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Intrathecal delivery of Nusinersen–an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction–is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.

Upper Palaeolithic sites in southwestern France attributed to the Upper Gravettian and the Solutrean yielded sub spherical gravels with a highly shiny appearance that have intrigued researchers since the 1930s. In this work, we analyze specimens from five sites, including the recently excavated Solutrean site of Landry, to establish whether their presence in archaeological layers and peculiar aspect are due to natural processes or human agency. We study the spatial distribution of gravels at Landry and submit archaeological gravels from the five sites, natural formations, Landry sediment sieving, and polishing experiments with a rotary tumbling machine to morphometric, colorimetric and textural analyses. Our results suggest that the lustrous gravels found at the five sites result from deliberate selection and their shiny appearance is the probable consequence of prolonged contact with a soft material such as animal skin. Ethnographic accounts indicate that these gravels may have been used for magico-religious ritual purposes (charms, sorcery, divination etc.), in games, as elements of musical instruments, and as items serving other social and personal purposes. We argue that these objects reflect a cultural innovation emerged during the Gravettian and continued into the Solutrean.

It has been suggested that engraved abstract patterns dating from the Middle and Lower Palaeolithic served as means of representation and communication. Identifying the brain regions involved in visual processing of these engravings can provide insights into their function. In this study, brain activity was measured during perception of the earliest known Palaeolithic engraved patterns and compared to natural patterns mimicking human-made engravings. Participants were asked to categorise marks as being intentionally made by humans or due to natural processes (e.g. erosion, root etching). To simulate the putative familiarity of our ancestors with the marks, the responses of expert archaeologists and control participants were compared, allowing characterisation of the effect of previous knowledge on both behaviour and brain activity in perception of the marks. Besides a set of regions common to both groups and involved in visual analysis and decision-making, the experts exhibited greater activity in the inferior part of the lateral occipital cortex, ventral occipitotemporal cortex, and medial thalamic regions. These results are consistent with those reported in visual expertise studies, and confirm the importance of the integrative visual areas in the perception of the earliest abstract engravings. The attribution of a natural rather than human origin to the marks elicited greater activity in the salience network in both groups, reflecting the uncertainty and ambiguity in the perception of, and decision-making for, natural patterns. The activation of the salience network might also be related to the process at work in the attribution of an intention to the marks. The primary visual area was not specifically involved in the visual processing of engravings, which argued against its central role in the emergence of engraving production.

Personal ornaments have become a key cultural proxy to investigate cognitive evolution, modern human dispersal, and population dynamics. Here, we reassess personal ornaments found at Zhoukoudian Upper Cave and compare them with those from other Late Paleolithic Northern Chinese sites. We reappraise the information provided by Pei Wen Chung on Upper Cave personal ornaments lost during World War II and analyze casts of 17 of them, along with two unpublished objects displayed at the Zhoukoudian Site Museum and three original perforated teeth rediscovered at the Zhoukoudian Site Museum. We apply archeozoological, technological and use-wear analyses to document variation in ornamental practices and their change throughout the site stratigraphy. Badger, fox, red deer, sika deer, marten, and tiger teeth as well as carp bone, bird bone, Anadara shell, limestone beads, and perforated pebble appear to have been the preferred objects used as ornaments by Upper Cave visitors. Multivariate analysis of technological data highlights a correspondence between cultural layers and perforation techniques, with radial incising being typical of layer L2 and bidirectional incising of L4. The three rediscovered badger canines display features suggesting they were sewed on clothing rather than suspended from necklaces or bracelets. Elemental scanning electron microscopy coupled with energy dispersive X-ray spectromety and mineralogical (μ-Raman) analyses of red residues adhering to the rediscovered teeth indicate these objects were originally coated with ochre and identify variations that match differences in technology. The two ornaments exhibited at the Zhoukoudian Site Museum are ancient teeth that were recently perforated and should be excluded from the Upper Cave assemblage. A seriation of Late Paleolithic ornaments found at Northern Chinese sites identifies a clear-cut difference in preferred ornament types between western and eastern sites, interpreted as reflecting two long-lasting traditions in garment symbolic codes. acceptedVersion

Schizophrenia (SCZ) is a mental illness characterized by aberrant synaptic plasticity and connectivity. A large bulk of evidence suggests genetic and functional links between postsynaptic abnormalities and SCZ. Here, we performed quantitative PCR and Western blotting analysis in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of SCZ patients to investigate the mRNA and protein expression of three key spine shapers: the actin-binding protein cyclase-associated protein 2 (

Lithic assemblages immediately following the Howiesons Poort, often loosely referred to as the ‘post- Howiesons Poort’ or MSA III, have attracted relatively little attention when compared to other wellknown phases of the South African Middle Stone Age (MSA) sequence. Current evidence from sites occurring in widely-differing environments suggests that these assemblages are marked by temporal and technological variability, with few features in common other than the presence of unifacial points. Here we present a technological and geometric morphometric analysis of ‘points’ from the new excavations of Members 2 BS, 2WA and the top of 3 BS members at Border Cave, KwaZulu-Natal, one of the key sites for studying modern human cultural evolution. Our complementary methodologies demonstrate that, at this site, hominins adopted a knapping strategy that primarily produced non-standardised unretouched points. Triangular morphologies were manufactured using a variety of reduction strategies, of which the discoidal and Levallois recurrent centripetal methods produced distinctive morphologies. We find technological and morphological variability increases throughout the post-Howiesons Poort sequence, with clear differences between and within chrono-stratigraphic groups. Finally, we assess the suitability of the ‘Sibudan’ cultural-technological typology proposed for post-Howiesons Poort assemblages at Sibhudu, another KwaZulu-Natal site, and find similarities in the morphological axes characterising the samples, despite differences in the shaping strategies adopted. Overall, our work contributes to the growing body of research that is helping to address historical research biases that have slanted our understanding of cultural evolution during the MSA of southern Africa towards the Still Bay and Howiesons Poort technocomplexes., UK Research & Innovation (UKRI), Arts & Humanities Research Council (AHRC) NGS-54810R-19, Wenner Gren Foundation CEOOP2020-1, Poroulis grant through Cambridge University, Spanish FEDER/Ministry of Science and Innovation 262618, National Geographic Explorer grant ANR-10-LABX-52, DSI- NRF Centre of Excellence in Palaeosciences grant 191022_001, Research Council of Norway through its Centres of Excellence funding scheme, LaScArBx research programme, Grand Programme de Recherche 'Human Past' of the Initiative d'Excellence (IdEx) of the Bordeaux University, Leakey Foundation (Movement, interaction, and structure: modelling population networks and cultural diversity in the African Middle Stone Age), Lithic Studies Society (Jacobi Bursary Awardee, 2020), SFF Centre for Early Sapiens Behaviour (SapienCE), Talents Programme AH/R012792/1 Gr. 10157 PID2019-1049449 GB-I00

Cueva de Ardales in Málaga, Spain, is one of the richest and best-preserved Paleolithic painted caves of southwestern Europe, containing over a thousand graphic representations. Here, we study the red pigment in panel II.A.3 of “Sala de las Estrellas,” dated by U-Th to the Middle Paleolithic, to determine its composition, verify its anthropogenic nature, infer the associated behaviors, and discuss their implications. Using optical microscopy, scanning electron microscopy coupled with energy dispersive X-ray spectroscopy, micro-Raman spectroscopy, and X-ray diffraction, we analyzed a set of samples from the panel and compared them to natural coloring materials collected from the floor and walls of the cave. The conspicuously different texture and composition of the geological samples indicates that the pigments used in the paintings do not come from the outcrops of colorant material known in the cave. We confirm that the paintings are not the result of natural processes and show that the composition of the paint is consistent with the artistic activity being recurrent. Our results strengthen the hypothesis that Neanderthals symbolically used these paintings and the large stalagmitic dome harboring them over an extended time span.

L- α -alanine has aroused considerable interest for use in radiation EPR dosimetry and has been formally accepted as a secondary standard for high-dose (kGy) and transfer dosimetry of high-energy photons and electrons. In this work, we extended the investigation of the energy response of alanine EPR films in the low energy range for X-photons (1–30 keV). Electron Paramagnetic Resonance (EPR) measurements were performed on Kodak BioMax alanine films exposed to low-energy X-rays from a Cu-, W- and Mo-targets tube operating at voltages up to 30 kV. Films were chosen because of the low penetration of the soft X-rays used. The response of alanine to low-energy X-rays was characterized experimentally and the relative response (with respect to high energy photons) was found to be between 0.8 and 0.9 for Cu- and W-tube X-rays, and 1.0 for Mo-tube X-rays. The attenuation profiles were investigated and it was found that 1 mm of film material reduces the intensity of the X-ray-beam by about 70%, 50% and 40% for Cu-, W- and Mo-tube X-rays, respectively. Monte Carlo simulations were performed to model the energy release as well as the depth dose profiles for the various radiation beams used. These data are considered relevant for dosimetric applications in low energy beams such the high-gradient treatment fields used in monoenergetic microbeam radiation therapy (MRT) with synchrotron radiation as well as in brachytherapy with low energy sources, for instance 169Yb.

In 2015, which marked 35 years since Beaumont had worked at the site, we renewed excavations at Border Cave. Our primary aims were to reassess the stratigraphic context of the sedimentary and cultural sequence, gain insight into site formation processes, make a detailed study of organic remains, identify long term cultural trends, and characterize expressions of complex behaviour and innovation. This contribution serves as an update on activities conducted in 2018 and 2019 and provides an overview of our research findings to date, placing them in the broader context of the Middle Stone Age in southern Africa. New luminescence ages based on feldspar grains in the sedimentary sequence are in broad agreement with the previous chronology established for the site. Geoarchaeology and faunal taphonomy have started to elucidate site formation processes, showing that the members should not be considered as homogeneous units, and that associated formation interpretations established by Beaumont are simplifications that are not representative of the diverse site formation processes active in the shelter. This finding is supported by lithic analysis of the Member 2 WA assemblage that shows differences in technology between artefacts from the top, middle, and lower part of the same member. In addition, the lithic artefacts from the middle and lower part of Member 2 WA show continuities with the lithics from the underlying Members 3 BS and 1 RGBS, which were attributed by Beaumont to a different industry. Grass mats/bedding layers are preserved throughout the sequence, the oldest of which dates to ∼200 ka. The use of ash and leaves with insecticidal properties in the bedding construction reflects complex cognition, as does the cooking of starchy rhizomes that come from layers dated to 170 ka. In addition to a rich mammal fauna found in all of the deposits, the remains of a new individual, a 3–4-year-old child, were recovered from Member 1 BS.LR C that has an ESR date of 42.6 ka.

Effective provisions of preparedness and response are necessary to protect human life, health, property, and the environment in any nuclear and radiological emergency. Recently, the International Commission on Radiological Protection recognized the need to provide more quantitative guidance on environmental radiation protection to integrate these analyses. A required assessment is a correlation between dose and its effects in non-human biota. Plants are highly sensitive environmental monitors for the assessment of potentially genotoxic agents and avoid the controversial use of animal models. The Allium test is commonly used to assess genotoxicity for a wide variety of chemical and physical factors, as it allows for estimates of possible DNA damage in eukaryotes in general, including humans. In this work, onion (Allium cepa) seedlings were exposed to 20–200 mGy of $$\alpha$$ -radiation. We studied the possibility of using cytogenetic analyses of irradiated onion cells to determine the biological dose. It was observed that the increase in the frequencies of chromosomal aberrations, mitotic abnormalities, and micronuclei occurred proportional to the radiation dose, but a reduction in cytological damage was observed from 100 mGy, suggesting the onset of cytotoxic activity. Our research shows the potential of Allium cepa as a sensitive support system for dosimetry, detection, and screening of cellular effects produced by low doses of environmental radiation.

The origin and evolution of hominin mortuary practices are topics of intense interest and debate1–3. Human burials dated to the Middle Stone Age (MSA) are exceedingly rare in Africa and unknown in East Africa1–6. Here we describe the partial skeleton of a roughly 2.5- to 3.0-year-old child dating to 78.3 ± 4.1 thousand years ago, which was recovered in the MSA layers of Panga ya Saidi (PYS), a cave site in the tropical upland coast of Kenya7,8. Recent excavations have revealed a pit feature containing a child in a flexed position. Geochemical, granulometric and micromorphological analyses of the burial pit content and encasing archaeological layers indicate that the pit was deliberately excavated. Taphonomical evidence, such as the strict articulation or good anatomical association of the skeletal elements and histological evidence of putrefaction, support the in-place decomposition of the fresh body. The presence of little or no displacement of the unstable joints during decomposition points to an interment in a filled space (grave earth), making the PYS finding the oldest known human burial in Africa. The morphological assessment of the partial skeleton is consistent with its assignment to Homo sapiens, although the preservation of some primitive features in the dentition supports increasing evidence for non-gradual assembly of modern traits during the emergence of our species. The PYS burial sheds light on how MSA populations interacted with the dead. Primary and intentional deposit Burial versus funerary caching Taxonomic assessment Implications for human cultural evolution Online content

Ionizing radiation is ubiquitous in the environment. Its source can be natural, such as radioactive materials present in soil and cosmic rays, or artificial, such as the fuel for nuclear power plants. Overexposure to ionizing radiation may damage living tissue and could cause severe health problems (i.e., mutations, radiation sickness, cancer, and death). Cytogenetic bio-dosimetry has the great advantage to take into account the inter-individual variation, and it is informative even when physical dosimetry is not applicable; moreover, it is the definitive method to assess exposure to ionizing radiation recommended by the World Health Organization (WHO). Such a procedure involves counting the frequency of dicentric chromosomes (DCs), which are the most studied chromosomal aberrations used as absorbed radiation biomarkers, during the metaphase of cells. A set of algorithms, tested on different programming languages to automatically identify DCs, is analyzed by the authors together with an Automated Dicentric Chromosome Identifying software (ADCI) mostly based on OpenCV programming libraries. The purpose of this work is to review the main results regarding the correlation between ionizing radiation and dicentric chromosomes in cytogenetic bio-dosimetry.

In recent decades, the increasing threats associated with Chemical and Radiological (CR) agents prompted the development of new tools to detect and collect samples without putting in danger first responders inside contaminated areas. A particularly promising branch of these technological developments relates to the integration of different detectors and sampling systems with Unmanned Aerial Vehicles (UAV). The adoption of this equipment may bring significant benefits for both military and civilian implementations. For instance, instrumented UAVs could be used in support of specialist military teams such as Sampling and Identification of Biological, Chemical and Radiological Agents (SIBCRA) team, tasked to perform sampling in contaminated areas, detecting the presence of CR substances in field and then confirming, collecting and evaluating the effective threats. Furthermore, instrumented UAVs may find dual-use application in the civil world in support of emergency teams during industrial accidents and in the monitoring activities of critical infrastructures. Small size drones equipped with different instruments for detection and collection of samples may enable, indeed, several applications, becoming a tool versatile and easy to use in different fields, and even featuring equipment normally utilized in manual operation. The authors hereby present the design of miniaturized sensors for a mission-oriented UAV application and the preliminary results from an experimental campaign performed in 2020.

Altered glutamatergic neurotransmission is thought to play a crucial role in the progression of Alzheimer’s disease (AD). Accordingly, the identification of peculiar biochemical patterns reflecting AD-related synaptopathy in blood and cerebrospinal fluid (CSF) could have relevant diagnostic and prognostic implications. In this study, we measured by High-Performance Liquid Chromatography the amount of glutamate, glutamine and glycine in post-mortem brain samples of AD patients, as well as in CSF and blood serum of drug-free subjects encompassing the whole AD clinical spectrum (pre-clinical AD, n = 18, mild cognitive impairment-AD, n = 29, dementia AD, n = 30). Interestingly, we found that glutamate and glycine levels, as well as total tau protein content, were significantly reduced in the superior frontal gyrus of patients with AD, compared with non-demented controls. No significant change was also found in glutamate, glutamine and glycine CSF concentrations between AD patients and neurological controls. Remarkably, serum glutamate levels were significantly higher in patients affected by early AD phases compared to controls, and were negatively correlated with CSF total tau levels. Conversely, serum glutamine concentration was significantly increased in AD patients, with a negative correlation with MMSE performances. Finally, we reported a significant correlation between seruml-glutamate concentrations and CDR score in female but not in male cohort of AD subjects. Overall, our results suggest that serum glutamate and glutamine levels in AD patients could vary across disease stages, potentially reflecting the progressive alteration of glutamatergic signaling during neurodegenerative processes.

Unconventional scenarios with hazardous radioactive levels are expected as consequences of accidents in the industrial sector of the nuclear energy production or following intentional releases of radioactive materials for terrorist purposes (dirty bombs, indoor contaminations, etc.). Nowadays, the need to balance the high standards of safety and security through an effective detection network is a matter of paramount importance. In this work, the authors’ challenge has been to design, realize and test a low-cost gamma detection and spectroscopy system which may be used in unmanned vehicles in general and/or drones with low payload capabilities. The designed platform may be used to carry out mapping or localization operations in order to reduce the risk factor for first responders or for the population affected by radiological and nuclear events. In this paper, the design process of a gamma ray detection and spectroscopy system based on affordable and commercially available technologies is presented along with the results of our ongoing characterization of the prototype.

The development of a tool to reduce the exposure of personnel in case of intentional or accidental toxic chemicals dispersion scenarios opens the field to new operational perspectives in the domain of operator safety and of critical infrastructure monitoring. The use of two sensors with different operating principles, metal oxide and photo-ionization detector, allows to confirm the presence of specific classes of chemicals in a contaminated area. All instruments are expected to be integrated into the payload of an unmanned aerial vehicle (UAV) and used for different purposes such as critical infrastructure surveillance focused on the volatile organic chemical and chemical warfare agents (CWA) detection and the post-incident of contamination level monitoring. In this paper, the authors presented the hardware set-up implemented and the test realized with CWAs simulants and will discuss the results obtained presenting advantages and disadvantages of this system in an application such as a UAV for the detection of chemical substances.

Conventional and non-conventional emergencies are among the most important safety and security concerns of the new millennium. Nuclear power and research plants, high-energy particle accelerators, radioactive substances for industrial and medical uses are all considered credible sources of threats both in warfare and in terror scenarios. Estimates of potential radiation releases of radioactive contamination related to these threats are therefore essential in order to prepare and respond to such scenarios. The goal of this paper is to demonstrate that computational modeling codes to simulate transport of radioactivity are extremely valuable to assess expected radiation levels and to improve risk analysis during emergencies helping the emergency planner and the first responders in the first hours of an occurring emergency.

Excessive extracellular concentrations of L-glutamate (L-Glu) can be neurotoxic and contribute to neurodegenerative processes in multiple sclerosis (MS). The association between cerebrospinal fluid (CSF) L-Glu levels, clinical features, and inflammatory biomarkers in patients with MS remains unclear. In 179MS patients (relapsing remitting, RR, N=157; secondary progressive/primary progressive, SP/PP, N=22), CSF levels of L-Glu at diagnosis were determined and compared with those obtained in a group of 40 patients with non-inflammatory/non-degenerative disorders. Disability at the time of diagnosis, and after 1year follow-up, was assessed using the Expanded Disability Status Scale (EDSS). CSF concentrations of lactate and of a large set of pro-inflammatory and anti-inflammatory molecules were explored. CSF levels of L-Glu were slightly reduced in MS patients compared to controls. In RR-MS patients, L-Glu levels correlated with EDSS after 1year follow-up. Moreover, in MS patients, significant correlations were found between L-Glu and both CSF levels of lactate and the inflammatory molecules interleukin (IL)-2, IL-6, and IL-1 receptor antagonist. Altered expression of L-Glu is associated with disability progression, oxidative stress, and inflammation. These findings identify CSF L-Glu as a candidate neurochemical marker of inflammatory neurodegeneration in MS. (Figure presented.).

Special nuclear materials hidden in shipping containers are extremely difficult to detect through their faint spontaneous emission of neutrons and photons. R&D efforts focus on active interrogation techniques, employing external beams of neutrons or high-energy X-rays to first trigger fission reactions and then detect prompt or delayed neutrons and/or photons. Our group created an active interrogation system based on detectors developed by Yale University and the University of Pisa. These detectors contain liquid droplets that vaporize when exposed to fast neutrons, but are insensitive to X-rays. The system was tested with an X-ray generator based on a 9 MeV electron LINAC available at an active interrogation facility. Copper is used as an X-ray production target at this facility, which prevents the production of photo-neutrons. With this system, we detected a sample of natural uranium either uncovered or shielded under heavy loads of wood or steel pipes. In order to interpret the experimental results, the response of our detector systems was assessed using Monte Carlo simulations with the code PHITS. Computational results are in good agreement with the experimental ones and open the way to simulations of real-world scenarios of interest to nonproliferation and homeland security, namely active interrogation at a standoff.

d-Amino acids were believed to occur only in bacteria and invertebrates. Today, it is well known that d-amino acids are also present in mammalian tissues in a considerable amount. In particular, high levels of free d-serine (d-Ser) and d-aspartate (d-Asp) are found in the brain. While the functions of d-Ser are well known, many questions remain unanswered regarding the role of d-Asp in the central nervous system. d-Asp is very abundant at the embryonic stage, while it strongly decreases after birth because of the expression of d-aspartate oxidase (Ddo) enzyme, which catalyzes the oxidation of this d-amino acid into oxaloacetate, ammonium, and hydrogen peroxide. Pharmacologically, d-Asp acts as an endogenous agonist of N-methyl d-aspartate and mGlu5 receptors, which are known to control fundamental brain processes, including brain development, synaptic plasticity, and cognition. In this work, we studied a recently generated knockin mouse model (R26ddo/ddo), which was designed to express DDO beginning at the zygotic stage. This strategy enables d-Asp to be almost eliminated in both prenatal and postnatal lives. To understand which biochemical pathways are affected by depletion of d-Asp, in this study, we carried out a metabolomic and lipidomic study of ddo knockin brains at different stages of embryonic and postnatal development, combining nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) techniques. Our study shows that d-Asp deficiency in the brain influences amino acid pathways such as threonine, glycine, alanine, valine, and glutamate. Interestingly, d-Asp is also correlated with metabolites involved in brain development and functions such as choline, creatine, phosphocholine (PCho), glycerophosphocholine (GPCho), sphingolipids, and glycerophospholipids, as well as metabolites involved in brain energy metabolism, such as GPCho, glucose, and lactate.

Classical sensor security relies on cryptographic algorithms executed on trusted hardware. This approach has significant shortcomings, however. Hardware can be manipulated, including below transistor level, and cryptographic keys are at risk of extraction attacks. A further weakness is that sensor media themselves are assumed to be trusted, and any authentication and encryption is done ex situ and a posteriori. Here we propose and demonstrate a different approach to sensor security that does not rely on classical cryptography and trusted electronics. We designed passive sensor media that inherently produce secure and trustworthy data, and whose honest and non-malicious nature can be easily established. As a proof-of-concept, we manufactured and characterized the properties of non-electronic, physical unclonable, optically complex media sensitive to neutrons for use in a high-security scenario: the inspection of a military facility to confirm the absence or presence of nuclear weapons and fissile materials.

Early plant use is seldom described in the archaeological record because of poor preservation. We report the discovery of grass bedding used to create comfortable areas for sleeping and working by people who lived in Border Cave at least 200,000 years ago. Sheaves of grass belonging to the broad-leafed Panicoideae subfamily were placed near the back of the cave on ash layers that were often remnants of bedding burned for site maintenance. This strategy is one forerunner of more-complex behavior that is archaeologically discernible from ~100,000 years ago.

The irradiation facility of the University of Pisa (UNIPI) is a neutron and gamma irradiation facility of the University of Pisa used for calibration purposes and to evaluate detectors and dosemeters for mixed neutron and gamma fields. The facility consists of a fairly large room (5.0 × 7.8 × 2.5 m3) with concrete walls and roof designed to minimise radiation scattering. Sealed neutron and gamma radionuclide sources are stored in the facility for calibration and test purposes. In order to perform accurate response measurements, this study applied a methodology of general validity to assess the neutron and gamma room scatter contributions (albedo) to the fluence and to the ambient dose equivalent rates. The assessment was done for the standard irradiation points of the facility, using detailed Monte Carlo simulations and considering several source-to-wall and source-to-detector distances.

International audience; The recent identification of cave paintings dated to 42-40 ka BP in Borneo and Sulawesi highlights the antiquity of painted representations in this region. However, no instances of three-dimensional portable art, well attested in Europe since at least 40 ka BP, were documented thus far in East Asia prior to the Neolithic. Here, we report the discovery of an exceptionally well-preserved miniature carving of a standing bird from the site of Lingjing, Henan, China. Microscopic and microtomographic analyses of the figurine and the study of bone fragments from the same context reveal the object was made of bone blackened by heating and carefully carved with four techniques that left diagnostic traces on the entire surface of the object. Critical analysis of the site's research history and stratigraphy, the cultural remains associated with the figurine and those recovered from the other archeological layers , as well as twenty-eight radiometric ages obtained on associated archeological items, including one provided by a bone fragment worked with the same technique recorded on the object, suggest a Late Paleolithic origin for the carving, with a probable age estimated to 13,500 years old. The carving, which predates previously known comparable instances from this region by 8,500 years, demonstrates that three-dimensional avian representations were part of East Asian Late Pleistocene cultural repertoires and identifies technological and stylistic peculiarities distinguishing this newly discovered art tradition from previous and contemporary examples found in Western Europe and Siberia.

The advent of bone technology in Africa is often associated with behavioral modernity that began sometime in the Middle Stone Age. Yet, small numbers of bone tools are known from Early Pleistocene sites in East and South Africa, complicating our understanding of the evolutionary significance of osseous technologies. These early bone tools vary geographically, with those in South Africa indicating use in foraging activities such as termite extraction and those in East Africa intentionally shaped in a manner similar to lithic tool manufacture, leading some to infer multiple hominin species were responsible for bone technology in these regions, with Paranthropus robustus assumed to be the maker of South African bone tools and Homo erectus responsible for those in East Africa. Here we present on a largely unknown assemblage of 52 supposed bone tools primarily from Beds III and IV, Olduvai Gorge, Tanzania, that was excavated by Mary Leakey in the late 1960s and early 1970s. The majority of the sites from which the tools were recovered were deposited when only Homo erectus is known to have existed in the region, potentially allowing a direct link between this fossil hominin and bone technology. Our analysis confirms at least six bone tools in the assemblage, the majority of which are intentionally flaked large mammal bones and one of which is a preform of the oldest barbed bone point known to exist anywhere in the world pushing back the origins for this technology by 700 kyr., This research was funded by Wenner-Gren Foundation for Anthropological Research (grant numbers 7640 and 9245); the European Research Council (European Union's Seventh Framework Programme [FP7/2007-2013]/ERC grant agreement no 283366 [ORACEAF]), and the Rutgers University Center for Human Evolutionary Studies. I.d.l.T. is currently funded by a European Research Council-Advanced Grant (BICAEHFID; grant agreement no. 832980). F.d'E.'s work was partially funded by the Research Council of Norway through its Centre of Excellence funding scheme (SFF Centre for Early Sapiens Behaviour – SapienCE – project number 262618), and the Talents program of the University of Bordeaux ‘Initiative d’Excellence.’

African Middle Stone Age (MSA) populations used pigments, manufactured and wore personal ornaments, made abstract engravings, and produced fully shaped bone tools. However, ongoing research across Africa reveals variability in the emergence of cultural innovations in the MSA and their subsequent development through the Later Stone Age (LSA). When present, it appears that cultural innovations manifest regional variability, suggestive of distinct cultural traditions. In eastern Africa, several Late Pleistocene sites have produced evidence for novel activities, but the chronologies of key behavioral innovations remain unclear. The 3 m deep, well-dated, Panga ya Saidi sequence in eastern Kenya, encompassing 19 layers covering a time span of 78 kyr beginning in late Marine Isotope Stage 5, is the only known African site recording the interplay between cultural and ecological diversity in a coastal forested environment. Excavations have yielded worked and incised bones, ostrich eggshell beads (OES), beads made from seashells, worked and engraved ocher pieces, fragments of coral, and a belemnite fossil. Here, we provide, for the first time, a detailed analysis of this material. This includes a taphonomic, archeozoological, technological, and functional study of bone artifacts; a technological and morphometric analysis of personal ornaments; and a technological and geochemical analysis of ocher pieces. The interpretation of the results stemming from the analysis of OES beads is guided by an ethnoarcheological perspective and field observations. We demonstrate that key cultural innovations on the eastern African coast are evident by 67 ka and exhibit remarkable diversity through the LSA and Iron Age. We suggest the cultural trajectories evident at Panga ya Saidi were shaped by both regional traditions and cultural/demic diffusion. acceptedVersion

Middle Stone Age cooking Early evidence of cooked starchy plant food is sparse, yet the consumption of starchy roots is likely to have been a key innovation in the human diet. Wadley et al. report the identification of whole, charred rhizomes of plants of the genus Hypoxis from Border Cave, South Africa, dated up to 170,000 years ago. These archaeobotanical remains represent the earliest direct evidence for the cooking of underground storage organs. The edible Hypoxis rhizomes appear to have been cooked and consumed in the cave by the Middle Stone Age humans at the site. Hypoxis has a wide geographical distribution, suggesting that the rhizomes could have been a ready and reliable carbohydrate source for Homo sapiens in Africa, perhaps facilitating the mobility of human populations. Science , this issue p. 87

In Tupi, the word Sambaqui means “mound of shells”. These archaeological sites are cultural vestiges left by the prehistoric occupation of the Brazilian coast from five to six thousand years ago. Mollusks, fishes, and other marine edible foods were important for the survival of this population. The remains of foods, mainly shells, were heaped up, giving a mound of different proportions, which became part of the landscape of the Brazilian coastal plain. Due to the large number of Sambaquis in Brazil and considering that Sambaqui Santa Marta II, Laguna, SC, has not yet been dated, Electron Spin Resonance (ESR) measurements were performed in aragonite shells collected from different layers of Sambaqui Santa Marta II, starting from the base to the center of the Sambaqui. Radiocarbon analysis by Accelerator Mass Spectrometry (AMS) at Beta Analytic laboratory were also performed for comparison with ESR results. Before measurements, shells were chemically etched, after drying, were pulverized and sieved. The sediments were separated into small portions which were irradiated with gamma radiation from a 60Co source with doses from 5 up to 120 Gy. Ages around 2,000 to 4,000 years have been obtained. The results obtained are consistent with the dates of others Sambaquis of the region, possibly were built at the same time.

In a wide international cooperation, thin dosimetric films were developed for radiation protection and clinical dosimetry applications. The goal was providing proof of principle of a novel approach to entrance surface dosimetry, in general, and to extremity dosimetry, in particular. The latter is an extremely challenging task since ring and wrist dosimeters do not allow reliable estimates of the higher doses typically received by the fingertips, while solid-state detector chips worn on the fingertips interfere with the tactile sense of the workers. In our current system, tissue-equivalent polyethylene films are used to embed a variety of luminescent materials, particularly radiophotoluminescent (RPL) glass grains. This work illustrates the results we have achieved so far, proving that polyethylene films loaded with RPL glass grains provide a dosimetric response and have adequate mechanical and wearability properties. Additionally, the signal build-up associated with RPL glass is significantly accelerated when the glass is kept at body temperature, i.e., in contact with the worker's hands. Finally, the use of double gloves further improves the performance of our system.

The endogenous amino acids serine and aspartate occur at high concentrations in free D-form in mammalian organs, including the central nervous system and endocrine glands. D-serine (D-Ser) is largely localized in the forebrain structures throughout pre and postnatal life. Pharmacologically, D-Ser plays a functional role by acting as an endogenous coagonist at N-methyl-D-aspartate receptors (NMDARs). Less is known about the role of free D-aspartate (D-Asp) in mammals. Notably, D-Asp has a specific temporal pattern of occurrence. In fact, free D-Asp is abundant during prenatal life and decreases greatly after birth in concomitance with the postnatal onset of D-Asp oxidase expression, which is the only enzyme known to control endogenous levels of this molecule. Conversely, in the endocrine system, D-Asp concentrations enhance after birth during its functional development, thereby suggesting an involvement of the amino acid in the regulation of hormone biosynthesis. The substantial binding affinity for the NMDAR glutamate site has led us to investigate the in vivo implications of D-Asp on NMDAR-mediated responses. Herein we review the physiological function of free D-Asp and of its metabolizing enzyme in regulating the functions of the brain and of the neuroendocrine system based on recent genetic and pharmacological human and animal studies.

Background Autism spectrum disorders (ASD) comprise a heterogeneous group of neurodevelopmental conditions characterized by impairment in social interaction, deviance in communication, and repetitive behaviors. Dysfunctional ionotropic NMDA and AMPA receptors, and metabotropic glutamate receptor 5 activity at excitatory synapses has been recently linked to multiple forms of ASD. Despite emerging evidence showing that d -aspartate and d -serine are important neuromodulators of glutamatergic transmission, no systematic investigation on the occurrence of these D-amino acids in preclinical ASD models has been carried out. Methods Through HPLC and qPCR analyses we investigated d -aspartate and d -serine metabolism in the brain and serum of four ASD mouse models. These include BTBR mice, an idiopathic model of ASD, and Cntnap2−/−, Shank3−/−, and 16p11.2+/− mice, three established genetic mouse lines recapitulating high confidence ASD-associated mutations. Results Biochemical and gene expression mapping in Cntnap2−/−, Shank3−/−, and 16p11.2+/− failed to find gross cerebral and serum alterations in d -aspartate and d -serine metabolism. Conversely, we found a striking and stereoselective increased d -aspartate content in the prefrontal cortex, hippocampus and serum of inbred BTBR mice. Consistent with biochemical assessments, in the same brain areas we also found a robust reduction in mRNA levels of d -aspartate oxidase, encoding the enzyme responsible for d -aspartate catabolism. Conclusions Our results demonstrated the presence of disrupted d -aspartate metabolism in a widely used animal model of idiopathic ASD. General significance Overall, this work calls for a deeper investigation of D-amino acids in the etiopathology of ASD and related developmental disorders.

The free d-amino acid, d-aspartate, is abundant in the embryonic brain but significantly decreases after birth. Besides its intracellular occurrence, d-aspartate is also present at extracellular level and acts as an endogenous agonist for NMDA and mGlu5 receptors. These findings suggest that d-aspartate is a candidate signaling molecule involved in neural development, influencing brain morphology and behaviors at adulthood. To address this issue, we generated a knockin mouse model in which the enzyme regulating d-aspartate catabolism, d-aspartate oxidase (DDO), is expressed starting from the zygotic stage, to enable the removal of d-aspartate in prenatal and postnatal life. In line with our strategy, we found a severe depletion of cerebral d-aspartate levels (up to 95%), since the early stages of mouse prenatal life. Despite the loss of d-aspartate content, Ddo knockin mice are viable, fertile, and show normal gross brain morphology at adulthood. Interestingly, early d-aspartate depletion is associated with a selective increase in the number of parvalbumin-positive interneurons in the prefrontal cortex and also with improved memory performance in Ddo knockin mice. In conclusion, the present data indicate for the first time a biological significance of precocious d-aspartate in regulating mouse brain formation and function at adulthood.

In this work, we investigate theoretically and experimentally second harmonic generation (SHG) in three pyrazoline compounds, being two derivatives of dibenzylideneacetone (DBA) (C23H20N2 and C25H24N2O2) and one derivative of chalcone (C21H18N2). The compounds were synthesized after two steps employing a Claisen-Schmidt condensation followed by an addition-elimination reaction with phenylhydrazine. All compounds were characterized using NMR, FT-IR, UV-Vis, and XRD. We calculated the first-order hyperpolarizabilities of these molecules using program packages based on the time-dependent Hartree-Fock (TDHF) and density functional theory (DFT). SHG was characterized by Kurtz and Perry’s powder method. We observed that these organic crystals present SHG efficiencies up to 5 times larger than the KDP, and we associated these values to their molecular structure and crystalline arrangements. The values obtained experimentally and theoretically evidence that these compounds have good potential for application in electronic devices based on second-order nonlinear responses.

The diagnosis of Alzheimer's disease (AD) relies on the presence of amyloidosis and tauopathy, as reflected in cerebrospinal fluid (CSF), independently from the clinical stage. Recently, CSF d-serine has been proposed as a possible new AD biomarker, reflecting dysfunctional activation of neuronal glutamatergic N-methyl-d-aspartate receptor (NMDAR). In this study, we measured blood serum and CSF concentration of two NMDAR modulators, such as d-serine and d-aspartate, in a cohort of drug-free subjects encompassing the whole AD clinical spectrum. In addition, we also analyzed d-serine levels in a cohort of post-mortem AD and control cortex samples. We reported unaltered serum and CSF concentrations of d-serine and d-aspartate in AD patients both during the AD progression and compared to non-demented controls. Accordingly, no correlation was detected between serum or CSF d-serine content and mini-mental state examination or Clinical Dementia Rating. Similarly, cortical d-serine levels were also unaltered in post-mortem samples of AD patients. Overall, our results failed to confirm previous findings indicating the CSF d-serine as a novel biomarker for AD.

The world has changed. The global crisis related to the reduction of energy fossil resources, the reduction of potable water resources and the war for the control of energy sources are part of the causes which can lead to an intentional CBRNe (Chemical, Biological, Radiological, Nuclear, and explosive) event together with the potential misuse of CBRNe agents, once considered to be solely the concern of the military, now needs to be considered also in the public domain. This kind of events could also be the consequence of an unintentional release of substances (i.e., an accident of a truck containing a Toxic Industrial Chemical), or of natural events like a tsunami or an earthquake. Thus, the high percentage of risk connected to their occurrence is clear. The aim of this paper is to analyze the CBRNe risk scenario and propose a standardized CBRNe joint approach for the establishment of “CBRNe technical tables” composed by cluster Entities from around Europe to manage the production of technologies, research, education and training activities in order to: (1) establish and maintain a roster of capabilities and facilities, and (2) organize to share expertise, and (3) plan to pool resources. The authors will show the results in the “Italian case study” as a potential pilot project analyzing the strengths and weaknesses to propose new ideas to improve it.

Measurements of entrance doses and extremity doses in mix fields are quite complex, particularly when it comes to neutron radiation. For this reason, films of transparent and flexible polymers loaded with luminescent materials sensitive to photons and neutrons were developed experimentally. However, there is a demand for optimizing the shape and arrangement of the crystals in these films. Using Monte Carlo simulations with the PHITS code, we simulated a geometry so that it would be possible to measure the dose deposited by the primary neutrons and by neutrons scattered backwards by a water phantom. We evaluated the sensitivity of the films loaded with MgB4O7 produced with different boron isotopes. We found that, in the case of a photon source, the energy deposited in the MgB4O7 particles comes from the photons that directly impact the film and that there was no significant difference in sensitivity for the different isotopes. However, using neutron beams, the water phantom is responsible for backscattering the neutrons that deposit the dose in the film produced with B-10, indicating that films can be used to detect albedo neutrons from an irradiated body and differentiate them from gamma irradiation.

In this paper, the authors analyze the case study of the recovery of an orphan source of 60Co inside a maritime cargo full of metal wastes in the Italian Harbor of Genova carried out by the Italian Fire Fighters. Orphan radioactive sources or Radiological Dispersal Devices are a critical security issue in large geographical areas, and they result in a safety concern for people who may become accidentally exposed to ionizing radiation. The abandonment of orphan sources can usually be related to three factors: human errors, cost reasons (in order to avoid the payment of disposal procedures), or malevolent purposes (like the production of dirty bombs). The present data concern the nuclear safety measures implemented during the recovery event and the pool of procedures carried out in order to reduce the risks for the involved harbor operators. Following data collection and analysis, an important lesson about the management of such events and scenarios can be learned.

A method for Orthogonal Phase Encoding Reduction of Artifact (OPERA) was developed and tested. Because the position of ghosts and aliasing artifacts is predictable along columns or rows, OPERA combines the intensity values of two images acquired using the same parameters, but with swapped phase-encoding directions, to correct the artifacts. Simulations and phantom experiments were conducted to define the efficacy, robustness, and reproducibility. Clinical validation was performed on a total of 1003 images by comparing the OPERA-corrected images and the corresponding image standard in terms of Signal-to-Noise Ratio (SNR) and Contrast-to-Noise Ratio (CNR). The method efficacy was also rated using a Likert-type scale response by two experienced independent radiologists using a single-blinded procedure. Simulations and phantom experiments demonstrated the robustness and effectiveness of OPERA in reducing artifacts strength. OPERA application did not significantly change the SNR [+ 4.16%; inter-quartile range (IQR): 2.72–5.01%] and CNR (+ 4.30%; IQR: 2.86–6.04%) values. The two radiologists observed a total of 893 original images with artifacts (89.03% of the total images), a reduction in the perceived artifacts of 82.0% and 83.9% (p

Schizophrenia (SCZ) is a polygenic severe mental illness. Genome-wide association studies (GWAS) have detected genomic variants associated with this psychiatric disorder and pathway analyses have indicated immune system and dopamine signaling as core components of risk in dorsolateral-prefrontal cortex (DLPFC) and hippocampus, but the mechanistic links remain unknown. The RasGRP1 gene, encoding for a guanine nucleotide exchange factor, is implicated in dopamine signaling and immune response. RasGRP1 has been identified as a candidate risk gene for SCZ and autoimmune disease, therefore representing a possible point of convergence between mechanisms involving the nervous and the immune system. Here, we investigated RasGRP1 mRNA and protein expression in post-mortem DLPFC and hippocampus of SCZ patients and healthy controls, along with RasGRP1 protein content in the serum of an independent cohort of SCZ patients and control subjects. Differences in RasGRP1 expression between SCZ patients and controls were detected both in DLPFC and peripheral blood of samples analyzed. Our results indicate RasGRP1 may mediate risk for SCZ by involving DLPFC and peripheral blood, thus encouraging further studies to explore its possible role as a biomarker of the disease and/or a target for new medication.

Radiophotoluminescence (RPL) properties of Sm-doped CaSO4 for radiation dosimetry applications are reported. The samples with varying Sm concentrations are prepared via the solid-state reaction process. The as-prepared samples show photoluminescence due to typical 4f–f transitions of Sm3+ whereas, after X-ray irradiation, additional emission features appear with a broad band peaking at 630 nm as well as a set of multiple sharp lines across 680–820 nm, which are attributed to the 5d–4f and 4f–4f transitions of Sm2+, respectively. Therefore, the RPL in the present material system relies on the generation of Sm2+ centers. The sensitivity is about 3 times lower than that of Ag-doped phosphate glass, but no fading and build-up of signal are evident even immediately after the irradiation. The signal is reversible by heat-treatment at 500 °C, and is reproducible even after the thermal erasure, especially when the differential signal between pre- and post-irradiation is taken into account.

The chelator eriochrome cyanine R (ECR) in aqueous solutions forms metal complexes with Fe(III) ions with 1:1 (metal:ligand) stoichiometry. Because ECR absorbs light in the visible spectrum at different wavelengths for its free and complexed forms, this ligand may behave as a dose marker in a Fricke gel (FG) dosimeter. This is the first investigation of the influence of the organic ligand ECR in Fricke gels produced with a polyvinyl alcohol matrix cross-linked with glutaraldehyde (FGECR). The concentrations of sulfuric acid, ECR, and Fe(II) ions were varied in the FG synthesis in order to optimize the detector sensitivity to ionizing radiation. For comparison sake, FG synthesized with xylenol orange (FGXO) was also produced. The formation of the Fe(III)-ECR complex after irradiation has two absorption bands in the visible region. The absorbance intensities vary linearly with the absorbed dose in the range of 0.0–40.0 Gy. The FGECR and FGXO showed similar properties: sensitivity of (0.072 ± 0.001) Gy-1 and (0.079 ± 0.001) Gy-1; and diffusion of (0.192 ± 0.006) mm2 h-1 and (0.184 ± 0.022) mm2 h-1, respectively. FGECR has some advantages for application in radiotherapy, as it presented sensitivity for low doses, whose minimum detectable dose was 0.67 Gy, with maximum optical absorption at low energy wavelengths, ideal for measuring radiation dose by optical tomography, and it has a high saturation dose. Therefore, FGECR has the potential for dosimetric studies in radiotherapy, including flash radiotherapy, which deposits high doses in extremely short times.