PhosMap: An ensemble bioinformatic platform to empower interactive analysis of quantitative phosphoproteomics.

BACKGROUND: Liquid chromatography-mass spectrometry (LC-MS)-based quantitative phosphoproteomics has been widely used to detect thousands of protein phosphorylation modifications simultaneously from the biological specimens. However, the complicated procedures for analyzing phosphoproteomics data has become a bottleneck to widening its application. METHODS: Here, we develop PhosMap, a versatile and scalable tool to accomplish phosphoproteomics data analysis. A standardized phosphorylation data format was created for data analyses, from data preprocessing to downstream bioinformatic analyses such as dimension reduction, differential phosphorylation analysis, kinase activity, survival analysis, and so on. For better usability, we distribute PhosMap as a Docker image for easy local deployment upon any of Windows, Linux, and Mac system. RESULTS: The source code is deposited at https://github.com/BADD-XMU/PhosMap. A free PhosMap webserver (https://huggingface.co/spaces/Bio-Add/PhosMap), with easy-to-follow fashion of dashboards, is curated for interactive data analysis. CONCLUSIONS: PhosMap fills the technical gap of large-scale phosphorylation research by empowering researchers to process their own phosphoproteomics data expediently and efficiently, and facilitates better data interpretation.

SIMarker: Cellular similarity detection and its application to diagnosis and prognosis of liver cancer.

BACKGROUND: The emergence of single-cell technology offers a unique opportunity to explore cellular similarity and heterogeneity between precancerous diseases and solid tumors. However, there is lacking a systematic study for identifying and characterizing similarities at single-cell resolution. METHODS: We developed SIMarker, a computational framework to detect cellular similarities between precancerous diseases and solid tumors based on gene expression at single-cell resolution. Taking hepatocellular carcinoma (HCC) as a case study, we quantified the cellular and molecular connections between HCC and cirrhosis. Core analysis modules of SIMarker is publicly available at https://github.com/xmuhuanglab/SIMarker ("SIM" means "similarity" and "Marker" means "biomarkers). RESULTS: We found PGA5+ hepatocytes in HCC showed cirrhosis-like characteristics, including similar transcriptional programs and gene regulatory networks. Consequently, the genes constituting the gene expression program of these cirrhosis-like subpopulations were designated as cirrhosis-like signatures (CLS). Strikingly, our utilization of CLS enabled the development of diagnosis and prognosis biomarkers based on within-sample relative expression orderings of gene pairs. These biomarkers achieved high precision and concordance compared with previous studies. CONCLUSIONS: Our work provides a systematic method to investigate the clinical translational significance of cellular similarities between HCC and cirrhosis, which opens avenues for identifying similar paradigms in other categories of cancers and diseases.

Ambient PM2.5 components and prevalence of chronic kidney disease: a nationwide cross-sectional survey in China.

OBJECTIVES: Chronic kidney disease (CKD) is a global public health concern, and accumulating evidence has indicated that air pollution increases the odds of CKD. However, a limited number of studies have examined the long-term effects of ambient fine particulate matter (PM2.5) components on the risk of CKD among general population; thus, major knowledge gaps remain. METHODS: Using data from a nationwide representative cross-sectional survey in China and a validated PM2.5 composition dataset, we established generalized linear models to quantify the association between five major components of PM2.5 and CKD prevalence. RESULTS: There were significant associations between long-term exposure to three PM2.5 components [including black carbon (BC), sulfate (SO42-), organic matter (OM)] and increased odds of CKD prevalence. Along with an interquartile range (IQR) increment in BC (3.3 µg/m3), SO42- (9.7 µg/m3), and OM (16.2 µg/m3) at a 4-year moving average, the odds ratios (ORs) for CKD prevalence were 1.28 (95% CI 1.07, 1.54), 1.23 (95% CI 1.03, 1.45), and 1.23 (95% CI 1.02, 1.47), respectively. We did not detect any significant association of the other two PM2.5 components [nitrate (NO3-) or ammonium (NH4+)] with CKD prevalence. Stratified analyses revealed no differences (P ≥ 0.05) in the effect estimates of subgroups based on administrative region, sex, age, and other demographic characteristics. For instance, along with an IQR increment in BC at a 4-year moving average, the ORs of CKD prevalence among males and females were 1.30 (95% CI 0.98, 1.73) and 1.29 (95% CI 1.01, 1.65), respectively. The odds of CKD were generally higher with increasing PM2.5 composition concentration. CONCLUSIONS: Our study demonstrated that long-term exposure to specific PM2.5 components including BC, SO42-, and OM increased CKD risk in the general population. This study could provide new insights into source-directed PM2.5 control and CKD prevention.

Self-Charging, Breathable, and Antibacterial Poly(lactic acid) Nanofibrous Air Filters by Surface Engineering of Ultrasmall Electroactive Nanohybrids.

Despite the great promise in the development of biodegradable and ecofriendly air filters by electrospinning of poly(lactic acid) (PLA) nanofibrous membranes (NFMs), the as-electrospun PLA nanofibers are generally characterized by poor electroactivity and smooth surface, challenging the exploitation of electrostatic adsorption and physical interception that are in need for efficient removal of pathogens and particulate matters (PMs). Herein, a combined "electrospinning-electrospray" strategy was disclosed to functionalize the PLA nanofibers by direct anchoring of highly dielectric BaTiO3@ZIF-8 nanohybrids (BTO@ZIF-8), conferring simultaneous promotion of surface roughness, electret properties (surface potential as high as 7.5 kV), and self-charging capability (∼190% increase in tribo-output voltage compared to that of pure PLA). Benefiting from the well-tailored morphology and increased electroactivity, the electrospun-electrosprayed PLA/BTO@ZIF-8 exhibited excellent PM-capturing performance (up to 96.54% for PM0.3 and 99.49% for PM2.5) while providing desirable air resistance (only 87 Pa at 32 L/min) due primarily to the slip flow of air molecules over the nanohybrid protrusions. This was accompanied by excellent antibacterial properties (99.9% inhibition against both Staphylococcus aureus and Escherichia coli), arising presumably from the synergistic effects of enhanced reactive oxygen species (ROS) generation, plentiful ion release, and surface charges. Our proposed strategy opens up pathways to afford exceptional combination of high-efficiency and low-resistance filtration, excellent antibacterial performance, and mechanical robustness without sacrificing the biodegradation profiles of PLA NFMs, holding potential implications for efficient and long-term healthcare.

The Mediating Role of Sarcopenia in the Association between Physical Activity and Falls among Chinese Older Adults: A Cross-Sectional Study.

Physical inactivity and sarcopenia are potentially modifiable risk factors for falls in older adults, but the strength of the association between physical activity (PA), sarcopenia, and falls in Chinese older adults is unclear. This study sought to investigate the potential mediation mechanism relationship in the connection between PA, sarcopenia, including its elements (muscle strength, physical performance, and skeletal muscle mass), and falls among Chinese older people. The subjects were 3592 community-dwelling Chinese aged 60 or over, selected from the China Health and Retirement Longitudinal Study (CHARLS). PA was evaluated through the International Physical Activity Questionnaire (IPAQ), and sarcopenia was determined through the Asian Working Group on Sarcopenia (AWGS) 2019 guidelines. We employed logistic regression to explore the link between physical activity, sarcopenia, and falls. Additionally, we applied Karlson, Holm and Breen's (KHB) method to estimate two different mediation models. The results demonstrated that PA lowers the risk of falls [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.48-0.61], whereas sarcopenia increases the risk of falls (OR 1.34, 95% CI 1.16-1.55). Sarcopenia mediated the association between PA and falls, explaining a total of 2.69% of the association (indirect effect = -0.02). PA also had a significant mediating effect on the association between sarcopenia and falls, explaining a total of 20.12% of the association (indirect effect = 0.06). The proportion mediated by sarcopenia was 2.69% for PA and falls (indirect effect = -0.02). Our findings suggest that PA and sarcopenia have a direct effect on falls as well as an indirect effect through each other. Enhancing PA levels and preventing sarcopenia may help prevent falls in older adults.

Biophysics in tumor growth and progression: from single mechano-sensitive molecules to mechanomedicine.

Evidence from physical sciences in oncology increasingly suggests that the interplay between the biophysical tumor microenvironment and genetic regulation has significant impact on tumor progression. Especially, tumor cells and the associated stromal cells not only alter their own cytoskeleton and physical properties but also remodel the microenvironment with anomalous physical properties. Together, these altered mechano-omics of tumor tissues and their constituents fundamentally shift the mechanotransduction paradigms in tumorous and stromal cells and activate oncogenic signaling within the neoplastic niche to facilitate tumor progression. However, current findings on tumor biophysics are limited, scattered, and often contradictory in multiple contexts. Systematic understanding of how biophysical cues influence tumor pathophysiology is still lacking. This review discusses recent different schools of findings in tumor biophysics that have arisen from multi-scale mechanobiology and the cutting-edge technologies. These findings range from the molecular and cellular to the whole tissue level and feature functional crosstalk between mechanotransduction and oncogenic signaling. We highlight the potential of these anomalous physical alterations as new therapeutic targets for cancer mechanomedicine. This framework reconciles opposing opinions in the field, proposes new directions for future cancer research, and conceptualizes novel mechanomedicine landscape to overcome the inherent shortcomings of conventional cancer diagnosis and therapies.

Electroactive, Antibacterial, and Biodegradable Poly(lactic acid) Nanofibrous Air Filters for Healthcare.

Poly(lactic acid) (PLA)-based nanofibrous membranes (NFMs) hold great potential in the field of biodegradable filters for air purification but are largely limited by the relatively low electret properties and high susceptibility to bacteria. Herein, we disclosed a facile approach to the fabrication of electroactive and antibacterial PLA NFMs impregnated with a highly dielectric photocatalyst. In particular, the microwave-assisted doping (MAD) protocol was employed to yield Zn-doped titanium dioxide (Zn-TIO), featuring the well-defined anatase phase, a uniform size of ∼65 nm, and decreased band gap (3.0 eV). The incorporation of Zn-TIO (2, 6, and 10 wt %) into PLA gave rise to a significant refinement of the electrospun nanofibers, decreasing from the highest diameter of 581 nm for pure PLA to the lowest value of 264 nm. More importantly, dramatical improvements in the dielectric constants, surface potential, and electret properties were simultaneously achieved for the composite NFMs, as exemplified by a nearly 94% increase in surface potential for 3-day-aged PLA/Zn-TIO (90/10) compared with that of pure PLA. The well regulation of morphological features and promotion of electroactivity contributed to a distinct increase in the air filtration performance, as demonstrated by 98.7% filtration of PM0.3 with the highest quality factor of 0.032 Pa-1 at the airflow velocity of 32 L/min for PLA/Zn-TIO (94/6), largely surpassing pure PLA (89.4%, 0.011 Pa-1). Benefiting from the effective generation of reactive radicals and gradual release of Zn2+ by Zn-TIO, the electroactive PLA NFMs were ready to profoundly inactivate Escherichia coli and Staphylococcus epidermidis. The exceptional combination of remarkable electret properties and excellent antibacterial performance makes the PLA membrane filters promising for healthcare.

Functional Interrogation of Ca2+ Signals in Human Cancer Cells In Vitro and Ex Vivo by Fluorescent Microscopy and Molecular Tools.

Genetically encoded calcium indicators (GECIs) and high-resolution confocal microscopy enable dynamic visualization of calcium signals in cells and tissues. Two-dimensional and 3D biocompatible materials mimic the mechanical microenvironments of tumor and healthy tissues in a programmable manner. Cancer xenograft models and ex vivo functional imaging of tumor slices reveal physiologically relevant functions of calcium dynamics in tumors at different progression stages. Integration of these powerful techniques allows us to quantify, diagnose, model, and understand cancer pathobiology. Here, we describe detailed materials and methods used to establish this integrated interrogation platform, from generating transduced cancer cell lines that stably express CaViar (GCaMP5G + QuasAr2) to in vitro and ex vivo calcium imaging of the cells in 2D/3D hydrogels and tumor tissues. These tools open the possibility for detailed explorations of mechano-electro-chemical network dynamics in living systems.

Hard-Soft Thermoset Alloy with Enhanced Toughness, Impact-Resistance, and Electric Conductivity via Interpenetrated Dynamic Crosslinked Interface.

Polymer alloys (PAs) are mixtures of two or more types of polymers to enhance the properties of polymeric materials. However, thermosets with crosslinked structures are immiscible and cannot be prepared PAs. Herein, two immiscible covalent adaptable networks containing phenoxy carbamate bonds are explored as the typical polymeric materials to prepare the hard-soft thermoset alloy (HSTA) by the interpenetrated dynamic crosslinked interface (IDCI) to enhance the toughness. Specifically, two types of polyurethane covalent adaptable networks with either high stiffness (thermoset) or extensibility (elastomer) are prepared, respectively. The granules of thermoset and elastomer are mixed and hot-pressed to prepare the HSTA. The HSTA shows improved mechanical properties with a toughness of 22.8 MJ m-3 which is 14 times higher than that of hard thermoset. In addition, the HSTA shows excellent impact-resistance property after 1000 punctures. Moreover, the obtained HSTA via addition of carbon nanotubes can significantly decrease the electric resistance over six orders of magnitudes as compared to the blending method, which is due to the distribution of the carbon nanotubes at the interfaces of the two networks.

Highly Tough and Reliable Poly(Amic Acid) with Ballistic Impact-Resistance through Modulation of Hydrogen Bonding Interactions.

Poly(amic acid) (PAA) materials as the precursor of polyimide generally show remarkably poor mechanical properties, thus limiting their application as the engineering plastics. In this study, it is demonstrated that the mechanical properties of PAA materials can be improved significantly for tens of folds with breaking strength >50 MPa, Young's modulus >400 MPa, and elongation at break >300% by incorporation of 20% (mol%) poly(propylene glycol) (PPO) soft segments. The optimization for suitable hard-soft composition with 20% PPO and the existence of various hydrogen bonds with different binding energies can dissipate energies efficiently, which simultaneously improve the material strength and toughness. In addition, PAA82 films exhibit excellent tolerance toward cyclic stretch, and have the capability to resist various harsh conditions including solar radiation testing (1 sun), heat (85 °C), alkalinity (pH 10), and acidity (pH 4) over one month. Noted that PAA82 films can be laminated with Kapton films, which show excellent resistance to ultrahigh (200 °C) and ultralow temperature (-196 °C). The laminated film also exhibits bulletproof property with a thickness of 6 mm. The strategy via modulation of hard-soft compositions and hydrogen bonds in PAA materials shows great potentials to improve the mechanical properties of polymeric materials.

Prioritizing prognostic-associated subpopulations and individualized recurrence risk signatures from single-cell transcriptomes of colorectal cancer.

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. There are few recurrence risk signatures for CRC patients. Single-cell RNA-sequencing (scRNA-seq) provides a high-resolution platform for prognostic signature detection. However, scRNA-seq is not practical in large cohorts due to its high cost and most single-cell experiments lack clinical phenotype information. Few studies have been reported to use external bulk transcriptome with survival time to guide the detection of key cell subtypes in scRNA-seq data. We proposed scRankXMBD, a computational framework to prioritize prognostic-associated cell subpopulations based on within-cell relative expression orderings of gene pairs from single-cell transcriptomes. scRankXMBD achieves higher precision and concordance compared with five existing methods. Moreover, we developed single-cell gene pair signatures to predict recurrence risk for patients individually. Our work facilitates the application of the rank-based method in scRNA-seq data for prognostic biomarker discovery and precision oncology. scRankXMBD is available at https://github.com/xmuyulab/scRank-XMBD. (XMBD:Xiamen Big Data, a biomedical open software initiative in the National Institute for Data Science in Health and Medicine, Xiamen University, China.).

Regional urbanicity levels modify the association between ambient air pollution and prevalence of obesity: A nationwide cross-sectional survey.

Ambient air pollution exposure may increase the risk of obesity, but the population susceptibility associated with urbanicity has been insufficiently investigated. Based on a nationwide representative cross-sectional survey on 44,544 adults, high-resolution night light satellite remote sensing products, and multi-source ambient air pollution inversion data, the present study evaluated the associations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) concentrations with the prevalence of obesity and abdominal obesity. We further calculated the associations in regions with different urbanicity levels characterized by both administrative classification of urban/rural regions and night light index (NLI). We found that 10 µg/m3 increments in PM2.5 at 1-year moving average and in NO2 at 5-year moving average were associated with increased prevalence of obesity [odds ratios (OR) = 1.16 (1.14, 1.19); 1.12 (1.09, 1.15), respectively] and abdominal obesity [OR = 1.08 (1.07, 1.10); 1.07 (1.05, 1.09), respectively]. People in rural regions experienced stronger adverse effects than those in urban regions. For instance, a 10 µg/m3 increment in PM2.5 was associated with stronger odds of obesity in rural regions than in urban regions [OR = 1.27 (1.23, 1.31) vs 1.10 (1.05, 1.14), P for interaction <0.001]. In addition, lower NLI values were associated with constantly amplified associations of PM2.5 and NO2 with obesity and abdominal obesity (all P for interaction <0.001). In summary, people in less urbanized regions are more susceptible to the adverse effects of ambient air pollution on obesity, suggesting the significance of collaborative planning of urbanization development and air pollution control, especially in less urbanized regions.

Human cancer cells generate spontaneous calcium transients and intercellular waves that modulate tumor growth.

Electrically excitable cells such as neurons transmit long-distance calcium or electrical signals to regulate their physiological functions. While the molecular underpinnings and down-stream effects of these intercellular communications in excitable cells have been well appreciated, little is known about whether and how non-excitable cancer cells spontaneously initiate and transmit long-distance intercellular signals. Here we report that non-excitable human colon and prostate cancer cells spontaneously initiate and spread intercellular calcium waves, in vitro and ex vivo. Xenograft model studies suggest that these calcium signals promote the growth rate of tumors in mice. Pharmacological studies elucidated that the inositol-trisphosphate-receptor (IP3R)-regulated calcium release from endoplasmic reticulum (ER), which is activated by the Gq-PLC-IP3R pathway, is a major cause for the initiation of spontaneous calcium transients. Further, the spatial-temporal characteristics of calcium dynamics can be tuned by the culture substrates of different mechanical stiffnesses. Our results provide evidence that calcium dynamics enables long-distance functional communication in non-excitable cancer cells and offer the potential to modulate calcium signaling for new cancer therapies.

Ambient ozone pollution and prevalence of chronic kidney disease: A nationwide study based on the China National survey of chronic kidney disease.

The health hazards of ambient ozone (O3) pollution are receiving increasing attention worldwide. However, the evidence on the association between O3 and risks of chronic kidney disease (CKD) remains insufficient and inconsistent, particularly in developing countries where there is an absence of macroscopic investigations at a large population scale. Based on data from a representative nationwide cross-sectional CKD survey in 13 Chinese provinces and a high resolution O3 air pollution inversion dataset, generalized linear models were used to evaluate the associations of O3 concentration with prevalence of CKD. The results of this study suggested that long-term O3 exposure was positively associated with the risk of CKD. A 10 µg/m3 increment in O3 concentration was associated with an increased odds of CKD prevalence [OR = 1.11 (95% CI: 1.03, 1.21)] among all the 47,086 participants. Stronger associations were found in urban regions, younger adults <65 years, and people with higher socio-economic status (income and education level). A 10 µg/m3 increment in O3 concentration was associated with a higher increased odds of CKD prevalence in urban regions [OR = 1.31 (95% CI: 1.16, 1.47)] compared to rural regions [OR = 0.95 (95% CI: 0.84, 1.08), P for subgroup difference<0.001]. A stronger association of O3 concentration with CKD prevalence was found among younger people aged <65 years [OR = 1.21 (95% CI: 1.10, 1.33)] compared to those aged ≥65 years [OR = 0.92 (95% CI: 0.79, 1.07), P for subgroup difference = 0.003]. Our study demonstrated that long-term O3 exposure may increase risk of CKD in the general Chinese population, and the findings stressed the importance of persistent efforts in air pollution prevention and control.

Towards an integrative understanding of cancer mechanobiology: calcium, YAP, and microRNA under biophysical forces.

An increasing number of studies have demonstrated the significant roles of the interplay between microenvironmental mechanics in tissues and biochemical-genetic activities in resident tumor cells at different stages of tumor progression. Mediated by molecular mechano-sensors or -transducers, biomechanical cues in tissue microenvironments are transmitted into the tumor cells and regulate biochemical responses and gene expression through mechanotransduction processes. However, the molecular interplay between the mechanotransduction processes and intracellular biochemical signaling pathways remains elusive. This paper reviews the recent advances in understanding the crosstalk between biomechanical cues and three critical biochemical effectors during tumor progression: calcium ions (Ca2+), yes-associated protein (YAP), and microRNAs (miRNAs). We address the molecular mechanisms underpinning the interplay between the mechanotransduction pathways and each of the three effectors. Furthermore, we discuss the functional interactions among the three effectors in the context of soft matter and mechanobiology. We conclude by proposing future directions on studying the tumor mechanobiology that can employ Ca2+, YAP, and miRNAs as novel strategies for cancer mechanotheraputics. This framework has the potential to bring insights into the development of novel next-generation cancer therapies to suppress and treat tumors.

Residential greenness and prevalence of chronic kidney disease: Findings from the China National Survey of Chronic Kidney Disease.

Green space is associated with many health benefits, but evidence concerning the effects on chronic kidney disease (CKD) has not been investigated. Using the nationwide cross-sectional study of 47,204 adults from the China National Survey of Chronic Kidney Disease dataset and residential greenness assessed by the normalized difference vegetation index (NDVI), this study evaluated the association between residential greenness and CKD prevalence. An interquartile range increase in NDVI1000m (0.26) was associated with decreased odds of CKD for all participants with an odds ratio (OR) of 0.79 (95% confidence interval [CI]: 0.73-0.86). Subgroup analyses demonstrated more apparent inverse associations in younger adults <65 years, male participants, people in higher socio-economic status, as well as people with smoking and alcohol drinking habit. In addition, more apparent inverse associations were found in regions with higher fine particulate matter (PM2.5) concentration levels, with OR of 0.56 (95% CI: 0.49, 0.65) for higher pollution regions, and OR of 0.95 (95% CI: 0.83, 1.09) for lower pollution regions (P for interaction <0.001). The exposure-response curves captured more apparent declines in OR of CKD when in lower NDVI1000m exposure ranges (<0.6), even controlling for the PM2.5 concentration. Our results indicated that residential greenness might be beneficial for the prevention and control of CKD at the population level, suggesting the positive significance of strengthening green space construction, particularly in regions with low greenness.

Urbanization, ambient air pollution, and prevalence of chronic kidney disease: A nationwide cross-sectional study.

An increasing number of studies have linked ambient air pollution to chronic kidney disease (CKD) prevalence. However, its potential effect modification by urbanization has not been investigated. Based on data of 47,204 adults from the China National Survey of Chronic Kidney Disease (CKSCKD) dataset, night light satellite remote sensing data and high-resolution air pollution inversion products, the present cross-sectional study investigated the association between fine particulate matter <2.5 mm in diameter (PM2.5), nitrogen dioxide (NO2), night light index (NLI) and CKD prevalence in China, and the effect modification by urbanization characterized by administrative classification and NLI on the pollutant-health associations. Our results showed that a 10-µg/m3 increase in PM2.5 at 3-year moving average, a 10-µg/m3 increase in NO2 at 5-year moving average, and a 10-U increase in NLI at 5-year moving average were significantly associated with increased odds of CKD prevalence [OR = 1.24 (95 %CI:1.14, 1.35); OR = 1.12 (95 %CI:1.09, 1.15); OR = 1.05 (95 %CI:1.02, 1.07)]. Meanwhile, the pollutant-health associations were more apparent in medium-urbanized areas compared to low- and high-urbanized areas. For instance, a 10-µg/m3 increase in PM2.5 concentration at 2-year moving average was associated with increased odds of CKD in the areas with NLI level in the second [OR = 2.78 (95 %CI:1.77, 4.36)] and third quartiles [OR = 1.49 (95 %CI:1.14, 1.95)], compared to the lowest [OR = 0.96 (95% CI: 0.73, 1.26)] and highest [OR = 0.63 (95% CI: 0.39-1.02)] quartiles. PM2.5 and NO2 were associated with increased odds of CKD prevalence, especially in areas with medium NLI levels, suggesting the necessity of strengthening environmental management in medium-urbanized regions.

Inhibition of the mevalonate pathway improves myocardial fibrosis.

The mevalonate (MVA) pathway serves an important role in ventricular remodeling. Targeting the MVA pathway has protective effects against myocardial fibrosis. The present study aimed to investigate the mechanism behind these effects. Primary cultured cardiac fibroblasts from C57BL/6 mice were treated in vitro in 5 groups: i) negative control; ii) angiotensin II (Ang II) model (1x10-5 mol/l); iii) Ang II + rosuvastatin (ROS); iv) Ang II + alendronate (ALE); and v) Ang II + fasudil (FAS). Collagen and crystal violet staining were used to assess morphological changes in cardiac fibroblasts. Reverse transcription quantitative PCR and western blotting were used to analyze the expression of key signaling molecules involved in the MVA pathway. Collagen staining in the ALE, FAS, and ROS groups was weak compared with the Ang II group, while the rate of cell proliferation in the ROS, ALE, and FAS groups was slower compared with that in the Ang II group. In addition, the expression of key signaling molecules in the MVA pathway, including transforming growth factor-ß1 (TGF-ß1), heat shock protein 47 (HSP47), collagen type I α1 (COL1A1), vascular endothelial growth factor 2 (VEGF2) and fibroblast growth factor 2 (FGF2), was decreased in the FAS and ROS groups compared with the Ang II model. Compared with the Ang II group, 3-Hydroxy-3-Methylglutaryl-CoA reductase (HMGCR) gene expression was significantly lowered in the drug intervention groups, whereas farnesyl pyrophosphate synthase (FDPS) expression was downregulated in the ALE group, but elevated in the FAS and ROS groups. Compared with that in the Ang II group, ras homolog family member A (RhoA) expression was downregulated in the FAS and ROS groups, whilst mevalonate kinase expression was reduced in the ROS group. Protein expression of TGF-ß1, COL1A1 and HSP47 were decreased following intervention with each of the three drugs compared with the Ang II group. Overall, rosuvastatin, aledronate and fasudil decreased the proliferation of myocardial fibroblasts and inhibited collagen synthesis. Rosuvastatin had the strongest protective effects against myocardial fibrosis compared with the other drugs tested, suggesting this to be a potential agent for the clinical treatment of cardiovascular disease.

All-optical Mechanobiology Interrogation of Yes-associated Protein in Human Cancer and Normal Cells using a Multi-functional System.

Long-term multi-functional imaging and analysis of live cells require streamlined, functional coordination of various hardware and software platforms. However, manual control of various equipment produced by different manufacturers is labor-intensive and time-consuming, potentially decreasing the accuracy, reproducibility, and quality of acquired data. Therefore, an all-in-one and user-programmable system that enables automatic, multi-functional, and long-term image acquisition and is compatible with most fluorescent microscopy platforms can benefit the scientific community. This paper introduces the complete operating protocols of utilizing a novel integrated software system that consists of (1) a home-built software program, titled "Automatic Multi-functional Integration Program (AMFIP)," which enables automatic multi-channel imaging acquisition, and (2) a suite of quantitative imaging analysis and cell traction computation packages. This integrated system is applied to reveal the previously unknown relationship between the spatial-temporal distribution of mechano-sensitive Yes-associated protein (YAP) and the cell mechanics, including cell spreading and traction, in CRISPR/Cas9-engineered human normal cells (B2B) and lung cancer cells (PC9). Leveraging this system's capability of multi-channel control and readout, the result shows: (1) B2B normal cells and PC9 cancer cells show a distinct relationship between YAP expression, traction, and cell dynamics during cell spreading and migration processes; and (2) PC9 cancer cells apply noticeable peri-nuclear forces on substrates. In summary, this paper presents a detailed stepwise protocol on how to utilize an integrated user-programmable system that enables automatic multi-functional imaging and analysis to elucidate YAP mechano-sensitivity. These tools open the possibility for detailed explorations of multifaceted signaling dynamics in the context of cell physiology and pathology.

Long-Term Exposure to Ambient PM2.5, Sunlight, and Obesity: A Nationwide Study in China.

Background: Accumulated researches revealed that both fine particulate matter (PM2.5) and sunlight exposure may be a risk factor for obesity, while researches regarding the potential effect modification by sunlight exposure on the relationship between PM2.5 and obesity are limited. We aim to investigate whether the effect of PM2.5 on obesity is affected by sunlight exposure among the general population in China. Methods: A sample of 47,204 adults in China was included. Obesity and abdominal obesity were assessed based on body mass index, waist circumference and waist-to-hip ratio, respectively. The five-year exposure to PM2.5 and sunlight were accessed using the multi-source satellite products and a geochemical transport model. The relationship between PM2.5, sunshine duration, and the obesity or abdominal obesity risk was evaluated using the general additive model. Results: The proportion of obesity and abdominal obesity was 12.6% and 26.8%, respectively. Levels of long-term PM2.5 ranged from 13.2 to 72.1 µg/m3 with the mean of 46.6 µg/m3. Each 10 µg/m3 rise in PM2.5 was related to a higher obesity risk [OR 1.12 (95% CI 1.09-1.14)] and abdominal obesity [OR 1.10 (95% CI 1.07-1.13)]. The association between PM2.5 and obesity varied according to sunshine duration, with the highest ORs of 1.56 (95% CI 1.28-1.91) for obesity and 1.66 (95% CI 1.34-2.07) for abdominal obesity in the bottom quartile of sunlight exposure (3.21-5.34 hours/day). Conclusion: Long-term PM2.5 effect on obesity risk among the general Chinese population are influenced by sunlight exposure. More attention might be paid to reduce the adverse impacts of exposure to air pollution under short sunshine duration conditions.