Decipher non-canonical SPAST splicing mutations with the help of functional assays in patients affected by spastic paraplegia 4 (SPG4)

Flowchart showing the molecular approach used to decipher the non-canonical splicing mutations

Orbital-selective metal skin induced by alkali-metal-dosing Mott-insulating Ca2RuO4

Doped Mott insulators are the starting point for interesting physics such as high temperature superconductivity and quantum spin liquids. For multi-band Mott insulators, orbital selective ground states have been envisioned. However, orbital selective metals and Mott insulators have been difficult to realize experimentally. Here we demonstrate by photoemission spectroscopy how Ca$_{2}$RuO$_{4}$, upon alkali-metal surface doping, develops a single-band metal skin. Our dynamical mean field theory calculations reveal that homogeneous electron doping of Ca$_{2}$RuO$_{4}$ results in a multi-band metal. All together, our results provide evidence for an orbital-selective Mott insulator breakdown, which is unachievable via simple electron doping. Supported by a cluster model and cluster perturbation theory calculations, we demonstrate a type of skin metal-insulator transition induced by surface dopants that orbital-selectively hybridize with the bulk Mott state and in turn produce coherent in-gap states

Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

Sub-movement cueing and motor sequence execution in patients with Huntington's disease

Objectives: We investigated whether the type of sub-movement cueing during the execution of motor sequences influences the movement time in patients with Huntington's disease. Methods: The kinematic variables of rapid sequential free arm movements executed with different types of sub-movement cueing externally-triggered (ET) and self-initiated (SI) tasks - were analyzed in 7 patients and 7 healthy controls. The ET task required subjects to initiate movements in response to consecutive visual go signals; the SI task allowed them to start at will. Results: HD patients performed ET and SI tasks slower than normal subjects. Both groups executed ET sequences slower than SI, but movement times for the two tasks differed less in patients than in controls. Patients paused normally between sub-movements during the SI task, but they had slower reaction times for all the sub-movements of the ET task. Conclusions: Slower execution of both motor tasks indicates that HD patients are bradykinetic in performing sequential free arm movements. Our finding that total movement times for SI and ET tasks differ less in patients than in controls suggests that HD impairs internal more than external cueing mechanisms. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved

Spin-orbital nature of the high-field magnetic state in the Sr4Ru3O10

We perform a spin-polarized neutron-diffraction study to investigate the nature of the high-field magnetic state of the trilayered Sr4Ru3O10. The analysis indicates that a high field applied within the ab plane leads to an unbalance of the spin and orbital moments with a spatial profile that is strongly tied to the layers where the electrons are located in the unit cell. We provide evidence of a layer dependent magnetic anisotropy with the inner layers having larger spin and orbital magnetic moments than the outer ones and show that such behavior is robust to temperature variation being persistent above the Curie temperature. By means of an effective model that includes the coupling between the spin-orbital degrees of freedom at inequivalent Ru sites we ascribe the origin of the layer anisotropy to the cooperative effects between octahedral distortions, spin orbit, and Coulomb interactions

Pattern Formation by Electric-Field Quench in a Mott Crystal

The control of the Mott phase is intertwined with thespatial reorganizationof the electronic states. Out-of-equilibrium driving forces typicallylead to electronic patterns that are absent at equilibrium, whosenature is however often elusive. Here, we unveil a nanoscale patternformation in the Ca2RuO4 Mott insulator. Wedemonstrate how an applied electric field spatially reconstructs theinsulating phase that, uniquely after switching off the electric field,exhibits nanoscale stripe domains. The stripe pattern has regionswith inequivalent octahedral distortions that we directly observethrough high-resolution scanning transmission electron microscopy.The nanotexture depends on the orientation of the electric field;it is nonvolatile and rewritable. We theoretically simulate the chargeand orbital reconstruction induced by a quench dynamics of the appliedelectric field providing clear-cut mechanisms for the stripe phaseformation. Our results open the path for the design of nonvolatileelectronics based on voltage-controlled nanometric phases

Current-driven insulator-to-metal transition without Mott breakdown in Ca2RuO4

The electrical control of a material's conductivity is at the heart of modern electronics. Conventionally, this control is achieved by tuning the density of mobile charge carriers. A completely different approach is possible in Mott insulators such as Ca2RuO4, where an insulator-to-metal transition (IMT) can be induced by a weak electric field or current. While the driving force of the IMT is poorly understood, it has been thought to be a breakdown of the Mott state. Using in operando angle-resolved photoemission spectroscopy, we show that this is not the case: The current-induced conductivity is caused by the formation of in-gap states with only a minor reorganization of the Mott state. Electronic structure calculations show that these in-gap states form at the boundaries of structural domains that emerge during the IMT. At such boundaries, the overall gap is drastically reduced, even if the structural difference between the domains is small and the individual domains retain their Mott character. The inhomogeneity of the sample is thus key to understanding the IMT, as it leads to a nonequilibrium semimetallic state that forms at the interface of Mott domains

Orbital-selective metal skin induced by alkali-metal-dosing Mott-insulating Ca2RuO4

Doped Mott insulators are the starting point for interesting physics such as high temperature superconductivity and quantum spin liquids. For multi-band Mott insulators, orbital selective ground states have been envisioned. However, orbital selective metals and Mott insulators have been difficult to realize experimentally. Here we demonstrate by photoemission spectroscopy how Ca2RuO4, upon alkali-metal surface doping, develops a single-band metal skin. Our dynamical mean field theory calculations reveal that homogeneous electron doping of Ca2RuO4 results in a multi-band metal. All together, our results provide evidence for an orbital-selective Mott insulator breakdown, which is unachievable via simple electron doping. Supported by a cluster model and cluster perturbation theory calculations, we demonstrate a type of skin metal-insulator transition induced by surface dopants that orbital-selectively hybridize with the bulk Mott state and in turn produce coherent in-gap states

Intracellular HIV-1 Tat protein represses constitutive LMP2 transcription increasing proteasome activity by interfering with the binding of IRF-1 to STAT1

The Tat protein is the transcriptional activator of HIV-1 gene expression, which is not only essential for viral replication, but also important in the complex HIV-induced pathogenesis of AIDS, as both an intracellular and an extracellular released protein. Accordingly, Tat is able to profoundly affect cellular gene expression, regulating several cellular functions, also in non-infected cells. We showed recently that Tat induces modification of immunoproteasomes in that it up-regulates LMP7 (low-molecular-mass polypeptide 7) and MECL1 (multicatalytic endopeptidase complex-like 1) subunits and down-modulates the LMP2 subunit, resulting in a change in the generation and presentation of epitopes in the context of MHC class I. In particular, Tat increases presentation of subdominant and cryptic epitopes. In the present study, we investigated the molecular mechanism responsible for the Tat-induced LMP2 down-regulation and show that intracellular Tat represses transcription of the LMP2 gene by competing with STAT1 (signal transducer and activator of transcription 1) for binding to IRF-1 (interferon-regulatory factor-1) on the overlapping ICS-2 (interferon consensus sequence-2)–GAS (γ-interferon-activated sequence) present in the LMP2 promoter. This element is constitutively occupied in vivo by the unphosphorylated STAT1–IRF-1 complex, which is responsible for the basal transcription of the gene. Sequestration of IRF-1 by intracellular Tat impairs the formation of the complex resulting in lower LMP2 gene transcription and LMP2 protein expression, which is associated with increased proteolytic activity. On the other hand, extracellular Tat induces the expression of LMP2. These effects of Tat provide another effective mechanism by which HIV-1 affects antigen presentation in the context of the MHC class I complex and may have important implications in the use of Tat for vaccination strategies