Kindlin-1 regulates epidermal growth factor receptor signalling

Kindler syndrome (KS) is an autosomal recessive genodermatosis that results from mutations in the FERMT1 gene encoding kindlin-1. Kindlin-1 localises to focal adhesion and is known to contribute to the activation of integrin receptors. Most cases of KS show a reduction or complete absence of kindlin-1 in keratinocytes, resulting in defective integrin activation, cell adhesion and migration. However, roles for kindlin-1 beyond integrin activation remain poorly defined. In the current study we show that skin and keratinocytes from KS patients have significantly reduced expression levels of the epidermal growth factor receptor (EGFR), resulting in defective EGF-dependent signalling and cell migration. Mechanistically, we demonstrate that kindlin-1 can associate directly with EGFR in vitro and in keratinocytes in an EGF-dependent, integrin-independent manner and that formation of this complex is required for EGF-dependent migration. We further demonstrate that kindlin-1 acts to protect EGFR from lysosomal-mediated degradation. This reveals a new role for kindlin-1 that has implications for understanding KS disease pathology

Pre-complexation of talin and vinculin without tension is required for efficient nascent adhesion maturation

Talin and vinculin are mechanosensitive proteins that are recruited early to integrin- based nascent adhesions (NAs). In two epithelial cell systems with well-delineated NA formation, we find these molecules concurrently recruited to the subclass of NAs maturing to focal adhesions. After the initial recruitment under minimal load, vinculin accumulates in maturing NAs at a ~ fivefold higher rate than in non-maturing NAs, and is accompanied by a faster traction force increase. We identify the R8 domain in talin, which exposes a vinculin-binding-site (VBS) in the absence of load, as required for NA maturation. Disruption of R8 domain function reduces load- free vinculin binding to talin, and reduces the rate of additional vinculin recruitment. Taken together, these data show that the concurrent recruitment of talin and vinculin prior to mechanical engagement with integrins is essential for the traction-mediated unfolding of talin, exposure of additional VBSs, further recruitment of vinculin, and ultimately, NA maturation

Formation of talin-vinculin pre-complexes dictates maturation of nascent adhesions by accelerated force transmission and vinculin recruitment

Talin, vinculin, and paxillin are mechanosensitive proteins that are recruited early to nascent integrin-based adhesions (NAs). Using machine learning, high-resolution traction force microscopy, single-particle-tracking and fluorescence fluctuation time-series analysis, we find that, only in the NAs that eventually mature to focal adhesions, all three molecules are recruited concurrently and in synchrony with force onset. Thereafter, vinculin assembles at ~5 fold higher rates than in non-maturing NAs. We identify a domain in talin, R8, which exposes a vinculin- binding-site (VBS) without requiring tension. Stabilizing this domain via mutation lowers tension- free vinculin binding in conjunction with talin, impairs maturation of NAs, and reduces the rate of additional vinculin recruitment after force onset. Taken together, our data show that talin forms a complex with vinculin, before association with integrins, which is essential for NA maturation by talin’s effective unfolding and exposure of additional VBSs that induce fast force growth and further vinculin binding

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

State of the climate in 2013

In 2013, the vast majority of the monitored climate variables reported here maintained trends established in recent decades. ENSO was in a neutral state during the entire year, remaining mostly on the cool side of neutral with modest impacts on regional weather patterns around the world. This follows several years dominated by the effects of either La Niña or El Niño events. According to several independent analyses, 2013 was again among the 10 warmest years on record at the global scale, both at the Earths surface and through the troposphere. Some regions in the Southern Hemisphere had record or near-record high temperatures for the year. Australia observed its hottest year on record, while Argentina and New Zealand reported their second and third hottest years, respectively. In Antarctica, Amundsen-Scott South Pole Station reported its highest annual temperature since records began in 1957. At the opposite pole, the Arctic observed its seventh warmest year since records began in the early 20th century. At 20-m depth, record high temperatures were measured at some permafrost stations on the North Slope of Alaska and in the Brooks Range. In the Northern Hemisphere extratropics, anomalous meridional atmospheric circulation occurred throughout much of the year, leading to marked regional extremes of both temperature and precipitation. Cold temperature anomalies during winter across Eurasia were followed by warm spring temperature anomalies, which were linked to a new record low Eurasian snow cover extent in May. Minimum sea ice extent in the Arctic was the sixth lowest since satellite observations began in 1979. Including 2013, all seven lowest extents on record have occurred in the past seven years. Antarctica, on the other hand, had above-average sea ice extent throughout 2013, with 116 days of new daily high extent records, including a new daily maximum sea ice area of 19.57 million km2 reached on 1 October. ENSO-neutral conditions in the eastern central Pacific Ocean and a negative Pacific decadal oscillation pattern in the North Pacific had the largest impacts on the global sea surface temperature in 2013. The North Pacific reached a historic high temperature in 2013 and on balance the globally-averaged sea surface temperature was among the 10 highest on record. Overall, the salt content in nearsurface ocean waters increased while in intermediate waters it decreased. Global mean sea level continued to rise during 2013, on pace with a trend of 3.2 mm yr-1 over the past two decades. A portion of this trend (0.5 mm yr-1) has been attributed to natural variability associated with the Pacific decadal oscillation as well as to ongoing contributions from the melting of glaciers and ice sheets and ocean warming. Global tropical cyclone frequency during 2013 was slightly above average with a total of 94 storms, although the North Atlantic Basin had its quietest hurricane season since 1994. In the Western North Pacific Basin, Super Typhoon Haiyan, the deadliest tropical cyclone of 2013, had 1-minute sustained winds estimated to be 170 kt (87.5 m s-1) on 7 November, the highest wind speed ever assigned to a tropical cyclone. High storm surge was also associated with Haiyan as it made landfall over the central Philippines, an area where sea level is currently at historic highs, increasing by 200 mm since 1970. In the atmosphere, carbon dioxide, methane, and nitrous oxide all continued to increase in 2013. As in previous years, each of these major greenhouse gases once again reached historic high concentrations. In the Arctic, carbon dioxide and methane increased at the same rate as the global increase. These increases are likely due to export from lower latitudes rather than a consequence of increases in Arctic sources, such as thawing permafrost. At Mauna Loa, Hawaii, for the first time since measurements began in 1958, the daily average mixing ratio of carbon dioxide exceeded 400 ppm on 9 May. The state of these variables, along with dozens of others, and the 2013 climate conditions of regions around the world are discussed in further detail in this 24th edition of the State of the Climate series. © 2014, American Meteorological Society. All rights reserved

Effects of the F94L myostatin gene mutation in beef × dairy crossed cattle on strip loin steak dimensionality, shear force, and sensory attributes

Carcasses (n = 115) from steers resulting from the mating of four Limousin × Angus sires heterozygous for the F94L myostatin mutation to Jersey, Jersey × Holstein, and Holstein dams were utilized to evaluate the effects of one copy of the F94L allele on strip loin dimensionality, Warner–Bratzler shear force and slice shear force, and sensory panel ratings. In phase I of a two-phase study, 57 carcasses from two sires were utilized to obtain samples of longissimus dorsi (LD), psoas major (PM), gluteus medsius (GM), semitendinosus (ST), serratus ventralis, triceps brachii, and biceps femori muscles, which were vacuum packaged, aged until 10 d postmortem, and frozen. Frozen strip loins were cut into 14, 2.5-cm-thick steaks each, and individual strip loin steaks were imaged at a fixed height on a gridded background and processed through image analysis software. In phase II, to obtain a greater power of test for LD palatability attributes, 58 additional carcasses from three sires were utilized to obtain LD samples only for sensory panel and shear force analysis. Cooked steak sensory attributes evaluated by trained panelists were tenderness, juiciness, beef flavor, browned flavor, roasted flavor, umami flavor, metallic flavor, fat-like flavor, buttery flavor, sour flavor, oxidized flavor, and liver-like flavor. In strip loin steaks from carcasses with one F94L allele, LD muscle area was larger in steaks 4, 5, 7, 8, and 9, and steaks 1, 6, 7, and 9 were less angular than those from carcasses with no F94L allele (P 0.20). F94L genotype did not affect sensory panel ratings of LD and GM steaks (P > 0.07). Cooked ST steaks from carcasses with one F94L rated lower in fat-like flavor compared to those from carcasses with no F94L allele (P = 0.035). Cooked PM steaks from carcasses with one F94L allele rated lower in juiciness, fat-like flavor, buttery flavor, and umami flavor compared to those with no copies of the F94L (P < 0.04). In summary, one copy of the F94L allele utilized in beef × dairy cross steers improved strip loin steak dimensionality, did not affect cooked steak tenderness across seven muscles, and decreased fat-associated flavors in the PM and ST. The use of F94L homozygous terminal beef sires would be an easily implemented strategy for dairy producers to improve steak portion size and shape in carcasses from nonreplacement calves.12 month embargo; first published 26 September 2023This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]