Search

Abstract Organic electrochemical transistors (OECTs) underpin a range of emerging technologies, from bioelectronics to neuromorphic computing, owing to their unique coupling of electronic and ionic charge carriers. In this context, various OECT systems exhibit significant hysteresis in their transfer curve, which is frequently leveraged to achieve non-volatility. Meanwhile, a general understanding of its physical origin is missing. Here, we introduce a thermodynamic framework that readily explains the emergence of bistable OECT operation via the interplay of enthalpy and entropy. We validate this model through temperature-resolved characterizations, material manipulation, and thermal imaging. Further, we reveal deviations from Boltzmann statistics for the subthreshold swing and reinterpret existing literature. Capitalizing on these findings, we finally demonstrate a single-OECT Schmitt trigger, thus compacting a multi-component circuit into a single device. These insights provide a fundamental advance for OECT physics and its application in non-conventional computing, where symmetry-breaking phenomena are pivotal to unlock new paradigms of information processing.

Among domestic species, pigs experienced the greatest brain size reduction, but the extent and factors of this reduction remain unclear. Here, we used the brain endocast volume collected from 92 adult skulls of wild, captive, feral and domestic Sus scrofa to explore the effects of domestication, feralization and captivity over the brain size variation of this species. We found a constant brain volume increase over 24 months, while body growth slowed down from month 20. We observed an 18% brain size reduction between wild boars and pigs, disagreeing with the 30%–40% reduction previously mentioned. We did not find significant sexual differences in brain volume, refuting the theory of the attenuation of male secondary sexual characteristics through the selection for reduced male aggression. Feralization in Australia led to brain size reduction—probably as an adaptation to food scarcity and drought, refuting the reversal to wild ancestral brain size. Finally, free-born wild boars raised in captivity showed a slight increase in brain size, potentially due to a constant and high-quality food supply as well as new allospecific interactions. These results support the need to further explore the influence of diet, environment and experience on brain size evolution during animal domestication.

Though models describing the operating mechanism of organic electrochemical transistors (OECTs) have been developed, these models are unable to accurately reproduce OECT electrical characteristics. Here, the authors report a thermodynamic-based framework that accurately models OECT operation.

‘Archaeogenetic analysis of black rat remains reveals that this species was introduced into temperate Europe twice, in the Roman and medieval periods. This population turnover was likely associated with multiple historical and environmental factors.’

Reduced mobility associated with captivity induces changes in biomechanical stress on the skeleton of domesticated animals. Due to bone plasticity, bone’s morphology and internal structure can respond to these new biomechanical stresses over individuals’ lifetime. In a context where documenting early process of animal domestication is challenging, this study will test the hypothesis that change in mobility patterns during a wild ungulate’s life will alter the internal structure of its limb bones and provide a proof of concept for the application of this knowledge in Zooarchaeology. Using the calcaneus as a phenotypic marker through qualitative and quantitative 3D microanatomical analyses, we relied on a comparative study across wild boars (Sus scrofa) populations from controlled experimental conditions with different mobility patterns (natural habitat, large pen, and stall) and archaeological specimens collected from middle and late Mesolithic as surrogate for the norm of reaction in European wild boar phenotype before the spread of agriculture and domestic pigs. Results provide evidence for compressive and tensile forces as the main elements affecting the variation in the cortical thickness along the calcaneus. Furthermore, changes in the internal structure of the calcaneus between mobility patterns are observed but their intensity is not directly associated with the degree of mobility restriction and only weakly impacted by the size or weight of the individuals. Despite having greater bone volume, the calcaneus of the Mesolithic wild boars displays a very similar microanatomy compared to the present-day hunted or captive wild boars. These results suggest that calcaneal microanatomy is more affected by population differences than by locomotor variation. For all these reasons, this preliminary study doesn’t support the use of microanatomy of the calcaneus as an indicator of change in locomotor behaviour induced by captivity in the archaeological record.

Abstract Epipaleolithic hunter-gatherers from the Near East introduced wild boars (Sus scrofa) to Cyprus, with the Early Pre-Pottery Neolithic (PPN) settlers hunting the wild descendants of these boars. However, the geographic origin of the Cypriot boar and how they were integrated into the earliest forms of pig husbandry remain unsolved. Here, we present data on 11,000 to 9000 cal. BP Sus scrofa from the PPN sites of Klimonas and Shillourokambos. We compared them to contemporaneous populations from the Near East and to Neolithic and modern populations in Corsica, exploring their origin and evolution using biosystematic signals from molar teeth and heel bones (calcanei), using 2D and 3D geometric morphometrics. We found that the Cypriot PPN lineage of Sus scrofa originates from the Northern Levant. Yet, their phenotypic idiosyncrasy suggest that they evolved into an insular sub-species that we named Sus scrofa circeus, referring to Circe, the metamorphosis goddess that changed Ulysses companions into pigs. The phenotypic homogeneity among PPNA Klimonas wild boars and managed populations of PPNB Shillourokambos suggests that local domestication has been undertaken on the endemic S. s. circeus, strengthening the idea that Cyprus was integrated into the core region of animal domestication.

Abstract We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches.

Abstract The current framework of radiological protection of occupational exposed medical workers reduced the eye-lens equivalent dose limit from 150 to 20 mSv per year requiring an accurate dosimetric evaluation and an increase understanding of radiation induced effects on Lens cells considering the typical scenario of occupational exposed medical operators. Indeed, it is widely accepted that genomic damage of Lens epithelial cells (LEC) is a key mechanism of cataractogenesis. However, the relationship between apoptosis and cataractogenesis is still controversial. In this study biological and physical data are combined to improve the understanding of radiation induced effects on LEC. To characterize the occupational exposure of medical workers during angiographic procedures an INNOVA 4100 (General Electric Healthcare) equipment was used (scenario A). Additional experiments were conducted using a research tube (scenario B). For both scenarios, the frequencies of binucleated cells, micronuclei, p21-positive cells were assessed with different doses and dose rates. A Monte-Carlo study was conducted using a model for the photon generation with the X-ray tubes and with the Petri dishes considering the two different scenarios (A and B) to reproduce the experimental conditions and validate the irradiation setups to the cells. The simulation results have been tallied using the Monte Carlo code MCNP6. The spectral characteristics of the different X-ray beams have been estimated. All irradiated samples showed frequencies of micronuclei and p21-positive cells higher than the unirradiated controls. Differences in frequencies increased with the delivered dose measured with Gafchromic films XR-RV3. The spectrum incident on eye lens and Petri, as estimated with MCNP6, was in good agreement in the scenario A (confirming the experimental setup), while the mean energy spectrum was higher in the scenario B. Nevertheless, the response of LEC seemed mainly related to the measured absorbed dose. No effects on viability were detected. Our results support the hypothesis that apoptosis is not responsible for cataract induced by low doses of X-ray (i.e. 25 mGy) while the induction of transient p21 may interfere with the disassembly of the nuclear envelop in differentiating LEC, leading to cataract formation. Further studies are needed to better clarify the relationship we suggested between DNA damage, transient p21 induction and the inability of LEC enucleation.

Deciphering the plastic (non-heritable) changes induced by human control over wild animals in the archaeological record is challenging. We hypothesized that changes in locomotor behaviour in a wild ungulate due to mobility control could be quantified in the bone anatomy. To test this, we experimented with the effect of mobility reduction on the skeleton of wild boar (Sus scrofa), using the calcaneus shape as a possible phenotypic marker. We first assessed differences in shape variation and covariation in captive-reared and wild-caught wild boars, taking into account differences in sex, body mass, available space for movement and muscle force. This plastic signal was then contrasted with the phenotypic changes induced by selective breeding in domestic pigs. We found that mobility reduction induces a plastic response beyond the shape variation of wild boars in their natural habitat, associated with a reduction in the range of locomotor behaviours and muscle loads. This plastic signal of captivity in the calcaneus shape differs from the main changes induced by selective breeding for larger muscle and earlier development that impacted the pigs' calcaneus shape in a much greater extent than the mobility reduction during the domestication process of their wild ancestors.

The role of the lattice in the correlated metal-insulator transition of Ca2RuO4 has led to significant interest but experiments that are at the same time sensitive to crystal and electronic structure are difficult. Riccò et al. successfully combine ARPES measurements with in situ strain tuning across the Mott transition.

BCATs catabolize leucine and other BCAAs. Here the authors show that BCAA metabolism affects the broken Krebs cycle, reprogramming macrophages to be less proinflammatory, and show that BCAT1 inhibitor ERG240 can treat arthritis in mice and glomerulonephritis in rats.

PIN1 is a promising therapeutic target for cancer treatment. In this study, the authors identify a covalent inhibitor of PIN1 with anti-tumour and anti-metastatic properties thanks to PIN1 inactivation and to the release, after binding to PIN1, of a quinone-mimicking compound that elicits reactive oxygen generation and causes DNA damage.

Radiation therapy is a useful and standard tumor treatment strategy. Despite recent advances in delivery of ionizing radiation, survival rates for some cancer patients are still low because of recurrence and radioresistance. This is why many novel approaches have been explored to improve radiotherapy outcome. Some strategies are focused on enhancement of accuracy in ionizing radiation delivery and on the generation of greater radiation beams, for example with a higher dose rate. In the present study we proposed an in vitro research of the biological effects of very high dose rate beam on SK-Mel28 and A375, two radioresistant human melanoma cell lines. The beam was delivered by a pulsed plasma device, a "Mather type" Plasma Focus for medical applications. We hypothesized that this pulsed X-rays generator is significantly more effective to impair melanoma cells survival compared to conventional X-ray tube. Very high dose rate treatments were able to reduce clonogenic efficiency of SK-Mel28 and A375 more than the X-ray tube and to induce a greater, less easy-to-repair DNA double-strand breaks. Very little is known about biological consequences of such dose rate. Our characterization is preliminary but is the first step toward future clinical considerations.

The Plio–Pleistocene evolution of Equus and the subsequent domestication of horses and donkeys remains poorly understood, due to the lack of phenotypic markers capable of tracing this evolutionary process in the palaeontological/archaeological record. Using images from 345 specimens, encompassing 15 extant taxa of equids, we quantified the occlusal enamel folding pattern in four mandibular cheek teeth with a single geometric morphometric protocol. We initially investigated the protocol accuracy by assigning each tooth to its correct anatomical position and taxonomic group. We then contrasted the phylogenetic signal present in each tooth shape with an exome-wide phylogeny from 10 extant equine species. We estimated the strength of the phylogenetic signal using a Brownian motion model of evolution with multivariate K statistic, and mapped the dental shape along the molecular phylogeny using an approach based on squared-change parsimony. We found clear evidence for the relevance of dental phenotypes to accurately discriminate all modern members of the genus Equus and capture their phylogenetic relationships. These results are valuable for both palaeontologists and zooarchaeologists exploring the spatial and temporal dynamics of the evolutionary history of the horse family, up to the latest domestication trajectories of horses and donkeys.

Pigs have played a major role in the economic, social and symbolic systems of China since the Early Neolithic more than 8,000 years ago. However, the interaction between the history of pig domestication and transformations in Chinese society since then, have not been fully explored. In this paper, we investigated the co-evolution from the earliest farming communities through to the new political and economic models of state-like societies, up to the Chinese Empire, using 5,000 years of archaeological records from the Xiawanggang (XWG) and Xinzhai (XZ) sites (Henan Province). To trace the changes of pig populations against husbandry practices, we combined the geometric morphometric analysis of dental traits with a study of the stable carbon and nitrogen isotope ratios from bone collagen. The domestication process intensified during the Neolithic Yangshao, prompted by greater selective pressure and/or better herd control against wild introgression. After that, pig farming, in XWG, relied on local livestock and a gradual change of husbandry practices overtime. This was characterized by a gentle increase in millet foddering and animal protein intake, until a complete change over to household management during the Han dynasty. The only rupture in this steady trend of husbandry occurred during the Longshan period, with the appearance of small sized and idiosyncratic pigs with specific feeding practices (relying on millet and household scraps). From three exploratory hypothesis, we explored the possibility of anti-elite pig production in XWG during the Longshan period, as a means to resist incorporation into a new economic model promoting intensified domestic production. This exploratory hypothesis is the most suitable to our dataset; however, numerous areas need to be explored further in order to adequately document the role of pigs in the rise of China's complex societies.

The ancestor of all modern domestic cats is the wildcat, Felis silvestris lybica, with archaeological evidence indicating it was domesticated as early as 10,000 years ago in South-West Asia. A recent study, however, claims that cat domestication also occurred in China some 5,000 years ago and involved the same wildcat ancestor (F. silvestris). The application of geometric morphometric analyses to ancient small felid bones from China dating between 5,500 to 4,900 BP, instead reveal these and other remains to be that of the leopard cat (Prionailurus bengalensis). These data clearly indicate that the origins of a human-cat 'domestic' relationship in Neolithic China began independently from South-West Asia and involved a different wild felid species altogether. The leopard cat's 'domestic' status, however, appears to have been short-lived--its apparent subsequent replacement shown by the fact that today all domestic cats in China are genetically related to F. silvestris.

Cancer patients are frequently admitted to hospital due to acute conditions or refractory symptoms. This occurs through the emergency departments and requires medical oncologists to take an active role. The use of acute-care hospital increases in the last months of life.We aimed to describe the admissions to a medical oncology inpatient service within a 16-month period with respect to patients and tumor characteristics, and the outcome of the hospital stay.672 admissions of 454 patients were analysed. The majority of admissions were urgent (74.1%), and were due to uncontrolled symptoms (79.6%). Among the chief complaints, dyspnoea occurred in 15.7%, pain in 15.2%, and neurological symptoms in 14.5%. The majority of the hospitalizations resulted in discharge to home (60.6%); in 26.5% the patient died and in 11.0% was transferred to a hospice. Admissions due to symptoms correlated with a longer hospital stay and a higher incidence of in-hospital death.We suggest that hospital use is not necessarily a sign of inappropriately aggressive care: inpatient care is probably an unavoidable step in the cancer trajectory. Optimization of inpatient supportive procedures should be a specific task of modern medical oncology.

Bradykinin (BK) induces angiogenesis by promoting vessel permeability, growth and remodeling. This study aimed to demonstrate that the B2R antagonist, fasitibant, inhibits the BK pro-angiogenic effects.We assesed the ability of fasibitant to antagonize the BK stimulation of cultured human cells (HUVEC) and circulating pro-angiogenic cells (PACs), in producing cell permeability (paracellular flux), migration and pseocapillary formation. The latter parameter was studied in vitro (matrigel assay) and in vivo in mice (matrigel plug) and in rat model of experimental osteoarthritis (OA). We also evaluated NF-κB activation in cultured cells by measuring its nuclear translocation and its downstream effectors such as the proangiogenic ciclooxygenase-2 (COX-2), prostaglandin E-2 and vascular endothelial growth factor (VEGF).HUVEC, exposed to BK (1-10 µM), showed increased permeability, disassembly of adherens and tight-junction, increased cell migration, and pseudocapillaries formation. We observed a significant increase of vessel density in the matrigel assay in mice and in rats OA model. Importantly, B2R stimulation elicited, both in HUVEC and PACs, NF-κB activation, leading to COX-2 overexpression, enhanced prostaglandin E-2 production. and VEGF output. The BK/NF-κB axis, and the ensuing amplification of inflammatory/angiogenic responses were fully prevented by fasitibant as well as by IKK VII, an NF-κB. Inhibitor.This work illustrates the role of the endothelium in the inflammation provoked by the BK/NF-κB axis. It also demonstates that B2R blockade by the antaogonist fasibitant, abolishes both the initial stimulus and its amplification, strongly attenuating the propagation of inflammation.

Modern rapidly expanding cities generate intricate patterns of species diversity owing to immense complexity in urban spatial structure and current growth trajectories. We propose to identify and uncouple the drivers that give rise to these patterns by looking at the effect of urbanism on species diversity over a previously unexplored long temporal frame that covers early developments in urbanism. To provide this historical perspective we analyzed archaeozoological remains of small mammals from ancient urban and rural sites in the Near East from the 2nd to the 1st millennium BCE, and compared them to observations from modern urban areas. Our data show that ancient urban assemblages consistently comprised two main taxa (Mus musculus domesticus and Crocidura sp.), whereas assemblages of contemporaneous rural sites were significantly richer. Low species diversity also characterizes high-density core areas of modern cities, suggesting that similar ecological drivers have continued to operate in urban areas despite the vast growth in their size and population densities, as well as in the complexity of their technologies and social organization. Research in urban ecology has tended to emphasize the relatively high species diversity observed in low-density areas located on the outskirts of cities, where open and vegetated patches are abundant. The fact that over several millennia urban evolution did not significantly alter species diversity suggests that low diversity is an attribute of densely-populated settlements. The possibility that high diversity in peripheral urban areas arose only recently as a short-term phenomenon in urban ecology merits further research based on long-term data.

The goat (Capra hircus) is one of the earliest domesticated species ca. 10,500 years ago in the Middle-East where its wild ancestor, the bezoar (Capra aegagrus), still occurs. During the Neolithic dispersal, the domestic goat was then introduced in Europe, including the main Mediterranean islands. Islands are interesting models as they maintain traces of ancient colonization, historical exchanges or of peculiar systems of husbandry. Here, we compare the mitochondrial genetic diversity of both medieval and extant goats in the Island of Corsica that presents an original and ancient model of breeding with free-ranging animals. We amplified a fragment of the Control Region for 21 medieval and 28 current goats. Most of them belonged to the A haplogroup, the most worldwide spread and frequent today, but the C haplogroup is also detected at low frequency in the current population. Present Corsican goats appeared more similar to medieval goats than to other European goat populations. Moreover, 16 out of the 26 haplotypes observed were endemic to Corsica and the inferred demographic history suggests that the population has remained constant since the Middle Ages. Implications of these results on management and conservation of endangered Corsican goats currently decimated by a disease are addressed.