Syndecan-4 tunes cell mechanics by activating the kindlin-integrin-RhoA pathway.

Extensive research over the past decades has identified integrins to be the primary transmembrane receptors that enable cells to respond to external mechanical cues. We reveal here a mechanism whereby syndecan-4 tunes cell mechanics in response to localized tension via a coordinated mechanochemical signalling response that involves activation of two other receptors: epidermal growth factor receptor and ß1 integrin. Tension on syndecan-4 induces cell-wide activation of the kindlin-2/ß1 integrin/RhoA axis in a PI3K-dependent manner. Furthermore, syndecan-4-mediated tension at the cell-extracellular matrix interface is required for yes-associated protein activation. Extracellular tension on syndecan-4 triggers a conformational change in the cytoplasmic domain, the variable region of which is indispensable for the mechanical adaptation to force, facilitating the assembly of a syndecan-4/α-actinin/F-actin molecular scaffold at the bead adhesion. This mechanotransduction pathway for syndecan-4 should have immediate implications for the broader field of mechanobiology.

Mechanotransduction in talin through the interaction of the R8 domain with DLC1.

The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.

GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment.

The mechanical properties of the tumor microenvironment are emerging as attractive targets for the development of therapies. Tamoxifen, an agonist of the G protein-coupled estrogen receptor (GPER), is widely used to treat estrogen-positive breast cancer. Here, we show that tamoxifen mechanically reprograms the tumor microenvironment through a newly identified GPER-mediated mechanism. Tamoxifen inhibits the myofibroblastic differentiation of pancreatic stellate cells (PSCs) in the tumor microenvironment of pancreatic cancer in an acto-myosin-dependent manner via RhoA-mediated contractility, YAP deactivation, and GPER signaling. This hampers the ability of PSCs to remodel the extracellular matrix and to promote cancer cell invasion. Tamoxifen also reduces the recruitment and polarization to the M2 phenotype of tumor-associated macrophages. Our results highlight GPER as a mechanical regulator of the tumor microenvironment that targets the three hallmarks of pancreatic cancer: desmoplasia, inflammation, and immune suppression. The well-established safety of tamoxifen in clinics may offer the possibility to redirect the singular focus of tamoxifen on the cancer cells to the greater tumor microenvironment and lead a new strategy of drug repurposing.

Tamoxifen mechanically reprograms the tumor microenvironment via HIF-1A and reduces cancer cell survival.

The tumor microenvironment is fundamental to cancer progression, and the influence of its mechanical properties is increasingly being appreciated. Tamoxifen has been used for many years to treat estrogen-positive breast cancer. Here we report that tamoxifen regulates the level and activity of collagen cross-linking and degradative enzymes, and hence the organization of the extracellular matrix, via a mechanism involving both the G protein-coupled estrogen receptor (GPER) and hypoxia-inducible factor-1 alpha (HIF-1A). We show that tamoxifen reduces HIF-1A levels by suppressing myosin-dependent contractility and matrix stiffness mechanosensing. Tamoxifen also downregulates hypoxia-regulated genes and increases vascularization in PDAC tissues. Our findings implicate the GPER/HIF-1A axis as a master regulator of peri-tumoral stromal remodeling and the fibrovascular tumor microenvironment and offer a paradigm shift for tamoxifen from a well-established drug in breast cancer hormonal therapy to an alternative candidate for stromal targeting strategies in PDAC and possibly other cancers.

Retinoic Acid Receptor-ß Is Downregulated in Hepatocellular Carcinoma and Cirrhosis and Its Expression Inhibits Myosin-Driven Activation and Durotaxis in Hepatic Stellate Cells.

Hepatic stellate cells (HSCs) are essential perisinusoidal cells in both healthy and diseased liver. HSCs modulate extracellular matrix (ECM) homeostasis when quiescent, but in liver fibrosis, HSCs become activated and promote excess deposition of ECM molecules and tissue stiffening via force generation and mechanosensing. In hepatocellular carcinoma (HCC), activated HSCs infiltrate the stroma and migrate to the tumor core to facilitate paracrine signaling with cancer cells. Because the function of HSCs is known to be modulated by retinoids, we investigated the expression profile of retinoic acid receptor beta (RAR-ß) in patients with cirrhosis and HCC, as well as the effects of RAR-ß activation in HSCs. We found that RAR-ß expression is significantly reduced in cirrhotic and HCC tissues. Using a comprehensive set of biophysical methods combined with cellular and molecular biology, we have elucidated the biomechanical mechanism by which all trans-retinoic acid promotes HSC deactivation via RAR-ß-dependent transcriptional downregulation of myosin light chain 2 expression. Furthermore, this also abrogated mechanically driven migration toward stiffer substrates. Conclusion: Targeting mechanotransduction in HSCs at the transcriptional level may offer therapeutic options for a range of liver diseases.

FAK controls the mechanical activation of YAP, a transcriptional regulator required for durotaxis.

Focal adhesion kinase (FAK) is a key molecule in focal adhesions and regulates fundamental processes in cells such as growth, survival, and migration. FAK is one of the first molecules recruited to focal adhesions in response to external mechanical stimuli and therefore is a pivotal mediator of cell mechanosignaling, and relays these stimuli to other mechanotransducers within the cytoplasm. Yes-associated protein (YAP) has been identified recently as one of these core mechanotransducers. YAP translocates to the nucleus following changes in cell mechanics to promote the expression of genes implicated in motility, apoptosis, proliferation, and organ growth. Here, we show that FAK controls the nuclear translocation and activation of YAP in response to mechanical activation and submit that the YAP-dependent process of durotaxis requires a cell with an asymmetric distribution of active and inactive FAK molecules.-Lachowski, D., Cortes, E., Robinson, B., Rice, A., Rombouts, K., Del Río Hernández, A. E. FAK controls the mechanical activation of YAP, a transcriptional regulator required for durotaxis.

Improved landfill leachate quality using ozone, UV solar radiation, hydrogen peroxide, persulfate and adsorption processes.

Advanced oxidation processes based on ozonation, UV solar radiation, hydrogen peroxide, and persulfate were tested for the complete treatment of a specific landfill leachate. As a post-treatment of the advanced oxidation process, an additional adsorption process was carried out using a natural zeolite. Application of the UVsolar/O3/H2O2 process required 140 min of irradiation and the consumption of 0.67 g/L H2O2 to eliminate 56% and 17% of colour and chemical oxygen demand (COD), respectively. When adding persulfate to the system (UVsolar/O3/H2O2/S2O8-2), colour and COD were reduced by 29% and 77%, respectively, with a 0.2 g/L concentration of S2O8-2 requiring 250 min of irradiation time. In an experimental run with landfill leachate, adsorption post-treatment with a natural zeolite resulted in 36%, 99%, and 18% total reductions in COD, ammonium, and chloride, respectively. In another experimental run, adsorption with a zeolite was used as a pre-treatment for the advanced oxidation process (UVsolar/O3/H2O2 and UVsolar/O3/H2O2/S2O8-2). The results were similar to those for adsorption post-treatment, with 30%, 90%, and 20% total reductions in COD, ammonium, and chloride, respectively. Despite improvements, some measured parameters of treated landfill leachate still exceeded Chilean regulations for water quality. Furthermore, Lactuca sativa seeds did not germinate after irrigation with 100% treated landfill leachate or dilutions above 3%. Finally, EC50 values were enhanced during treatment, going from 0.002% for raw landfill leachate to 1.179% after the adsorption process.

Insights into hydrothermal treatment of biomass blends: Assessing energy yield and ash content for biofuel enhancement.

This study explores the Hydrothermal Carbonization (HTC) treatment of lignocellulosic biomass blends, delving into the influence of several key parameters: temperature, additive nature and dosage, residence time, and biomass composition. Rapeseeds, Pinus radiata sawdust, oat husks, and pressed olive served as the studied biomasses. One hundred twenty-eight experiments were conducted to assess the effects on mass yield (MY), energy yield (EY), higher heating value (HHV), and final ash content (ASH) by a Factorial Experimental Design. The derived model equations demonstrated a robust fit to the experimental data, averaging an R2 exceeding 0.94, affirming their predictive accuracy. The observed energy yield ranged between 65% and 80%, notably with sawdust and olive blends securing EY levels surpassing 70%, while rapeseed blends exhibited the highest HHV at 25 MJ/kg. Temperature emerged as the most influential factor, resulting in an 11% decrease in MY and a substantial 2.20 MJ/kg increase in HHV. Contrastingly, blend composition and additive presence significantly impacted ASH and EY, with all blends exhibiting increased ASH in the presence of additives. Higher initial hemicellulose and aqueous extractive content in raw biomass correlated proportionally with heightened HHV.

Use of vinasse and coffee waste as chelating agent of photo-Fenton landfill leachate treatment.

This research studies the use of vinasse (VS) coming from Pisco and caffeic acid (Caa) from solid coffee waste as chelating agents of this process, to carry out a photo-Fenton process using UVc lamps of 254-nm wavelength for 60 min, at the natural pH of the landfill leachate (8.9). Without the chelating agent, there was a removal of UV 254 and COD of 54.2% and 54.7%, respectively, when the photo-Fenton reaction was carried out at pH 3; at pH 6, the removal of UV 254 and COD was 13.1% and 39.2%, respectively, and at pH 8.9, the elimination of UV 254 and COD was 10.8% and 16.1%, respectively. When Caa was used in the landfill leachate (LL) for the photo-catalytic processes carried out at pH 8.9, a removal of 24.1%, 43.0%, and 47.4% of UV 254 was obtained using 5 mg/L, 50 mg/L, and 100 mg/L of Caa. The removal of UV 254 was 27.3%, 30.7%, and 36.3% using 5 mg/L, 50 mg/L, and 100 mg/L of VS, respectively, and the removal of COD was 32.2%, 35.4%, and 39.2% using 5 mg/L, 50 mg/L, and 100 mg/L of VS, respectively. When Caa was used in the LL at pH 8.9, the concentration of total Fe went from 37.5 to 33.2, from 40.2 to 36.8, and from 45.2 to 42.1, using 5 mg/L, 50 mg/L, and 100 mg/L of caffeic acid, respectively. Using VS in the LL at pH 8.9, the concentration of total Fe along the run went from 35.1 to 32.2, from 39.4 to 34.8, and from 42.1 to 40.2, using 5 mg/L, 50 mg/L, and 100 mg/L of VS, respectively. As a result of these processes, it was noted that the use of Caa and VS increases the solubility of Fe at a higher pH.

Retinoic acid receptor ß modulates mechanosensing and invasion in pancreatic cancer cells via myosin light chain 2.

Pancreatic ductal adenocarcinoma (PDAC) is the most common and lethal form of pancreatic cancer, characterised by stromal remodelling, elevated matrix stiffness and high metastatic rate. Retinoids, compounds derived from vitamin A, have a history of clinical use in cancer for their anti-proliferative and differentiation effects, and more recently have been explored as anti-stromal therapies in PDAC for their ability to induce mechanical quiescence in cancer associated fibroblasts. Here, we demonstrate that retinoic acid receptor ß (RAR-ß) transcriptionally represses myosin light chain 2 (MLC-2) expression in pancreatic cancer cells. As a key regulatory component of the contractile actomyosin machinery, MLC-2 downregulation results in decreased cytoskeletal stiffness and traction force generation, impaired response to mechanical stimuli via mechanosensing and reduced ability to invade through the basement membrane. This work highlights the potential of retinoids to target the mechanical drivers of pancreatic cancer.

Effect of Adding Bovine Skin Gelatin Hydrolysates on Antioxidant Properties, Texture, and Color in Chicken Meat Processing.

(1) Background: Phosphates are used in the food industry to improve water retention and product quality. However, when consumed in excess, they can be harmful to health. Instead, bovine skin gelatin hydrolysates present health benefits such as being a rejuvenating agent, stimulating collagen production, and improving food quality, in addition to being a source of protein. The effect of the addition of bovine skin gelatin hydrolysates on the texture and color of thermally processed chicken meat (boiled type) and antioxidant activity was evaluated. (2) Methods: Hydrolysates were prepared with subtilisin with the degree of hydrolysis being 6.57 and 13.14%, which were obtained from our previous study. (3) Results: The hydrolysates improved the firmness of the meat matrix compared to the control. Additionally, the hydrolysate with a 13.14% degree of hydrolysis reached the same firmness (p > 0.05) as the commercial ingredient sodium tripolyphosphate at its maximum limit allowed in the food industry when it was applied at 5% (w/w meat) in the meat matrix, improving firmness over the control by 63%. Furthermore, both hydrolysates reached a similar color difference to sodium tripolyphosphate at its maximum allowed limit when applied at a concentration of 2% (w/w meat). Additionally, it was found that these hydrolysates obtained the same antioxidant activity as sodium tripolyphosphate, capturing free radicals at 10%. (4) Conclusion: The findings of this study suggest that bovine skin gelatin hydrolysates can be applied as an ingredient with functional properties, being an alternative to phosphates to improve the quality of meat products.

Hybrid porous media gasification of urban solid waste pre-treated by hydrothermal carbonization.

Global population growth and rising consumption levels have significantly increased resource use and energy demand, leading to higher greenhouse gas concentrations and increased waste output. As a result, alternative waste treatment methods for sustainable municipal solid waste (MSW) management are crucial. This research evaluates the efficiency of integrating hydrothermal carbonization (HTC) and gasification for an optimized MSW biomass blend. HTC was conducted for one hour at 220°C in a 5 L reactor, followed by gasification in a hybrid porous medium gasifier. The study investigated the effects of different filtration speeds on combustion temperature and hydrogen concentrations. The results showed that a filtration speed of 35 cm/s resulted in a maximum combustion temperature of 1035.7°C. The temperature remained consistent across filter speeds, while higher velocities yielded higher hydrogen concentrations. Additionally, increasing the filtration velocity raised temperatures in the hybrid bed while increasing the volumetric fraction of biomass decreased maximum temperatures. This research contributes to the understanding of merging HTC and gasification for MSW biomass blend treatment, aiming to reduce environmental impacts and costs while promoting renewable resources for long-term energy production.

Carbon dioxide emission control of a vermicompost process using fly ash.

Composting and vermicomposting generate a valuable product rich in plant nutrients and at the same time, reduce environmental pollution. However, along with these processes and in relation to the metabolism of the microorganism and the worms present in the vermicomposting, CO2 is emitted to the atmosphere, contributing to the greenhouse effect. Taking these issues into account, different masses of fly ash were used to study the control of the CO2 of the gas coming from a vermicomposting process and to evaluate the possibility of using the adsorbent as fertilizer in the culture of lettuce Lactuca sativa. Along the vermicomposting process, an increase in the concentration of CO2 emissions was observed, with a maximum level of emission at the day 20 of the process and an average of 770 mg/L in air. After the adsorption process, the CO2 concentration was lower due to the effect of the fly ash that was able to trap the emitted gas. The percentage of CO2 adsorption shows maximum values of 55.5, 58.1 and 63.8% with 0.5, 1 and 1.5 kg of fly ash, respectively. The CO2 uptake capacities of the different loads of fly ash used were 3.39, 7.03 and 6.84 mmol CO2/g sorbent with 0.5, 1 and 1.5 kg of fly ash, respectively. After five weeks of sowing L. sativa, it was observed that when no fly ash was used in the soil, the length of the stem was 10.2 cm. Then, the length of the stem was 22 cm, and 16 cm when 10% of fly ash was applied and not applied in the adsorption process, getting a significant correlation between the load of fly ash and the length of the stem. The r when fly ash was used in the adsorption process was 0.9817 and 0.9811 when no ash fly was used in the process.

An environmental assessment for municipal organic waste and sludge treated by hydrothermal carbonization.

Climate change is the world's greatest challenge today, the reason why it is urgent to optimize industrial processes and find new renewable energy sources. Hydrothermal carbonization (HTC) is one of the Waste-to-Energy technologies with greater projections due to its operative advantages. However, for its large-scale implementation, there are challenges related to the variability of the composition of the waste biomass and the seasonal and geographical availability. This research applied the Life Cycle Analysis methodology to evaluate the environmental impacts caused by three biomasses blends as raw material in the HTC process at laboratory scale. The blends analyzed considered different organic fractions of municipal solid waste (food and pruning) and sewage sludge. The results showed that blend 1 had a lower environmental impact for the case of production in the experimental laboratory level, compared with blends 2 and 3. This is mainly due to its greater calorific value and mass yield, which allows obtaining more hydrochar compared with the other blends, increasing the energy efficiency of the process. Also, between 87.94% and 98.00% of the energy reduction is required to obtain neutral impacts regarding the energy requirements in the experimental laboratory level scenario and the Chilean energy matrix. The processing of blends in HTC has excellent potential in a context where municipal solid wastes have been disposed in sanitary landfills or dumps, as in most emerging countries. Since this study incorporated data from the literature, future studies should perform an elemental analysis to provide experimental and differentiated data.

Substrate Stiffness-Driven Membrane Tension Modulates Vesicular Trafficking via Caveolin-1.

Liver fibrosis, a condition characterized by extensive deposition and cross-linking of extracellular matrix (ECM) proteins, is idiosyncratic in cases of chronic liver injury. The dysregulation of ECM remodeling by hepatic stellate cells (HSCs), the main mediators of fibrosis, results in an elevated ECM stiffness that drives the development of chronic liver disease such as cirrhosis and hepatocellular carcinoma. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is a key element in the regulation of ECM remodeling, which modulates the degradation and turnover of ECM components. We have previously reported that a rigid, fibrotic-like substrate can impact TIMP-1 expression at the protein level in HSCs without altering its mRNA expression. While HSCs are known to be highly susceptible to mechanical stimuli, the mechanisms through which mechanical cues regulate TIMP-1 at the post-translational level remain unclear. Here, we show a mechanism of regulation of plasma membrane tension by matrix stiffness. We found that this effect is orchestrated by the ß1 integrin/RhoA axis and results in elevated exocytosis and secretion of TIMP-1 in a caveolin-1- and dynamin-2-dependent manner. We then show that TIMP-1 and caveolin-1 expression increases in cirrhosis and hepatocellular carcinoma. These conditions are associated with fibrosis, and this effect can be recapitulated in 3D fibrosis models consisting of hepatic stellate cells encapsulated in a self-assembling polypeptide hydrogel. This work positions stiffness-dependent membrane tension as a key regulator of enzyme secretion and function and a potential target for therapeutic strategies that aim at modulating ECM remodeling in chronic liver disease.

Processing methodology of global anthropogenic emissions for air quality modeling.

The Global Emissions Initiative (GEIA) stores and offers global datasets of emission inventories developed in the last 30 years. One of the most recently updated global datasets covering anthropogenic source emissions is the Copernicus Atmosphere Monitoring Service (CAMS). This study applied NetCDF Command Operator (NCO) software to preprocess the anthropogenic sources included in the CAMS datasets and converted those files as an input in the Sparse Matrix Operator Kerner Emissions (SMOKE) model for future air quality modeling. As a result, six steps were applied to obtain the required file format. The case of the central coast in Chile was analyzed to compare the global database and official reports for the on-road transport sector. As a result, some differences were shown in the most populated locations of the domain of analysis. The rest of the zones registered similar values. The methodology exposed in this report could be applied in any other region of the planet for air quality modeling studies. The development of global datasets such as CAMS is useful for hemispheric analysis and could bring an estimation on the mesoscale. It represents an opportunity for those locations without official reports of non-updated data.•This study applied NCO commands available for the preprocessing of the CAMS dataset files.•The emissions and temporal profile registered in CAMS datasets must be compared to official reports of transport sectors.•The development of global datasets such as CAMS is useful for hemispheric analysis and could bring an estimation on the mesoscale.

Self-Assembling Polypeptide Hydrogels as a Platform to Recapitulate the Tumor Microenvironment.

The tumor microenvironment plays a critical role in modulating cancer cell migration, metabolism, and malignancy, thus, highlighting the need to develop in vitro culture systems that can recapitulate its abnormal properties. While a variety of stiffness-tunable biomaterials, reviewed here, have been developed to mimic the rigidity of the tumor extracellular matrix, culture systems that can recapitulate the broader extracellular context of the tumor microenvironment (including pH and temperature) remain comparably unexplored, partially due to the difficulty in independently tuning these parameters. Here, we investigate a self-assembled polypeptide network hydrogel as a cell culture platform and demonstrate that the culture parameters, including the substrate stiffness, extracellular pH and temperature, can be independently controlled. We then use this biomaterial as a cell culture substrate to assess the effect of stiffness, pH and temperature on Suit2 cells, a pancreatic cancer cell line, and demonstrate that these microenvironmental factors can regulate two critical transcription factors in cancer: yes-associated protein 1 (YAP) and hypoxia inducible factor (HIF-1A).

The black carbon dispersion in the Southern Hemisphere and its transport and fate to Antarctica, an Anthropocene evidence for climate change policies.

Black carbon (BC) has been measured in Antarctica's air, and its global warming effect can potentially speed up the ice melting in the most solid water reservoir of the planet. However, the primary responsible sources are not well evidenced in this region. The dispersion of black carbon emissions from the Southern Hemisphere was conducting using atmospheric chemical transport model and we compared the results with satellite registries from March 1st to April 30th in 2014. The emission inventory considered the anthropogenic and biomass burning emissions from global datasets. The largest and most populated cities in Southern Hemisphere showed the higher emission of BC. As a result, the average daily concentrations of atmospheric BC were around 4 ng/m3 in most regions of Antarctica according to its pristine characteristics. We analyzed fifteen relevant sites in coastal zones of Antartica and some peaks registered by the satellite records were not replicated by model outputs and it was mainly associated with the lack of emissions. Finally, we made simulations in the same period without biomass burning emissions and we observed decreased concentrations of BC in the range of 20-50%. As a result, we show that the black carbon transportation from the continental land to the polar region took place in 17-24 days during the Austral summer and the biomass burning emissions were the primary source. Black Carbon deposition in Antarctica is not permanent, but the uncontrolled emissions from Southern Hemisphere can increase its transportation to the white continent and make its accumulation during the period when the weak polar vortex occurs.

Ultrasound and heterogeneous photocatalysis for the treatment of vinasse from pisco production.

Production of the distilled alcohol pisco results in vinasse, dark brown wastewater with high polyphenols contents and chemical oxygen demand (COD). No prior research exists on the efficiency of advanced oxidations processes (AOPs) in treating pisco vinasse. Therefore, the purpose of this study was to assess the efficiency of ultraviolet (UV), ultrasound (US), US + UV, heterogeneous photocatalysis (HP), and HP + US treatments. Polyphenols, COD, and color removal, as well as oxidation-reduction potential, were monitored over a 60-minute treatment period. Energy consumption levels and synergies were also calculated. The HP + US treatment achieved the best removal ratios for polyphenols (68%), COD (70%), and color (48%). While the HP treatment was the second most efficient in terms of polyphenols (62%), COD (58%), and color (40%) removal, this AOP comparatively required the least amount of energy. Considering the energy efficiency and relatively high pollutant-removal rates of the HP treatment, this AOP is recommended as a practical alternative for treating pisco vinasse.

G Protein-Coupled Estrogen Receptor Regulates Actin Cytoskeleton Dynamics to Impair Cell Polarization.

Mechanical forces regulate cell functions through multiple pathways. G protein-coupled estrogen receptor (GPER) is a seven-transmembrane receptor that is ubiquitously expressed across tissues and mediates the acute cellular response to estrogens. Here, we demonstrate an unidentified role of GPER as a cellular mechanoregulator. G protein-coupled estrogen receptor signaling controls the assembly of stress fibers, the dynamics of the associated focal adhesions, and cell polarization via RhoA GTPase (RhoA). G protein-coupled estrogen receptor activation inhibits F-actin polymerization and subsequently triggers a negative feedback that transcriptionally suppresses the expression of monomeric G-actin. Given the broad expression of GPER and the range of cytoskeletal changes modulated by this receptor, our findings position GPER as a key player in mechanotransduction.