A systems approach to the Digital Transformation of Public Administration

The dematerialization with the progressive increase in digital management of documents and processes, leads to digital transformation redesigning all internal processes to increase efficiency and improve the organizational performance. Digitizing the organization activities, is not a mere replacement of the paper document with its electronic version, means designing and managing all organizational processes in an integrated and collaborative way changing the business models, operational processes, and customer experiences. To understand how digital transformation deeply affects the organizational processes in Italian Public Administration, we use the Systems Thinking (ST) and System Dynamics (SD) approaches to analyze the advantages that be can pursue through the digitalization of their processes, in terms of organizational change, productivity and economic savings

Subclinical systolic dysfunction in genotype-positive phenotype-negative relatives of dilated cardiomyopathy patients: A systematic review and meta-analysis

The absence of left ventricular (LV) dilatation and systolic dysfunction, as assessed by LV ejection fraction (LVEF), in family members of genetically confirmed dilated cardiomyopathy (DCM) patients, carrying pathogenic (P) or likely pathogenic (LP) familial gene variants categorizes them as a subgroup called genotype-positive phenotype-negative (GEN+ PHEN−). Identifying GEN+ PHEN− who are at the highest risk of developing the disease throughout their lifetime is crucial

Case report: Sodium-glucose cotransporter 2 inhibitors induce left ventricular reverse remodeling in anthracycline-related cardiac dysfunction—a case series

PurposeTo describe the efficacy and safety of sodium-glucose cotransporter 2 inhibitors as a specific treatment for anthracycline-related cardiac dysfunction in a small real-world population.MethodsSeven patients with anthracycline-related cardiac dysfunction were clinically and echocardiographically evaluated before and after the introduction of sodium-glucose cotransporter 2 inhibitors.ResultsAfter a median period of 24 weeks with uninterrupted sodium-glucose cotransporter 2 inhibitors treatment, a significant clinical improvement was observed with at least one New York Heart Association Functional Class (NHYA FC) improvement in all patients (median NYHA FC: I vs. III, p < 0.010). A noteworthy left ventricular reserve remodeling (median left ventricular end diastolic volume indexed: 53 vs. 82.5 ml/m2, p = 0.018; median left ventricular ejection fraction: 50% vs. 40%, p = 0.17) was also observed. Sodium-glucose cotransporter 2 inhibitors therapy was well tolerated by every patients; no cases of discontinuation or relevant side effects were observed.ConclusionSodium-glucose cotransporter 2 inhibitors induce a significant clinical improvement and left ventricular reserve remodeling in patients affected by anthracycline-related cardiac dysfunction

Nuclear organisation and replication timing are coupled through RIF1-PP1 interaction

Three-dimensional genome organisation and replication timing are known to be correlated, however, it remains unknown whether nuclear architecture overall plays an instructive role in the replication-timing programme and, if so, how. Here we demonstrate that RIF1 is a molecular hub that co-regulates both processes. Both nuclear organisation and replication timing depend upon the interaction between RIF1 and PP1. However, whereas nuclear architecture requires the full complement of RIF1 and its interaction with PP1, replication timing is not sensitive to RIF1 dosage. The role of RIF1 in replication timing also extends beyond its interaction with PP1. Availing of this separation-of-function approach, we have therefore identified in RIF1 dual function the molecular bases of the co-dependency of the replication-timing programme and nuclear architecture

Nuclear architecture organized by Rif1 underpins the replication-timing program

DNA replication is temporally and spatially organized in all eukaryotes, yet the molecular control and biological function of the replication-timing program are unclear. Rif1 is required for normal genome-wide regulation of replication timing, but its molecular function is poorly understood. Here we show that in mouse embryonic stem cells, Rif1 coats late-replicating domains and, with Lamin B1, identifies most of the late-replicating genome. Rif1 is an essential determinant of replication timing of non-Lamin B1-bound late domains. We further demonstrate that Rif1 defines and restricts the interactions between replication-timing domains during the G1 phase, thereby revealing a function of Rif1 as organizer of nuclear architecture. Rif1 loss affects both number and replication-timing specificity of the interactions between replication-timing domains. In addition, during the S phase, Rif1 ensures that replication of interacting domains is temporally coordinated. In summary, our study identifies Rif1 as the molecular link between nuclear architecture and replication-timing establishment in mammals

The Digitization Process in the Italian Public Administrations

In the last few years, a new stream of research sharply raised its attention on digital transformation (Hinings et al., 2018; Nambisan et al., 2017; Svahn et al., 2017; Yoo et al., 2012). Digital transformation is a complex issue that may affect many areas within an organization. The term "Digital Transformation" has no a univocal meaning (Hess et al., 2016), nerveless new digital technologies “demand different mindsets and skillsets than previous waves of transformative technology,” (Fitzgerald et al., 2014) that in turn transform the organizations (Markowitsch et al., 2002). At the same time, the term “transformation” expresses the comprehensiveness of the actions that need to be taken when organizations face these new technologies. Therefore, digital transformation goes beyond merely digitizing resources (McDonald, and Rowsell-Jones; 2015), it will take place when organizations embrace all the potential of social learning in the design and the process of delivering contents, and it involves a company-wide digital strategy. To ensure that an organization captures the business value of a digital transformation, it should carefully formulate a digital transformation strategy that coordinates the many independent threads of it and helps it to navigate the complexity and ambiguity of identifying its own digital “sweet spots.” (Hess et al., 2016). The digital transformation has also led to a new use of Systems Thinking in the organizational studies. In fact, unlike traditional approaches, which typically focus on separating the problem into individual pieces into pieces (for example, the great success of Design Thinking today, seen as an innovation but still anchored to a linear reasoning), Systemic Thought, in contrast, focuses on how the object of analysis interacts, and where it intersects, the other components of the entire system. Now, it is possible to see digital transformation as a fusion between customer demand, technologies, and general business objectives: socio-cultural changes have an impact on customer demand and technologies are implemented to satisfy this new demand in a way that is beneficial to the business and in line with the global business strategy, which often leads to changes in the management structure and style as well as to the re-engineering of the business processes themselves. The Digital Transformation has, therefore, become the most significant managerial challenge in the development of an organization. Internally, it affects the entire organization, while externally, it influences the strategic position of the organization on the market, along with the likelihood of its longevity or disappearance. Furthermore, it influences the nature of the relationships between individuals and organizational units, which becomes complex, particularly in larger organizations, and ultimately provides organizations with enormous potential in terms of growth and development, although, of course, not in a way that is free of challenges and significant risks. So the challenge of undertaking the transformation and realizing its benefits must be faced by leaders who can understand both the planned and unplanned consequences and those in store for the organization. In other words, the key to digital transformation is Systems Thinking. Nevertheless, digital transformation cannot take place without eliminating paper documents to make an organization paperless and obtain many advantages and benefits: there is no digital transformation without digitization (Armenia et al., 2008). Although different definitions exist, digitization refers to the reduction of the throughput of materials in human societies (Van der Voet et al., 2004). In this study, the concept of “digitization” indicates the progressive increase in digital and computerized management of documents and processes within public and private bodies, with the consequent takeover of dedicated solutions at the expense of traditional supports. Digital documents allow money, time and labor savings since, if they were sent, received and stored in electronic format, documents do not have to be every time: transcribed, recorded, inserted in files, classified, moved, and searched between cabinets, drawers, folders, and boxes. Then, the processes became more efficient. The possible evolution of digitization could be seen not only as a way to define a new strategy but also as a factor that outlines a specific organizational structure (Resca et al., 2013). Digitizing the organization activities means designing and managing the entire processes, internal and external, in an integrated and collaborative way: it is not a mere replacement of the paper document with its electronic version, but a complete redesign of the process to obtain an increase in financial and organizational performance and an improvement in all operations carried out. As a result, digital transformation changes the business models, operational processes, and customer experiences (Berman; 2012), creating new challenges for individuals and organizations

GC content but not nucleosome positioning directly contributes to intron-splicing efficiency in Paramecium

ABSTRACT Eukaryotic genes are interrupted by introns that must be accurately spliced from mRNA precursors. With an average length of 25 nt, the >90,000 introns of Paramecium tetraurelia stand among the shortest introns reported in eukaryotes. The mechanisms specifying the correct recognition of these tiny introns remain poorly understood. Splicing can occur co-transcriptionally and it has been proposed that chromatin structure might influence splice site recognition. To investigate the roles of nucleosome positioning in intron recognition, we determined the nucleosome occupancy along the P. tetraurelia genome. We showed that P. tetraurelia displays a regular nucleosome array with a nucleosome repeat length of ∼151 bp, amongst the smallest periodicities reported. Our analysis revealed that introns are frequently associated with inter-nucleosomal DNA, pointing to an evolutionary constraint to locate introns at the AT-rich nucleosome edge sequences. Using accurate splicing efficiency data from cells depleted for the nonsense-mediated decay effectors, we showed that introns located at the edge of nucleosomes display higher splicing efficiency than those at the centre. However, multiple regression analysis indicated that the GC content, rather than nucleosome positioning, directly contributes to intron splicing efficiency. Our data reveal a complex link between GC content, nucleosome positioning and intron evolution in Paramecium

Unscheduled origin building in S-phase upon tight CDK1 inhibition suppresses CFS instability

Summary Genome integrity requires replication to be completed before chromosome segregation. This coordination essentially relies on replication-dependent activation of a dedicated checkpoint that inhibits CDK1, delaying mitotic onset. Under-replication of Common Fragile Sites (CFSs) however escapes surveillance, which triggers chromosome breakage. Using human cells, we asked here whether such leakage results from insufficient CDK1 inhibition under modest stresses used to destabilize CFSs. We found that tight CDK1 inhibition suppresses CFS instability. Repli-Seq and molecular combing analyses consistently showed a burst of replication initiations in mid S phase across large origin-poor domains shaped by transcription, including CFSs. Strikingly, CDC6 or CDT1 depletion or CDC7-DBF4 inhibition during the S phase prevented both extra-initiations and CFS rescue, showing that CDK1 inhibition promotes targeted and mistimed building of functional extra-origins. In addition to delay mitotic onset, checkpoint activation therefore advances replication completion of chromosome domains at risk of under-replication, two complementary roles preserving genome stability

Mistimed origin licensing and activation stabilize common fragile sites under tight DNA-replication checkpoint activation

International audienceGenome integrity requires replication to be completed before chromosome segregation. The DNA-replication checkpoint (DRC) contributes to this coordination by inhibiting CDK1, which delays mitotic onset. Under-replication of Common Fragile Sites (CFSs) however escapes surveillance, resulting in mitotic chromosome breaks. Here we asked whether loose DRC activation induced by modest stresses commonly used to destabilize CFSs could explain this leakage. We found that tightening DRC activation or CDK1 inhibition stabilizes CFSs in human cells. Repli-Seq and molecular combing analyses showed a burst of replication initiations implemented in mid S-phase across a subset of late-replicating sequences, including CFSs, while the bulk genome was unaffected. CFS rescue and extra-initiations required CDC6 and CDT1 availability in S-phase, implying that CDK1 inhibition permits mistimed origin licensing and firing. In addition to delaying mitotic onset, tight DRC activation therefore supports replication completion of late origin-poor domains at risk of under-replication, two complementary roles preserving genome stability