Explore the vast range of titles available.

During the stepwise specification and differentiation of tissue-specific multipotent progenitors, lineage-specific transcriptional networks are activated or repressed to orchestrate cell specification. The gas-exchange niche in the lung contains two major epithelial cell types, alveolar type 1 (AT1) and AT2 cells, and the timing of lineage specification of these cells is critical for the correct formation of this niche and postnatal survival. Integrating cell-specific lineage tracing studies, spatially specific mRNA transcript and protein expression, and single-cell RNA-sequencing analysis, we demonstrate that specification of alveolar epithelial cell fate begins concomitantly with the proximal–distal specification of epithelial progenitors and branching morphogenesis earlier than previously appreciated. By using a newly developed dual-lineage tracing system, we show that bipotent alveolar cells that give rise to AT1 and AT2 cells are a minor contributor to the alveolar epithelial population. Furthermore, single-cell assessment of the transcriptome identifies specified AT1 and AT2 progenitors rather than bipotent cells during sacculation. These data reveal a paradigm of organ formation whereby lineage specification occurs during the nascent stages of development coincident with broad tissue-patterning processes, including axial patterning of the endoderm and branching morphogenesis.

Alveolar epithelial regeneration is essential for recovery from devastating lung diseases. This process occurs when type II alveolar pneumocytes (AT2 cells) proliferate and transdifferentiate into type I alveolar pneumocytes (AT1 cells). We used genome-wide analysis of chromatin accessibility and gene expression following acute lung injury to elucidate repair mechanisms. AT2 chromatin accessibility changed substantially following injury to reveal STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways. Single-cell transcriptome analysis identified brain-derived neurotrophic factor (Bdnf) as a STAT3 target gene with newly accessible chromatin in a unique population of regenerating AT2 cells. Furthermore, the BDNF receptor tropomyosin receptor kinase B (TrkB) was enriched on mesenchymal alveolar niche cells (MANCs). Loss or blockade of AT2-specific Stat3, Bdnf or mesenchyme-specific TrkB compromised repair and reduced Fgf7 expression by niche cells. A TrkB agonist improved outcomes in vivo following lung injury. These data highlight the biological and therapeutic importance of the STAT3–BDNF–TrkB axis in orchestrating alveolar epithelial regeneration.Paris et al. show that after injury or influenza infection alveolar type II cells signal via a STAT3–BDNF axis that activates the TrkB receptor on mesenchymal niche cells and enhances alveolar repair.

Lymphangioleiomyomatosis (LAM) is a rare fatal cystic lung disease due to bi-allelic inactivating mutations in tuberous sclerosis complex (TSC1/TSC2) genes coding for suppressors of the mechanistic target of rapamycin complex 1 (mTORC1). The origin of LAM cells is still unknown. Here, we profile a LAM lung compared to an age- and sex-matched healthy control lung as a hypothesis-generating approach to identify cell subtypes that are specific to LAM. Our single-cell RNA sequencing (scRNA-seq) analysis reveals novel mesenchymal and transitional alveolar epithelial states unique to LAM lung. This analysis identifies a mesenchymal cell hub coordinating the LAM disease phenotype. Mesenchymal-restricted deletion of Tsc2 in the mouse lung produces a mTORC1-driven pulmonary phenotype, with a progressive disruption of alveolar structure, a decline in pulmonary function, increase of rapamycin-sensitive expression of WNT ligands, and profound female-specific changes in mesenchymal and epithelial lung cell gene expression. Genetic inactivation of WNT signaling reverses age-dependent changes of mTORC1-driven lung phenotype, but WNT activation alone in lung mesenchyme is not sufficient for the development of mouse LAM-like phenotype. The alterations in gene expression are driven by distinctive crosstalk between mesenchymal and epithelial subsets of cells observed in mesenchymal Tsc2 -deficient lungs. This study identifies sex- and age-specific gene changes in the mTORC1-activated lung mesenchyme and establishes the importance of the WNT signaling pathway in the mTORC1-driven lung phenotype. The cellular origins of lymphangioleiomyomatosis (LAM), a rare fatal lung disease, are poorly understood. Here the authors identify a mesenchymal cell hub coordinating the LAM phenotype and develop a LAM mouse model where they investigate the co-operative dysregulation of mTORC1 and WNT growth pathways in the sex- and age-specific changes leading to structural and functional decline.

In today's world, antibiotic-resistant microorganisms are a major concern. There is solid evidence that metal nanoparticles (NPs) tend to have antimicrobial properties. The most effective substitute for antibiotic resistance is the incorporation of metal NPs. The antibacterial properties of NPs are currently being explored and shown to be successful. Zinc (Zn) NPs that are biosynthesized from marine Actinobacterium proved to be more biocompatible, bioactive, and affordable.  Aim: This study aims to investigate the synthesis of ZnNPs from Actinobacterium species and their antimicrobial effects against gram-positive and gram-negative bacteria. The current study uses natural, considerably safer processes to synthesize ZnNPs from marine Actinobacteria with little to no negative side effects. It involves sample collection, identification, and isolation of Actinobacterium species. The isolated sample was air-dried, and extracts of ZnNPs were taken. Among the isolates from marine sediment, two Actinobacteria that generate bioactive secondary metabolites- species (MOSEL-ME28) and (MOSEL-ME29)-were selected for extracellular synthesis of ZnNPs. The antimicrobial activity of the biosynthesized ZnNPs from marine Actinobacteria was analyzed against  (MRSA), , and The results were statistically analyzed and graphs were created. ZnNPs obtained from Actinobacterium species exhibited antimicrobial effects against (MRSA), , . At 280 nm wavelength, analysis of the UV spectrum showed a notable absorbance value of 1.8. The antibacterial efficacy against MRSA, species, and was assessed by measuring the zone of inhibition in diameter. The zones of inhibition were 8, 8, and 7 mm on the evaluation for , , and species, respectively, at a dose of 75 μg/mL. When the dosage was increased to 100 μg/mL, the inhibition zones were found to be 9.5, 9, and 7.5 mm for the respective bacterial strains. ZnNPs are biosynthesized from marine Actinobacterium species in this research study. They have a significant antimicrobial activity against both gram-positive and negative bacteria. This indicates that ZnNPs have enormous antimicrobial potential and have an extensive spectrum of applications. However, clinical trials must be completed before it can be used safely on patients.

Vascular dementia is the second most common form of dementia. Yet, the mechanisms by which cerebrovascular damage progresses are insufficiently understood. Here, we create bilateral common carotid artery stenosis in mice, which effectively impairs blood flow to the brain, a major cause of the disease. Through imaging and single-cell transcriptomics of the mouse cortex, we uncover that blood vessel venous cells undergo maladaptive structural changes associated with increased Epas1 expression and activation of developmental angiogenic pathways. In a human cell model comparing arterial and venous cells, we observe that low-oxygen condition leads to sustained EPAS1 signaling specifically in venous cells. EPAS1 inhibition reduces cerebrovascular abnormalities, microglial activation, and improves markers of cerebral perfusion in vivo. In human subjects, levels of damaged endothelial cells from venous vessels are correlated with white matter injury in the brain and poorer cognitive functions. Together, these findings indicate EPAS1 as a potential therapeutic target to restore cerebrovascular integrity and mitigate neuroinflammation. How changes in brain blood vessels lead to a chronic reduction in blood flow and, consequently, to vascular dementia is poorly understood. Here, the authors show that venous endothelial dysfunction driven by EPAS1 promotes abnormal vascular remodeling and contributes to cognitive decline.

Despite epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), how it senses extracellular matrix (ECM) rigidity remain elusive in the context of the increasing role of tissue rigidity on various hallmarks of cancer development. Here it is shown that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR‐driven mouse models, and human specimens. Agrin expression confers substrate stiffness‐dependent oncogenic attributes to EGFR‐reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)‐dependent and independent modes, thereby sensitizing its activity toward localized cancer cell‐ECM adherence and bulk rigidity by fostering interactions with integrin β1. Notably, a feed‐forward loop linking agrin–EGFR rigidity response to YAP–TEAD mechanosensing is essential for tumorigenesis. Together, the combined inhibition of EGFR–YAP/TEAD may offer a strategy to reduce lung tumorigenesis by disrupting agrin‐EGFR mechanotransduction, uncovering a therapeutic vulnerability for EGFR‐addicted lung cancers. The study identifies agrin‐EGFR mechanotransduction as a critical driver of lung adenocarcinoma which enhances EGFR signaling through an integrin‐FAK‐actomyosin dependent positive feedback on YAP/TAZ ‐TEAD in response to matrix stiffness. Targeting this oncogenic loop through combinatorial treatments inhibits lung cancer due to agrin impairment. Thus, agrin may serve as a biomarker for predicting response to these therapies.

Purpose of Review Throughout the lifespan, lung injury impedes the primary critical function essential for life-respiration. To repair quickly and efficiently is critical and is orchestrated by a diverse repertoire of progenitor cells and their niche. This review incorporates knowledge gained from early studies in lung epithelial morphogenesis and cell fate and explores its relevance to more recent findings of lung progenitor and stem cells in development and regeneration. Recent Findings Cell fate in the lung is organized into an early specification phase and progressive differentiation phase in lung development. The advent of single-cell analysis combined with lineage analysis and projections is uncovering new functional cell types in the lung, providing a topographical atlas for progenitor cell lineage commitment during development, homeostasis, and regeneration. Summary Lineage commitment of lung progenitor cells is spatiotemporally regulated during development. Single-cell sequencing technologies have significantly advanced our understanding of the similarities and differences between developmental and regenerative cell fate trajectories. Subsequent unraveling of the molecular mechanisms underlying these cell fate decisions will be essential to manipulating progenitor cells for regeneration.

During embryonic development, organ morphogenesis is driven by coordination and alignment of local cellular behaviors with the three body axes: dorsal-ventral (DV), anterior-posterior (AP) and left-right (LR) axes. This involves translation and amplification of molecular chirality defined by genetically encoded spatial cues into asymmetric cell behavior that is critical for defining the organ’s form and function. The gastrointestinal tract, displaying profound LR asymmetries, presents itself as a powerful model to study the asymmetric mechanisms involved in the establishment of its stereotypical looping topology and patterning of its vasculature. Asymmetric looping morphogenesis of the gut initiates with a critical leftward tilt directed by the evolutionarily conserved LR pathway. Failure to do so leads to gut malrotation and the catastrophic midgut volvulus, highlighting an urgent need to define the molecular basis of this process. Previous research in mice and birds has shown that the leftward tilt of the gut is established by cellular and extracellular asymmetries across the LR axis of the dorsal mesentery (DM), which suspends the gut tube. The left DM condenses while the right expands causing the DM to tilt the gut tube leftward, and this critical bias determines gut chirality. Concomitantly, vasculogenesis of the gut proceeds within the left DM but is excluded on the right, suggesting that the cellular processes within the DM are also employed to pattern abdominal blood vessels. While the left DM has been shown to be under the control of the left-determining transcription factor Pitx2, the mechanisms that regulate the expansion and vascular exclusion specific to the right DM have remained unknown. Surprisingly, my research demonstrates that the expansion of the right DM precedes all other cell asymmetries that collectively deform this structure, suggesting that the key initiator of asymmetric gut tilting derives from the right side. Hyaluronan (HA), a unique and highly conserved glycosaminoglycan, predominates in the extracellular matrix (ECM) of the right DM. Targeted degradation of HA in the right DM ablates expansion, gut tilting and results in aberrant retention of vasculature in the right DM. This unexpected finding demonstrates that HA is a critical regulator of the ECM expansion and vascular exclusion necessary for asymmetric gut looping and vascular morphogenesis. Investigating into how HA enacts its functions, I show that the tumor necrosis factor alpha-inducible protein 6 (Tsg6/Tnfaip6), an enzyme that covalently modifies HA to form a stable heavy chain (HC) HA complex, is restricted to the right DM. Knockdown of Tsg6 on the right prevents ECM expansion, gut tilting, and disrupts the normal process of vascular exclusion, leading to aberrant gut vascular patterning. Furthermore, misexpression of Tsg6 in the left DM prevents the formation of abdominal blood vessels demonstrating that Tsg6 is both necessary and sufficient to inhibit gut vascular development. The ability of Tsg6 to mediate ECM expansion and vascular exclusion is dependent on its enzymatic ability to covalent modify HA. Further analysis of Tsg6 knockout mice revealed randomized gut looping chirality and gut malrotations in Tsg6 mutant embryos that predispose them volvulus. Collectively, my study identifies a new pathway during LR organogenesis initiated by HA-rich ECM on the right side of the embryo and presents a novel mouse model to understand the origin of gut malrotations and vascular anomalies.

We build a system that enables any human to control a robot hand and arm, simply by demonstrating motions with their own hand. The robot observes the human operator via a single RGB camera and imitates their actions in real-time. Human hands and robot hands differ in shape, size, and joint structure, and performing this translation from a single uncalibrated camera is a highly underconstrained problem. Moreover, the retargeted trajectories must effectively execute tasks on a physical robot, which requires them to be temporally smooth and free of self-collisions. Our key insight is that while paired human-robot correspondence data is expensive to collect, the internet contains a massive corpus of rich and diverse human hand videos. We leverage this data to train a system that understands human hands and retargets a human video stream into a robot hand-arm trajectory that is smooth, swift, safe, and semantically similar to the guiding demonstration. We demonstrate that it enables previously untrained people to teleoperate a robot on various dexterous manipulation tasks. Our low-cost, glove-free, marker-free remote teleoperation system makes robot teaching more accessible and we hope that it can aid robots in learning to act autonomously in the real world. Videos at https://robotic-telekinesis.github.io/