Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with PlexinC1.

Repulsive signaling by Semaphorins and Plexins is crucial for the development and homeostasis of the nervous, immune, and cardiovascular systems. Sema7A acts as both an immune and a neural Semaphorin through PlexinC1, and A39R is a Sema7A mimic secreted by smallpox virus. We report the structures of Sema7A and A39R complexed with the Semaphorin-binding module of PlexinC1. Both structures show two PlexinC1 molecules symmetrically bridged by Semaphorin dimers, in which the Semaphorin and PlexinC1 beta propellers interact in an edge-on, orthogonal orientation. Both binding interfaces are dominated by the insertion of the Semaphorin's 4c-4d loop into a deep groove in blade 3 of the PlexinC1 propeller. A39R appears to achieve Sema7A mimicry by preserving key Plexin-binding determinants seen in the mammalian Sema7A complex that have evolved to achieve higher affinity binding to the host-derived PlexinC1. The complex structures support a conserved Semaphorin-Plexin recognition mode and suggest that Plexins are activated by dimerization.

A cryptic Tudor domain links BRWD2/PHIP to COMPASS-mediated histone H3K4 methylation.

Histone H3 Lys4 (H3K4) methylation is a chromatin feature enriched at gene cis-regulatory sequences such as promoters and enhancers. Here we identify an evolutionarily conserved factor, BRWD2/PHIP, which colocalizes with histone H3K4 methylation genome-wide in human cells, mouse embryonic stem cells, and Drosophila Biochemical analysis of BRWD2 demonstrated an association with the Cullin-4-RING ubiquitin E3 ligase-4 (CRL4) complex, nucleosomes, and chromatin remodelers. BRWD2/PHIP binds directly to H3K4 methylation through a previously unidentified chromatin-binding module related to Royal Family Tudor domains, which we named the CryptoTudor domain. Using CRISPR-Cas9 genetic knockouts, we demonstrate that COMPASS H3K4 methyltransferase family members differentially regulate BRWD2/PHIP chromatin occupancy. Finally, we demonstrate that depletion of the single Drosophila homolog dBRWD3 results in altered gene expression and aberrant patterns of histone H3 Lys27 acetylation at enhancers and promoters, suggesting a cross-talk between these chromatin modifications and transcription through the BRWD protein family.

Health economics study of paliperidone palmitate in the treatment of schizophrenia: a 12-month cohort study.

BACKGROUND: To analyze the economic benefits of paliperidone palmitate in the treatment of schizophrenia. METHODS: We collected 546 patients who met the diagnostic criteria for schizophrenia according to the 《International Statistical Classification of Diseases and Related Health Problems,10th》(ICD-10). We gathered general population data such as gender, age, marital status, and education level, then initiated treatment with paliperidone palmitate. Then Follow-up evaluations were conducted at 1, 3, 6, 9, and 12 months after the start of treatment to assess clinical efficacy, adverse reactions, and injection doses. We also collected information on the economic burden before and after 12 months of treatment, as well as the number of outpatient visits and hospitalizations in the past year to analyze economic benefits. RESULTS: The baseline patients totaled 546, with 239 still receiving treatment with paliperidone palmitate 12 months later. After 12 months of treatment, the number of outpatient visits per year increased compared to before (4 (2,10) vs. 12 (4,12), Z=-5.949, P < 0.001), while the number of hospitalizations decreased (1 (1,3) vs. 1 (1,2), Z = 5.625, P < 0.001). The inpatient costs in the direct medical expenses of patients after 12 months of treatment decreased compared to before (5000(2000,12000) vs. 3000 (1000,8050), P < 0.05), while there was no significant change in outpatient expenses and direct non-medical expenses (transportation, accommodation, meal, and family accompanying expenses, etc.) (P > 0.05); the indirect costs of patients after 12 months of treatment (lost productivity costs for patients and families, economic costs due to destructive behavior, costs of seeking non-medical assistance) decreased compared to before (300(150,600) vs. 150(100,200), P < 0.05). CONCLUSION: Palmatine palmitate reduces the number of hospitalizations for patients, as well as their direct and indirect economic burdens, and has good economic benefits.

Developing integrated person-centered care quality indicators for home health agencies in Shanghai, China: A modified Delphi-analytic hierarchy process study.

OBJECTIVES: To develop person-centered integrated care quality indicators for home health agencies in Shanghai, China. DESIGN: The study combined the Delphi method and the analytic hierarchy process (AHP). MATERIAL AND METHODS: The Delphi consultation questionnaire was distributed to experts in home healthcare in Shanghai, China. A panel of experts with experience in home healthcare in Shanghai, China, was selected. Purposive sampling was used to choose experts. In this study, ten experts were selected from within sub-fields of home healthcare, including nursing, health policy, quality improvement, person-centered care (PCC), and integrated care. RESULTS: The authority coefficient (Cr) in this study was 0.835. The coordination degree of experts' opinions, which is expressed by Kendall coordination coefficient W (a higher value, better coordination of the item), ranged from 0.352 to 0.386 (p < 0.001). The consistency ratio (CR) values for each level were less than 0.1. The quality indicator system included three first-level indicators, 15 second-level indicators, and 56 third-level indicators. CONCLUSIONS: A person-centered integrated care quality indicator system was developed for home health agencies. The findings from this study enable nurses, managers, and policymakers in home and community-based settings to evaluate person-centered integrated care quality using a robust framework. In addition, these indicators can also be used as a standardized tool to guide the development of long-term care services and supports (LTSS) for home-bound elderly.

Gold-Catalyzed [4 + 1] Heterocyclization of Hydroxamic Acid and Nonactivated Alkyne: A Protocol to Construct 5-Methyl-1,4,2-dioxazole.

A novel gold-catalyzed [4 + 1] heterocyclization of nonactivated alkyne and hydroxamic acid is developed for the regiospecific synthesis of 5-methyl-1,4,2-dioxazole, which is an important structural motif in various bioactive molecules. The current methodology is characterized by high efficiency, simple operation, mild reaction conditions, and good functional group compatibility. Moreover, gram-scale synthesis and synthetic application toward bioactive molecular skeletons have been realized.

Non-invasive ventilation versus invasive weaning in critically ill adults: a systematic review and meta-analysis.

BACKGROUND: Extubation to non-invasive ventilation (NIV) has been investigated as a strategy to wean critically ill adults from invasive ventilation and reduce ventilator-related complications. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, proceedings of four conferences and bibliographies (to June 2020) for randomised and quasi-randomised trials that compared extubation with immediate application of NIV to continued invasive weaning in intubated adults and reported mortality (primary outcome) or other outcomes. Two reviewers independently screened citations, assessed trial quality and abstracted data. RESULTS: We identified 28 trials, of moderate-to-good quality, involving 2066 patients, 44.6% with chronic obstructive pulmonary disease (COPD). Non-invasive weaning significantly reduced mortality (risk ratio (RR) 0.57, 95% CI 0.44 to 0.74; high quality), weaning failures (RR 0.59, 95% CI 0.43 to 0.81; high quality), pneumonia (RR 0.30, 95% CI 0.22 to 0.41; high quality), intensive care unit (ICU) (mean difference (MD) -4.62 days, 95% CI -5.91 to -3.34) and hospital stay (MD -6.29 days, 95% CI -8.90 to -3.68). Non-invasive weaning also significantly reduced the total duration of ventilation, duration of invasive ventilation and duration of ventilation related to weaning (MD -0.57, 95% CI -1.08 to -0.07) and tracheostomy rate. Mortality, pneumonia, reintubation and ICU stay were significantly lower in trials enrolling COPD (vs mixed) populations. CONCLUSION: Non-invasive weaning significantly reduced mortality, pneumonia and the duration of ventilation related to weaning, particularly in patients with COPD. Beneficial effects are less clear (or more careful patient selection is required) in non-COPD patients. PROSPERO REGISTRATION NUMBER: CRD42020201402.

Identifying patterns of clinical conditions among high-cost older adult health care users using claims data: a latent class approach.

OBJECTIVES: To identify patterns of clinical conditions among high-cost older adults health care users and explore the associations between characteristics of high-cost older adults and patterns of clinical conditions. METHODS: We analyzed data from the Shanghai Basic Social Medical Insurance Database, China. A total of 2927 older adults aged 60 years and over were included as the analysis sample. We used latent class analysis to identify patterns of clinical conditions among high-cost older adults health care users. Multinomial logistic regression models were also used to determine the associations between demographic characteristics, insurance types, and patterns of clinical conditions. RESULTS: Five clinically distinctive subgroups of high-cost older adults emerged. Classes included "cerebrovascular diseases" (10.6% of high-cost older adults), "malignant tumor" (9.1%), "arthrosis" (8.8%), "ischemic heart disease" (7.4%), and "other sporadic diseases" (64.1%). Age, sex, and type of medical insurance were predictors of high-cost older adult subgroups. CONCLUSIONS: Profiling patterns of clinical conditions among high-cost older adults is potentially useful as a first step to inform the development of tailored management and intervention strategies.

Immunophenotypic characterization and therapeutics effects of human bone marrow- and umbilical cord-derived mesenchymal stromal cells in an experimental model of sepsis.

Sepsis is a complicated multi-system disorder characterized by a dysregulated host response to infection. Despite substantial progress in the understanding of mechanisms of sepsis, translation of these advances into clinically effective therapies remains challenging. Mesenchymal Stromal Cells (MSCs) possess immunomodulatory properties that have shown therapeutic promise in preclinical models of sepsis. The therapeutic effects of MSCs may vary depending on the source and type of these cells. In this comparative study, the gene expression pattern and surface markers of bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs) as well as their therapeutic effects in a clinically relevant mouse model of polymicrobial sepsis, cecal ligation and puncture (CLP), were investigated. The results showed remarkable differences in gene expression profile, surface markers and therapeutic potency in terms of enhancing survival and pro/anti-inflammatory responses between the two MSC types. BM-MSCs improved survival concomitant with an enhanced systemic bacterial clearance and improved inflammatory profile post CLP surgery. Despite some improvement in the inflammatory profile of the septic animals, treatment with UC-MSCs did not enhance survival or bacterial clearance. Overall, the beneficial therapeutic effects of BM-MSCs over UC-MSCs may likely be attributed to their pro-inflammatory function, and to some extent anti-inflammatory features, reflected in their gene expression pattern enhancing macrophage polarization to M1/M2 phenotypes resulting in a balanced pro- and anti-inflammatory response against polymicrobial sepsis.

A cleanup method of serum extracts with molecular sieves as SPE sorbents for the analysis of polybrominated diphenyl ethers.

Based on the size- and shape-selective sorption, 13X molecular sieves were developed as solid-phase extraction adsorbents to cleanup serum extract for the determination of polybrominated diphenyl ethers. The important parameters affecting the cleanup efficiency were investigated including the amount of sorbents, the type, and volume of solvents. Under the optimized conditions, the capacity for removing impurities was evaluated via gel permeation chromatography and gas chromatography with mass spectrometry. The results demonstrated that up to 99% of lipids in corn oil (13 mg) can be removed after cleanup, and endogenous compounds in serum can also be effectively eliminated. The cleanup efficiency is not only superior to hydrophile-lipophile balance column, but also close to acid silica gel and multifunction impurity sorbents. Generally, the developed cleanup method exhibited higher recovery for polybrominated diphenyl ethers with more than four bromines, especially for nona- and deca-brominated diphenyl ethers (99.1-117.8%). The cleanup method can be coupled with gas chromatography and tandem mass spectrometry for polybrominated diphenyl ethers analysis in human serum. The method detection limits were 0.01-0.27 ng/mL and average recovery was 50.9-113.3%, except 2,3',4',6-tetrabrominated, 2,3',4,4',6-pentabrominated, and 2,3,3',4,4',5',6-heptabrominated diphenyl ethers. 2,2',4,5'-Tetrabrominated diphenyl ethers had the highest detection frequency (95%) in human serum, whereas decabrominated diphenyl ethers had the maximum mean concentration (0.50 ng/mL).

Microfluidic Generation of Monodisperse Nanobubbles by Selective Gas Dissolution.

Nanotechnology currently enables the fabrication of uniform solid nanoparticles and liquid nano-emulsions, but not uniform gaseous nanobubbles (NBs). In this article, for the first time, a method based on microfluidics that directly produces monodisperse NBs is reported. Specifically, a two-component gas mixture of water-soluble nitrogen and water-insoluble octafluoropropane as the gas phase are used in a microfluidic bubble generator. First, monodisperse microbubbles (MBs) with a classical microfluidic flow-focusing junction is generated, then the MBs shrink down to ≈100 nm diameter, due to the dissolution of the water-soluble components in the gas mixture. The degree of shrinkage is controlled by tuning the ratio of water-soluble to water-insoluble gas components. This technique maintains the monodispersity of the NBs, and enables precise control of the final NB size. It is found that the monodisperse NBs show better homogeneity than polydisperse NBs in in vitro ultrasound imaging experiments. Proof-of-concept in vivo kidney imaging is performed in live mice, demonstrating enhanced contrast using the monodisperse NBs. The NB monodispersity and imaging results make microfluidically generated NBs promising candidates as ultrasound contrast and molecular imaging agents.

The structural basis of R-spondin recognition by LGR5 and RNF43.

R-spondins (RSPOs) enhance Wnt signaling, affect stem cell behavior, bind to leucine-rich repeat-containing G-protein-coupled receptors 4-6, (LGR4-6) and the transmembrane E3 ubiquitin ligases RING finger 43/zinc and RING finger 3 (RNF43/ZNRF3). The structure of RSPO1 bound to both LGR5 and RNF43 ectodomains confirms their physical linkage. RSPO1 is sandwiched by LGR5 and RNF43, with its rod module of the cysteine-rich domain (CRD) contacting LGR5 and a hairpin inserted into RNF43. LGR5 does not contact RNF43 but increases the affinity of RSPO1 to RNF43, supporting LGR5 as an engagement receptor and RNF43 as an effector receptor. Disease mutations map to the RSPO1-RNF43 interface, which promises therapeutic targeting.

Oxidize Amines to Nitrile Oxides: One Type of Amine Oxidation and Its Application to Directly Construct Isoxazoles and Isoxazolines.

A facile oxidative heterocyclization of commercially available amines and tert-butyl nitrite with alkynes or alkenes leading to isoxazoles or isoxazolines is described. The unprecedented strategy of the oxidation of an amine directly to a nitrile oxide was used in this cyclization process. This reaction is highly efficient, regiospecific, operationally simple, mild, and tolerant of a variety of functional groups. Control experiments support a nitrile oxide intermediate mechanism for this novel class of oxidative cyclization reactions. Moreover, synthetic applications toward bioactive molecular skeletons and the late-stage modification of drugs were realized.

Hematite photoanode modified with inexpensive hole-storage layer for highly efficient solar water oxidation.

Hematite is recognized as an excellent photocatalyst for photoelectrochemical photoanodes for water oxidation because of its favorable band gap, excellent anti-photocorrosion and structural stability in alkaline solution. However, slow charge transport and fast carrier recombination in the bulk and at the hematite photoanode/electrolyte interface, have limited its applications for water splitting. Herein, we report a highly efficient hematite/ferrhydrite (Fh) core-shell photoanode system, consisting of hematite (α-Fe2O3) semiconductor nanorods which dramatically enhance light harvesting, and ferrhydrite as the hole-storage shell. Our integrated hematite/ferrhydrite core-shell photoanode shows 2.7 times increased photo-current density under simulated sun light irradiation.

RcPAL, a key gene in lignin biosynthesis in Ricinus communis L.

BACKGROUND: Castor (Ricinus communis L.) is an important seed oil crop. Castor oil is a highly demanded oil for several industrial uses. Current castor bean varieties suffer from low productivity and high risk of insect pests and diseases. High productive and pest/disease resistance varieties are needed. Lignin has been associated to the resistance for pest, disease and lodging. Lignin is produced from several metabolites of the phenylpropanoid pathway. PAL is the key enzyme of the phenylpropanoid pathway. The gene PAL may assist in the improvement of resistance of castor bean. RESULTS: The RcPAL CDs was amplified and its function was examined by transgenic overexpression and antisense expression, lignin histochemical staining, real-time PCR, lignin content measurement and morphological investigation. Its full length was 2145 bp, encoding 714 amino acids. The overexpression of RcPAL (7.2 times) increased significantly the PAL activity, dyeing depth of xylem cells and lignin content (14.44%), resulting in a significantly lower plant height, deeper and thicker blade, more green leaves, shorter internode, thicker stem diameter, and opposite in antisense expression plants (lignin content lowered by 27.1%), demonstrated that the gene RcPAL was a key gene in castor lignin biosynthesis. CONCLUSIONS: The gene RcPAL is a key gene in castor lignin biosynthesis and can be induced to express under mechanical damage stress. When up-regulated, it increased the lignin content significantly and dwarfed the plant height, and opposite when down-regulated. The gene RcPAL may assist in the improvement of resistance and plant type of castor bean.

Q-switched 1064-nm dymium-doped yttrium aluminum garnet laser irradiation induces skin collagen synthesis by stimulating MAPKs pathway.

The 1064-nm Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is widely used in clinical practice. However, the effects of 1064-nm Q-switched Nd:YAG laser on skin collagen generation have not been fully elucidated. The objectives of the present study were to investigate whether the 1064-nm Q-switched Nd:YAG laser can be used for non-ablative rejuvenation and to explore the possible mechanism underlying the effects. Six-week-old SKH-1 hairless mice were irradiated by the 1064-nm Nd:YAG laser at fluences of 0, 0.5, 1, 1.5, and 2 J/cm2, respectively. The contents of hydroxyproline and hydration were detected after laser irradiation. Moreover, hematoxylin-eosin (HE) staining was preformed to evaluate the dermal thickness. Immunofluorescence was used to detect the expressions of MMP-2 and TIMP-1 in the skin after laser irradiation. Furthermore, qRT-PCR was performed to determine the expressions of TGF-ß1 and Smad3. In addition, the expressions of ERK1/2, p-ERK1/2, p38, p-p38, JNK, ERK5, and collagen were evaluated by Western blotting. The results indicated that the levels of hydroxyproline, hydration, and collagen were markedly increased; both the thickness of dermal was enhanced after low dose of laser treatment. Moreover, the expression of TIMP-1 was significantly increased, whereas the expression of MMP-2 was remarkably decreased after laser irradiation. Meanwhile, TGF-ß1, Smad3, p-ERK1/2, p-P38, and JNK productions were significantly enhanced in irradiated group compared with the ones non-irradiated. Nevertheless, no significant changes were observed in the expression of ERK5 after irradiation. In summary, our study demonstrated that Q-switched 1064-nm Nd:YAG laser can induce collagen generation, at least in part, through activating TGF-ß1/Smad3/MAPK signaling pathway.

Costunolide promotes imatinib-induced apoptosis in chronic myeloid leukemia cells via the Bcr/Abl-Stat5 pathway.

Costunolide, a sesquiterpene lactone, is a small molecular monomer extracted from Inula helenium (Compositae). In the present study, we assessed the antileukemia effects of costunolide on the human chronic myeloid leukemia cell line K562 and its combined activity with imatinib. A Cell Counting Kit-8 assay demonstrated that costunolide significantly inhibited K562 cell proliferation and enhanced imatinib-induced anti-proliferative activity. We found that costunolide significantly induced mitochondrial apoptosis in K562 cells by modulating the protein levels of Bcl-2 family members and by inducing caspase activation. Costunolide promoted imatinib-induced apoptosis via the Bcr/Abl-signal transducer and activator of transcription 5 pathway. Costunolide inhibited proliferation by inducing cell cycle arrest in the G2 /M phase by decreasing cyclin B1 and cyclin-dependent kinase 2 expression and increasing p21 expression. Together, these results demonstrate that costunolide may be a potent therapeutic agent against chronic myeloid leukemia.

Tß4-overexpression based on the piggyBac transposon system in cashmere goats alters hair fiber characteristics.

Increasing cashmere yield is one of the vital aims of cashmere goats breeding. Compared to traditional breeding methods, transgenic technology is more efficient and the piggyBac (PB) transposon system has been widely applied to generate transgenic animals. For the present study, donor fibroblasts were stably transfected via a PB donor vector containing the coding sequence of cashmere goat thymosin beta-4 (Tß4) and driven by a hair follicle-specific promoter, the keratin-associated protein 6.1 (KAP6.1) promoter. To obtain genetically modified cells as nuclear donors, we co-transfected donor vectors into fetal fibroblasts of cashmere goats. Five transgenic cashmere goats were generated following somatic cell nuclear transfer (SCNT). Via determination of the copy numbers and integration sites, the Tß4 gene was successfully inserted into the goat genome. Histological examination of skin tissue revealed that Tß4-overexpressing, transgenic goats had a higher secondary to primary hair follicle (S/P) ratio compared to wild type goats. This indicates that Tß4-overexpressing goats possess increased numbers of secondary hair follicles (SHF). Our results indicate that Tß4-overexpression in cashmere goats could be a feasible strategy to increase cashmere yield.

Biopolymer microencapsulations of Bacillus thuringiensis crystal preparations for increased stability and resistance to environmental stress.

Parasporal crystals synthesized by Bacillus thuringiensis (Bt) have been widely used as microbial pesticides because of their toxicity to the larval stages of specific insects. However, parasporal crystals can be damaged by environmental stresses, such as high temperature, ultraviolet radiation, and desiccation. To reduce environmental susceptibility of parasporal crystals and extend the duration of their activity, we developed a new type of protection by making microcapsules of crystals (MCs). The microcapsules were self-assembled by alternate deposition (layer by layer) of low-cost chitosan and sodium alginate (or sodium carboxymethyl cellulose) on the crystal surface. Crystal toxins (Cry1Ac) were released from microcapsules at pH values above 9.0. Bioassay results demonstrated that microencapsulated preparations had larvicidal toxicity equivalent to the non-encapsulated form. Microencapsuled crystals were protected from environmental stresses such as high temperature and desiccation. The results indicate that microcapsule protection can enhance the efficacy of Bt in pest control, especially to Lepidoptera larvae that have a alkaline midgut.

Impact of microorganisms, humidity, and temperature on the enantioselective degradation of imazethapyr in two soils.

Imazethapyr (IM) is a chiral herbicide composed of an (-)-R-enantiomer and an (+)-S-enantiomer with differential herbicidal activity. In this study, the effects of microbial organisms, humidity, and temperature on the selective degradation of the (-)-R- and (+)-S-enantiomers of IM were determined in silty loam (SL) and clay loam (CL) soil with different pH values. The (-)-R-enantiomer of IM was preferentially degraded in two soils under different microorganism, humidity, and temperature conditions. The average half-lives of R-IM ranged from 43 to 66.1 days and were significantly shorter (P < 0.05) than those of S-IM, which ranged from 51.4 to 79.8 days. The enantiomer fraction (EF = (+)-S-enantiomer/((-)-R-enantiomer + (+)-S-enantiomer)) values were used to describe the enantioselectivity of degradation of IM were >0.5 (P < 0.05) in two unsterilized soils under different humidity and temperature conditions. The highest EF values were observed at unsterilized CL soil samples under 50% maximum water-holding capacity (MWHC) and 25 °C environmental conditions. The EF values of the IM enantiomers were significantly higher (P < 0.05) in CL soils (higher pH = 5.81) and were 0.581 (unsterilized) and 0.575 (50% MWHC; 25 °C) compared with those recorded in SL soil (lower pH = 4.85). In addition, this study revealed that microbial organisms preferentially utilized the more herbicidal active IM enantiomer.

YAP/TAZ Are Mechanoregulators of TGF-ß-Smad Signaling and Renal Fibrogenesis.

Like many organs, the kidney stiffens after injury, a process that is increasingly recognized as an important driver of fibrogenesis. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are related mechanosensory proteins that bind to Smad transcription factors, the canonical mediators of profibrotic TGF-ß responses. Here, we investigated the role of YAP/TAZ in the matrix stiffness dependence of fibroblast responses to TGF-ß In contrast to growth on a stiff surface, fibroblast growth on a soft matrix led to YAP/TAZ sequestration in the cytosol and impaired TGF-ß-induced Smad2/3 nuclear accumulation and transcriptional activity. YAP knockdown or treatment with verteporfin, a drug that was recently identified as a potent YAP inhibitor, elicited similar changes. Furthermore, verteporfin reduced YAP/TAZ levels and decreased the total cellular levels of Smad2/3 after TGF-ß stimulation. Verteporfin treatment of mice subjected to unilateral ureteral obstruction similarly reduced YAP/TAZ levels and nuclear Smad accumulation in the kidney, and attenuated renal fibrosis. Our data suggest that organ stiffening cooperates with TGF-ß to induce fibrosis in a YAP/TAZ- and Smad2/3-dependent manner. Interference with this YAP/TAZ and TGF-ß/Smad crosstalk likely underlies the antifibrotic activity of verteporfin. Finally, through repurposing of a clinically used drug, we illustrate the therapeutic potential of a novel mechanointerference strategy that blocks TGF-ß signaling and renal fibrogenesis.