Correlates of calcaneal quantitative ultrasound parameters in patients with diabetes: the study on the assessment of determinants of muscle and bone strength abnormalities in diabetes

OBJECTIVE: Quantitative ultrasound (QUS) provides an estimate of bone mineral density (BMD) and also evaluates bone quality, which has been related to increased fracture risk in people with diabetes. This study aimed at assessing the correlates of calcaneal QUS parameters in diabetic subjects encompassing various degrees of micro and macrovascular complications and a wide-range of peripheral nerve function. METHODS: Four hundred consecutive diabetic patients were examined by QUS to obtain values of broadband ultrasound attenuation (BUA), the speed of sound (SOS), quantitative ultrasound index (QUI), and BMD. RESULTS: Among surrogate measures of complications, sensory and motor nerve amplitude and heart rate response to cough test and standing correlated with QUS parameters at univariate analysis, together with age, body mass index (BMI), waist circumference, lipid profile, and renal function. Multivariate analysis revealed that BUA, SOS, QUI, and BMD were independently associated with age, male gender, hemoglobin A1c, BMI (or fat, but not fat-free mass), and somatic and autonomic nerve function parameters. CONCLUSIONS: These data indicate that peripheral nerve dysfunction is associated with worse QUS parameters, possibly contributing to increased fracture risk in diabetes. The positive relation of QUS measures with adiposity needs further investigation. This trial is registered with ClinicalTrials.gov (NCT01600924)

A novel trajectory concept for a mission to the Inner Large Moons of Saturn

We present a novel concept for a small mission to the four inner large satellites of Saturn. Leveraging the high efficiency of electric propulsion, the concept enables orbit insertion around each of the moons, for arbitrarily long close observation periods. The mission starts with a EVVES interplanetary segment, where a combination of multiple gravity assist and deep space low thrust enables reduced relative arrival velocity at Saturn. As a result, an unpowered capture via a sequence of resonant flybys with Titan is possible. The transfers between moons use a low-thrust control law that connects unstable and stable branches of the invariant manifolds of planar Lyapunov orbits from the circular restricted three-body problem of each moon and Saturn. The exploration of the moons relies on homoclinic and heteroclinic connections of the Lyapunov orbits around the L$_1$ and L$_2$ equilibrium points. These science orbits can be extended for arbitrary lengths of time with negligible propellant usage. The strategy enables a comprehensive scientific exploration of the inner large moons, located deep inside the gravitational well of Saturn, which is unfeasible with conventional impulsive maneuvers due to excessive fuel consumption

What drives bank coverage ratios? Evidence from Europe

We analyse micro and macro drivers of coverage ratios, as well as of their components, in a cross-country sample of European banks. Among the former, we find that credit risk variables, including forward-looking indicators, are the most relevant bank-specific factors explaining bank coverage ratios, together with the level of capitalization in high-NPL banks. Among the latter, coverage ratios increase with GDP growth, suggesting they behave countercyclically, more stringent macro-prudential policies, and deeper NPL secondary markets. Finally, we find evidence of peer imitation behaviour in banks with coverage ratios below the country average.JRC.B.1-Finance and Econom

A feed-forward pathway drives LRRK2 kinase membrane recruitment and activation

Activating mutations in the leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease, and previously we showed that activated LRRK2 phosphorylates a subset of Rab GTPases (Steger et al., 2017). Moreover, Golgi-associated Rab29 can recruit LRRK2 to the surface of the Golgi and activate it there for both auto- and Rab substrate phosphorylation. Here, we define the precise Rab29 binding region of the LRRK2 Armadillo domain between residues 360–450 and show that this domain, termed ‘site #1,’ can also bind additional LRRK2 substrates, Rab8A and Rab10. Moreover, we identify a distinct, N-terminal, higher-affinity interaction interface between LRRK2 phosphorylated Rab8 and Rab10 termed ‘site #2’ that can retain LRRK2 on membranes in cells to catalyze multiple, subsequent phosphorylation events. Kinase inhibitor washout experiments demonstrate that rapid recovery of kinase activity in cells depends on the ability of LRRK2 to associate with phosphorylated Rab proteins, and phosphorylated Rab8A stimulates LRRK2 phosphorylation of Rab10 in vitro. Reconstitution of purified LRRK2 recruitment onto planar lipid bilayers decorated with Rab10 protein demonstrates cooperative association of only active LRRK2 with phospho-Rab10-containing membrane surfaces. These experiments reveal a feed-forward pathway that provides spatial control and membrane activation of LRRK2 kinase activity

Genome-wide screen reveals Rab12 GTPase as a critical activator of Parkinson's disease-linked LRRK2 kinase

Activating mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) cause Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases, particularly Rab10 and Rab8A, and we showed previously that these phosphoRabs play an important role in LRRK2 membrane recruitment and activation (Vides et al., 2022). To learn more about LRRK2 pathway regulation, we carried out an unbiased, CRISPR-based genome-wide screen to identify modifiers of cellular phosphoRab10 levels. A flow cytometry assay was developed to detect changes in phosphoRab10 levels in pools of mouse NIH-3T3 cells harboring unique CRISPR guide sequences. Multiple negative and positive regulators were identified; surprisingly, knockout of the Rab12 gene was especially effective in decreasing phosphoRab10 levels in multiple cell types and knockout mouse tissues. Rab-driven increases in phosphoRab10 were specific for Rab12, LRRK2 dependent and PPM1H phosphatase reversible, and did not require Rab12 phosphorylation; they were seen with wild type and pathogenic G2019S and R1441C LRRK2. As expected for a protein that regulates LRRK2 activity, Rab12 also influenced primary cilia formation. Alphafold modeling revealed a novel Rab12 binding site in the LRRK2 Armadillo domain and we show that residues predicted to be essential for Rab12 interaction at this site influence phosphoRab10 and phosphoRab12 levels in a manner distinct from Rab29 activation of LRRK2. Our data show that Rab12 binding to a new site in the LRRK2 Armadillo domain activates LRRK2 kinase for Rab phosphorylation and could serve as a new therapeutic target for a novel class of LRRK2 inhibitors that do not target the kinase domain.</p

Characterizing the building blocks of Problematic Use of the Internet (PUI): The role of obsessional impulses and impulsivity traits among Italian young adults

BACKGROUND: Problematic Use of the Internet (PUI) is a considerable issue of the modern era, but its risk factors are still poorly understood. Impulsivity and obsessive-compulsive symptoms have been associated with PUI, but this relationship is still debated. In this article we focus on the relationships of PUI with obsessive-compulsive and impulsive symptoms in a cohort of Italian young adults, in order to identify possible vulnerability factors for PUI.METHODS: A sample of 772 Italian individuals aged 18-30 (mean age 23.3±3.3years old; 38% males and 62% females) was assessed via online survey using the Internet Addiction Test (IAT), the Mini International Neuropsychiatric Interview (MINI) Screen, the Padua Inventory-Washington State University Revision (PI-WSUR) and the Barratt Impulsiveness Scale (BIS-11).RESULTS: Ninety-seven subjects (12.6% of the sample) reported IAT scores at risk for PUI. PUI participants reported higher levels of impulsivity, obsessive-compulsive symptoms and a higher burden of co-occurrent psychiatric symptoms. In a logistic regression model, obsessional impulses to harm (OR =1.108, p&lt;0.001), attentional impulsivity (OR=1.155, p&lt;0.001) and depressive symptomatology (OR=1.246, p=0.012) had significant association with PUI. Finally, higher severity of PUI has been associated with manic/psychotic symptoms and with attentional impulsivity.CONCLUSIONS: Our findings confirmed the role of impulsivity in PUI, while also underling the association of obsessional impulses with this pathological behavior. We could hypothesize a trigger role of obsessive impulses for the engagement in PUI, together with factors as negative affective states. Further research is needed with respect to more severe forms of PUI, also for establishing tailored interventions