Modelling desiccation cracking in a homogenous soil clay layer: comparison between different hypotheses on constitutive behaviour

Desiccation cracks are usually thought to start from the surface of an evaporating soil layer, and the available simplified models for crack initiation and propagation are based on this hypothesis. On the contrary, experimental results on a Dutch river clay showed that cracks in an evaporating soil layer may start and propagate below the surface, confirming earlier findings by other researchers. A simple one-dimensional model was set up to analyse the consequences of different hypotheses about the material behaviour on the crack onset in a homogenous soil layer undergoing surface drying. The results of the model show that dependence of the material behaviour on the rate of water content change is a necessary requirement for cracks to initiate below the surface. The conclusion suggests that, to properly understand cracking in an evaporating soil layer, an intrinsic time scale for the mechanical response must be accounted for, among all the other factors which were previously highlighted by other researchers. The key factor to predict crack onset below the surface is the dependence of the drying branch of the water retention curve of the compressible soil on the rate of drying, which would be justified by a rate dependent fabric evolution

Mechanism and disease-association of E2 conjugating enzymes:lessons from UBE2T and UBE2L3

Ubiquitin signalling is a fundamental eukaryotic regulatory system, controlling diverse cellular functions. A cascade of E1, E2, and E3 enzymes is required for assembly of distinct signals, whereas an array of deubiquitinases and ubiquitin-binding modules edit, remove, and translate the signals. In the centre of this cascade sits the E2-conjugating enzyme, relaying activated ubiquitin from the E1 activating enzyme to the substrate, usually via an E3 ubiquitin ligase. Many disease states are associated with dysfunction of ubiquitin signalling, with the E3s being a particular focus. However, recent evidence demonstrates that mutations or impairment of the E2s can lead to severe disease states, including chromosome instability syndromes, cancer predisposition, and immunological disorders. Given their relevance to diseases, E2s may represent an important class of therapeutic targets. In the present study, we review the current understanding of the mechanism of this important family of enzymes, and the role of selected E2s in disease

Reinterpreting the saturated clayey soil behaviour undergoing desiccation

LAUREA MAGISTRALEDesiccation cracks affect the stability of earth-works or natural slopes. The available simplified models for crack initiation and propagation are based on the hypothesis that desiccation cracks start from the surface of an evaporating soil layer. Experimental results available at Politecnico di Milano and at Delft University of Technology shows that in some conditions the cracks may start and propagate in the core of the layer. The presence of embedded cracks can compromise the reliability of a geotechnical structures. Based upon experimental results, a simple one-dimensional model was set up to analyse the behaviour of a homogeneous soil layer undergoing surface drying. In particular the role of geometrical constrains, the soil properties dependence on water content and the dependence on desiccation rate were discussed. In the model the idealised crack initiation condition is defined as the moment when the total tensile stress attains the same value as the tensile strength. The theoretical formulation point out that the governing equation of total horizontal stress is dominated by shear modulus. The results of the model show that dependence of material behaviour on the rate of water content change is a necessary requirement for cracks to initiate below the surface. The key factor is the dependence of the drying branch of water retention curve of the compressible soil on the rate of drying. This would be justified by a rate dependent fabric evolution. For this reason MIP analysis were performed on clay samples. The results show that different drying paths has different pore size distribution. In conclusion this framework was used in order to reinterpret tensile tests performed at the Delft University of Technology

E2 superfamily of ubiquitin-conjugating enzymes: constitutively active or activated through phosphorylation in the catalytic cleft

Protein phosphorylation is a modification that offers a dynamic and reversible mechanism to regulate the majority of cellular processes. Numerous diseases are associated with aberrant regulation of phosphorylation-induced switches. Phosphorylation is emerging as a mechanism to modulate ubiquitination by regulating key enzymes in this pathway. The molecular mechanisms underpinning how phosphorylation regulates ubiquitinating enzymes, however, are elusive. Here, we show the high conservation of a functional site in E2 ubiquitin-conjugating enzymes. In catalytically active E2s, this site contains aspartate or a phosphorylatable serine and we refer to it as the conserved E2 serine/aspartate (CES/D) site. Molecular simulations of substrate-bound and -unbound forms of wild type, mutant and phosphorylated E2s, provide atomistic insight into the role of the CES/D residue for optimal E2 activity. Both the size and charge of the side group at the site play a central role in aligning the substrate lysine toward E2 catalytic cysteine to control ubiquitination efficiency. The CES/D site contributes to the fingerprint of the E2 superfamily. We propose that E2 enzymes can be divided into constitutively active or regulated families. E2s characterized by an aspartate at the CES/D site signify constitutively active E2s, whereas those containing a serine can be regulated by phosphorylation

Modelling desiccation cracking in a homogenous soil clay layer: comparison between different hypotheses on constitutive behaviour

Desiccation cracks are usually thought to start from the surface of an evaporating soil layer, and the available simplified models for crack initiation and propagation are based on this hypothesis. On the contrary, experimental results on a Dutch river clay showed that cracks in an evaporating soil layer may start and propagate below the surface, confirming earlier findings by other researchers. A simple one-dimensional model was set up to analyse the consequences of different hypotheses about the material behaviour on the crack onset in a homogenous soil layer undergoing surface drying. The results of the model show that dependence of the material behaviour on the rate of water content change is a necessary requirement for cracks to initiate below the surface. The conclusion suggests that, to properly understand cracking in an evaporating soil layer, an intrinsic time scale for the mechanical response must be accounted for, among all the other factors which were previously highlighted by other researchers. The key factor to predict crack onset below the surface is the dependence of the drying branch of the water retention curve of the compressible soil on the rate of drying, which would be justified by a rate dependent fabric evolution

Potentially Cured Follicular Lymphoma (PC-FL). an Analysis of 56 Cases with Prognostic Factors Evaluation

Abstract Introduction: Advanced stage follicular lymphoma (FL) is generally considered incurable. Although multiple remissions after treatment are possible, relapse is considered the rule, and the time to progression tends to become shorter after each relapse (Johnson, JCO 1995). Over the last decades, after the introduction of monoclonal anti-CD20 antibodies and of better treatment programs, the prognosis of FL has markedly improved from a median OS of 7 years to a 10-year OS rate &gt;80%. Moreover, clinical observations of patients (pts) experiencing very long progression-free periods despite more than one previous treatment failure, have become not rare, suggesting that some pts could achieve operational FL cure. To assess the frequency of those prolonged long-term remissions and search for potential predictive factors, we have retrospectively analyzed the consecutive series of pts with FL seen at our institution. Methods: FL pts, aged &gt;18 years, in maintained remission for more than 5 years after at least two lines of treatment were selected as "potentially cured" FL (PC-FL) and analyzed in detail. Their main characteristics at diagnosis and at last relapse, the different lines of treatment received and the time intervals (time to next treatment: TTNT) between them, were recorded and compared with those of FL pts seen in the same period (control group). Treatment strategies used were grouped and defined as follows: radiotherapy or surgery, for stage I-II (local), anthracycline and/or alkylating agents regimens (Alk/Ant), purine analogues regimens (Pur), monoclonal antibodies/radioimmunoconjugates as single agent (MoAb), autologous transplantation (ASCT). Results and discussion: Among 385 consecutive FL pts seen from January 1987 to December 2011, 56 (14,5%) met criteria for PC-FL. Their clinicopathological features at diagnosis, compared to controls, are shown in Table I. There were no significant differences except for a younger age (51 vs 58 years, p&lt;0.00016) and for a lower frequency of grade 3a histology (p=0.04) in PC-FL pts. First line treatment used did also not differ (p=0.29). Among PC-FL pts, 33 received two, 16 received 3 and 7 more than 3 treatment lines. The median duration of last complete remission was 118+ months, whereas the median duration of the remission preceding the last treatment had been 24 months; disease duration from diagnosis to the last relapse preceding long term remission had been 50,5 months. The last treatments received before long-term remission were variable including local in 10 (18%), Alk/Ant in 5 (9%), Pur in 11 (19%), MoAb in 10 (18%) and ASCT in 20 (36%). Pts characteristics at last relapse and remission duration were similar among different treatment subgroups, except that more pts in localized stage received local treatments. Comparing clinicopathological characteristics of PC-FL pts at diagnosis and at last relapse there were no differences except for FLIPI score, which was significantly lower at relapse (low FLIPI 34% at diagnosis, 68% at relapse, p=0.002). First-line and last treatments were similar except that more pts underwent ASCT as last treatment, as expected since frontline ASCT is not recommended. In 10 pts TTNT after first-line was longer than 5 years and 7 of them are still in prolonged remission (median 11+ years) after second-line treatment, representing a particularly favorable subgroup. In 26 (46%) of PC-FL pts TTNT was shorter than 24 months after first line therapy. Among 14 of them who received R-chemo at diagnosis (POD24, Casulo, JCO 2015), 8 (57%) obtained long remission after ASCT, given in second line in six. Conversely, ASCT was used in only 1 of 12 pts not receiving Rituximab at diagnosis. Conclusions: Approximately 15% of FL pts could currently achieve a very prolonged remission of about 10 years, even after multiple relapses. Its duration was 5x that of the last treatment line and more than twice that of active lymphoma, strongly suggesting the possibility of having achieved lymphoma cure. Younger age and grade 1-2 FL histology at diagnosis, and FLIPI low risk at relapse favored the achievement of PC-FL status. No specific treatment was associated with PC-FL and even an early relapse after first line treatment did not preclude to reach PC-FL, although early ASCT may be more effective for POD24 patients. Whether the achievement of PC-FL status may be related to biological factors will be interesting to be investigated in the next future. Disclosures Rossi: Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. </jats:sec