Search

Hutchinson Gilford progeria syndrome (HGPS) is a rare genetic disease with symptoms of aging at a very early age. Its molecular basis is not entirely clear, although profound gene expression changes have been reported, and there are some known and other presumed overlaps with normal aging process. Identification of genes with aging - or HGPS-associated expression changes is thus an important problem. However, standard regression approaches are currently unsuitable for this task due to limited sample sizes, thus motivating development of alternative approaches. Here, we report a novel iterative multiple regression approach that leverages co-expressed gene clusters to identify gene clusters whose expression co-varies with age and/or HGPS. We have applied our approach to novel RNA-seq profiles in fibroblast cell cultures at three different cellular ages, both from HGPS patients and normal samples. After establishing the robustness of our approach, we perform a comparative investigation of biological processes underlying normal aging and HGPS. Our results recapitulate previously known processes underlying aging as well as suggest numerous unique processes underlying aging and HGPS. The approach could also be useful in detecting phenotype-dependent co-expression gene clusters in other contexts with limited sample sizes.

In order to overcome the high volatility caused by single-phase voltage curve and improve the accuracy of judging whether the two substation areas belong to the same 10 kV line. The reduction method of outlet voltage of transformer with unbalanced three-phase load is proposed in this paper. Simulation models have also been built to calculate the outlet voltage of transformer. The results of simulation and reduction method have been compared. Results show that the results of reduction method are consistent with the simulation results. Although there exist differences between simulation and reduction method, but the differences are tolerable. It also can be concluded that the reduction method proposed in this paper has good adaptability.

With the increasing penetration of renewable energy sources (RES) and strong coupling between electric power systems and other forms of energy, there are vast opportunities and challenges for every practitioner in energy field, especially so many stochastic characteristics to suppress, such as wind, photovoltaic and load demand. This manuscript establishes an integrated optimal operation model of energy internet considering the multi-time-scale stochastic characteristics of RES. Finally, the particle swarm optimization (PSO) algorithm is applied to the optimization of the proposed model and the simulation results show that the proposed model is correct and effective.

Alternative splicing contributes to phenotypic diversity at multiple biological scales, and its dysregulation is implicated in both ageing and age-associated diseases in human. Cross-tissue variability in splicing further complicates its links to age-associated phenotypes and elucidating these links requires a comprehensive map of age-associated splicing changes across multiple tissues. Here, we generate such a map by analyzing ~8500 RNA-seq samples across 48 tissues in 544 individuals. Employing a stringent model controlling for multiple confounders, we identify 49,869 tissue-specific age-associated splicing events of 7 distinct types. We find that genome-wide splicing profile is a better predictor of biological age than the gene and transcript expression profiles, and furthermore, age-associated splicing provides additional independent contribution to age-associated complex diseases. We show that the age-associated splicing changes may be explained, in part, by concomitant age-associated changes of the upstream splicing factors. Finally, we show that our splicing-based model of age can successfully predict the relative ages of cells in 8 of the 10 paired longitudinal data as well as in 2 sets of cell passage data. Our study presents the first systematic investigation of age-associated splicing changes across tissues, and further strengthening the links between age-associated splicing and age-associated diseases.

Oxidative stress is the major cause of skin aging that includes wrinkles, pigmentation, and weakened wound healing ability. Application of antioxidants in skin care is well accepted as an effective approach to delay the skin aging process. Methylene blue (MB), a traditional mitochondrial-targeting antioxidant, showed a potent ROS scavenging efficacy in cultured human skin fibroblasts derived from healthy donors and from patients with progeria, a genetic premature aging disease. In comparison with other widely used general and mitochondrial-targeting antioxidants, we found that MB was more effective in stimulating skin fibroblast proliferation and delaying cellular senescence. The skin irritation test, performed on an in vitro reconstructed 3D human skin model, indicated that MB was safe for long-term use, and did not cause irritation even at high concentrations. Application of MB to this 3D skin model further demonstrated that MB improved skin viability, promoted wound healing and increased skin hydration and dermis thickness. Gene expression analysis showed that MB treatment altered the expression of a subset of extracellular matrix proteins in the skin, including upregulation of elastin and collagen 2A1, two essential components for healthy skin. Altogether, our study suggests that MB has a great potential for skin care.

The reliability evaluation of the electrical distribution networks (EDN) requires sufficient consideration of the effects of planned outages. The planned outages of the EDN can be divided, by outage models and their effects on the reliability into two major categories: by equipment and by feeder. After studying the characteristics of different categories of planned outages, this paper expands the classification of load points by outage time from 4 types to 7 types and defines corresponding reliability parameters for the different types. By using the section algorithm, this paper proposes a reliability evaluation technique of EDN considering equipment random failures and two categories of planned outages. The proposed technique has been applied to the RBTS-BUS6 test system and some practical EDNs in China. The study results demonstrate that the proposed technique is of higher practical value and can be used for evaluating the reliability performance of EDN more efficiently considering the planned outages.

MicroRNAs (miRNAs) have gained much attention due to their critical roles in diverse biological events, including tumorigenesis. In this study, we demonstrate that miR-136 is down-regulated in two cohorts of patients with glioma. Furthermore, the low-level expression of miR-136 is significantly associated with a more aggressive and/or poor prognostic phenotype of patients with gliomas. Both gain- and loss-of-function experiments showed that miR-136 expression can reverse cisplatin resistance and enhance the response to cisplatin treatment. Furthermore, we identified a novel direct target of miR-136, the E2F transcription factor 1 (E2F1) oncogene. Depletion of E2F1 recapitulated the tumor-suppressive functions of miR-136, whereas re-expression of E2F1 attenuated the function of miR-136 in glioma cells. Finally, we revealed that miR-136 is inversely correlated with E2F1 expression in human glioma samples. The present study provides functional and mechanistic links between the tumor suppressor miR-136 and the oncogene E2F1 for the development of chemoresistance in human glioma. Our results indicate that targeting of the miR-136/E2F1 axis may provide a promising therapeutic approach to treat glioma.

The effects of strain rate and temperature on the tension stress–strain responses of polycarbonate are experimentally investigated over a wide range of strain rates (0.001–1700 s−1) and temperatures (0–120 °C). A modified split Hopkinson tension bar is used for high-rate uniaxial tension tests. Experimental results indicate that the stress–strain responses of polycarbonate at high strain rates exhibit the nonlinear characteristics including the obvious yielding and strain softening. The tension behavior is strongly dependent on the strain rate and temperature. The values of yield stress and strain at yield present a dramatic increase at higher strain rates and decrease with the increase in temperature. Moreover, there exists a significant rate-sensitivity transition in the polycarbonate tension yield behavior. Based on the experimental investigation, a physically based three-dimensional elastoplastic constitutive model for the finite deformation of glassy polymers is used to characterize the rate-temperature dependent yield and post-yield behavior of polycarbonate when subjected to tension loading. The model results are shown close to the experimental data within the investigated strain-rate and temperature ranges.

Lamin A is a major component of the lamina, which creates a dynamic network underneath the nuclear envelope. Mutations in the lamin A gene (LMNA) cause severe genetic disorders, one of which is Hutchinson-Gilford progeria syndrome (HGPS), a disease triggered by a dominant mutant named progerin. Unlike the wild-type lamin A, whose farnesylated C-terminus is excised during post-translational processing, progerin retains its farnesyl tail and accumulates on the nuclear membrane, resulting in abnormal nuclear morphology during interphase. In addition, membrane-associated progerin forms visible cytoplasmic aggregates in mitosis. To examine the potential effects of cytoplasmic progerin, nuclear localization signal (NLS) deleted progerin and lamin A (PGΔNLS and LAΔNLS, respectively) have been constructed. We find that both ΔNLS mutants are farnesylated in the cytosol and associate with a sub-domain of the ER via their farnesyl tails. While the farnesylation on LAΔNLS can be gradually removed, which leads to its subsequent release from the ER into the cytoplasm, PGΔNLS remains permanently farnesylated and membrane-bounded. Moreover, both ΔNLS mutants dominantly affect emerin’s nuclear localization. These results reveal new insights into lamin A biogenesis and lamin A-emerin interaction.

Compelling evidence suggests that defective DNA damage response (DDR) plays a key role in the premature aging phenotypes in Hutchinson-Gilford progeria syndrome (HGPS). Studies document widespread alterations in histone modifications in HGPS cells, especially, the global loss of histone H3 trimethylated on lysine 9 (H3K9me3). In this study, we explore the potential connection(s) between H3K9me3 loss and the impaired DDR in HGPS. When cells are exposed to a DNA-damaging agent Doxorubicin (Dox), double strand breaks (DSBs) are generated that result in the phosphorylation of histone H2A variant H2AX (gammaH2AX) within an hour. We find that the intensities of gammaH2AX foci appear significantly weaker in the G0/G1 phase HGPS cells compared to control cells. This reduction is associated with a delay in the recruitment of essential DDR factors. We further demonstrate that ataxia-telangiectasia mutated (ATM) is responsible for the amplification of gammaH2AX signals at DSBs during G0/G1 phase, and its activation is inhibited in the HGPS cells that display significant loss of H3K9me3. Moreover, methylene (MB) blue treatment, which is known to save heterochromatin loss in HGPS, restores H3K9me3, stimulates ATM activity, increases gammaH2AX signals and rescues deficient DDR. In summary, this study demonstrates an early DDR defect of attenuated gammaH2AX signals in G0/G1 phase HGPS cells and provides a plausible connection between H3K9me3 loss and DDR deficiency.

The current design method of the pot rubber bearing and the existing problems have been analysised.It was ensured that dimension driving method was applied in the SolidWorks modeling driven by Visual Basic. The pre-processing of FEA on the upper bearing plate based on SolidWorks Simulation was ensured, and took the part as an example to show how to use Visual Basic to drive SolidWorks Simulation to realize FEA.

Further development of SolidWorks with VB is carried out in this paper. Program and dimension driving methods are utilized for parametric design to realize the automatic generation of three dimension component and engineering drawing in SolidWorks. Intelligent generation of drawing is achieved by adjusting the view scale of engineering drawing, generating view size and cutaway view in order to improve the design efficiency and quality.

Lipodystrophies, characterized by partial or complete loss of adipose tissue, have been associated with mutations in the lamin A gene. It remains unclear how lamin A mutants interfere with adipose tissue formation. Hutchinson–Gilford progeria syndrome (HGPS) presents the most severe form of lamin A-associated diseases, whose patients show a complete loss of subcutaneous fat. Using iPSCs reprogrammed from HGPS fibroblasts, we induced adipocyte formation from iPSC derived embryoid bodies or from iPSC derived mesenchymal stem cells. Both approaches revealed a severe lipid storage defect in HGPS cells at late differentiation stage, faithfully recapitulating HGPS patient phenotype. Expression analysis further indicated that progerin inhibited the transcription activation of PPARγ2 and C/EBPα, but had little effects on the early adipogenic regulators. Our experiments demonstrate two comparable approaches of in vitro modeling lipodystrophies with patient-specific iPSCs, and support a regulatory role of lamin A in the terminal differentiation stage of adipogenesis.

According to the measured results of loads, the method of theoretical calculation is used to analysis the composition, distribution and influencing factors of line losses for main network of Hubei power grid on the representative day. Considering the current situation of large-scale wind power integration on power system recent years, the impacts of wind power integration on line losses of power grid are also analyzed in this paper with Suizhou area as an example.

Tension stress–strain responses of polycarbonate are presented for strain rates of 1 × 10 −3 s −1 –1700 s −1 and temperatures ranging from −60 to 20 °C. The high rate tension tests are performed using a split Hopkinson tension bar apparatus. The influence of strain rate and temperature on the tension behavior of polycarbonate is investigated. Experimental results indicate that the tension behavior of polycarbonate exhibits nonlinear characteristics and rate-temperature sensitivity. The values of yield strength and strain at yield increase with the increase of strain rate and decrease with increasing temperature. A viscoelastic constitutive model consisting of a nonlinear spring and a nonlinear Maxwell element is proposed to characterize the rate and temperature dependent deformation behavior of polycarbonate prior to yielding.

The premature aging disorder, Hutchinson-Gilford progeria syndrome (HGPS), is caused by mutant lamin A, which affects the nuclear scaffolding. The phenotypic hallmark of HGPS is nuclear blebbing. Interestingly, similar nuclear blebbing has also been observed in aged cells from healthy individuals. Recent work has shown that treatment with rapamycin, an inhibitor of the mTOR pathway, reduced nuclear blebbing in HGPS fibroblasts. However, the extent of blebbing varies considerably within each cell population, which makes manual blind counting challenging and subjective. Here, we show a novel, automated and high throughput nuclear shape analysis that quantitatively measures curvature, area, perimeter, eccentricity and additional metrics of nuclear morphology for large populations of cells. We examined HGPS fibroblast cells treated with rapamycin and RAD001 (an analog to rapamycin). Our analysis shows that treatment with RAD001 and rapamycin reduces nuclear blebbing, consistent with blind counting controls. In addition, we find that rapamycin treatment reduces the area of the nucleus, but leaves the eccentricity unchanged. Our nuclear shape analysis provides an unbiased, multidimensional "fingerprint" for a population of cells, which can be used to quantify treatment efficacy and analyze cellular aging.

Due to the lack of feeder corridors, the Chinese utility companies frequently choose the technique of putting multiple overhead feeders on a same tower (MFST) to meet the load demand in a heavy load area. In many situations, the distance among the feeders of MFST in an electrical distribution network (EDN) is usually too small to meet the requirements of safety regulation for repairing and maintenance. Therefore, when a fault occurs on a feeder of MFST, the other feeders have to be in a triggered passive outage (TPO) state to assist the repairing of the failed feeder. This paper presents a reliability evaluation algorithm for EDNs containing MFST using the section technique. The definition of TPO and the equivalent TPO rate and TPO duration are also proposed. Based on the TPO parameters and the section technique, the reliability evaluation algorithm containing the MFST can be obtained. Case studies on the modified RBTS-BUS6 and the EDNs of three districts in Dongguan city, China, show that the MFST has a significant impact on the EDN reliability and should be considered in the reliability evaluation. The results also show the effectiveness and applicability of the proposed approach.

Virtual synchronous generators (VSGs) present attractive technical advantages and contribute to enhanced system operation and reduced oscillation damping in dynamic systems. Traditional VSGs often lack an interworking during power oscillation. In this paper, a coordinated control strategy for multiple VSGs is proposed for mitigating power oscillation. Based on a theoretical analysis of the parameter impact of VSGs, a coordinated approach considering uncertainty is presented by utilizing polytopic linear differential inclusion (PLDI) and a D-stable model to enhance the small-signal stability of system. Subsequently, the inertia and damping of multiple VSGs are jointly exploited to reduce oscillation periods and overshoots during transient response. Simulation, utilizing a two-area four-machine system and a typical microgrid test system, demonstrates the benefits of the proposed strategy in enhancing operation stability and the anti-disturbing ability of multiple VSGs. The results conclusively confirm the validity and applicability of the method.

The effect of strain rate on the tensile behavior of polycarbonate was investigated under uniaxial tension loading conditions. The experiments were carried out using a conventional servo-hydraulic testing machine, a moderate strain-rate testing apparatus and a split-Hopkinson tension bar system. The tension stress–strain responses at various strain rates ranging from 0.001 s −1 up to 1700 s −1 were obtained. Experimental results show that the strain rate greatly influences the tensile behavior of polycarbonate. The value of yield strength is found to increase with increasing strain rate. A viscoelastic constitutive model consisting of a nonlinear spring and a nonlinear Maxwell element was proposed to describe the tension stress–strain behavior of polycarbonate over a wide range of strain rates. The correlation between the experimental data and the model results is good.

Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic form of human premature aging. Death occurs at a mean age of 13 years, usually from heart attack or stroke. Almost all cases of HGPS are caused by a de novo point mutation in the lamin A ( LMNA ) gene that results in production of a mutant lamin A protein termed progerin. This protein is permanently modified by a lipid farnesyl group, and acts as a dominant negative, disrupting nuclear structure. Treatment with farnesyltransferase inhibitors (FTIs) has been shown to prevent and even reverse this nuclear abnormality in cultured HGPS fibroblasts. We have previously created a mouse model of HGPS that shows progressive loss of vascular smooth muscle cells in the media of the large arteries, in a pattern that is strikingly similar to the cardiovascular disease seen in patients with HGPS. Here we show that the dose-dependent administration of the FTI tipifarnib (R115777, Zarnestra) to this HGPS mouse model can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of existing cardiovascular disease. These observations provide encouraging evidence for the current clinical trial of FTIs for this rare and devastating disease.

Alternative splicing significantly contributes to proteomic diversity and mis-regulation of splicing can cause diseases in human. Although both genomic and chromatin features have been shown to associate with splicing, the mechanisms by which various chromatin marks influence splicing is not clear for the most part. Moreover, it is not known whether the influence of specific genomic features on splicing is potentially modulated by the chromatin context. Here we report a deep neural network (DNN) model for predicting exon inclusion based on comprehensive genomic and chromatin features. Our analysis in three cell lines shows that, while both genomic and chromatin features can predict splicing to varying degrees, genomic features are the primary drivers of splicing, and the predictive power of chromatin features can largely be explained by their correlation with genomic features; chromatin features do not yield substantial independent contribution to splicing predictability. However, our model identified specific interactions between chromatin and genomic features suggesting that the effect of genomic elements may be modulated by chromatin context.

Plenty of uncertainty and correlation factors exist in power systems. These factors have important influence on power system operation. The probabilistic load flow (PLF) algorithm considering correlation between input random variables is an efficacious tool to handle these factors. Three commonly used modeling techniques of correlated input random variables are analyzed, including Nataf transformation, polynomial normal transformation and Copula theory. The procedure, feature, advantage and disadvantage of different PLF algorithms, such as Monte Carlo simulation method, cumulant method and point estimate method, are reviewed considering correlation between input random variables.

Hutchinson–Gilford progeria syndrome (HGPS) is a severe human premature aging disorder caused by a lamin A mutant named progerin. Death occurs at a mean age of 13 y from cardiovascular problems. Previous studies revealed loss of vascular smooth muscle cells (SMCs) in the media of large arteries in a patient with HGPS and two mouse models, suggesting a causal connection between the SMC loss and cardiovascular malfunction. However, the mechanisms of how progerin leads to massive SMC loss are unknown. In this study, using SMCs differentiated from HGPS induced pluripotent stem cells, we show that HGPS SMCs exhibit a profound proliferative defect, which is primarily caused by caspase-independent cell death. Importantly, progerin accumulation stimulates a powerful suppression of PARP1 and consequently triggers an activation of the error-prone nonhomologous end joining response. As a result, most HGPS SMCs exhibit prolonged mitosis and die of mitotic catastrophe. This study demonstrates a critical role of PARP1 in mediating SMC loss in patients with HGPS and elucidates a molecular pathway underlying the progressive SMC loss in progeria.

The gamma-tubulin ring complex (gammaTuRC) is important for microtubule nucleation from the centrosome. In addition to gamma-tubulin, the Drosophila gammaTuRC contains at least six subunits, three of which [Drosophila gamma ring proteins (Dgrips) 75/d75p, 84, and 91] have been characterized previously. Dgrips84 and 91 are present in both the small gamma-tubulin complex (gammaTuSC) and the gammaTuRC, while the remaining subunits are found only in the gammaTuRC. To study gammaTuRC assembly and function, we first reconstituted gammaTuSC using the baculovirus expression system. Using the reconstituted gammaTuSC, we showed for the first time that this subcomplex of the gammaTuRC has microtubule binding and capping activities. Next, we characterized two new gammaTuRC subunits, Dgrips128 and 163, and showed that they are centrosomal proteins. Sequence comparisons among all known gammaTuRC subunits revealed two novel sequence motifs, which we named grip motifs 1 and 2. We found that Dgrips128 and 163 can each interact with gammaTuSC. However, this interaction is insufficient for gammaTuRC assembly.

Background: Hutchinson Gilford progeria syndrome (HGPS) is a rare genetic disease with symptoms of aging manifested at a very early age. Molecular basis of HGPS is not entirely clear, although there are some known and other presumed overlaps with normal aging process. Comparative investigation of biological processes associated with HGPS and normal aging may reveal common and distinctive pathways underlying these two conditions. Results: To investigate transcriptome changes through aging we have performed RNA-seq profiling in fibroblast cell cultures at three different cellular ages as measured by number of passages through culture growth, both from HGPS patients and matched normal samples. We then developed a novel iterative multiple regression approach that leverages co-expressed gene clusters to identify gene clusters whose expression changes significantly with age and/or disease state. We establish the robustness of our approach. Finally, we perform a comparative investigation of biological processes underlying normal aging and HGPS. Conclusion: Based on an iterative multiple regression approach applied to novel RNA-seq data in HGPS and aging our results recapitulate the previously known processes underlying aging while at the same time suggests numerous unique processes underlying aging and HGPS.

Cell heterogeneity and the inherent complexity due to the interplay of multiple molecular processes within the cell pose difficult challenges for current single-cell biology. We introduce an approach that identifies a disease phenotype from multiparameter single-cell measurements, which is based on the concept of "supercell statistics", a single-cell-based averaging procedure followed by a machine learning classification scheme. We are able to assess the optimal tradeoff between the number of single cells averaged and the number of measurements needed to capture phenotypic differences between healthy and diseased patients, as well as between different diseases that are difficult to diagnose otherwise. We apply our approach to two kinds of single-cell datasets, addressing the diagnosis of a premature aging disorder using images of cell nuclei, as well as the phenotypes of two non-infectious uveitides (the ocular manifestations of Behçet's disease and sarcoidosis) based on multicolor flow cytometry. In the former case, one nuclear shape measurement taken over a group of 30 cells is sufficient to classify samples as healthy or diseased, in agreement with usual laboratory practice. In the latter, our method is able to identify a minimal set of 5 markers that accurately predict Behçet's disease and sarcoidosis. This is the first time that a quantitative phenotypic distinction between these two diseases has been achieved. To obtain this clear phenotypic signature, about one hundred CD8+ T cells need to be measured. Although the molecular markers identified have been reported to be important players in autoimmune disorders, this is the first report pointing out that CD8+ T cells can be used to distinguish two systemic inflammatory diseases. Beyond these specific cases, the approach proposed here is applicable to datasets generated by other kinds of state-of-the-art and forthcoming single-cell technologies, such as multidimensional mass cytometry, single-cell gene expression, and single-cell full genome sequencing techniques., Instituto de Física de Líquidos y Sistemas Biológicos

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant-negative lamin A protein, known as progerin. Here we show that primary HGPS skin fibroblasts experience genome-wide correlated alterations in patterns of H3K27me3 deposition, DNA-lamin A/C associations, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin–lamina interactions. These changes may result in transcriptional misregulation and eventually trigger the global loss of spatial chromatin compartmentalization in late passage HGPS fibroblasts.

The A- and B-type lamins are nuclear intermediate filament proteins in eukaryotic cells with a broad range of functions, including the organization of nuclear architecture and interaction with proteins in many cellular functions. Over 180 disease-causing mutations, termed 'laminopathies,' have been mapped throughout LMNA, the gene for A-type lamins in humans. Laminopathies can range from muscular dystrophies, cardiomyopathy, to Hutchinson-Gilford progeria syndrome. A number of mouse lines carrying some of the same mutations as those resulting in human diseases have been established. These LMNA-related mouse models have provided valuable insights into the functions of lamin A biogenesis and the roles of individual A-type lamins during tissue development. This review groups these LMNA-related mouse models into three categories: null mutants, point mutants, and progeroid mutants. We compare their phenotypes and discuss their potential implications in laminopathies and aging.

Cell biologists love to think outside the box, pursuing many surprising twists and unexpected turns in their quest to unravel the mysteries of how cells work. But can cell biologists think outside the bench? We are certain that they can, and clearly some already do. To encourage more cell biologists to venture into the realm of translational research on a regular basis, we would like to share a handful of the many lessons that we have learned in our effort to develop experimental treatments for Hutchinson-Gilford progeria syndrome (HGPS), an endeavor that many view as a “poster child” for how basic cell biology can be translated to the clinic.

The nuclear lamina is the main architectural component of a eukaryotic nucleus. More than an inert scaffold, the lamina is essential for maintaining proper nuclear organisation, epigenetic composition, transcriptional regulation and cell cycle progression. Mutations within lamin genes lead to a wide range of diseases known as laminopathies, among which the striking premature aging disease Hutchinson–Gilford progeria syndrome (HGPS) is the most well known. Studies regarding the cellular basis of laminopathies have advanced our knowledge of the nuclear lamina and yielded remarkable insights into the process of normal human aging. Understanding the molecular mechanisms responsible for disease manifestations has also led to the development of novel therapeutic strategies to address lamina-related diseases. Ultimately, scientists and clinicians seek to provide treatment options to laminopathy patients to alleviate symptoms and perhaps to cure these diseases in the future. Key Concepts: Mutations in genes encoding lamin proteins lead to a wide range of diseases known as laminopathies. The nuclear lamina plays essential roles in maintaining nuclear architecture, chromatin organisation, cellular differentiation and gene expression. Studies of the molecular mechanisms underlying laminopathies have led to advances in the understanding of lamin structure and function. Progerin, the mutant form of lamin A expressed in Hutchinson–Gilford progeria syndrome, is also present in normal individuals, albeit at a low level. Recent advances have led to the development of noval therapeutic options for patients suffering from HGPS. Keywords: nuclear lamina; lamins; laminopathies; muscular dystrophy; Hutchison–Gilford progeria syndrome; epigenetics; farnesylation; morpholino

While rapamycin has been in use for years in transplant patients as an antirejection drug, more recently it has shown promise in treating diseases of aging, such as neurodegenerative disorders and atherosclerosis. We recently reported that rapamycin reverses the cellular phenotype of fibroblasts from children with the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS). We found that the causative aberrant protein, progerin, was cleared through autophagic mechanisms when the cells were treated with rapamycin, suggesting a new potential treatment for HGPS. Recent evidence shows that progerin is also present in aged tissues of healthy individuals, suggesting that progerin may contribute to physiological aging. While it is intriguing to speculate that rapamycin may affect normal aging in humans, as it does in lower organisms, it will be important to identify safer analogues of rapamycin for chronic treatments in humans in order to minimize toxicity. In addition to its role in HGPS and normal aging, we discuss the potential of rapamycin for the treatment of age-dependent neurodegenerative diseases.

Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS.

A comparative experimental investigation was carried out for heat transfer and resistance characteristics of smooth tube and 9 spirally fluted tubes with various structural parameters. The results show that the heat transfer and flow resistance performances of spirally fluted tubes are better than smooth tube. The heat transfer coefficient of the spirally fluted tubes are as 2.46∼3.08 times as the smooth tube's. The flow resistance coefficient of the fluted tubes are as 2.1∼7 times as the plain tube. The correlations with relatively high precision have been obtained regarding heat transfer coefficient and resistance factor of the mentioned fluted tubes by adopting a multivariable linear regression method. This paper also analyzes the main influence factors of heat transfer and flow characteristics of spirally fluted tubes and points out that using small pitch and groove depth can obtain better heat transfer effect.

Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause-and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process.

Objective— Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. Methods and Results— We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year ( P Conclusion— We find concordance among many aspects of cardiovascular pathology in both HGPS and geriatric patients. HGPS generates a more prominent adventitial fibrosis than typical CVD. Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in cardiovascular aging of the general population.

A new method is developed for tracing the unreliability contributions of system components and recognizing the system weak parts using the fault tree analysis (FTA). The method is based on the minimum cut set (MCS) algorithm for evaluating the system reliability using the FTA and the proportional sharing principle (PSP). The fault tree can be expressed as MCSs and the system unreliability can be mathematically expressed by a certain terms of probability of occurrence of MCSs. A unreliability tracing (UT) principle is proposed for allocating the probability of each term to the basic events fairly and reasonably, and then the direct contribution relationship between the system unreliability and basic events can be established. The system UT sharing factors (UTSFs) are derived to easily identify the weakness parts in a system. The applicability of the proposed methods is illustrated by case studies of a simple system and a multiple-output power distribution system.

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGPS is caused by a de novo point mutation in exon 11 (residue 1824, C → T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A (LA) protein termed “progerin/LAΔ50” that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LAΔ50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LAΔ50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LAΔ50 mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation. These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LAΔ50. Furthermore, we demonstrate that small amounts of progerin/LAΔ50 exist in normal fibroblasts, and a significant percentage of these progerin/LAΔ50-expressing normal cells are binucleated, implicating progerin/LAΔ50 as causing similar mitotic defects in the normal aging process. Our findings present evidence of mitotic abnormality in HGPS and may shed light on the general phenomenon of aging.

Proper chromosome segregation requires the attachment of sister kinetochores to microtubules from opposite spindle poles to form bi-oriented chromosomes on the metaphase spindle. The chromosome passenger complex containing Survivin and the kinase Aurora B regulates this process from the centromeres. We report that a de-ubiquitinating enzyme, hFAM, regulates chromosome alignment and segregation by controlling both the dynamic association of Survivin with centromeres and the proper targeting of Survivin and Aurora B to centromeres. Survivin is ubiquitinated in mitosis through both Lys 48 and Lys 63 ubiquitin linkages. Lys 63 de-ubiquitination mediated by hFAM is required for the dissociation of Survivin from centromeres, whereas Lys 63 ubiquitination mediated by the ubiquitin binding protein Ufd1 is required for the association of Survivin with centromeres. Thus, ubiquitinaton regulates dynamic protein-protein interactions and chromosome segregation independently of protein degradation.

The AAA ATPase Cdc48/p97 together with its adaptors, Ufd1-Npl4, regulate membrane-related functions and mitotic spindle disassembly by directly binding to membrane-associated proteins or spindle assembly factors, modulating their interactions with membranes or spindles, respectively. Here, we discuss the possibility that the Cdc48/ p97-Ufd1-Npl4 complex has a more general role in mediating morphological transitions as the cell exits mitosis and enters G(1).

The small GTPase Ran has a well-established role in nucleocytoplasmic trafficking. In recent years, the repertoire of Ran has expanded to include regulation of spindle assembly, formation of the nuclear envelope and DNA replication. Now, new studies further extend the role of Ran to regulating the spindle checkpoint during mitosis.

International audience; The activated form of Ran (Ran-GTP) stimulates spindle assembly in Xenopus laevis egg extracts, presumably by releasing spindle assembly factors, such as TPX2 (target protein for Xenopus kinesin-like protein 2) and NuMA (nuclear-mitotic apparatus protein) from the inhibitory binding of importin-alpha and -beta. We report here that Ran-GTP stimulates the interaction between TPX2 and the Xenopus Aurora A kinase, Eg2. This interaction causes TPX2 to stimulate both the phosphorylation and the kinase activity of Eg2 in a microtubule-dependent manner. We show that TPX2 and microtubules promote phosphorylation of Eg2 by preventing phosphatase I (PPI)-induced dephosphorylation. Activation of Eg2 by TPX2 and microtubules is inhibited by importin-alpha and -beta, although this inhibition is overcome by Ran-GTP both in the egg extracts and in vitro with purified proteins. As the phosphorylation of Eg2 stimulated by the Ran-GTP-TPX2 pathway is essential for spindle assembly, we hypothesize that the Ran-GTP gradient established by the condensed chromosomes is translated into the Aurora A kinase gradient on the microtubules to regulate spindle assembly and dynamics.