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Introduction: Charged Particle Therapy plays a key role in the treatment of deep-seated tumours, because of the advantageous energy deposition culminating in the Bragg peak. However, knowledge of the dose delivered in the entrance channel is limited by the lack of data on the beam and fragmentation of the target.Methods: The FOOT experiment has been designed to measure the cross sections of the nuclear fragmentation of projectile and target with two different detectors: an electronic setup for the identification of Z ≥ 3 fragments and a nuclear emulsion spectrometer for Z ≤ 3 fragments. In this paper, we analyze the data taken by exposing four nuclear emulsion spectrometers, with C and C2H4 targets, to 200 MeV/n and 400 MeV/n oxygen beams at GSI Helmholtzzentrum für Schwerionenforschung (Darmstadt, Germany), and we report the charge identification of produced fragments based on the controlled fading induced on nuclear emulsion films.Results: The goal of identifying fragments as heavy as lithium has been achieved.Discussion: The results will contribute to a better understanding of the nuclear fragmentation process in charged particle therapy and have implications for refining treatment planning in the presence of deep-seated tumors.

The study of nuclear fragmentation plays a central role in many important applications: from the study of Particle Therapy (PT) up to radiation protection for space (RPS) missions and the design of shielding for nuclear reactors. The FragmentatiOn Of Target (FOOT) collaboration aims to study the nuclear reactions that describe the interactions with matter of different light ions (like H1, He4, C12, O16) of interest for such applications, performing double differential fragmentation cross section measurements in the energy range of interest for PT and RPS. In this manuscript, we present the analysis of the data collected in the interactions of an oxygen ion beam of 400 MeV/u with a graphite target using a partial FOOT setup, at the GSI Helmholtz Center for Heavy Ion Research facility in Darmstadt. During the data taking the magnets, the silicon trackers and the calorimeter foreseen in the final FOOT setup were not yet available, and hence precise measurements of the fragments kinetic energy, momentum and mass were not possible. However, using the FOOT scintillator detectors for the time of flight (TOF) and energy loss (ΔE) measurements together with a drift chamber, used as beam monitor, it was possible to measure the elemental fragmentation cross sections. The reduced detector set-up and the limited available statistics allowed anyway to obtain relevant results, providing statistically significant measurements of cross sections eagerly needed for PT and RPS applications. Whenever possible the obtained results have been compared with existing measurements helping in discriminating between conflicting results in the literature and demonstrating at the same time the proper functioning of the FOOT ΔE-TOF system. Finally, the obtained fragmentation cross sections are compared to the Monte Carlo predictions obtained with the FLUKA software.

In this paper, we present the work carried out to characterize the spatial variability of seismic site response related to local soil conditions in the city of Milan and its surroundings, an area with ∼3 million inhabitants and a high density of industrial facilities. The area is located at the northwestern end of the Po Plain, a large and deep sedimentary basin in northern Italy. An urban-scale seismo-stratigraphic model is developed based on new passive and active seismic data, supported by the available geological data and stratigraphic information from shallow and deep vertical wells. In particular, 33 single-station and 4 ambient-vibration array measurements are acquired, together with 4 active multichannel analyses of surface waves (MAWS). To estimate the resonant frequencies of the sediments, the horizontal to vertical spectral ratio technique (HVSR) is applied to the ambient-vibration recordings, whereas to determine the Rayleigh-wave dispersion curves from the passive array, the data are analysed using the conventional frequency-wavenumber, the modified spatial autocorrelation and the extended spatial autocorrelation (ESAC) techniques. The array data are used to determine the local shear wave velocity profiles, VS, via joint inversion of the Rayleigh-wave dispersion and ellipticity curves deduced from the HVSR. The results from HVSR show three main bands of amplified frequencies, the first in the range 0.17–0.23 Hz, the second from 0.45 to 0.65 Hz and the third from 3 to 8 Hz. A decreasing trend of the main peaks is observed from the northern to the southern part of the city, allowing us to hypothesize a progressive deepening of the relative regional chrono-stratigraphic unconformities. The passive ambient noise array and MASW highlight the dispersion of the fundamental mode of the Rayleigh-wave in the range 0.4–30 Hz, enabling to obtain detailed Vs. profiles with depth down to about 1.8 km. The seismo-stratigraphic model is used as input for 1D numerical modelling assuming linear soil conditions. The theoretical 1D transfer functions are compared to the HVSR curves evaluated from both ambient noise signals and earthquake waveforms recorded by the IV. MILN station in the last 10 years.

Within the framework of the European collaborative research initiative AlpArray (http://www.alparray.ethz.ch), the Istituto Nazionale di Geofisica e Vulcanolgia (INGV) deployed overall 20 broad-band seismic stations in Northern Italy and on two islands in the Tyrrhenian Sea (Capraia and Montecristo) during Fall-Winter 2015. The temporary deployment (16 stations) will run for two to three years and 4 INGV National Seismic Network accelerometric sites are now equipped with additional permanent broad-band sensors. The 16 temporary stations are equipped with REF TEK 130 digitizers and Nanometrics Trillium Compact 120 s sensors, a couple have Nanometrics Trillium 120P sensors and one a Streckeisen STS2. For each site we describe the settings and discuss the noise levels, the site effects and the preliminary sensitivity analysis.

Infrared thermography is a very versatile non destructive technique which among other uses, can be applied to the study of moisture in buildings. However, this particular application can present some problems strictly related to the characteristics of the thermocamera device. In this case the available equipment works in the IR range of 2.5 to 5.6 μm. In this part of the spectrum, there exists a small and not very intense band of emission of the water molecules (approximately centered at 2.7 μm), in such a way that detection can be difficult through thermovision. In the present paper, a complementary technique to the IR thermography being able of favouring the emission of water on the mentioned band, has been developed. It enhances the capacity of detection of the instrument. Likewise, the process which takes place in the material has been numerically modelled.

The Huanghe (Yellow River), one of the largest turbid river systems in the world, has long been recognized as a major contributor of suspended particulate matter (SPM) to the ocean. However, over the last few decades, the SPM export flux of the Huanghe has decreased over 90 % due to the high management, impacting the global export of particulate organic carbon (POC). To better constrain sources and modes of transport of POC beyond the previously investigated transportation of POC near the channel surface, SPM samples were for the first time collected over a whole channel cross-section in the lower Huanghe. Riverine SPM samples were analyzed for particle size and major element contents, as well as for POC content and dual carbon isotopes (13C and 14C). Clear vertical and lateral heterogeneities of the physical and chemical properties of SPM are observed within the river cross-section. For instance, finer SPM carry more POC in general with higher 14C activity near the surface of the right bank. Notably, we discuss how bank erosion in the alluvial plain is likely to generate lateral heterogeneity in POC composition. The Huanghe POC is millennial-aged (4020 ± 500 radiocarbon years) and dominated by organic carbon (OC) from the biosphere, while the lithospheric fraction is ca. 12 %. The mobilization of aged and refractory OC, including radiocarbon-dead biospheric OC, from deeper soil horizons of the loess–paleosol sequence through erosion in the Chinese Loess Plateau is an important mechanism contributing to fluvial POC in the Huanghe drainage basin. Altogether, anthropogenic activities can drastically change the compositions and transport dynamics of fluvial POC, consequentially altering the feedback of the source-to-sink trajectory of a river system to regional and global carbon cycles.

Every year Africa is hit by extreme floods which, combined with high levels of vulnerability and increasing population exposure, often result in humanitarian crises and population displacement. Impact-based forecasting and early warning for natural hazards is recognized as a step forward in disaster risk reduction, thanks to its focus on people, livelihoods, and assets at risk. Yet, the majority of the African population is not covered by any sort of early warning system. This article describes the setup and the methodological approach of Flood-PROOFS East Africa, an impact-based riverine flood forecasting and early warning system for the Greater Horn of Africa (GHA), with a forecast range of 5 d. The system is based on a modeling cascade relying on distributed hydrological simulations forced by ensemble weather forecasts, link to inundation maps for specific return period, and application of a risk assessment framework to estimate population and assets exposed to upcoming floods. The system is operational and supports the African Union Commission and the Disaster Operation Center of the Intergovernmental Authority on Development (IGAD) in the daily monitoring and early warning from hydro-meteorological disasters in eastern Africa. Results show a first evaluation of the hydrological reanalysis at 78 river gauging stations and a semi-quantitative assessment of the impact forecasts for the catastrophic floods in Sudan and in the Nile River basin in summer 2020. More extensive quantitative evaluation of the system performance is envisaged to provide its users with information on the model reliability in forecasting extreme events and their impacts.

Background: Psychological distress is recognised as the most common mental health difficulty in emerging adult (18-to-24-year-old) female academic students. This study aimed to test a novel model positing physical activity habits as a protective factor for psychological distress through the mediating role of physical and psychological parameters. Adherence to the Mediterranean diet and self-reported physical health status were included as physical parameters. Self-reported psychological health status and time spent on leisure activities were the psychological parameters considered. Method: Data were collected between April and May 2021. Correlation analyses and a multiple mediation model were computed on 411 online questionnaires filled out by 18-to-24-year-old female students from the University of blind (Italy). Results: The multiple indirect effects were significant (β = −0.088; p

Introduction: The possibility of intentionally triggering non targeted effects (NTEs) using spatially fractionated radiotherapy (SFRT) alone or combined with immunotherapy is an intriguing and fascinating area of research. Among different techniques for SFRT, stereotactic body radiotherapy targeting exclusively the central hypoxic segment of bulky tumors, (SBRT-PATHY) might trigger immunogenic cell death more efficiently. This in silico study aims to identify the best possible dosimetric trade-off for prescribing SFRT with volumetric modulated arc (VMAT) based stereotactic radiotherapy (SRT). Material and methods: Eight spherical volumes defined “Gross Tumor Volumes” (GTVs) were generated with diameters of 3–10 cm (with incremental steps of 1 cm), simulating tumor lesions. The inner third part of each GTV (GTVcentral) was selected to simulate the central hypoxic area and a ring structure was derived around it to simulate the tumor periphery (GTVperipheral). Volumetric modulated arc radiation treatment (VMAT) plans were calculated to deliver a single fraction of 10 Gy to each GTVcentral with different dose prescription methods: target mean and isodose driven (40, 50, 60, 70, 80 and 90%).The volume of GTVperipheral receiving less than 2 Gy was recorded as dosimetric performance indicator. Results: 56 possible dosimetric scenarios were analyzed. The largest percentage of GTVperipheral spared from the dose of 2 Gy was achieved with dose prescription methods to the 70% isodose line for lesions smaller than 6 cm (range 42.9–48.4%) and to the target mean for larger ones (range 52.9–64.5%). Conclusions: Optimizing the dose prescription method may reduce the dose to tumor periphery in VMAT-based SFRT, thus potentially sparing tumor infiltrating immune cells. The optimal method may vary according to the size of the lesion. This should be taken into account when designing prospective trials using SFRT.

In August 2000 and July 2001 two seismic sequences, characterized by mainshocks with Ml (local magnitude) respectively 5.1 and 4.8, occurred in the Monferrato region (Italy). The regional seismic network of North-western Italy (RSNI) recorded more than 250 foreshocks and aftershocks. The routine locations, obtained from the Hypoellipse code, show a seismic activity concentrated in a circular area, of a radius of about 15 km, located near Acqui Terme, and randomly distributed in depth. Location errors, due to an uneven azimuthal station distribution of the regional seismic network, prevent recognition of the geometry of the active zone. Waveform analysis revealed the presence of several multiplets. In order to discriminate and successively relocate them, an automatic cross-correlation procedure was applied. Normalized cross-correlation matrixes, for the RSNI stations which recorded almost 90% of considered events, on the basis of a signal to noise ratio analysis, were computed using only S wave time windows. The use of a relocation procedure, based on the double-difference method which incorporates ordinary absolute travel-time measurements and/or cross-correlation differential travel-times, allowed us to overcome the constraints of the uneven distribution of stations giving a quite different frame of seismicity. The improved locations showed that the seismic activity is mainly arranged along a NE-SW oriented volume, at a depth range of 8–20 km, involving the basement crystalline units. This orientation is confirmed by the analysis of the focal mechanisms: most focal solutions show a strike slip component with one of the nodal planes consistent with the main orientation of the seismic events. [ABSTRACT FROM AUTHOR]

В данной статье раскрывается понятие наказания с учетом его важности для общества. Наказание есть средство для установления порядка в обществе, цель наказания многогранна. Автор подчеркивает важность наказания как средства предупреждения и профилактики правонарушений. Ключевые слова: наказание, закон, право, правило, дисциплина, обычаи, общество, государство.

Multiple myeloma (MM) derives from malignant transformation of plasma cells (PC), which accumulate in the bone marrow (BM), where microenvironment supports tumor growth and inhibits anti-tumor immune responses. Adenosine (ADO), an immunosuppressive molecule, is produced within MM patients' BM by adenosinergic ectoenzymes, starting from ATP (CD39/CD73) or NAD+ [CD38/CD203a(PC-1)/CD73]. These ectoenzymes form a discontinuous network expressed by different BM cells. We investigated the expression and function of ectoenzymes on microvesicles (MVs) isolated from BM plasma samples of patients with MM, using asymptomatic forms of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) as controls. The percentage of MVs expressing ectoenzymes at high levels was higher when derived from MM patients than controls. BM CD138+ PC from MM patients expressed high levels of all ectoenzymes. Paired MVs samples confirmed a higher percentage of MVs with high ectoenzymes expression in MM patients than controls. Pooled MVs from MM patients or controls were tested for ADO production. The catabolism of ATP, NAD+, ADPR and AMP to ADO was higher in MVs from MM patients than in those from controls. In conclusion, our results confirmed the hypothesis that MVs in MM niche are main contributor of ADO production. The ability of MVs to reach biological fluids strongly support the view that MVs may assume diagnostic and pathogenetic roles.

Invasive mammalian predators are linked to terrestrial vertebrate extinctions worldwide. Prey naïveté may explain the large impact invasive predators have on native prey; prey may fail to detect and react appropriately to the cues of novel predators, which results in high levels of depredation. In Australia, the feral cat (Felis catus) and the red fox (Vulpes vulpes) are implicated in more than 30 animal extinctions and the naïveté of native prey is often used to explain this high extinction rate. Reptiles are one group of animals that are heavily preyed upon by F. catus and V. vulpes. However, very few studies have examined whether reptiles are naive to their cues. In this study, we examine the ability of two native reptile species (Morethia boulengeri and Christinus marmoratus) to detect and distinguish between the chemical cues of two invasive predators (V. vulpes and F. catus) and three native predators (spotted-tailed quoll, Dasyurus maculatus; dingo, Canis lupus dingo; eastern brown snake, Pseudonaja textilis), as well as two non-predator controls (eastern grey kangaroo, Macropus giganteus and water). We conducted experiments to quantify the effects of predator scents on lizard foraging (the amount of food eaten) during 1 h trials within Y-maze arenas. We found both study species reduced the amount they consumed when exposed to predator scents—both native and invasive—indicating that these species are not naive to invasive predators. An evolved generalized predator-recognition system, rapid evolution or learned behaviour could each explain the lack of naïveté in some native Australian reptiles towards invasive predators.

We have fabricated and characterized a set of slotted photonic crystal (SPhC) waveguides in silicon-on-insulator (SOI) with a length of up to 300 $\mu\hbox{m}$ and slot widths ranging between 115 and 145 nm. We observe an upper limit for the loss of 11 dB/cm.

Objective. Pulmonary hypertension is a severe and rapidly progressive disease, particularly frequent in patients with rheumatic diseases. The aims of this study were the following: to determine the prevalence of pulmonary hypertension in Italian patients with autoimmune rheumatic diseases, and to evaluate if the presence of a rheumatic disease in general, or of a specific autoimmune rheumatic disease, is a risk factor for the development of pulmonary hypertension. Patients and Methods. One hundred and thirteen Italian patients with connective tissue diseases (105 females, 8 males), aged 19 to 83 yrs, entered the study. Fifty-one had systemic sclerosis (SSc): 49 were females, 2 males, aged 34 to 83 yrs; 41 had limited cutaneous SSc, 8 diffuse cutaneous SSc, and 2 SSc sine scleroderma. Thirty-three patients had systemic lupus erythematosus (SLE): all but one were females, their age ranged from 19 to 82 yrs. Twenty-five had rheumatoid arthritis (RA): 21 females, 4 males, aged 26 to 45 yrs. Three females and one male, 51-77 yrs, had mixed connective tissue disease (MCTD). Systolic pulmonary arterial pressure (SPAP) was assessed by Doppler echocardiography. Results. Twenty three patients had pulmonary hypertension, which was more frequent in MCTD than in SLE (75% vs 6.1%, p=0.0002) or in AR (20%, p=0.0313). Pulmonary hypertension was more frequent in SSc than in SLE (25.5% vs 6.1%, p=0.0028) and in limited than in diffuse SSc(21.6% vs 3.9%). SPAP was significanly related to age (R=0.35, P=0.0275), with patients with pulmonary hypertension older than patients with normal SPAP (66±13 vs 52±16 yrs, p=0.0003). Conclusions. These data show a significant association between pulmonary hypertension and autoimmune rheumatic diseases. Therefore pulmonary hypertension assessment seems mandatory, at least in MCTD and SSc. However, more studies are needed to clarify the relationship between age and pulmonary hypertension and to verify whether the low prevalence of pulmonary hypertension we found in our SLE patients is related or not to their lower age.

The world importance of goat husbandry as a genetic source for the production of meat, milk, textile fibre and skin, especially in tropical and sub-tropical areas and in Developing Countries is wide documented (Husain et al., 1996). Goat rearing annually produce about 177.6 millions tons of milk (FAO, 1992) and about 3.5 millions tons of meat (FAO, 1996), with an increasing request of product, that in the last decade has driven the increase of the number of heads reared (Knights et al., 1997). Because of the peculiar behaviour of goats, the above mentioned increase has been observed mainly in Developing Countries as well as in marginal lands of the Mediterranean areas (Southern Italy and Greece, in particular). In Molise, for instance, an increase in goats consistency has been recorded over 15 years (AIA, 1997). The emerging requests by the final consumer of typical and healthy products with origin and quality certified have also contributed to the survival of certain goats population as an exploitation tool of marginal lands, otherwise voted to be abandoned...

Introduction: pain is a frequent and relevant problem in children with severe cognitive impairments. Assessing pain in these patients can be difficult. Specific observational tools such as the Collignon Giusiano Questionnaire or the Non-communicating Children’s Pain Checklist ( NCCPC) are available, but their use is not widespread. Children with severe cognitive impairment are frequently in need of painful procedures but data about availability of procedural sedation in this setting are limited. Objective of the study: to evaluate paediatricians’ attitudes toward pain in children with severe cognitive impairment by measuring the use of specific pain scales and the use of analgesia or procedural sedation in course of a frequent procedure such as botulinum toxin injection. Methods: phone interview with the doctor on duty of 56 paediatric wards in 3 regions of the North East of Italy, addressing the routine use of pain scales, and the use of specific observational tools for non communicating children. A phone interview was also conducted in 4 centers routinely practicing botulinum toxin injection about the use of analgesia or procedural sedation. Results: 1 centre out of 55 reported to use specific scales for children with cognitive impairment, specifically the Collignon Giusiano Questionnaire. No centre used procedural sedation for botulinum toxin injection. Conclusion: in the investigated area there is a lack of attention to pain in children with severe cognitive impairment. Specific educational efforts should be done to improve the quality of care in this setting.

A series of 75 cases of Gilles de la Tourette syndrome (GTS) from Argentina, whose ages ranged from 6 to 55 with a mean of 20.02, were evaluated to compare findings with those reported for other countries. Mean age at onset was 7.44 years and mean overall duration of symptoms was 12.58 years; 6.7% of cases were mild, 49% moderate and 44.3% severe. Most frequent presenting motor tics were excessive blinking in 41 followed by head jerking in 16 and eye winking in six, while phonic tics included coprolalia in 28.0%, echolalia in 17.5% and palilalia in 10.8%. Abnormal perinatal events were reported in 40.5%, while positive family history for tics was present in 26.66%. Obsessive–compulsive behaviour was evident in 66% and attention deficit disorder in 16% of cases. Self-injurious behaviour comprised onychophagia in 28 patients, lip-biting in seven and self-slapping in eight cases. Almost half of our patients were initially interpreted as having a psychogenic disorder indicating that GTS in Argentina is most likely underdiagnosed. It may be concluded that the overall pattern of GTS is not dissimilar to that described for European, Asian and American populations, thus highlighting the previously recognized cross-cultural uniformity.

We study a uniform flow in a parallel plate geometry to model contaminant transport through a saturated porous medium in a semi-infinite domain in order to simulate an experimental apparatus mainly constituted by a chamber filled with a glass beads bed. The general solution of the advection dispersion equation in a porous medium was obtained by utilizing the Jacobi θ3 Function. The analytical solution here presented has been provided when the inlet (Dirac) and the boundary conditions (Dirichelet, Neumann, and mixed types) are fixed. The proposed solution was used to study experimental data acquired by using a noninvasive technique.

Phthalates are a class of chemicals predominantly used as plasticizers in many plastics since the 1930's, in a wide variety of manufacturing applications and consumer products. Given their extensive use and their leakage from plastics, they are ubiquitous environmental contaminants with potential detrimental health effects. Di(2-ethylhexyl)phthalate (DEHP) is the most commonly used phthalate plasticizer. There is widespread exposure to phthalates in the general population and therefore it is importat to investigate the toxic potential of these compounds. In particular, phthalate exposure has been shown to cause developmental and reproductive anomalies in animal models, and there is concern that these compounds may be causing adverse effects on human reproductive health. Phthalate effects are suspected to be much more severe after in uterus exposure. Phthalate esters are considered endocrine balance and development of the mammalian testis, thus exerting harmful effects on mammalian reproduction and fertility. Health risk assessments for the phthalate exposure of the general population should be performed and current PVC plasticizers, especially the ones used for infants should be replaces with high quality materials.

Since 2008, higher education (HE) policies that aimed to diversify university student recruitment have increased enrolments from equity backgrounds. Supporting these students during their transition to university has been prioritised with the aim of enhancing retention, completion, and support for their future employment outcomes. Low student retention or program completion rates may impact federal government funding models and HE institutional reputations. Thus, a wide range of implemented strategies have sought to support HE success for all students, including those from equity backgrounds. Students transitioning to HE have different academic experiences and expertise. Thus, the online module, known as Skills for Academic Success (SAS), developed in this study was introduced to promote an enhanced understanding of HE expectations and academic skills needed for success. The module was completed by commencing students during the initial weeks of their university enrolment. Students perceived that the SAS module significantly enhanced their transition to HE, their understanding of university expectations, bolstered their academic confidence, and honed their study skills for success. This study showed that adaptive online modules can engage and assist students, especially those from diverse and equity-rich backgrounds, supporting them to develop a comprehensive grasp of HE academic expectations and essential academic skills. Student feedback highlighted that the resource prepared them for success as they embarked on their academic journey in the unfamiliar territory of HE. --- Equitable education: Enhancing academic skills and confidence through a first-year online module by Brooke E. Harris-Reeves, Andrew G. Pearson, Barbara J. Hadley &Helen M. Massa is licensed under CC BY 4.0

Abstract Background 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal interstitial-deletion disorder, occurring in approximately 1 in 2000 to 6000 live births. Affected individuals exhibit variable clinical phenotypes that can include velopharyngeal anomalies, heart defects, T-cell-related immune deficits, dysmorphic facial features, neurodevelopmental disorders, including autism, early cognitive decline, schizophrenia, and other psychiatric disorders. Developing comprehensive treatments for 22q11.2DS requires an understanding of both the psychophysiological and neural mechanisms driving clinical outcomes. Our project probes the core psychophysiological abnormalities of 22q11.2DS in parallel with molecular studies of stem cell-derived neurons to unravel the basic mechanisms and pathophysiology of 22q11.2-related psychiatric disorders, with a primary focus on psychotic disorders. Our study is guided by the central hypothesis that abnormal neural processing associates with psychophysiological processing and underlies clinical diagnosis and symptomatology. Here, we present the scientific background and justification for our study, sharing details of our study design and human data collection protocol. Methods Our study is recruiting individuals with 22q11.2DS and healthy comparison subjects between the ages of 16 and 60 years. We are employing an extensive psychophysiological assessment battery (e.g., EEG, evoked potential measures, and acoustic startle) to assess fundamental sensory detection, attention, and reactivity. To complement these unbiased measures of cognitive processing, we will develop stem-cell derived neurons and examine neuronal phenotypes relevant to neurotransmission. Clinical characterization of our 22q11.2DS and control participants relies on diagnostic and research domain criteria assessments, including standard Axis-I diagnostic and neurocognitive measures, following from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and the North American Prodrome Longitudinal Study (NAPLS) batteries. We are also collecting measures of autism spectrum (ASD) and attention deficit/hyperactivity disorder (ADHD)-related symptoms. Discussion Studying 22q11.2DS in adolescence and adulthood via deep phenotyping across multiple clinical and biological domains may significantly increase our knowledge of its core disease processes. Our manuscript describes our ongoing study’s protocol in detail. These paradigms could be adapted by clinical researchers studying 22q11.2DS, other CNV/single gene disorders, or idiopathic psychiatric syndromes, as well as by basic researchers who plan to incorporate biobehavioral outcome measures into their studies of 22q11.2DS.

A new concept of wiggler has been designed and realized at SOLEIL to produce high energy photons in low/intermediate electron storage rings. Instead of using the superconducting technology which requires new equipment and instrumentation, heavy maintenance, and additional running costs, we have proposed to build a compact in-vacuum small gap short period wiggler that operates rather at moderate field than at high field. The wiggler composed of 38 periods of 50 mm produces 2.1 T at a gap of 5.5 mm. The moderate value of the magnetic field enables one to limit the effects on the beam dynamics and to avoid excessive power and magnetic forces. In this purpose, the narrow magnetic system has been equipped with a counterforce device made of nonmagnetic springs. The roll-off resulting from the small size of poles has been compensated in situ by permanent magnet magic fingers. This paper reports the phases of design, construction, magnetic measurements, and on-beam tests of the in-vacuum wiggler WSV50.

Motor rehabilitation strategies after unilateral stroke suggest that the immobilization of the healthy, unimpaired limb can promote the functional recovery of a paretic limb. In rodents, this has been modeled using casts, harnesses, and other means of restricting the use of the non-paretic forelimb in models of experimental stroke. Here, we evaluated an alternative approach, using botulinum toxin injections to limit the function of the non-paretic forelimb. Adult male rats were subjected to permanent ligation of the left distal middle cerebral artery, resulting in right forelimb paresis. The rats were then subjected to: (1) no treatment; (2) botulinum toxin injections 1 day post stroke; or (3) cast placement 5 days post stroke. Casts were removed after 5 weeks, while the botulinum toxin injection effectively immobilized subjects for approximately the same duration. Rats with bilateral forelimb impairment due to the stroke plus casting or botulinum injections were still able to feed and groom normally. Both immobilization groups showed modest recovery following the stroke compared to those that did not receive immobilization, but the casting approach led to unacceptable levels of animal stress. The botulinum toxin approach to limb immobilization had both advantages and disadvantages over traditional physical limb immobilization. The major advantage was that it was far less stress-inducing to the subject animals and appeared to be well tolerated. A disadvantage was that the paresis took roughly 10 weeks to fully resolve, and any degree of residual paresis could confound the interpretation of the behavioral assessments.

Abstract Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75NTR signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.

BackgroundOtitis media (OM) is one of the most common infections in young children, arising from bacterial and/or viral infection of the middle ear. Globally, Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are the predominant bacterial otopathogens. Importantly, common upper respiratory viruses are increasingly recognized contributors to the polymicrobial pathogenesis of OM. This study aimed to identify predominant bacteria and viruses in the nasopharynx, adenoids and middle ears of peri-urban/urban South-East Queensland Australian children, with and without clinical history of chronic otitis media with effusion (COME) and/or recurrent acute otitis media (RAOM).MethodsSixty children, 43 diagnosed with OM and 17 controls with no clinical history of OM from peri-urban/urban South-East Queensland community were recruited to the study. Respiratory tract bacterial and viral presence were examined within nasopharyngeal swabs (NPS), middle ear effusions (MEE) and adenoids, using real-time polymerase chain reaction (RT-PCR) and bacterial culture.ResultsAt least one otopathogen present was observed in all adenoid samples, 86.1% and 82.4% of NPS for children with and without OM, respectively, and 47.1% of the MEE from the children with OM. NTHi was the most commonly detected bacteria in both the OM and control cohorts within the adenoids (90.0% vs 93.8%), nasopharynx (67.4% vs 58.8%) respectively, and in the MEE (OM cohort 25.9%). Viruses were detected in all adenoid samples, 67.4% vs 47.1% of the NPS from the OM and control cohorts, respectively, and 37% of the MEE. Rhinovirus was the predominant virus identified in the adenoids (85.0% vs 68.8%) and nasopharynx (37.2% vs 41.2%) from the OM and control cohorts, respectively, and the MEE (19.8%).ConclusionsNTHi and rhinovirus are predominant otopathogens within the upper respiratory tract of children with and without OM from peri-urban and urban South-East Queensland, Australia. The presence of bacterial otopathogens within the middle ear is more predictive of concurrent URT infection than was observed for viruses, and the high otopathogen carriage within adenoid tissues confirms the complex polymicrobial environment in children, regardless of OM history.

Abstract In tauopathies, phosphorylation, acetylation, cleavage and other modifications of tau drive intracellular generation of diverse forms of toxic tau aggregates and associated seeding activity, which have been implicated in subsequent synaptic failure and neurodegeneration. Suppression of this wide range of pathogenic species, seeding and toxicity mechanisms, while preserving the physiological roles of tau, presents a key therapeutic goal. Identification and targeting of signaling networks that influence a broad spectrum of tau pathogenic mechanisms might prevent or reverse synaptic degeneration and modify disease outcomes. The p75 neurotrophin receptor (p75NTR) modulates such networks, including activation of multiple tau kinases, calpain and rhoA-cofilin activity. The orally bioavailable small-molecule p75NTR modulator, LM11A-31, was administered to tauP301S mice for 3 months starting at 6 months of age, when tau pathology was well established. LM11A-31 was found to reduce: excess activation of hippocampal cdk5 and JNK kinases and calpain; excess cofilin phosphorylation, tau phosphorylation, acetylation and cleavage; accumulation of multiple forms of insoluble tau aggregates and filaments; and, microglial activation. Hippocampal extracts from treated mice had substantially reduced tau seeding activity. LM11A-31 treatment also led to a reversal of pyramidal neuron dendritic spine loss, decreased loss of dendritic complexity and improvement in performance of hippocampal behaviors. These studies identify a therapeutically tractable upstream signaling module regulating a wide spectrum of basic mechanisms underlying tauopathies.

Degeneration of basal forebrain cholinergic neurons (BFCNs) in the nucleus basalis of Meynert (NBM) and vertical diagonal band (VDB) along with their connections is a key pathological event leading to memory impairment in Alzheimer's disease (AD). Aberrant neurotrophin signaling via Trks and the p75 neurotrophin receptor (p75NTR) contributes importantly to BFCN dystrophy. While NGF/TrkA signaling has received the most attention in this regard, TrkB and TrkC signaling also provide trophic support to BFCNs and these receptors may be well located to preserve BFCN connectivity. We previously identified a small molecule TrkB/TrkC ligand, LM22B-10, that promotes cell survival and neurite outgrowth in vitro and activates TrkB/TrkC signaling in the hippocampus of aged mice when given intranasally, but shows poor oral bioavailability. An LM22B-10 derivative, PTX-BD10–2, with improved oral bioavailability has been developed and this study examined its effects on BFCN atrophy in the hAPPLond/Swe (APPL/S) AD mouse model. Oral delivery of PTX-BD10–2 was started after appreciable amyloid and cholinergic pathology was present to parallel the clinical context, as most AD patients start treatment at advanced pathological stages. PTX-BD10–2 restored cholinergic neurite integrity in the NBM and VDB, and reduced NBM neuronal atrophy in symptomatic APPL/S mice. Dystrophy of cholinergic neurites in BF target regions, including the cortex, hippocampus, and amygdala, was also reduced with treatment. Finally, PTX-BD10–2 reduced NBM tau pathology and improved the survival of cholinergic neurons derived from human induced pluripotent stem cells (iPSCs) after amyloid-β exposure. These data provide evidence that targeting TrkB and TrkC signaling with PTX-BD10–2 may be an effective disease-modifying strategy for combating cholinergic dysfunction in AD. The potential for clinical translation is further supported by the compound's reduction of AD-related degenerative processes that have progressed beyond early stages and its neuroprotective effects in human iPSC-derived cholinergic neurons.

Otitis media (OM) encompasses a spectrum of clinical presentations ranging from the readily identifiable Acute OM (AOM), which is characterised by otalgia and fever, to chronic otitis media with effusion (COME) where impaired hearing due to middle ear effusion may be the only clinical symptom. Chronic suppurative OM (CSOM) presents as a more severe form of OM, involving perforation of the tympanic membrane. The pathogenesis of OM in these varied clinical presentations is unclear but activation of the innate inflammatory responses to viral and/or bacterial infection of the upper respiratory tract performs an integral role. This localised inflammatory response can persist even after pathogens are cleared from the middle ear, eustachian tubes and, in the case of respiratory viruses, even the nasal compartment. Children prone to OM may experience an over exuberant inflammatory response that underlies the development of chronic forms of OM and their sequelae, including hearing impairment. Treatments for chronic effusive forms of OM are limited, with current therapeutic guidelines recommending a “watch and wait” strategy rather than active treatment with antibiotics, corticosteroids or other anti-inflammatory drugs. Overall, there is a clear need for more targeted and effective treatments that either prevent or reduce the hyper-inflammatory response associated with chronic forms of OM. Improved treatment options rely upon an in-depth understanding of OM pathogenesis, particularly the role of the host innate immune response during acute OM. In this paper, we review the current literature regarding the innate immune response within the middle ear to bacterial and viral otopathogens alone, and as co-infections. This is an important consideration, as the role of respiratory viruses as primary pathogens in OM is not yet fully understood. Furthermore, increased reporting from PCR-based diagnostics, indicates that viral/bacterial co-infections in the middle ear are more common than bacterial infections alone. Increasingly, the mechanisms by which viral/bacterial co-infections may drive or maintain complex innate immune responses and inflammation during OM as a chronic response require investigation. Improved understanding of the pathogenesis of chronic OM, including host innate immune response within the middle ear is vital for development of improved diagnostic and treatment options for our children.

En los últimos años ha aumentado el interés en la adquisición de imágenes médicas digitales, las cuales se almacenan y distribuyen mediante PACS (Picture Archiving and Communication Systems). También han surgido numerosas herramientas para diagnóstico remoto, para lo cual se han propuesto Web-PACS para el manejo de las imágenes. Sin embargo, la mayoría de los navegadores no permiten visualizar imágenes DICOM (Digital Imaging and Communication in Medicine) de forma nativa, requiriendo la instalación de alguna aplicación en el cliente web. En este trabajo se presenta el desarrollo de un visor web de imágenes DICOM que se ejecuta en cualquier navegador que soporte HTML5 sin requerir instalación previa (visores zerofootprint). Se utiliza un esquema de transmisión de imágenes progresivo para minimizar los tiempos de visualización y que garantiza la calidad diagnóstica de las imágenes. La performance del algoritmo de trasmisión de imágenes progresivo ha sido evaluada mediante la métrica Time-To-Display.

ABSTRACT Parathyroid hormone (PTH) and bisphosphonates (BPs), including alendronate (ALN), have opposing effects on bone dynamics. The extent to which PTH remains effective in the treatment of stress fracture (SFx) in the presence of an ongoing BP treatment has not been tested. SFx was induced in 150 female Wistar rats, divided into five equal groups (n = 30). All rats were pretreated with ALN (1 μg/kg−1/day−1) for 14 days prior to SFx induction, followed by ALN cessation or continuation for the duration of the experiment; this was combined with daily PTH (8 μg/100 g−1/day−1) on SFx induction for 14 days, followed by cessation or continuation of ALN after SFx induction or an equivalent vehicle as a control. Ulnas were examined 2 weeks or 6 weeks following SFx. Two toluidine blue‐ and two tartrate‐resistant acid phosphatase‐stained sections were examined for histomorphometric analysis using Osteomeasure software. There was a significant interaction between the effects of time and treatment type on the woven bone width and apposition rate, as well as an improvement in the woven bone architecture. However, woven bone variables remained unaffected by the cessation or continuation of ALN. Cessation of ALN increased osteoclast number when compared with the ALN‐PTH continuation group (p = 0.006), and vehicle (p = 0.024) after 2 weeks. There was a significant interaction between the effects of time and treatment type on the number of osteoclasts per unit BMU area and length. The number of osteoclasts per unit BMU area and length was significantly greater in ALN cessation groups. It was concluded that intermittent short‐duration iPTH treatment effectively increased remodeling of SFx with a concurrent BP treatment, provided that BP was ceased at the time of SFx. Our results could help develop shorter iPTH treatment protocols for the clinical management of SFxs and guide clinical decision‐making to cease BP treatment in cases of SFx. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

The modification of protein cysteine residues underlies some of the diverse biological functions of nitric oxide (NO) in physiology and disease. The formation of stable nitrosothiols occurs under biologically relevant conditions and time scales. However, the factors that determine the selective nature of this modification remain poorly understood, making it difficult to predict thiol targets and thus construct informatics networks. In this review, the biological chemistry of NO will be considered within the context of nitrosothiol formation and degradation whilst considering how specificity is achieved in this important post-translational modification. Since nitrosothiol formation requires a formal one-electron oxidation, a classification of reaction mechanisms is proposed regarding which species undergoes electron abstraction: NO, thiol or S-NO radical intermediate. Relevant kinetic, thermodynamic and mechanistic considerations will be examined and the impact of sources of NO and the chemical nature of potential reaction targets is also discussed.

Several metabolic factors affect cellular glucose metabolism as well as the innate inflammatory response. Here, the authors show that glucose metabolism regulates pro-inflammatory responses through effects on the cytosolic NADH:NAD+ ratio and the NAD(H)-sensitive transcription co-repressor CtBP.