Transcription Regulation—Brain Development and Homeostasis—A Finely Tuned and Orchestrated Scenario in Physiology and Pathology

A finely tuned regulation of gene expression is essential for shaping the nervous system and for maintaining its homeostasis throughout life. Disruptions in gene regulation can impact brain development and physiology in ways that contribute to diverse pathologies. Classic and state-of-the art experimental models and technologies have advanced our knowledge of transcriptional regulators and the ways they interact in the healthy and diseased brain. Further in-depth characterization of the mechanisms of transcriptional regulation is needed to better understand how each element, from genes to cells, defines and maintains identities and functionalities in the nervous system. This Research Topic focuses on transcriptional regulation within the nervous system, with an emphasis on developmental and homeostatic processes, their dysregulation, and their association with neurodevelopmental disorders and neurodegenerative diseases. Eleven peer-reviewed manuscripts including six original articles, three reviews, one mini review, and one brief research report, encompass this special volume. Fifty-nine authors from research laboratories located in 10 countries: Argentina, Canada, China, Germany, Israel, Russia, Serbia, United Kingdom, United States, and Vietnam, took part in this initiative.Fil: Muñoz, Estela Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Silva Junqueira de Souza, Flavio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Rath, Martin F.. Universidad de Copenhagen; DinamarcaFil: Martínez Cerdeño, Verónica. University of California at Davis; Estados Unido

A quantitative assessment of the consistency of projections from five mathematical models of the HIV epidemic in South Africa: a model comparison study

Background: Mathematical models are increasingly used to inform HIV policy and planning. Comparing estimates obtained using different mathematical models can test the robustness of estimates and highlight research gaps. As part of a larger project aiming to determine the optimal allocation of funding for HIV services, in this study we compare projections from five mathematical models of the HIV epidemic in South Africa: EMOD-HIV, Goals, HIV-Synthesis, Optima, and Thembisa. // Methods: The five modelling groups produced estimates of the total population, HIV incidence, HIV prevalence, proportion of people living with HIV who are diagnosed, ART coverage, proportion of those on ART who are virally suppressed, AIDS-related deaths, total deaths, and the proportion of adult males who are circumcised. Estimates were made under a “status quo” scenario for the period 1990 to 2040. For each output variable we assessed the consistency of model estimates by calculating the coefficient of variation and examining the trend over time. // Results: For most outputs there was significant inter-model variability between 1990 and 2005, when limited data was available for calibration, good consistency from 2005 to 2025, and increasing variability towards the end of the projection period. Estimates of HIV incidence, deaths in people living with HIV, and total deaths displayed the largest long-term variability, with standard deviations between 35 and 65% of the cross-model means. Despite this variability, all models predicted a gradual decline in HIV incidence in the long-term. Projections related to the UNAIDS 95–95-95 targets were more consistent, with the coefficients of variation below 0.1 for all groups except children. // Conclusions: While models produced consistent estimates for several outputs, there are areas of variability that should be investigated. This is important if projections are to be used in subsequent cost-effectiveness studies

COrE (Cosmic Origins Explorer) A White Paper

COrE (Cosmic Origins Explorer) is a fourth-generation full-sky, microwave-band satellite recently proposed to ESA within Cosmic Vision 2015-2025. COrE will provide maps of the microwave sky in polarization and temperature in 15 frequency bands, ranging from 45 GHz to 795 GHz, with an angular resolution ranging from 23 arcmin (45 GHz) and 1.3 arcmin (795 GHz) and sensitivities roughly 10 to 30 times better than PLANCK (depending on the frequency channel). The COrE mission will lead to breakthrough science in a wide range of areas, ranging from primordial cosmology to galactic and extragalactic science. COrE is designed to detect the primordial gravitational waves generated during the epoch of cosmic inflation at more than $3\sigma$ for $r=(T/S)>=10^{-3}$. It will also measure the CMB gravitational lensing deflection power spectrum to the cosmic variance limit on all linear scales, allowing us to probe absolute neutrino masses better than laboratory experiments and down to plausible values suggested by the neutrino oscillation data. COrE will also search for primordial non-Gaussianity with significant improvements over Planck in its ability to constrain the shape (and amplitude) of non-Gaussianity. In the areas of galactic and extragalactic science, in its highest frequency channels COrE will provide maps of the galactic polarized dust emission allowing us to map the galactic magnetic field in areas of diffuse emission not otherwise accessible to probe the initial conditions for star formation. COrE will also map the galactic synchrotron emission thirty times better than PLANCK. This White Paper reviews the COrE science program, our simulations on foreground subtraction, and the proposed instrumental configuration.Comment: 90 pages Latex 15 figures (revised 28 April 2011, references added, minor errors corrected

Case report: Sustained complete remission with all-oral MEPED therapy in a patient with Hodgkin’s disease developing resistance to pembrolizumab

Targeted chemotherapy and immune checkpoint inhibitors (ICPi) have expanded the spectrum of therapies for patients with relapsed/refractory (r/r) Hodgkin’s disease and significantly improved the proportion of patients with long-term disease control. However, there is no standardized therapeutic option in case of further progression. Recently, we demonstrated that therapy with MEPED (metronomic chemotherapy, everolimus, pioglitazone, etoricoxib, dexamethasone) is highly effective in patients with r/r Hodgkin’s disease. The benefit after pre-treatment with ICPi has not been studied, yet. Here, we report a patient with progressive Hodgkin’s disease on Pembrolizumab for the first time who achieved sustained complete remission (CR) after initiation of MEPED therapy. A 57-year-old patient was pre-treated with brentuximab vedotin for relapsed advanced Hodgkin’s disease and had received Pembrolizumab for progression from November 2020 to July 2022. Due to further progression, MEPED therapy was started in August 2022 and continued until May 2023. It consisted of a strictly oral daily (28-day cycle) application of low-dose treosulfan 250 mg, everolimus 15 mg, pioglitazone 45 mg, etoricoxib 60 mg, and dexamethasone 0.5 mg. Treatment response was evaluated by F-18 FDG-PET/CT (PET/CT). CR was defined by a negative Deauville score (DS) of 1-3. Already 3 months after starting MEPED, a CR (DS: 3) was confirmed by PET/CT in November 2022. The next follow-up in May 2023 continued to show CR (DS: 3). The therapy was very well tolerated. No hematological or other organ toxicity was observed. However, in May 2023 the patient presented with leg edema and weight gain, most likely due to pioglitazone and the PET/CT revealed suspected everolimus-induced pneumonitis, so MEPED was discontinued and diuretic therapy and treatment with prednisolone was started with gradual dose reduction. This resulted in a rapid complete resolution of the symptoms. The next PET-CT in July 2023 continued to show CR (DS: 3) without evidence of pneumonitis. Currently, therapy with MEPED has not been resumed. In conclusion, we demonstrate for the first time that MEPED therapy is highly effective in a patient with Hodgkin’s disease who has been refractory to ICPi. Sustained CR was achieved over 11 months after initiation of MEPED therapy. Further studies on a larger patient cohort should be performed

Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer

The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy