Mechanical Forces in the Skin : Roles in Tissue Architecture, Stability, and Function

Tissue shape emerges from the collective mechanical properties and behavior of individual cells and the ways by which they integrate into the surrounding tissue. Tissue architecture and its dynamic changes subsequently feed back to guide cell behavior. The skin is a dynamic, self-renewing barrier that is subjected to large-scale extrinsic mechanical forces throughout its lifetime. The ability to withstand this constant mechanical stress without compromising its integrity as a barrier requires compartment-specific structural specialization and the capability to sense and adapt to mechanical cues. This review discusses the unique mechanical properties of the skin and the importance of signals that arise from mechanical communication between cells and their environment.Peer reviewe

Increased Expression of Fatty Acid Synthase Provides a Survival Advantage to Colorectal Cancer Cells via Upregulation of Cellular Respiration

Fatty acid synthase (FASN), a lipogenic enzyme, is upregulated in colorectal cancer (CRC). Increased de novo lipid synthesis is thought to be a metabolic adaptation of cancer cells that promotes survival and metastasis; however, the mechanisms for this phenomenon are not fully understood. We show that FASN plays a role in regulation of energy homeostasis by enhancing cellular respiration in CRC. We demonstrate that endogenously synthesized lipids fuel fatty acid oxidation, particularly during metabolic stress, and maintain energy homeostasis. Increased FASN expression is associated with a decrease in activation of energy-sensing pathways and accumulation of lipid droplets in CRC cells and orthotopic CRCs. Immunohistochemical evaluation demonstrated increased expression of FASN and p62, a marker of autophagy inhibition, in primary CRCs and liver metastases compared to matched normal colonic mucosa. Our findings indicate that overexpression of FASN plays a crucial role in maintaining energy homeostasis in CRC via increased oxidation of endogenously synthesized lipids. Importantly, activation of fatty acid oxidation and consequent downregulation of stress-response signaling pathways may be key adaptation mechanisms that mediate the effects of FASN on cancer cell survival and metastasis, providing a strong rationale for targeting this pathway in advanced CRC

Preclinical Evaluation of Novel Fatty Acid Synthase Inhibitors in Primary Colorectal Cancer Cells and a Patient-Derived Xenograft Model of Colorectal Cancer

Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity in vitro and in vivo and a favorable tolerability profile in a Phase I clinical trial. However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition. CRC cells and PDXs showed a wide range of sensitivity to FASN inhibition. TVB-3664 treatment showed significant response (reduced tumor volume) in 30% of cases. Anti-tumor effect of TVB-3664 was associated with a significant decrease in a pool of adenine nucleotides and alterations in lipid composition including a significant reduction in fatty acids and phospholipids and an increase in lactosylceramide and sphingomyelin in PDXs sensitive to FASN inhibition. Moreover, Akt, Erk1/2 and AMPK were major oncogenic pathways altered by TVBs. In summary, we demonstrated that novel TVB inhibitors show anti-tumor activity in CRC and this activity is associated with a decrease in activation of Akt and Erk1/2 oncogenic pathways and significant alteration of lipid composition of tumors. Further understanding of genetic and metabolic characteristics of tumors susceptible to FASN inhibition may enable patient selection and personalized medicine approaches in CRC

Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression

Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality yet anti-stromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor β (TGF-β) signaling have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several Kras-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby Stat3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial Stat3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 and mechanics as key drivers of this phenotype

Functional Changes in the Snail Statocyst System Elicited by Microgravity

BACKGROUND: The mollusk statocyst is a mechanosensing organ detecting the animal's orientation with respect to gravity. This system has clear similarities to its vertebrate counterparts: a weight-lending mass, an epithelial layer containing small supporting cells and the large sensory hair cells, and an output eliciting compensatory body reflexes to perturbations. METHODOLOGY/PRINCIPAL FINDINGS: In terrestrial gastropod snail we studied the impact of 16- (Foton M-2) and 12-day (Foton M-3) exposure to microgravity in unmanned orbital missions on: (i) the whole animal behavior (Helix lucorum L.), (ii) the statoreceptor responses to tilt in an isolated neural preparation (Helix lucorum L.), and (iii) the differential expression of the Helix pedal peptide (HPep) and the tetrapeptide FMRFamide genes in neural structures (Helix aspersa L.). Experiments were performed 13-42 hours after return to Earth. Latency of body re-orientation to sudden 90° head-down pitch was significantly reduced in postflight snails indicating an enhanced negative gravitaxis response. Statoreceptor responses to tilt in postflight snails were independent of motion direction, in contrast to a directional preference observed in control animals. Positive relation between tilt velocity and firing rate was observed in both control and postflight snails, but the response magnitude was significantly larger in postflight snails indicating an enhanced sensitivity to acceleration. A significant increase in mRNA expression of the gene encoding HPep, a peptide linked to ciliary beating, in statoreceptors was observed in postflight snails; no differential expression of the gene encoding FMRFamide, a possible neurotransmission modulator, was observed. CONCLUSIONS/SIGNIFICANCE: Upregulation of statocyst function in snails following microgravity exposure parallels that observed in vertebrates suggesting fundamental principles underlie gravi-sensing and the organism's ability to adapt to gravity changes. This simple animal model offers the possibility to describe general subcellular mechanisms of nervous system's response to conditions on Earth and in space

Extensive Intracardiac and Deep Venous Thromboses in a Young Woman with Heparin-Induced Thrombocytopenia and May-Thurner Syndrome

A 38-year-old woman with a history of recurrent deep venous thromboses (DVTs) on chronic anticoagulation presented with acute left leg swelling. The patient was diagnosed with an acute left lower extremity (LLE) DVT in the setting of May-Thurner syndrome for which treatment with unfractionated heparin was started. Her hospital course was complicated by a new diagnosis of heparin-induced thrombocytopenia (HIT), with an incidental discovery of a large tricuspid valve mobile mass on a transthoracic echocardiogram (TTE). Subsequent imaging confirmed multiple right atrial thrombi along with LLE venous stent thrombosis and a new right LE acute DVT. Anticoagulation with argatroban for HIT thrombosis was started. She underwent a right atrial percutaneous thrombectomy and bilateral lower extremity thrombectomy with directed angioplasty and stent placement. This presentation is a rare manifestation of HIT with extensive intracardiac and deep venous thrombi, with successful staged interventions

Нотации Big-O и Small-O

This article provides an in-depth exploration of Big-Oh and small-oh notations, shedding light on their practical implications in the analysis of algorithm complexity. Big-Oh notation offers a valuable tool for estimating an upper bound on the growth rate of an algorithm's running time, whereas small-oh notation delineates a lower limit on this growth rate. The piece delves into a comprehensive examination of various complexity classes that emerge through the application of Big-Oh notation, underscoring the significance of small-oh notation as it complements and enriches complexity analysis. In the realm of programming and computer science, the employment of these notations holds paramount importance. They empower developers and researchers to make informed decisions regarding algorithm selection and optimization. It is crucial to recognize that while complexity analysis is a vital facet of effective programming, ongoing research endeavors may yield more refined methodologies and approaches within this domain. By understanding and harnessing the power of Big-Oh and small-oh notations, professionals can effectively evaluate algorithm efficiency and scalability. This knowledge equips them with the ability to design and implement algorithms that meet specific performance criteria, which is pivotal in the ever-evolving landscape of technology and computation. As pushing the boundaries of what is possible in the field of algorithm design is being continued, these notations remain invaluable tools for navigating the complex terrain of algorithmic analysis and optimization. By embracing Big-Oh and small-oh notations, professionals can finely assess algorithmic efficiency, ensuring they meet performance criteria in the evolving technological landscape. These notations remain indispensable for algorithmic analysis.Статья предоставляет исследование нотаций Big-Oh и small-oh, проливая свет на их практические применения в анализе сложности алгоритмов. Нотация Big-Oh представляет собой ценный инструмент для оценки верхней границы скорости роста времени выполнения алгоритма, в то время как small-oh нотация определяет нижнюю границу этой скорости роста. Статья рассматривает подробное исследование различных классов сложности, возникающих при применении нотации Big-Oh, подчеркивая важность small-oh нотации как дополняющей и обогащающей анализ сложности. В области программирования и компьютерных наук применение этих нотаций имеет первостепенное значение. Они дарят разработчикам и исследователям возможность принимать информированные решения относительно выбора и оптимизации алгоритмов. Важно понимать, что анализ сложности - это важный аспект эффективного программирования, и дальнейшие исследования могут привести к более уточненным методологиям и подходам в этой области. Понимание и использование нотаций Big-Oh и small-oh позволяет профессионалам эффективно оценивать эффективность и масштабируемость алгоритмов. Эти знания снабжают их способностью проектировать и внедрять алгоритмы, соответствующие определенным критериям производительности, что крайне важно в постоянно меняющемся мире технологий и вычислений. По мере того, как мы продолжаем расширять границы возможного в области проектирования алгоритмов, эти нотации остаются неоценимыми инструментами для навигации по сложной области анализа и оптимизации алгоритмов. Применение нотаций Big-Oh и small-oh позволяет профессионалам точно оценивать эффективность алгоритмов, обеспечивая соответствие критериям производительности в нашей меняющейся технологической среде. Эти нотации остаются неотъемлемой частью анализа алгоритмов

The Effect of Numbered Jerseys on Directed Commands, Teamwork, and Clinical Performance During Simulated Emergencies

Communication and teamwork are essential during inpatient emergencies such as cardiac arrest and rapid response (RR) codes. We investigated whether wearing numbered jerseys affect directed commands, teamwork, and performance during simulated codes. Eight teams of 6 residents participated in 64 simulations. Four teams were randomized to the experimental group wearing numbered jerseys, and four to the control group wearing work attire. The experimental group used more directed commands (49% vs. 31%, p < .001) and had higher teamwork score (25 vs. 18, p < .001) compared with control group. There was no difference in time to initiation of chest compression, bag-valve-mask ventilation, and correct medications. Time to defibrillation was longer in the experimental group (190 vs. 140 seconds, p = .035). Using numbered jerseys during simulations was associated with increased use of directed commands and better teamwork. Time to performance of clinical actions was similar except for longer time to defibrillation in the jersey group