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More effective approaches are needed in the treatment of blood cancers, in particular acute myeloid leukemia (AML), that are able to eliminate resistant leukemia stem cells (LSCs) at the bone marrow (BM), after a chemotherapy session, and then enhance hematopoietic stem cell (HSC) engraftment for the re-establishment of the HSC compartment. Here, we investigate whether light-activatable nanoparticles (NPs) encapsulating all-trans-retinoic acid (RA+NPs) could solve both problems. Our in vitro results show that mouse AML cells transfected with RA+NPs differentiate towards antitumoral M1 macrophages through RIG.1 and OASL gene expression. Our in vivo results further show that mouse AML cells transfected with RA+NPs home at the BM after transplantation in an AML mouse model. The photo-disassembly of the NPs within the grafted cells by a blue laser enables their differentiation towards a macrophage lineage. This macrophage activation seems to have systemic anti-leukemic effect within the BM, with a significant reduction of leukemic cells in all BM compartments, of animals treated with RA+NPs, when compared with animals treated with empty NPs. In a separate group of experiments, we show for the first time that normal HSCs transfected with RA+NPs show superior engraftment at the BM niche than cells without treatment or treated with empty NPs. This is the first time that the activity of RA is tested in terms of long-term hematopoietic reconstitution after transplant using an in situ activation approach without any exogenous priming or genetic conditioning of the transplanted cells. Overall, the approach documented here has the potential to improve consolidation therapy in AML since it allows a dual intervention in the BM niche: to tackle resistant leukemia and improve HSC engraftment at the same time.

Antibodies are critical reagents to detect and characterize proteins. It is commonly understood that many commercial antibodies do not recognize their intended targets, but information on the scope of the problem remains largely anecdotal, and as such, feasibility of the goal of at least one potent and specific antibody targeting each protein in a proteome cannot be assessed. Focusing on antibodies for human proteins, we have scaled a standardized characterization approach using parental and knockout cell lines (Laflamme et al., 2019) to assess the performance of 614 commercial antibodies for 65 neuroscience-related proteins. Side-by-side comparisons of all antibodies against each target, obtained from multiple commercial partners, have demonstrated that: (i) more than 50% of all antibodies failed in one or more applications, (ii) yet, ~50–75% of the protein set was covered by at least one high-performing antibody, depending on application, suggesting that coverage of human proteins by commercial antibodies is significant; and (iii) recombinant antibodies performed better than monoclonal or polyclonal antibodies. The hundreds of underperforming antibodies identified in this study were found to have been used in a large number of published articles, which should raise alarm. Encouragingly, more than half of the underperforming commercial antibodies were reassessed by the manufacturers, and many had alterations to their recommended usage or were removed from the market. This first study helps demonstrate the scale of the antibody specificity problem but also suggests an efficient strategy toward achieving coverage of the human proteome; mine the existing commercial antibody repertoire, and use the data to focus new renewable antibody generation efforts.

Volcanic soils cover 1% of the Earth’s surface but support 10% of the world’s population. They are among the most fertile soils in the world, due to their excellent physical properties and richness in available nutrients. The major limiting factor for plant growth in volcanic soils is phosphate fixation, which is mainly attributable to active species of aluminium and iron. The sorption and desorption of phosphate is studied on the surface horizons of two African agricultural soils, a silandic Andosol (Rwanda) and a vitric Andosol (São Tomé and Principe). Both soils are slightly acid. The silandic Andosol is rich in active aluminium forms, while the vitric Andosol has high amounts of crystalline iron and aluminium oxides. Sorption isotherms were determined by equilibrating at 293K soil samples with phosphate solutions of concentrations between 0 and 100 mg P L−1 in NaNO3; phosphate was determined by visible spectrophotometry in the equilibrium solution. To study desorption, the soil samples from the sorption experiment were equilibrated with 0.02 M NaNO3. The isotherms were adjusted to mathematical models. In almost all the concentration range, the adsorption of phosphate by the silandic Andosol was greater than 90% of the amount added, being lower in the vitric Andosol but always higher than 65%. The high sorption by the silandic Andosol is attributed to its richness in non-crystalline Fe and Al, while in the vitric Andosol crystalline iron species seem to play a relevant role in the adsorption. The sorption isotherms of both soils fitted to the Temkin model, the adjustment to the Langmuir or Freundlich models being unsatisfactory; throughout the range studied, the sorption increases with increasing phosphorus concentration, a maximum sorption is not predictable (as occurs when the sorption is adjusted to the Langmuir model). For an added P concentration of 100 mg L−1 (3.2 mmol L−1), the sorption is 47.7 µmol P g−1 in the silandic Andosol and 41.6 µmol P g−1 in the vitric Andosol. The desorption is low and the comparison of the sorption and desorption isotherms reveals a pronounced hysteresis, that is, the irreversibility of the sorption. The high phosphate sorption and its irreversibility are comparable to those published for other volcanic soils with high contents of allophane, active aluminium and free iron. The strong phosphate adsorption is a serious limiting factor for plant growth, which requires a careful management of phosphorus fertilization.

Background Jumping and landing tests are frequently used as a tool to assess muscle function. However, they are performed in a controlled and predictable environment. The physical tests commonly used as part of the criteria for return to sport after injury are often performed with little or no cognitive load and low coordinative demand compared to game-specific actions. The aim of this systematic review was to examine the influence of performing a dual task (DT) or sport-specific task constrains during jump-landing tests on biomechanical variables related to lower limb injury risk in team sports. Methods This systematic review followed the specific methodological guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search was conducted in the databases Medline (PubMed), Web of Science, Cochrane Plus, and SportDiscus for studies published from 2013 until June 30, 2023. To be eligible, studies had to include: (1) kinematic and/or kinetic assessment of injury risk factors in the lower extremity; (2) a comparison between a simple jump or landing test and a DT jump or landing test which included cognitive information. The risk of bias in the selected articles was analyzed using the recommendations of the Cochrane Collaboration. Results Of the 656 records identified, 13 met the established criteria. Additionally, two more articles were manually included after screening references from the included articles and previous related systematic reviews. Regarding the Risk of bias assessment, 12 studies did not surpass a score of 3 points (out of a total of 7). Only three studies exceeded a score of 3 points, with one article achieving a total score of 6. From the included studies, comparative conditions included actions influenced by the inclusion of a sports ball (n = 6), performing tasks in virtual environments or with virtual feedback (n = 2), participation in cognitive tasks (n = 6), and tasks involving dual processes (n = 7). The execution of decision-making (DM) during the jump-landing action resulted in biomechanical changes such as lower peak angles of hip flexion and knee flexion, along with increased vertical ground reaction force, knee abduction, and tibial internal rotation. Regarding limitations, discrepancies arise in defining what constitutes DT. As a result, it is possible that not all studies included in this review fit all conceptual definitions of DT. The inclusion of DT or constraints in jump-landing tests significantly alters biomechanical variables related to lower extremity injury risk in team sports. In future research, it would be beneficial to incorporate tasks into jumping tests that simulate the specific cognitive demands of team sports. This systematic review was registered in PROSPERO (registration number: CRD42023462102) and this research received no external funding.

Introduction: This study aimed to evaluate the validity of the HandyGym portable flywheel device with an integrated rotary encoder in measuring force and power during iso-inertial exercises compared to a traditional reference system. Methods: In total, 10 trained volunteers (3 women, 7 men; age 25.2 ± 3.8 years) performed half-squats with five different load configurations using the HandyGym device. Concurrent measurements were obtained from HandyGym’s rotary encoder and a criterion system (MuscleLab 6000 strain gauge and linear encoder). Five load configurations were tested, with 15 repetitions recorded per condition. The validity of the HandyGym measurements was assessed through mean bias, typical error of estimation (TEE), and Pearson correlation coefficients, with Bland–Altman plots used to analyze the agreement between the two systems. Results: The HandyGym showed high correlations with the reference system for both force (r = 0.76–0.90) and power (r = 0.60–0.94). However, systematic biases were observed, with the HandyGym consistently underestimating force and power at lower loads and overestimating power at higher loads. The TEE values indicated moderate to large errors, particularly in power measurements. Conclusion: The HandyGym provides valid force measurements with moderate bias, suitable for general monitoring. However, power measurements are less consistent, especially at higher loads, limiting the device’s utility for precise assessments. Adjustments or corrections may be necessary for accurate application in professional contexts.

Abstract Background A key step for comparative genomics is to group open reading frames into functionally and evolutionarily meaningful gene clusters. Gene clustering is complicated by intraspecific duplications and horizontal gene transfers that are frequent in prokaryotes. In consequence, gene clustering methods must deal with a trade-off between identifying vertically transmitted representatives of multicopy gene families, which are recognizable by synteny conservation, and retrieving complete sets of species-level orthologs. We studied the implications of adopting homology, orthology, or synteny conservation as formal criteria for gene clustering by performing comparative analyses of 125 prokaryotic pangenomes. Results Clustering criteria affect pangenome functional characterization, core genome inference, and reconstruction of ancestral gene content to different extents. Species-wise estimates of pangenome and core genome sizes change by the same factor when using different clustering criteria, allowing robust cross-species comparisons regardless of the clustering criterion. However, cross-species comparisons of genome plasticity and functional profiles are substantially affected by inconsistencies among clustering criteria. Such inconsistencies are driven not only by mobile genetic elements, but also by genes involved in defense, secondary metabolism, and other accessory functions. In some pangenome features, the variability attributed to methodological inconsistencies can even exceed the effect sizes of ecological and phylogenetic variables. Conclusions Choosing an appropriate criterion for gene clustering is critical to conduct unbiased pangenome analyses. We provide practical guidelines to choose the right method depending on the research goals and the quality of genome assemblies, and a benchmarking dataset to assess the robustness and reproducibility of future comparative studies.

The scarcity of potable water emphasizes the urgent need to develop and implement more sustainable treatment technologies, considering both energy consumption and environmental impact. These technologies require effective disinfection systems that avoid the use of chemicals. Innovations in this area, utilizing UV-LED technology, can significantly improve efficiency, reduce costs, and mitigate environmental impacts. This study aimed to evaluate the antimicrobial properties of various encapsulated UV light-emitting diodes (LEDs) to identify the most suitable candidate for constructing an LED array capable of disinfecting large volumes of water. Different devices from various manufacturers, with differing costs and wavelengths, were examined, leading to the selection of the optimal candidate (LED 2) based on its antimicrobial effectiveness and cost-effectiveness. The impact of parameters such as bacterial concentration, sample volume, exposure time, and conditions on disinfection capacity was thoroughly investigated. Exposure to LED 2 resulted in substantial reductions in the viability of bacteria and yeast, demonstrating efficacy even against Clostridium perfringens endospores. Subsequently, an LED array was developed based on these findings and rigorously evaluated for efficacy, confirming its effectiveness as an efficient and environmentally friendly water treatment device.

Summary: Despite the symmetrical structure of nucleosomes, in vitro studies have shown that transcription proceeds with different efficiency depending on the orientation of the DNA sequence around them. However, it is unclear whether this functional asymmetry is present in vivo and whether it could regulate transcriptional directionality. Here, we report that the proximal and distal halves of nucleosomal DNA contribute differentially to nucleosome stability in the genome. In +1 nucleosomes, this asymmetry facilitates or hinders transcription depending on the orientation of its underlying DNA, and this difference is associated with an asymmetrical interaction between DNA and histones. These properties are encoded in the DNA signature of +1 nucleosomes, since its incorporation in the two orientations into downstream nucleosomes renders them asymmetrically accessible to MNase and inverts the balance between sense and antisense transcription. Altogether, our results show that nucleosomal DNA endows nucleosomes with asymmetrical properties that modulate the directionality of transcription.

A GWAS in a large case-control cohort of European ancestry identifies two genomic regions, the MHC class II gene HLA-DRB1 and an upstream locus of VRK1, that are associated with the most severe phenotype of spermatogenic failure.

Hip range of movement (ROM) impairments could affect individuals’ quality of life. The aim of this study is to describe a new flexometric method (FM) as a means to estimate hip ROM and to determine its concurrent validity and inter-rater and intra-rater reliability. Hip ROM was measured by performing the straight leg raise test (SLR) and hip abduction test (HA). The WIMU system is the gold standard. ROM was calculated in degrees using a trigonometric function based on values derived from measurements with a flexometer. The SLR and the HA showed high concurrent validity and good inter- and intra-rater reliability with an interclass correlation coefficient value that was at all times > 0.9. The minimal detectable change at the 90% confidence level for inter- and intra-rater reliability was equal to or greater than 5.7° in SLR-Right, 5.6° in SLR-Left, 5.1° in HA, 6.3° in SLR-Right, 4.9° in SLR-Left, and 5.4° in HA, respectively. This study suggests that the FM is a valid and reliable tool for assessing hip ROM. Due to its convenience and cost-effectiveness, this method could be widely used to measure the ROM of several joints in field-based tests.

The aim of this study was to assess and compare performance and movement variability (MV) in both bilateral and unilateral vertical drop jumps (DVJs) under conditions involving the incorporation or exclusion of ball catching. Twelve amateur basketball players were recruited for participation in the study (seven females and five males). Participants performed three jumps in each of the six conditions analyzed in randomized order: bilateral DVJ without (BNB) and with ball (BB); unilateral DVJ right leg without (RNB) and with ball (RB); and unilateral DVJ left leg without (LNB) and with ball (LB). MV and DVJ performance parameters were analyzed with an accelerometer and a force platform. MV was quantified using the sample entropy (sample entropy; SampEn) derived from the acceleration of the lower back. Differences between the different DVJ conditions were determined with the Wilcoxon test, with a significance level set at p < 0.05. The comparisons were also assessed via standardized mean differences (Cohen’s d). No significant differences were observed in jump height, contact time and reactive strength index between conditions. However, the RB condition reported higher MV compared to RNB (effect size = 0.79; p = 0.016). Similarly, LNB showed greater MV compared to RNB (effect size = −0.62; p = 0.042). The inclusion of the ball in the DVJ increased the MV in the bilateral condition and in the right leg, but not in the unilateral condition with the left leg. The asymmetry between legs (right vs. left) in MV values in NOBALL conditions was higher (≈15%) compared to the BALL condition (≈5%).

The central nervous system (CNS) is considered as an immune privilege organ, based on experiments in the mid 20th century showing that the brain fails to mount an efficient immune response against an allogeneic graft. This suggests that in addition to the presence of the blood-brain barrier (BBB), the apparent absence of classical lymphatic vasculature in the CNS parenchyma limits the capacity for an immune response. Although this view is partially overturned by the recent discovery of the lymphatic-like hybrid vessels in the Schlemm’s canal in the eye and the lymphatic vasculature in the outmost layer of the meninges, the existence of lymphatic vessels in the CNS parenchyma has not been reported. Two potential mechanisms by which lymphatic vasculature may arise in the organs are: 1) sprouting and invasion of lymphatic vessels from the surrounding tissues into the parenchyma and 2) differentiation of blood endothelial cells into lymphatic endothelial cells in the parenchyma. Considering these mechanisms, we here discuss what causes the dearth of lymphatic vessels specifically in the CNS parenchyma.

Background: Severe spermatogenic failure (SPGF) represents one of the most relevant causes of male infertility. This pathological condition can lead to extreme abnormalities in the seminal sperm count, such as severe oligozoospermia (SO) or non-obstructive azoospermia (NOA). Most cases of SPGF have an unknown aetiology, and it is known that this idiopathic form of male infertility represents a complex condition. In this study, we aimed to evaluate whether common genetic variation in TEX15, which encodes a key player in spermatogenesis, is involved in the susceptibility to idiopathic SPGF.Materials and Methods: We designed a genetic association study comprising a total of 727 SPGF cases (including 527 NOA and 200 SO) and 1,058 unaffected men from the Iberian Peninsula. Following a tagging strategy, three tag single-nucleotide polymorphisms (SNPs) of TEX15 (rs1362912, rs323342, and rs323346) were selected for genotyping using TaqMan probes. Case-control association tests were then performed by logistic regression models. In silico analyses were also carried out to shed light into the putative functional implications of the studied variants.Results: A significant increase in TEX15-rs1362912 minor allele frequency (MAF) was observed in the group of SO patients (MAF = 0.0842) compared to either the control cohort (MAF = 0.0468, OR = 1.90, p = 7.47E-03) or the NOA group (MAF = 0.0472, OR = 1.83, p = 1.23E-02). The genotype distribution of the SO population was also different from those of both control (p = 1.14E-02) and NOA groups (p = 4.33–02). The analysis of functional annotations of the human genome suggested that the effect of the SO-associated TEX15 variants is likely exerted by alteration of the binding affinity of crucial transcription factors for spermatogenesis.Conclusion: Our results suggest that common variation in TEX15 is involved in the genetic predisposition to SO, thus supporting the notion of idiopathic SPGF as a complex trait.

This paper assessed the evolution of the performance ratio (PR) of a utility-scale photovoltaic (PV) installation that operates at subtropical climate conditions. The period of study encompassed 8 years, and the PR was calculated according to the ICE 61724 standard with a monthly resolution. A linear mixed effects model (LME) is a suitable tool for analyzing longitudinal data. Three LME models were assessed to provide the degradation rate. The “null model” evaluates the general relationship between PR and time with a monthly declination rate (ΔPR%) of 0.0391%/month. The “typology model” considered the relationship between PR and, as covariates, time, Manufacturer, Technology, and NominalP. Only the ΔPR% related to NominalP was found to be significant, so that, when the nominal power of a type of PV module used for a PV production unit is increased by one unit, the ΔPR% of the corresponding unit increases by 0.000897%/month. Finally, the “location model” took into account the relationship between PR and, as covariates, time, Edge, and LengthSt. These last two factors were significant, resulting in an increase of 0.0132%/month for a PV unit located at the edge of the facility and 0.00117%/month and per PV production unit when considering the length of a street, respectively.

In this work, the performance of a new ethylene-vinyl acetate-based low temperature encapsulation method, conceived to protect perovskite samples from UV irradiation in ambient conditions, has been analyzed. To this purpose, perovskite samples consisting of a set of MAPbI3 (CH3NH3PbI3) films and MAPbI3 with an ETL layer were deposited over glass substrates by spin-coating techniques and encapsulated using the new method. The samples were subjected to an UV lamp or to full solar irradiation in ambient conditions, with a relative humidity of 60–80%. Microscope imaging, spectroscopic ellipsometry and Fourier-transform infrared spectroscopy (FTIR) techniques were applied to analyze the samples. The obtained results indicate UV energy is responsible for the degradation of the perovskite layer. Thus, the cut-UV characteristics of the EVA encapsulate acts as an efficient barrier, allowing the laminated samples to remain stable above 350 h under full solar irradiation compared with non-encapsulated samples. In addition, the FTIR results reveal perovskite degradation caused by UV light. To extend the study to encompass whole PSCs, simulations were carried out using the software SCAPS-1D, where the non-encapsulated devices present a short-circuit current reduction after exposure to UV irradiation, while the encapsulated ones maintained their efficiency.

The H2A.Z histone variant is deposited into the chromatin by the SWR1 complex, affecting multiple aspects of meiosis. We describe here a SWR1-independent localization of H2A.Z at meiotic telomeres and the centrosome. We demonstrate that H2A.Z colocalizes and interacts with Mps3, the SUN component of the linker of nucleoskeleton, and cytoskeleton (LINC) complex that spans the nuclear envelope and links meiotic telomeres to the cytoskeleton, promoting meiotic chromosome movement. H2A.Z also interacts with the meiosis-specific Ndj1 protein that anchors telomeres to the nuclear periphery via Mps3. Telomeric localization of H2A.Z depends on Ndj1 and the N-terminal domain of Mps3. Although telomeric attachment to the nuclear envelope is maintained in the absence of H2A.Z, the distribution of Mps3 is altered. The velocity of chromosome movement during the meiotic prophase is reduced in the htz1Δ mutant lacking H2A.Z, but it is unaffected in swr1Δ cells. We reveal that H2A.Z is an additional LINC-associated factor that contributes to promote telomere-driven chromosome motion critical for error-free gametogenesis.

Abstract Background Advances in automated image-based microscopy platforms coupled with high-throughput liquid workflows have facilitated the design of large-scale screens utilising multicellular model organisms such as Caenorhabditis elegans to identify genetic interactions, therapeutic drugs or disease modifiers. However, the analysis of essential genes has lagged behind because lethal or sterile mutations pose a bottleneck for high-throughput approaches, and a systematic way to analyse genetic interactions of essential genes in multicellular organisms has been lacking. Results In C. elegans, non-conditional lethal mutations can be maintained in heterozygosity using chromosome balancers, commonly expressing green fluorescent protein (GFP) in the pharynx. However, gene expression or function is typically monitored by the use of fluorescent reporters marked with the same fluorophore, presenting a challenge to sort worm populations of interest, particularly at early larval stages. Here, we develop a sorting strategy capable of selecting homozygous mutants carrying a GFP stress reporter from GFP-balanced animals at the second larval stage. Because sorting is not completely error-free, we develop an automated high-throughput image analysis protocol that identifies and discards animals carrying the chromosome balancer. We demonstrate the experimental usefulness of combining sorting of homozygous lethal mutants and automated image analysis in a functional genomic RNA interference (RNAi) screen for genes that genetically interact with mitochondrial prohibitin (PHB). Lack of PHB results in embryonic lethality, while homozygous PHB deletion mutants develop into sterile adults due to maternal contribution and strongly induce the mitochondrial unfolded protein response (UPRmt). In a chromosome-wide RNAi screen for C. elegans genes having human orthologues, we uncover both known and new PHB genetic interactors affecting the UPRmt and growth. Conclusions The method presented here allows the study of balanced lethal mutations in a high-throughput manner. It can be easily adapted depending on the user’s requirements and should serve as a useful resource for the C. elegans community for probing new biological aspects of essential nematode genes as well as the generation of more comprehensive genetic networks.

Abstract Background Clinical signs are a fundamental aspect of human pathologies. While disease diagnosis is problematic or impossible in many cases, signs are easier to perceive and categorize. Clinical signs are increasingly used, together with molecular networks, to prioritize detected variants in clinical genomics pipelines, even if the patient is still undiagnosed. Here we analyze the ability of these network-based methods to predict genes that underlie clinical signs from the human interactome. Results Our analysis reveals that these approaches can locate genes associated with clinical signs with variable performance that depends on the sign and associated disease. We analyzed several clinical and biological factors that explain these variable results, including number of genes involved (mono- vs. oligogenic diseases), mode of inheritance, type of clinical sign and gene product function. Conclusions Our results indicate that the characteristics of the clinical signs and their related diseases should be considered for interpreting the results of network-prediction methods, such as those aimed at discovering disease-related genes and variants. These results are important due the increasing use of clinical signs as an alternative to diseases for studying the molecular basis of human pathologies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in Madrid, Spain, on 25 February 2020. It increased in frequency very fast and by the end of May more than 70,000 cases had been confirmed by reverse transcription-polymerase chain reaction (RT-PCR). To study the lineages and the diversity of the viral population during this first epidemic wave in Madrid we sequenced 224 SARS-CoV-2 viral genomes collected from three hospitals from February to May 2020. All the known major lineages were found in this set of samples, though B.1 and B.1.5 were the most frequent ones, accounting for more than 60% of the sequences. In parallel with the B lineages and sublineages, the D614G mutation in the Spike protein sequence was detected soon after the detection of the first coronavirus disease 19 (COVID-19) case in Madrid and in two weeks became dominant, being found in 80% of the samples and remaining at this level during all the study periods. The lineage composition of the viral population found in Madrid was more similar to the European population than to the publicly available Spanish data, underlining the role of Madrid as a national and international transport hub. In agreement with this, phylodynamic analysis suggested multiple independent entries before the national lockdown and air transportation restrictions.

(1) Background:The quality of neutron beams for Boron Neutron Capture Therapy (BNCT) is currently defined by its physical characteristics in air. Recommendations exist to define whether a designed beam is useful for clinical treatment. This work presents a new way to evaluate neutron beams based on their clinical performance and on their safety, employing radiobiological quantities. (2) Methods: The case study is a neutron beam for deep-seated tumors from a 5 MeV proton beam coupled to a beryllium target. Physical Figures of Merit were used to design five beams; however, they did not allow a clear ranking of their quality in terms of therapeutic potential. The latter was then evaluated based on in-phantom dose distributions and on the calculation of the Uncomplicated Tumor Control Probability (UTCP). The safety of the beams was also evaluated calculating the in-patient out-of-beam dosimetry. (3) Results: All the beams ensured a UTCP comparable to the one of a clinical beam in phantom; the safety criterion allowed to choose the best candidate. When this was tested in the treatment planning of a real patient treated in Finland, the UTCP was still comparable to the one of the clinical beam. (4) Conclusions: Even when standard physical recommendations are not met, radiobiological and dosimetric criteria demonstrate to be a valid tool to select an effective and safe beam for patient treatment.

Chronic pain is one of the most debilitating human diseases and represents a social and economic burden for our society. Great efforts are being made to understand the molecular and cellular mechanisms underlying the pathophysiology of pain transduction. It is particularly noteworthy that some types of chronic pain, such as migraine, display a remarkable sex dimorphism, being up to three times more prevalent in women than in men. This gender prevalence in migraine appears to be related to sex differences arising from both gonadal and genetic factors. Indeed, the functionality of the somatosensory, immune, and endothelial systems seems modulated by sex hormones, as well as by X-linked genes differentially expressed during development. Here, we review the current data on the modulation of the somatosensory system functionality by gonadal hormones. Although this is still an area that requires intense investigation, there is evidence suggesting a direct regulation of nociceptor activity by sex hormones at the transcriptional, translational, and functional levels. Data are being accumulated on the effect of sex hormones on TRP channels such as TRPV1 that make pivotal contributions to nociceptor excitability and sensitization in migraine and other chronic pain syndromes. These data suggest that modulation of TRP channels' expression and/or activity by gonadal hormones provide novel pathways for drug intervention that may be useful for targeting the sex dimorphism observed in migraine.

Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects.