The strategic timing of R&D agreements.

We present a model of endogenous formation of R&D agreements among firms in which also the timing of R&D investment is made endogenous. The purpose is to bridge two usually separate streams of literature, the noncooperative formation of R&D alliances and the endogenous timing literature. Our approach allows to consider the formation of R&D agreements over time. It is shown that, when both R&D spillovers and investment costs are sufficiently low, firms may find difficult to maintain a stable R&D agreement due to the strong incentive to invest noncooperatively as leaders. In such a case, to be stable a R&D agreement requires that the joint investment occurs at the initial stage, avoiding any delay. When instead R&D spillover rates are sufficiently high, the cooperation in R&D constitutes a profitable option, although firms also possess the incentive to sequence their investment over time. Finally, when spillovers are asymmetric and the knowledge leaks mainly from the leader to the follower, to invest as follower becomes extremely profitable, making R&D alliances hard to sustain unless firms strategically delay their joint investment in R&D.R&D investment, Spillovers, Endogenous Timing.

Pharmacogenetics of osteoporosis

Osteoporosis is a complex bone disorder with a strong genetic basis. The genetics of osteoporosis encompasses two main areas: genetics of disease susceptibility and pharmacogenetics of drug response. The former has been widely studied in the past few decades, while the latter is still largely untouched. This review will provide an overview of the pharmacogenetics of osteoporosis, focusing on the major recent advances in the past two years

Genetic Determinants of Osteoporosis: Common Bases to Cardiovascular Diseases?

Osteoporosis is the most common and serious age-related skeletal disorder, characterized by a low bone mass and bone microarchitectural deterioration, with a consequent increase in bone fragility and susceptibility to spontaneous fractures, and it represents a major worldwide health care problem with important implications for health care costs, morbidity and mortality. Today is well accepted that osteoporosis is a multifactorial disorder caused by the interaction between environment and genes that singularly exert modest effects on bone mass and other aspects of bone strength and fracture risk. The individuation of genetic factors responsible for osteoporosis predisposition and development is fundamental for the disease prevention and for the setting of novel therapies, before fracture occurrence. In the last decades the interest of the Scientific Community has been concentrated in the understanding the genetic bases of this disease but with controversial and/or inconclusive results. This review tries to summarize data on the most representative osteoporosis candidate genes. Moreover, since recently osteoporosis and cardiovascular diseases have shown to share common physiopathological mechanisms, this review also provides information on the current understanding of osteoporosis and cardiovascular diseases common genetic bases

What Is New in the miRNA World Regarding Osteosarcoma and Chondrosarcoma?

Despite the availability of multimodal and aggressive therapies, currently patients with skeletal sarcomas, including osteosarcoma and chondrosarcoma, often have a poor prognosis. In recent decades, advances in sequencing technology have revealed the presence of RNAs without coding potential known as non-coding RNAs (ncRNAs), which provides evidence that protein-coding genes account for only a small percentage of the entire genome. This has suggested the influence of ncRNAs during development, apoptosis and cell proliferation. The discovery of microRNAs (miRNAs) in 1993 underscored the importance of these molecules in pathological diseases such as cancer. Increasing interest in this field has allowed researchers to study the role of miRNAs in cancer progression. Regarding skeletal sarcomas, the research surrounding which miRNAs are involved in the tumourigenesis of osteosarcoma and chondrosarcoma has rapidly gained traction, including the identification of which miRNAs act as tumour suppressors and which act as oncogenes. In this review, we will summarize what is new regarding the roles of miRNAs in chondrosarcoma as well as the latest discoveries of identified miRNAs in osteosarcoma

Epigenetic Mechanisms in Bone Biology and Osteoporosis: Can They Drive Therapeutic Choices?

Osteoporosis is a complex multifactorial disorder of the skeleton. Genetic factors are important in determining peak bone mass and structure, as well as the predisposition to bone deterioration and fragility fractures. Nonetheless, genetic factors alone are not sufficient to explain osteoporosis development and fragility fracture occurrence. Indeed, epigenetic factors, representing a link between individual genetic aspects and environmental influences, are also strongly suspected to be involved in bone biology and osteoporosis. Recently, alterations in epigenetic mechanisms and their activity have been associated with aging. Also, bone metabolism has been demonstrated to be under the control of epigenetic mechanisms. Runt-related transcription factor 2 (RUNX2), the master transcription factor of osteoblast differentiation, has been shown to be regulated by histone deacetylases and microRNAs (miRNAs). Some miRNAs were also proven to have key roles in the regulation of Wnt signalling in osteoblastogenesis, and to be important for the positive or negative regulation of both osteoblast and osteoclast differentiation. Exogenous and environmental stimuli, influencing the functionality of epigenetic mechanisms involved in the regulation of bone metabolism, may contribute to the development of osteoporosis and other bone disorders, in synergy with genetic determinants. The progressive understanding of roles of epigenetic mechanisms in normal bone metabolism and in multifactorial bone disorders will be very helpful for a better comprehension of disease pathogenesis and translation of this information into clinical practice. A deep understanding of these mechanisms could help in the future tailoring of proper individual treatments, according to precision medicine’s principles

MicroRNA Role in Thyroid Cancer Development

MicroRNAs (miRNAs) are endogenous noncoding RNAs that negatively regulate gene expression by binding the 3′ noncoding region of the messenger RNA targets inducing their cleavage or blocking the protein translation. They play important roles in multiple biological and metabolic processes, including developmental timing, signal transduction, and cell maintenance and differentiation. Their deregulation can predispose to diseases and cancer. miRNA expression has been demonstrated to be deregulated in many types of human tumors, including thyroid cancers, and could be responsible for tumor initiation and progression. In this paper we reviewed the available data on miRNA deregulation in different thyroid tumors and describe the putative role of miRNA in thyroid cancer development

Noise-induced periodicity in a frustrated network of interacting diffusions

We investigate the emergence of a collective periodic behavior in a frustrated network of interacting diffusions. Particles are divided into two communities depending on their mutual couplings. On the one hand, both intra-population interactions are positive; each particle wants to conform to the average position of the particles in its own community. On the other hand, inter-population interactions have different signs: the particles of one population want to conform to the average position of the particles of the other community, while the particles in the latter want to do the opposite. We show that this system features the phenomenon of noise-induced periodicity: in the infinite volume limit, in a certain range of interaction strengths, although the system has no periodic behavior in the zero-noise limit, a moderate amount of noise may generate an attractive periodic law.Comment: 32 pages, 8 figure

Genetic aspects of Paget’s disease of bone

Paget’s disease of bone (PDB) is a metabolic bone disease characterized by excessive bone resorption and formation due to increased osteoclasts activity. PDB mostly runs asymptomatically, although increased bone turnover can be present and in approximately 30% of patients bone abnormalities, such as bone pain and deformities, pathological fractures and deafness may occur. The existence of familial aggregation of PDB has been reported in numerous papers, describing the occurrence of disease in successive generations. It has been clearly established that PDB is genetically heterogeneous with several loci able to confer an increased susceptibility to develop this bone metabolic disorder. In particular, the PDB3 locus in chromosome 5q35-qter hosts the sequestosome1/ p62 (SQSTM1/p62) gene whose mutations account for most of the sporadic and familial forms of PDB reported in literature. SQSTM1/p62 gene encodes the SQSTM1/p62 protein, component of the NF-kB signaling pathway and mediating intracellular signaling from IL-1/TNF toward NF-kB, crucial for osteoclast differentiation and activity. A functional study suggests that the S Q S T M 1 mutation may predispose to PDB affecting the interaction between SQSTM1/p62 protein and a hitherto unidentified protein(s) modulating the bone turnover, but the underlying molecular mechanism need to be elucidated. However, independently from the knowledge of the functional aspects of S Q S T M 1 / p 6 2 mutation, the opportunity to perform germline mutational analysis in PDB patients may be helpful in detecting new genetic carriers in potentially familial forms of PDB and in studying the co-segregation of such DNA variants with the PDB phenotype. All together these studies could open new possibilities in the prevention and therapy of PDB and of other metabolic bone disorder