Differences at brain SPECT between depressed females with and without adult ADHD and healthy controls: etiological considerations

<p>Abstract</p> <p>Background</p> <p>Comorbidity between Attention Deficit Hyperactivity Disorder (ADHD) and mood disorders is common. Alterations of the cerebellum and frontal regions have been reported in neuro-imaging studies of ADHD and major depression.</p> <p>Methods</p> <p>Thirty chronically depressed adult females of whom 16 had scores below, and 14 scores above, cut-offs on the 25-items Wender Utah Retrospective Scale (WURS-25) and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) were divided into subgroups designated "Depression" and "Depression + ADHD", respectively. Twenty-one of the patients had some audiological symptom, tinnitus and/or hearing impairment. The patients were investigated with other rating scales and ^99mTc-HMPAO SPECT. Controls for ^99mTc-HMPAO SPECT were 16 healthy females. SPECT was analyzed by both statistical parametric mapping (SPM2) and the computerized brain atlas (CBA). Discriminant analysis was performed on the volumes of interest generated by the CBA, and on the scores from rating scales with the highest group differences.</p> <p>Results</p> <p>The mean score of a depression rating scale (MADRS-S) was significantly lower in the "Depression" subgroup compared to in the "Depression + ADHD" subgroup. There was significantly decreased tracer uptake within the bilateral cerebellum at both SPM and CBA in the "Depression + ADHD" subgroup compared to in the controls. No decrease of cerebellar tracer uptake was observed in "Depression". Significantly increased tracer uptake was found at SPM within some bilateral frontal regions (Brodmann areas 8, 9, 10, 32) in the "Depression + ADHD" subgroup compared to in "Depression". An accuracy of 100% was obtained for the discrimination between the patient groups when thalamic uptake was used in the analysis along with scores from Socialization and Impulsivity scales.</p> <p>Conclusion</p> <p>The findings confirm the previous observation of a cerebellar involvement in ADHD. Higher bilateral frontal ^99mTc-HMPAO uptake in "Depression + ADHD" compared to in "Depression" indicate a difference between these subgroups. ^99mTc-HMPAO uptake mechanisms are discussed.</p

pH-Controlled Liposomes for Enhanced Cell Penetration in Tumor Environment

An innovative pH-switchable colloidal system that can be exploited for site-selective anticancer drug delivery has been generated by liposome decoration with a new novel synthetic non-peptidic oligo-arginine cell-penetration enhancer (CPE) and a quenching PEGylated counterpart that detaches from the vesicle surface under the acidic conditions of tumors. The CPE module (Arg(4)-DAG) is formed by four arginine units conjugated to a first-generation (G1) 2,2-bis(hydroxymethyl)propionic acid (bis-MPA)/2,2-bis(aminomethyl)propionic acid (bis-AMPA) polyester dendron terminating with 1,2-distearoyl-3-azidopropane for liposome bilayer insertion. The zeta potential of the Arg(4)-DAG-decorated liposomes increased up to +32 mV as the Arg(4)-DAG/lipids molar ratio increased. The Arg(4)-DAG liposome shielding at pH 7.4 was provided by methoxy-PEGS(5 kDa)-polymethacryloyl sulfadimethoxine (mPEG(5) (kDa)-SDM8) with 7.1 apparent pK(a). Zeta potential, surface plasmon resonance and synchrotron small-angle X-ray scattering analyses showed that at pH 7.4 mPEG(5) (kDa)-SDM8 associates with polycationic Arg(4)-DAG-decorated liposomes yielding liposomes with neutral zeta potential. At pH 6.5, which mimics the tumor environment, mPEG(5) (kDa)-SDM8 detaches from the liposome surface yielding Arg(4)-DAG exposure. Flow cytometry and confocal microscopy showed a 30-fold higher HeLa cancer cell association of the Arg(4)-DAG-decorated liposomes compared to non-decorated liposomes. At pH 7.4, the mPEG(5) (kDa)-SDM8-coated liposomes undergo low cell association while remarkable cell association occurred at pH 6.5, which allowed for the controlled intracellular delivery of model macromolecules and small molecules loaded in the liposome under tumor conditions.Peer reviewe

Thermal titration molecular dynamics (TTMD): shedding light on the stability of RNA-small molecule complexes

Ribonucleic acids are gradually becoming relevant players among putative drug targets, thanks to the increasing amount of structural data exploitable for the rational design of selective and potent binders that can modulate their activity. Mainly, this information allows employing different computational techniques for predicting how well would a ribonucleic-targeting agent fit within the active site of its target macromolecule. Due to some intrinsic peculiarities of complexes involving nucleic acids, such as structural plasticity, surface charge distribution, and solvent-mediated interactions, the application of routinely adopted methodologies like molecular docking is challenged by scoring inaccuracies, while more physically rigorous methods such as molecular dynamics require long simulation times which hamper their conformational sampling capabilities. In the present work, we present the first application of Thermal Titration Molecular Dynamics (TTMD), a recently developed method for the qualitative estimation of unbinding kinetics, to characterize RNA-ligand complexes. In this article, we explored its applicability as a post-docking refinement tool on RNA in complex with small molecules, highlighting the capability of this method to identify the native binding mode among a set of decoys across various pharmaceutically relevant test cases

Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset

Specific biological markers for Autism Spectrum Disorder (ASD) have not yet been established. Functional studies have shown abnormalities in the anatomo-functional connectivity of the limbic-striatal "social" brain. This study aimed to investigate regional cerebral blood flow (rCBF) at rest. Thirteen patients with ASD of normal intelligence and ten IQ-, sex- and age-matched healthy controls (HC) underwent PET/CT using [1- 11 C]butanol, a perfusion tracer. As compared to HC, ASD showed significant CBF increases in the right parahippocampal, posterior cingulate, primary visual and temporal cortex, putamen, caudatus, substantia nigra and cerebellum. No statistically significant correlation between CBF and IQ was found. The limbic, posterior associative and cerebellar cortices showed increased blood flow in ASD, confirming previous findings about the neurobiology of ASD

Alpine freshwater fish biodiversity assessment: an inter-calibration test for metabarcoding method set up

The analysis of environmental DNA (eDNA) by high throughput sequencing (HTS) is proving to be a promising tool for freshwater fish biodiversity assessment in Europe within the Water Framework Directive (WFD, 2000/60/EC), especially for large rivers and lakes where current fish monitoring techniques have known shortcomings. These new biomonitoring methods based on eDNA show several advantages compared to classical morphological methods. The sampling procedures are easier and cheaper and eDNA metabarcoding is non-invasive and very sensitive, allowing for the detection of traces of DNA. However, eDNA metabarcoding methods need careful standardization to make the results of different surveys comparable. The aim of the EU project Eco-AlpsWater is to test and validate molecular biodiversity monitoring tools for aquatic ecosystems (i.e., eDNA metabarcoding) to improve the traditional WFD monitoring approaches in Alpine waterbodies. To this end, an inter-calibration test was performed using fish mock community samples containing either tissue-extracted DNA, eDNA collected from aquaculture tanks and eDNA samples collected from Lake Bourget (France). Samples were analysed using a DNA metabarcoding approach, relying on the amplification and HTS of a 12S rDNA marker, in two separate laboratories, to evaluate if different laboratory and bioinformatic protocols can provide a reliable and comparable description of the fish communities in both mock and natural samples. Our results highlight good replicability of the molecular laboratory protocols for HTS and good amplification success of selected primers, providing essential information concerning the taxonomic resolution of the 12S mitochondrial marker in describing the Alpine fish communities. Interestingly, different concentrations of species DNA in the mock samples were well represented by the relative DNA reads abundance. These tests confirm the reproducibility of eDNA metabarcoding analyses for the biomonitoring of freshwater fish inhabiting Alpine and peri-Alpine lakes and river

Design and advancement status of the Beam Expander Testing X-ray facility (BEaTriX)

The BEaTriX (Beam Expander Testing X-ray facility) project is an X-ray apparatus under construction at INAF/OAB to generate a broad (200́60 mm2), uniform and low-divergent X-ray beam within a small lab (6́15 m2). BEaTriX will consist of an X-ray source in the focus a grazing incidence paraboloidal mirror to obtain a parallel beam, followed by a crystal monochromation system and by an asymmetrically-cut diffracting crystal to perform the beam expansion to the desired size. Once completed, BEaTriX will be used to directly perform the quality control of focusing modules of large X-ray optics such as those for the ATHENA X-ray observatory, based on either Silicon Pore Optics (baseline) or Slumped Glass Optics (alternative), and will thereby enable a direct quality control of angular resolution and effective area on a number of mirror modules in a short time, in full X-ray illumination and without being affected by the finite distance of the X-ray source. However, since the individual mirror modules for ATHENA will have an optical quality of 3-4 arcsec HEW or better, BEaTriX is required to produce a broad beam with divergence below 1-2 arcsec, and sufficient flux to quickly characterize the PSF of the module without being significantly affected by statistical uncertainties. Therefore, the optical components of BEaTriX have to be selected and/or manufactured with excellent optical properties in order to guarantee the final performance of the system. In this paper we report the final design of the facility and a detailed performance simulation

Low luminosity Type II supernovae - IV. SN 2020cxd and SN 2021aai, at the edges of the sub-luminous supernovae class

Photometric and spectroscopic data for two Low Luminosity Type IIP Supernovae (LL SNe IIP) 2020cxd and 2021aai are presented. SN 2020cxd was discovered 2 d after explosion at an absolute magnitude of Mr = -14.02 ± 0.21 mag, subsequently settling on a plateau which lasts for ∼120 d. Through the luminosity of the late light curve tail, we infer a synthesized 56Ni mass of (1.8 ± 0.5) × 10-3 M⊙. During the early evolutionary phases, optical spectra show a blue continuum ($T\, \gt$8000 K) with broad Balmer lines displaying a P Cygni profile, while at later phases, Ca ii, Fe ii, Sc ii, and Ba ii lines dominate the spectra. Hydrodynamical modelling of the observables yields $R\, \simeq$ 575 R⊙ for the progenitor star, with Mej = 7.5 M⊙ and $E\, \simeq$ 0.097 foe emitted during the explosion. This low-energy event originating from a low-mass progenitor star is compatible with both the explosion of a red supergiant (RSG) star and with an Electron Capture Supernova arising from a super asymptotic giant branch star. SN 2021aai reaches a maximum luminosity of Mr = -16.57 ± 0.23 mag (correcting for AV = 1.92 mag), at the end of its remarkably long plateau (∼140 d). The estimated 56Ni mass is (1.4 ± 0.5) × 10-2 M⊙. The expansion velocities are compatible with those of other LL SNe IIP (few 103 km s-1). The physical parameters obtained through hydrodynamical modelling are $R\, \simeq$ 575 R⊙, Mej = 15.5 M⊙, and E = 0.4 foe. SN 2021aai is therefore interpreted as the explosion of an RSG, with properties that bridge the class of LL SNe IIP with standard SN IIP events.GV acknowledges INAF for funding his PhD fellowship within the PhD School in Astronomy at the University of Padova. MLP acknowledges support from the plan ‘programma ricerca di ateneo UNICT 2020-22 linea 2” of the University of Catania. AR acknowledges support from ANID BECAS/DOCTORADO NACIONAL 21202412. NER acknowledges partial support from MIUR, PRIN 2017 (grant 20179ZF5KS), from the Spanish MICINN grant PID2019-108709GB-I00 and FEDER funds, and from the programme Unidad de Excelencia María de Maeztu CEX2020-001058-M. LG acknowledges financial support from the Spanish Ministerio de Ciencia e Innovación (MCIN), the Agencia Estatal de Investigación (AEI) 10.13039/501100011033, and the European Social Fund (ESF) ‘Investing in your future’ under the 2019 Ramón y Cajal programme RYC2019-027683-I and the PID2020-115253GA-I00 HOSTFLOWS project, from Centro Superior de Investigaciones Científicas (CSIC) under the PIE project 20215AT016, and the programme Unidad de Excelencia María de Maeztu CEX2020-001058-M. TMB acknowledges financial support from the Spanish Ministerio de Ciencia e Innovación (MCIN), the Agencia Estatal de Investigación (AEI) 10.13039/501100011033 under the PID2020-115253GA-I00 HOSTFLOWS project, and from Centro Superior de Investigaciones Científicas (CSIC) under the PIE project 20215AT016, and the programme Unidad de Excelencia María de Maeztu CEX2020-001058-M. Y-ZC is funded by China Postdoctoral Science Foundation (grant no. 2021M691821

Brain hypermetabolism in amyotrophic lateral sclerosis: A FDG PET study in ALS of spinal and bulbar onset.

Abstract Purpose To identify the neurobiological traits of amyotrophic lateral sclerosis (ALS) and to elucidate functional differences between ALS of spinal and bulbar onset. We hypothesized that glucose metabolism distribution might vary between groups. Methods The study groups comprised 32 patients with ALS of either bulbar (n=13) or spinal (n=19) onset and 22 subjects as controls. They were investigated by [ 18 F]fluorodeoxyglucose (FDG) positron emission tomography (FDG PET), comparing the patient groups with each other and with the controls by statistical parametric mapping. Results Highly significant relative increases in glucose metabolism distribution were found in the group comprising all 32 ALS patients as compared with the controls in the bilateral amygdalae, midbrain, pons and cerebellum. Relative hypermetabolism was also found in patients with spinal onset as compared with the controls in the right midbrain. In patients with bulbar onset compared with the controls and with patients with spinal onset, large relatively hypometabolic areas were found in the bilateral frontal cortex, right insula, anterior cingulate, precuneus and inferior parietal lobe. Patients with spinal onset had significantly higher scores in a neuropsychological test assessing verbal fluency compared with patients with bulbar onset. Conclusion This large FDG PET investigation provided unprecedented evidence of relatively increased metabolism in the amygdalae, midbrain and pons in ALS patients as compared with control subjects, possibly due to local activation of astrocytes and microglia. Highly significant relative decreases in metabolism were found in large frontal and parietal regions in the bulbar onset patients as compared with the spinal onset patients and the controls, suggesting a differential metabolic and neuropsychological state between the two conditions

L-citrulline is protective in hyperoxic lung damage and improves matrix remodelling and alveolarization

Moderate hyperoxia alters alveolar and vascular lung morphogenesis. Nitric oxide (NO) and matrix metalloproteinases (MMP) have a crucial role in the homeostasis of the matrix and bronchoalveolar structure and may be regulated abnormally by exposure to hyperoxia. Disruption of vascular endothelial growth factor (VEGF)-NO signaling impairs vascular growth and contributes to hyperoxia-induced vascular disease in bronchopulmonary dysplasia (BPD). We hypothesize that L-citrulline, by raising the serum levels of L-arginine and enhancing endogenous NO synthesis, might attenuate hyperoxia-induced lung injury in an experimental model of BPD. Neonatal rats (1 day old) were exposed to 60% oxygen or room air for 14 days and administered L-citrulline or a vehicle (sham). Lung morphometry were performed; Serum was tested for arginine level; Matrix metalloproteinases2 (MMP2) gene expression, VEGF gene and protein expression and endothelial NO synthase (eNOS) protein expression were compared. Mean linear intercept was higher in the hyperoxia and sham groups when compared with the room air (RA) and L-citr+hyperoxia treated group (p&lt;0.02). Secondary crests number was higher in L-citrulline treated and RA when compared to hyperoxia and sham group (p&lt;0.02). L-Arginine level rose in the L-citrulline-treated group (p&lt;0.05). L-citrulline did not affect MMP2 gene expression, but it regulated the MMP2 active protein, which rose in bronchoalveolar lavage fluid (p&lt;0.05), presumably due to a post-transductional effect. Compared with RA controls, hyperoxia significantly decreased VEGF and eNOS protein expression. At the same time, an increased lung VEGF gene and protein expression (p&lt;0.05) were also seen in the rats treated with L-citrulline. We conclude that: (i) hyperoxia decreases growth and disrupts VEGF-NO signaling of lung; (ii) the main effects of L-citrulline are an increased serum level of arginine, as a promoter and a substrate of the nitric oxide synthase; and (ii) a better alveolar growth and matrix control than in hyperoxia-induced lung damage seems promising

X-ray tests of the ATHENA mirror modules in BEaTriX: from design to reality

The BEaTriX (Beam Expander Testing X-ray) facility is now operative at the INAF-Osservatorio Astronomico Brera (Merate, Italy). This facility has been specifically designed and built for the X-ray acceptance tests (PSF and Effective Area) of the ATHENA Silicon Pore Optics (SPO) Mirror Modules (MM). The unique setup creates a parallel, monochromatic, large X-ray beam, that fully illuminates the aperture of the MMs, generating an image at the ATHENA focal length of 12 m. This is made possible by a microfocus X-ray source followed by a chain of optical components (a paraboloidal mirror, 2 channel cut monochromators, and an asymmetric silicon crystal) able to expand the X-ray beam to a 6 cm × 17 cm size with a residual divergence of 1.5 arcsec (vertical) × 2.5 arcsec (horizontal). This paper reports the commissioning of the 4.5 keV beam line, and the first light obtained with a Mirror Module