SUN/KASH interactions facilitate force transmission across the nuclear envelope.

LINC complexes (Linker of Nucleoskeleton and Cytoskeleton), consisting of inner nuclear membrane SUN (Sad1, UNC-84) proteins and outer nuclear membrane KASH (Klarsicht, ANC-1, and Syne Homology) proteins, are essential for nuclear positioning, cell migration and chromosome dynamics. To test the in vivo functions of conserved interfaces revealed by crystal structures, Cain et al used a combination of Caenorhabditis elegans genetics, imaging in cultured NIH 3T3 fibroblasts, and Molecular Dynamic simulations, to study SUN-KASH interactions. Conserved aromatic residues at the -7 position of the C-termini of KASH proteins and conserved disulfide bonds in LINC complexes play important roles in force transmission across the nuclear envelope. Other properties of LINC complexes, such as the helices preceding the SUN domain, the longer coiled-coils spanning the perinuclear space and higher-order organization may also function to transmit mechanical forces generated by the cytoskeleton across the nuclear envelope

Laminopathies: Too Much SUN Is a Bad Thing

SummarySUN proteins accelerate the pathological progression of laminopathies. Although the mechanisms remain to be elucidated, an intriguing possibility is that high levels of SUN proteins lead to a hyperactive DNA damage response

Structure and correlates of cognitive aging in a narrow age cohort

Aging-related changes occur for multiple domains of cognitive functioning. An accumulating body of research indicates that, rather than representing statistically independent phenomena, aging-related cognitive changes are moderately to strongly correlated across domains. However, previous studies have typically been conducted in age-heterogeneous samples over longitudinal time lags of 6 or more years, and have failed to consider whether results are robust to a comprehensive set of controls. Capitalizing on 3-year longitudinal data from the Lothian Birth Cohort of 1936, we took a longitudinal narrow age cohort approach to examine cross-domain cognitive change interrelations from ages 70 to 73 years. We fit multivariate latent difference score models to factors representing visuospatial ability, processing speed, memory, and crystallized ability. Changes were moderately interrelated, with a general factor of change accounting for 47% of the variance in changes across domains. Change interrelations persisted at close to full strength after controlling for a comprehensive set of demographic, physical, and medical factors including educational attainment, childhood intelligence, physical function, APOE genotype, smoking status, diagnosis of hypertension, diagnosis of cardiovascular disease, and diagnosis of diabetes. Thus, the positive manifold of aging-related cognitive changes is highly robust in that it can be detected in a narrow age cohort followed over a relatively brief longitudinal period, and persists even after controlling for many potential confounders

Role of KASH domain lengths in the regulation of LINC complexes.

The linker of the nucleoskeleton and cytoskeleton (LINC) complex is formed by the conserved interactions between Sad-1 and UNC-84 (SUN) and Klarsicht, ANC-1, SYNE homology (KASH) domain proteins, providing a physical coupling between the nucleoskeleton and cytoskeleton that mediates the transfer of physical forces across the nuclear envelope. The LINC complex can perform distinct cellular functions by pairing various KASH domain proteins with the same SUN domain protein. For example, in Caenorhabditis elegans, SUN protein UNC-84 binds to two KASH proteins UNC-83 and ANC-1 to mediate nuclear migration and anchorage, respectively. In addition to distinct cytoplasmic domains, the luminal KASH domain also varies among KASH domain proteins of distinct functions. In this study, we combined in vivo C. elegans genetics and in silico molecular dynamics simulations to understand the relation between the length and amino acid composition of the luminal KASH domain, and the function of the SUN-KASH complex. We show that longer KASH domains can withstand and transfer higher forces and interact with the membrane through a conserved membrane proximal EEDY domain that is unique to longer KASH domains. In agreement with our models, our in vivo results show that swapping the KASH domains of ANC-1 and UNC-83, or shortening the KASH domain of ANC-1, both result in a nuclear anchorage defect in C. elegans

Age-related changes to human stratum corneum lipids detected using time-of-flight secondary ion mass spectrometry following in vivo sampling

This work demonstrates the ability to detect changes in both quantity and spatial distribution of human stratum corneum (SC) lipids from samples collected in vivo. The SC functions as the predominant barrier to the body, protecting against the penetration of xenobiotic substances. Changes to the SC lipid composition have been associated with barrier impairment and consequent skin disorders and it is therefore important to monitor and quantify changes to this structure. This work demonstrates the first reported use of time of flight secondary ion mass spectrometry (ToF-SIMS) to assess physiological changes to human SC as a function of depth. This technique provides exceptional sensitivity and chemical specificity, al-lowing analysis of single tape stripped samples taken from volunteers. Using this methodology we were able to successfully identify chemical differences in human SC resulting from both intrinsic and extrinsic (photo) aging. Samples were collected from women of two age groups (under 27 and post-menopausal) and from two body sites with varying UV exposure (inner forearm and dorsal hand) and differences were identified using multivariate data analysis. The key finding was the signifi-cant aged-related increase and change in spatial distribution of the sterol cholesterol sulfate, a membrane stabilizing lipid. Significant changes in the prevalence of both lignoceric acid (C24:0) and hexacosanoic acid (C26:0) were also observed. This work describes previously unreported age-related chemical changes to human SC, providing an insight into aging mechanisms which may improve the design of both pharmaceutical and cosmetic topical products

Inflammatory Cytokine Gene Expression in Mesenteric Adipose Tissue during Acute Experimental Colitis

BACKGROUND: Production of inflammatory cytokines by mesenteric adipose tissue (MAT) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Animal models of colitis have demonstrated inflammatory changes within MAT, but it is unclear if these changes occur in isolation or as part of a systemic adipose tissue response. It is also unknown what cell types are responsible for cytokine production within MAT. The present study was designed to determine whether cytokine production by MAT during experimental colitis is depot-specific, and also to identify the source of cytokine production within MAT. METHODS: Experimental colitis was induced in 6-month-old C57BL/6 mice by administration of dextran sulfate sodium (2% in drinking water) for up to 5 days. The induction of cytokine mRNA within various adipose tissues, including mesenteric, epididymal, and subcutaneous, was analyzed by qRT-PCR. These adipose tissues were also examined for histological evidence of inflammation. The level of cytokine mRNA during acute colitis was compared between mature mesenteric adipocytes, mesenteric stromal vascular fraction (SVF), and mesenteric lymph nodes. RESULTS: During acute colitis, MAT exhibited an increased presence of infiltrating mononuclear cells and fibrotic structures, as well as decreased adipocyte size. The mRNA levels of TNF-α, IL-1β, and IL-6 were significantly increased in MAT but not other adipose tissue depots. Within the MAT, induction of these cytokines was observed mainly in the SVF. CONCLUSIONS: Acute experimental colitis causes a strong site-specific inflammatory response within MAT, which is mediated by cells of the SVF, rather than mature adipocytes or mesenteric lymph nodes

Kinesin-1 and dynein at the nuclear envelope mediate the bidirectional migrations of nuclei

The molecular motors kinesin-1 dynein navigate migrating nuclei around cytoplasmic roadblocks