Mammalian models of extended healthy lifespan

Over the last two centuries, there has been a significant increase in average lifespan expectancy in the developed world. One unambiguous clinical implication of getting older is the risk of experiencing age-related diseases including various cancers, dementia, type-2 diabetes, cataracts and osteoporosis. Historically, the ageing process and its consequences were thought to be intractable. However, over the last two decades or so, a wealth of empirical data has been generated which demonstrates that longevity in model organisms can be extended through the manipulation of individual genes. In particular, many pathological conditions associated with the ageing process in model organisms, and importantly conserved from nematodes to humans, are attenuated in long-lived genetic mutants. For example, several long-lived genetic mouse models show attenuation in age-related cognitive decline, adiposity, cancer and glucose intolerance. Therefore, these long-lived mice enjoy a longer period without suffering the various sequelae of ageing. The greatest challenge in the biology of ageing is to now identify the mechanisms underlying increased healthy lifespan in these model organisms. Given that the elderly are making up an increasingly greater proportion of society, this focused approach in model organisms should help identify tractable interventions that can ultimately be translated to humans

Predictive value of hematological and phenotypical parameters on postchemotherapy leukocyte recovery

Background: Grade IV chemotherapy toxicity is defined as absolute neutrophil count <500/μL. The nadir is considered as the lowest neutrophil number following chemotherapy, and generally is not expected before the 7th day from the start of chemotherapy. The usual prophylactic dose of rHu-G-CSF (Filgrastim) is 300 μg/day, starting 24-48 h after chemotherapy until hematological recovery. However, individual patient response is largely variable, so that rHu-G-CSF doses can be different. The aim of this study was to verify if peripheral blood automated flow cytochemistry and flow cytometry analysis may be helpful in predicting the individual response and saving rHu-G-CSF. Methods: During Grade IV neutropenia, blood counts from 30 cancer patients were analyzed daily by ADVIA 120 automated flow cytochemistry analyzer and by Facscalibur flow cytometer till the nadir. "Large unstained cells" (LUCs), myeloperoxidase index (MPXI), blasts, and various cell subpopulations in the peripheral blood were studied. At nadir rHu-G-CSF was started and 81 chemotherapy cycles were analyzed. Cycles were stratified according to their number and to two dose-levels of rHuG-CSF needed to recovery (300-600 vs. 900-1200 μg) and analyzed in relation to mean values of MPXI and mean absolute number of LUCs in the nadir phase. The linear regressions of LUCs % over time in relation to two dose-levels of rHu-G-CSF and uni-multivariate analysis of lymphocyte subpopulations, CD34+ cells, MPXI, and blasts were also performed. Results: In the nadir phase, the increase of MPXI above the upper limit of normality (>10; median 27.7), characterized a slow hematological recovery. MPXI levels were directly related to the cycle number and inversely related to the absolute number of LUCs and CD34 +/CD45+ cells. A faster hematological recovery was associated with a higher LUC increase per day (0.56% vs. 0.25%), higher blast (median 36.7/μL vs. 19.5/μL) and CD34+/CD45+ cell (median 2.2/μL vs. 0.82/μL) counts. Conclusions: Our study showed that some biological indicators such as MPXI, LUCs, blasts, and CD34 +/CD45+ cells may be of clinical relevance in predicting individual hematological response to rHu-G-CSF. Special attention should be paid when nadir MPXI exceeds the upper limit of normality because the hematological recovery may be delayed. © 2009 Clinical Cytometry Society

Selection Signatures in Italian Livestock Guardian and Herding Shepherd Dogs

Simple Summary Livestock guardian and herding shepherd dogs are morphologically and behaviourally different, due to the long selection for different tasks made by farmers and breeders. This study aimed to identify genomic regions that best distinguish and characterise four livestock guardian and five herding Italian dog breeds. Genomic SNP data of 158 dogs were compared using two analyses, allowing for the identification of regions harbouring 29 genes. Sixteen runs of homozygosity islands were found in livestock guardians, four of which were partially shared with the fifteen found in herding shepherd dogs. The identified genes were related to dog domestication and behaviour, including herding behaviour, body size and muscle development, the prick or drop ear phenotype, and eye development and functionality. These results contribute to a better understanding of how human selection shaped the genome of dogs selected for different tasks, even considering a limited geographic area. Livestock guardian (LGD) and herding shepherd (HSD) dogs have distinct morphological and behavioural characteristics, long selected by farmers and breeders, to accomplish different tasks. This study aimed to find the genomic regions that best differentiate and characterise Italian LGD and HSD. Genomic data of 158 dogs of four LGD and five HSD breeds, obtained with the 170K canine SNPchip, were collected. The two groups were compared using F-ST and XP-EHH analyses, identifying regions containing 29 genes. Moreover, 16 islands of runs of homozygosity were found in LGD, and 15 in HSD; 4 of them were partially shared. Among the genes found that better differentiated HSD and LGD, several were associated with dog domestication and behavioural aspects; particularly, MSRB3 and LLPH were linked to herding behaviour in previous studies. Others, DYSK, MAP2K5, and RYR, were related to body size and muscle development. Prick ears prevailed in sampled HSD, and drop ears in LGD; this explains the identification of WIF1 and MSRB3 genes. Unexpectedly, a number of genes were also associated with eye development and functionality. These results shed further light on the differences that human selection introduced in dogs aimed at different duties, even in a limited geographic area such as Italy

Electronic Instability in a Zero-Gap Semiconductor: The Charge-DensityWave in (TaSe4)(2)I

We report a comprehensive study of the paradigmatic quasi-1D compound (TaSe4)(2)I performed by means of angle-resolved photoemission spectroscopy (ARPES) and first-principles electronic structure calculations. We find it to be a zero-gap semiconductor in the nondistorted structure, with non-negligible interchain coupling. Theory and experiment support a Peierls-like scenario for the charge-density wave formation below T-CDW = 263 K, where the incommensurability is a direct consequence of the finite interchain coupling. The formation of small polarons, strongly suggested by the ARPES data, explains the puzzling semiconductor-to-semiconductor transition observed in transport at T-CDW.open114sciescopu

Enhancer SINEs Link Pol III to Pol II Transcription in Neurons

Spatiotemporal regulation of gene expression depends on the cooperation of multiple mechanisms, including the functional interaction of promoters with distally located enhancers. Here, we show that, in cortical neurons, a subset of short interspersed nuclear elements (SINEs) located in the proximity of activity-regulated genes bears features of enhancers. Enhancer SINEs (eSINEs) recruit the Pol III cofactor complex TFIIIC in a stimulus-dependent manner and are transcribed by Pol III in response to neuronal depolarization. Characterization of an eSINE located in proximity to the Fos gene (FosRSINE1) indicated that the FosRSINE1-encoded transcript interacts with Pol II at the Fos promoter and mediates Fos relocation to Pol II factories, providing an unprecedented molecular link between Pol III and Pol II transcription. Strikingly, knockdown of the FosRSINE1 transcript induces defects of both cortical radial migration in vivo and activity-dependent dendritogenesis in vitro, demonstrating that FosRSINE1 acts as a strong enhancer of Fos expression in diverse physiological contexts

Biomarkers and prognostic stratification in psoriatic arthritis

In rheumatic diseases, biomarkers may serve as surrogate endpoints for diagnosis, prognosis, disease activity, therapeutic response and disease outcome. In recent years a great effort has been made to identify useful tools to establish early diagnosis, prognosis and therapeutic response especially in rheumatoid arthritis (RA). In psoriatic arthritis (PsA) serological biomarkers have been frequently borrowed from RA, but this approach have sometimes lead to inappropriate choices of biomarkers and incorrect conclusions. Furthermore, the heterogeneous spectrum of articular manifestation of PsA and the variable course of the disease can make diagnosis and prognosis difficult. Recently, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) identified two key areas for biomarkers development in psoriasis and PsA: the diagnosis of the articular disease in patients with psoriasis and the evaluation of joint damage in PsA. In this review we revised the currently available and the new potential markers for PsA, such as serum, genetic, cellular and histological biomarkers, clinical and imaging data, with particular attention on the prognostic aspect in order to identify progressive disease suitable for a more aggressive treatment

Stearoyl CoA desaturase gene polymorphism in Italian cattle breeds

AbstractStearoyl COA desaturase (SCD) is a rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids. In cattle, a number of studies support the hypothesis that SCD gene regulation and polymorphism may affect fatty acid composition and fat quality in meat and milk. In ruminant-derived food products, SCD activity has been correlated to the content of conjugated linoleic acid (CLA), a mixture of geometrical and positional isomers of linoleic acid C18:2 having several positive effects on human health (i.e. anticarginogenic, antiatherogenic and immunomodulating effects).Aim of this study was to assess the polymorphism of 3 previously reported Single Nucleotide Polymorphisms (SNPs) in exon 5 of SCD gene in 12 cattle breeds raised in Italy, to evaluate the genetic variability and the genetic differences due to breed and/or selection purpose. Breeds sampled cover the whole geographic area of Italian peninsula and represent different selective purposes: 6 meat-purpose or meat-prevalence breeds (Pied..

Two-Dimensional and Three-Dimensional Biomechanical Factors During 90° Change of Direction are Associated to Non-Contact ACL injury in Female Soccer Players

Background The two-dimensional (2D) video-analysis of the change of direction (COD) technique has never been used to attempt to predict the risk of ACL injury in female football players. Hypothesis/Purpose The purpose of the present pilot study was to prospectively investigate the biomechanical predictors of ACL injury during a COD task in female football players using both gold standard 3D motion capture and a qualitative scoring system based on 2D video-analysis. Study Design Prospective cohort study Methods Sixteen competitive female football (soccer) players (age 21.4 ± 4.3) performed a series of pre-planned 90° COD tasks. 3D motion data was recorded through 10 stereophotogrammetric cameras and a force platform. 2D frontal and transverse plane joint kinematics were computed through video-analysis from three high-speed cameras. A scoring system based on five criteria was adopted: limb stability, pelvis stability, trunk stability, shock absorption, and movement strategy. The players were prospectively followed for the next two consecutive football seasons and the occurrence of severe knee injuries was registered. Results Four players (25%) experienced an ACL injury. In 3D analysis, ACL-injured players showed greater knee valgus, knee internal rotation, and lower knee flexion (p= 0.017 – 0.029). Lower hip flexion coupled with greater external rotation (p= 0.003 – 0.042), ankle eversion, and contralateral pelvic drop (p<0.001) were also noted. In 2D analysis, ACL-injured players showed greater internal foot rotation, contralateral pelvic drop, lower knee flexion, and contralateral trunk tilt (moderate-to-large effect size). Pelvis stability and trunk stability showed the highest predictive value towards ACL injury. Total score was significantly lower in ACL-injured players with a moderate effect size (d=0.45). Conclusions Both 3D and 2D methodologies depicted biomechanical risk factors and offered predictive insights towards the ACL injury risk. Awareness should rise in women’s football regarding the high risk of ACL injury and the strategies to assess and mitigate it