The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer’s Disease Pathogenesis

Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) encodes p35, the main activatory subunit of cyclin-dependent kinase 5 (CDK5). The p35/CDK5 active complex plays a fundamental role in brain development and functioning, but its deregulated activity has also been implicated in various neurodegenerative disorders, including Alzheimer\u2019s disease (AD). CDK5R1 displays a large and highly evolutionarily conserved 3\u2032-untranslated region (3\u2032-UTR), a fact that has suggested a role for this region in the post-transcriptional control of CDK5R1 expression. Our group has recently demonstrated that two miRNAs, miR-103 and miR-107, regulate CDK5R1 expression and affect the levels of p35. MiR-103 and miR-107 belong to the miR-15/107 family, a group of evolutionarily conserved miRNAs highly expressed in human cerebral cortex. In this work, we tested the hypothesis that other members of this group of miRNAs, in addition to miR-103 and miR-107, were able to modulate CDK5R1 expression. We provide evidence that several miRNAs belonging to the miR-15/107 family regulate p35 levels. BACE1 expression levels were also found to be modulated by different members of this family. Furthermore, overexpression of these miRNAs led to reduced APP phosphorylation levels at the CDK5-specific Thr668 residue. We also show that miR-15/107 miRNAs display reduced expression levels in hippocampus and temporal cortex, but not in cerebellum, of AD brains. Moreover, increased CDK5R1 mRNA levels were observed in AD hippocampus tissues. Our results suggest that the downregulation of the miR-15/107 family might have a role in the pathogenesis of AD by increasing the levels of CDK5R1/p35 and consequently enhancing CDK5 activity

Variational Foundations and Generalized Unified Theory of RVE-Based Multiscale Models

A unified variational theory is proposed for a general class of multiscale models based on the concept of Representative Volume Element. The entire theory lies on three fundamental principles: (1) kinematical admissibility, whereby the macro- and micro-scale kinematics are defined and linked in a physically meaningful way; (2) duality, through which the natures of the force- and stress-like quantities are uniquely identified as the duals (power-conjugates) of the adopted kinematical variables; and (3) the Principle of Multiscale Virtual Power, a generalization of the well-known Hill-Mandel Principle of Macrohomogeneity, from which equilibrium equations and homogenization relations for the force- and stress-like quantities are unequivocally obtained by straightforward variational arguments. The proposed theory provides a clear, logically-structured framework within which existing formulations can be rationally justified and new, more general multiscale models can be rigorously derived in well-defined steps. Its generality allows the treatment of problems involving phenomena as diverse as dynamics, higher order strain effects, material failure with kinematical discontinuities, fluid mechanics and coupled multi-physics. This is illustrated in a number of examples where a range of models is systematically derived by following the same steps. Due to the variational basis of the theory, the format in which derived models are presented is naturally well suited for discretization by finite element-based or related methods of numerical approximation. Numerical examples illustrate the use of resulting models, including a non-conventional failure-oriented model with discontinuous kinematics, in practical computations

Dental Health and Mortality in People With End-Stage Kidney Disease Treated With Hemodialysis: A Multinational Cohort Study

Background Dental disease is more extensive in adults with chronic kidney disease, but whether dental health and behaviors are associated with survival in the setting of hemodialysis is unknown. Study Design Prospective multinational cohort. Setting & Participants 4,205 adults treated with long-term hemodialysis, 2010 to 2012 (Oral Diseases in Hemodialysis [ORAL-D] Study). Predictors Dental health as assessed by a standardized dental examination using World Health Organization guidelines and personal oral care, including edentulousness; decayed, missing, and filled teeth index; teeth brushing and flossing; and dental health consultation. Outcomes All-cause and cardiovascular mortality at 12 months after dental assessment. Measurements Multivariable-adjusted Cox proportional hazards regression models fitted with shared frailty to account for clustering of mortality risk within countries. Results During a mean follow-up of 22.1 months, 942 deaths occurred, including 477 cardiovascular deaths. Edentulousness (adjusted HR, 1.29; 95% CI, 1.10-1.51) and decayed, missing, or filled teeth score ≥ 14 (adjusted HR, 1.70; 95% CI, 1.33-2.17) were associated with early all-cause mortality, while dental flossing, using mouthwash, brushing teeth daily, spending at least 2 minutes on oral hygiene daily, changing a toothbrush at least every 3 months, and visiting a dentist within the past 6 months (adjusted HRs of 0.52 [95% CI, 0.32-0.85], 0.79 [95% CI, 0.64-0.97], 0.76 [95% CI, 0.58-0.99], 0.84 [95% CI, 0.71-0.99], 0.79 [95% CI, 0.65-0.95], and 0.79 [95% CI, 0.65-0.96], respectively) were associated with better survival. Results for cardiovascular mortality were similar. Limitations Convenience sample of clinics. Conclusions In adults treated with hemodialysis, poorer dental health was associated with early death, whereas preventive dental health practices were associated with longer survival

Monitoraggio del Comportamento Dinamico di un Edificio Isolato Sismicamente

Torino (Italia

Experiments on Rest-to-Rest Motion of a Flexible Arm

Sant’Angelo D’Ischia (Italia

Selenite transiently represses transcription of photosynthesis-related genes in potato leaves

A striking response of potato leaves to aspersion with selenite was observed at the transcriptional level by means of cDNA microarrays analysis. This response is characterized by a general transient repression of genes coding for components of photosynthetic systems and of other light-regulated genes. In particular, maximal repression was observed 8 hours after selenite aspersion, while 24 hours after the treatment a complete recovery of normal transcriptional levels was detected. Another general feature of the transcriptional response to selenite is represented by the transcriptional induction of genes related to amino acid metabolism, and to stress defense; interestingly, two genes coding for glutathione S-transferases were found early-induced upon selenite treatment