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The extraordinary preservation of Cueva de Los Murciélagos (Albuñol, Spain) provides a unique opportunity to identify the materials and the techniques involved in archery during the Early Neolithic period. Arrows with preserved feathers, tied fibres, adhesive substance, and two probable bowstrings have been studied trough an unprecedented multi-proxy investigation, including microscopy and biomolecular methods, to unravel archery techniques. The study has identified the oldest known sinew bowstrings, the first evidence for the use of olive tree (Olea europaea) and reed (Phragmites sp.) to produce arrow shafts in prehistoric European archery, and the identification of birch bark tar as a coating on the shafts. The results of this study provide insights into ancient craft, technological solutions, and adaptations to local resources in the production of these reed-shafted hardwood tipped arrows and bowstrings. Their deposition in a burial cave sheds new light on the role of these artefacts in a Neolithic farming community., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Laser-Plasma ion acceleration is acquiring importance on a daily basis due to incipient applicability in certain research fields. However, the energy and divergence control of these brilliant sources can be considered a bottleneck in the development of some applications. In this work, we present the commissioning of a compact proton beamline based on a triplet of quadrupoles dedicated to focus and collect short and energetic pulses, open to the user community. The focused proton beam characterization has been carried out by imaging of scintillation detectors with different particle filters. Experimental results have been compared with numerical simulations performed with Monte Carlo code (MCNP6) and TSTEP that have been used to retrieve the deposited energy, the particle tracking, and the particle distribution in different focal configurations, respectively. Charges of nC (∼ [Formula: see text] protons with energies up to 17.25 MeV) have been measured at the focal planes reducing the beam to spot sizes of a few millimetres in RMS (root mean square). The percentage fluctuation of the transported charges values has been studied. Finally, the beam rigidity has been measured by transverse moving of the quadrupoles and subsequent beam centroid shift, allowing to cross correlate the deflected energy with the energy ranges resulting from the filtering process., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Gold nanoparticles (AuNPs) are potentially applicable in drug/nucleic acid delivery systems. Low toxicity, high stability, and bioavailability are crucial for the therapeutic use of AuNPs and they are mainly determined by their interactions with proteins and lipids on their route to the target cells. In this work, we investigated the interaction of two pegylated gold nanoparticles, AuNP14a and AuNP14b, with human serum proteins albumin (HSA) and transferrin (Tf) as well as dimyristoyl-phosphatidylcholine (DMPC) liposomes, which can be a representative of biomembranes. We showed that AuNP14a/b interacted with HSA and Tf changing their electrical, thermodynamic, and structural properties as evidenced by dynamic light scattering, zeta potential, transmission electron microscopy, circular dichroism, fluorescence quenching, and isothermal titration calorimetry. These nanoparticles penetrated the DMPC membrane suggesting their ability to reach a target inside the cell. In most of the effects, AuNP14b was more effective than AuNP14a, which might result from its more positive charge. Further studies are needed to evaluate whether the interaction of AuNP14a/b with HSA and Tf is safe for the cell/organism and whether they may safely penetrate natural membranes., (© 2024. The Author(s).)

The incorporation of digital pathology in clinical practice will require the training of pathologists in digital skills. Our study aimed to assess the reliability among pathologists in determining tumor percentage in whole slide images (WSI) of non-small cell lung cancer (NSCLC) using digital image analysis, and study how the results correlate with the molecular findings. Pathologists from nine centers were trained to quantify epithelial tumor cells, tumor-associated stromal cells, and non-neoplastic cells from NSCLC WSI using QuPath. Then, we conducted two consecutive ring trials. In the first trial, analyzing four WSI, reliability between pathologists in the assessment of tumor cell percentage was poor (intraclass correlation coefficient (ICC) 0.09). After performing the first ring trial pathologists received feedback. The second trial, comprising 10 WSI with paired next-generation sequencing results, also showed poor reliability (ICC 0.24). Cases near the recommended 20% visual threshold for molecular techniques exhibited higher values with digital analysis. In the second ring trial reliability slightly improved and human errors were reduced from 5.6% to 1.25%. Most discrepancies arose from subjective tasks, such as the annotation process, suggesting potential improvement with future artificial intelligence solutions., (© 2024. The Author(s).)

The extended period of coexistence between Neanderthals and Homo sapiens in Europe coincided with the emergence of regionally distinctive lithic industries, signalling the onset of the Upper Palaeolithic. The Iberian Peninsula was on the periphery of pioneering Upper Palaeolithic developments, with archaeological remains primarily found in northern territories. We report the discovery of an initial Upper Palaeolithic lithic industry at Cueva Millán in the hinterlands of Iberia. This industry, termed here Arlanzian, not only represents the earliest and southernmost evidence of such industries in Iberia but also lacks a direct counterpart. However, it exhibits chronological and technological parallels with the lithic industries associated with the earliest expansion of Homo sapiens throughout Eurasia. We interpret this as potential evidence of its intrusive nature, but not necessarily associated with a migration event, as more complex scenarios derived from inter-population connectivity must be also considered. The biological identity of the Arlanzian makers remains unknown, but they coexisted with declining Neanderthal groups from neighbouring territories., (© 2024. The Author(s).)

Protein kinase C is a family of kinases that play important roles in carcinogenesis. Medicinal plants from Plectranthus spp. (Lamiaceae) are a well-known source of interesting abietanes, such as 7α-acetoxy-6β-hydroxyroyleanone (Roy). This study aimed to extract and isolate Roy from P. grandidentatus Gürke, comparing two extraction methods (CO 2 supercritical and ultrasound-assisted acetonic extraction), and design new royleanone derivatives for PKC modulation focusing on breast cancer therapy. The concentration of Roy in the extracts was determined by HPLC-DAD. The supercritical extraction method yielded 3.6% w/w, with the presence of 42.7 μg mg -1 of Roy (yield of 0.13%), while ultrasound-assisted acetonic extraction yielded 2.3% w/w, with the presence of 55.2 μg mg -1 of Roy (yield of 0.15%). The reactivity of Roy was investigated aiming at synthetizing new ester derivatives through standard benzoylation and esterification reactions. The benzoylated (Roy-12-Bz) and acetylated (Roy-12-Ac) derivatives in the C12 position were consistently prepared with overall good yields (33-86%). These results indicate the 12-OH position as the most reactive for esterification, affording derivatives under mild conditions. The reported di-benzoylated (RoyBz) and di-acetylated (RoyAc) derivatives were also synthesized after increasing the temperature (50 °C), reaction time, and using an excess of reagents. The cytotoxic potential of Roy and its derivatives was assessed against breast cancer cell lines, with RoyBz emerging as the most promising compound. Derivatization at position C-12 did not offer advantages over di-esterification at positions C-12 and C-6 or over the parent compound Roy and the presence of aromatic groups favored cytotoxicity. Evaluation of royleanones as PKC-α, βI, δ, ε, and ζ activators revealed DeRoy's efficacy across all isoforms, while RoyPr showed promising activation of PKC-δ but not PKC-ζ, highlighting the influence of slight structural changes on isoform selectivity. Molecular docking analysis emphasized the importance of microenvironmental factors in isoform specificity, underscoring the complexity of PKC modulation and the need for further exploration., (© 2024. The Author(s).)

Multiple-choice test generation is one of the most complex NLP problems, especially in languages other than English, where there is a lack of prior research. After a review of the literature, it has been verified that some methods like the usage of rule-based systems or primitive neural networks have led to the application of a recent architecture, the Transformer architecture, in the tasks of Answer Extraction (AE) and Question Generation (QG). Thereby, this study is centred in searching and developing better models for the AE and QG tasks in Spanish, using an answer-aware methodology. For this purpose, three multilingual models (mT5-base, mT0-base and BLOOMZ-560 M) have been fine-tuned using three different datasets: a translation to Spanish of the SQuAD dataset; SQAC, which is a dataset in Spanish; and their union (SQuAD + SQAC), which shows slightly better results. Regarding the models, the performance of mT5-base has been compared with that found in two newer models, mT0-base and BLOOMZ-560 M. These models were fine-tuned for multiple tasks in literature, including AE and QG, but, in general, the best results are obtained from the mT5 models trained in our study with the SQuAD + SQAC dataset. Nonetheless, some other good results are obtained from mT5 models trained only with the SQAC dataset. For their evaluation, the widely used BLEU1-4, METEOR and ROUGE-L metrics have been obtained, where mT5 outperforms some similar research works. Besides, CIDEr, SARI, GLEU, WER and the cosine similarity metrics have been calculated to present a benchmark within the AE and QG problems for future work., (© 2024. The Author(s).)

This investigation explored the presence of microplastics (MPs) and artificial cellulosic particles (ACPs) in commercial water marketed in single use 1.5 L poly(ethylene terephthalate) bottles. In this work we determined a mass concentration of 1.61 (1.10-2.88) µg/L and 1.04 (0.43-1.82) µg/L for MPs and ACPs respectively in five top-selling brands from the Spanish bottled water market. Most MPs consisted of white and transparent polyester and polyethylene particles, while most ACPs were cellulosic fibers likely originating from textiles. The median size of MPs and ACPs was 93 µm (interquartile range 76-130 µm) and 77 µm (interquartile range 60-96 µm), respectively. Particle mass size distributions were fitted to a logistic function, enabling comparisons with other studies. The estimated daily intake of MPs due to the consumption of bottled water falls within the 4-18 ng kg -1  day -1 range, meaning that exposure to plastics through bottled water probably represents a negligible risk to human health. However, it's worth noting that the concentration of plastic found was much higher than that recorded for tap water, which supports the argument in favour of municipal drinking water., (© 2024. The Author(s).)

Cutaneous and Head and Neck squamous cell carcinoma (CSCC, HNSCC) are among the most prevalent cancers. Both types of cancer can be treated with photodynamic therapy (PDT) by using the photosensitizer Temoporfin in HNSCC and the prodrug methyl-aminolevulinate (MAL) in CSCC. However, PDT is not always effective. Therefore, it is mandatory to correctly approach the therapy according to the characteristics of the tumour cells. For this reason, we have used cell lines of CSCC (A431 and SCC13) and HNSCC (HN5 and SCC9). The results obtained indicated that the better response to MAL-PDT was related to its localization in the plasma membrane (A431 and HN5 cells). However, with Temoporfin all cell lines showed lysosome localization, even the most sensitive ones (HN5). The expression of mesenchymal markers and migratory capacity was greater in HNSCC lines compared to CSCC, but no correlation with PDT response was observed. The translocation to the nucleus of β-catenin and GSK3β and the activation of NF-κβ is related to the poor response to PDT in the HNSCC lines. Therefore, we propose that intracellular localization of GSK3β could be a good marker of response to PDT in HNSCC. Although the molecular mechanism of response to PDT needs further elucidation, this work shows that the most MAL-resistant line of CSCC is more sensitive to Temoporfin., (© 2024. The Author(s).)

The use of dendrimers as drug and nucleic acid delivery systems requires knowledge of their interactions with objects on their way to the target. In the present work, we investigated the interaction of a new class of carbosilane dendrimers functionalized with polyphenolic and caffeic acid residues with human serum albumin, which is the most abundant blood protein. The addition of dendrimers to albumin solution decreased the zeta potential of albumin/dendrimer complexes as compared to free albumin, increased density of the fibrillary form of albumin, shifted fluorescence spectrum towards longer wavelengths, induced quenching of tryptophan fluorescence, and decreased ellipticity of circular dichroism resulting from a reduction in the albumin α-helix for random coil structural form. Isothermal titration calorimetry showed that, on average, one molecule of albumin was bound by 6-10 molecules of dendrimers. The zeta size confirmed the binding of the dendrimers to albumin. The interaction of dendrimers and albumin depended on the number of caffeic acid residues and polyethylene glycol modifications in the dendrimer structure. In conclusion, carbosilane polyphenolic dendrimers interact with human albumin changing its structure and electrical properties. However, the consequences of such interaction for the efficacy and side effects of these dendrimers as drug/nucleic acid delivery system requires further research., (© 2024. The Author(s).)

Huntington's disease (HD) is caused by an aberrant expansion of CAG repeats in the HTT gene that mainly affects basal ganglia. Although striatal dysfunction has been widely studied in HD mouse models, other brain areas can also be relevant to the pathology. In this sense, we have special interest on the retina as this is the most exposed part of the central nervous system that enable health monitoring of patients using noninvasive techniques. To establish the retina as an appropriate tissue for HD studies, we need to correlate the retinal alterations with those in the inner brain, i.e., striatum. We confirmed the malfunction of the transgenic R6/1 retinas, which underwent a rearrangement of their transcriptome as extensive as in the striatum. Although tissue-enriched genes were downregulated in both areas, a neuroinflammation signature was only clearly induced in the R6/1 retina in which the observed glial activation was reminiscent of the situation in HD patient's brains. The retinal neuroinflammation was confirmed in the slow progressive knock-in zQ175 strain. Overall, these results demonstrated the suitability of the mouse retina as a research model for HD and its associated glial activation., (© 2024. The Author(s).)

We explored whether isotope ratio mass spectrometry (IRMS) is useful to investigate the origin of falsified antimalarials. Forty-four falsified and genuine antimalarial samples (artesunate, artemether-lumefantrine, dihydroartemisinin-piperaquine and sulphamethopyrazine-pyrimethamine) were analyzed in bulk for carbon (C), nitrogen (N), and oxygen (O) element concentrations and stable isotope ratios. The insoluble fraction ("starch") was extracted from 26 samples and analyzed. Samples of known geographical origin maize, a common source of excipient starch, were used to produce a comparison dataset to predict starch source. In both an initial (n = 18) and a follow-on set of samples that contained/claimed to contain artesunate/artemether (n = 26), falsified antimalarials had a range of C concentrations less than genuine comparator antimalarials and δ 13 C values higher than genuine comparators. The δ 13 C values of falsified antimalarials suggested that C 4 plant-based organic material (e.g., starch derived from maize) had been included. Using the known-origin maize samples, predictions for growth water δ 18 O values for the extracted "starch" ranged from - 6.10 to - 1.62‰. These findings suggest that IRMS may be a useful tool for profiling falsified antimalarials. We found that C 4 ingredients were exclusively used in falsified antimalarials versus genuine antimalarials, and that it may be possible to predict potential growth water δ 18 O values for the starch present in falsified antimalarials., (© 2024. The Author(s).)

X-ray sources have a strong social impact, being implemented for biomedical research, material and environmental sciences. Nowadays, compact and accessible sources are made using lasers. We report evidence of nontrivial spectral-angular correlations in a laser-driven betatron X-ray source. Furthermore, by angularly-resolved spectral measurements, we detect the signature of spatial phase modulations by the electron trajectories. This allows the lateral coherence function to be retrieved, leading to the evaluation of the coherence area of the source, determining its brightness. Finally, the proposed methodology allows the unprecedented reconstruction of the size of the X-ray source and the electron beam emittance in the two main emission planes in a single shot. This information will be of fundamental interest for user applications of new radiation sources., (© 2024. The Author(s).)

The on-ground operation of Mars rovers is a complex task that requires comprehensive planning in which path planning plays a fundamental role. The selection of paths has to be carefully chosen considering the scientific objectives, terrain, energy, and safety. In this regard, operators are assisted by path-planning algorithms that generate candidate paths based on cost functions. Distance traveled has always been considered one of the primary criteria when comparing paths. Other metrics such as the run-time to generate the solution or the number of expanded nodes are common measures considered in the literature. However, we want to analyze if those metrics provide useful information in challenging and partially known terrain. In this paper, we will review those metrics using two-path planning algorithms on real Mars maps. Based on our experience operating Mars rovers, we propose new metrics for assessing paths in real-world applications., (© 2023. The Author(s).)

The mechanisms driving SARS-CoV-2 susceptibility remain poorly understood, especially the factors determining why unvaccinated individuals remain uninfected despite high-risk exposures. To understand lipid and metabolite profiles related with COVID-19 susceptibility and disease progression. We collected samples from an exceptional group of unvaccinated healthcare workers heavily exposed to SARS-CoV-2 but not infected ('non-susceptible') and subjects who became infected during the follow-up ('susceptible'), including non-hospitalized and hospitalized patients with different disease severity providing samples at early disease stages. Then, we analyzed their plasma metabolomic profiles using mass spectrometry coupled with liquid and gas chromatography. We show specific lipids profiles and metabolites that could explain SARS-CoV-2 susceptibility and COVID-19 severity. More importantly, non-susceptible individuals show a unique lipidomic pattern characterized by the upregulation of most lipids, especially ceramides and sphingomyelin, which could be interpreted as markers of low susceptibility to SARS-CoV-2 infection. This study strengthens the findings of other researchers about the importance of studying lipid profiles as relevant markers of SARS-CoV-2 pathogenesis., (© 2023. Springer Nature Limited.)

Colonization of new habitat patches is a key aspect of metacommunity dynamics, particularly for sessile organisms. Mosses can establish in new patches through fragmentation, with different vegetative structures acting as propagules. Despite the importance of these propagules for successful colonization the specific aspects that favour moss colonization by vegetative propagules remain poorly understood, including the effect of propagule size. We examine the intra- and interspecific variation of establishment and colonization success in culture of propagules of different sizes in six widespread soil moss species of contrasting growth form (Dicranum scoparium, Homalothecium aureum, Hypnum cupressiforme, Ptychostomum capillare, Syntrichia ruralis and Tortella squarrosa). We obtained three different size classes of propagules from artificially fragmented vegetative material, and assessed their establishment under controlled light and temperature conditions. We characterize the size, shape, apparent viability, morphological type and size changes due to hydration states of the propagules, all of them traits with potentially significant influence in their dispersal pattern and establishment. Then we assess the effect of these traits on moss establishment, using indicators of surface establishment (number of established shoots and colonized surface) and biomass production (viable biomass) as proxies of colonization success. The establishment indicators related to colonization surface and biomass production differ among species and propagule sizes. The magnitude of the interspecific differences of all indicators of establishment success was larger at the smaller propagule size class. T. squarrosa was the most successful species, and D. scoparium showed the lowest performance. We also found interspecific differences in the hydration dynamics of the propagules. The process of establishment by vegetative fragments operates differently among moss species. Besides, differences between hydration states in propagules of some species could be part of syndromes for both dispersal and establishment. This study unveils several functional traits relevant for moss colonization, such as wet versus dry area and length of fragments, which may improve our understanding of their spatial dynamics., (© 2022. The Author(s).)

The mediating and moderating associations of cardiorespiratory fitness (CRF) and handgrip strength on the association between dietary patterns and several health outcomes have been previously studied. For instance, handgrip strength has been found as a moderator of the relationship between excess weight and cardiometabolic risk factors in young adults. Similarly, CRF has been shown as a mediator of the association between diet and obesity in children. However, to our knowledge, the role of CRF and handgrip strength on the association between sugar-sweetened beverage (SSB) consumption and adiposity is still unclear. The aim of this study was to determine whether CRF and handgrip strength moderate the association between SSB consumption and adiposity in a population-based sample of Spanish schoolchildren. This cross-sectional study involved 475 schoolchildren (52.0% girls), aged 8-12, from ten schools in Cuenca (Spain). Adiposity was determined as body fat (in kg), which was measured using a bioimpedance analysis system. Data on SSB consumption were gathered by using the Children's Eating Habits Questionnaire, which was completed by parents. The CRF level was determined by the 20-m Shuttle Run test and Nevill's curvilinear allometric model. Handgrip strength was determined using a digital dynamometer with adjustable grip. For each unit (in ml/kg/min) of CRF increased, the association between SSB consumption and adiposity was moderated (B = - 0.09, CI 95% - 0.14 to - 0.04). This significant moderation was also found for each 0.01 unit of increased normalized handgrip strength (B = - 0.07; CI 95% - 0.11 to - 0.02). Similarly, the Johnson-Neymann technique established three different regions. The first region shows that the association of SSB consumption on adiposity in participants who had levels of CRF < 43.4 ml/kg/min or handgrip strength < 0.34 was greater and statistically significant. The second region (43.4-57.4 ml/kg/min for CRF; 0.34-0.58 for normalized handgrip strength) depicted that the association between SSB consumption and adiposity was not statistically significant in those with a CRF level or normalized handgrip strength between the lower and upper thresholds. The third region was found at > 57.4 ml/kg/min (for CRF level) and > 0.58 (for normalized handgrip strength), indicating that the association between SSB consumption and adiposity was lower and statistically significant in children above these moderator values. Our results showed that certain levels of CRF and normalized handgrip strength moderate the association between SSB consumption and adiposity in a sample of Spanish schoolchildren. It might be possible that higher physical fitness level in childhood may contribute to reducing the association between SSB consumption and adiposity., (© 2022. The Author(s).)

Different phenotypes exhibiting no evidences of disease progression have been described in ART-naïve HIV-1 positive individuals. Long-term non progressors (LTNP) and elite controllers (EC) are low frequent examples of immunological and virological control in HIV-1 positive subjects, respectively. The combination of both phenotypes is even less frequent and studied despite being considered as models of HIV-1 functional cure. A multicenter, prospective study in retrospect including clinical and epidemiological data collected from 313 LTNP of 21 Spanish hospitals was carried out. LTNPs maintaining CD4+ T cell counts over 500 cells/µl and viral loads (VL) under 10,000 copies/mL for at least 10 years in the absence of antiretroviral therapy were followed for a median of 20.8 years (IQR = 15.6-25.5). A 52.1% were considered EC (undetectable VL) and LTNP (EC-LTNP) and a total of 171 (54.8%) and 42 (13.5%) out of the 313 participants maintained LTNP status for at least 20 and 30 years, respectively. EC-LTNP showed lower CD4+ T cell count loss (9.9 vs 24.2 cells/µl/year), higher CD4/CD8 ratio (0.01 vs - 0.09 in ratio), and lesser VL increase (no increase vs 197.2 copies/mL/year) compared with LTNPs with detectable VL (vLTNP). Survival probabilities for all-cause mortality at 30 years from HIV + diagnosis were 0.90 for EC-LTNP and 0.70 for vLTNP (p = 2.0 × 10 -3 ), and EC-LTNP phenotype was the only factor associated with better survival in multivariate analyses (HR = 0.28; 95% CI 0.10-0.79). The probability to preserve LTNP status at 30 years was 0.51 for EC-LTNP and 0.18 for vLTNP (p < 2.2 × 10 -16 ). Risk factors associated to the loss of LTNP status was: higher age at diagnosis and the increase of VL, whereas the increase of CD4+ T cell counts and CD4/CD8 ratio, the initial EC-LTNP phenotype and HCV coinfection were protective factors. EC-LTNP phenotype was associated with improved survival and slower disease progression compared with other phenotypes of LTNP. EC-LTNP individuals represent one of the most favorable phenotypes of immune activation against HIV-1 found in nature and, therefore, are strong candidates to be considered a model of functional cure of HIV-1 infection., (© 2022. The Author(s).)

The purpose of our study was to develop a predictive model to rule out pheochromocytoma among adrenal tumours, based on unenhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) features. We performed a retrospective multicentre study of 1131 patients presenting with adrenal lesions including 163 subjects with histological confirmation of pheochromocytoma (PHEO), and 968 patients showing no clinical suspicion of pheochromocytoma in whom plasma and/or urinary metanephrines and/or catecholamines were within reference ranges (non-PHEO). We found that tumour size was significantly larger in PHEO than non-PHEO lesions (44.3 ± 33.2 versus 20.6 ± 9.2 mm respectively; P < 0.001). Mean unenhanced CT attenuation was higher in PHEO (52.4 ± 43.1 versus 4.7 ± 17.9HU; P < 0.001). High lipid content in CT was more frequent among non-PHEO (83.6% versus 3.8% respectively; P < 0.001); and this feature alone had 83.6% sensitivity and 96.2% specificity to rule out pheochromocytoma with an area under the receiver operating characteristics curve (AUC-ROC) of 0.899. The combination of high lipid content and tumour size improved the diagnostic accuracy (AUC-ROC 0.961, sensitivity 88.1% and specificity 92.3%). The probability of having a pheochromocytoma was 0.1% for adrenal lesions smaller than 20 mm showing high lipid content in CT. Ninety percent of non-PHEO presented loss of signal in the "out of phase" MRI sequence compared to 39.0% of PHEO (P < 0.001), but the specificity of this feature for the diagnosis of non-PHEO lesions low. In conclusion, our study suggests that sparing biochemical screening for pheochromocytoma might be reasonable in patients with adrenal lesions smaller than 20 mm showing high lipid content in the CT scan, if there are no typical signs and symptoms of pheochromocytoma., (© 2022. The Author(s).)

Although there is growing interest in safeguarding the Tree of Life to preserve the human benefits that are directly provided by biodiversity, their evolutionary distribution remains unknown, which has hampered our understanding of the potential of phylodiversity indicators to evince them. Here, I drew on a global review of plant benefits and comprehensive phylogenetic information to breakdown their evolutionary distribution and thereby show why the commonly used Phylogenetic Diversity and Evolutionary Distinctiveness indicators can unequivocally help to preserve these natural services. Beneficial species clumped within phylogenetically overdispersed genera and closely related species often contributed very few and redundant benefits, suggesting that multiple plant lineages are required to maintain a wide variety of services. Yet, a reduced number of species stood out as multi-beneficial and evolutionarily distinct plants relative to both the entire phylogeny and the subset of beneficial species, and they collectively contributed a higher-than-expected number of records for most types of benefits. In addition to providing a clear mechanistic understanding for the recently proved success of Phylogenetic Diversity in capturing plant benefits, these findings stress the decisive role that conservation programmes aimed at protecting evolutionarily distinct taxa will play in safeguarding the beneficial potential of biodiversity for the future., (© 2021. The Author(s).)

During the latest Cretaceous, the European Archipelago was characterized by highly fragmented landmasses hosting putative dwarfed, insular dinosaurs, claimed as fossil evidence of the "island rule". The Villaggio del Pescatore quarry (north-eastern Italy) stands as the most informative locality within the palaeo-Mediterranean region and represents the first, multi-individual Konservat-Lagerstätte type dinosaur-bearing locality in Italy. The site is here critically re-evaluated as early Campanian in age, thus preceding the final fragmentation stages of the European Archipelago, including all other European localities preserving hypothesized dwarfed taxa. New skeletal remains allowed osteohistological analyses on the hadrosauroid Tethyshadros insularis indicating subadult features in the type specimen whereas a second, herein newly described, larger individual is likely somatically mature. A phylogenetic comparative framework places the body-size of T. insularis in range with other non-hadrosaurid Eurasian hadrosauroids, rejecting any significant evolutionary trend towards miniaturisation in this clade, confuting its 'pygmy' status, and providing unmatched data to infer environmentally-driven body-size trends in Mesozoic dinosaurs., (© 2021. The Author(s).)

To evaluate the diagnostic accuracy of the different tests commonly used in the evaluation of adrenal incidentalomas (AIs) for the identification of autonomous cortisol secretion (ACS) and comorbidities potentially related to ACS. In a retrospective study of patients with AIs ≥ 1 cm, we evaluated the diagnostic reliability and validity of the dexamethasone suppression test (DST), urinary free cortisol (UFC), ACTH, late-night salivary cortisol (LNSC), and dehydroepiandrosterone-sulphate (DHEAS) for the diagnosis of comorbidities potentially related to ACS. Diagnostic indexes were also calculated for UFC, ACTH, LNSC, and DHEAS considering DST as the gold standard test for the diagnosis of ACS, using three different post-DST cortisol thresholds (138 nmol/L, 50 nmol/L and 83 nmol/L). We included 197 patients with AIs in whom the results of the five tests abovementioned were available. At diagnosis, 85.9% of patients with one or more AIs had any comorbidity potentially related to ACS, whereas 9.6% had ACS as defined by post-DST cortisol > 138 nmol/L. The reliability of UFC, ACTH, LNSC, and DHEAS for the diagnosis of ACS was low (kappa index < 0.30). Of them, LNSC reached the highest diagnosis accuracy for ACS identification (AUC = 0.696 [95% CI 0.626-0.759]). The diagnostic performances of these tests for comorbidities potentially related to ACS was poor; of them, the DST was the most accurate (AUC = 0.661 [95% CI 0.546-0.778]) and had the strongest association with these comorbidities (OR 2.6, P = 0.045). Patients presenting with increased values of both DST and LNSC had the strongest association with hypertension (OR 7.1, P = 0.002) and with cardiovascular events (OR 3.6, P = 0.041). In conclusion, LNSC was the test showing the highest diagnosis accuracy for the identification of ACS when a positive DST was used as the gold standard for its diagnosis. The DST test showed the strongest association with comorbidities potentially related to ACS. The definition of ACS based on the combination of elevated DST and LNSC levels improved the identification of patients with increased cardiometabolic risk., (© 2021. The Author(s).)

The present work reports an efficient way of capturing real-time crack propagation in concrete structures. The modified spectral analysis based algorithm and finite element modeling (FEM) were utilised for crack detection and quantitative analysis of crack propagation. Crack propagation was captured in cement-based composite (CBC) containing saw dust and M20 grade concrete under compressive loading using a simple and inexpensive 8-megapixel mobile phone camera. The randomly selected images showing crack initiation and propagation in CBCs demonstrated the crack capturing capability of developed algorithm. A measure of oriented energy was provided at crack edges to develop a similarity spatial relationship among the pairwise pixels. FE modelling was used for distress anticipation, by analysing stresses during the compressive test in constituents of CBCs. FE modeling jointly with the developed algorithm, can provide real-time inputs from the crack-prone areas and useful in early crack detection of concrete structures for preventive support and management., (© 2021. The Author(s).)

We determined sex differences in the prevalence of obstructive sleep apnea (OSA) among patients hospitalized with pulmonary embolism (PE) in Spain (2016-2018). We also compared outcomes according to the presence of OSA, and identified variables associated with in-hospital-mortality (IHM) after PE using the Spanish National Hospital Discharge Database. We identified 46,794 hospital admissions for PE; of these, 5.47% had OSA. OSA was more prevalent among men than women (7.57% vs. 3.65%, p < 0.001), as in the general population. Propensity score matching did not reveal differences in concomitant conditions or procedures between patients with and without OSA, except for the use of non-invasive ventilation, which was more frequent in patients with OSA. IHM was similar in patients with and without OSA (3.58% vs. 4.31% for men and 4.39% vs. 4.93% for women; p > 0.05). Older age, cancer, atrial fibrillation, non-septic shock, and need for mechanical ventilation increased IHM in men and women with OSA hospitalized with PE. The logistic regression model showed no sex differences in IHM among patients with OSA., (© 2021. The Author(s).)

Pines are the dominant conifers in Mediterranean forests. As long-lived sessile organisms that seasonally have to cope with drought periods, they have developed a variety of adaptive responses. However, during last decades, highly intense and long-lasting drought events could have contributed to decay and mortality of the most susceptible trees. Among conifer species, Pinus pinaster Ait. shows remarkable ability to adapt to different environments. Previous molecular analysis of a full-sib family designed to study drought response led us to find active transcriptional activity of stress-responding genes even without water deprivation in tolerant genotypes. To improve our knowledge about communication between above- and below-ground organs of maritime pine, we have analyzed four graft-type constructions using two siblings as rootstocks and their progenitors, Gal 1056 and Oria 6, as scions. Transcriptomic profiles of needles from both scions were modified by the rootstock they were grafted on. However, the most significant differential gene expression was observed in drought-sensitive Gal 1056, while in drought-tolerant Oria 6, differential gene expression was very much lower. Furthermore, both scions grafted onto drought-tolerant rootstocks showed activation of genes involved in tolerance to abiotic stress, and is most remarkable in Oria 6 grafts where higher accumulation of transcripts involved in phytohormone action, transcriptional regulation, photosynthesis and signaling has been found. Additionally, processes, such as those related to secondary metabolism, were mainly associated with the scion genotype. This study provides pioneering information about rootstock effects on scion gene expression in conifers.

Proximal tubular cells (PTC) are particularly vulnerable to hypoxia-induced apoptosis, a relevant factor for kidney disease. We hypothesized here that PTC death under hypoxia is mediated by cyclo-oxygenase (COX-2)-dependent production of prostaglandin E 2 (PGE 2 ), which was confirmed in human proximal tubular HK-2 cells because hypoxia (1% O 2 )-induced apoptosis (i) was prevented by a COX-2 inhibitor and by antagonists of prostaglandin (EP) receptors and (ii) was associated to an increase in intracellular PGE 2 (iPGE 2 ) due to hypoxia-inducible factor-1α-dependent transcriptional up-regulation of COX-2. Apoptosis was also prevented by inhibitors of the prostaglandin uptake transporter PGT, which indicated that iPGE 2 contributes to hypoxia-induced apoptosis (on the contrary, hypoxia/reoxygenation-induced PTC death was exclusively due to extracellular PGE 2 ). Thus, iPGE 2 is a new actor in the pathogenesis of hypoxia-induced tubular injury and PGT might be a new therapeutic target for the prevention of hypoxia-dependent lesions in renal diseases.

Obstructive sleep apnea (OSA) is a recognized risk factor for the development of diabetic kidney disease (DKD). Our objectives were to compare the urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) of patients with DKD according to OSA severity, and to evaluate the contribution of sleep parameters to their renal function. In a multicenter, observational, cross-sectional study, 214 patients with DKD were recruited. After a sleep study, UACR and eGFR were measured, as well as serum creatinine, fasting glucose, glycated hemoglobin, insulin resistance, lipid profile and C-reactive protein. UACR was higher in severe OSA patients (920 ± 1053 mg/g) than in moderate (195 ± 232 mg/g, p < 0.001) or mild OSA/non-OSA subjects (119 ± 186 mg/g, p < 0.001). At the same time, eGFR showed an OSA severity-dependent reduction (48 ± 23 vs. 59 ± 21 vs. 73 ± 19 ml/min per 1.73 m 2 , respectively; p < 0.001). Apnea-hypopnea index (AHI and desaturation index (ODI) were identified as independent predictors for UACR and eGFR, respectively. Therefore, in patients with DKD under optimized treatment, severe OSA is associated with a higher UACR and a lower eGFR, reflecting an additional contribution to the impairment of their renal function, although no causality can be inferred.

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease. Although hyperglycaemia has been determined as the most important risk factor, hypoxia also plays a relevant role in the development of this disease. In this work, a comprehensive metabolomic study of the response of HK-2 cells, a human cell line derived from normal proximal tubular epithelial cells, to hyperglycemic, hypoxic diabetic-like milieu has been performed. Cells simultaneously exposed to high glucose (25 mM) and hypoxia (1% O 2 ) were compared to cells in control conditions (5.5 mM glucose/18.6% O 2 ) at 48 h. The combination of advanced metabolomic platforms (GC-TOF MS, HILIC- and CSH-QExactive MS/MS), freely available metabolite annotation tools, novel databases and libraries, and stringent cut-off filters allowed the annotation of 733 metabolites intracellularly and 290 compounds in the extracellular medium. Advanced bioinformatics and statistical tools demonstrated that several pathways were significantly altered, including carbohydrate and pentose phosphate pathways, as well as arginine and proline metabolism. Other affected metabolites were found in purine and lipid metabolism, the protection against the osmotic stress and the prevention of the activation of the β-oxidation pathway. Overall, the effects of the combined exposure of HK-cells to high glucose and hypoxia are reasonably compatible with previous in vivo works.

Uraemic toxins increase in serum parallel to a decline in the glomerular filtration rate and the development of sarcopenia in patients with chronic kidney disease (CKD). This study analyses the role of uraemic toxins in sarcopenia at different stages of CKD, evaluating changes in the muscular regeneration process. Cultured C 2 C 12 cells were incubated with a combination of indoxyl sulphate and p-cresol at high doses (100 µg/mL) or low doses (25 µg/mL and 10 µg/mL) resembling late or early CKD stages, respectively. Cell proliferation (analysed by scratch assays and flow cytometry) was inhibited only by high doses of uraemic toxins, which inactivated the cdc2-cyclin B complex, inhibiting mitosis and inducing apoptosis (analysed by annexin V staining). By contrast, low doses of uraemic toxins did not affect proliferation, but reduced myogenic differentiation, primed with 2% horse serum, by inhibiting myogenin expression and promoting fibro-adipogenic differentiation. Finally, to assess the in vivo relevance of these results, studies were performed in gastrocnemii from uraemic rats, which showed higher collagen expression and lower myosin heavy chain expression than those from healthy rats. In conclusion, uraemic toxins impair the skeletal muscular regeneration process, even at low concentrations, suggesting that sarcopenia can progress from the early stages of CKD.

Human immunodeficiency virus (HIV) remains incurable due to latent viral reservoirs established in non-activated CD4 T cells that cannot be eliminated via antiretroviral therapy. Current efforts to cure HIV are focused on identifying drugs that will induce viral gene expression in latently infected cells, commonly known as latency reversing agents (LRAs). Some drugs have been shown to reactivate latent HIV but do not cause a reduction in reservoir size. Therefore, finding new LRAs or new combinations or increasing the round of stimulations is needed to cure HIV. However, the effects of these drugs on viral rebound after prolonged treatment have not been evaluated. In a previous clinical trial, antiretroviral therapy intensification with maraviroc for 48 weeks caused an increase in residual viremia and episomal two LTR-DNA circles suggesting that maraviroc could reactivate latent HIV. We amended the initial clinical trial to explore additional virologic parameters in stored samples and to evaluate the time to viral rebound during analytical treatment interruption in three patients. Maraviroc induced an increase in cell-associated HIV RNA during the administration of the drug. However, there was a rapid rebound of viremia after antiretroviral therapy discontinuation. HIV-specific T cell response was slightly enhanced. These results show that maraviroc can reactivate latent HIV in vivo but further studies are required to efficiently reduce the reservoir size.

Native livestock breeds, i.e. those autochthonous to a specific region, are locally adapted domesticated animals that conserve genetic resources, guaranty food security and provide agroecosystem services. Native breeds are largely threatened worldwide by agricultural intensification and rural areas abandonment processes related to recent changes in production schemes and planning. Yet, our gap of knowledge regarding livestock breed-environment relationships may prevent the design of successful conservation measures. In this work, we analyse the links between livestock diversity -i.e. richness of native breeds- and a selection of environmental factors that express at broad scales, with a temporal perspective. We compare native breeds distributional patterns before and after the agricultural intensification, in the context of land-use change in mainland Spain. Our results confirm the existence of strong associations between the distribution of native livestock breeds and environmental factors. These links, however, weaken for contemporary distributions. In fact, changes in breed distribution reflect a shift towards more productive environments. Finally, we found that the areas having higher breed richness are undergoing land abandonment processes. Succeeding in the conservation of threatened native breeds will require going beyond merely genetic and production-oriented views. Ecological and sociocultural perspectives should also be accounted for as global change processes are determinant for livestock agrobiodiversity.

Adipose tissue secretes molecules that can promote activity in Crohn's disease. We aimed to evaluate the role of serum adipokines as possible biomarkers in Crohn's disease. Serum samples were obtained from 40 patients with endoscopically active or quiescent Crohn's disease and 36 healthy controls. Serum leptin, ghrelin, resistin and adiponectin levels were analysed by Multiplex in a Luminex 200 system technology. Receiver Operating Characteristic curves were performed to evaluate the adipokines discriminatory capacity. A logistic regression adjusted by possible confounders (i.e. gender, age, BMI) was performed for those adipokines that showed an area under the curve > 0.7. No differences were found in age, gender or BMI among groups. Distribution for serum resistin was different among the three groups of study, and only this adipokine showed an area under the curve of 0.75 comparing actives patients and healthy control groups. Resistin median concentration was selected as a cut-off for a logistic regression analysis; odds ratio along its 95% confidence interval adjusted by gender, age, and BMI yielded a value of 5.46 (1.34-22.14) comparing actives patients and healthy controls. High concentration of serum resistin is probably associated to activity, being this association independent of gender, age or BMI.

A large proportion of end-stage renal disease (ESRD) patients under long-term haemodialysis, have persistent anaemia and require high doses of recombinant human erythropoietin (rhEPO). However, the underlying mechanisms of renal anaemia have not been fully elucidated in these patients. In this study, we will be focusing on anaemia and plasma proteins in ESRD patients on high-flux haemodialysis (HF) and on-line haemodiafiltration (HDF), to investigate using two proteomic approaches if patients undergoing these treatments develop differences in their plasma protein composition and how this could be related to their anaemia. The demographic and biochemical data revealed that HDF patients had lower anaemia and much lower rhEPO requirements than HF patients. Regarding their plasma proteomes, HDF patients had increased levels of a protein highly similar to serotransferrin, trypsin-1 and immunoglobulin heavy constant chain alpha-1, and lower levels of alpha-1 antitrypsin, transthyretin, apolipoproteins E and C-III, and haptoglobin-related protein. Lower transthyretin levels in HDF patients were further confirmed by transthyretin-peptide quantification and western blot detection. Since ESRD patients have increased transthyretin, a protein that can aggregate and inhibit transferrin endocytosis and erythropoiesis, our finding that HDF patients have lower transthyretin and lower anaemia suggests that the decrease in transthyretin plasma levels would allow an increase in transferrin endocytosis, contributing to erythropoiesis. Thus, transthyretin could be a critical actor for anaemia in ESRD patients and a novel player for haemodialysis adequacy.

The West African Monsoon (WAM) system is the main source of rainfall in the agriculturally based region of the Sahel. Understanding transport across the WAM is of crucial importance due to the strong impact of humidity and dust pathways on local cloud formation. However, the description of this transport is challenging due to its 3D complex nature. Lagrangian Coherent Structures (LCS) simplify transport description across the WAM by providing a geometrical partition of the troposphere into domains. Air parcels within each domain have similar dynamical characteristics. LCS make it possible to achieve an integrated vision of transport pathways across this system. Using this approach we unveil new connections in the WAM system. In particular, we identify transport pathways between the Tropical Easterly Jet (TEJ) and the African Easterly Jet (AEJ). Furthermore, the clockwise circulation associated with the divergent upper part of the Sahara heat low is clearly delimitated. Additionally, we show the presence of mixing regions in the AEJ and the lower part of the TEJ that are linked to pathways to sources of dust and humidity.

In the Era of exponential data generation, increasing the number of paleoclimate records to improve climate field reconstructions might not always be the best strategy. By using pseudo-proxies from different model ensembles, we show how biologically-inspired artificial intelligence can be coupled with different reconstruction methods to minimize the spatial bias induced by the non-homogeneous distribution of available proxies. The results indicate that small subsets of records situated over representative locations can outperform the reconstruction skill of the full proxy network, even in more realistic pseudo-proxy experiments and observational datasets. These locations highlight the importance of high-latitude regions and major teleconnection areas to reconstruct annual global temperature fields and their responses to external forcings and internal variability. However, low frequency temperature variations such as the transition between the Medieval Climate Anomaly and the Little Ice Age are better resolved by records situated at lower latitudes. According to our idealized experiments a careful selection of proxy locations should be performed depending on the targeted time scale of the reconstructed field.

Millions of individuals worldwide suffer from impaired vision, a condition with multiple origins that often impinge upon the light sensing cells of the retina, the photoreceptors, affecting their integrity. The molecular components contributing to this integrity are however not yet fully understood. Here we have asked whether Secreted Frizzled Related Protein 1 (SFRP1) may be one of such factors. SFRP1 has a context-dependent function as modulator of Wnt signalling or of the proteolytic activity of A Disintegrin And Metalloproteases (ADAM) 10, a main regulator of neural cell-cell communication. We report that in Sfrp1 -/- mice, the outer limiting membrane (OLM) is discontinuous and the photoreceptors disorganized and more prone to light-induced damage. Sfrp1 loss significantly enhances the effect of the Rpe65 Leu450Leu genetic variant -present in the mouse genetic background- which confers sensitivity to light-induced stress. These alterations worsen with age, affect visual function and are associated to an increased proteolysis of Protocadherin 21 (PCDH21), localized at the photoreceptor outer segment, and N-cadherin, an OLM component. We thus propose that SFRP1 contributes to photoreceptor fitness with a mechanism that involves the maintenance of OLM integrity. These conclusions are discussed in view of the broader implication of SFRP1 in neurodegeneration and aging.

A new family of paratanaoidean Tanaidacea - Paranarthrurellidae fam. nov. - is erected to accommodate two genera without family classification (Paratanaoidea incertae sedis), namely Armatognathia Kudinova-Pasternak, 1987 and Paranarthrurella Lang, 1971. Seven new species of Paranarthrurella and two of Armatognathia are described from material taken in different deep-sea areas of the Atlantic and Pacific oceans. The type species of Paranarthrurella - P. caudata (Kudinova-Pasternak, 1965) - is redescribed based on the paratype. The genus Cheliasetosatanais Larsen and Araújo-Silva, 2014 originally classified within Colletteidae is synonymised with Paranarthrurella, and Arthrura shiinoi Kudinova-Pasternak, 1973 is transferred to Armatognathia. Amended diagnoses of Armatognathia and Paranarthrurella genera are given. Choosing characters for distinguishing and defining both genera was supported by Principal Component Analysis. Designation of the new family is supported by molecular phylogenetic analysis of COI and 18S datasets. The distribution of all species currently included in the new family was visualised and their bathymetric distribution analysed.

Renal hypoxia and loss of proximal tubular cells (PTC) are relevant in diabetic nephropathy. Hypoxia inhibits hypoxia-inducible factor-1α (HIF-1α) degradation, which leads to cellular adaptive responses through HIF-1-dependent activation of gene hypoxia-responsive elements (HRE). However, the diabetic microenvironment represses the HIF-1/HRE response in PTC. Here we studied the mechanism and consequences of impaired HIF-1α regulation in human proximal tubular HK-2 cells incubated in hyperglycemia. Inhibition at different levels of the canonical pathway of HIF-1α degradation did not activate the HIF-1/HRE response under hyperglycemia, except when proteasome was inhibited. Further studies suggested that hyperglycemia disrupts the interaction of HIF-1α with Hsp90, a known cause of proteasomal degradation of HIF-1α. Impaired HIF-1α regulation in cells exposed to hyperglycemic, hypoxic diabetic-like milieu led to diminished production of vascular endothelial growth factor-A and inhibition of cell migration (responses respectively involved in tubular protection and repair). These effects, as well as impaired HIF-1α regulation, were reproduced in normoglycemia in HK-2 cells incubated with microparticles released by HK-2 cells exposed to diabetic-like milieu. In summary, these results highlight the role of proteasome-dependent mechanisms of HIF-1α degradation on diabetes-induced HK-2 cells dysfunction and suggest that cell-derived microparticles may mediate negative effects of the diabetic milieu on PTC.

Whereas a healthy endothelium maintains physiological vascular functions, endothelial damage contributes to the development of cardiovascular diseases. Endothelial senescence is the main determinant of endothelial dysfunction and thus of age-related cardiovascular disease. The objective of this study is to test the involvement of microRNA-126 and HIF-1α in a model of replicative endothelial senescence and the interrelationship between both molecules in this in vitro model. We demonstrated that senescent endothelial cells experience impaired tube formation and delayed wound healing. Senescent endothelial cells failed to express HIF-1α, and the microvesicles released by these cells failed to carry HIF-1α. Of note, HIF-1α protein levels were restored in HIF-1α stabilizer-treated senescent endothelial cells. Finally, we show that microRNA-126 was downregulated in senescent endothelial cells and microvesicles. With regard to the interplay between microRNA-126 and HIF-1α, transfection with a microRNA-126 inhibitor downregulated HIF-1α expression in early passage endothelial cells. Moreover, while HIF-1α inhibition reduced tube formation and wound healing closure, microRNA-126 levels remained unchanged. These data indicate that HIF-1α is a target of miRNA-126 in protective and reparative functions, and suggest that their therapeutic modulation could benefit age-related vascular disease.

The immune checkpoint based therapy targeting the programmed death-1 (PD-1) receptor and its PD-L1 ligand has recently been approved for the therapy of different malignant conditions, but not yet for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this context, we evaluated the expression of PD-1 and PD-L1 in GEP-NETs and its potential correlations with clinical outcomes. Expression of PD-1/PD-L1 was analyzed by immunohistochemistry in 116 GEP-NETs and 48 samples of peritumoral tissue. In addition, the expression of these molecules was assessed by flow cytometry in peripheral blood mononuclear cells (PBMC) from patients with GEP-NETs (n = 32) and healthy controls (n = 32) and in intratumoral mononuclear cells (TMCs) (n = 3). Expression of PD-L1 and PD-1 was detected by immunohistochemistry in 6% and 1% of tumor tissue samples, respectively, and in 8% of peritumoral tissue samples, for both markers. We also observed that PD-1 expression by TMCs was associated with metastatic disease at diagnosis, and the levels of circulating PD-1+ PBMCs were associated with progressive disease upon follow-ups. In addition, circulating PD-1+ PBMCs were significantly correlated with PD-L1 expression by tumor cells. Our data suggest that PD-1/PD-L1 is expressed in 1 to 8% of GEP-NETs, and that this feature is significantly associated with disease evolution (p < 0.01).

The reconstruction of deep-time diversity trends is key to understanding current and future species richness. Studies that statistically evaluate potential factors affecting paleodiversity have focused on continental and global, clade-wide datasets, and thus we ignore how community species richness build-up to generate large-scale patterns over geological timescales. If community diversity is shaped by biotic interactions and continental and global diversities are governed by abiotic events, which are the modulators of diversity in subcontinental regions? To address this question, we model Iberian mammalian species richness over 13 million years (15 to 2 Ma) using exhaustive fossil evidence for subcontinental species' ecomorphology, environmental context, and biogeographic affinities, and quantitatively evaluate their impact on species richness. We find that the diversity of large Iberian mammals has been limited over time, with species richness showing marked fluctuations, undergoing substantial depletions as diversity surpasses a critical limit where a significant part of the niches is unviable. The strength of such diversity-dependence has also shifted. Large faunal dispersals and environmental heterogeneity increased the system's critical diversity limit. Diversity growth rate (net migration and diversification) also oscillated, mainly modulated by functional saturation, patchiness of canopy cover, and local temperature and aridity. Our study provides quantitative support for subcontinental species pools being complex and dynamic systems where diversity is perpetually imbalanced over geological timescales. Subcontinental diversity-dependence dynamics are mainly modulated by a multi-scale interplay of biotic and abiotic factors, with abiotic factors playing a more relevant role.

Hypoglycosylation of α-dystroglycan (α-DG) resulting from deficiency of protein O-mannosyltransferase 1 (POMT1) may cause severe neuromuscular dystrophies with brain and eye anomalies, named dystroglycanopathies. The retinal involvement of these disorders motivated us to generate a conditional knockout (cKO) mouse experiencing a Pomt1 intragenic deletion (exons 3-4) during the development of photoreceptors, mediated by the Cre recombinase expressed from the cone-rod homeobox (Crx) gene promoter. In this mouse, retinal α-DG was unglycosylated and incapable of binding laminin. Retinal POMT1 deficiency caused significant impairments in both electroretinographic recordings and optokinetic reflex in Pomt1 cKO mice, and immunohistochemical analyses revealed the absence of β-DG and of the α-DG-interacting protein, pikachurin, in the outer plexiform layer (OPL). At the ultrastructural level, noticeable alterations were observed in the ribbon synapses established between photoreceptors and bipolar cells. Therefore, O-mannosylation of α-DG in the retina carried out by POMT1 is crucial for the establishment of proper synapses at the OPL and transmission of visual information from cones and rods to their postsynaptic neurons.

Time and circumstances for the disappearance of Neanderthals and its relationship with the advent of Modern Humans are not yet sufficiently resolved, especially in case of the Iberian Peninsula. Reconstructing palaeoenvironmental conditions during the last glacial period is crucial to clarifying whether climate deteriorations or competition and contacts with Modern Humans played the pivotal role in driving Neanderthals to extinction. A high-resolution loess record from the Upper Tagus Basin in central Spain demonstrates that the Neanderthal abandonment of inner Iberian territories 42 kyr ago coincided with the evolvement of hostile environmental conditions, while archaeological evidence testifies that this desertion took place regardless of modern humans' activities. According to stratigraphic findings and stable isotope analyses, this period corresponded to the driest environmental conditions of the last glacial apart from an even drier period linked to Heinrich Stadial 3. Our results show that during Marine Isotope Stages (MIS) 4 and 2 climate deteriorations in interior Iberia temporally coincided with northern hemisphere cold periods (Heinrich stadials). Solely during the middle MIS 3, in a period surrounding 42 kyr ago, this relation seems not straightforward, which may demonstrate the complexity of terrestrial climate conditions during glacial periods.

Transoceanic Gliders are Autonomous Underwater Vehicles (AUVs) for which there is a developing and expanding range of applications in open-seas research, technology and underwater clean transport. Mature glider autonomy, operating depth (0-1000 meters) and low energy consumption without a CO 2 footprint enable evolutionary access across ocean basins. Pursuant to the first successful transatlantic glider crossing in December 2009, the Challenger Mission has opened the door to long-term, long-distance routine transoceanic AUV missions. These vehicles, which glide through the water column between 0 and 1000 meters depth, are highly sensitive to the ocean current field. Consequently, it is essential to exploit the complex space-time structure of the ocean current field in order to plan a path that optimizes scientific payoff and navigation efficiency. This letter demonstrates the capability of dynamical system theory for achieving this goal by realizing the real-time navigation strategy for the transoceanic AUV named Silbo, which is a Slocum deep-glider (0-1000 m), that crossed the North Atlantic from April 2016 to March 2017. Path planning in real time based on this approach has facilitated an impressive speed up of the AUV to unprecedented velocities resulting in major battery savings on the mission, offering the potential for routine transoceanic long duration missions.