736 patients (77% female, mean age 42±1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia.