The Hierarchical Random Energy Model

We introduce a Random Energy Model on a hierarchical lattice where the interaction strength between variables is a decreasing function of their mutual hierarchical distance, making it a non-mean field model. Through small coupling series expansion and a direct numerical solution of the model, we provide evidence for a spin glass condensation transition similar to the one occuring in the usual mean field Random Energy Model. At variance with mean field, the high temperature branch of the free-energy is non-analytic at the transition point

Association of a homozygous GCK missense mutation with mild diabetes

Background: Homozygous inactivating GCK mutations have been repeatedly reported to cause severe hyperglycemia, presenting as permanent neonatal diabetes mellitus (PNDM). Conversely, only two cases of GCK homozygous mutations causing mild hyperglycemia have been so far described. We here report a novel GCK mutation (c.1116G>C, p.E372D), in a family with one homozygous member showing mild hyperglycemia. Methods: GCK mutational screening was carried out by Sanger sequencing. Computational analyses to investigate pathogenicity and molecular dynamics (MD) were performed for GCK-E372D and for previously described homozygous mutations associated with mild (n = 2) or severe (n = 1) hyperglycemia, used as references. Results: Of four mildly hyperglycemic family-members, three were heterozygous and one, diagnosed in the adulthood, was homozygous for GCK-E372D. Two nondiabetic family members carried no mutations. Fasting glucose (p = 0.016) and HbA1c (p = 0.035) correlated with the number of mutated alleles (0–2). In-silico predicted pathogenicity was not correlated with the four mutations’ severity. At MD, GCK-E372D conferred protein structure flexibility intermediate between mild and severe GCK mutations. Conclusions: We present the third case of homozygous GCK mutations associated with mild hyperglycemia, rather than PNDM. Our in-silico analyses support previous evidences suggesting that protein stability plays a role in determining clinical severity of GCK mutations

Superconductor-semiconductor magnetic microswitch

A hybrid superconductor--two-dimensional electron gas microdevice is presented. Its working principle is based on the suppression of Andreev reflection at the superconductor-semiconductor interface caused by a magnetic barrier generated by a ferromagnetic strip placed on top of the structure. Device switching is predicted with fields up to some mT and working frequencies of several GHz, making it promising for applications ranging from microswitches and storage cells to magnetic field discriminators.Comment: 4 pages, 3 figures, minor changes to tex

Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis

Tumor microenvironment is enriched in plasma membrane microvesicles (MV) shed from all cell types that constitute the tumor mass, reflecting the antigenic profile of the cells they originate from. Fibroblasts and tumor cells mutually communicate within tumor microenvironment. Recent evidences suggest that tumor-derived MVs (TMV) exert a broad array of biological functions in cell-to-cell communication. To elucidate their role in cancer-to-fibroblast cell communication, TMV obtained from two prostate carcinoma cell lines with high and weak metastatic potential (PC3 and LnCaP, respectively) have been characterized. TMV exhibit matrix metalloproteinases (MMP) and extracellular MMP inducer at their surface, suggesting a role in extracellular matrix degradation. Moreover, TMV not only induce the activation of fibroblasts assessed through extracellular signal-regulated kinase 1/2 phosphorylation and MMP-9 up-regulation, increase motility and resistance to apoptosis but also promote MV shedding from activated fibroblasts able in turn to increase migration and invasion of highly metastatic PC3 cells but not LnCaP cells. PC3 cell chemotaxis seems, at least partially, dependent on membrane-bound CX3CL1/fractalkine ligand for chemokine receptor CX3CR1. The present results highlight a mechanism of mutual communication attributable not only to soluble factors but also to determinants harbored by MV, possibly contributing to the constitution of a favorable niche for cancer development. [Cancer Res 2009;69(3):785–93

Role of the Tracy-Widom distribution in the finite-size fluctuations of the critical temperature of the Sherrington-Kirkpatrick spin glass

We investigate the finite-size fluctuations due to quenched disorder of the critical temperature of the Sherrington-Kirkpatrick spin glass. In order to accomplish this task, we perform a finite-size analysis of the spectrum of the susceptibility matrix obtained via the Plefka expansion. By exploiting results from random matrix theory, we obtain that the fluctuations of the critical temperature are described by the Tracy-Widom distribution with a non-trivial scaling exponent 2/3

The ultrasound risk stratification systems for thyroid nodule have been evaluated against papillary carcinoma. A meta-analysis

Thyroid imaging reporting and data systems (TIRADS) are used to stratify the malignancy risk of thyroid nodule by ultrasound (US) examination. We conducted a meta-analysis to evaluate the pooled cancer prevalence and the relative prevalence of papillary, medullary, follicular thyroid cancer (PTC, MTC, and FTC) and other malignancies among nodules included in studies evaluating their performance. Four databases were searched until February 2020. Original articles with at least 1000 nodules, evaluating the performance of at least one TIRADS among AACE/ACE/AME, ACR-TIRADS, ATA, EU-TIRADS, or K-TIRADS, and reporting data on the histological diagnosis of malignant lesions were included. The number of malignant nodules, PTC, FTC, MTC and other malignancies in each study was extracted. For statistical pooling of data, a random-effects model was used. Nine studies were included, evaluating 19,494 thyroid nodules. The overall prevalence of malignancy was 34% (95%CI 21 to 49). Among 6162 histologically proven malignancies, the prevalence of PTC, FTC, MTC and other malignancies was 95%, 2%, 1%, and 1%, respectively. A high heterogeneity was found for all the outcomes. A limited number of studies generally conducted using a retrospective design was found, with possible selection bias. Acknowledging this limitation, TIRADSs should be regarded as accurate tools to diagnose PTC only. Proposed patterns and/or cut-offs should be revised and other strategies considered to improve their performance in the assessment of FTC, MTC and other malignancies

The Modified Five-Point Test (MFPT): normative data for a sample of Italian elderly

INTRODUCTION: Non-verbal figural fluency is related to executive functions and specifically to the ability to create as many unique designs as possible, while minimizing their repetitions. An Italian version of figural fluency is the Modified Five-Point Test (MFPT), which is highly employed in the clinical practice of neuropsychologists. To date, reference data of Italian population are limited to a sample aged between 16 and 60 years old. Thus, the current study aims to provide normative data of the MFPT in the context of a population-based setting, conducted in Southern Italy. MATERIAL AND METHODS: We collected N = 340 Italian healthy subjects, aged over 65 years old (range: 65-91), pooled across subgroups for age, sex, and education. Multiple regression analyses were performed to estimate the effect of age, education, and sex on the participant's performance. Equivalent scores and cut-off scores were also defined for the number of unique designs (UDs) and the number of strategies (CSs). RESULTS: Multiple regression analyses revealed that UDs increase with decreasing age and increasing educational level. CSs are influenced by higher educational levels but neither by age nor sex. A significant inverse correlation between the UDs and percentage of errors occurred, suggesting that a higher number of UDs are associated with a fewer number of errors and higher CSs employed. CONCLUSION: The MFPT provides a measure of cognitive functioning in terms of the ability to initiate and realize designs, affording useful hints for clinical settings. The MFPT may represent a handy and useful tool with a specific focus in the differentiation of healthy versus pathological aging

Monuments unveiled: Genetic characterization of large old chestnut (Castanea sativa Mill.) trees using comparative nuclear and chloroplast DNA analysis

Large old trees are extraordinary organisms. They not only represent a historical, landscape and environmental heritage of inestimable value, but they also witness a long history of environmental changes and human interventions, and constitute an as yet poorly known reserve of genetic variability which can be considered a great resource for management programs of forest species. This is the first genetic study on Italian, large, old chestnut trees (Castanea sativa Mill.). Ninety-nine trees were surveyed and analysed. For each tree, more than one sample from canopy and root suckers was collected to test for the genetic integrity of the individuals. All samples were genotyped using nine nuclear microsatellite markers (nSSRs) and 106 unique genetic profiles were identified. A Bayesian analysis performed with the software STRUCTURE revealed the occurrence of two main gene pools and unveiled the genetic relationships existing among the genotyped individuals, and with the natural chestnut populations living in proximity. A phylogeographic structure of the plastid diversity was also obtained by the use of DNA sequence variation at two marker regions, revealing different origins and probable connections of the old trees with different glacial refugia. Our results contribute to an improved evaluation of the European chestnut genetic resources and provide useful insights into the species’ history and domestication in Italy. The importance of carefully targeted conservation strategies for these invaluable organisms is reaffirmed

TuberOus SClerosis registry to increase disease Awareness (TOSCA) – baseline data on 2093 patients

Angiomiolipoma; Epilepsia; TOSCAAngiomyolipoma; Epilepsy; TOSCAAngiomyolipoma; Epilèpsia; TOSCABackground Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Many gaps remain in the understanding of TSC because of the complexity in clinical presentation. The TuberOus SClerosis registry to increase disease Awareness (TOSCA) is an international disease registry designed to address knowledge gaps in the natural history and management of TSC. Here, we present the baseline data of TOSCA cohort. Methods Patients of any age diagnosed with TSC, having a documented visit for TSC within the preceding 12 months, or newly diagnosed individuals were included. The registry includes a “core” section designed to record detailed background information on each patient including disease manifestations, interventions, and outcomes collected at baseline and updated annually. “Subsections” of the registry recorded additional data related to specific features of TSC. Results Baseline “core” data from 2093 patients enrolled from 170 sites across 31 countries were available at the cut-off date September 30, 2014. Median age of patients at enrollment was 13 years (range, 0–71) and at diagnosis of TSC was 1 year (range, 0–69). The occurrence rates of major manifestations of TSC included – cortical tubers (82.2%), subependymal nodules (78.2%), subependymal giant cell astrocytomas (24.4%), renal angiomyolipomas (47.2%), lymphangioleiomyomatosis (6.9%), cardiac rhabdomyomas (34.3%), facial angiofibromas (57.3%), forehead plaque (14.1%), ≥ 3 hypomelanotic macules (66.8%), and shagreen patches (27.4%). Epilepsy was reported in 1748 (83.5%) patients, of which 1372 were diagnosed at ≤ 2 years (78%). Intellectual disability was identified in 451 (54.9%) patients of those assessed. TSC-associated neuropsychiatric disorders (TAND) were diagnosed late, and not evaluated in 30–50% of patients. Conclusion TOSCA is the largest clinical case series of TSC to date. It provided a detailed description of the disease trajectory with increased awareness of various TSC manifestations. The rates of different features of TSC reported here reflect the age range and referral patterns of clinics contributing patients to the cohort. Documentation of TAND and LAM was poor. A widespread adoption of the international TSC assessment and treatment guidelines, including use of the TAND Checklist, could improve surveillance. The registry provides valuable insights into the necessity for monitoring, timing, and indications for the treatment of TSC.This study was funded by Novartis Pharma AG