Phosphodiesterase 4D inhibition improves the functional and molecular outcome in a mouse and human model of Charcot Marie Tooth disease 1 A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited peripheral neuropathy caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. It is primarily marked by Schwann cell dedifferentiation and demyelination, leading to motor and sensory deficits. Cyclic adenosine monophosphate (cAMP) is crucial for Schwann cell differentiation and maturation.

Boundary-layer structures arising in linear transport theory.

We consider boundary-layer structures that arise in connection with the transport of neutral particles (e.g., photons or neutrons) through a participating medium.

Application of coincidence index in the discovery of co-expressed metabolic pathways.

Analyzing transcription data requires intensive statistical analysis to obtain useful biological information and knowledge. A significant portion of this data is affected by random noise or even noise intrinsic to the modeling of the experiment. Without robust treatment, the data might not be explored thoroughly, and incorrect conclusions could be drawn.

Amelioration of functional and histopathological consequences after spinal cord injury through phosphodiesterase 4D (PDE4D) inhibition.

Spinal cord injury (SCI) is a life-changing event that severely impacts the patient's quality of life. Modulating neuroinflammation, which exacerbates the primary injury, and stimulating neuro-regenerative repair mechanisms are key strategies to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes.

Ablation of specific long PDE4D isoforms increases neurite elongation and conveys protection against amyloid-β pathology.

Inhibition of phosphodiesterase 4D (PDE4D) enzymes has been investigated as therapeutic strategy to treat memory problems in Alzheimer's disease (AD). Although PDE4D inhibitors are effective in enhancing memory processes in rodents and humans, severe side effects may hamper their clinical use. PDE4D enzymes comprise different isoforms, which, when targeted specifically, can increase treatment efficacy and safety.

Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients.

Rivaroxaban Prophylaxis in Noncirrhotic Portal Vein Thrombosis.

BACKGROUND: In patients with noncirrhotic chronic portal vein thrombosis (PVT), the benefit of long-term anticoagulation is unknown. We assessed the effects of rivaroxaban on the risk of venous thromboembolism and portal hypertension-related bleeding in such patients. METHODS: In this multicenter, controlled trial, we randomly assigned patients with noncirrhotic chronic PVT without major risk factors for thrombosis to receive either rivaroxaban 15 mg/day or no anticoagulation.

Using Satellite Observations to Evaluate Model Microphysical Representation of Arctic Mixed-Phase Clouds.

Mixed-phase clouds play an important role in determining Arctic warming, but are parametrized in models and difficult to constrain with observations. We use two satellite-derived cloud phase metrics to investigate the vertical structure of Arctic clouds in two global climate models that use the Community Atmosphere Model version 6 (CAM6) atmospheric component. We report a model error limiting ice nucleation, produce a set of Arctic-constrained model runs by adjusting model microphysical variables to match the cloud phase metrics, and evaluate cloud feedbacks for all simulations.

Improved wood species identification based on multi-view imagery of the three anatomical planes.

Background: The identification of tropical African wood species based on microscopic imagery is a challenging problem due to the heterogeneous nature of the composition of wood combined with the vast number of candidate species. Image classification methods that rely on machine learning can facilitate this identification, provided that sufficient training material is available. Despite the fact that the three main anatomical sections contain information that is relevant for species identification, current methods only rely on transverse sections.

Contrast-enhanced CT and liver surface nodularity for the diagnosis of porto-sinusoidal vascular disorder: A case-control study.

Background And Aims: Porto-sinusoidal vascular disorder (PSVD) is a rare and commonly overlooked cause of portal hypertension. The interest of CT analysis, including quantification of liver surface nodularity (LSN) for PSVD diagnosis has not been established. This study aimed at assessing the performance of LSN and CT features for a PSVD diagnosis in patients with signs of portal hypertension.

The Pyrazolyl-Urea Gege3 Inhibits the Activity of ANXA1 in the Angiogenesis Induced by the Pancreatic Cancer Derived EVs.

The pyrazolyl-urea Gege3 molecule has shown interesting antiangiogenic effects in the tumor contest. Here, we have studied the role of this compound as interfering with endothelial cells activation in response to the paracrine effects of annexin A1 (ANXA1), known to be involved in promoting tumor progression. ANXA1 has been analyzed in the extracellular environment once secreted through microvesicles (EVs) by pancreatic cancer (PC) cells.

Skin effect in neutron transport theory.

We identify a neutron-flux "skin effect" in the context of neutron transport theory. The skin effect, which emerges as a boundary layer at material interfaces, plays a critical role in a correct description of transport phenomena. A correct accounting of the boundary-layer structure helps bypass computational difficulties reported in the literature over the last several decades, and should lead to efficient numerical methods for neutron transport in two and three dimensions.

New Series of Pyrazoles and Imidazo-Pyrazoles Targeting Different Cancer and Inflammation Pathways.

(1) Background: different previously synthesized pyrazoles and imidazo-pyrazoles showed interesting anti-angiogenic action, being able to interfere with ERK1/2, AKT and p38MAPK phosphorylation in different manners and with different potency; (2) Methods: here, a new small compound library, endowed with the same differently decorated chemical scaffolds, has been synthetized to obtain new agents able to inhibit different pathways involved in inflammation, cancer and human platelet aggregation. (3) Results: most of the new synthesized derivatives resulted able to block ROS production, platelet aggregation and p38MAPK phosphorylation both in platelets and Human Umbilical Vein Endothelial cells (HUVEC). This paves the way for the development of new agents with anti-angiogenic activity.

Synthesis, functional proteomics and biological evaluation of new 5-pyrazolyl ureas as potential anti-angiogenic compounds.

Based on biological results of previous synthesized pyrazolyl ureas able to interfere with angiogenesis process, we planned and synthesized the new benzyl-urea derivatives 2-4; some of them showed an interesting anti-proliferative profile and particularly 4e potently inhibited HUVEC proliferation. To shed light on the mechanism of action of 4e, its interactome has been deeply inspected to identify the most prominent protein partners, mainly taking into account kinome and phosphatome, through drug affinity responsive target stability experiments, followed by targeted limited proteolysis analysis. From these studies, PP1γ emerged as the most reliable 4e potential target in HUVEC.

A Home-Care Service for Frail Older Adults: Findings from a Quasi-Experiment in Milan.

Population aging is particularly pronounced in Italy. Recently, home-care services emerged as one of the desirable strategy when dealing with such situations of fragility. In this framework, we present the evaluation of a home-care service which was experimentally implemented by Fondazione Sacra Famiglia and Casa di Cura Ambrosiana in the 2017-2018 biennium.

Novel insights on the molecular mechanism of action of the anti-angiogenic pyrazolyl-urea GeGe-3 by functional proteomics.

In recent years, 5-pyrazolyl-ureas have mostly been known for their attractive poly-pharmacological outline and, in particular, ethyl 1-(2-hydroxypentyl)-5-(3-(3-(trifluoromethyl) phenyl) ureido)-1H-pyrazole-4-carboxylate (named GeGe-3) has emerged as a capable anti-angiogenic compound. This paper examines its interactome by functional proteomics using a label-free mass spectrometry based platform, coupling Drug Affinity Responsive Target Stability and targeted Limited Proteolysis-Multiple Reaction Monitoring. Calreticulin has been recognized as the GeGe-3 principal target and this evidence has been supported by immunoblotting and in silico molecular docking.

On the Use of Topological Features of Metabolic Networks for the Classification of Cancer Samples.

Background: The increasing availability of omics data collected from patients affected by severe pathologies, such as cancer, is fostering the development of data science methods for their analysis.

Introduction: The combination of data integration and machine learning approaches can provide new powerful instruments to tackle the complexity of cancer development and deliver effective diagnostic and prognostic strategies.

Methods: We explore the possibility of exploiting the topological properties of sample-specific metabolic networks as features in a supervised classification task.

Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors.

Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme.

Automatic Stomatal Segmentation Based on Delaunay-Rayleigh Frequency Distance.

The CO and water vapor exchange between leaf and atmosphere are relevant for plant physiology. This process is done through the stomata. These structures are fundamental in the study of plants since their properties are linked to the evolutionary process of the plant, as well as its environmental and phytohormonal conditions.

Social interaction layers in complex networks for the dynamical epidemic modeling of COVID-19 in Brazil.

We are currently living in a state of uncertainty due to the pandemic caused by the SARS-CoV-2 virus. There are several factors involved in the epidemic spreading, such as the individual characteristics of each city/country. The true shape of the epidemic dynamics is a large, complex system, considerably hard to predict.

[Long-term survival after small doses of radioiodine therapy for brain metastases of thyroid cancer].

Differentiated thyroid cancer is generally accompanied by a long term survival. However, in some cases distant metastases can develop and among them, brain localizations are of poor prognosis. The aim of this presentation is to communicate the clinical case of a 65 year-old woman who consulted for diplopia in vertical gaze which had appeared one month earlier.