Country-specific net-zero strategies of the pulp and paper industry.

The pulp and paper industry is an important contributor to global greenhouse gas emissions1,2. Country-specific strategies are essential for the industry to achieve net-zero emissions by 2050, given its vast heterogeneities across countries3,4. Here we develop a comprehensive bottom-up assessment of net greenhouse gas emissions of the domestic paper-related sectors for 30 major countries from 1961 to 2019-about 3.2% of global anthropogenic greenhouse gas emissions from the same period5-and explore mitigation strategies through 2,160 scenarios covering key factors. Our results show substantial differences across countries in terms of historical emissions evolution trends and structure. All countries can achieve net-zero emissions for their pulp and paper industry by 2050, with a single measure for most developed countries and several measures for most developing countries. Except for energy-efficiency improvement and energy-system decarbonization, tropical developing countries with abundant forest resources should give priority to sustainable forest management, whereas other developing countries should pay more attention to enhancing methane capture rate and reducing recycling. These insights are crucial for developing net-zero strategies tailored to each country and achieving net-zero emissions by 2050 for the pulp and paper industry.

Metabolic reprogramming and lipid droplets are involved in Zika virus replication in neural cells.

Zika virus (ZIKV) infection is a global public health concern linked to adult neurological disorders and congenital diseases in newborns. Host lipid metabolism, including lipid droplet (LD) biogenesis, has been associated with viral replication and pathogenesis of different viruses. However, the mechanisms of LD formation and their roles in ZIKV infection in neural cells are still unclear. Here, we demonstrate that ZIKV regulates the expression of pathways associated with lipid metabolism, including the upregulation and activation of lipogenesis-associated transcription factors and decreased expression of lipolysis-associated proteins, leading to significant LD accumulation in human neuroblastoma SH-SY5Y cells and in neural stem cells (NSCs). Pharmacological inhibition of DGAT-1 decreased LD accumulation and ZIKV replication in vitro in human cells and in an in vivo mouse model of infection. In accordance with the role of LDs in the regulation of inflammation and innate immunity, we show that blocking LD formation has major roles in inflammatory cytokine production in the brain. Moreover, we observed that inhibition of DGAT-1 inhibited the weight loss and mortality induced by ZIKV infection in vivo. Our results reveal that LD biogenesis triggered by ZIKV infection is a crucial step for ZIKV replication and pathogenesis in neural cells. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development.

Lipid droplets in Zika neuroinfection: Potential targets for intervention?

Lipid droplets (LD) are evolutionarily conserved lipid-enriched organelles with a diverse array of cell- and stimulus-regulated proteins. Accumulating evidence demonstrates that intracellular pathogens exploit LD as energy sources, replication sites, and part of the mechanisms of immune evasion. Nevertheless, LD can also favor the host as part of the immune and inflammatory response to pathogens. The functions of LD in the central nervous system have gained great interest due to their presence in various cell types in the brain and for their suggested involvement in neurodevelopment and neurodegenerative diseases. Only recently have the roles of LD in neuroinfections begun to be explored. Recent findings reveal that lipid remodelling and increased LD biogenesis play important roles for Zika virus (ZIKV) replication and pathogenesis in neural cells. Moreover, blocking LD formation by targeting DGAT-1 in vivo inhibited virus replication and inflammation in the brain. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development. Here, we review the progress in understanding LD functions in the central nervous system in the context of the host response to Zika infection.

The Endolysosomal System: The Acid Test for SARS-CoV-2.

This review aims to describe and discuss the different functions of the endolysosomal system, from homeostasis to its vital role during viral infections. We will initially describe endolysosomal system's main functions, presenting recent data on how its compartments are essential for host defense to explore later how SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) and other coronaviruses subvert these organelles for their benefit. It is clear that to succeed, pathogens' evolution favored the establishment of ways to avoid, escape, or manipulate lysosomal function. The unavoidable coexistence with such an unfriendly milieu imposed on viruses the establishment of a vast array of strategies to make the most out of the invaded cell's machinery to produce new viruses and maneuvers to escape the host's defense system.

Digital photography vs. clinical assessment of resin composite restorations.

PURPOSE: To compare direct clinical and indirect digital photographic assessment of resin composite restorations. Ninety-two posterior resin composite restorations were classified using World Dental Federation (FDI) criteria by two different clinical examiners (C1 and C2). In the same appointment of clinical assessment, intraoral high-quality digital photographs were taken and posteriorly two different digital examiners (D1 and D2) classified the images of each restoration. Restorations of each patient were assessed once by C1 and C2 independently. D1 and D2 assessed the digital images from different locations and in different time. Data were analyzed using the Cohen's kappa coefficient, Kruskal-Wallis non-parametric test and Dunn's multiple shared test, with 95% confidence. Agreement levels varied from very good (0.81-1.00) to fair (0.21-0.40). Statistically significant differences (p < 0.05) between assessments were found for surface lustre, staining, color match and translucency, esthetic anatomical form, fracture of material and retention and marginal adaptation. The classification of the resin composite restorations varied significantly according to clinical or high-quality digital photographic assessments. Overall, clinical assessment detected more demand for repair or replacement.

Clinical, double blind, randomized controlled trial of experimental adhesive protocols in caries-affected dentin.

OBJECTIVE: To evaluate the clinical performance of posterior resin composite restorations regarding experimental and regular adhesive protocols in caries affected-dentin (CAD). MATERIAL AND METHODS: A total of 92 class I and class II cavities with carious lesions were selected and randomly assigned to the following groups: (1) bioactive glass-ceramic powder/two-step etch and rinse system, (2) control/two-step etch and rinse system, (3) bioactive glass-ceramic powder/two-step self-etching system, and (4) control/two-step self-etching system. Two operators carried out the adhesive protocols and restored the cavities with a nano-hybrid resin composite. Participants were followed up at 1 week and 6, 12, and 18 months for clinical evaluation performed by two blinded examiners and calibrated according to FDI criteria. Data were analyzed using Kruskal-Wallis and Dunn tests with a confidence of 95%. RESULTS: The clinical performance of resin composite restoration was not affected by the experimental use of an adhesive protocol including a bioactive glass-ceramic powder for 18 months post-procedure. However, there was a significant difference between group 2 and group 4 (p < 0.05) for marginal adaptation (18 months). Group 2 was significantly different from group 3 (p < 0.05) for fracture of material/retention (18 months) and marginal adaptation (1 week); group 2 showed a better performance. CONCLUSION: Adhesive protocols can alter the clinical performance of posterior restorations in terms of marginal adaptation and the fracture of material/retention in CAD. CLINICAL SIGNIFICANCE: Adhesive protocols may influence the success of resin composite restorations in CAD; this is important because failure can lead to caries, re-incidence, and/or clinical re-work.

The effect of electronic cigarettes on dental enamel color.

OBJECTIVE: The use of electronic cigarettes (ECIGs) has recently increased as an alternative to conventional smoking tobacco products. The literature is scarce on the effects of ECIGs on dental and oral structures. Therefore, the objective of this study was to observe whether ECIG aerosol could alter the color of dental enamel. MATERIALS AND METHODS: Sixty-three bovine enamel specimens were randomly separated into groups (n = 7) and treated with aerosols with different e-liquid flavors (neutral, menthol, and tobacco) and nicotine content (0, 12, and 18 mg). The initial color assessment was performed using a spectrophotometer (Easy Shade-Vita). Dental enamel was exposed to 20 cycles of ECIG aerosol in a smoking machine, and the final color was measured. The color change was evaluated using ΔEab, ΔE00, and Whiteness Index (WID ) formulae. Differences in L* a* b* coordinates were calculated, and data were analyzed (two-way ANOVA, uncorrected Fisher's LSD post hoc test, α = 0.05). RESULTS: Luminosity (ΔL) was reduced by aerosols with almost all levels of nicotine content and neutral and menthol flavors. Flavored e-liquids caused more color change (P < .05) according to ΔEab and ΔE00. ΔE values from both formulae exceeded the thresholds for perceptible visual alterations of color. WID increased after ECIGs exposure for menthol and tobacco and decreased for neutral flavors. CONCLUSIONS: ECIG aerosol from e-liquids with different nicotine contents and flavors altered enamel color. Menthol and tobacco e-liquids may alter the enamel color decreasing the yellowness of the enamel compared to neutral e-liquid. CLINICAL SIGNIFICANCE: Electronic cigarettes can cause perceptible changes in tooth color, altering dental esthetics.

GILT--A randomised phase III study of oral vinorelbine and cisplatin with concomitant radiotherapy followed by either consolidation therapy with oral vinorelbine and cisplatin or best supportive care alone in stage III non-small cell lung cancer.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is considered standard for inoperable stage III non-small cell lung cancer (NSCLC). Consolidation chemotherapy (CC) following CRT is intended to further improve outcomes, yet studies have shown discordant results. This phase III study assessed CRT followed by best supportive care (BSC) or consolidation with oral vinorelbine and cisplatin. METHODS: Patients received two cycles of oral vinorelbine (50 mg/m(2) days 1, 8 and 15) + cisplatin (20 mg/m(2) days 1-4) q4w + radiotherapy (RT; 66 Gy). Patients with at least stable disease (SD) were randomised to either two cycles oral vinorelbine (60-80 mg/m(2) days 1 and 8) + cisplatin (80 mg/m(2) day 1) q3w + BSC or BSC alone. Primary endpoint was progression-free survival (PFS). RESULTS: A total of 279 patients were enrolled for CRT and 201 patients were randomised to CC or BSC. Both CRT and CC were well tolerated, with limited radiation-mediated grade 3/4 toxicities (CRT/CC/BSC: oesophagitis-related events 12.9 %/3.1 %/0 %; grade 3 pneumonitis 0 %/0 %/2 %) and chemotherapy-mediated grade 3/4 toxicities (CRT/CC: neutropenia 11.2 %/22.1 %; leukopenia 18.3 %/26.7 %; grade 3 nausea 5.0 %/2.3 %, grade 3 vomiting 3.2 %/3.5 %). Median PFS from randomisation was 6.4 (5.0-8.7) and 5.5 (3.8-7.4) months in the CC and BSC arms (hazard ratio, HR = 0.93 [0.69-1.26]; p = 0.63), respectively; median overall survival (OS) 20.8 (13.5-25.3) and 18.5 (13.6-24.7) months, respectively. DISCUSSION: Consolidation chemotherapy after concurrent CRT did not prolong PFS or OS. Concurrent RT with oral vinorelbine and cisplatin demonstrated a favourable safety profile and represents a suitable treatment regimen for inoperable stage III NSCLC.

Dynamics of ecosystem services and nonlinear responses to increased anthropogenic pressure.

Escalating global human activities elicit diverse ecosystem service responses, yet understanding remains limited. This study establishes a framework to clarify these responses, focusing on the Yangtze River Economic Belt in China. Analyzing 2000-2020 data, it calculates ecosystem service economic value and human footprint index. It introduces the ecosystem services response index and comprehensive responsiveness index to assess response characteristics and intensity to anthropogenic pressures. Results show a fluctuating decline in ecosystem services and an increase in anthropogenic pressures. There is a nonlinear relationship: ecosystem services decline with rising pressures, following a U-shaped trend. Notably, nonurban agglomerations experience more significant ecosystem service evolution than urban agglomerations due to differing environmental conditions. This highlights regional disparities in human activity impacts on ecosystems, crucial for planning.

Single-agent metronomic versus weekly oral vinorelbine as first-line chemotherapy in patients with HR-positive/HER2-negative advanced breast cancer: The randomized Tempo Breast study.

INTRODUCTION: Single-agent oral vinorelbine is a standard of care for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) that has progressed on endocrine therapy. Metronomic administration may offer a better balance of efficacy and safety than standard regimens, but data from previous trials are scarce. METHODS: In this open-label, multicenter, phase II trial, patients were randomized to oral vinorelbine administered on a metronomic (50 mg three times weekly) or weekly (60 mg/m2 in cycle 1, increasing to 80 mg/m2 if well tolerated) schedule. Treatment was continued until disease progression or intolerance. The primary endpoint was disease control rate (DCR, the proportion of patients with a best overall confirmed response of CR, PR, or stable disease lasting 6 months or more). RESULTS: One-hundred sixty-three patients were randomized and treated. The DCR was 63.4% (95% confidence interval [CI]: 52.0-73.8) with metronomic vinorelbine and 72.8% (95% CI: 61.8-82.1) with weekly vinorelbine. Weekly vinorelbine was also associated with longer progression-free survival (5.6 vs 4.0 months) and overall survival (26.7 vs 22.3 months) than metronomic vinorelbine, but was associated with more adverse events. CONCLUSIONS: In this randomized phase II trial, single-agent metronomic oral vinorelbine was effective and well tolerated as first-line chemotherapy for patients with HR-positive/HER2-negative ABC. Formal comparisons are not done in this phase II study and one can simply observe that confidence intervals of all endpoints overlap. When deciding for a chemotherapy after failure of endocrine therapy and CDK 4/6 inhibitors, oral vinorelbine might be an option to be given with either schedule. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2014-003860-19.

Lipid compartments and lipid metabolism as therapeutic targets against coronavirus.

Lipids perform a series of cellular functions, establishing cell and organelles' boundaries, organizing signaling platforms, and creating compartments where specific reactions occur. Moreover, lipids store energy and act as secondary messengers whose distribution is tightly regulated. Disruption of lipid metabolism is associated with many diseases, including those caused by viruses. In this scenario, lipids can favor virus replication and are not solely used as pathogens' energy source. In contrast, cells can counteract viruses using lipids as weapons. In this review, we discuss the available data on how coronaviruses profit from cellular lipid compartments and why targeting lipid metabolism may be a powerful strategy to fight these cellular parasites. We also provide a formidable collection of data on the pharmacological approaches targeting lipid metabolism to impair and treat coronavirus infection.

Intracultural variation in the knowledge of medicinal plants in an urban-rural community in the atlantic forest from northeastern Brazil.

This study assessed the intracultural knowledge of the use of medicinal plants in an urban-rural community in an Atlantic forest fragment in northeastern Brazil. We examined the importance of native and exotic species and the effects of gender and age on that knowledge. We also compared data obtained from different groups of informants (local experts and general community). We conducted 194 interviews between June 2007 and January 2008, using the freelist technique and semistructured forms to collect ethnobotanical data. Information obtained from the community was compared with that from six local experts who participated in a survey in 2003. From a total of 209 ethnospecies, exotic and herbaceous plants presented higher richness. With respect to the number of citations, women and older informants were shown to know a higher number of medicinal plants. Comparing knowledge of local experts with that of the general community, we noted that experts know a similar wealth of plant families and therapeutic indications, but the community knows a greater species richness. These results indicate that local experts may provide useful information for studies that search for a quick diagnosis of the knowledge of a given community.

Comparative study of the antimicrobial activity of native and exotic plants from the Caatinga and Atlantic Forest selected through an ethnobotanical survey.

CONTEXT: The idea that many commonly used medicinal plants may lead to the discovery of new drugs has encouraged the study of local knowledge of these resources. OBJECTIVE: An ethnobotanical survey of species traditionally used for the treatment of infectious diseases was undertaken in two areas of northeastern Brazil: one in the Caatinga (dry forest) and another in the Atlantic Forest (humid forest). MATERIALS: Initially, diffusion tests using paper disks and subsequently, for extracts presenting significant results (inhibition halos above 15 mm), minimum inhibitory concentrations were determined. The activity was evaluated as a percentage for each species, comparing the diameters of the inhibition halos and the number of positive results against the seven microorganisms studied. Extracts were classified into three categories: strong activity-species with halos exceeding 16 mm, moderate activity-species with halos between 13 mm and 15 mm and low activity-species with halos below 12 mm. We selected 34 species, 20 from the Caatinga and 14 from the Atlantic Forest. RESULTS: In the Caatinga, 50% of the 20 plant extracts studied had strong antimicrobial activity, 25% had moderate activity and 15% had low activity. In the Atlantic Forest, 28.5% of the 14 plant extracts studied showed strong activity, with 14.5% having moderate activity and 28.5% having low activity. The microorganism that was most susceptible to the extracts from the Caatinga, was Mycobacterium smegmatis; 85% of the species tested were able to inhibit its growth. The organism that was susceptible to the highest number of plant species (71%) from the Atlantic Forest was Staphylococcus aureus. DISCUSSION AND CONCLUSIONS: Extracts from the Caatinga showed a trend of superior antimicrobial activity compared to the species from the Atlantic Forest, in terms of both inhibiting a greater variety of microorganisms and demonstrating higher activity against susceptible strains.

Simvastatin Downregulates the SARS-CoV-2-Induced Inflammatory Response and Impairs Viral Infection Through Disruption of Lipid Rafts.

Coronavirus disease 2019 (COVID-19) is currently a worldwide emergency caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In observational clinical studies, statins have been identified as beneficial to hospitalized patients with COVID-19. However, experimental evidence of underlying statins protection against SARS-CoV-2 remains elusive. Here we reported for the first-time experimental evidence of the protective effects of simvastatin treatment both in vitro and in vivo. We found that treatment with simvastatin significantly reduced the viral replication and lung damage in vivo, delaying SARS-CoV-2-associated physiopathology and mortality in the K18-hACE2-transgenic mice model. Moreover, simvastatin also downregulated the inflammation triggered by SARS-CoV-2 infection in pulmonary tissue and in human neutrophils, peripheral blood monocytes, and lung epithelial Calu-3 cells in vitro, showing its potential to modulate the inflammatory response both at the site of infection and systemically. Additionally, we also observed that simvastatin affected the course of SARS-CoV-2 infection through displacing ACE2 on cell membrane lipid rafts. In conclusion, our results show that simvastatin exhibits early protective effects on SARS-CoV-2 infection by inhibiting virus cell entry and inflammatory cytokine production, through mechanisms at least in part dependent on lipid rafts disruption.

Insights into the search for new drugs from traditional knowledge: an ethnobotanical and chemical-ecological perspective.

CONTEXT: The variety of pathways for the introduction of a species into the medical collection of traditional communities has led many researchers to question the processes of selection and the use of these resources. A better comprehension of these processes will allow us to understand the cultural dynamics that are related to traditional medical practices, as well as to provide us with new ways in which to facilitate the exploration of natural products. OBJECTIVE: This study aims to test the predictive power of the plant apparency hypothesis as it relates to medicinal plant selection by the rural communities of the Caatinga and the Atlantic Forest in northeast Brazil. MATERIAL AND METHODS: Initially, a survey of the medicinal plants used by these communities was conducted using semistructured interviews. Subsequently, data on the life strategies and the habits of each species were collected. More detailed data on the specific plant parts indicated in interviews were also collected. A phytochemical screening for seven classes of chemical compounds was carried out to test the predictions of the plant apparency hypothesis. RESULTS: The medicinal plants from the Caatinga (especially those that are considered to be trees in habit) have a strong ability to accumulate quantitative compounds, and these species are most likely to be plants with significant biological activity related to these compounds; the medicinal plants from the Atlantic Forest, on the other hand, tend to have a high occurrence of qualitative compounds, especially in herbaceous life forms. DISCUSSION AND CONCLUSION: It was concluded that the plant apparency hypothesis does not adequately explain the selection of medicinal plants in the two environments studied. Our findings highlight some important implications for bioprospecting that need to be further tested experimentally, and through systematic studies, in different regions.

Clinical decision-making in anterior resin composite restorations: a multicenter evaluation.

OBJECTIVE: This study investigated whether a sample of anterior resin composite restorations could be differently evaluated in different centers of evaluation by clinical and lay evaluators. METHODS: Anterior resin composite restorations on high-quality intraoral digital photography were evaluated using FDI criteria (1-5 score) by pairs of clinical and lay evaluators in Brazil (BR), France (FR), Peru (PE), and the United States of America (USA). Scores were allocated as maintenance (1, 2, 3), repair (4) and replacement (5) when comparing clinical evaluators and, as acceptable (1, 2, 3) and unacceptable (4, 5) when comparing clinical vs. lay evaluators and lay vs. lay evaluators. The Chi-square test compared the frequencies of scores among the centers. RESULTS: The frequencies of maintaining, repairing, or replacing anterior resin composite restorations given by clinical evaluators varied depending on the evaluation center. BR and PE showed the highest frequencies for repair and replacement, while FR and USA showed the highest frequencies for maintenance. The comparison of frequencies of anterior resin composite restorations accepted or unaccepted by the clinical vs lay evaluators in the same centers showed a significantly higher frequency of acceptable dental restorations coming from clinical evaluators. Comparison between lay evaluators from different centers showed significant higher frequency of unacceptable dental restorations by BR, compared to other centers. CONCLUSIONS: In the evaluation of anterior resin composite restorations, the maintenance, repair, or replacement trends can vary among different centers. The unacceptable rate came more frequently from lay than from clinical evaluators. Lay evaluators from different centers differed significantly. CLINICAL SIGNIFICANCE: Clinical and lay evaluators in distant evaluation centers can present different trends when assessing anterior resin composite restoration. Multicenter evaluations can help to understand such differences and it is important because clinical decision-making based on scientific evidence comes from clinical studies done in different research centers.

Peripheral leptin signaling persists in innate immune cells during diet-induced obesity.

Leptin is a pleiotropic adipokine that regulates immunometabolism centrally and peripherally. Obese individuals present increased levels of leptin in the blood and develop hypothalamic resistance to this adipokine. Here we investigated whether leptin effects on the periphery are maintained despite the hypothalamic resistance. We previously reported that leptin injection induces in vivo neutrophil migration and peritoneal macrophage activation in lean mice through TNF-α- and CXCL1-dependent mechanisms. However, leptin effects on leukocyte biology during obesity remain unclear. In this study, we investigated the in vivo responsiveness of leukocytes to i.p. injected leptin in mice with diet-induced obesity (DIO). After 14-16 wk, high-sucrose, high-fat diet (HFD)-fed mice showed hyperglycemia, hyperleptinemia, and dyslipidemia compared to normal-sucrose, normal-fat diet (ND). Exogenous leptin did not reduce food intake in DIO mice in contrast to control mice, indicating that DIO mice were centrally resistant to leptin. Regardless of the diet, we found increased levels of TNF-α and CXCL1 in the animals injected with leptin, alongside a pronounced neutrophil migration to the peritoneal cavity and enhanced biogenesis of lipid droplets in peritoneal macrophages. Supporting our in vivo results, data from ex vivo leptin stimulation experiments confirmed hypothalamic resistance in DIO mice, whereas bone marrow cells responded to leptin stimulation through mTOR signaling despite obesity. Altogether, our results show that leukocytes responded equally to leptin in ND- or HFD-fed mice. These results support a role for leptin in the innate immune response also in obesity, contributing to the inflammatory status that leads to the development of metabolic disease.

Caveolin-1 expression determines the route of neutrophil extravasation through skin microvasculature.

Interleukin-8 plays a key role in the acute inflammatory response by mediating recruitment of neutrophils through vessel walls into affected tissues. During this process, molecular signals guide circulating blood neutrophils to target specific vessels for extravasation and to migrate through such vessels via particular routes. Our results show that levels of endothelial caveolin-1, the protein responsible for the induction of the membrane domains known as caveolae, are critical to each of these processes. We demonstrate that, in response to the intradermal injection of interleukin-8, neutrophils are preferentially recruited to a unique subset of venules that express high levels of intercellular adhesion molecule-1 and low levels of caveolin-1. Our results show that neutrophils traverse human dermal microvascular endothelial cells using one of two pathways: a transcellular route directly through the cell or a paracellular route through cellular junctions. Caveolin-1 expression appears to favor the transcellular path while down-regulation of caveolin-1 promotes the paracellular route.

Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis.

OBJECTIVE: Recent studies have implicated caveolin 1 in the regulation of transforming growth factor beta (TGFbeta) downstream signaling. Given the crucial role of TGFbeta in the pathogenesis of systemic sclerosis (SSc), we sought to determine whether caveolin 1 is also involved in the pathogenesis of tissue fibrosis in SSc. We analyzed the expression of CAV1 in affected SSc tissues, studied the effects of lack of expression of CAV1 in vitro and in vivo, and analyzed the effects of restoration of caveolin 1 function on the fibrotic phenotype of SSc fibroblasts in vitro. METHODS: CAV1 expression in tissues was analyzed by immunofluorescence and confocal microscopy. The extent of tissue fibrosis in Cav1-knockout mice was assessed by histologic/histochemical analyses and quantified by hydroxyproline assays. Cav1-null and SSc fibroblast phenotypes and protein production were analyzed by real-time polymerase chain reaction, immunofluorescence, Western blot, and multiplexed enzyme-linked immunosorbent assay techniques. The effects of restoration of caveolin 1 function in SSc fibroblasts in vitro were also examined using a cell-permeable recombinant CAV1 peptide. RESULTS: CAV1 was markedly decreased in the affected lungs and skin of SSc patients. Cav1-knockout mice developed pulmonary and skin fibrosis. Down-regulation of caveolin 1 was maintained in cultured SSc fibroblasts, and restoration of caveolin 1 function in vitro normalized their phenotype and abrogated TGFbeta stimulation through inhibition of Smad3 activation. CONCLUSION: Caveolin 1 appears to participate in the pathogenesis of tissue fibrosis in SSc. Restoration of caveolin 1 function by treatment with a cell-permeable peptide corresponding to the CAV1 scaffolding domain may be a novel therapeutic approach in SSc.