Identification of the macromolecular complex responsible for PI3Kγ -dependent regulation of cAMP levels

Abstract PI3Kγ is a phosphoinositide 3-kinase characterized by both lipid and protein kinase activity. It is activated by G-protein-coupled receptors and is predominantly expressed in leucocytes; in addition, recent work showed its presence in the heart and its involvement in regulating cardiac functions. In this tissue, PI3Kγ acts as a negative modulator of contractility, by decreasing cAMP concentration through a kinase-independent mechanism. Indeed, whereas PI3Kγ -deficient mice show an abnormal cAMP elevation, cAMP levels in knockin mouse mutants, expressing a kinase-dead PI3Kγ , are comparable with wild-type controls. PI3Kγ regulates cardiac cAMP homoeostasis by forming a macromolecular complex containing PDE3B (phosphodiesterase 3B). In this complex, PI3Kγ could regulate PDE3B activity through protein kinase A, a PDE activator. PI3Ks (phosphoinositide 3-kinases) are best known as a family of lipid and protein kinases involved in a large variety of cellular functions, ranging from regulation of metabolism, proliferation and survival to cytoskeletal organization and cell migration. Depending on their substrate and their structural properties, PI3Ks are organized in at least three different classes. Among these, the best characterized is the class I, which comprises four members that, based on their activation mechanisms, are further subdivided into two subgroups, A and B. Whereas the three class IA PI3Ks, named α, β and δ, bind an adaptor subunit of the p85 family and are activated by tyrosine kinase receptors, the only class IB PI3K, PI3Kγ , is triggered by G-protein-coupled receptors and binds adaptor proteins of the p101 famil

Complexity of dipolar exciton Mott transition in GaN/(AlGa)N nanostructures

The Mott transition from a dipolar excitonic liquid to an electron-hole plasma is demonstrated in a wide GaN/(Al,Ga)N quantum well at $T=7$K by means of spatially-resolved magneto-photoluminescence spectroscopy. Increasing optical excitation density we drive the system from the excitonic state, characterized by a diamagnetic behavior and thus a quadratic energy dependence on the magnetic field, to the unbound electron-hole state, characterized by a linear shift of the emission energy with the magnetic field. The complexity of the system requires to take into account both the density-dependence of the exciton binding energy and the exciton-exciton interaction and correlation energy that are of the same order of magnitude. We estimate the carrier density at Mott transition as $n_\mathrm{Mott}\approx 2\times 10^{11}$cm$^{-2}$ and address the role played by excitonic correlations in this process. Our results strongly rely on the spatial resolution of the photoluminescence and the assessment of the carrier transport. We show, that in contrast to GaAs/(Al,Ga)As systems, where transport of dipolar magnetoexcitons is strongly quenched by the magnetic field due to exciton mass enhancement, in GaN/(Al,Ga)N the band parameters are such that the transport is preserved up to $9$T.Comment: 15 pages 13 figure

The Italian registry of pulmonary non-tuberculous mycobacteria - IRENE:The study protocol

Background: A substantial increase in pulmonary and extra-pulmonary diseases due to non-tuberculous mycobacteria (NTM) has been documented worldwide, especially among subjects suffering from chronic respiratory diseases and immunocompromised patients. Many questions remain regarding the epidemiology of pulmonary disease due to NTM (NTM-PD) mainly because reporting of NTM-PD to health authorities is not mandated in several countries, including Italy. This manuscript describes the protocol of the first Italian registry of adult patients with respiratory infections caused by NTM (IRENE). Methods: IRENE is an observational, multicenter, prospective, cohort study enrolling consecutive adult patients with either a NTM respiratory isolate or those with NTM-PD. A total of 41 centers, including mainly pulmonary and infectious disease departments, joined the registry so far. Adult patients with all of the following are included in the registry: 1) at least one positive culture for any NTM species from any respiratory sample; 2) at least one positive culture for NTM isolated in the year prior the enrolment and/or prescribed NTM treatment in the year prior the enrolment; 3) given consent to inclusion in the study. No exclusion criteria are applied to the study. Patients are managed according to standard operating procedures implemented in each IRENE clinical center. An online case report form has been developed to collect patients' demographics, comorbidities, microbiological, laboratory, functional, radiological, clinical, treatment and outcome data at baseline and on an annual basis. An IRENE biobank has also been developed within the network and linked to the clinical data of the registry. Conclusions: IRENE has been developed to inform the clinical and scientific community on the current management of adult patients with NTM respiratory infections in Italy and acts as a national network to increase the disease's awareness

Deep RNA Sequencing Reveals Novel Cardiac Transcriptomic Signatures for Physiological and Pathological Hypertrophy

Although both physiological hypertrophy (PHH) and pathological hypertrophy (PAH) of the heart have similar morphological appearances, only PAH leads to fatal heart failure. In the present study, we used RNA sequencing (RNA-Seq) to determine the transcriptomic signatures for both PHH and PAH. Approximately 13–20 million reads were obtained for both models, among which PAH showed more differentially expressed genes (DEGs) (2,041) than PHH (245). The expression of 417 genes was barely detectable in the normal heart but was suddenly activated in PAH. Among them, Foxm1 and Plk1 are of particular interest, since Ingenuity Pathway Analysis (IPA) using DEGs and upstream motif analysis showed that they are essential hub proteins that regulate the expression of downstream proteins associated with PAH. Meanwhile, 52 genes related to collagen, chemokines, and actin showed opposite expression patterns between PHH and PAH. MAZ-binding motifs were enriched in the upstream region of the participating genes. Alternative splicing (AS) of exon variants was also examined using RNA-Seq data for PAH and PHH. We found 317 and 196 exon inclusions and exon exclusions, respectively, for PAH, and 242 and 172 exon inclusions and exclusions, respectively for PHH. The AS pattern was mostly related to gains or losses of domains, changes in activity, and localization of the encoded proteins. The splicing variants of 8 genes (i.e., Fhl1, Rcan1, Ndrg2, Synpo, Ttll1, Cxxc5, Egfl7, and Tmpo) were experimentally confirmed. Multilateral pathway analysis showed that the patterns of quantitative (DEG) and qualitative (AS) changes differ depending on the type of pathway in PAH and PHH. One of the most significant changes in PHH is the severe downregulation of autoimmune pathways accompanied by significant AS. These findings revealed the unique transcriptomic signatures of PAH and PHH and also provided a more comprehensive understanding at both the quantitative and qualitative levels

Effect of the COVID-19 pandemic on surgery for indeterminate thyroid nodules (THYCOVID): a retrospective, international, multicentre, cross-sectional study

Background Since its outbreak in early 2020, the COVID-19 pandemic has diverted resources from non-urgent and elective procedures, leading to diagnosis and treatment delays, with an increased number of neoplasms at advanced stages worldwide. The aims of this study were to quantify the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic; and to evaluate whether delays in surgery led to an increased occurrence of aggressive tumours.Methods In this retrospective, international, cross-sectional study, centres were invited to participate in June 22, 2022; each centre joining the study was asked to provide data from medical records on all surgical thyroidectomies consecutively performed from Jan 1, 2019, to Dec 31, 2021. Patients with indeterminate thyroid nodules were divided into three groups according to when they underwent surgery: from Jan 1, 2019, to Feb 29, 2020 (global prepandemic phase), from March 1, 2020, to May 31, 2021 (pandemic escalation phase), and from June 1 to Dec 31, 2021 (pandemic decrease phase). The main outcomes were, for each phase, the number of surgeries for indeterminate thyroid nodules, and in patients with a postoperative diagnosis of thyroid cancers, the occurrence of tumours larger than 10 mm, extrathyroidal extension, lymph node metastases, vascular invasion, distant metastases, and tumours at high risk of structural disease recurrence. Univariate analysis was used to compare the probability of aggressive thyroid features between the first and third study phases. The study was registered on ClinicalTrials.gov, NCT05178186.Findings Data from 157 centres (n=49 countries) on 87 467 patients who underwent surgery for benign and malignant thyroid disease were collected, of whom 22 974 patients (18 052 [78 center dot 6%] female patients and 4922 [21 center dot 4%] male patients) received surgery for indeterminate thyroid nodules. We observed a significant reduction in surgery for indeterminate thyroid nodules during the pandemic escalation phase (median monthly surgeries per centre, 1 center dot 4 [IQR 0 center dot 6-3 center dot 4]) compared with the prepandemic phase (2 center dot 0 [0 center dot 9-3 center dot 7]; p<0 center dot 0001) and pandemic decrease phase (2 center dot 3 [1 center dot 0-5 center dot 0]; p<0 center dot 0001). Compared with the prepandemic phase, in the pandemic decrease phase we observed an increased occurrence of thyroid tumours larger than 10 mm (2554 [69 center dot 0%] of 3704 vs 1515 [71 center dot 5%] of 2119; OR 1 center dot 1 [95% CI 1 center dot 0-1 center dot 3]; p=0 center dot 042), lymph node metastases (343 [9 center dot 3%] vs 264 [12 center dot 5%]; OR 1 center dot 4 [1 center dot 2-1 center dot 7]; p=0 center dot 0001), and tumours at high risk of structural disease recurrence (203 [5 center dot 7%] of 3584 vs 155 [7 center dot 7%] of 2006; OR 1 center dot 4 [1 center dot 1-1 center dot 7]; p=0 center dot 0039).Interpretation Our study suggests that the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic period could have led to an increased occurrence of aggressive thyroid tumours. However, other compelling hypotheses, including increased selection of patients with aggressive malignancies during this period, should be considered. We suggest that surgery for indeterminate thyroid nodules should no longer be postponed even in future instances of pandemic escalation.Funding None.Copyright (c) 2023 Published by Elsevier Ltd. All rights reserved

Monolithically integrated white light LEDs on (11-22) semi-polar GaN templates

Carrier transport issues in a (11–22) semi-polar GaN based white light emitting diode (consisting of yellow and blue emissions) have been investigated by detailed simulations, demonstrating that the growth order of yellow and blue InGaN quantum wells plays a critically important role in achieving white emission. The growth order needs to be yellow InGaN quantum wells first and then a blue InGaN quantum well after the growth of n-type GaN. The fundamental reason is due to the poor hole concentration distribution across the whole InGaN quantum well region. In order to effectively capture holes in both the yellow InGaN quantum wells and the blue InGaN quantum well, a thin GaN spacer has been introduced prior to the blue InGaN quantum well. The detailed simulations of the band diagram and the hole concentration distribution across the yellow and the blue quantum wells have been conducted, showing that the thin GaN spacer can effectively balance the hole concentration between the yellow and the blue InGaN quantum wells, eventually determining their relative intensity between the yellow and the blue emissions. Based on this simulation, we have demonstrated a monolithically multi-colour LED grown on our high quality semi-polar (11–22) GaN templates