KRASG12D drives immunosuppression in lung adenocarcinoma through paracrine signaling.

Lung cancer is the leading cause of cancer deaths in the United States. New targeted therapies against the once-deemed undruggable oncogenic KRAS are changing current therapeutic paradigms. However, resistance to targeted KRAS inhibitors almost inevitably occurs; resistance can be driven by tumor cell-intrinsic changes or by changes in the microenvironment.

Satellite DNA shapes dictate pericentromere packaging in female meiosis.

The abundance and sequence of satellite DNA at and around centromeres is evolving rapidly despite the highly conserved and essential process through which the centromere directs chromosome inheritance. The impact of such rapid evolution is unclear. Here we find that sequence-dependent DNA shape dictates packaging of pericentromeric satellites in female meiosis through a conserved DNA-shape-recognizing chromatin architectural protein, high mobility group AT-hook 1 (HMGA1).

Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo.

The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic GC repeat expansion in C9orf72. The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy.

Genetically Engineered and Implantable Mouse Brain Tumor Models: Characterization by Immunohistochemistry and Flow Cytometry.

Gliomas are aggressive tumors with a poor prognosis. The protocols presented here outline the methods used to study tumor progression, the tumor microenvironment (TME), and the effects of experimental treatments. The Sleeping Beauty (SB) transposase system induces tumors de novo to generate mouse models that recapitulate human gliomas.

Microscopy and spatial-metabolomics identify tissue-specific metabolic pathways uncovering salinity and drought tolerance mechanisms in Avicennia marina and Phoenix dactylifera roots.

In arid and semi-arid climates, native plants have developed unique strategies to survive challenging conditions. These adaptations often rely on molecular pathways that shape plant architecture to enhance their resilience. Date palms (Phoenix dactylifera) and mangroves (Avicennia marina) endure extreme heat and high salinity, yet the metabolic pathways underlying this resilience remain underexplored.

Activity of the mammalian DNA transposon piggyBat from Myotis lucifugus is restricted by its own transposon ends.

Members of the piggyBac superfamily of DNA transposons are widely distributed in host genomes ranging from insects to mammals. The human genome has retained five piggyBac-derived genes as domesticated elements although they are no longer mobile. Here, we have investigated the transposition properties of piggyBat from Myotis lucifugus, the only known active mammalian DNA transposon, and show that its low activity in human cells is due to subterminal inhibitory DNA sequences.

Epithelial outgrowth through mesenchymal rings drives alveologenesis.

Determining how alveoli are formed and maintained is critical to understanding lung organogenesis and regeneration after injury. To study the cellular dynamics of this critical stage of lung development, we have used scanned oblique-plane illumination microscopy of living lung slices to observe alveologenesis in real time at high resolution over several days. Contrary to the prevailing notion that alveologenesis occurs by airspace subdivision via ingrowing septa, we find that alveoli form by ballooning epithelial outgrowth supported by contracting mesenchymal ring structures.

Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional "aberrant" epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells.

Fine-Tuned Expression of Evolutionarily Conserved Signaling Molecules in the Notochord.

The notochord is an axial structure required for the development of all chordate embryos, from sea squirts to humans. Over the course of more than half a billion years of chordate evolution, in addition to its structural function, the notochord has acquired increasingly relevant patterning roles for its surrounding tissues. This process has involved the co-option of signaling pathways and the acquisition of novel molecular mechanisms responsible for the precise timing and modalities of their deployment.

Chemokine CXCL12 Activates CXC Receptor 4 Metastasis Signaling Through the Upregulation of a CXCL12/CXCR4/MDMX (MDM4) Axis.

Background: The metastasis-promoting G-protein-coupled receptor CXC Receptor 4 (CXCR4) is activated by the chemokine CXCL12, also known as stromal cell-derived factor 1 (SDF-1). The CXCL12/CXCR4 pathway in cancer promotes metastasis but the molecular details of how this pathway cross-talks with oncogenes are understudied. An oncogene pathway known to promote breast cancer metastasis in MDA-MB-231 xenografts is that of Mouse Double Minute 2 and 4 (MDM2 and MDM4, also known as MDMX).

PEAR1 Promotes Myoblast Proliferation Through Notch Signaling Pathway.

PEAR1, also known as platelet endothelial aggregation receptor 1, is known to play a crucial role in the migration and differentiation of muscle satellite cells (MuSCs). However, its specific effects on skeletal muscle development and regeneration require further exploration. In this study, the expression of PEAR1; the proliferation marker proteins of Pax7, CCNB1, and PCNA; and the key molecules of N1-ICD, N2-ICD, and Hes1 were all increased gradually during the process of C2C12 cell proliferation.

Generation of a human induced pluripotent stem cell line (CRICKi021-A) from a patient with Ullrich congenital muscular dystrophy carrying a pathogenic mutation in the COL6A1 gene.

Ullrich congenital muscular dystrophy (UCMD) represents the most severe subtype of collagen VI-related dystrophies (COL6-RDs), a spectrum of rare extracellular matrix disorders affecting skeletal muscle and connective tissue. Here, we generated an induced pluripotent stem cell (iPSC) line (CRICKi021-A) from a UCMD patient with de novo dominant-negative mutation in COL6A1 gene by reprogramming dermal fibroblasts using a non-integrating mRNA-based protocol. The resulting human iPSCs displayed normal morphology, expressed pluripotency-associated markers and differentiated into the three germ layers.

Estimation of Central Aortic Pressure Waveforms by Combination of a Meta-Learning Neural Network and a Physics-Driven Method.

The accurate non-invasive detection and estimation of central aortic pressure waveforms (CAPW) are crucial for reliable treatments of cardiovascular system diseases. But the accuracy and practicality of current estimation methods need to be improved. Our study combines a meta-learning neural network and a physics-driven method to accurately estimate CAPW based on personalized physiological indicators.

The sole essential low molecular weight tropomyosin isoform of is essential for pharyngeal muscle function.

Tropomyosin is an actin-binding protein that plays roles ranging from regulating muscle contraction to controlling cytokinesis and cell migration. The simple nematode provides a useful model for studying the core functions of tropomyosin in an animal, having a relatively simple anatomy, and a single tropomyosin gene, , that produces seven isoforms. Three higher molecular weight isoforms (LEV-11A, D, O) regulate contraction of body wall and other muscles, but comparatively less is known of the functions of four lower molecular weight isoforms (LEV-11C, E, T, U).

MCL-1 regulates cellular transitions during oligodendrocyte development.

Oligodendrocytes are the myelinating cells of the central nervous system. Regulation of the early stages of oligodendrocyte development is critical to the function of the cell. Specifically, myelin sheath formation is an energetically demanding event that requires precision, as alterations may lead to dysmyelination.

Gene expression and immunohistochemistry analysis of ADAMTS-1 and its substrates in odontogenic keratocyst.

Background: Considering the significant participation of the microenvironment in the local aggressiveness of odontogenic keratocysts, this study aims to evaluate the expression of ADAMTS-1 and its substrates, versican, aggrecan and brevican in this locally invasive odontogenic cyst.

Methods: Immunohistochemistry and polymerase chain reaction (PCR) were conducted on 30 cases of odontogenic keratocysts (OKCs) and 20 dental follicles (DFs).

Results: The immunohistochemical expression of these proteins was predominantly cytoplasmic and granular across all samples.

SUMO-mediated regulation of H3K4me3 reader SET-26 controls germline development in C. elegans.

Sumoylation is a posttranslational modification essential for multiple cellular functions in eukaryotes. ULP-2 is a conserved SUMO protease required for embryonic development in Caenorhabditis elegans. Here, we revealed that ULP-2 controls germline development by regulating the PHD-SET domain protein, SET-26.

Klotho mutation does not accelerate intervertebral disc aging in mice.

Aging is a risk factor for several chronic conditions, including intervertebral disc degeneration and associated back pain. Disc pathologies include loss of reticular-shaped nucleus pulposus cells, disorganization of annulus fibrosus lamellae, reduced disc height, and increased disc bulging. Sonic hedgehog, cytokeratin 19, and extracellular matrix proteins are markers of healthy disc.

A scoping review of diffuse hemispheric glioma, H3 G34-mutant: Epigenetic and molecular profiles, clinicopathology, and treatment avenues.

Background: Survival of pediatric and young adults with malignant glioma remains poor despite progress in treatment. This is especially true for diffuse hemispheric glioma (DHG), H3 G34-mutant, which is often present in adolescent and young adult patients. This scoping review consolidates existing knowledge of DHG H3 G34-mutant and identifies future targets and therapeutic options.

Comparative species delimitation of a biological conservation icon.

The United States Endangered Species Act (ESA) of 1973 set a precedent for biodiversity conservation across the globe. A key requirement of protections afforded by the ESA is the accurate delimitation of imperiled species. We present a comparative reference-based taxonomic approach to species delimitation that integrates genomic and morphological data for objectively assessing the distinctiveness of species targeted for protection by governmental agencies.

SMORE: spatial motifs reveal patterns in cellular architecture of complex tissues.

Deciphering the link between tissue architecture and function requires methods to identify and interpret patterns in spatial arrangement of cells. We present SMORE, an approach to detect patterns in sequential arrangements of cells and examine their associated gene expression specializations. Applied to retina, brain, and embryonic tissue maps, SMORE identifies novel spatial motifs, including one that offers a new mechanism of action for type 1b bipolar cells.

Functional differences between rodent and human PD-1 linked to evolutionary divergence.

Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and mouse PD-1 share only 59.6% amino acid identity. Here, we found that human PD-1 is more inhibitory than mouse PD-1, owing to stronger interactions with the ligands PD-L1 and PD-L2 and more efficient recruitment of the effector phosphatase Shp2.

Deriving a genetic regulatory network from an optimization principle.

Many biological systems operate near the physical limits to their performance, suggesting that aspects of their behavior and underlying mechanisms could be derived from optimization principles. However, such principles have often been applied only in simplified models. Here, we explore a detailed mechanistic model of the gap gene network in the embryo, optimizing its 50+ parameters to maximize the information that gene expression levels provide about nuclear positions.