Psoriasis: A STAT3-centric view

Signal Transducer and Activator of Transcription (STAT)3 has recently emerged as a key player in the development and pathogenesis of psoriasis and psoriatic-like inflammatory conditions. Indeed, STAT3 hyperactivation has been reported in virtually every cell type involved in disease initiation and maintenance, and this factor mediates the signal of most cytokines that are involved in disease pathogenesis, including the central Interleukin (IL)-23/IL-17/IL-22 axis. Despite the recent availability of effective biological agents (monoclonal antibodies) against IL-17 and IL-23, which have radically changed the current standard of disease management, the possibility of targeting either STAT3 itself or, even better, the family of upstream activators Janus kinases (JAK1, 2, 3, and TYK2) offers additional therapeutic options. Due to the oral/topical administration modality of these small molecule drugs, their lower cost, and the reduced risk of eliciting adverse immune responses, these compounds are being actively scrutinized in clinical settings. Here, we summarize the main pathological features of psoriatic conditions that provide the rationale for targeting the JAK/STAT3 axis in disease treatment

Dynamics of motor network overactivation after striatocapsular stroke: a longitudinal PET study using a fixed-performance paradigm.

BACKGROUND AND PURPOSE: Although excessive brain activation during affected hand motion after stroke is well documented, its time course has been rarely studied, and when studied, this has either been with passive movement or with active but cognitively complex task and uncontrolled performance over time, complicating interpretation. METHODS: According to a prospective and longitudinal design, we studied 5 right-handed patients with right-sided hemiparesis due to first-ever left striatocapsular infarction. Three-dimensional PET H(2)O(15) studies were performed twice ( approximately 7 and approximately 31 weeks after stroke [PET1 and PET2, respectively]) during right thumb-to-index tapping executed at the same rate in both studies (1.26 Hz, auditory cued). With SPM96 software, significant group and individual overactivations (P<0.05, corrected for multiple comparisons) were computed by comparison with a group of 7 healthy age-matched right-handed control subjects performing the same task. RESULTS: Motor recovery was significant from PET1 to PET2. Both the group and individual analyses revealed striking overactivations at PET1, affecting notably the cortical hand area and the whole motor network bilaterally. These overactivations were less prominent at PET2 over both hemispheres, not only in terms of Z score but also in terms of spatial extent (almost reaching statistical significance in the affected hemisphere for the latter, P=0.09). However, new overactivations were found at PET2 in the left prefrontal areas, the putamen, and the premotor cortex. CONCLUSIONS: This study is the first to document that to perform the same simple movement of the paretic fingers, the brain with subcortical infarction shows less overactivations at the late than at the early timepoint, especially on the affected side, suggesting reduced recruitment of affected-hemisphere motor networks. However, unaffected-hemisphere prefrontal, premotor, and putaminal overactivations, observed at PET2 only, may suggest late-appearing compensatory reorganization

Querying Data Exchange Settings Beyond Positive Queries

Data exchange, the problem of transferring data from a source schema to a target schema, has been studied for several years. The semantics of answering positive queries over the target schema has been defined in early work, but little attention has been paid to more general queries. A few proposals of semantics for more general queries exist but they either do not properly extend the standard semantics under positive queries, giving rise to counterintuitive answers, or they make query answering undecidable even for the most important data exchange settings, e.g., with weakly-acyclic dependencies. The goal of this paper is to provide a new semantics for data exchange that is able to deal with general queries. At the same time, we want our semantics to coincide with the classical one when focusing on positive queries, and to not trade-off too much in terms of complexity of query answering. We show that query answering is undecidable in general under the new semantics, but it is \co\NP\complete when the dependencies are weakly-acyclic. Moreover, in the latter case, we show that exact answers under our semantics can be computed by means of logic programs with choice, thus exploiting existing efficient systems. For more efficient computations, we also show that our semantics allows for the construction of a representative target instance, similar in spirit to a universal solution, that can be exploited for computing approximate answers in polynomial time. Under consideration in Theory and Practice of Logic Programming (TPLP).Comment: Under consideration in Theory and Practice of Logic Programming (TPLP

ROCK ‘n TOR: An Outlook on Keratinocyte Stem Cell Expansion in Regenerative Medicine via Protein Kinase Inhibition

Keratinocyte stem cells play a fundamental role in homeostasis and repair of stratified epithelial tissues. Transplantation of cultured keratinocytes autografts provides a landmark example of successful cellular therapies by restoring durable integrity in stratified epithelia lost to devastating tissue conditions. Despite the overall success of such procedures, failures still occur in case of paucity of cultured stem cells in therapeutic grafts. Strategies aiming at a further amplification of stem cells during keratinocyte ex vivo expansion may thus extend the applicability of these treatments to subjects in which endogenous stem cells pools are depauperated by aging, trauma, or disease. Pharmacological targeting of stem cell signaling pathways is recently emerging as a powerful strategy for improving stem cell maintenance and/or amplification. Recent experimental data indicate that pharmacological inhibition of two prominent keratinocyte signaling pathways governed by apical mTOR and ROCK protein kinases favor stem cell maintenance and/or amplification ex vivo and may improve the effectiveness of stem cell-based therapeutic procedures. In this review, we highlight the pathophysiological roles of mTOR and ROCK in keratinocyte biology and evaluate existing pre-clinical data on the effects of their inhibition in epithelial stem cell expansion for transplantation purposes

Oblivious Chase Termination:The Sticky Case

The chase procedure is one of the most fundamental algorithmic tools in database theory. A key algorithmic task is uniform chase termination, i.e., given a set of tuple-generating dependencies (tgds), is it the case that the chase under this set of tgds terminates, for every input database? In view of the fact that this problem is undecidable, no matter which version of the chase we consider, it is natural to ask whether well-behaved classes of tgds, introduced in different contexts such as ontological reasoning, make our problem decidable. In this work, we consider a prominent decidability paradigm for tgds, called stickiness. We show that for sticky sets of tgds, uniform chase termination is decidable if we focus on the (semi-)oblivious chase, and we pinpoint its exact complexity: PSpace-complete in general, and NLogSpace-complete for predicates of bounded arity. These complexity results are obtained via graph-based syntactic characterizations of chase termination that are of independent interest