Significance of LIF/LIFR Signaling in the Progression of Obesity-Driven Triple-Negative Breast Cancer.

American women with obesity have an increased incidence of triple-negative breast cancer (TNBC). The impact of obesity conditions on the tumor microenvironment is suspected to accelerate TNBC progression; however, the specific mechanism(s) remains elusive. This study explores the hypothesis that obesity upregulates leukemia inhibitory factor receptor (LIFR) oncogenic signaling in TNBC and assesses the efficacy of LIFR inhibition with EC359 in blocking TNBC progression.

Regulation of synapse density by Pumilio RNA-binding proteins.

The formation, stabilization, and elimination of synapses are tightly regulated during neural development and into adulthood. Pumilio RNA-binding proteins regulate the translation and localization of many synaptic mRNAs and are developmentally downregulated in the brain. We found that simultaneous downregulation of Pumilio 1 and 2 increases both excitatory and inhibitory synapse density in primary hippocampal neurons and promotes synapse maturation.

Cylindrical compression of thin wires by irradiation with a Joule-class short-pulse laser.

Equation of state measurements at Jovian or stellar conditions are currently conducted by dynamic shock compression driven by multi-kilojoule multi-beam nanosecond-duration lasers. These experiments require precise design of the target and specific tailoring of the spatial and temporal laser profiles to reach the highest pressures. At the same time, the studies are limited by the low repetition rate of the lasers.

(Sub-)Picosecond Surface Correlations of Femtosecond Laser Excited Al-Coated Multilayers Observed by Grazing-Incidence X-ray Scattering.

Femtosecond high-intensity laser pulses at intensities surpassing 10 W/cm can generate a diverse range of functional surface nanostructures. Achieving precise control over the production of these functional structures necessitates a thorough understanding of the surface morphology dynamics with nanometer-scale spatial resolution and picosecond-scale temporal resolution. In this study, we show that single XFEL pulses can elucidate structural changes on surfaces induced by laser-generated plasmas using grazing-incidence small-angle X-ray scattering (GISAXS).

CD32 captures committed haemogenic endothelial cells during human embryonic development.

During embryonic development, blood cells emerge from specialized endothelial cells, named haemogenic endothelial cells (HECs). As HECs are rare and only transiently found in early developing embryos, it remains difficult to distinguish them from endothelial cells. Here we performed transcriptomic analysis of 28- to 32-day human embryos and observed that the expression of Fc receptor CD32 (FCGR2B) is highly enriched in the endothelial cell population that contains HECs.

The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling.

Endometrial cancer (ECa) is the most common female gynecologic cancer. When comparing the two histological subtypes of endometrial cancer, Type II tumors are biologically more aggressive and have a worse prognosis than Type I tumors. Current treatments for Type II tumors are ineffective, and new targeted therapies are urgently needed.

An optimized temporally controlled Gal4 system in reveals degeneration caused by adult-onset neuronal Vps13D knockdown.

Mutations in the human gene VPS13D cause the adult-onset neurodegenerative disease ataxia. Our previous work showed that disruptions in the Vps13D gene in neurons causes mitochondrial defects. However, developmental lethality caused by Vps13D loss limited our understanding of the long-term physiological effects of Vps13D perturbation in neurons.

CREB3L2-ATF4 heterodimerization defines a transcriptional hub of Alzheimer's disease gene expression linked to neuropathology.

Gene expression is changed by disease, but how these molecular responses arise and contribute to pathophysiology remains less understood. We discover that β-amyloid, a trigger of Alzheimer's disease (AD), promotes the formation of pathological CREB3L2-ATF4 transcription factor heterodimers in neurons. Through a multilevel approach based on AD datasets and a novel chemogenetic method that resolves the genomic binding profile of dimeric transcription factors (ChIPmera), we find that CREB3L2-ATF4 activates a transcription network that interacts with roughly half of the genes differentially expressed in AD, including subsets associated with β-amyloid and tau neuropathologies.

Resolving molecular diffusion and aggregation of antibody proteins with megahertz X-ray free-electron laser pulses.

X-ray free-electron lasers (XFELs) with megahertz repetition rate can provide novel insights into structural dynamics of biological macromolecule solutions. However, very high dose rates can lead to beam-induced dynamics and structural changes due to radiation damage. Here, we probe the dynamics of dense antibody protein (Ig-PEG) solutions using megahertz X-ray photon correlation spectroscopy (MHz-XPCS) at the European XFEL.

Automated matching of two-time X-ray photon correlation maps from phase-separating proteins with Cahn-Hilliard-type simulations using auto-encoder networks.

Machine learning methods are used for an automated classification of experimental two-time X-ray photon correlation maps from an arrested liquid-liquid phase separation of a protein solution. The correlation maps are matched with correlation maps generated with Cahn-Hilliard-type simulations of liquid-liquid phase separations according to two simulation parameters and in the last step interpreted in the framework of the simulation. The matching routine employs an auto-encoder network and a differential evolution based algorithm.

Noninvasive Antemortem Detection of Retinal Prions by a Fluorescent Tracer.

Background: Neurodegenerative diseases are widespread yet challenging to diagnose and stage antemortem. As an extension of the central nervous system, the eye harbors retina ganglion cells vulnerable to degeneration, and visual symptoms are often an early manifestation of neurodegenerative disease.

Objective: Here we test whether prion protein aggregates could be detected in the eyes of live mice using an amyloid-binding fluorescent probe and high-resolution retinal microscopy.

Gelation Dynamics upon Pressure-Induced Liquid-Liquid Phase Separation in a Water-Lysozyme Solution.

Employing X-ray photon correlation spectroscopy, we measure the kinetics and dynamics of a pressure-induced liquid-liquid phase separation (LLPS) in a water-lysozyme solution. Scattering invariants and kinetic information provide evidence that the system reaches the phase boundary upon pressure-induced LLPS with no sign of arrest. The coarsening slows down with increasing quench depths.

Chemically-defined generation of human hemogenic endothelium and definitive hematopoietic progenitor cells.

Human hematopoietic stem cells (HSCs), which arise from aorta-gonad-mesonephros (AGM), are widely used to treat blood diseases and cancers. However, a technique for their robust generation in vitro is still missing. Here we show temporal manipulation of Wnt signaling is sufficient and essential to induce AGM-like hematopoiesis from human pluripotent stem cells.

Identification of a retinoic acid-dependent haemogenic endothelial progenitor from human pluripotent stem cells.

The generation of haematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. During embryonic development, HSCs derive from haemogenic endothelium (HE) in a NOTCH- and retinoic acid (RA)-dependent manner. Although a WNT-dependent (WNTd) patterning of nascent hPSC mesoderm specifies clonally multipotent intra-embryonic-like HOXA definitive HE, this HE is functionally unresponsive to RA.

Generation of pancreatic progenitors from human pluripotent stem cells by small molecules.

Human pluripotent stem cell (hPSC)-derived pancreatic progenitors (PPs) provide promising cell therapies for type 1 diabetes. Current PP differentiation requires a high amount of Activin A during the definitive endoderm (DE) stage, making it economically difficult for commercial ventures. Here we identify a dose-dependent role for Wnt signaling in controlling DE differentiation without Activin A.

Diagnosing newborns with suspected mitochondrial disorders: an economic evaluation comparing early exome sequencing to current typical care.

Purpose: To determine the value of early exome sequencing (eES) relative to the current typical care (TC) in the diagnosis of newborns with suspected severe mitochondrial disorders (MitD).

Methods: We used a decision tree-Markov hybrid to model neonatal intensive care unit (NICU)-related outcomes and costs, lifetime costs and quality-adjusted life-years among patients with MitD. Probabilities, costs, and utilities were populated using published literature, expert opinion, and the Pediatric Health Information System database.

Long-term outcomes of patients with mucopolysaccharidosis VI treated with galsulfase enzyme replacement therapy since infancy.

Objective: Long-term outcomes of patients with mucopolysaccharidosis (MPS) VI treated with galsulfase enzyme replacement therapy (ERT) since infancy were evaluated.

Methods: The study was a multicenter, prospective evaluation using data from infants with MPS VI generated during a phase 4 study (ASB-008; Clinicaltrials.govNCT00299000) and clinical data collected ≥5 years after completion of the study.

Nanoscale Transient Magnetization Gratings Created and Probed by Femtosecond Extreme Ultraviolet Pulses.

We utilize coherent femtosecond extreme ultraviolet (EUV) pulses from a free electron laser (FEL) to generate transient periodic magnetization patterns with periods as short as 44 nm. Combining spatially periodic excitation with resonant probing at the M-edge of cobalt allows us to create and probe transient gratings of electronic and magnetic excitations in a CoGd alloy. In a demagnetized sample, we observe an electronic excitation with a rise time close to the FEL pulse duration and ∼0.

Assessment of Facial Morphologic Features in Patients With Congenital Adrenal Hyperplasia Using Deep Learning.

Importance: Congenital adrenal hyperplasia (CAH) is the most common primary adrenal insufficiency in children, involving excess androgens secondary to disrupted steroidogenesis as early as the seventh gestational week of life. Although structural brain abnormalities are seen in CAH, little is known about facial morphology.

Objective: To investigate differences in facial morphologic features between patients with CAH and control individuals with use of machine learning.

High-affinity mutant Interleukin-13 targeted CAR T cells enhance delivery of clickable biodegradable fluorescent nanoparticles to glioblastoma.

Glioblastoma (GBM), the deadliest form of brain cancer, presents long-standing problems due to its localization. Chimeric antigen receptor (CAR) T cell immunotherapy has emerged as a powerful strategy to treat cancer. IL-13-receptor-α2 (IL13Rα2), present in over 75% of GBMs, has been recognized as an attractive candidate for anti-glioblastoma therapy.

Fluorescent indicators for continuous and lineage-specific reporting of cell-cycle phases in human pluripotent stem cells.

Proper cell-cycle progression is essential for the self-renewal and differentiation of human pluripotent stem cells (hPSCs). The fluorescent ubiquitination-based cell-cycle indicator (FUCCI) has allowed the dual-color visualization of the G and S/G /M phases in various dynamic models, but its application in hPSCs is not widely reported. In addition, lineage-specific FUCCI reporters have not yet been developed to analyze complex tissue-specific cell-cycle progression during hPSC differentiation.