Magnetoelastic Coupling Evidence by Anisotropic Crossed Thermal Expansion in Magnetocaloric RSrCoFeO6 (R = Sm, Eu) Double Perovskites.

Double perovskite oxides, characterized by their tunable magnetic properties and robust interconnection between the lattice and magnetic degrees of freedom, present an enticing foundation for advanced magnetic refrigeration materials. Herein, we delve into the influence of rare-earth elements on RSrCoFeO6 (R = Sm, Eu) disordered double perovskites by examining their structural, electronic, magnetic, and magnetocaloric properties. Temperature-dependent synchrotron X-ray diffraction analysis confirmed the stability of the orthorhombic phase (Pnma) across a wide temperature range. X-ray photoemission spectroscopy revealed that both Sm and Eu are in the 3+ state, whereas multiple states for Co2+/3+ and Fe3+/4+ are identified. The magnetic investigation and magnetocaloric effect (MCE) analysis brought to light the presence of a long-range antiferromagnetic (AFM) order with a second-order phase transition (SOPT) in both samples. The maximum magnetic entropy change ΔSMmax was approximately 0.9 J/kg K for both samples at applied field 0-7 T, manifesting prominently above Neel temperatures TN ≈ 93 K (Sm) and 84 K (Eu). Nevertheless, different relative cooling powers (RCP) of 112.6 J/kg (Sm) and 95.5 J/kg (Eu) were observed. A detailed analysis of the temperature-dependent lattice parameters shed light on a distinct magnetocaloric effect across the magnetic transition temperature, unveiling an anisotropic thermal expansion [αV = 1.41 × 10-5 K-1 (Sm) and αV = 1.54 × 10-5 K-1 (Eu)] wherein the thermal expansion axial ratio αbSm/αbEu = 0.61 became lower with increasing temperature, which suggests that the Eu sample experiences a greater thermal expansion in the b-axis direction. At the atomic bonding level, the evidence for magnetoelastic coupling around the magnetic transition temperatures TN was found through the anomalies along the average Co/Fe-O bond distance, formal valence, octahedral distortion, as well as an anisotropic lattice expansion.

Multimodal neuroimaging in post-COVID syndrome and correlation with cognition.

Brain changes have been reported in the first weeks after SARS-CoV-2 infection. However, limited literature exists about brain alterations in post-COVID syndrome, a condition increasingly associated with cognitive impairment. The present study aimed to evaluate brain functional and structural alterations in patients with post-COVID syndrome, and assess whether these brain alterations were related to cognitive dysfunction. Eighty-six patients with post-COVID syndrome and 36 healthy controls were recruited and underwent neuroimaging acquisition and a comprehensive neuropsychological assessment. Cognitive and neuroimaging examinations were performed 11 months after the first symptoms of SARS-CoV-2. Whole-brain functional connectivity analysis was performed. Voxel-based morphometry was performed to evaluate grey matter volume, and diffusion tensor imaging was carried out to analyse white-matter alterations. Correlations between cognition and brain changes were conducted and Bonferroni corrected. Post-COVID syndrome patients presented with functional connectivity changes, characterized by hypoconnectivity between left and right parahippocampal areas, and between bilateral orbitofrontal and cerebellar areas compared to controls. These alterations were accompanied by reduced grey matter volume in cortical, limbic and cerebellar areas, and alterations in white matter axial and mean diffusivity. Grey matter volume loss showed significant associations with cognitive dysfunction. These cognitive and brain alterations were more pronounced in hospitalized patients compared to non-hospitalized patients. No associations with vaccination status were found. The present study shows persistent structural and functional brain abnormalities 11 months after the acute infection. These changes are associated with cognitive dysfunction and contribute to a better understanding of the pathophysiology of the post-COVID syndrome.

Persistent olfactory dysfunction after COVID-19 is associated with reduced perfusion in the frontal lobe.

BACKGROUND: Olfactory dysfunction is common during SARS-CoV-2 infection. The pathophysiology of the persistence of this symptom and the potential relationship with central nervous system involvement is unknown. AIM OF THE STUDY: To evaluate the neural correlates of persistent olfactory dysfunction in a series of patients with post-COVID syndrome. METHODS: Eighty-two patients with post-COVID syndrome were assessed with the Brief Smell Identification Test and a multimodal MRI study including 3D-T1, T2-FLAIR, diffusion-tensor imaging, and arterial spin labeling. Olfactory and neuroimaging examinations were performed 11.18 ± 3.78 months after the acute infection. Voxel-based brain mapping analyses were conducted to correlate the olfactory test with brain volumes, white matter microstructure, and brain perfusion. RESULTS: Olfactory dysfunction was associated with lower tissue perfusion in the orbital and medial frontal regions in the arterial spin labeling sequence. Conversely, no statistically significant findings were detected in brain volumes and diffusion-tensor imaging. Mild changes in paranasal sinuses and nasal cavities were detected in 9.75% of cases, with no association with olfactory deficits. CONCLUSIONS: We provide new insights regarding the pathophysiology of persistent olfactory dysfunction after COVID-19, involving the main brain regions associated with the olfactory system.

Raman amplification in the ultra-small limit of Ag nanoparticles on SiO2 and graphene: Size and inter-particle distance effects.

Size, shape and hot spots are crucial to optimize Raman amplification from metallic nanoparticle (NPs). The amplification from radius = 1.8 ± 0.4 nm ultra-small silver NPs was explored. Increasing NP density redshifts and widens their plasmon that, according to simulations for NPs arrays, is originated by the reduction of the interparticle distance, d, becoming remarkable for d ≤ R. Inter-particle interaction red-shifts (N130 nm) and widens (N90 nm) the standard plasmon of non-interacting spherical particles. Graphene partly delocalizes the carriers enhancing the NIR spectral weight. Raman amplification of graphene phonons is moderate and depends smoothly on d while that of Rhodamine 6G (R6G) varies almost exponentially due to their location at hotspots that depend strongly on d. The experimental correlation between amplification and plasmon position is well reproduced by simulations. The amplification originated by the ultra-small NPs is compared to that of larger particles, granular silver films with 7 < R < 15 nm grains, with similar extinction values. The amplification is found to be larger for the 1.8nm NPs due to the higher surface/volume ration that allows higher density of hot spots. It is demonstrated that Raman amplification can be efficiently increased by depositing low density layers of ultra-small NPs on top of granular films.

Net contribution and predictive ability of the CUN-BAE body fatness index in relation to cardiometabolic conditions.

BACKGROUND: The CUN-BAE (Clínica Universidad de Navarra-Body adiposity estimator) index is an anthropometric index based on age, sex and body mass index (BMI) for a refined prediction of body fatness in adults. CUN-BAE may help detect metabolically unhealthy individuals with otherwise normal weight according to BMI or waist circumference (WC). The aim of this study was to evaluate whether CUN-BAE, independent of its components (BMI, age and sex), was associated with cardiometabolic conditions including arterial hypertension, diabetes mellitus and metabolic syndrome (MetS). METHODS: The ENRICA study was based on a cross-sectional sample of non-institutionalized men and women representative of the adult Spanish population. Body weight, height, and WC were measured in all participants. The residual of CUN-BAE (rCUN-BAE), i.e. the part of the index not explained by its components, was calculated. The associations of CUN-BAE, rCUN-BAE, BMI and WC with hypertension, diabetes and MetS were analysed by multivariate logistic regression, and the Akaike information criterion (AIC) was calculated. RESULTS: The sample included 12,122 individuals. rCUN-BAE was associated with hypertension (OR 1.14, 95% CI 1.07-1.21) and MetS (OR 1.48, 1.37-1.60), but not with diabetes (OR 1.05, 0.94-1.16). In subjects with a BMI < 25 kg/m2, CUN-BAE was significantly associated with all three outcome variables. CUN-BAE was more strongly associated with the cardiometabolic conditions than BMI and WC and fit similar AICs. CONCLUSIONS: The CUN-BAE index for body fatness was positively associated with hypertension, diabetes and MetS in adults independent of BMI or WC. CUN-BAE may help to identify individuals with cardiometabolic conditions beyond BMI, but this needs to be confirmed in prospective settings.

Synergic antibacterial coatings combining titanium nanocolumns and tellurium nanorods.

Nanocolumnar titanium coatings have been fabricated in two sputtering systems with very different characteristics (a laboratory setup and semi-industrial equipment), thus possessing different morphologies (150 nm long columns tilted 20° from the normal and 300 nm long ones tilted 40°, respectively). These coatings exhibit similar antibacterial properties against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli) bacteria. When a synergic route is followed and these coatings are functionalized with tellurium (Te) nanorods, the antibacterial properties are enhanced, especially for the long nanocolumns case. The biocompatibility is preserved in all the nanostructured coatings.

Effects of Enterococcus faecalis UGRA10 and the enterocin AS-48 against the fish pathogen Lactococcus garvieae. Studies in vitro and in vivo.

The aim of this study was to evaluate the effects of Enterococcus faecalis UGRA10 and its enterocin AS-48 against the fish pathogen Lactococcus garvieae. The minimum bactericidal concentrations of AS-48 against L. garvieae CECT 5807, 5806, and 5274 were 15.62, 15.62, and 7.81 µg/ml respectively. In broth cultures, enterocin at 100, 50, and 25 µg/ml reduced 108 CFU/ml lactococci after 2, 5, and 10 h, respectively. In co-cultures of UGRA10/L. garvieae at a 1/10 CFU/ml ratio, lactococci were eliminated after 24 h. Studies on UGRA10 biosafety and AS-48 toxicity in R1 cells and in rainbow trout have shown a lack of adverse effects from both the strain and bacteriocin. Trout challenged with L. garvieae and UGRA10 administered in diet 30 days before infection had a cumulative survival rate of 50% compared with 0% for control fish. Trout inoculated with the pathogen and treated by regular dipping in AS-48 baths had a survival rate of 60% after 20 days compared with that of untreated fish (0%). These results indicate the protective effect of the UGRA10 strain and the bacteriocin AS-48 against L. garvieae and the potential of these natural products as alternatives to antibiotics for controlling diseases in aquaculture.

Ipsilateral hemiparesis: the forgotten history of this paradoxical neurological sign.

OBJECTIVE: Establishing the neurological localization doctrine for the contralateral hemispheric control of motor functions in the second half of the 19th century, researchers faced the challenge of recognizing false localizing signs, in particular paradoxical or ipsilateral hemiparesis (IH). Despite tremendous progress in current methods of neuroradiological and electrophysiological exploration, a complete understanding of this phenomenon has yet to be attained. METHODS: The authors researched the well-described cases of hemiparesis/hemiplegia ipsilateral to an intracranial lesion published in the scientific literature in the pre-MRI era (before 1980). A comprehensive review of the physiopathological mechanisms proposed for paradoxical hemiparesis throughout this period, as well as the pathological evidence substantiating them, is provided. RESULTS: A collection of 75 patients with hemiparesis/hemiplegia ipsilateral to the primary intracranial lesion reported between 1858 and 1979 were eligible for analysis. Most cases occurred in adults with supratentorial, slowly developing, extraparenchymatous mass lesions, such as neoplasms (38%) or chronic subdural hematomas (36%). Physiopathological theories proposed by the neurologists who investigated IH can be grouped into 4 major concepts: 1) lack of anatomical decussation of the corticospinal tract; 2) impaired functional activation of the contralateral hemisphere by the lesioned dominant hemisphere through the callosal connections; 3) Kernohan's notch phenomenon, or mechanical injury of the contralateral cerebral peduncle against the free edge of the tentorium; and 4) cerebrovascular dysfunction involving the contralateral hemisphere owing to kinking and mechanical flattening of the carotid artery contralateral to the primary intracranial lesion. CONCLUSIONS: IH represents a still underdiagnosed paradoxical neurological phenomenon. With the aid of modern neuroradiological and neurophysiological methods, Kernohan's peduncle notch mechanism has been confirmed to cause IH in many of the cases reported in recent decades. Nevertheless, alternative functional and/or vascular mechanisms must be investigated further for unexplained IH cases, in particular for transitory IH without evidence of peduncle injury. The historical theories reviewed in this paper represent a conceptual framework that may be helpful for this purpose.

Cardiac deficiency of single cytochrome oxidase assembly factor scox induces p53-dependent apoptosis in a Drosophila cardiomyopathy model.

The heart is a muscle with high energy demands. Hence, most patients with mitochondrial disease produced by defects in the oxidative phosphorylation (OXPHOS) system are susceptible to cardiac involvement. The presentation of mitochondrial cardiomyopathy includes hypertrophic, dilated and left ventricular noncompaction, but the molecular mechanisms involved in cardiac impairment are unknown. One of the most frequent OXPHOS defects in humans frequently associated with cardiomyopathy is cytochrome c oxidase (COX) deficiency caused by mutations in COX assembly factors such as Sco1 and Sco2. To investigate the molecular mechanisms that underlie the cardiomyopathy associated with Sco deficiency, we have heart specifically interfered scox expression, the single Drosophila Sco orthologue. Cardiac-specific knockdown of scox reduces fly lifespan, and it severely compromises heart function and structure, producing dilated cardiomyopathy. Cardiomyocytes with low levels of scox have a significant reduction in COX activity and they undergo a metabolic switch from OXPHOS to glycolysis, mimicking the clinical features found in patients harbouring Sco mutations. The major cardiac defects observed are produced by a significant increase in apoptosis, which is dp53-dependent. Genetic and molecular evidence strongly suggest that dp53 is directly involved in the development of the cardiomyopathy induced by scox deficiency. Remarkably, apoptosis is enhanced in the muscle and liver of Sco2 knock-out mice, clearly suggesting that cell death is a key feature of the COX deficiencies produced by mutations in Sco genes in humans.

Cancer chemoprevention by an adenosine derivative in a model of cirrhosis-hepatocellular carcinoma induced by diethylnitrosamine in rats.

Hepatocellular carcinoma is one of the most common cancers, and approximately 80% develop from cirrhotic livers. We have previously shown that the aspartate salt of adenosine prevents and reverses carbon tetrachloride-induced liver fibrosis in rats. Considering the hepatoprotective role of this adenosine derivative in fibrogenesis, we were interested in evaluating its effect in a hepatocarcinogenesis model induced by diethylnitrosamine in rats, where multinodular cancer is preceded by cirrhosis. Rats were injected with diethylnitrosamine for 12 weeks to induce cirrhosis and for 16 weeks to induce hepatocarcinogenesis. Groups of rats were treated with aspartate salt of adenosine from the beginning of carcinogen administration for 12 or 18 weeks total, and another group received the compound from weeks 12 to 18. Fibrogenesis was estimated and the proportion of preneoplastic nodules and tumors was measured. The apoptotic and proliferation rates in liver tissues were evaluated, as well as the expression of cell signaling and cell cycle proteins participating in hepatocarcinogenesis. The adenosine derivative treatment reduced diethylnitrosamine-induced collagen expression and decreased the proportion of nodules positive for the tumor marker γ-glutamyl transferase. This compound down-regulated the expression of thymidylate synthase and hepatocyte growth factor, and augmented the protein level of the cell cycle inhibitor p27; these effects could be part of its chemopreventive mechanism. These findings suggest a hepatoprotective role of aspartate salt of adenosine that could be used as a therapeutic compound in the prevention of liver tumorigenesis as described earlier for hepatic fibrosis.

Characterization of a stepwise approach in cavotricuspid isthmus ablation for typical atrial flutter: A randomized study comparing three catheters.

INTRODUCTION: Our aim was to characterize a stepwise approach in cavotricuspid isthmus ablation for typical atrial flutter in a prospective, noncrossover randomized study. METHODS: One hundred and fifty patients referred for cavotricuspid isthmus (CTI)-dependent atrial flutter ablation were randomized to undergo an ablation with an 8-mm-tip catheter (group 1), a 3.5-mm open irrigation-tip catheter (group 2), and a 3.5-mm open irrigation porous-tip catheter (group 3). A stepwise approach was performed, changing the ablation site from medial to septal aspects of the CTI, in case it was not effective without crossover between catheters. RESULTS: CTI block was achieved in all the patients using only one catheter. There was a 68% efficacy in group 1, 40% in group 2, and 28% in group 3 to achieve CTI block within 10 minutes (P  =  0.001) and 96%, 70%, and 70% in groups 1, 2, and 3, respectively, within 20 minutes (P  =  0.002) of radiofrequency ablation. The 8-mm catheter was also faster in fluoroscopy time and CTI block time. There were no differences in efficiency in the both irrigated catheters. There were no significant differences in complications among three catheters. CONCLUSIONS: With this stepwise approach, it is possible to achieve CTI block in all cases, using a single catheter without crossover, with good times of procedure and with a low complication rate. The 8-mm solid catheter is faster than the other irrigated-tip catheters. The 3.5-mm open irrigation porous-tip catheter is as effective and safe as the conventional irrigated-tip catheter.

Long-Term Effective Thalamic Deep Brain Stimulation for Neuropathic Tremor in Two Patients with Charcot-Marie-Tooth Disease.

BACKGROUND: It has been described that many Charcot-Marie-Tooth syndrome type 2 patients are affected by a very disabling type of tremor syndrome, the pathophysiology of which remains unclear. Deep brain stimulation (DBS) has been successfully applied to treat most types of tremors by implanting electrodes in the ventral intermediate nucleus of the thalamus (Vim). METHODS: We used DBS applied to the Vim in 2 patients with severe axonal inherited polyneuropathies who developed a disabling tremor. RESULTS: Both patients responded positively to stimulation, with a marked reduction of the tremor and with an improvement of their quality of life. CONCLUSION: We report 2 cases of tremor associated with a hereditary neuropathy with a good response to DBS.

In vivo cell tracking of mouse embryonic myoblasts and fast fibers during development.

Fast and slow TnI are co-expressed in E11.5 embryos, and fast TnI is present from the very beginning of myogenesis. A novel green fluorescent protein (GFP) reporter mouse lines (FastTnI/GFP lines) that carry the primary and secondary enhancer elements of the mouse fast troponin I (fast TnI), in which reporter expression correlates precisely with distribution of the endogenous fTnI protein was generated. Using the FastTnI/GFP mouse model, we characterized the early myogenic events in mice, analyzing the migration of GFP+ myoblasts, and the formation of primary and secondary myotubes in transgenic embryos. Interestingly, we found that the two contractile fast and slow isoforms of TnI are expressed during the migration of myoblasts from the somites to the limbs and body wall, suggesting that both participate in these events. Since no sarcomeres are present in myoblasts, we speculate that the function of fast TnI in early myogenesis is, like Myosin and Tropomyosin, to participate in cell movement during the initial myogenic stages. genesis

Quantitative sensory testing defines the trajectory of sensory neuropathy after severe COVID-19.

AIMS: To assess sensory neuropathy development after severe COVID-19. METHODS: Patients with severe COVID-19 underwent assessment of neuropathic symptoms, tendon reflexes, and quantitative sensory testing to evaluate vibration (VPT), cold (CPT), warm (WPT) and heat perception thresholds (HPT) within 1-3 weeks of admission and after 1-year. RESULTS: 32 participants with severe COVID-19 aged 68.6 ± 12.4 (18.8 % diabetes) were assessed. At baseline, numbness and neuropathic pain were present in 56.3 % and 43.8 % of participants, respectively. On the feet, VPT, WPT, and HPT were abnormal in 81.3 %, CPT was abnormal in 50.0 % and HPT on the face was abnormal in 12.5 % of patients. At 1-year follow-up, the prevalence of abnormal VPT (81.3 % vs 50.0 %, P < 0.01), WPT (81.3 % vs 43.8 %, P < 0.01), and HPT (81.3 % vs 50.0 %, P < 0.01) decreased, with no change in CPT (P = 0.21) on the feet or HPT on the face (P = 1.0). Only participants without diabetes recovered from an abnormal VPT, CPT, and WPT. Patients with long-COVID (37.5 %) had comparable baseline VPT, WPT and CPT with those without long-COVID (P = 0.07-0.69). CONCLUSIONS: Severe COVID-19 is associated with abnormal vibration and thermal thresholds which are sustained for up to 1 year in patients with diabetes. Abnormal sensory thresholds have no association with long-COVID development.

Decoding the best automated segmentation tools for vascular white matter hyperintensities in the aging brain: a clinician's guide to precision and purpose.

White matter hyperintensities of vascular origin (WMH) are commonly found in individuals over 60 and increase in prevalence with age. The significance of WMH is well-documented, with strong associations with cognitive impairment, risk of stroke, mental health, and brain structure deterioration. Consequently, careful monitoring is crucial for the early identification and management of individuals at risk. Luckily, WMH are detectable and quantifiable on standard MRI through visual assessment scales, but it is time-consuming and has high rater variability. Addressing this issue, the main aim of our study is to decipher the utility of quantitative measures of WMH, assessed with automatic tools, in establishing risk profiles for cerebrovascular deterioration. For this purpose, first, we work to determine the most precise WMH segmentation open access tool compared to clinician manual segmentations (LST-LPA, LST-LGA, SAMSEG, and BIANCA), offering insights into methodology and usability to balance clinical precision with practical application. The results indicated that supervised algorithms (LST-LPA and BIANCA) were superior, particularly in detecting small WMH, and can improve their consistency when used in parallel with unsupervised tools (LST-LGA and SAMSEG). Additionally, to investigate the behavior and real clinical utility of these tools, we tested them in a real-world scenario (N = 300; age > 50 y.o. and MMSE > 26), proposing an imaging biomarker for moderate vascular damage. The results confirmed its capacity to effectively identify individuals at risk comparing the cognitive and brain structural profiles of cognitively healthy adults above and below the resulted threshold.

Decoding the Best Automated Segmentation Tools for Vascular White Matter Hyperintensities in the Aging Brain: A Clinician's Guide to Precision and Purpose.

Cerebrovascular damage from small vessel disease (SVD) occurs in healthy and pathological aging. SVD markers, such as white matter hyperintensities (WMH), are commonly found in individuals over 60 and increase in prevalence with age. WMHs are detectable on standard MRI by adhering to the STRIVE criteria. Currently, visual assessment scales are used in clinical and research scenarios but is time-consuming and has rater variability, limiting its practicality. Addressing this issue, our study aimed to determine the most precise WMH segmentation software, offering insights into methodology and usability to balance clinical precision with practical application. This study employed a dataset comprising T1, FLAIR, and DWI images from 300 cognitively healthy older adults. WMHs in this cohort were evaluated using four automated neuroimaging tools: Lesion Prediction Algorithm (LPA) and Lesion Growth Algorithm (LGA) from Lesion Segmentation Tool (LST), Sequence Adaptive Multimodal Segmentation (SAMSEG), and Brain Intensity Abnormalities Classification Algorithm (BIANCA). Additionally, clinicians manually segmented WMHs in a subsample of 45 participants to establish a gold standard. The study assessed correlations with the Fazekas scale, algorithm performance, and the influence of WMH volume on reliability. Results indicated that supervised algorithms were superior, particularly in detecting small WMHs, and can improve their consistency when used in parallel with unsupervised tools. The research also proposed a biomarker for moderate vascular damage, derived from the top 95th percentile of WMH volume in healthy individuals aged 50 to 60. This biomarker effectively differentiated subgroups within the cohort, correlating with variations in brain structure and behavior.

Usefulness of the H-Reflex for Intraoperative Monitoring of Thoracoabdominal Aneurysms.

PURPOSE: Intraoperative neurophysiologic monitoring in thoracoabdominal aneurysms (TAAA) is essential to avoid intraoperative spinal cord injury). Motor and somatosensory evoked potentials may be considered intraoperative tools for detecting spinal cord injury. H-reflex is a well-known neurophysiologic technique to evaluate L5-S1 root. Current evidence supports the observation that H-reflex changes may occur with spinal cord damage as high as the cervical level. This study aimed to evaluate the usefulness of the H-reflex in these surgeries. METHODS: The use of intraoperative H-reflex in TAAA monitoring was evaluated in 12 patients undergoing open or endovascular repair of TAAA for a period of four years (2016-2020) using somatosensory evoked potentials (SSEPs) and transcranial motor evoked potentials (TcMEPs) and bilateral H-reflex. RESULTS: Six neurophysiologic alarms were recorded in five of the 12 patients. Summarizing the neurophysiologic changes of our series, we considered a peripheral change when we detected a unilateral loss of SSEPs, TcMEPs, and H-reflex. Instead, we assumed a central change when we detected a unilateral or bilateral loss of TcMEPs and H-reflex with normal SSEPs, which we considered a sign of spinal cord ischemia. Interestingly H-reflex always changed significantly in combination with TcMEPs in the same fashion. CONCLUSIONS: According to our series, H-reflex can detect intraoperative changes with the same sensitivity as TcMEPs in TAAA surgeries. With the support of other techniques, it can be useful to localize the origin of the lesion (peripheral or central spinal cord), to help in surgical decision-making to avoid postoperative neurologic damage. Based on our results, we recommend the systematic use of H-reflex in TAAA surgeries.

Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells.

Gasdermin (GSDM)-mediated pyroptosis is functionally involved in multiple diseases, but Gasdermin-B (GSDMB) exhibit cell death-dependent and independent activities in several pathologies including cancer. When the GSDMB pore-forming N-terminal domain is released by Granzyme-A cleavage, it provokes cancer cell death, but uncleaved GSDMB promotes multiple pro-tumoral effects (invasion, metastasis, and drug resistance). To uncover the mechanisms of GSDMB pyroptosis, here we determined the GSDMB regions essential for cell death and described for the first time a differential role of the four translated GSDMB isoforms (GSDMB1-4, that differ in the alternative usage of exons 6-7) in this process. Accordingly, we here prove that exon 6 translation is essential for GSDMB mediated pyroptosis, and therefore, GSDMB isoforms lacking this exon (GSDMB1-2) cannot provoke cancer cell death. Consistently, in breast carcinomas the expression of GSDMB2, and not exon 6-containing variants (GSDMB3-4), associates with unfavourable clinical-pathological parameters. Mechanistically, we show that GSDMB N-terminal constructs containing exon-6 provoke cell membrane lysis and a concomitant mitochondrial damage. Moreover, we have identified specific residues within exon 6 and other regions of the N-terminal domain that are important for GSDMB-triggered cell death as well as for mitochondrial impairment. Additionally, we demonstrated that GSDMB cleavage by specific proteases (Granzyme-A, Neutrophil Elastase and caspases) have different effects on pyroptosis regulation. Thus, immunocyte-derived Granzyme-A can cleave all GSDMB isoforms, but in only those containing exon 6, this processing results in pyroptosis induction. By contrast, the cleavage of GSDMB isoforms by Neutrophil Elastase or caspases produces short N-terminal fragments with no cytotoxic activity, thus suggesting that these proteases act as inhibitory mechanisms of pyroptosis. Summarizing, our results have important implications for understanding the complex roles of GSDMB isoforms in cancer or other pathologies and for the future design of GSDMB-targeted therapies.

Phytochemicals Determination, and Antioxidant, Antimicrobial, Anti-Inflammatory and Anticancer Activities of Blackberry Fruits.

A comprehensive characterization of the phytochemicals present in a blackberry fruit extract by HPLC-TOF-MS has been carried out. The main compounds in the extract were ursane-type terpenoids which, along with phenolic compounds, may be responsible for the bioactivity of the extract. In vitro antioxidant capacity was assessed through Folin-Ciocalteu (31.05 ± 4.9 mg GAE/g d.w.), FRAP (637.8 ± 3.2 µmol Fe2+/g d.w.), DPPH (IC50 97.1 ± 2.4 µg d.w./mL) and TEAC (576.6 ± 8.3 µmol TE/g d.w.) assays. Furthermore, the extract exerted remarkable effects on in vitro cellular antioxidant activity in HUVEC cells at a concentration of 5 mg/mL. Antimicrobial activity of the extract was also tested. Most sensible microorganisms were Gram-positive bacteria, such as E. faecalis, B. cereus and Gram-negative E. coli (MBC of 12.5 mg/mL). IC50 values against colon tumoral cells HT-29 (4.9 ± 0.2 mg/mL), T-84 (5.9 ± 0.3 mg/mL) and SW-837 (5.9 ± 0.2 mg/mL) were also obtained. Furthermore, blackberry extract demonstrated anti-inflammatory activity inhibiting the secretion of pro-inflammatory IL-8 cytokines in two cellular models (HT-29 and T-84) in a concentration-dependent manner. These results support that blackberry fruits are an interesting source of bioactive compounds that may be useful in the prevention and treatment of different diseases, mainly related to oxidative stress.