Multifocal diffusion of a KPC-3 producing ST512 K. pneumoniae clone in Northern Italy

Sequence Type 258 (ST258) together with its allelic single- and double-locus variants have mostly been associated with the dissemination of KPC-producing Klebsiella pneumoniae in Europe. A total of 56 nonreplicate K. pneumoniae isolates with decreased carbapenem-susceptibility, collected at 7 different hospitals located in Northern Italy were investigated for the occurrence of blaKPC-type genes. PCR and sequencing results highlighted the presence of blaKPC-2 or blaKPC-3 determinants in 10/56 and 5/56 cases respectively. Here we describe the intra- and inter-hospital spread in Northern Italy of a K. pneumoniae ST512 clone harboring the blaKPC-3 gene

Activating Killer Immunoglobulin Receptors and HLA-C: A successful combination providing HIV-1 control

Several studies demonstrated a relevant role of polymorphisms located within the HLA-B and -C loci and the Killer Immunoglobulin Receptors (KIRs) 3DL1 and 3DS1 in controlling HIV-1 replication. KIRs are regulatory receptors expressed at the surface of NK and CD8+ T-cells that specifically bind HLA-A and -B alleles belonging to the Bw4 supratype and all the -C alleles expressing the C1 or C2 supratype. We here disclose a novel signature associated with the Elite Controller but not with the long-term nonprogressor status concerning 2DS activating KIRs and HLA-C2 alleles insensitive to miRNA148a regulation. Overall, our findings support a crucial role of NK cells in the control of HIV-1 viremia

The legacy of Corrado Gini in population studies

This volume contains 12 papers that range over many different research subjects, taking in many of the population questions that, directly or indirectly, absorbed Corrado Gini as demographer and social scientist over several decades. They vary from the analysis of the living conditions and behaviours of the growing foreign population (measurements and methods of analysis, socio-economic conditions and health, ethnic residential segregation, sex-ratio at birth), to studies on the homogamy of couples; from population theories (with reference to the cyclical theory of populations) to the modelling approach to estimating mortality in adult ages or estimating time transfers, by age and sex, related to informal child care and adult care; from historical studies that take up themes dear to Gini (such as the estimates of Italian military deaths in WWI), to the application of Gini’s classical measurements to studying significant phenomena today (transition to adulthood and leaving the parental home, health care, disabled persons and social integration). The subjects and measurements that appear here are not intended to exhaust the broad spectrum of Gini’s research work in the demographic and social field (nor could they), but they can make up a part of the intersection between his vast legacy and some interesting topics in current research, some of which were not even imaginable in the mid twentieth century. Looking at the many contributions that celebrated Gini in Treviso and thinking about his legacy, it seems possible to identify at least two typologies of approach, to be found in this issue of the journal, too. On the one hand, there are contributions that aim to retrieve and discuss themes, methodologies and measurements dealt with or used by Gini so as to evaluate their present relevance and importance in the current scholarly debate. On the other, there are contributions that deal with topics that are far from Gini’s work, as they study very recent phenomena, but actually, among other things, make use of methods and indicators devised by Gini that are now so much part of the common currency of methodology, so they don’t require explicit reference to their Author

The Recently Identified P2Y-Like Receptor GPR17 Is a Sensor of Brain Damage and a New Target for Brain Repair

Deciphering the mechanisms regulating the generation of new neurons and new oligodendrocytes, the myelinating cells of the central nervous system, is of paramount importance to address new strategies to replace endogenous damaged cells in the adult brain and foster repair in neurodegenerative diseases. Upon brain injury, the extracellular concentrations of nucleotides and cysteinyl-leukotrienes (cysLTs), two families of endogenous signaling molecules, are markedly increased at the site of damage, suggesting that they may act as “danger signals” to alert responses to tissue damage and start repair. Here we show that, in brain telencephalon, GPR17, a recently deorphanized receptor for both uracil nucleotides and cysLTs (e.g., UDP-glucose and LTD4), is normally present on neurons and on a subset of parenchymal quiescent oligodendrocyte precursor cells. We also show that induction of brain injury using an established focal ischemia model in the rodent induces profound spatiotemporal-dependent changes of GPR17. In the lesioned area, we observed an early and transient up-regulation of GPR17 in neurons expressing the cellular stress marker heat shock protein 70. Magnetic Resonance Imaging in living mice showed that the in vivo pharmacological or biotechnological knock down of GPR17 markedly prevents brain infarct evolution, suggesting GPR17 as a mediator of neuronal death at this early ischemic stage. At later times after ischemia, GPR17 immuno-labeling appeared on microglia/macrophages infiltrating the lesioned area to indicate that GPR17 may also acts as a player in the remodeling of brain circuitries by microglia. At this later stage, parenchymal GPR17+ oligodendrocyte progenitors started proliferating in the peri-injured area, suggesting initiation of remyelination. To confirm a specific role for GPR17 in oligodendrocyte differentiation, the in vitro exposure of cortical pre-oligodendrocytes to the GPR17 endogenous ligands UDP-glucose and LTD4 promoted the expression of myelin basic protein, confirming progression toward mature oligodendrocytes. Thus, GPR17 may act as a “sensor” that is activated upon brain injury on several embryonically distinct cell types, and may play a key role in both inducing neuronal death inside the ischemic core and in orchestrating the local remodeling/repair response. Specifically, we suggest GPR17 as a novel target for therapeutic manipulation to foster repair of demyelinating wounds, the types of lesions that also occur in patients with multiple sclerosis

Multi-Messenger Astronomy with Extremely Large Telescopes

The field of time-domain astrophysics has entered the era of Multi-messenger Astronomy (MMA). One key science goal for the next decade (and beyond) will be to characterize gravitational wave (GW) and neutrino sources using the next generation of Extremely Large Telescopes (ELTs). These studies will have a broad impact across astrophysics, informing our knowledge of the production and enrichment history of the heaviest chemical elements, constrain the dense matter equation of state, provide independent constraints on cosmology, increase our understanding of particle acceleration in shocks and jets, and study the lives of black holes in the universe. Future GW detectors will greatly improve their sensitivity during the coming decade, as will near-infrared telescopes capable of independently finding kilonovae from neutron star mergers. However, the electromagnetic counterparts to high-frequency (LIGO/Virgo band) GW sources will be distant and faint and thus demand ELT capabilities for characterization. ELTs will be important and necessary contributors to an advanced and complete multi-messenger network.Comment: White paper submitted to the Astro2020 Decadal Surve

Clinical and molecular characterization of a cohort of patients with novel nucleotide alterations of the Dystrophin gene detected by direct sequencing

<p>Abstract</p> <p>Background</p> <p>Duchenne and Becker Muscular dystrophies (DMD/BMD) are allelic disorders caused by mutations in the dystrophin gene, which encodes a sarcolemmal protein responsible for muscle integrity. Deletions and duplications account for approximately 75% of mutations in DMD and 85% in BMD. The implementation of techniques allowing complete gene sequencing has focused attention on small point mutations and other mechanisms underlying complex rearrangements.</p> <p>Methods</p> <p>We selected 47 patients (41 families; 35 DMD, 6 BMD) without deletions and duplications in <it>DMD </it>gene (excluded by multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction analysis). This cohort was investigated by systematic direct sequence analysis to study sequence variation. We focused our attention on rare mutational events which were further studied through transcript analysis.</p> <p>Results</p> <p>We identified 40 different nucleotide alterations in DMD gene and their clinical correlates; altogether, 16 mutations were novel. DMD probands carried 9 microinsertions/microdeletions, 19 nonsense mutations, and 7 splice-site mutations. BMD patients carried 2 nonsense mutations, 2 splice-site mutations, 1 missense substitution, and 1 single base insertion. The most frequent stop codon was TGA (n = 10 patients), followed by TAG (n = 7) and TAA (n = 4). We also analyzed the molecular mechanisms of five rare mutational events. They are two frame-shifting mutations in the <it>DMD </it>gene 3'end in BMD and three novel splicing defects: IVS42: c.6118-3C>A, which causes a leaky splice-site; c.9560A>G, which determines a cryptic splice-site activation and c.9564-426 T>G, which creates pseudoexon retention within IVS65.</p> <p>Conclusion</p> <p>The analysis of our patients' sample, carrying point mutations or complex rearrangements in <it>DMD </it>gene, contributes to the knowledge on phenotypic correlations in dystrophinopatic patients and can provide a better understanding of pre-mRNA maturation defects and dystrophin functional domains. These data can have a prognostic relevance and can be useful in directing new therapeutic approaches, which rely on a precise definition of the genetic defects as well as their molecular consequences.</p

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16(+) monocyte population via the IL-10/STAT3 axis

The human CD14+ monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16+ monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by theCD16+CD163+MerTK+pSTAT3+ phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16+CD163+MerTK+pSTAT3+ cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16+CD163+MerTK+pSTAT3+ monocyte-to-macrophage differentiation program and its potential as a target for TB therapy,and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoringof treatment efficacy.Fil: Lastrucci, Claire. Centre National de la Recherche Scientifique; FranciaFil: Bénard, Alan. Centre National de la Recherche Scientifique; FranciaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pingris, Karine. Centre National de la Recherche Scientifique; FranciaFil: Souriant, Shanti. Centre National de la Recherche Scientifique; FranciaFil: Poincloux, Renaud. Centre National de la Recherche Scientifique; FranciaFil: Al Saati, Talal. Inserm; FranciaFil: Rasolofo, Voahangy. Pasteur Institute in Antananarivo; MadagascarFil: González Montaner, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Inwentarz, Sandra. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Moraña, Eduardo José. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Kondova, Ivanela. Biomedical Primate Research Centre; Países BajosFil: Verreck, Franck A. W.. Biomedical Primate Research Centre; Países BajosFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Neyrolles, Olivier. Centre National de la Recherche Scientifique; FranciaFil: Maridonneau Parini, Isabel. Centre National de la Recherche Scientifique; FranciaFil: Lugo Villarino, Geanncarlo. Centre National de la Recherche Scientifique; FranciaFil: Cougoule, Celine. Centre National de la Recherche Scientifique; Franci

NeuroBench:A Framework for Benchmarking Neuromorphic Computing Algorithms and Systems

Neuromorphic computing shows promise for advancing computing efficiency and capabilities of AI applications using brain-inspired principles. However, the neuromorphic research field currently lacks standardized benchmarks, making it difficult to accurately measure technological advancements, compare performance with conventional methods, and identify promising future research directions. Prior neuromorphic computing benchmark efforts have not seen widespread adoption due to a lack of inclusive, actionable, and iterative benchmark design and guidelines. To address these shortcomings, we present NeuroBench: a benchmark framework for neuromorphic computing algorithms and systems. NeuroBench is a collaboratively-designed effort from an open community of nearly 100 co-authors across over 50 institutions in industry and academia, aiming to provide a representative structure for standardizing the evaluation of neuromorphic approaches. The NeuroBench framework introduces a common set of tools and systematic methodology for inclusive benchmark measurement, delivering an objective reference framework for quantifying neuromorphic approaches in both hardware-independent (algorithm track) and hardware-dependent (system track) settings. In this article, we present initial performance baselines across various model architectures on the algorithm track and outline the system track benchmark tasks and guidelines. NeuroBench is intended to continually expand its benchmarks and features to foster and track the progress made by the research community

First light of BEaTriX, the new testing facility for the modular X-ray optics of the ATHENA mission

Aims: The Beam Expander Testing X-ray facility (BEaTriX) is a unique X-ray apparatus now operated at the Istituto Nazionale di Astrofisica (INAF), Osservatorio Astronomico di Brera (OAB), in Merate, Italy. It has been specifically designed to measure the point spread function (PSF) and the effective area (EA) of the X-ray mirror modules (MMs) of the Advanced Telescope for High-ENergy Astrophysics (ATHENA), based on silicon pore optics (SPO) technology, for verification before integration into the mirror assembly. To this end, BEaTriX generates a broad, uniform, monochromatic, and collimated X-ray beam at 4.51 keV. The beam collimation is better than a few arcseconds, ensuring reliable tests of the ATHENA MMs, in their focus at a 12 m distance. Methods: In BEaTriX, a micro-focus X-ray source with a titanium anode is placed in the focus of a paraboloidal mirror, which generates a parallel beam. A crystal monochromator selects the 4.51 keV line, which is expanded to the final size by a crystal asymmetrically cut with respect to the crystalline planes. An in-house-built Hartmann plate was used to characterize the X-ray beam divergence, observing the deviation of X-ray beams from the nominal positions, on a 12-m-distant CCD camera. After characterization, the BEaTriX beam has the nominal dimensions of 170 mm × 60 mm, with a vertical divergence of 1.65 arcsec and a horizontal divergence varying between 2.7 and 3.45 arcsec, depending on the monochromator setting: either high collimation or high intensity. The flux per area unit varies from 10 to 50 photons/s/cm2 from one configuration to the other. Results: The BEaTriX beam performance was tested using an SPO MM, whose entrance pupil was fully illuminated by the expanded beam, and its focus was directly imaged onto the camera. The first light test returned a PSF and an EA in full agreement with expectations. As of today, the 4.51 keV beamline of BEaTriX is operational and can characterize modular X-ray optics, measuring their PSF and EA with a typical exposure of 30 min. Another beamline at 1.49 keV is under development and will be integrated into the current equipment. We expect BEaTriX to be a crucial facility for the functional test of modular X-ray optics, such as the SPO MMs for ATHENA