Atomic-Scale Description of the Magnetic TiN|FeCo Multilayers.

Motivated by the experimental findings of Wolff et al., we investigated the TiN|FeCo multilayers at the atomic scale. Four different models were employed to investigate the interface, considering both Fe and Co surface terminations of the FeCo compounds. The interface formation energy formalism was employed to study the thermodynamic stability of these models. The results show that an interface mediated by Co atoms is most likely to appear in the experiment. Also, the Fe surface termination is more viable than a Co surface termination. The magnetic moments of Co at the interface are 1.48 µB/atom, which denotes a decay compared to bulk (1.76 µB/atom). Besides, Ti acquires a very small induced magnetization of -0.05 µB/atom. Our proposed atomistic model of the TiN|FeCo multilayer system fits perfectly with the structure obtained in experiments, and it is a step forward in the theoretical-experimental design of wear-resistant coatings with outstanding magnetic and mechanical properties.

Histone deacetylase inhibition mitigates fibrosis-driven disease progression in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a blistering disease caused by mutations in the gene encoding type VII collagen (C7). RDEB is associated with fibrosis, which is responsible for severe complications. The phenotypic variability observed in RDEB siblings suggests that epigenetic modifications contribute to disease severity. Identifying epigenetic changes may help to uncover molecular mechanisms underlying RDEB pathogenesis and new therapeutic targets. OBJECTIVES: To investigate histone acetylation in RDEB skin and to explore histone deacetylase inhibitors (HDACis) as therapeutic molecules capable of counteracting fibrosis and disease progression in RDEB mice. METHODS: Acetylated histone levels were detected in human skin by immunofluorescence and in RDEB fibroblasts by ELISA. The effects of Givinostat and valproic acid (VPA) on RDEB fibroblast fibrotic behaviour were assessed by collagen-gel contraction assay, Western blot and immunocytofluorescence for α-smooth muscle actin, ELISA for released transforming growth factor-ß1 (TGF-ß1). RNA-seq was performed in HDACi- and vehicle-treated RDEB fibroblasts. VPA was systemically administered to RDEB mice, and effects on overt phenotype were monitored. Fibrosis was investigated in the skin using histological and immunofluorescence analyses. Eye and tongue defects were examined microscopically. Mass spectrometry proteomics was performed on skin protein extracts from VPA-treated RDEB and control mice. RESULTS: Histone acetylation decreases in RDEB skin and primary fibroblasts. RDEB fibroblasts treated with HDACis lowered fibrotic traits including contractility, TGF-ß1 release, and proliferation. VPA administration to RDEB mice mitigated severe manifestations affecting eyes and paws. These effects were associated with fibrosis inhibition. Proteomic analysis of mouse skin revealed that VPA almost normalised protein sets involved in protein synthesis and immune response, processes linked to the increased susceptibility to cancer and bacterial infections observed in RDEB patients. CONCLUSIONS: Dysregulated histone acetylation contributes to RDEB pathogenesis by facilitating the progression of fibrosis. Repurposing of HDACi could be considered for disease-modifying treatments of RDEB.

ChatGPT as an information tool in rhinology. Can we trust each other today?

PURPOSE: ChatGPT (Chat-Generative Pre-trained Transformer) has proven to be a powerful information tool on various topics, including healthcare. This system is based on information obtained on the Internet, but this information is not always reliable. Currently, few studies analyze the validity of these responses in rhinology. Our work aims to assess the quality and reliability of the information provided by AI regarding the main rhinological pathologies. METHODS: We asked to the default ChatGPT version (GPT-3.5) 65 questions about the most prevalent pathologies in rhinology. The focus was learning about the causes, risk factors, treatments, prognosis, and outcomes. We use the Discern questionnaire and a hexagonal radar schema to evaluate the quality of the information. We use Fleiss's kappa statistical analysis to determine the consistency of agreement between different observers. RESULTS: The overall evaluation of the Discern questionnaire resulted in a score of 4.05 (± 0.6). The results in the Reliability section are worse, with an average score of 3.18. (± 1.77). This score is affected by the responses to questions about the source of the information provided. The average score for the Quality section was 3.59 (± 1.18). Fleiss's Kappa shows substantial agreement, with a K of 0.69 (p < 0.001). CONCLUSION: The ChatGPT answers are accurate and reliable. It generates a simple and understandable description of the pathology for the patient's benefit. Our team considers that ChatGPT could be a useful tool to provide information under prior supervision by a health professional.

Human Hsp70 Substrate-Binding Domains Recognize Distinct Client Proteins.

The 13 Hsp70 proteins in humans act on unique sets of substrates with diversity often being attributed to J-domain-containing protein (Hsp40 or JDP) cofactors. We were therefore surprised to find drastically different binding affinities for Hsp70-peptide substrates, leading us to probe substrate specificity among the 8 canonical Hsp70s from humans. We used peptide arrays to characterize Hsp70 binding and then mined these data using machine learning to develop an algorithm for isoform-specific prediction of Hsp70 binding sequences. The results of this algorithm revealed recognition patterns not predicted based on local sequence alignments. We then showed that none of the human isoforms can complement heat-shocked DnaK knockout Escherichia coli cells. However, chimeric Hsp70s consisting of the human nucleotide-binding domain and the substrate-binding domain of DnaK complement during heat shock, providing further evidence in vivo of the divergent function of the Hsp70 substrate-binding domains. We also demonstrated that the differences in heat shock complementation among the chimeras are not due to loss of DnaJ binding. Although we do not exclude JDPs as additional specificity factors, our data demonstrate substrate specificity among the Hsp70s, which has important implications for inhibitor development in cancer and neurodegeneration.

Bow and Lean Test for Rare Variants of Vertical Semicircular Canal BPPV.

OBJECTIVE: The objective of this study was to assess the clinical significance of the Bow and Lean Test (BLT) for the diagnosis of different variants of vertical canal Benign Paroxysmal Positional Vertigo (BPPV). BLT is commonly used for diagnoses of lateral semicircular canal (LSC) BPPV. However, vertical nystagmus in the BLT may indicate the presence of other variants such as PSC-BPPV. METHODS: 567 patients with vertical canal BPPV were recruited. Patients with anterior semicircular canal (ASC) or PSC-BPPV were weekly examined until the negativization of BPPV. Nystagmus characteristics during BLT were analyzed. RESULTS: Of 567 patients with vertical canal BPPV, 1.4% had ASC-BPPV. BLT was positive in 155 patients, showing patterns like down-beating nystagmus in bowing and no nystagmus in leaning (15.52% of patients), and down-beating in bowing and up-beating in leaning (6.17%), which was predominantly present in PSC-canalolithiasis. Statistically significant differences were observed in the direction of nystagmus provoked by BLT in PSC-BPPV subtypes. No significant differences were found in nystagmus latency or duration during BLT positions. Among BPPV subtypes, there was a significant difference in nystagmus duration and latency, especially between cupulolithiasis and other variants. BLT's sensitivity was 0.93 in bowing and 1 in a leaning position, while specificity was 0.93 and 0.82 respectively. CONCLUSION: Beyond the LSC, the BLT has expanded to other variants. However, study results differ likely due to variations in patient characteristics and test execution. Currently, no specific features for ASC have been found to differentiate it from PSC-BPPV limiting the test's use for this variant. LEVEL OF EVIDENCE: 3, according to Oxford Center for Evidence-Based Medicine Laryngoscope, 134:2405-2410, 2024.

Atomic-scale study of TiO2-GR nanohybrid formation by ALD: the effect of the gas phase precursor.

In the present work, we report on a theoretical-computational study of the growth mechanism of the TiO2-Graphene nanohybrid by atomic layer deposition. Hydroxyl groups (OH) are anchoring sites for interacting with the main ALD titanium precursors (Tetrakis (dimethylamino) Titanium, Titanium Tetrachloride, and Titanium Isopropoxide). Results demonstrate that the chemical nature of the precursor directly affects the reaction mechanism in each ALD growth step. Tetrakis(dimethylamino)titanium is the precursor that presents a higher affinity (lower energy barriers for the reaction) to hydroxylated graphene in the growth process. A complete reaction mechanism for each precursor was proposed. The differences between precursors were discussed through the non-covalent interactions index. Finally, the water molecules help reduce the energy barriers and consequently favor the formation of the TiO2-graphene nanohybrid.

Transfusion with Blood Plasma from Young Mice Affects rTg4510 Transgenic Tau Mice Modeling of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the buildup of plaques and tangles in the brain. Tangles are formed when the stabilizing protein, tau, becomes hyperphosphorylated and clumps together. There are limited treatments for AD; therefore, the exploration of new treatments is warranted. Previous research showed that plasma transfusion from young donor mice improved spatial memory and increased synaptic proteins in old transgenic APP/PS1 mice, suggesting a remediation of memory and synaptic function. In the current study, plasma was transfused from 2-3-month-old young wildtype mice (WT) to 8-month-old rTg4510 mice expressing human tau (Tau). One week after the transfusions, behavior and tau pathology were examined. We found that Tau mice injected with plasma had lower expression of phosphorylated tau (ptau) in the brain, accompanied by fewer tau tangles in the cortex and CA1 region of the hippocampus and smaller tau tangles in the cortex, when compared to Tau mice injected with saline. Despite no improvement in behavior, the decreased level of ptau and tangles open the door to future studies involving plasma transfusions.

Potential long consequences from internal and external ecology: loss of gut microbiota antifragility in children from an industrialized population compared with an indigenous rural lifestyle.

Human health is strongly mediated by the gut microbiota ecosystem, which, in turn, depends not only on its state but also on its dynamics and how it responds to perturbations. Healthy microbiota ecosystems tend to be in criticality and antifragile dynamics corresponding to a maximum complexity configuration, which may be assessed with information and network theory analysis. Under this complex system perspective, we used a new analysis of published data to show that a children's population with an industrialized urban lifestyle from Mexico City exhibits informational and network characteristics similar to parasitized children from a rural indigenous population in the remote mountainous region of Guerrero, México. We propose then, that in this critical age for gut microbiota maturation, the industrialized urban lifestyle could be thought of as an external perturbation to the gut microbiota ecosystem, and we show that it produces a similar loss in criticality/antifragility as the one observed by internal perturbation due to parasitosis by the helminth A. lumbricoides. Finally, several general complexity-based guidelines to prevent or restore gut ecosystem antifragility are discussed.

Strain Effects on the Two-Dimensional Cr2N MXene: An Ab Initio Study.

Structural, electronic, and magnetic properties of two-dimensional Cr2N MXene under strain were studied. The uniaxial and biaxial strain was considered from -5 to 5%. Phonon dispersion was calculated; imaginary frequency was not found for both kinds of strain. Phonon density of states displays an interesting relation between strain and optical phonon gaps (OPGs), that it implies tunable thermal conductivity. When we apply biaxial tensile strain, the OPG increases; however, this is not appreciable under uniaxial strain. The electronic properties of the dynamically stable systems were investigated by calculating the band structure and electron localization function (ELF) along the (110) plane. The band structure showed a metallic behavior under compressive strain; nevertheless, under tensile strain, the system has a little indirect band gap of 0.16 eV. By analyzing, the ELF interactions between Cr-N are determined to be a weaker covalent bonding Cr2N under tensile strain. On the other hand, if the Cr atoms reduce or increase their self-distance, the magnetization alignment changes, also the magnetic anisotropy energy displays out-of-plane spin alignment. These properties extend the potential applications of Cr2N in the spintronic area as long as they can be grown on substrates with high lattice mismatch, conserving their magnetic properties.

Long-Term Evolution of Vestibular Compensation, Postural Control, and Perceived Disability in a Population of Patients with Vestibular Neuritis.

OBJECTIVES: The aim was to analyze and compare the compensatory process, vestibular dysfunction, postural control, and perceived disability in a population of patients with vestibular neuritis (VN). MATERIAL AND METHODS: This is a prospective and longitudinal study of 67 patients diagnosed with VN. Inclusion criteria were sudden onset of vertigo, unidirectional spontaneous horizontal nystagmus, and impairment in vestibular test. Exclusion criteria were imaging or clinical findings of any neurotologic disorder. All vestibular tests were performed; vHIT, vestibular evoked myogenic potentials (VEMPs), caloric test and computerized dynamic posturography (CDP), dizziness handicap inventory (DHI), and visual analogue scale (VAS) were also performed at every follow up. RESULTS: We observed a correlation between the composite score of CDP and baseline vestibular function elicited either by caloric test, VEMPs, or vHIT. There was a significant correlation between baseline vestibular function and first visit questionnaire scores. The main gain recovery for the horizontal canal was 0.1 ± 0.04 for the first three months. After that, the gain recovery significantly decreased. The presence of covert and overt saccades', latency and amplitude decreased, respectively, after the 6-month period, when compared to the baseline results. We also observed a decrease in the PR score from 3 months after the vestibular insult until the last follow up. We observed a significant decrease in DHI and VAS from the first visit until the last one. Those patients with an initial HC gain below 0.5 had significantly higher DHI and VAS scores at every follow up. CONCLUSIONS: There are different measurements that could become a complete measurement of the state of compensation, postural control, and disability of the patients. There is a time window in which the vestibular restoration could give us clinical insights regarding the management of VN patients.

Incorporating the Concept of Relevance in Clinical Rehabilitation Research and Its Reviews May Improve Uptake by Stakeholders.

ABSTRACT: The "relevance" of research to stakeholders is an important factor in influencing the uptake of new knowledge into practice; however, this concept is neither well defined nor routinely incorporated in clinical rehabilitation research. Developing a uniform definition, measurement standards, stakeholder engagement strategies, and guiding frameworks that bolster relevance may help incorporate the concept as a key element in research planning and design. This article presents a conceptual argument for why relevance matters, proposes a working definition, and suggests strategies for operationalizing the construct in the context of clinical rehabilitation research. We place special emphasis on the importance of promoting relevance to patients, caregivers, and clinicians and provide preliminary frameworks and innovative study designs that can assist clinical rehabilitation researchers in doing so. We argue that researchers who include a direct statement regarding why and to whom a study is relevant and who incorporate considerations of relevance throughout all phases of study design produce more useful research for patients, caregivers, and clinicians, increasing its chance of uptake into practice. Consistent consideration of relevance, particularly to nonacademic audiences, during the conceptualization, study design, presentation, and dissemination of clinical rehabilitation research may promote the uptake of findings by patients, caregivers, and providers.

A Biomechanical Analysis of Prophylactic Mesh Reinforced Porcine Laparotomy Incisions.

INTRODUCTION: Research indicates that prophylactic mesh may help prevent incisional hernia after laparotomy, but best practice patterns in these situations are still evolving. Here, we compare the failure loads (FLs) and biomechanical stiffness (BMS) of 35 porcine abdominal wall laparotomy incisions reinforced with meshes of various widths and fixation distances using biomechanical testing. METHODS: In each specimen, a 10-cm incision was made and closed using continuous 1-0 Maxon suture. Specimens were randomized to mesh width (none, 2.5 cm, 3 cm, 4 cm, 6 cm, 8 cm) and tack separation (1.5 cm, 2 cm apart) and the meshes secured in an onlay fashion. Cyclic loads oscillating from 15 N to 140 N were applied to simulate abdominal wall stress, and the specimens subsequently loaded to failure. FLs (N) and BMS (N/mm) were comparatively analyzed. RESULTS: All specimens failed via suture pull-through. FLs and BMS were lowest in specimens with suture-only (421.43 N; 11.69 N/mm). FLs and BMS were significantly higher in 4-cm mesh specimens (567.51 N) than those with suture, 2.5-cm, and 3.0-cm mesh (all P < 0.05). FLs in specimens with a greater number of tacks were consistently higher in meshes of similar sizes, although these did not reach significance. CONCLUSIONS: A 4-cm mesh reenforcement was superior to suture-only and smaller meshes at preserving strength in laparotomy closure in a porcine model but larger meshes (6 cm, 8 cm) did not provide an additional benefit. Meshes with more fixation points may be advantageous, but additional data are needed to make definitive conclusions.

High-Resolution Structure of the Nuclease Domain of the Human Parvovirus B19 Main Replication Protein NS1.

Two new structures of the N-terminal domain of the main replication protein, NS1, of human parvovirus B19 (B19V) are presented here. This domain (NS1-nuc) plays an important role in the "rolling hairpin" replication of the single-stranded B19V DNA genome, recognizing origin of replication sequences in double-stranded DNA, and cleaving (i.e., nicking) single-stranded DNA at a nearby site known as the terminal resolution site (trs). The three-dimensional structure of NS1-nuc is well conserved between the two forms, as well as with a previously solved structure of a sequence variant of the same domain; however, it is shown here at a significantly higher resolution (2.4 Å). Using structures of NS1-nuc homologues bound to single- and double-stranded DNA, models for DNA recognition and nicking by B19V NS1-nuc are presented that predict residues important for DNA cleavage and for sequence-specific recognition at the viral origin of replication. IMPORTANCE The high-resolution structure of the DNA binding and cleavage domain of the main replicative protein, NS1, from the human-pathogenic virus human parvovirus B19 is presented here. Included also are predictions of how the protein recognizes important sequences in the viral DNA which are required for viral replication. These predictions can be used to further investigate the function of this protein, as well as to predict the effects on viral viability due to mutations in the viral protein and viral DNA sequences. Finally, the high-resolution structure facilitates structure-guided drug design efforts to develop antiviral compounds against this important human pathogen.

Predicting the stability and electronic structure of alkali metal aurides.

Density functional theory calculations of phonon modes predict that some compounds of the alkali metal aurides family, general formulaA2MAu6(A= K, Rb or Cs;M= Ti, Zr, Hf, Sn or Pb), have stable three-dimensional phase with a double perovskite-type structure and cubicFm3¯mspace group (K2PtCl6-type). Bader's charge analysis shows that most electron density is located within the six atoms at the octahedra vertices like double perovskite halides. However, the short spacing between Au anions enables d-orbital interactions between them. Compounds of this family, with group 4 metals only, carry conduction states around the Γ point (k= 0). On the other hand, compounds with group 14 metals possess more conduction states around all the Brillouin zone and have electron pockets in their band structures. These compounds provide further insights into the unusual anionic behavior of gold and present other alternatives for the construction of divergent nanodevices.

Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

Clinical Subtypes and vHIT Parameters in a Population With Bilateral Vestibulopathy.

Objective: To evaluate the different peripheral, neurological, genetic, and systemic etiologies of bilateral vestibulopathy (BVP) and the value of vHIT in the diagnostic process. Materials and methods: A retrospective case review was performed on 176 patients diagnosed with BVP in a tertiary referral center, between 2010 and 2020. Inclusion criteria comprised imbalance and/or oscillopsia during locomotion and horizontal angular VOR gain on both sides <0.8. We classified patients into different groups according to (1) their fulfillment of the Barany guideline for bilateral vestibulopathy (2) the definite etiology of BVP and (3) the four clinical subtypes distributed in our population (recurrent vertigo with BVP, rapidly progressive BVP, slowly progressive BVP, and slowly progressive BVP with ataxia). Medical history of vertigo, hypoacusis or migraine, and family background of imbalance and/or oscillopsia were assessed. Horizontal, posterior, and superior semicircular canal angular VOR gain was registered along with saccadic parameters such as velocity, and dispersion of the saccades' latency values. Results: Barany's Society diagnostic criteria for BVP was accomplished in 89 patients. Among our patients, 13.6% had migraines in their medical history and the idiopathic group accounted for 50% of the population. All four clinical subtypes were found in our population, slowly progressive bilateral vestibulopathy without vertigo was the most frequent one. A percentage of our population could not be categorized into any of the former subtypes, many of these patients were diagnosed with BVP after suffering a single vertigo episode. Lower vHIT gains were found in those patients with Barany's criteria for BVP and oscillopsia was significantly more prevalent in this group. Conclusions: Bilateral vestibulopathy manifests with very different patterns representing a very heterogeneous condition. The distribution of the clinical subtypes and Barany's criteria are a useful clinical tool to differentiate groups of patients. The vHIT can serve as an initial tool for identifying patients with BVP. The finding of bilateral vestibular involvement in a clinically suspected unilateral vestibulopathy should be considered in some patients.

Long-term follow-up of olfactory and gustatory dysfunction in COVID-19: 6 months case-control study of health workers.

PURPOSE: The study aimed to determine the incidence and long-term evolution of COVID-related olfactory (OD) and gustatory (GD) dysfunction, the recovery timeline, and the association with other symptoms. The secondary objective was to identify the predictive clinical factors for the evolution of these symptoms. METHODS: A prospective case-control study was conducted from March 15 to October 15, 2020, in health workers with COVID-19 related symptoms in a tertiary care hospital. 320 patients were included after 6 months of follow-up: 195 in the case group and 125 in the control group. Olfactory dysfunction (OD), dysosmia, and gustatory dysfunction (GD) onset and recovery rate after 6 months follow-up are analyzed in both groups. RESULTS: There were 125 (64.1%) in case group patients with OD and 118 (60.5%) with GD. Total or partial recovery OD and GD was found in 89%, mainly in the first 2 months. In the control group, there were 14 (11.2%) patients with OD and 33 (26.4%) patients with GD, with 100% of total/partial recovery. CONCLUSION: In both groups, OD and GD showed high-resolution rates during the first two months after the onset of symptoms. Nevertheless, 11% of the case group patients did not show any recovery, and the partial resolution was present in 30% of our patients, at the 6 months follow-up. We found a high correlation between OD and GD, both in the appearance of symptoms and in their recovery. Nasal obstruction and dyspnea have been identified as risk factors for the persistence of symptoms.

Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment.

CADASIL is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the EGF-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraine, psychiatric disturbances, recurrent strokes and dementia, being executive function characteristically impaired. The molecular pathways altered by this receptor aggregation need to be studied further. A genome-wide transcriptome study (four cases paired with three healthy siblings) was carried out, in addition to a qRT-PCR for validation purposes (ten new cases and eight new controls). To study the expression profile by cell type of the significant mRNAs found, we performed an in situ hybridization (ISH) (nine cases and eight controls) and a research in the Single-nuclei Brain RNA-seq expression browser (SNBREB). Pathway analysis enrichment was carried out with Gene Ontology and Reactome. Neuropsychological tests were performed in five of the qRT-PCR cases. The two most significant differentially expressed mRNAs (BANP, p-value = 7.23 × 10-4 and PDCD6IP, p-value = 8.36 × 10-4) were selected for the validation study by qRT-PCR. Additionally, we selected two more mRNAs (CAMK2G, p-value = 4.52 × 10-3 and E2F4, p-value = 4.77 × 10-3) due to their association with ischemic neuronal death. E2F4 showed differential expression in the genome-wide transcriptome study and in the qRT-PCR (p = 1.23 × 10-3), and it was upregulated in CADASIL cases. Furthermore, higher E2F4 expression was associated with worse executive function (p = 2.04 × 10-2) and attention and information processing speed (IPS) (p = 8.73 × 10-2). In situ hibridization showed E2F4 expression in endothelial and vascular smooth vessel cells. In silico studies indicated that E2F4 is also expressed in brain endothelial cells. Among the most significant pathways analyzed, there was an enrichment of vascular development, cell adhesion and vesicular machinery terms and autophagy process. E2F4 is more highly expressed in the skin biopsy of CADASIL patients compared to controls, and its expression is present in endothelial cells and VSMCs. Further studies are needed to understand whether E2F4 could be useful as a biomarker, to monitor the disease or be used as a therapeutic target.

Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma.

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 × 10-5 were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 × 10-8) were characterized by in silico functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 × 10-8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 × 10-8; OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.