Roles of CCN2 as a mechano-sensing regulator of chondrocyte differentiation

Cellular communication network factor 2 (CCN2) is a cysteine-rich secreted matricellular protein that regulates various cellular functions including cell differentiation. CCN2 is highly expressed under several types of mechanical stress, such as stretch, compression, and shear stress, in mesenchymal cells including chondrocytes, osteoblasts, and fibroblasts. In particular, CCN2 not only promotes cell proliferation and differentiation of various cells but also regulates the stability of mRNA of TRPV4, a mechanosensitive ion channel in chondrocytes. Of note, CCN2 behaves like a biomarker to sense suitable mechanical stress, because CCN2 expression is down-regulated when chondrocytes are subjected to excessive mechanical stress. These findings suggest that CCN2 is a mechano-sensing regulator. CCN2 expression is regulated by the activation of various mechano-sensing signaling pathways, e.g., mechanosensitive ion channels, integrin-focal adhesion-actin dynamics, Rho GTPase family members, Hippo-YAP signaling, and G protein-coupled receptors. This review summarizes the characterization of mechanoreceptors involved in CCN2 gene regulation and discusses the role of CCN2 as a mechano-sensing regulator of mesenchymal cell differentiation, with particular focus on chondrocytes

Brain-mediated Transfer Learning of Convolutional Neural Networks

The human brain can effectively learn a new task from a small number of samples, which indicate that the brain can transfer its prior knowledge to solve tasks in different domains. This function is analogous to transfer learning (TL) in the field of machine learning. TL uses a well-trained feature space in a specific task domain to improve performance in new tasks with insufficient training data. TL with rich feature representations, such as features of convolutional neural networks (CNNs), shows high generalization ability across different task domains. However, such TL is still insufficient in making machine learning attain generalization ability comparable to that of the human brain. To examine if the internal representation of the brain could be used to achieve more efficient TL, we introduce a method for TL mediated by human brains. Our method transforms feature representations of audiovisual inputs in CNNs into those in activation patterns of individual brains via their association learned ahead using measured brain responses. Then, to estimate labels reflecting human cognition and behavior induced by the audiovisual inputs, the transformed representations are used for TL. We demonstrate that our brain-mediated TL (BTL) shows higher performance in the label estimation than the standard TL. In addition, we illustrate that the estimations mediated by different brains vary from brain to brain, and the variability reflects the individual variability in perception. Thus, our BTL provides a framework to improve the generalization ability of machine-learning feature representations and enable machine learning to estimate human-like cognition and behavior, including individual variability

Auto-Drawing and Functionalization by Vapor-Phase Assisted Polymerization on Solid Surface

Formation of two- and three-dimensional micro architectures with chemical functions was verified by photo-vapor phase assisted surface polymerization (VASP) of functional monomer vapors combined with an auto-drawing system manipulated by prescribed programs. The surface modification by the photo-VASP of styrene vapor progressed rapidly, and a fine lines-pattern of photo-mask was transcribed as the corresponding polymer accumulations on poly(methyl methacrylate) (PMMA) substrate surfaces. Substrate surface modified by photo-VASP of acrylic acid showed reversible changes in hydrophilic/hydrophobic properties according to repeating external chemical stimuli. The successive auto-drawing by photo-VASP of three kinds of monomer vapors was examined under spot illumination from a fine optical fiber on an X-Y stage manipulated by a prescribed program, resulting in the production of a pre-designed functional structure by successful accumulations of corresponding polymers on the substrate surface

Short Bamboo Fibers Coated by Lignin during Super-Heated Steam Treatment and Bio-composites using Same

In order to apply short bamboo fiber (sBF) as a functional reinforcement of bio-composites having specific electrical properties, lignin-surfaced sBF was prepared via super-heated steam (SHS) treatment of bamboo. The sBF was easily isolated from the intrinsic fibrovascular bundle structure of bamboo after SHS treatment and pulverization. The isolated sBF was surfaced by brown-colored hydrophobic compounds, which were lignin-derived compounds generated during the SHS treatment. The functional bio-composites were prepared from the SHS-treated sBF and polypropylene and showed specific antistatic properties. Surface electrical resistance values of the composites decreased significantly with increase in the aspect ratio (AR) value of sBF. It is considered that the lignin-derived surfacing of sBF functions as an electron carrier in the composite, in particular, the longer sBF acts as an effective bridge for transporting electrons over long distances along conductive paths. From a cross-sectional microscopic image of the bio-composite, orientated sBFs were observed in its surface layer, supporting the suggestion of conductive path formation. Further, it was confirmed that the reinforcing effect of the presence of sBF was increased with increasing AR value

Effect of Angiotensin II on Chondrocyte Degeneration and Protection via Differential Usage of Angiotensin II Receptors

The renin-angiotensin system (RAS) controls not only systemic functions, such as blood pressure, but also local tissue-specific events. Previous studies have shown that angiotensin II receptor type 1 (AT(1)R) and type 2 (AT(2)R), two RAS components, are expressed in chondrocytes. However, the angiotensin II (ANG II) effects exerted through these receptors on chondrocyte metabolism are not fully understood. In this study, we investigated the effects of ANG II and AT(1)R blockade on chondrocyte proliferation and differentiation. Firstly, we observed that ANG II significantly suppressed cell proliferation and glycosaminoglycan content in rat chondrocytic RCS cells. Additionally, ANG II decreased CCN2, which is an anabolic factor for chondrocytes, via increased MMP9. In Agtr1a-deficient RCS cells generated by the CRISPR-Cas9 system, Ccn2 and Aggrecan (Acan) expression increased. Losartan, an AT(1)R antagonist, blocked the ANG II-induced decrease in CCN2 production and Acan expression in RCS cells. These findings suggest that AT(1)R blockade reduces ANG II-induced chondrocyte degeneration. Interestingly, AT(1)R-positive cells, which were localized on the surface of the articular cartilage of 7-month-old mice expanded throughout the articular cartilage with aging. These findings suggest that ANG II regulates age-related cartilage degeneration through the ANG II-AT(1)R axis

Fibroblast Growth Factors and Cellular Communication Network Factors: Intimate Interplay by the Founding Members in Cartilage

Fibroblast growth factors (FGFs) constitute a large family of signaling molecules that act in an autocrine/paracrine, endocrine, or intracrine manner, whereas the cellular communication network factors (CCN) family is composed of six members that manipulate extracellular signaling networks. FGFs and CCNs are structurally and functionally distinct, except for the common characteristics as matricellular proteins. Both play significant roles in the development of a variety of tissues and organs, including the skeletal system. In vertebrates, most of the skeletal parts are formed and grow through a process designated endochondral ossification, in which chondrocytes play the central role. The growth plate cartilage is the place where endochondral ossification occurs, and articular cartilage is left to support the locomotive function of joints. Several FGFs, including FGF-2, one of the founding members of this family, and all of the CCNs represented by CCN2, which is required for proper skeletal development, can be found therein. Research over a decade has revealed direct binding of CCN2 to FGFs and FGF receptors (FGFRs), which occasionally affect the biological outcome via FGF signaling. Moreover, a recent study uncovered an integrated regulation of FGF and CCN genes by FGF signaling. In this review, after a brief introduction of these two families, molecular and genetic interactions between CCN and FGF family members in cartilage, and their biological effects, are summarized. The molecular interplay represents the mutual involvement of the other in their molecular functions, leading to collaboration between CCN2 and FGFs during skeletal development

Adverse effect profile of trichlormethiazide: a retrospective observational study

<p>Abstract</p> <p>Background</p> <p>Trichlormethiazide, a thiazide diuretic, was introduced in 1960 and remains one of the most frequently used diuretics for treating hypertension in Japan. While numerous clinical trials have indicated important side effects of thiazides, e.g., adverse effects on electrolytes and uric acid, very few data exist on serum electrolyte levels in patients with trichlormethiazide treatment. We performed a retrospective cohort study to assess the adverse effects of trichlormethiazide, focusing on serum electrolyte and uric acid levels.</p> <p>Methods</p> <p>We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2010, to identify cohorts of new trichlormethiazide users (n = 99 for 1 mg, n = 61 for 2 mg daily dosage) and an equal number of non-users (control). We used propensity-score matching to adjust for differences between users and control for each dosage, and compared serum chemical data including serum sodium, potassium, uric acid, creatinine and urea nitrogen. The mean exposure of trichlormethiazide of 1 mg and 2 mg users was 58 days and 64 days, respectively.</p> <p>Results</p> <p>The mean age was 66 years, and 55% of trichlormethiazide users of the 1 mg dose were female. In trichlormethiazide users of the 2 mg dose, the mean age was 68 years, and 43% of users were female. There were no statistically significant differences in all covariates (age, sex, comorbid diseases, past drugs, and current antihypertensive drugs) between trichlormethiazide users and controls for both doses. In trichlormethiazide users of the 2 mg dose, the reduction of serum potassium level and the elevation of serum uric acid level were significant compared with control, whereas changes of mean serum sodium, creatinine and urea nitrogen levels were not significant. In trichlormethiazide users of the 1 mg dose, all tests showed no statistically significant change from baseline to during the exposure period in comparison with control.</p> <p>Conclusions</p> <p>Our study showed adverse effects of decreased serum potassium and increased serum uric acid with trichlormethiazide treatment, and suggested that a lower dose of trichlormethiazide may minimize these adverse effects. These findings support the current trend in hypertension therapeutics to shift towards lower doses of thiazides.</p

Molecular and Genetic Interactions between CCN2 and CCN3 behind Their Yin-Yang Collaboration

Cellular communication network factor (CCN) 2 and 3 are the members of the CCN family that conduct the harmonized development of a variety of tissues and organs under interaction with multiple biomolecules in the microenvironment. Despite their striking structural similarities, these two members show contrastive molecular functions as well as temporospatial emergence in living tissues. Typically, CCN2 promotes cell growth, whereas CCN3 restrains it. Where CCN2 is produced, CCN3 disappears. Nevertheless, these two proteins collaborate together to execute their mission in a yin-yang fashion. The apparent functional counteractions of CCN2 and CCN3 can be ascribed to their direct molecular interaction and interference over the cofactors that are shared by the two. Recent studies have revealed the mutual negative regulation systems between CCN2 and CCN3. Moreover, the simultaneous and bidirectional regulatory system of CCN2 and CCN3 is also being clarified. It is of particular note that these regulations were found to be closely associated with glycolysis, a fundamental procedure of energy metabolism. Here, the molecular interplay and metabolic gene regulation that enable the yin-yang collaboration of CCN2 and CCN3 typically found in cartilage development/regeneration and fibrosis are described

Mechanism-Independent Method for Predicting Response to Multidrug Combinations in Bacteria

Drugs are commonly used in combinations larger than two for treating bacterial infection. However, it is generally impossible to infer directly from the effects of individual drugs the net effect of a multidrug combination. Here we develop a mechanism-independent method for predicting the microbial growth response to combinations of more than two drugs. Performing experiments in both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria, we demonstrate that for a wide range of drugs, the bacterial responses to drug pairs are sufficient to infer the effects of larger drug combinations. To experimentally establish the broad applicability of the method, we use drug combinations comprising protein synthesis inhibitors (macrolides, aminoglycosides, tetracyclines, lincosamides, and chloramphenicol), DNA synthesis inhibitors (fluoroquinolones and quinolones), folic acid synthesis inhibitors (sulfonamides and diaminopyrimidines), cell wall synthesis inhibitors, polypeptide antibiotics, preservatives, and analgesics. Moreover, we show that the microbial responses to these drug combinations can be predicted using a simple formula that should be widely applicable in pharmacology. These findings offer a powerful, readily accessible method for the rational design of candidate therapies using combinations of more than two drugs. In addition, the accurate predictions of this framework raise the question of whether the multidrug response in bacteria obeys statistical, rather than chemical, laws for combinations larger than two.Molecular and Cellular Biolog

Adhesion Control of Interface between Cellulose and Polypropylene by Vapor-Phase Assisted Surface Copolymerization

In order to achieve the effective interface bonding between biomass microfiller and commodity plastics, consecutive copolymerization of hydrophilic acrylic acid (AA) and hydrophobic butyl acrylate (BA) using vapor-phase assisted surface polymerization (VASP) technology was applied to prepare micro composites consisting of cellulose micro crystal (CμC) and polypropylene (PP). After the copolymerization by VASP, CμC surfaces were covered by accumulated polymers: P(AA-co-BA) including block-type copolymer and homopolymers of 6.2-25.3 wt% versus CμC. Although structures of the products were unspecified, it was expected to be mixtures of block copolymers and homopolymers. Subsequently prepared P(AA-co-BA) on CμC/PP (5/95 wt/wt) composites expressed a superior mechanical toughness, which had increased threefold when compared to intact CμC/PP composite. This increase in toughness was mainly based on an increase in elongation rate, reflecting improvement of the adhesion strength at the interface between CμC surface and PP. The trace amounts: 0.31 wt% of accumulated P(AA-co-BA) on CμC surface must function as an effective adhesive/compatibilizer at the interface