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Gheorghe Cojoc Emanuele Roscioli Lijuan Zhang Alfonso García-Ulloa Jagesh V. Shah Michael W. Berns Nenad Pavin Daniela Cimini Iva M. Toli? Juraj Gregan 《The Journal of cell biology》2016,212(7):767-776
Accurate chromosome segregation depends on proper kinetochore–microtubule attachment. Upon microtubule interaction, kinetochores are subjected to forces generated by the microtubules. In this work, we used laser ablation to sever microtubules attached to a merotelic kinetochore, which is laterally stretched by opposing pulling forces exerted by microtubules, and inferred the mechanical response of the kinetochore from its length change. In both mammalian PtK1 cells and in the fission yeast Schizosaccharomyces pombe, kinetochores shortened after microtubule severing. Interestingly, the inner kinetochore–centromere relaxed faster than the outer kinetochore. Whereas in fission yeast all kinetochores relaxed to a similar length, in PtK1 cells the more stretched kinetochores remained more stretched. Simple models suggest that these differences arise because the mechanical structure of the mammalian kinetochore is more complex. Our study establishes merotelic kinetochores as an experimental model for studying the mechanical response of the kinetochore in live cells and reveals a viscoelastic behavior of the kinetochore that is conserved in yeast and mammalian cells. 相似文献
814.
Nunzio Vicario Federica M. Spitale Daniele Tibullo Cesarina Giallongo Angela M. Amorini Grazia Scandura Graziana Spoto Miriam W. Saab Simona DAprile Cristiana Alberghina Renata Mangione Joshua D. Bernstock Cirino Botta Massimo Gulisano Emanuele Buratti Giampiero Leanza Robert Zorec Michele Vecchio Michelino Di Rosa Giovanni Li Volti Giuseppe Lazzarino Rosalba Parenti Rosario Gulino 《Cell death & disease》2021,12(7)
Motoneuronal loss is the main feature of amyotrophic lateral sclerosis, although pathogenesis is extremely complex involving both neural and muscle cells. In order to translationally engage the sonic hedgehog pathway, which is a promising target for neural regeneration, recent studies have reported on the neuroprotective effects of clobetasol, an FDA-approved glucocorticoid, able to activate this pathway via smoothened. Herein we sought to examine functional, cellular, and metabolic effects of clobetasol in a neurotoxic mouse model of spinal motoneuronal loss. We found that clobetasol reduces muscle denervation and motor impairments in part by restoring sonic hedgehog signaling and supporting spinal plasticity. These effects were coupled with reduced pro-inflammatory microglia and reactive astrogliosis, reduced muscle atrophy, and support of mitochondrial integrity and metabolism. Our results suggest that clobetasol stimulates a series of compensatory processes and therefore represents a translational approach for intractable denervating and neurodegenerative disorders.Subject terms: Biochemistry, Diseases of the nervous system, Glial biology, Physiology 相似文献
815.
G Palestro G Valente F Botto Micca D Novero L Godio A Stramignoni 《Virchows Archiv. B, Cell pathology including molecular pathology》1982,41(3):253-265
Tissue sections of lymph nodes, appendices and tonsils, together with smears of immunologically separated peripheral lymphoid cells from a B-CLL and lymphomatous cells from an immunocytoma were submitted to combined enzyme cytochemical investigations with acid alpha-naphthyl acetate esterase (ANAE), beta-glucuronidase (B-G), acid phosphatase (AcPh), adenosine triphosphatase (ATPase), a,d 5'nucleotidase (5'N). T-cells were Acph+, ATPase- and 5'N-. The vast majority of T- and B-cells displayed ANAE and B-G activities with two distinct staining patterns (T-like and B-like pattern). A high proportion of lymphoid cells in the germinal centre (G.C.) and the vast majority of lymphoid cells in the mantle-zone (M.Z.) were shown to belong to B-cell system because of the expression of ATPase and 5'N in their membranes. Some lymphoid cells positive for ANAE and B-G with a B-like pattern and for AcPh were recognizable in the G.C. In the M.Z. only a few lymphoid cells being ANAE+, with a T-like pattern, and AcPh+ were shown to belong to the T-cell system. In contrast, in this zone a high proportion of small lymphoid cells (64% +/- 10%) showed ANAE activity, mostly with B-like pattern. Therefore, these findings indicate that in the M.Z. a high proportion of B-cells ATPase+ and 5'N+ also display ANAE activity. By comparison of the results obtained from lymphoid tissue sections, B-CLL and immunocytoma cell suspensions and normal circulating lymphocytes we can conclude that B-ANAE-positive cells of the M.Z. do not usually appear in the peripheral blood. They circulate in large numbers only in some pathological conditions (like our reported B-CLL). Therefore, B-ANAE-positive lymphoid cells of the mantle, with a B-like staining pattern, include a wide range of subsets which exclude large lymphoid cells and plasma cells. 相似文献
816.
David Pantoja-Uceda Cristiana Stuani Douglas V. Laurents Ann E. McDermott Emanuele Buratti Miguel Mompen 《PLoS biology》2021,19(4)
Transactive response DNA-binding Protein of 43 kDa (TDP-43) assembles various aggregate forms, including biomolecular condensates or functional and pathological amyloids, with roles in disparate scenarios (e.g., muscle regeneration versus neurodegeneration). The link between condensates and fibrils remains unclear, just as the factors controlling conformational transitions within these aggregate species: Salt- or RNA-induced droplets may evolve into fibrils or remain in the droplet form, suggesting distinct end point species of different aggregation pathways. Using microscopy and NMR methods, we unexpectedly observed in vitro droplet formation in the absence of salts or RNAs and provided visual evidence for fibrillization at the droplet surface/solvent interface but not the droplet interior. Our NMR analyses unambiguously uncovered a distinct amyloid conformation in which Phe-Gly motifs are key elements of the reconstituted fibril form, suggesting a pivotal role for these residues in creating the fibril core. This contrasts the minor participation of Phe-Gly motifs in initiation of the droplet form. Our results point to an intrinsic (i.e., non-induced) aggregation pathway that may exist over a broad range of conditions and illustrate structural features that distinguishes between aggregate forms.The prion-like domain of TDP-43 assembles biomolecular condensates which mature into amyloid fibrils that accumulate at the condensate/solvent interface. In vitro reconstitution of these fibrils reveals an amyloid core stabilized by residues that are not necessarily essential to create the droplet form. 相似文献
817.
Phenological models are important tools for planning viticultural practices in the short term and for projecting the impact
of climate change on grapevine (Vitis vinifera) in the long term. However, the difficulties in obtaining phenological models which provide accurate predictions on a regional
scale prevent them from being exploited to their full potential. The aim of this work was to obtain a robust phenological
model for V. vinifera cv. Chardonnay. During calibration of the sub-models for budburst, flowering and veraison we implemented a series of measures
to prevent overfitting and to give greater physiological meaning to the models. Among these were the use of experimental information
on the response of Chardonnay to forcing temperatures, restriction of parameter space into physiologically meaningful limits
prior to calibration, and simplification of the previously selected sub-models. The resulting process-based model had good
internal validity and a good level of accuracy in predicting phenological events from external datasets. Model performance
was especially high for the prediction of flowering and veraison, and comparison with other models confirmed it as a better
predictor of phenology, even in extremely warm years. The modelling study highlighted a different phenological behaviour at
the only mountain station, Cembra. We hypothesised that phenotypical plasticity could lead to growth rates adapting to a lower
mean temperature, a mechanism not usually accounted for by phenological models. 相似文献
818.
Vincenza Calabrò Emanuele Ricca Maria Gabriela De Paola Stefano Curcio Gabriele Iorio 《Bioprocess and biosystems engineering》2010,33(6):701-710
In this paper, the reaction of enzymatic trans-esterification of glycerides with ethanol in a reaction medium containing hexane
at a temperature of 37 °C has been studied. The enzyme was Lipase from Mucor miehei, immobilized on ionic exchange resin, aimed at achieving high catalytic specific surface and recovering, regenerating and
reusing the biocatalyst. A kinetic analysis has been carried out to identify the reaction path; the rate equation and kinetic
parameters have been also calculated. The kinetic model has been validated by comparison between predicted and experimental
results. Mass transport resistances estimation was undertaken in order to verify that the kinetics found was intrinsic. Model
potentialities in terms of reactors design and optimization are also shown. 相似文献
819.
Luanluan Sun Lisa Pennells Stephen Kaptoge Christopher P. Nelson Scott C. Ritchie Gad Abraham Matthew Arnold Steven Bell Thomas Bolton Stephen Burgess Frank Dudbridge Qi Guo Eleni Sofianopoulou David Stevens John R. Thompson Adam S. Butterworth Angela Wood John Danesh Nilesh J. Samani Michael Inouye Emanuele Di Angelantonio 《PLoS medicine》2021,18(1)
BackgroundPolygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD.Methods and findingsUsing data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703–0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009–0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40–75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to <10%) 10-year CVD risk could help prevent 1 additional CVD event for approximately every 340 individuals screened. Such a targeted strategy could help prevent 7% more CVD events than conventional risk prediction alone. Potential gains afforded by assessment of PRSs on top of conventional risk factors would be about 1.5-fold greater than those provided by assessment of C-reactive protein, a plasma biomarker included in some risk prediction guidelines. Potential limitations of this study include its restriction to European ancestry participants and a lack of health economic evaluation.ConclusionsOur results suggest that addition of PRSs to conventional risk factors can modestly enhance prediction of first-onset CVD and could translate into population health benefits if used at scale.Luanluan Sun and colleagues investigate whether adding polygenic risk scores to conventional risk factors of cardiovascular disease helps predict disease risk. 相似文献
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