Grupos de Investigación

Optimizing surgical approaches for patients with inherited factor VII deficiency

2026-06-10T00:00:08Z

[EN]Inherited factor VII deficiency (FVIID) presents a highly variable bleeding phenotype. The weak correlation between plasma FVII levels (FVII:C) and bleeding severity results in diverse management strategies and complicates surgical decision-making.To describe surgical management and bleeding outcomes in patients with FVIID, and to identify key decision-making variables and predictors of surgical bleeding.We conducted a multicenter, retrospective study of 380 surgeries performed in 215 patients with FVIID. Patients were classified by FVII:C levels as mild, moderate, or severe deficiency. Bleeding score (BS) was defined according to ISTH-BAT. Surgeries were categorized as low-moderate risk (LR) or high risk (HR) for bleeding. A decision-tree simulation was performed.Most patients had mild FVIID (76%), and 68% of surgeries were classified as LR. Prophylactic treatment with tranexamic acid (TA) and/or rFVIIa was administered in 42.8% of LR and 62.8% of HR surgeries. Prophylaxis was given to 73.9% of moderate/severe and 41% of mild FVIID patients, especially for HR procedures. FVII:C levels and surgical bleeding risk were key factors that influenced the selection of treatment. The overall bleeding rate was 3.1% (HR: 9%; LR: 0.4%). Most bleeding events occurred in mild FVIID patients with BS ≥3. Our algorithm recommends hemostatic treatment for all moderate/severe, and for mild patients HR surgeries and LR procedures when BS is ≥3.FVII:C levels and surgery type influence prophylactic hemostatic treatment strategies. Patients with mild FVIID, higher BS, and no hemostatic treatment had a greater risk of bleeding. Bleeding score and procedural risk were identified as predictors of surgical bleeding.

Robust sliding-induced electrostatic domain patterns in exfoliated ReS2 flakes

2026-06-09T00:00:44Z

[EN]nterlayer sliding in low-symmetry van der Waals materials has emerged as a mechanism to generate out-of-plane electric polarization without conventional ionic displacements, yet its experimental manifestation in realistic multilayer flakes remains difficult to identify unambiguously. Here, we provide evidence that exfoliated ReS flakes exhibit unanticipated arrangements of electrostatic₂ domains that are consistent with sliding-induced ferroelectric polarization. A correlative approach is used in which Kelvin probe force microscopy (KPFM), low-energy and UV-photoemission electron microscopies (LEEM and UV-PEEM) and Raman micro-spectroscopy are combined. KPFM reveals rich patterns of surface-potential domains which are not related to any topographic feature. A subset of such domains is detectable by dark-field LEEM and UV-PEEM images while there is no detectable correlation with spatially resolved micro-Raman. Data analysis allows us to rule out ferroelastic reorientation, strain gradients or thickness variations as the primary origin of the electrostatic contrast, and points to a stacking-sensitive electrostatic categorization. The results are consistently explained by sliding-induced ferroelectric polarization in multilayer ReS . Sliding ferroelectricity in₂ this system manifests as a reconfigurable electrostatic texture that can be directly accessed by local surface-potential mapping and is sensitive to thermal and electrical perturbations. Correlative studies involving KPFM prove to be a powerful strategy to identify sliding ferroelectricity in low-symmetry two-dimensional materials, beyond conventional but complex to interpret transport- or piezoelectric force microscopy-based approaches

Insights into the clinical, platelet and genetic landscape of inherited thrombocytopenia with malignancy risk

2026-06-09T00:00:41Z

[EN]Inherited thrombocytopenia (IT) with germline variants in RUNX1, ETV6 or ANKRD26 carries a high risk (10%-45%) of developing haematological malignancy (IT-HM). We evaluated the clinical, platelet and molecular characteristics in 37 patients with RUNX1-related thrombocytopenia (RT), 9 with ETV6-RT and 20 with ANRKD26-RT. Genetic diagnosis was delayed by about 20 years from the identification of thrombocytopenia. Bleeding tendency was present in 25%-30% of RUNX1-RT and ANKRD26-RT patients. Platelet aggregation was impaired in 90% of all patients, while reduced activation and granule secretion were heterogeneous. Most RUNX1-RT patients had low glycoprotein Ia (GPIa) levels, which may be a useful disease biomarker. Sixteen distinct genetic variants in RUNX1, four in ETV6 and four in ANKRD26 were identified in patients. The clinical profile showed immune, skin, gastrointestinal and other comorbidities in many patients. One third of the cases developed a malignancy: This included eight RUNX1-RT patients with myelodysplastic syndrome (MDS), five with acute myeloid leukaemia (AML), and one with chronic myeloid leukaemia (CML) Ph+. One patient with ETV6-RT subsequently developed B-cell acute lymphoblastic leukaemia (B-ALL) during childhood. Three cases with ANKRD26-RT demonstrated a multifaceted clinical presentation, including B-ALL Ph+, MDS and breast cancer. The high incidence of HM development highlights the importance of early diagnosis in life.

Platelet transcriptome analysis in patients with germline RUNX1 mutations

2026-06-04T00:02:22Z

[EN]Germline mutations in RUNX1 can cause a familial platelet disorder that may lead to acute myeloid leukemia, an autosomal dominant disorder characterized by moderate thrombocytopenia, platelet dysfunction, and a high risk of developing acute myeloid leukemia or myelodysplastic syndrome. Discerning the pathogenicity of novel RUNX1 variants is critical for patient management. To extend the characterization of RUNX1 variants and evaluate their effects by transcriptome analysis. Three unrelated patients with long-standing thrombocytopenia carrying heterozygous RUNX1 variants were included: P1, who is a subject with recent development of myelodysplastic syndrome, with c.802 C>T[p.Gln268∗] de novo; P2 with c.586A>G[p.Thr196Ala], a variant that segregates with thrombocytopenia and myeloid neoplasia in the family; and P3 with c.476A>G[p.Asn159Ser], which did not segregate with thrombocytopenia or neoplasia. Baseline platelet evaluations were performed. Ultrapure platelets were prepared for platelet transcriptome analysis. In P1 and P2, but not in P3, transcriptome analysis confirmed aberrant expression of genes recognized as RUNX1 targets. Data allowed grouping patients by distinct gene expression profiles, which were partitioned with clinical parameters. Functional studies and platelet mRNA expression identified alterations in the actin cytoskeleton, downregulation of GFI1B, defective GPVI downstream signaling, and reduction of alpha granule proteins, such as thrombospondin-1, as features likely implicated in thrombocytopenia and platelet dysfunction. Platelet phenotype, familial segregation, and platelet transcriptomics support the pathogenicity of RUNX1 variants p.Gln268∗ and p.Thr196Ala, but not p.Asn159Ser. This study is an additional proof of concept that platelet RNA analysis could be a tool to help classify pathogenic RUNX1 variants and identify novel RUNX1 targets.

Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation

2026-06-04T00:02:33Z

[EN]Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in GNE, SLC35A1, GALE and B4GALT is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications.

Expanding the genetic spectrum of TUBB1-related thrombocytopenia

2026-06-04T00:02:06Z

[EN]β1-Tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet anisocytosis (TUBB1-RT). To date, the reported number of pedigrees with TUBB1-RT and of rare TUBB1 variants with experimental demonstration of pathogenicity is limited. Here, we report 9 unrelated families presenting with thrombocytopenia carrying 6 β1-tubulin variants, p.Cys12LeufsTer12, p.Thr107Pro, p.Gln423*, p.Arg359Trp, p.Gly109Glu, and p.Gly269Asp, the last of which novel. Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size, and a minority had no abnormalities. Moreover, only homozygous carriers of the p.Gly109Glu variant displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT. The p.Arg359Trp, p.Gly269Asp, and p.Gly109Glu variants deranged β1-tubulin incorporation into the microtubular marginal ring in platelets but had a negligible effect on platelet activation, secretion, or spreading, suggesting that β1-tubulin is dispensable for these processes. Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network. In addition, TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes. Our study, using in vitro modeling, molecular characterization, and clinical investigations provides a deeper insight into the pathogenicity of rare TUBB1 variants. These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants.

A novel GATA1 variant in the C-Terminal zinc finger compared with the platelet phenotype of patients with a likely pathogenic variant in the N-Terminal zinc finger

2026-06-04T00:02:20Z

[EN]The GATA1 transcription factor is essential for normal erythropoiesis and megakaryocytic differentiation. Germline GATA1 pathogenic variants in the N-terminal zinc finger (N-ZF) are typically associated with X-linked thrombocytopenia, platelet dysfunction, and dyserythropoietic anemia. A few variants in the C-terminal ZF (C-ZF) domain are described with normal platelet count but altered platelet function as the main characteristic. Independently performed molecular genetic analysis identified a novel hemizygous variant (c.865C>T, p.H289Y) in the C-ZF region of GATA1 in a German patient and in a Spanish patient. We characterized the bleeding and platelet phenotype of these patients and compared these findings with the parameters of two German siblings carrying the likely pathogenic variant p.D218N in the GATA1 N-ZF domain. The main difference was profound thrombocytopenia in the brothers carrying the p.D218N variant compared to a normal platelet count in patients carrying the p.H289Y variant; only the Spanish patient occasionally developed mild thrombocytopenia. A functional platelet defect affecting αIIbβ3 integrin activation and α-granule secretion was present in all patients. Additionally, mild anemia, anisocytosis, and poikilocytosis were observed in the patients with the C-ZF variant. Our data support the concept that GATA1 variants located in the different ZF regions can lead to clinically diverse manifestations.

Montes, vacarizas y donaciones regias: el acceso de los monasterios a los comunales y las transformaciones en las comunidades locales (Castilla y Rioja Alta, siglos X-XII)

2026-06-04T00:02:17Z

[ES] Este artículo analiza el papel de las donaciones relacionadas con comunales realizadas por reyes y condes, en el caso de la Castilla Condal, a favor de ciertos monasterios. Se estudia la zona de la antigua Castilla condal y la Rioja Alta entre los siglos X al XII. Se observa cómo las donaciones no conllevaron la privatización de los comunales, a pesar de que determinadas zonas, las vacarizas, quedaron integradas dentro de los comunales, pero con usos privados. Los monasterios que recibieron esas donaciones se convirtieron en vecinos exigentes o en señores protectores, sin destruir los comunales. Sin embargo, se transformaron las prácticas sociales y políticas, dando lugar a la construcción de nuevas formas de dominio social que tomaban como punto de partida las micropolíticas en torno a los comunales. La ganadería actuó como un agente que favoreció el desarrollo del señorío local.

GALE variants associated with syndromic manifestations, macrothrombocytopenia, bleeding, and platelet dysfunction

2026-06-04T00:02:16Z

[EN]GALE gene encodes the uridine diphosphate [UDP]-galactose-4-epimerase, which catalyzes the bidirectional interconversion of UDP-glucose to UDP-galactose, and UDP-N-acetyl-glucosamine to UDP-N-acetyl-galactosamine. In that way, GALE balances, through reversible epimerization, the pool of four sugars that are essential during the biosynthesis of glycoproteins and glycolipids. GALE-related disorder presents an autosomal recessive inheritance pattern, and it is commonly associated with galactosemia. Peripheral galactosemia generally associates with non-generalized forms or even asymptomatic presentations, while classical galactosemia may be related to complications such as learning difficulties, developmental delay, cardiac failure, or dysmorphic features. Recently, GALE variants have been related to severe thrombocytopenia, pancytopenia, and in one patient, to myelodysplastic syndrome.

Distinct mutational pattern of myelodysplastic syndromes with and without 5q- treated with lenalidomide

2026-06-02T00:02:25Z

[EN]Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterised by ineffective haematopoiesis leading to peripheral blood cytopenias and an increased risk of transformation to acute myeloid leukaemia (AML) (Haferlach et al., 2014; Makishima et al., 2017). One of the most common cytogenetic alterations is the deletion of the long arm of chromosome 5q [del(5q)], which can be found isolated or with other alterations (10–30% of patients with MDS). Lenalidomide (LEN) has been approved for the treatment of patients with del(5q) low-risk MDS and transfusion dependence. Almost 50% of patients with del(5q) will show a complete cytogenetic remission and 70% of them will reach transfusion independence (List et al., 2006). LEN has also been approved for MDS non-del(5q) transfusion dependent and resistant to erythropoietin-stimulating agents (Santini et al., 2016), suggesting that other factors besides del(5q) modulate response to LEN (Negoro et al., 2016). Herein, we aimed to define the mutational spectrum of patients with MDS with and without del(5q) and define a signature of mutations influencing response to LEN. We collected peripheral blood and/or bone marrow samples from patients with MDS treated with LEN from eight institutions at the Josep Carreras Leukaemia Research Institute (on behalf of the MDS Spanish Group and the MDS French Group) according to the institutional ethic committees and the revised Declaration of Helsinki. We collected 74 samples from patients with MDS at diagnosis or treatment- naïve with LEN follow-up treatment of two or more cycles; 32 patients presented with del(5q), while 42 patients did not have del(5q) in their karyotype (Table S1). The World Health Organization (WHO) classification (2017), Revised International Prognostic Scoring System (IPSS-R) and International Working Group response criteria (IWGc) (Cheson et al., 2006; Greenberg et al., 2012; Dolatshad et al., 2015) were used to classify patients. Responders to LEN included patients with complete and partial response, haematological response and cytogenetic response, while non-responders included patients with treatment failure, stable disease or relapse. We combined results of multi amplicon targeted sequencing with Ion Torrent (Thermo Fisher Scientific, Inc., Waltham, MA, USA) (28 cases) and captured-based targeted sequencing with MiSeq (Illumina, San Diego, CA, USA) (46 cases). Amplicon and capture custom panels included 39 and 82 most recurrently mutated genes in MDS, respectively (Table S2). Capture libraries were generated using the KAPA Library Preparation Kit (Kapa Biosystems, Wilmington, MA, USA), enriched with the SeqCap EZ capture chemistry (Roche, Basel, Switzerland) and sequenced on MiSeq sequencers following a 150 base pairs (bp) paired-end reads Illumina standard protocol. Average coverage per gene was 777×. Reads were aligned against human genome build 19 (hg19) using Burrows-Wheeler Aligner (BWA) 0.7.12 and post-alignment was performed using Genome Analysis Toolkit (GATK) 3.4.46 software package. Libraries for the amplicon-based panel were prepared with Ampliseq (Thermo Fisher Scientific, Inc.) and sequenced in an ion torrent proton sequencer according to the manufacturer’s instructions. Average coverage per genes was 567×. Primary bioinformatic analysis [SAMtools 1.2 (http://www.htslib.org/), VarScan 2.4.0 (http://dkoboldt.github.io/varscan/), and ANNOtate VARiation (https://doc-openbio.readthedocs.io/projects/annovar/en/latest/)] was performed and followed by an in-house protocol (Ibáñez et al., 2016). Variants at highly variable regions, with low coverage (<100×), or a minor allele frequency >1% according to available population databases [Exome Aggregation Consortium (ExAC), Exome Variant Server, 1000 Genomes Project] were filtered out. Mutations were called when the variant allelic frequency (VAF) was >5%. Continuous variable comparisons were performed with Wilcoxon signed-rank tests, while Fisher’s exact test was used to compare variables. Survival curves were calculated using the Kaplan–Meier method and log-rank test were used for comparisons. Two-sided P values < 0·05 were considered as statistically significant.

Filamentation-assisted isolated attosecond pulse generation

2026-06-02T00:02:32Z

[EN]The advancement of attosecond science relies on achieving stable generation of isolated attosecond pulses (IAPs), which are essential for capturing ultrafast dynamics in atoms, molecules and solids. Our study in an extended gas medium demonstrates filamentation-assisted spatiotemporal reshaping of the infrared driving pulse, enabling transient phase-matching gating and the generation of bright, high-contrast IAPs. Our experimental and theoretical results reveal that a semi-infinite gas cell naturally forms a stable propagation region, where the driving pulse undergoes controlled self-compression and spatial cleaning. In an argon-filled gas cell, filamentation reduces the duration of Ytterbium-based 1030 nm pulses from 4.7 fs to 3.5 fs, while simultaneously producing high-contrast IAPs of 200 as, at 65 eV, with an excellent output beam profile. Similar filamentation-assisted transient gating is observed in neon and helium, yielding pulses of 69 as at 100 eV and 65 as at 135 eV. This filamentation-enabled transient phase-matching mechanism opens a simple and robust route to provide high-contrast attosecond sources, advancing both post-compression techniques and attosecond-based technologies.

Conflictos rurales y edificios. La Meseta del Duero (siglos XI-XIII)

2026-06-02T00:02:24Z

[EN] This study examines conflicts surrounding buildings within the rural context of the Duero Plateau. These conflicts can be analysed from various perspectives, but this work focuses on integrating them into the role of ‘micropolitics’ in organizing rural society during this period. The concept refers to local decision-making and political management practices, often informal yet prevalent in local populations. A key aspect is collective action, involving diverse groups (families, clients, local communities) and generating tensions among different collectives. During the high medieval period in this region, resident communities were the most visible actors in collective actions, though not the only ones. This study emphasizes the role of these rural communities due to their visibility and strongly rooted identity, which included distinct political notions.

Not only Food. Marine, Terrestrial and Freshwater Molluscs in Archaeological Sites

2026-05-30T00:02:17Z

[EN] Proceedings of the 2nd Meeting of the ICAZ Archaeomalocology Working Group (Santander, February 19th-22nd 2008).

Shell Midden people in Northern Iberia. New data from the Mesolithic rock shelter of J3 (Basque Country, Spain).

2026-05-30T00:02:16Z

[EN] In the course of a sondage dug in the rock shelter of J3, in the Jaizkibel mountains (at the north-western tip of Guipúzcoa), the body of a adult man was located buried inside a shell midden. This shell midden had not been disturbed and presented internal stratigraphy features. In any case, the outer edge of the shell midden does show some interesting interdigitation with the adjacent habitational layers, with evidence of different stages of occupation. Within the shell midden itself, under the individual buried there, it was possible to observe layers without any ceramics, whereas the layers covering said individual included ceramic fragments. This individual has been dated to 8300 BP and therefore corresponds to a Mesolithic context

Archaeological Data On The Exploitation Of The Goose Barnacle Pollicipes Pollicipes (Gmelin, 1790) in Europe

2026-05-30T00:02:15Z

[EN] Barnacles of the species Pollicipes pollicipes are crustaceans that nowadays live on wave-beaten rocky substrates in the intertidal and low-shore zones on the coasts of Atlantic Europe and North Africa. At the present time, the exploitation of this species is profitable, especially in northern Spain where this seafood is highly valued, as well as expensive. However, the gathering of this resource, which is carried out manually by the percebeiros or ‘‘goose barnacle fishers’’ entails great risks. The exploitation of goose barnacles is, however, not a recent activity, as evidence of it has been seen in southwest Europe in the Mesolithic (about 8000 BP), and above all from the early Neolithic (about 6000 BP). This paper analyses the archaeological evidence of barnacles (tergum, scutum and carina, calcareous plates located in the capitulum) that have been found at one Spanish Neolithic site located in the north of the Iberian Peninsula (Los Gitanos Cave, in Cantabrian Spain).

Shell beads of the Last Hunther-Gatherers and Earliest Farmersin South-Western Europe

2026-05-30T00:02:14Z

[EN] This paper analyses the suspended objects of adornment made from marine mollusc shells that have been recorded at Mesolithic and Neolithic sites in southwest Europe. Particular attention will be given to taxonomic determination, technological aspects and the strategies utilised to obtain the raw materials for these objects. The distribution of certain species and the types of ornamentation used by the last hunter-gatherers and first farming communities will also be discussed.