FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation

FUsed in Sarcoma (FUS) is a multifunctional RNA binding protein (RBP). FUS mutations lead to its cytoplasmic mislocalization and cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Here, we use mouse and human models with endogenous ALS-associated mutations to study the early consequences of increased cytoplasmic FUS. We show that in axons, mutant FUS condensates sequester and promote the phase separation of fragile X mental retardation protein (FMRP), another RBP associated with neurodegeneration. This leads to repression of translation in mouse and human FUS-ALS motor neurons and is corroborated in vitro, where FUS and FMRP copartition and repress translation. Last, we show that translation of FMRP-bound RNAs is reduced in vivo in FUS-ALS motor neurons. Our results unravel new pathomechanisms of FUS-ALS and identify a novel paradigm by which mutations in one RBP favor the formation of condensates sequestering other RBPs, affecting crucial biological functions, such as protein translation

Business Models and E-Services: an Ontological Approach in a Cross-border Environment

Monograph's chapter

I progetti di gestione della conoscenza e lo sviluppo delle competenze dinamiche

Knowledge Management (KM) projects and practices can serve as a means to develop dynamic capabilities in order to stimulate optimization and innovation activities. The aim of this paper is to analyse how KM projects can contribute to the development of dynamic capabilities; the study is based on four case studies of KM projects implemented by some Italian small and medium size enterprises. Results show that under some conditions KM projects can give an important contribution to the development of dynamic capabilities for both optimization and innovation activitie

The different modes for absorbing knowledge: an analytic lens on absorptive capacity from a process perspective

Absorptive capacity is perceived as the firm\u2019s ability to extract external knowledge from the firm\u2019s environment. Despite numerous studies, little is known about the multifaceted processes with regard to how firms select knowledge from outside and embed it into the firm\u2019s knowledge base. In this paper we investigate, on the basis of exemplary case studies, the entire process with regard to how firms recognise new knowledge and how it is captured and incorporated. Our findings show that knowledge absorption is based on routines which govern knowledge selection and integration into the existing knowledge structure. Knowledge complexity shapes the routine\u2019s characteristics. The absorption of complex knowledge requires more interaction and connectedness between knowledge provider and receiver for developing a similar frame of reference that serves as a carrier of newly absorbed knowledge. Finally, firms need to deal with the paradox that simple routines enhance recognition of new knowledge while a complex set of routines facilitate its incorporation in the subsequent stages

Pulsed Radiofrequency Therapy at Different Voltages on Dorsal Root Ganglia Using Multifunctional Catheter to Treat Low Back Pain: A Comparative Retrospective Study

Background: Applying pulsed radiofrequency (PRF) to the dorsal root ganglion (DRG) is an electrical neuromodulation technique, a valid complementary therapeutic treatment for failed back surgery syndrome (FBBS). Peridurolysis, when applied to vertebral canal adhesions, can be performed with dedicated catheters, providing patients with the benefits of mechanical, electrical, and pharmacological techniques. Objectives: The aim of this study was to evaluate PRF’s effects on the DRG as part of FBSS treatment at different follow-up times, comparing 2 groups of patients exposed to distinct levels of voltage (100 V vs. 45 V) from a PRF generator. Study Design: A retrospective observational study was performed. Setting: The study was conducted on a sample of patients from an Italian hospital. Methods: PRF’s effects on the DRG as part of FBSS treatment were evaluated through the Numeric Rating Scale (NRS) and the monitoring of 155 patients’ opioid consumption at 3, 6, and 9 months. A Cosman® G4 model PRF generator was used. During follow-up periods, the Friedman test was applied to detect differences in outcomes between the 2 groups of patients, who were treated with different levels of voltage. Results: The most frequent diagnosis (61.29%) was FBBS in patients at a mean age of 64 (± 11.8) years old. All patients were treated with PRF on the dorsal ganglion, with the addition of a drug mixture. Most were treated with 100 V (62%). A statistically significant decrease (P < 0.001) in the NRS score emerged both as a whole and in the 2 distinct groups. Moreover, the group of 100 V patients showed a significant (P = 0.0360) reduction in the use of opioids. Limitations: This observational retrospective study was based on a convenience sampling that involved a limited number of patients. Conclusions: E-field technology is the only way to generate a constant 38°/42° PRF and 100 V level throughout surgical interventions (respecting the exposure times “set” by the operator). The patient will not feel any pain or electric current because the generated milliamperes will be greatly reduced