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In this work, we consider a Shallow‐Water Quasi Geostrophic equation on the sphere, as a model for global large‐scale atmospheric dynamics. This equation, previously studied by Verkley (2009, https://doi.org/10.1175/2008jas2837.1) and Schubert et al. (2009, https://doi.org/10.3894/james.2009.1.2), possesses a rich geometric structure, called Lie‐Poisson, and admits an infinite number of conserved quantities, called Casimirs. In this paper, we develop a Casimir preserving numerical method for long‐time simulations of this equation. The method develops in two steps: first, we construct an N‐dimensional Lie‐Poisson system that converges to the continuous one in the limit N → ∞; second, we integrate in time the finite‐dimensional system using an isospectral time integrator, developed by Modin and Viviani (2020, https://doi.org/10.1017/jfm.2019.944). We demonstrate the efficacy of this computational method by simulating a flow on the entire sphere for different values of the Lamb parameter. We particularly focus on rotation‐induced effects, such as the formation of jets. In agreement with shallow water models of the atmosphere, we observe the formation of robust latitudinal jets and a decrease in the zonal wind amplitude with latitude. Furthermore, spectra of the kinetic energy are computed as a point of reference for future studies. Plain Language Summary We conducted a study on a model that represents the movements of planetary flows. This model has important physical and mathematical properties that are related to its long‐term behavior, which is essential for understanding geophysical turbulence. In this work, we developed a numerical method for simulation that preserves the key mathematical structure of the model through a two‐step process. We applied our method to simulate global atmospheric flow and investigate the impact of varying strengths of planetary rotation. Our findings demonstrate the expected formation of wind patterns known as zonal jets, where stronger winds occur near the equator and weaker winds near the poles. We also present energy spectra that illustrate the influence of planetary rotation on the transfer of turbulent energy, which aligns with existing theoretical predictions found in literature. These results highlight the potential of our numerical method for studying fundamental problems in geophysical fluid dynamics. Key Points We develop a numerical method preserving Casimirs to simulate balanced shallow water flow on the sphere We perform global high‐resolution simulations while accurately accounting for latitude‐dependent effects Our simulations show the formation of robust zonal jets and provide key insights into quasi‐geostrophic turbulence

Predicting the behavior of turbulent flows using large-eddy simulation requires modeling of the subgrid-scale stress tensor. This tensor can be approximated using mixed models, which combine the dissipative nature of functional models with the capability of structural models to approximate out-of-equilibrium effects. We propose a mathematical basis to mix (functional) eddy-viscosity models with the (structural) Bardina model. By taking an anisotropic minimum-dissipation (AMD) model for the eddy viscosity, we obtain the (single-layer) AMD-Bardina model. In order to also obtain a physics-conforming model for wall-bounded flows, we further develop this mixed model into a two-layer approach: the near-wall region is parameterized with the AMD-Bardina model, whereas the outer region is computed with the Bardina model. The single-layer and two-layer AMD-Bardina models are tested in turbulent channel flows at various Reynolds numbers, and improved predictions are obtained when the mixed models are applied in comparison to the computations with the AMD and Bardina models alone. The results obtained with the two-layer AMD-Bardina model are particularly remarkable: both first- and second-order statistics are extremely well predicted and even the inflection of the mean velocity in the channel center is captured. Hence, a very promising model is obtained for large-eddy simulations of wall-bounded turbulent flows at moderate and high Reynolds numbers.

Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD’s therapeutic outcomes.

Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2, and SATB1. They are organized convergently in genetically diverse subtypes of AML and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control.

Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase , and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here they show that SYNCRIP safeguards HSC self-renewal during regenerative stress by maintaining both proteostasis and CDC42-regulated cell polarity.

Different neuromodulatory systems are involved in long-term energy balance and body weight and, among these, evidence shows that the endocannabinoid system, in particular the activation of type-1 cannabinoid receptor, plays a key role. We here review current literature focusing on the role of the gene encoding type-1 cannabinoid receptors in the CNS and on the modulation of its expression by food intake and specific eating behaviors. We point out the importance to further investigate how environmental cues might have a role in the development of obesity as well as eating disorders through the transcriptional regulation of this gene in order to prevent or to treat these pathologies.

OBJECTIVES Health related quality of life (HRQOL) inventories are multi-dimensional measures of patient-centred health status developed for clinical research. The MS quality of life 54 (MSQOL-54) is an MS-specific HRQOL inventory originally devised for English speaking patients. It consists of a core measure, the 36-item short form health survey (SF-36) previously adapted into Italian, and 18 additional items exploring domains relevant to patients with MS (MS-18 module). The authors translated and culturally adapted into Italian the MS-18 module of the MSQOL-54 questionnaire, and clinically validated the whole questionnaire. METHODS The MS-18 module was translated following the methodology of the International Quality of Life Assessment (IQOLA) project. The MSQOL-54 was validated in 204 consecutive patients with MS seen between April and September 1997 at three participating centres. The questionnaire was explained by the physician who also administered the expanded disability status scale (EDSS) and mini mental status scale examination, and the patient filled in the MSQOL-54 and Beck depression inventory questionnaires (BDI), with assistance if required. The contribution of impairments and disabilities to MSQOL-54 scores were assessed, and mean scores were compared with normative data for the general Italian population, and with the original sample of United States MS patients. RESULTS The mean age of the 204 patients was 42 years; mean EDSS score was 4.5 (range 0-8.5). Patients’ participation in the assessment was satisfactory, and all scales satisfied the usual psychometric standards. The characteristics of the United States sample matched those of our patients in all but gender (72% United States patientsv 52% Italian patients were women), and education (90% United States patients and 44% Italian patients completed high school); MSQOL-54 profiles were also similar. The EDSS was significantly associated with the physical health composite but not with the mental health composite score. Multiple linear regression modelling showed that age and BDI independently predicted physical health composite (p < 0.001), and mental health composite (p < 0.001). Clinical worsening in the previous year had an independent effect on the physical health composite (p < 0.001). CONCLUSIONS The Italian version of MSQOL-54 is easy to administer and is well accepted by patients. Neurological impairment has a limited influence on perceived quality of life, while age and depressive symptoms has a major influence.

The exclusion of T cells causes immune escape of pancreatic ductal adenocarcinoma (PDA). T cell exclusion is mediated by the interaction between CXCR4 on T cells and its ligand, CXCL12, which is complexed to keratin-19 (KRT19) on the surface of PDA cells. KRT19 secretion by PDA cells is essential to this process but is unusual because KRT19 lacks an endoplasmic reticulum (ER)-directing signal peptide (SP). By using biotinylation by an ER-restricted TurboID system and a split-GFP assay in PDA cells, we demonstrate that KRT19 enters the ER via its \"head\" domain. Additionally, KRT19 is shown to interact with the signal recognition particle and its secretion is sensitive to canonical protein secretion inhibitors. In vivo, mouse tumors formed with ER-TurboID-expressing PDA cells contain biotinylated KRT19. In contrast, keratin-8 (KRT8), which colocalizes with KRT19 on the surface of PDA cells, does not enter the ER. Rather, KRT8 is externalized via secretory autophagy possibly in a complex with KRT19. Thus, despite lacking a classical SP, PDA cells secrete KRT19 to capture CXCL12 and protect against immune attack.

ABSTRACT Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2 and SATB1. They are organized convergently in genetically diverse subtypes of AML, and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control. Competing Interest Statement A patent application related to this work has been submitted to the U.S. Patent and Trademark Office entitled [Agents and methods for treating CREB binding protein-dependent cancers] (application PCT/US2017/059579). AK is a consultant for Novartis and Rgenta. Footnotes * This version was revised in response to Review Commons reviewers, whose comments and responses are enclosed. * https://doi.org/10.5281/zenodo.3780648