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The transport sector plays a crucial role in the social and economic development of our society. Nevertheless, it is responsible for one quarter of the global CO2 emission worldwide. Although sustainable mobility could drastically reduce transport-related emissions, its adoption is still underdeveloped. In this paper, an impact innovation methodology has been used to generate a solution that could boost sustainable mobility development by creating an efficient offline tracking method that combines transactions and GPS data. The results suggest that incentive-based solutions could increase the adoption of sustainable mobility. This study generates the basis for the development of a sophisticated algorithms, able to track mobility and to incentivize people’s sustainable habits., CERN IdeaSquare Journal of Experimental Innovation, Vol. 4 No. 2 (2020)

In recent years, ALMA has been able to observe large-scale substructures within protoplanetary disks. Comparison with the predictions from models of planet-disk interaction has indicated that most of these disk substructures can be explained by the presence of planets with the mass of Neptune or larger at orbital radii of $\approx 5 - 100$ au. Better resolution is needed to observe structures closer to the star, where terrestrial planets are expected to form, as well as structures opened by planets with masses lower than Neptune. We investigate the capabilities of a possible extension to ALMA that would double the longest baseline lengths in the array to detect and resolve disk substructures opened by Earth-mass and Super Earth planets at orbital radii of $1-5$ au. By simulating observations of a family of disk models using this extended configuration in ALMA Bands 6 and 7, we show that an upgraded ALMA would detect gaps in disks formed by super-Earths as close as 1 au, as well as Earth-mass planets down to $2-3$ au from the young host stars in nearby star forming regions., Comment: 16 pages, 10 figures, accepted for publication in The Astrophysical Journal

This article seeks to provide a new analysis for the phenomenon of anatomical votive offerings in Central Italy. Traditionally, these items��� distribution was examined in relation to Roman colonization. Simply put, the extension of Rome���s power into Central Italy and the consequent establishment of colonial settlements were thought to be the foundational causes behind the popularity of these votives. This paper debunks such a view, examining the evidence in light of production, distribution and consumption. By doing so, the failures and unsuitability of Romanocentric explanations will become apparent: namely, Rome���s centrality played a limited role at all three aforementioned levels. What the evidence highlights, instead, is a more dynamic interplay among various Central Italian settlements, further emphasizing the importance of localized decision-making. The final result is the formation of a Central Italian koine in which these localized strands took part., PHASIS, No. 23 (2020)

The Successive Approximation (SAR) Analog-to-Digital converter is one of the most energy-efficient A/D converter. In this thesis, the development of a SAR ADC in a 28-nm CMOS technology based on charge redistribution is presented.The implemented SAR ADC uses a switching procedure based on a modified version of the mono- tonic switching algorithm to reduce the switching energy and area of the DAC. The DAC is a binary- weighted array of unit capacitors. A unit custom capacitor has been designed with a value of 0.8 fF to reduce the DAC energy consumption. Two comparators have been implemented, a dynamic comparator and a static comparator. The dynamic implementation allows to obtain better performance. Therefore, the dynamic comparator is chosen for the SAR ADC. The sampling switches are bootstrapped to reduce the non-linearity introduced when the input signal is sampled. The SAR operations are controlled by an asynchronous logic implemented as a behavioural model in Verilog-A.The effect of the designed circuits on the linearity of the converter is assessed with the integral non- linearity (INL) and differential non-linearity (DNL). Moreover, the performance of the ADC are assessed in terms of signal-to-noise-and-distortion ratio (SNDR). The co-simulation of Verilog-A behavioural models with circuit schematics allowed to evaluate the effect of each block on the overall performance of the ADC. The co-simulations show that the ADC is able to achieve an ENOB of 10.9 at a sampling rate of 200 MSps with a power consumption of 2.83 mW. The resulting FoM is 7.4 fJ/conv-step. SAR (Analog-Digital-omvandlaren) är en av de mest energieffektiva omvandlare. I den här avhandlingen är utvecklingen av en SAR ADC i en 28-nm CMOS-teknik baserad på laddning omfördelning presen- teras.Den implementerade SAR ADC använder en omkopplingsprocedur baserad på en modifierad version av den monotoniska omkopplingsalgoritm för att reducera omkopplingsenergin och DAC-området. DAC är en binärviktad matris med enhetskondensatorer. En anpassad kondensator för enheten har utformats med ett värde av 0,8 fF för att minska DAC-energiförbrukningen. Två komparatorer har implementerats, en dynamisk komparator och en statisk komparator. Den dynamiska implementering gör det möjligt att få bättre prestanda. Därför väljs den dynamiska komparatorn SAR ADC. Provtagningsomkopplarna startas upp för att minska icke-lineariteten introduceras när insignalen samplas. SAR-operationerna styrs av en asynkron logik implementerad som en beteendemodell i Verilog-A.Effekten av de designade kretsarna på konverterarens linearitet bedöms med integralen icke-linearitet (INL) och differentiell icke-linearitet (DNL). Dessutom är ADC: s prestanda bedömdes i termer av signal-till-brus-och-distorsionsförhållande (SNDR). Samsimulering av Verilog-A beteendemodeller och scheman tillåts utvärdera effekten av varje block på prestandan hos ADC. Omvandlaren kan uppnå en ENOB på 10,9 med en samplingshastighet på 200 MSps, vilket resulterar i en FoM eller 7,4 fJ / konv.- steg.

Focusing on the four years long, large-scale EU project Be SpectACTive!, the authors observe its initial, artistic and strategic, aims and the results in the light of the recent social and political changes as well as the notion of “inter-locality”. The EU priority Audience Development (AD) program and the organizations involved are analyzed highlighting successes and failures as well as their impact on cultural organizations and artists who have taken part in the program.

Modern astronomy has finally been able to observe protoplanetary disks in reasonable resolution and detail, unveiling the processes happening during planet formation. These observed processes are understood under the framework of disk-planet interaction, a process studied analytically and modeled numerically for over 40 years. Long a theoreticians' game, the wealth of observational data has been allowing for increasingly stringent tests of the theoretical models. Modeling efforts are crucial to support the interpretation of direct imaging analyses, not just for potential detections but also to put meaningful upper limits on mass accretion rates and other physical quantities in current and future large-scale surveys. This white paper addresses the questions of what efforts on the computational side are required in the next decade to advance our theoretical understanding, explain the observational data, and guide new observations. We identified the nature of accretion, ab initio planet formation, early evolution, and circumplanetary disks as major fields of interest in computational planet formation. We recommend that modelers relax the approximations of alpha-viscosity and isothermal equations of state, on the grounds that these models use flawed assumptions, even if they give good visual qualitative agreement with observations. We similarly recommend that population synthesis move away from 1D hydrodynamics. The computational resources to reach these goals should be developed during the next decade, through improvements in algorithms and the hardware for hybrid CPU/GPU clusters. Coupled with high angular resolution and great line sensitivity in ground based interferometers, ELTs and JWST, these advances in computational efforts should allow for large strides in the field in the next decade., White paper submitted to the Astro2020 decadal survey

International audience; Discoveries over the past few decades show that planets are common. However, most discovered exoplanets are mature, so their orbital properties have gone through dynamics alteration. To test planet formation theory, it is crucial to constrain the young planet population right after they are born in protoplanetary disks. Recent high resolution imaging in millimeter interferometry reveal a variety of disk features, some of which may be imprinted by young protoplanets. Our recent ALMA Large Program, "The Disk Substructures at High Angular Resolution Project" (DSHARP), provides the first homogeneous overview of disk substructures. In this work, we explore the possibility that these gaps/rings are induced by young planets, by carrying out a grid of hydrodynamics simulations with different values for viscosity, scale height and planet mass. I will first introduce our simulations including dust particles with drift and explain how they are scaled to the dust emission at DSHARP observation wavelength. Then I will highlight our simulation demonstrating that the intricate series of gaps in the AS 209 disk can be explained by a single planet. I will also demonstrate that the angular resolution and sensitivity of DSHARP observations are able to reveal disk structures induced by giant planets in the young solar system and HR 8799 analogs. Finally, I will explore the potential young planet population on the planet mass-semimajor axis diagram. We find the occurrence rate of giant planet > 5 MJ is consistent with direct imaging constraints. We also probe a new parameter space of Neptune to Jupiter mass planets beyond 10 au, which are not accessible to other planet searching techniques.

Understanding the origin of the astonishing diversity of exoplanets is a key question for the coming decades. ALMA has revolutionized our view of the dust emission from protoplanetary disks, demonstrating the prevalence of ring and spiral structures that are likely sculpted by young planets in formation. To detect kinematic signatures of these protoplanets and to probe the chemistry of their gas accretion reservoir will require the imaging of molecular spectral line emission at high angular and spectral resolution. However, the current sensitivity of ALMA limits these important spectral studies to only the nearest protoplanetary disks. Although some promising results are emerging, including the identification of the snowlines of a few key molecules and the first attempt at detecting a protoplanet's spiral wake, it is not yet possible to search for these important signatures in a population of disks in diverse environments and ages. Harnessing the tremendous power of (sub)mm observations to pinpoint and characterize the chemistry of planets in formation will require a major increase of ALMA's spectral sensitivity (5-10x), increase in instantaneous bandwidth (2x) at high spectral resolution, and improved angular resolution (2x) in the 2030 era., Comment: Astro2020 White Paper

Interferometric observations at sub-millimeter/millimeter wavelengths can provide images of nearby young disks with spatial resolutions of a few astronomical units. I will present the recent results obtained from the ALMA Large Program of proto-planetary disks, which have identified a number of disk substructures in the dust continuum emission all the way down to a few au from the central star. Some of these substructures are likely associated with the presence of one or more proto-planets in the disk. I will also describe the potential of the Next Generation Very Large Array (ngVLA) in the study of the disk inner regions. The ngVLA is a future large interferometric array that will investigate the structure of disks with spatial resolutions < 1 au in nearby star forming regions.

We present moderate (${\sim}5^{\prime\prime}$) and high angular resolution (${\sim}1^{\prime\prime}$) observations of $^{12}\rm{CO\,}(J=2-1)$ emission toward nearby, interacting galaxy NGC 3627 taken with the Submillimeter Array (SMA). These SMA mosaic maps of NGC 3627 reveal a prominent nuclear peak, inter-arm regions, and diffuse, extended emission in the spiral arms. A velocity gradient of ${\sim}400$-$450$ km s$^{-1}$ is seen across the entire galaxy with velocity dispersions ranging from $\lesssim 80$ km s$^{-1}$ toward the nuclear region to $\lesssim 15$ km s$^{-1}$ in the spiral arms. We also detect unresolved $^{13}\rm{CO\,}(J=2-1)$ line emission toward the nuclear region, southern bar end, and in a relatively isolated clump in the southern portion of the galaxy, while no $\rm{C}^{18}O(J=2-1)$ line emission is detected at a $3\sigma$ rms noise level of 42 mJy beam$^{-1}$ per 20 km s$^{-1}$ channel. Using RADEX modeling with a large velocity gradient approximation, we derive kinetic temperatures ranging from ${\sim}5$-$10$ K (in the spiral arms) to ${\sim}25$ K (at the center) and H$_2$ number densities from ${\sim}$400-1000 cm$^{-3}$ (in the spiral arms) to ${\sim}$12500 cm$^{-3}$ (at the center). From this density modeling, we find a total H$_2$ mass of $9.6\times10^9 M_{\odot}$, which is ${\sim}50\%$ higher than previous estimates made using a constant H$_2$-CO conversion factor but is largely dependent on the assumed vertical distribution of the CO gas. With the exception of the nuclear region, we also identify a tentative correlation between star formation efficiency and kinetic temperature. We derive a galactic rotation curve, finding a peak velocity of ${\sim}207$ km s$^{-1}$ and estimate a total dynamical mass of $4.94 \pm 0.70 \times 10^{10} M_{\odot}$ at a galactocentric radius of ${\sim}6.2$ kpc ($121^{\prime\prime}$)., Comment: 18 pages, 10 figures, accepted for publication in ApJ

Human hematopoiesis is a complex and dynamic system where morphologically and functionally diverse mature cell types are generated and maintained throughout life by bone marrow (BM) Hematopoietic Stem/Progenitor Cells (HSPC). Congenital and acquired hematopoietic disorders are often diagnosed through the detection of aberrant frequency or composition of hematopoietic cell populations. We here describe a novel protocol, called “Whole Blood Dissection” (WBD), capable of analyzing in a single test-tube, hematopoietic progenitors and all major mature cell lineages composing either BM or peripheral blood (PB) through a multiparametric flow-cytometry analysis. WBD allows unambiguously identifying in the same tube up to 23 different blood cell types including HSPC subtypes and all the major myeloid and lymphoid lineage compartments at different stages of maturation, through a combination of 17 surface and 1 viability cell markers. We assessed the efficacy of WBD by analyzing BM and PB samples from adult (n = 8) and pediatric (n = 9) healthy donors highlighting age-related shift in cell composition. We also tested the capability of WBD on detecting aberrant hematopoietic cell composition in clinical samples of patients with primary immunodeficiency or leukemia unveiling expected and novel hematopoietic unbalances. Overall, WBD allows unambiguously identifying >99% of the cell subpopulations composing a blood sample in a reproducible, standardized, cost-, and time-efficient manner. This tool has a wide range of potential pre-clinical and clinical applications going from the characterization of hematopoietic disorders to the monitoring of hematopoietic reconstitution in patients after transplant or gene therapy. © 2017 The Authors. Cytometry Part A Published by Wiley Periodicals, Inc. on behalf of ISAC.

The discovery of thousands of exoplanets has shown that the birth of planets is a very efficient process in nature. Several physical mechanisms have been proposed to describe the assembly of planets in disks surrounding young stars. However, observational constraints have been sparse on account of insufficient sensitivity and resolution, especially for imaging the inner $10 - 20$ au from the star, where most of planets are observed. Thanks to its unprecedented angular resolution and sensitivity at wavelengths where the emission from the circumstellar material is optically thin, the ngVLA has the potential to transform our understanding of planet formation. In this chapter, we present state-of-the-art theoretical models of planetary systems in the act of forming that demonstrate ngVLA capabilities of imaging and follow the temporal evolution of young solar system analogues up to the distance of the Orion Nebula. These images will unveil how planets form and interact with their parental disks, and will shed light on the diverse properties of exoplanetary systems., Comment: 8 pages, 2 figures, to be published in the ASP Monograph Series, "Science with a Next-Generation VLA", ed. E. J. Murphy (ASP, San Francisco, CA)

Planetary systems form in the discs of gas and dust that orbit young stars. In the past few years, observations of these discs at (sub-)millimetre wavelengths with very fine angular resolution have started to uncover the hallmarks of small-scale substructures in the spatial distributions of their pebble-sized particles. These are some of the fundamental signatures of the planet formation epoch, since they trace localised concentrations of material that facilitate the formation of much larger planetary building blocks, and may themselves be created by young planets interacting with their birth environments., Published in The Messenger vol. 174, pp. 19-23, December 2018.

A deeper understanding of T lymphocytes survival and differentiation potential in humans is paramount for the development of effective gene/cell therapies based on T-cell engineering. We here performed a comprehensive study of T-cells dynamics and plasticity in humans by a unique combination of phenotypic/functional studies and high-throughput integration sites (IS) analyses. We analyzed samples from hematopoietic stem cells (HSC) (n=10) or mature lymphocytes (PBL) gene therapy (GT) (n=4) treated ADA (adenosine deaminase) deficient-SCID patients. For comparative analyses, we also collected data from pediatric (n=19) and adult (n=52) healthy donors (HD), and from bone marrow transplanted patients (BMT) with primary immunodeficiencies (n=10, 4 with ADA-SCID). We observed that vector-positive CD62L+/CD45RA+ putative T naïve cells were detectable 12 years after last infusion of gene-corrected lymphocytes in peripheral blood of PBL-GT patients that lack the support of transduced lymphocytes precursors. We then unveiled that the vast majority of these CD62L+/CD45RA+ cells (80.3%) in PBL-GT patients could be actually classified phenotypically (CD95, IL2Rβ and IL7Rα surface expression) and functionally (IFNγ production and aCD3/aCD28 in vitro differentiation) as active long-lasting T memory stem cells (Tscm). The peculiar Tscm frequency found in PBL-GT patients was most likely due to a combinatorial in vitro and in vivo effect. Indeed, by a series of in vitro assays, we showed that Tscm relative enrichment in CD45RA+CD62L+ compartment have occurred during the in vitro manipulation of T cells before infusion. Additionally, we found higher-then-normal Tscm contribution among CD45RA+/CD62L+ cells even in ADA-SCID patients receiving HSC-GT and BMT, suggesting a role of disease background on in vivo Tscm persistence. Analyzing our cohorts of healthy donors and treated individuals we were able to further correlate Tscm contribution in vivo with age, conditioning regimen, disease background, cell source, and long-term T-cell reconstitution. One unique aspect of our study consisted in the opportunity to track Tscm clonal dynamics in vivo in humans since each gene-corrected cell infused in our GT patients is univocally and permanently tagged by a retroviral integration site.To perform in vivo molecular tracing of individual T-cell clones we sorted T naïve, Tscm, central memory and effector memory subtypes. We then collected from these subpopulations, by LAM-PCR+Illumina-Miseq sequencing, 2.584.137 integration sites (IS) sequences mapped to 1.746 unique chromosomal positions, corresponding to 910 integrations from 5 HSC-GT patients in vivo, 79 integrations from 2 PBL-GT samples of transduced cell products prior to infusion and 754 integrations from 4 PBL-GT patients in vivo. Firstly, to establish a relationship between precursors and terminally differentiated T cells we searched for the presence of identical insertion sites detected in multiple T-cell subtypes, applying stringent analytical filters for cross-contaminations. Strikingly, the level of shared integrations in each subtype was directly correlated to its stage of differentiation with Tscm, isolated from PBL-GT patients, showing the highest proportion of integration sites shared with the other T-cell subsets. Importantly, the results of the same analysis performed on HSC-GT patients were outstandingly coherent with the progressive developmental model of memory T-cell differentiation. We then assessed the survival of individual Tscm clones by performing a longitudinal IS analysis of different T-cell subtypes isolated from 3 PBL-GT patients over a 2 to 5 years timeframe up to 12 years after last infusion. We were able to formally prove the persistence of individual Tscm by re-capturing identical IS tagging specific Tscm clones in two independent timepoints in a 5- years window. Importantly, the same IS were also detected in multiple T-cell subtypes, representing the best indirect evidence that these clones were endowed with long-term precursor activity. We also documented, by IS sequencing reads, the long-term polyclonal composition of each subtype and we did not observe enrichment for IS flanking proto-oncogenes. Overall, this study validates, for the first time in humans, the safe and functional decade-long survival of engineered Tscm, paving the way for their future application in clinical settings. Disclosures No relevant conflicts of interest to declare.

This paper discusses compelling science cases for a future long-baseline interferometer operating at millimeter and centimeter wavelengths, like the proposed Next Generation Vary Large Array (ngVLA). We report on the activities of the Cradle of Life science working group, which focused on the formation of low- and high-mass stars, the formation of planets and evolution of protoplanetary disks, the physical and compositional study of Solar System bodies, and the possible detection of radio signals from extraterrestrial civilizations. We propose 19 scientific projects based on the current specification of the ngVLA. Five of them are highlighted as possible Key Science Projects: (1) Resolving the density structure and dynamics of the youngest HII regions and high-mass protostellar jets, (2) Unveiling binary/multiple protostars at higher resolution, (3) Mapping planet formation regions in nearby disks on scales down to 1 AU, (4) Studying the formation of complex molecules, and (5) Deep atmospheric mapping of giant planets in the Solar System. For each of these projects, we discuss the scientific importance and feasibility. The results presented here should be considered as the beginning of a more in-depth analysis of the science enabled by such a facility, and are by no means complete or exhaustive., 51 pages, 12 figures, 1 table. For more information visit https://science.nrao.edu/futures/ngvla

This paper will deal with the survival of material culture in Late Antique Egypt, focusing on the fourth and fifth centuries AD. I will survey the main issues related to the study of the pagan material world in Late Antique Egypt. These issues relate to the various objects at our disposal, which in some instances have been hard to date. Moreover, even when items have been ordered into temporal categories, it has been difficult to distinguish between “religious” and “neutral” usage of material culture. Then I will examine the state of fourth-century pagan Egyptian religion, arguing that, as a lack of epigraphical material indicates a steady decline of public cult, a particular phenomenon was taking place: the “privatisation” of pagan cults, as demonstrated by the case study of Karanis. In addition, I shall focus on both apotropaic and “neutral” usage, as attested by the development of amuletic objects from the fourth to the fifth century AD. Objects of personal adornment will be analysed in relation to magical practices to verify what role decorative paraphernalia played in the survival of pagan material culture. Finally, I shall examine the syncretic process between paganism and Christianity. In particular, through the influences paganism had on Christianity, it may be possible to infer that pagan objects were still in use in late fifth-century Egypt, though with a different purpose.

Deep HST broad-band images taken with ACS and WFPC2 of the giant ($\sim 1000$ AU diameter) dark silhouette proplyd 114-426 in the Orion Nebula show that this system is tilted, asymmetric, warped and photoevaporated. The exquisite angular resolution of ACS allows us to map the distribution of dust grains at the northern translucent edge of the disk, dominated by the photoevaporative flow. Using the Mie theory for standard circumstellar disk grains, we find evidence for a spatial gradient in grain size. The typical dust radius, $\simeq 0.2-0.7 \mu$m (less than what reported by previous studies) becomes smaller as the distance from the disk center increases, consistent with the expectations for the dynamic of dust entrained in a gaseous photoevaporative wind. Our analysis of the disk morphology and location within the nebula indicates that this system is photoevaporated by the diffuse radiation field of the Orion Nebula, while being shielded from the radiation coming directly from the central Trapezium stars. We estimate the mass-loss rate from the disk surface and the time-scale for total disk dissipation, which turns out to be of the order of $10^4$yr. Such a short time, of the order of 1/100 of the cluster age, indicates that this system is seen on the verge of destruction. This is compatible with the exceptional nature of the disk, namely its combination of huge size and low mass. Finally, we briefly discuss the viability of possible mechanisms that may lead to the peculiar morphology of this system: external UV flux, binary star and past close encounter., Comment: Ap.J.87356; accepted Aug.1, 2012; Scheduled for the September 20, 2012, V757 issue

Does capital flow from rich to poor countries? We revisit the Lucas paradox and explore the role of capital account restrictions in shaping capital flows at various stages of economic development. We find that, when accounting for the degree of capital account openness, the prediction of the neoclassical theory is confirmed: less developed countries tend to experience net capital inflows and more developed countries tend to experience net capital outflows, conditional on various countries' characteristics.

This paper uses a newly assembled multi-country multi-industry fi…rm-level dataset to test the effect of productivity and networking on the export probability of …firms. Results are in line with the new-new trade theory and with the literature on the information value of networks. Firms are more likely to export if they are more productive, larger, and if they bene…fit from foreign networks (ownership and …financial linkages), domestic networks (chamber of commerce, links to regulation), and communication networks (E-mail, internet). Firms bear a lower probability of exporting if they have state or labor networks. Overall, …firms with better network connections by one standard deviation enjoy a 15% higher probability of exporting.

This paper develops a two-country model to investigate the circumstances under which it is beneficial to participate in a currency area. It captures both the real and monetary arguments suggested by the optimum currency area literature in a simple monetary model of trade with nominal rigidities. The net benefits that one country expects from participation in a currency union increase with: the correlation of real shocks between countries; the degree of international labor mobility; the degree of adjustment provided by a fiscal tool; the difference between the inflationary bias of the domestic authority and the inflationary bias of the authority of the currency union; the variability of domestic monetary shocks; the extent of the deadweight and efficiency gains deriving from the adoption of a single currency. The same net benefits decrease with: the variability of real shocks; the variability of foreign monetary shocks; and the correlation of monetary shocks between countries. The effect of the degree of openness on the net benefits is ambiguous. This last result contrasts with the usual argument that the more open economies are the better candidates they make for a currency area.

This paper investigates the impact of the distribution sector on the real exchange rate, controlling for the Balassa-Samuelson effect, as well as other macro variables. Long-run coefficients are estimated using a panel dynamic OLS estimator. The main result is that an increase in the productivity and competitiveness of the distribution sector with respect to foreign countries leads to an appreciation of the real exchange rate, similarly to what a relative increase in the domestic productivity of tradables does. This contrasts with the result that one would expect by considering the distribution sector as belonging to the non-tradable sector. One explanation may lie in the use of the services from the distribution sector in the tradable sector. Our results also contribute to explaining the so-called PPP puzzle.

This paper provides a new model of firm's location choices. It integrates a Ricardian model of comparative advantage with the location effects deriving from trade costs, increasing returns to scale, product differentiation, and monopolistic competition. In a two-region, two-differentiated-good, one-factor framework, the regional degree of specialization depends positively on the extent of the comparative advantage in productivity and on the degree of returns to scale; it depends negatively on the magnitude of the trade costs. Hence, the model accommodates high levels of intra-industry trade among countries with similar level of development, as well as high levels of inter-industry trade among countries with different technologies.

This paper investigates the relation between agglomeration of economic activity and the pattern of specialization of countries. We develop a model encompassing a Ricardian comparative advantage, increasing returns to scale, product differentiation, monopolistic competition, trade costs, and factor mobility. Several interesting results arise. An endogenous relative increase in the size of one country makes this country less specialized in the homogeneous constant returns commodity and more specialized in the differentiated increasing returns IRS sectors; within the IRS industry, this country will become less specialized in the differentiated good in which it has a comparative advantage. Agglomeration occurs not only in large markets, but also in locations with a high average efficiency in the increasing return industry. Ceteris paribus, comparative advantage drives specialization, while absolute advantage drives agglomeration.

This paper provides a new model of firm's location choices. It integrates a Ricardian model of comparative advantage with the location effects deriving from trade costs, increasing returns to scale, product differentiation, and monopolistic competition. In a two-region, two-differentiated-good, one-factor framework, the regional degree of specialization depends positively on the extent of the comparative advantage in productivity and on the degree of returns to scale; it depends negatively on the magnitude of the trade costs. Hence, the model accommodates high levels of intra-industry trade among countries with similar level of development, as well as high levels of inter-industry trade among countries with different technologies.

This paper investigates the relation between agglomeration of economic activity and the pattern of specialization of countries. We develop a model encompassing a Ricardian comparative advantage, increasing returns to scale, product differentiation, monopolistic competition, trade costs, and factor mobility. Several interesting results arise. An endogenous relative increase in the size of one country makes this country less specialized in the homogeneous constant returns commodity and more specialized in the differentiated increasing returns IRS sectors; within the IRS industry, this country will become less specialized in the differentiated good in which it has a comparative advantage. Agglomeration occurs not only in large markets, but also in locations with a high average efficiency in the increasing return industry. Ceteris paribus, comparative advantage drives specialization, while absolute advantage drives agglomeration.

This paper investigates the effects of fixed versus flexible exchange rate regimes on location choices of firms and on the degree of specialization of countries. In a two-country two-differentiated-good monetary model, demand, supply, and monetary shocks arise after wages are set and prices are optimally chosen. The exchange rate performs then an adjustment role for firms located in the country relatively specialized in the good they produce, but it constitutes a factor of disturbance for the others. As firms choose ex-ante the location that offers the higher expected profits for their industry, we find that countries are more specialized under flexible exchange rates than under fixed rates. One important implication is that the adoption of a fixed exchange rate regime increases the desirability of such a currency area, as it induces sectoral dispersion of production and consequently reduces the degree of asymmetry of shocks.

The discovery of thousands of exoplanets over the last couple of decades has shown that the birth of planets is a very efficient process in nature. Theories invoke a multitude of mechanisms to describe the assembly of planets in the disks around pre-main-sequence stars, but observational constraints have been sparse on account of insufficient sensitivity and resolution. Understanding how planets form and interact with their parental disk is crucial also to illuminate the main characteristics of a large portion of the full population of planets that is inaccessible to current and near-future observations. This White Paper describes some of the main issues for our current understanding of the formation and evolution of planets, and the critical contribution expected in this field by the Next Generation Very Large Array., 6 pages, 3 figures, White Paper submitted to the National Academies of Science, Engineering, and Medicine's Exoplanet Science Strategy Call for Papers

We present the atlas of protoplanetary disks in the Orion Nebula based on the ACS/WFC images obtained for the HST Treasury Program on the Orion Nebula Cluster. The observations have been carried out in 5 photometric filters nearly equivalent to the standard B, V, Halpha, I, and z passbands. Our master catalog lists 178 externally ionized proto-planetary disks (proplyds), 28 disks seen only in absorption against the bright nebular background (silhouette disks), 8 disks seen only as dark lanes at the midplane of extended polar emission (bipolar nebulae or reflection nebulae) and 5 sources showing jet emission with no evidence of neither external ionized gas emission nor dark silhouette disks. Many of these disks are associated with jets seen in Halpha and circumstellar material detected through reflection emission in our broad-band filters; approximately 2/3 have identified counterparts in x-rays. A total of 47 objects (29 proplyds, 7 silhouette disks, 6 bipolar nebulae, 5 jets with no evidence of proplyd emission or silhouette disk) are new detections with HST. We include in our list 4 objects previously reported as circumstellar disks which have not been detected in our HST/ACS images either because they are hidden by the bleeding trails of a nearby saturated bright star or because of their location out of the HST/ACS Treasury Program field. Other 31 sources previously reported as extended objects do not harbor a stellar source in our HST/ACS images. We also report on the detection of 16 red, elongated sources. Their location at the edges of the field, far from the Trapezium Cluster core (> 10'), suggests that these are probably background galaxies observed through low extinction regions of the Orion Molecular Cloud OMC-1., 59 pages, 30 figures, 6 tables. Accepted for publication in AJ

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for autosomal recessive osteopetrosis caused by defects in the TCIRG1 gene. Despite recent progress in conditioning, an important number of patients are not eligible for allogeneic stem cell transplantation because of the severity of the disease and significant transplant-related morbidity. We exploited peripheral CD34(+) cells, known to circulate at high frequency in the peripheral blood of TCIRG1-deficient patients, as a novel cell source for autologous transplantation of gene corrected cells. Detailed phenotypical analysis showed that circulating CD34(+). cells have a cellular composition that resembles bone marrow (BM), supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPC). To overcome the limit of BM harvest/HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex vivo expansion of HSPC coupled with lentiviral gene transfer. Circulating CD34(+). cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector expressing TCIRG1 under the control of phosphoglycerate promoter and expanded ex vivo. Expanded cells maintained long-term engraftment capacity and multi-lineage repopulating potential when transplanted in vivo both in primary and secondary NOD scid gamma common chain (NSG) recipients. Moreover, when CD34(+) cells were differentiated in vitro, genetically corrected osteoclasts resorbed the bone efficiently. Overall, we provide evidence that expansion of circulating HSPC coupled to gene therapy can overcome the limit of stem cell harvest in osteopetrotic patients, thus opening the way to future gene-based treatment of skeletal diseases caused by BM fibrosis.

BACKGROUND. The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. β-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce. METHODS. MSCs were isolated and characterized from BM aspirates of healthy donors (HDs) and BT patients. The state of IO was assessed and correlated with the presence of primitive MSCs in vitro and in vivo. Hematopoietic supportive capacity of MSCs was evaluated by transwell migration assay and 2D coculture of MSCs with human CD34+ HSCs. In vivo, the ability of MSCs to facilitate HSC engraftment was tested in a xenogenic transplant model, whereas the capacity to sustain human hematopoiesis was evaluated in humanized ossicle models. RESULTS. We report that, despite iron chelation, BT BM contains high levels of iron and ferritin, indicative of iron accumulation in the BM niche. We found a pauperization of the most primitive MSC pool caused by increased ROS production in vitro which impaired MSC stemness properties. We confirmed a reduced frequency of primitive MSCs in vivo in BT patients. We also discovered a weakened antioxidative response and diminished expression of BM niche–associated genes in BT-MSCs. This caused a functional impairment in MSC hematopoietic supportive capacity in vitro and in cotransplantation models. In addition, BT-MSCs failed to form a proper BM niche in humanized ossicle models. CONCLUSION. Our results suggest an impairment in the mesenchymal compartment of BT BM niche and highlight the need for novel strategies to target the niche to reduce IO and oxidative stress before transplantation. FUNDING. This work was supported by the SR-TIGET Core grant from Fondazione Telethon and by Ricerca Corrente.

Summary Hematopoietic stem/progenitor cells (HSPCs) are capable of supporting the lifelong production of blood cells exerting a wide spectrum of functions. Lentiviral vector HSPC gene therapy generates a human hematopoietic system stably marked at the clonal level by vector integration sites (ISs). Using IS analysis, we longitudinally tracked >89,000 clones from 15 distinct bone marrow and peripheral blood lineages purified up to 4 years after transplant in four Wiskott-Aldrich syndrome patients treated with HSPC gene therapy. We measured at the clonal level repopulating waves, populations' sizes and dynamics, activity of distinct HSPC subtypes, contribution of various progenitor classes during the early and late post-transplant phases, and hierarchical relationships among lineages. We discovered that in-vitro-manipulated HSPCs retain the ability to return to latency after transplant and can be physiologically reactivated, sustaining a stable hematopoietic output. This study constitutes in vivo comprehensive tracking in humans of hematopoietic clonal dynamics during the early and late post-transplant phases., Graphical Abstract, Highlights • Hematopoietic reconstitution occurs in two distinct clonal waves • A few thousand HSPC clones stably sustain multilineage blood cell production • Steady-state hematopoiesis after transplant is maintained by both HSCs and MPPs • Natural killer clones have closer relationships to myeloid cells than to lymphoid cells, Biasco et al. report a clonal tracking study on the dynamics and nature of hematopoietic reconstitution in humans after transplant. Using integration sites as molecular tags, they measured, in gene therapy patients, repopulating waves, population size and dynamics, activity of progenitor subtypes during the early and late post-transplant phases, and hierarchical relationships among lineages.

Multi-wavelength observations of protoplanetary disks in the sub-millimeter continuum have measured spectral indices values which are significantly lower than what is found in the diffuse interstellar medium. Under the assumption that mm-wave emission of disks is mostly optically thin, these data have been generally interpreted as evidence for the presence of mm/cm-sized pebbles in the disk outer regions. In this work we investigate the effect of possible local optically thick regions on the mm-wave emission of protoplanetary disks without mm/cm-sized grains. A significant local increase of the optical depth in the disk can be caused by the concentration of solid particles, as predicted to result from a variety of proposed physical mechanisms. We calculate the filling factors and implied overdensities these optically thick regions would need to significantly affect the millimeter fluxes of disks, and we discuss their plausibility. We find that optically thick regions characterized by relatively small filling factors can reproduce the mm-data of young disks without requesting emission from mm/cm-sized pebbles. However, these optically thick regions require dust overdensities much larger than what predicted by any of the physical processes proposed in the literature to drive the concentration of solids. We find that only for the most massive disks it is possible and plausible to imagine that the presence of optically thick regions in the disk is responsible for the low measured values of the mm spectral index. For the majority of the disk population, optically thin emission from a population of large mm-sized grains remains the most plausible explanation. The results of this analysis further strengthen the scenario for which the measured low spectral indices of protoplanetary disks at mm wavelengths are due to the presence of large mm/cm-sized pebbles in the disk outer regions., 13 pages, 2 figures, A&A in press