Regulatory roles of the cadherin superfamily

Charged with the task of providing a molecular link between adjacent cells, the cadherin superfamily consists of over 100 members and populates the genomes of organisms ranging from vertebrates to cniderians. This breadth hints at what decades of research has confirmed: that cadherin-based adhesion and signaling events regulate diverse cellular processes including cell-sorting, differentiation, cell survival, proliferation, cell polarity, and cytoskeletal organization

Techniques to stimulate and interrogate cell–cell adhesion mechanics

Cell–cell adhesions maintain the mechanical integrity of multicellular tissues and have recently been found to act as mechanotransducers, translating mechanical cues into biochemical signals. Mechanotransduction studies have primarily focused on focal adhesions, sites of cell-substrate attachment. These studies leverage technical advances in devices and systems interfacing with living cells through cell–extracellular matrix adhesions. As reports of aberrant signal transduction originating from mutations in cell–cell adhesion molecules are being increasingly associated with disease states, growing attention is being paid to this intercellular signaling hub. Along with this renewed focus, new requirements arise for the interrogation and stimulation of cell–cell adhesive junctions. This review covers established experimental techniques for stimulation and interrogation of cell–cell adhesion from cell pairs to monolayers

Quality of Life, Depression, and Healthcare Resource Utilization among Adults with Type 2 Diabetes Mellitus and Concomitant Hypertension and Obesity: A Prospective Survey

Background. This study compared quality of life, depression, and healthcare resource utilization among adults with type 2 diabetes mellitus (T2DM) and comorbid hypertension (HTN) and obesity with those of adults reporting T2DM alone. Methods. Respondents to the US SHIELD survey self-reported their height, weight, comorbid conditions, hospitalizations, and outpatient visits and completed the Short Form-12 (SF-12) and Patient Health Questionnaire (PHQ-9). Respondents reporting T2DM and HTN and obesity (body mass index, BMI, ≥30 kg/m2) were compared with a T2DM-alone group. Results. Respondents with T2DM, HTN, and obesity (n = 1292) had significantly lower SF-12 Physical and Mental Component Summary scores (37.3 and 50.9, resp.) than T2DM-alone respondents (n = 349) (45.8 and 53.5, resp., P < 0.0001). Mean PHQ-9 scores were significantly higher among T2DM respondents with comorbid HTN and obesity (5.0 versus 2.5, P < 0.0001), indicating greater depression burden. Respondents with T2DM, HTN, and obesity had significantly more resource utilization with respect to physician visits and emergency room visits but not hospitalizations than respondents with T2DM alone (P = 0.03). Conclusions. SHIELD respondents with comorbid conditions of T2DM, HTN, and obesity reported greater healthcare resource utilization, more depression symptoms, and lower quality of life than the T2DM-alone group

Trends in Method of Diagnosis of Type 2 Diabetes Mellitus: Results from SHIELD

Aims. This study assessed whether recent screening recommendations have led to increased diagnosis of type 2 diabetes mellitus (T2DM) through routine screening. Methods. Respondents to the 2006 US SHIELD survey reported whether a physician told them they had T2DM, age at diagnosis, specialty of the physician who made the diagnosis, and whether the diagnosis was made after having symptoms, during routine screening, or when being treated for another health problem. Results. Of 3 022 T2DM respondents, 36% of respondents reported that T2DM diagnosis was made during routine screening alone, 20% after having symptoms alone, and 6% when being treated for another health problem alone. The proportion of T2DM respondents reporting a diagnosis based only on screening increased approximately 42% over a 15+-year time span (absolute increase from 31% to 44%) (P < .001), whereas symptom-based diagnosis did not change significantly (P = .10). T2DM was diagnosed primarily by family physicians (88.3%). Conclusion. These findings highlight the importance of regular screening for diabetes and the vital role of primary care physicians in recognizing individuals with T2DM

p120 catenin associates with kinesin and facilitates the transport of cadherin–catenin complexes to intercellular junctions

p120 catenin (p120) is a component of adherens junctions and has been implicated in regulating cadherin-based cell adhesion as well as the activity of Rho small GTPases, but its exact roles in cell–cell adhesion are unclear. Using time-lapse imaging, we show that p120-GFP associates with vesicles and exhibits unidirectional movements along microtubules. Furthermore, p120 forms a complex with kinesin heavy chain through the p120 NH2-terminal head domain. Overexpression of p120, but not an NH2-terminal deletion mutant deficient in kinesin binding, recruits endogenous kinesin to N-cadherin. Disruption of the interaction between N-cadherin and p120, or the interaction between p120 and kinesin, leads to a delayed accumulation of N-cadherin at cell–cell contacts during calcium-initiated junction reassembly. Our analyses identify a novel role of p120 in promoting cell surface trafficking of cadherins via association and recruitment of kinesin

Defining desmosomal plakophilin-3 interactions

Plakophilin 3 (PKP3) is a recently described armadillo protein of the desmosomal plaque, which is synthesized in simple and stratified epithelia. We investigated the localization pattern of endogenous and exogenous PKP3 and fragments thereof. The desmosomal binding properties of PKP3 were determined using yeast two-hybrid, coimmunoprecipitation and colocalization experiments. To this end, novel mouse anti-PKP3 mAbs were generated. We found that PKP3 binds all three desmogleins, desmocollin (Dsc) 3a and -3b, and possibly also Dsc1a and -2a. As such, this is the first protein interaction ever observed with a Dsc-b isoform. Moreover, we determined that PKP3 interacts with plakoglobin, desmoplakin (DP) and the epithelial keratin 18. Evidence was found for the presence of at least two DP–PKP3 interaction sites. This finding might explain how lateral DP–PKP interactions are established in the upper layers of stratified epithelia, increasing the size of the desmosome and the number of anchoring points available for keratins. Together, these results show that PKP3, whose epithelial and epidermal desmosomal expression pattern and protein interaction repertoire are broader than those of PKP1 and -2, is a unique multiprotein binding element in the basic architecture of a vast majority of epithelial desmosomes

Intermediate filament–membrane attachments function synergistically with actin-dependent contacts to regulate intercellular adhesive strength

By tethering intermediate filaments (IFs) to sites of intercellular adhesion, desmosomes facilitate formation of a supercellular scaffold that imparts mechanical strength to a tissue. However, the role IF–membrane attachments play in strengthening adhesion has not been directly examined. To address this question, we generated Tet-On A431 cells inducibly expressing a desmoplakin (DP) mutant lacking the rod and IF-binding domains (DPNTP). DPNTP localized to the plasma membrane and led to dissociation of IFs from the junctional plaque, without altering total or cell surface distribution of adherens junction or desmosomal proteins. However, a specific decrease in the detergent-insoluble pool of desmoglein suggested a reduced association with the IF cytoskeleton. DPNTP-expressing cell aggregates in suspension or substrate-released cell sheets readily dissociated when subjected to mechanical stress whereas controls remained largely intact. Dissociation occurred without lactate dehydrogenase release, suggesting that loss of tissue integrity was due to reduced adhesion rather than increased cytolysis. JD-1 cells from a patient with a DP COOH-terminal truncation were also more weakly adherent compared with normal keratinocytes. When used in combination with DPNTP, latrunculin A, which disassembles actin filaments and disrupts adherens junctions, led to dissociation up to an order of magnitude greater than either treatment alone. These data provide direct in vitro evidence that IF–membrane attachments regulate adhesive strength and suggest furthermore that actin- and IF-based junctions act synergistically to strengthen adhesion

Ordered Assembly of the Adhesive and Electrochemical Connections within Newly Formed Intercalated Disks in Primary Cultures of Adult Rat Cardiomyocytes

The intercalated disk (ID) is a complex structure that electromechanically couples adjoining cardiac myocytes into a functional syncitium. The integrity of the disk is essential for normal cardiac function, but how the diverse elements are assembled into a fully integrated structure is not well understood. In this study, we examined the assembly of new IDs in primary cultures of adult rat cardiac myocytes. From 2 to 5 days after dissociation, the cells flatten and spread, establishing new cell-cell contacts in a manner that recapitulates the in vivo processes that occur during heart development and myocardial remodeling. As cells make contact with their neighbors, transmembrane adhesion proteins localize along the line of apposition, concentrating at the sites of membrane attachment of the terminal sarcomeres. Cx43 gap junctions and ankyrin-G, an essential cytoskeletal component of voltage gated sodium channel complexes, were secondarily recruited to membrane domains involved in cell-cell contacts. The consistent order of the assembly process suggests that there are specific scaffolding requirements for integration of the mechanical and electrochemical elements of the disk. Defining the relationships that are the foundation of disk assembly has important implications for understanding the mechanical dysfunction and cardiac arrhythmias that accompany alterations of ID architecture

Agricultural climate change mitigation : Carbon calculators as a guide for decision making

This is an Accepted Manuscript of an article published by Taylor & Francis Group in International Journal of Agricultural Sustainability on 9 November 2017, available online: https://doi.org/10.1080/14735903.2017.1398628. Under embargo. Embargo end date: 9 November 2018.The dairy industry is receiving considerable attention in relation to both its significant greenhouse gas (GHG) emissions, and it’s potential for reducing those emissions, contributing towards meeting national targets and driving the industry towards sustainable intensification. However, the extent to which improvements can be made is dependent on the decision making processes of individual producers, so there has been a proliferation of carbon accounting tools seeking to influence those processes. This paper evaluates the suitability of such tools for driving environmental change by influencing on-farm management decisions. Seven tools suitable for the European dairy industry were identified, their characteristics evaluated, and used to process data relating to six scenario farms, emulating process undertaken in real farm management situations. As a result of the range of approaches taken by the tools, there was limited agreement between them as to GHG emissions magnitude, and no consistent pattern as to which tools resulted in the highest/lowest results. Despite this it is argued, that as there was agreement as to the farm activities responsible for the greatest emissions, the more complex tools were still capable of performing a ‘decision support’ role, and guiding management decisions, whilst others could merely focus attention on key issues.Peer reviewe

A new optical system for the determination of deformations and strains: Calibration characteristics and experimental results

Many types of optical strain measurement systems have been used for the determination of deformations and strains in soft biological tissues. The purpose of this investigation is to report a new optical strain measurement system developed in our laboratory which offers distinct advantages over systems developed in the past. Our optical strain system has demonstrated excellent performance in calibration and experimental tests. Calibration tests illustrate the system's accuracy to 0.05% strain at 3.52% strain and 0.18% strain at 11.74% strain. Further, this system can measure strains to within 2% measurement error for strains in a 0-11.74% range when 100 [mu]m increments of motion are used for calibration. The resolution of our system appears to be at least as good as the linear micrometer (2 [mu]m) used as a calibrating standard. Errors in strain measurement due to whole specimen rotation or translation are quantified. Rotations about an in-plane axis perpendicular to the direction of strain and translations in/out of the plane of focus result in the largest sources of error. Finally, in an in vitro biomechanical study of the rabbit Achilles tendon, experimental failure strains are 4.3 +/- 0.9% using this system.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31312/1/0000221.pd