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12 páginas, 6 figuras, Coenzyme A (CoA) is an essential cofactor involved in a range of metabolic pathways including the activation of long-chain fatty acids for catabolism. Cells synthesize CoA de novo from vitamin B5 (pantothenate) via a pathway strongly conserved across prokaryotes and eukaryotes. In humans, it involves five enzymatic steps catalyzed by four enzymes: pantothenate kinase (PANK [isoforms 1-4]), 4'-phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), and CoA synthase (COASY). To date, inborn errors of metabolism associated with all of these genes, except PPCDC, have been described, two related to neurodegeneration with brain iron accumulation (NBIA), and one associated with a cardiac phenotype. This paper reports another defect in this pathway (detected in two sisters), associated with a fatal cardiac phenotype, caused by biallelic variants (p.Thr53Pro and p.Ala95Val) of PPCDC. PPCDC enzyme (EC 4.1.1.36) catalyzes the decarboxylation of 4'-phosphopantothenoylcysteine to 4'-phosphopantetheine in CoA biosynthesis. The variants p.Thr53Pro and p.Ala95Val affect residues highly conserved across different species; p.Thr53Pro is involved in the binding of flavin mononucleotide, and p.Ala95Val is likely a destabilizing mutation. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant. In summary, this work describes a new, ultra-rare, severe inborn error of metabolism due to pathogenic variants of PPCDC., This work was funded by the Instituto de Salud Carlos (ISCIII), the European Regional Development Fund [PI19/01155], the Ministerio de Economía, Industria y Competitividad, Spain (BFU2017-82574-P), and the Consejería de Educacion, Juventud y Deporte, Comunidad de Madrid [B2017/BMD3721].

The objective of this study was to determine if there are differences between the presentation patterns of hemorrhagic stroke (HS) associated to COVID-19.It was performed a systematic search based on PRISMA guidelines of the cases reported in PUBMED of HS associated to SARS-CoV-2 infection and we added to this sample cases from our own hospital cohort. Patients in the database were separated by groups according to presentation symptoms: if they debuted with neurological symptoms or debuted with pulmonary symptoms.Seventy cases were included in the study. Patients that debuted with pulmonary symptoms accounted for 68.6% of the cases with an interval between the development of symptoms and the presentation of HS of 15.6 days. We found that the use of anticoagulants during hospitalization, multifocal image pattern, and the elevation of D-dimer, Ferritin, and lactate dehydrogenase levels were significantly associated with the group of pulmonary presentation, whereas the presence of hypertension during hospitalization, and a lower hemoglobin level was associated with the group of neurologic symptoms.Although HS associated with COVID-19 is a clinical entity with increasing evidence, it is necessary to establish that there are two forms of presentation with their own characteristics.determinar si existen diferencias entre los patrones de presentación de hemorragia intracraneal asociada a COVID-19.Se realizó una búsqueda sistemática basada en la guía PRISMA de los casos reportados en PUBMED de hemorragia intracraneal asociados a infección por SARS-CoV-2 y se agregaron a esta muestra casos de nuestra propia cohorte hospitalaria.se incluyeron 70 casos. Los pacientes que debutaron con síntomas pulmonares representaron el 68.6% de los casos con un intervalo entre el desarrollo de los síntomas y la presentación de la hemorragia intracraneal de 15.6 días. Encontramos que el uso de anticoagulantes durante la hospitalización, el patrón de imagen multifocal y la elevación de los niveles de dímero D, ferritina y deshidrogenasa láctica se asociaron significativamente con el grupo de presentación pulmonar, mientras que la presencia de hipertensión durante la hospitalización, y un nivel de hemoglobina más bajo se asoció con el grupo que debutó con síntomas neurológicos.si bien la hemorragia intracraneal asociada a COVID-19 es una entidad clínica con evidencia creciente, es necesario establecer que existen dos formas de presentación con características propias.

New multi-stimuli responsive materials are required in smart systems applications to overcome current limitations in remote actuation and to achieve versatile operation in inaccessible environments. The incorporation of detection mechanisms to quantify in real time the response to external stimuli is crucial for the development of automated systems. Here, we present the first wireless opto-magnetic actuator with mechanochromic response. The device, based on a nanostructured-iron (Fe) layer transferred onto suspended elastomer structures with a periodically corrugated backside, can be actuated both optically (in a broadband spectral range) and magnetically. The combined opto-magnetic stimulus can accurately modulate the mechanical response (strength and direction) of the device. The structural coloration generated at the corrugated back surface enables to easily map and quantify, in 2D, the mechanical deflections by analyzing in real time the hue changes of images taken using a conventional RGB smartphone camera, with a precision of 0.05°. We demonstrate the independent and synergetic optical and magnetic actuation and detection with a detection limit of 1.8 mW·cm-2 and 0.34 mT, respectively. The simple operation, versatility, and cost-effectiveness of the wireless multiactuated device with highly sensitive mechanochromic mapping paves the way to a new generation of wirelessly controlled smart systems., We acknowledge funding from the Generalitat de Catalunya through the 2017-SGR-292 project. The funding from the Spanish Ministerio de Ciencia, Innovación y Universidades (MICINN) through the PID2019-106229RB-I00, MAT2016-77391-R, PCIN2016-093 (M-ERA-NET), DPI2015-68197-R, and RTI2018-096786-B-I00 projects and the Ramon y Cajal Fellowship (RyC2013-14479) is acknowledged. The PhD fellowship CIBAE-023-2014 (from SENESCYT) is also acknowledged. ICN2 is funded by the CERCA programme/Generalitat de Catalunya. The ICN2 is supported by the Severo Ochoa Centres of Excellence programme, funded by the Spanish Research Agency (AEI, grant no. SEV-2017-0706).

A global agreement in Central Nervous System (CNS) tumors classification is essential in order to decide treatment correctly, predict prognosis, evaluate treatment response, compare outcomes, and select adequate patients for clinical trials at international level.The last update of the World Health Organization (WHO) of CNS tumor classification and grading 2021 considered for the first time glioblastoma IDH-wildtype and astrocytoma IDH-mutant grade 4 as different tumors. IDH mutation produces a metabolic reprogramming of tumor cells, thus affecting the processes of hypoxia and vascularity. The differences in the aggressiveness of these gliomas, which affect patient survival, are evident, with a clear advantage for those patients who present IDH mutated tumors.Despite the clinical relevance of IDH mutation, current protocols do not include full sequencing for every patient. Alternative biomarkers could be useful and complementary to get a more reliable classification. In this sense, MRI-perfusion biomarkers, such as relative cerebral blood and flow (rCBV and rCBF), could be key because they are non-invasive, can be used from the presurgical moment, and do not suppose additional economical or effort costs.The main purpose of this work is to evaluate and validate the association between MRI-DSC biomarkers and IDH mutation status in high-grade astrocytomas. In addition, to get a deeper understanding of the vascular differences, we aim to study the transcriptomic bases of these vascular differences between these two high-grade astrocytomas.

Retroviral reverse transcriptases (RTs) have the ability to carry out strand displacement DNA synthesis in the absence of accessory proteins. Although studies with RTs and other DNA polymerases suggest that fingers subdomain residues participate in strand displacement, molecular determinants of this activity are still unknown. A mutant human immunodeficiency virus type 2 (HIV-2) RT (M41L/D67N/K70R/S215Y) with low strand displacement activity was identified after screening a panel of purified enzymes, including several antiretroviral drug-resistant HIV-1 and HIV-2 RTs. In HIV-1, resistance to zidovudine and other thymidine analogues is conferred by different combinations of M41L, D67N, K70R, L210W, T215F/Y, and K219E/Q (designated as thymidine analogue resistance-associated mutations (TAMs)). However, those changes are rarely selected in HIV-2. We show that the strand displacement activity of HIV-2ROD mutants M41L/S215Y and D67N/K70R was only slightly reduced compared to the wild-type RT. In contrast, mutants D67N/K70R/S215Y and M41L/D67N/K70R/S215Y were the most defective RTs in reactions carried out with nicked and gapped substrates. Moreover, these enzymes showed the lowest nucleotide incorporation rates in assays carried out with strand displacement substrates. Unlike in HIV-2, substitutions M41L/T215Y and D67N/K70R/T215Y/K219Q had no effect on the strand displacement activity of HIV-1BH10 RT. The strand displacement efficiencies of HIV-2ROD RTs were consistent with the lower replication capacity of HIV-2 strains bearing the four major TAMs in their RT. Our results highlight the role of the fingers subdomain in strand displacement. These findings might be important for the development of strand-displacement defective RTs., Ministry of Science, Innovation and Universities of Spain through grants BIO2016-76716-R (AEI/FEDER, UE) to L.M.-A. and SAF2016-75277-R to M.A.M.; S.M.-A. is a predoctoral fellow of the Ministry of Science, Innovation and Universities of Spain (BES-2017-079836). M.N. was supported by the Instituto de Salud Carlos III through the Spanish AIDS network (RD16-0025/0041). An institutional grant of the Fundación Ramón Areces to the CBMSO is also acknowledged

Healthcare workers (HCW) are at high risk for suicide, yet little is known about the onset of suicidal thoughts and behaviors (STB) in this important segment of the population in conjunction with the COVID-19 pandemic. We conducted a multicenter, prospective cohort study of Spanish HCW active during the COVID-9 pandemic. A total of n = 4809 HCW participated at baseline (May-September 2020; i.e., just after the first wave of the pandemic) and at a four-month follow-up assessment (October-December 2020) using web-based surveys. Logistic regression assessed the individual- and population-level associations of separate proximal (pandemic) risk factors with four-month STB incidence (i.e., 30-day STB among HCW negative for 30-day STB at baseline), each time adjusting for distal (pre-pandemic) factors. STB incidence was estimated at 4.2% (SE = 0.5; n = 1 suicide attempt). Adjusted for distal factors, proximal risk factors most strongly associated with STB incidence were various sources of interpersonal stress (scaled 0-4; odds ratio [OR] range = 1.23-1.57) followed by personal health-related stress and stress related to the health of loved ones (scaled 0-4; OR range 1.30-1.32), and the perceived lack of healthcare center preparedness (scaled 0-4; OR = 1.34). Population-attributable risk proportions for these proximal risk factors were in the range 45.3-57.6%. Other significant risk factors were financial stressors (OR range 1.26-1.81), isolation/quarantine due to COVID-19 (OR = 1.53) and having changed to a specific COVID-19 related work location (OR = 1.72). Among other interventions, our findings call for healthcare systems to implement adequate conflict communication and resolution strategies and to improve family-work balance embedded in organizational justice strategies. This work was supported by grants from the Instituto de Salud Carlos III (ISCIII)/Ministerio de Ciencia e Innovación/FEDER, Spain (Jordi Alonso, grant number COV20/00711); ISCIII-FEDER, Spain (Jordi Alonso, grant number PI17/00521); ISCIII-FSE, Spain: Sara Borrell and Miguel Servet grants (Philippe Mortier, grant number CD18/00049 and CP21/00078); Generalitat de Catalunya, Spain (2017SGR452); and PERIS, Departament de Salut, Spain (Itxaso Alayo; SLT017/20/000009). Additional partial funding was received from the Gerencia Regional de Salud de Castilla y León (SACYL), Spain (José María Pelayo Terán, grant number GRS COVID 32/A/20). Sí

Objective: To summarize evidence for use of advanced MRI techniques as monitoring biomarkers in the clinic, and to highlight the latest bench-to-bedside developments. Methods: The current evidence regarding the potential for monitoring biomarkers was reviewed and individual modalities of metabolism and/or chemical composition imaging discussed. Perfusion, permeability, and microstructure imaging were similarly analyzed in Part 1 of this two-part review article and are valuable reading as background to this article. We appraise the clinic readiness of all the individual modalities and consider methodologies involving machine learning (radiomics) and the combination of MRI approaches (multiparametric imaging). Results: The biochemical composition of high-grade gliomas is markedly different from healthy brain tissue. Magnetic resonance spectroscopy allows the simultaneous acquisition of an array of metabolic alterations, with choline-based ratios appearing to be consistently discriminatory in treatment response assessment, although challenges remain despite this being a mature technique. Promising directions relate to ultra-high field strengths, 2-hydroxyglutarate analysis, and the use of non-proton nuclei. Labile protons on endogenous proteins can be selectively targeted with chemical exchange saturation transfer to give high resolution images. The body of evidence for clinical application of amide proton transfer imaging has been building for a decade, but more evidence is required to confirm chemical exchange saturation transfer use as a monitoring biomarker. Multiparametric methodologies, including the incorporation of nuclear medicine techniques, combine probes measuring different tumor properties. Although potentially synergistic, the limitations of each individual modality also can be compounded, particularly in the absence of standardization. Machine learning requires large datasets with high-quality annotation; there is currently low-level evidence for monitoring biomarker clinical application. Conclusion: Advanced MRI techniques show huge promise in treatment response assessment. The clinical readiness analysis highlights that most monitoring biomarkers require standardized international consensus guidelines, with more facilitation regarding technique implementation and reporting in the clinic.

ObjectiveSummarize evidence for use of advanced MRI techniques as monitoring biomarkers in the clinic, and highlight the latest bench-to-bedside developments.MethodsExperts in advanced MRI techniques applied to high-grade glioma treatment response assessment convened through a European framework. Current evidence regarding the potential for monitoring biomarkers in adult high-grade glioma is reviewed, and individual modalities of perfusion, permeability, and microstructure imaging are discussed (in Part 1 of two). In Part 2, we discuss modalities related to metabolism and/or chemical composition, appraise the clinic readiness of the individual modalities, and consider post-processing methodologies involving the combination of MRI approaches (multiparametric imaging) or machine learning (radiomics).ResultsHigh-grade glioma vasculature exhibits increased perfusion, blood volume, and permeability compared with normal brain tissue. Measures of cerebral blood volume derived from dynamic susceptibility contrast-enhanced MRI have consistently provided information about brain tumor growth and response to treatment; it is the most clinically validated advanced technique. Clinical studies have proven the potential of dynamic contrast-enhanced MRI for distinguishing post-treatment related effects from recurrence, but the optimal acquisition protocol, mode of analysis, parameter of highest diagnostic value, and optimal cut-off points remain to be established. Arterial spin labeling techniques do not require the injection of a contrast agent, and repeated measurements of cerebral blood flow can be performed. The absence of potential gadolinium deposition effects allows widespread use in pediatric patients and those with impaired renal function. More data are necessary to establish clinical validity as monitoring biomarkers. Diffusion-weighted imaging, apparent diffusion coefficient analysis, diffusion tensor or kurtosis imaging, intravoxel incoherent motion, and other microstructural modeling approaches also allow treatment response assessment; more robust data are required to validate these alone or when applied to post-processing methodologies.ConclusionConsiderable progress has been made in the development of these monitoring biomarkers. Many techniques are in their infancy, whereas others have generated a larger body of evidence for clinical application.

[EN] Despite the complete treatment with surgery, chemotherapy and radiotherapy, patients with glioblastoma have a devasting prognosis. Although the role of extending temozolomide treatment has been explored, the results are inconclusive. Recent evidence suggested that tumor vascularity may be a modulating factor in combination with methylation of O6-methylguanine-DNA methyltransferase (MGMT) promotor gene on the effect of temozolomide-based therapies, opening new possibilities for personalized treatments. Before proposing a prospective interventional clinical study, it is necessary to confirm the beneficial effect of the combined effect of MGMT methylation and moderate tumor vascularity, as well as the lack of benefit of temozolomide in patients with a highly vascular tumor.In this study, we evaluated the benefit on survival of the combination of methylation of O6-methylguanine-DNA methyltransferase (MGMT) promotor gene and moderate vascularity in glioblastoma using a retrospective dataset of 123 patients from a multicenter cohort. MRI processing and calculation of relative cerebral blood volume (rCBV), used to define moderate- and high-vascular groups, were performed with the automatic ONCOhabitats method. We assessed the previously proposed rCBV threshold (10.7) and the new calculated ones (9.1 and 9.8) to analyze the association with survival for different populations according to vascularity and MGMT methylation status. We found that patients included in the moderate-vascular group had longer survival when MGMT is methylated (significant median survival difference of 174 days, p = 0.0129*). However, we did not find significant differences depending on the MGMT methylation status for the high-vascular group (p = 0.9119). In addition, we investigated the combined correlation of MGMT methylation status and rCBV with the prognostic effect of the number of temozolomide cycles, and only significant results were found for the moderate-vascular group. In conclusion, there is a lack of benefit of extending temozolomide treatment for patients with high vascular glioblastomas, even presenting MGMT methylation. Preliminary results suggest that patients with moderate vascularity and methylated MGMT glioblastomas would benefit more from prolonged adjuvant chemotherapy., M.A-T was supported by DPI2016-80054-R (Programa Estatal de Promocion del Talento y su Empleabilidad en I+D+i). This work was partially supported by the ALBATROSS project (National Plan for Scientific and Technical Research and Innovation 2017-2020, No. PID2019-104978RB-I00). This study was partially funded by the Fundacio La Marato TV3 (665/C/2013) (http://www.ccma.cat/tv3/marato/projectes-financats/2012/231/ Accessed on 8th September 2021). (JMGG); H2020-SC1-2016-CNECT Project (No. 727560) (JMGG), and H2020-SC1-BHC-2018-2020 (No. 825750) (JMGG). EFG was supported by the European Unions Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 844646 and South-Eastern Norway Regional Health Authority Grant 2021057.

Propionic acidemia (PA) disorder shows major involvement of the heart, among other alterations. A significant number of PA patients develop cardiac complications, and available evidence suggests that this cardiac dysfunction is driven mainly by the accumulation of toxic metabolites. To contribute to the elucidation of the mechanistic basis underlying this dysfunction, we have successfully generated cardiomyocytes through the differentiation of induced pluripotent stem cells (iPSCs) from a PCCB patient and its isogenic control. In this human cellular model, we aimed to examine microRNAs (miRNAs) profiles and analyze several cellular pathways to determine miRNAs activity patterns associated with PA cardiac phenotypes. We have identified a series of upregulated cardiac-enriched miRNAs and alterations in some of their regulated signaling pathways, including an increase in the expression of cardiac damage markers and cardiac channels, an increase in oxidative stress, a decrease in mitochondrial respiration and autophagy; and lipid accumulation. Our findings indicate that miRNA activity patterns from PA iPSC-derived cardiomyocytes are biologically informative and advance the understanding of the molecular mechanisms of this rare disease, providing a basis for identifying new therapeutic targets for intervention strategies.

Introduccion en la actual pandemia de COVID-19, existe evidencia creciente que ha identificado el neurotropismo del virus SARS-CoV-2 y sus complicaciones neurologicas, incluida la enfermedad cerebrovascular isquemica y escasamente hemorragia cerebral (HC). Objetivo describir las caracteristicas clinicas, radiologicas, de laboratorio y pronosticas de los pacientes con HC asociada al SARS-CoV-2. Metodos se incluyeron pacientes consecutivos con prueba de PCR confirmatoria para infeccion por SARS-CoV-2 y HC. Resultados en un periodo de 90 dias, en un centro de referencia COVID-19 en Mexico, de 1108 pacientes con infeccion por SARS-CoV-2, se encontraron 4 pacientes (0.36%) con HC. Tenian una edad de 71(±12.2) anos, 2 eran mujeres. Se encontro que dos tenian factores de riesgo cardiovascular previos. En dos casos se encontro el origen en el nucleo dentado mientras que los otros dos correspondieron al talamo. Tres de los cuatro pacientes murieron. Postulamos que el descontrol hipertensivo, coagulopatia, trombocitopenia y la respuesta inmune inducida por el virus SARS-CoV-2 podrian desencadenar HC en un paciente con riesgo previo. Conclusiones la HC se asocia a la infeccion por SARS-CoV-2 con mal pronostico cuando se presenta. Los equipos de neurocirugia deben estar preparados para el tratamiento oportuno de estos pacientes. Introduction In the current COVID-19 pandemic, there is a growing body of evidence that has identified the neurotropism of the SARS-CoV-2 virus and its neurological complications, including cerebrovascular disease, focusing mainly in ischemic and scarcely about hemorrhagic stroke (HS). Objective The objective of the study was to describe clinical, radiological, laboratory tests, and prognostic characteristics of patients with SARS-CoV-2 associated HS. Methods Consecutive patients with a confirmatory PCR test for SARS-CoV-2 infection and a HS demonstrated by head CT were included in the study. Results Over a period of 90 days, in a COVID-19 reference center in Mexico, out of a total of 1108 patients with SARS-CoV-2 infection, it found 4 patients (0.36%) who meet criteria. They had an age of 71 (±12.2) years, 2 were women. It was found that two had prior cardiovascular risk factors. Two of the HS originated in the dentate nucleus while the other two corresponded to the thalamus. Three of the four patients died. We suggest that catastrophic uncontrolled blood pressure, coagulopathy, thrombocytopenia, and immune response induced by SARS-CoV-2 could in a specific patient trigger HS. Conclusions HS is associated to SARS-CoV-2 infection with poor prognosis when it presented. Neurosurgery teams should prepare for the timely and appropriate treatment of this patients.

In this study we evaluated the benefit on survival of the combination of MGMT methylation and moderate vascularity in glioblastoma using a retrospective dataset of 123 patients from a multicenter cohort. MRI processing and calculation of relative cerebral blood volume (rCBV), used to define moderate- and high-vascular groups, were performed with the automatic ONCOhabitats method. We assessed the previously proposed rCBV threshold (10.7) and the new calculated ones (9.1 and 9.8) to analyze the association with survival for different populations according to vascularity and MGMT methylation status. We found that patients included at the moderate-vascular group had longer survival when MGMT is methylated (significant median survival difference of 174 days, p = 0.0129*). However, we did not find significant differences depending on the MGMT methylation status for the high-vascular group (p = 0.9119). In addition, we investigated the combined correlation of MGMT methylation status and rCBV with the prognostic effect of the number of temozolomide cycles, and only significant results were found for the moderate-vascular group. In conclusion, there is a lack of benefit of temozolomide for MGMT methylated patients with high vascular glioblastomas. Preliminary results suggest that patients with moderate vascularity and methylated MGMT would benefit more from prolonged adjuvant chemotherapy.Simple SummaryDespite the complete treatment with surgery, chemotherapy and radiotherapy, patients with glioblastoma have a devasting prognosis. Although the role of extending temozolomide treatment has been explored, the results are inconclusive. Recent evidence suggested that tumor vascularity may be a modulating factor in combination with MGMT methylation on the effect of temozolomide-based therapies, opening new possibilities for personalized treatments. Before proposing a prospective interventional clinical study, it is necessary to confirm the beneficial effect of the combined effect of MGMT methylation and moderate tumor vascularity. As well as the lack of benefit of temozolomide in patients with a highly vascular tumor.

A novel series of 3-hydroxyquinazoline-2,4(1H,3H)-diones derivatives has been designed and synthesized. Their biochemical characterization revealed that most of the compounds were effective inhibitors of HIV-1 RNase H activity at sub to low micromolar concentrations. Among them, II-4 was the most potent in enzymatic assays, showing an IC50 value of 0.41 ± 0.13 μM, almost five times lower than the IC50 obtained with β-thujaplicinol. In addition, II-4 was also effective in inhibiting HIV-1 IN strand transfer activity (IC50 = 0.85 ± 0.18 μM) but less potent than raltegravir (IC50 = 71 ± 14 nM). Despite its relatively low cytotoxicity, the efficiency of II-4 in cell culture was limited by its poor membrane permeability. Nevertheless, structure-activity relationships and molecular modeling studies confirmed the importance of tested 3-hydroxyquinazoline-2,4(1H,3H)-diones as useful leads for further optimization.

Cell macroencapsulation has shown a great potential overcoming the low survival of the transplanted pancreatic islets in the Type 1 Diabetes Mellitus (T1DM) treatment, as it avoids the need for lifelong immunosuppression. It is still not completely known how these devices interact with the host immune system when implanted. However, their surface properties seem to be crucial factors for a successful implant. In this context, the hydrophilicity and porosity of the surface of the macrocapsules are two of the most important properties that can affect the functionality of the graft; hydrophilicity defines the interactions with the host's immune cells, while the porosity determines the biosafety of the device while conditioning the oxygen, nutrients and insulin diffusion. Here, we report a novel β-cell macroencapsulation system that combines an injectable alginate hydrogel with an external 3D-printed implantable device. This external macrocapsule protects the inner hydrogel containing cells, while allowing the precise location of the implant in the body. In addition, it would allow the easy extraction of the grafted cells in the case the implant fails or the renewal of the therapeutic cells is required. This study evaluates the biological effect of the macroencapsulation devices' surface properties (hydrophilicity and porosity). We studied two different pore sizes and hydrophilicities in four different devices containing rat INS1E β-cells embedded in alginate hydrogels. All the devices showed great biocompatibility, although the hydrophilic ones exhibited higher fibroblast adhesion, which could potentially enhance the fibrotic response when implanted. Importantly, INS1E cells did not escape from the devices, denoting high biosafety. Cells grown within all devices and maintained their insulin secretory function. However, the hydrophobic device with a smaller pore size showed better cell viability values and, therefore, it might be the best candidate for the development of a safe β-cell replacement therapy in T1DM.

Despite significant advances in antiretroviral therapy, acquired immunodeficiency syndrome remains as one of the leading causes of death worldwide. New antiretroviral drugs combined with updated treatment strategies are needed to improve convenience, tolerability, safety, and antiviral efficacy of available therapies. In this work, a focused library of coumarin derivatives was exploited by cell phenotypic screening to discover novel inhibitors of HIV-1 replication. Five compounds (DW-3, DW-4, DW-11, DW-25 and DW-31) showed moderate activity against wild-type and drug-resistant strains of HIV-1 (IIIB and RES056). Four of those molecules were identified as inhibitors of the viral RT-associated RNase H. Structural modification of the most potent DW-3 and DW-4 led to the discovery of compound 8a. This molecule showed increased potency against wild-type HIV-1 strain (EC = 3.94 ± 0.22 μM) and retained activity against a panel of mutant strains, showing EC values ranging from 5.62 μM to 202 μM. In enzymatic assays, 8a was found to inhibit the viral RNase H with an IC of 12.3 μM. Molecular docking studies revealed that 8a could adopt a binding mode similar to that previously reported for other active site HIV-1 RNase H inhibitors., Natural Science Foundation of China (NSFC Nos. 81973181, 81903453), Shandong Provincial Key research and development project (Nos. 2019JZZY021011), Shandong Provincial Natural Science Foundation (ZR2019BH011, ZR2020YQ61, ZR2020JQ31), Foreign cultural and educational experts Project (GXL20200015001), Qilu Young Scholars Program of Shandong University, the Taishan Scholar Program at Shandong Province, and KU Leuven (GOA 10/014). Work in Madrid was supported by the Spanish Ministry of Science and Innovation (grant PID2019-104176RB-I00/AEI/10.13039/501100011033), and an institutional grant of Fundación Ramón Areces (Madrid, Spain).

BackgroundThe microvascular proliferation (MVP) and the microvessel area (MVA) are known as diagnostic and prognostic biomarkers for glioblastoma; nevertheless, its measurement is costly, labor-intense, and invasive. MRI perfusion biomarkers such as such as relative cerebral blood volume (rCBV) may be a feasible alternative to predict MVP and estimate MVA.PurposeThis study aims to evaluate the detection capacity of MRI markers such as rCBV to detect local microvascular proliferation in IDH wild-type glioblastoma. In addition, we aim to analyze the association between rCBV values and the microvessel area in different regions of the tumor.Study typeRetrospective study.Population and subjectsData from 71 tissue blocks belonging to 17 IDH wild-type glioblastoma patients were compiled from the Ivy GAP database.Field Strength/Sequence1.5T or 3.0T. Pregadolinium and postgadolinium-based contrast agent-enhanced T1-weighted MRI, T2- and FLAIR T2-weighted, and dynamic susceptibility contrast (DSC) T2* perfusion.AssessmentWe analyzed preoperative MRIs to establish the association between the maximum and mean relative cerebral blood volume (rCBVmax and rCBVmean) with the presence/absence of microvascular proliferation and with the microvessel area for each tumor block.Statistical testsSpearman’s correlation and Mann-Whitney test.ResultsSignificant positive correlations were found between rCBV and MVA in the analyzed tumor blocks (pData conclusionThe rCBV is shown as significantly different in those tissue blocks with microvascular proliferation from those blocks without it, and it is significantly correlated with microvessels area. This method allows a local detection and definition of MVP and MVA in different regions of the glioblastoma since the first diagnostic stage and in a non-invasive way.

© 2021 by the authors., HIV reverse transcriptases (RTs) convert viral genomic RNA into double-stranded DNA. During reverse transcription, polypurine tracts (PPTs) resilient to RNase H cleavage are used as primers for plus-strand DNA synthesis. Nonnucleoside RT inhibitors (NNRTIs) can interfere with the initiation of plus-strand DNA synthesis by enhancing PPT removal, while HIV RT connection subdomain mutations N348I and N348I/T369I mitigate this effect by altering RNase H cleavage specificity. Now, we demonstrate that among approved nonnucleoside RT inhibitors (NNRTIs), nevirapine and doravirine show the largest effects. The combination N348I/T369I in HIV-1BH10 RT has a dominant effect on the RNase H cleavage specificity at the PPT/U3 site. Biochemical studies showed that wild-type HIV-1 and HIV-2 RTs were able to process efficiently and accurately all tested HIV PPT sequences. However, the cleavage accuracy at the PPT/U3 junction shown by the HIV-2EHO RT was further improved after substituting the sequence YQEPFKNLKT of HIV-1BH10 RT (positions 342–351) for the equivalent residues of the HIV-2 enzyme (HQGDKILKV). Our results highlight the role of β-sheets 17 and 18 and their connecting loop (residues 342–350) in the connection subdomain of the large subunit, in determining the RNase H cleavage window of HIV RTs., This research was funded by the Spanish Ministry of Science and Innovation (grants BIO2016-76716-R (AEI/FEDER, UE), and PID2019-104176RB-I00/AEI/10.13039/501100011033), and an institutional grant of Fundación Ramón Areces (Madrid, Spain) to the CBMSO. J.L. was a postdoctoral fellow of the Juan de la Cierva program, funded by the Spanish Ministry of Economy and Competitiveness (grant FJCI-2015-23564). S.M.-A. is a predoctoral fellow of the Spanish Ministry of Science and Innovation (BES-2017-079836). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Over the last few years, the intestine has been extensively studied using in vitro microfluidic systems, commonly known as gut-on-a-chip (GOC) devices. This interest has been due not only to the importance of the intestine's proper functions but also to the relationship that this organ and the microbiota that inhabits it has with the rest of the body's organs. The increased complexity of these in vitro systems, together with the need to improve our understanding of intestinal physiology interdependencies, has led to greater focus on the integration of biosensors within these devices. However, the current number of GOC devices with integrated sensors for monitoring relevant physiological parameters are very limited and demand the use of external analytical techniques that delay the analysis and prevent real-time decision-making. This paper reviews the various materials, technologies, and structures that have been used both for mimicking the physiology of the intestine and monitoring relevant physiological parameters, such as permeability of the gut barrier, dissolved oxygen concentration, cytokines profile and the production of microbial short-chain fatty acids. We also propose alternative biosensing techniques demonstrated in other in vitro and lab-on-a-chip devices that could be translated to GOC models. A critical analysis of the requirements, limitations, and current challenges on the microenvironment replication and monitorization of GOC models is included, with a particular focus on the physiological parameters and biomarkers that should be detected simultaneously in real-time to get a proper framework of the gut function that until now, have not received the necessary attention.

Tissue barriers play a crucial role in human physiology by establishing tissue compartmentalization and regulating organ homeostasis. At the interface between the extracellular matrix (ECM) and flowing fluids, epithelial and endothelial barriers are responsible for solute and gas exchange. In the past decade, microfluidic technologies and organ-on-chip devices became popular as in vitro models able to recapitulate these biological barriers. However, in conventional microfluidic devices, cell barriers are primarily grown on hard polymeric membranes within polydimethylsiloxane (PDMS) channels that do not mimic the cell-ECM interactions nor allow the incorporation of other cellular compartments such as stromal tissue or vascular structures. To develop models that accurately account for the different cellular and acellular compartments of tissue barriers, researchers have integrated hydrogels into microfluidic setups for tissue barrier-on-chips, either as cell substrates inside the chip, or as self-contained devices. These biomaterials provide the soft mechanical properties of tissue barriers and allow the embedding of stromal cells. Combining hydrogels with microfluidics technology provides unique opportunities to better recreate in vitro the tissue barrier models including the cellular components and the functionality of the in vivo tissues. Such platforms have the potential of greatly improving the predictive capacities of the in vitro systems in applications such as drug development, or disease modeling. Nevertheless, their development is not without challenges in their microfabrication. In this review, we will discuss the recent advances driving the fabrication of hydrogel microfluidic platforms and their applications in multiple tissue barrier models.

Altres ajuts: ICN2 is funded by the CERCA programme/Generalitat de Catalunya. Ultrabroadband light absorbers are attracting increasing interest for applications in energy harvesting, photodetection, self-regulated devices or soft robotics. However, current absorbers show detrimental insufficient absorption spectral range, or light angle and polarization dependence. Here we show that the unexplored optical properties of highly-damped plasmonic materials combined with the infrared absorption of thin polymer films enable developing ultrabroadband light-absorbing soft metamaterials. The developed metamaterial, composed of a nanostructured Fe layer mechanically coupled to a thin polydimethylsiloxane (PDMS) film, shows unprecedented ultrabroadband and angle-independent optical absorption (averaging 84% within 300-18000 nm). The excellent photothermal efficiency and large thermal-expansion mismatch of the metamaterial is efficiently transformed into large mechanical deflections, which we exploit to show an artificial iris that self-regulates the transmitted light power from the ultraviolet to the long-wave infrared, an untethered light-controlled mechanical gripper and a light-triggered electrical switch.

[EN] Background and purpose Genetic classifications are crucial for understanding the heterogeneity of glioblastoma. Recently, perfusion MRI techniques have demonstrated associations molecular alterations. In this work, we investigated whether perfusion markers within infiltrated peripheral edema were associated with proneural, mesenchymal, classical and neural subtypes. Materials and methods ONCOhabitats open web services were used to obtain the cerebral blood volume at the infiltrated peripheral edema for MRI studies of 50 glioblastoma patients from The Cancer Imaging Archive: TCGA-GBM. ANOVA and Kruskal-Wallis tests were carried out in order to assess the association between vascular features and the Verhaak subtypes. For assessing specific differences, Mann-Whitney U-test was conducted. Finally, the association of overall survival with molecular and vascular features was assessed using univariate and multivariate Cox models. Results ANOVA and Kruskal-Wallis tests for the maximum cerebral blood volume at the infiltrated peripheral edema between the four subclasses yielded false discovery rate corrected p-values of, This work was partially supported by: MTS4up project (National Plan for Scientific and Technical Research and Innovation 2013-2016, No. DPI2016-80054-R) (JMGG); H2020-SC1-2016CNECT Project (No. 727560) (JMGG), Fundacio Bancaria laCaixa (LCF/TR/CI16/10010016) and H2020-SC1-BHC-2018-2020 (No. 825750) (JMGG); PID2019-104978RB-I00 (Ministerio de Ciencia e Innovacion) (JMGG). MAT was supported by DPI2016-80054-R (Programa Estatal de Promocion del Talento y su Empleabilidad en I+D +i). EFG was supported by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 844646. There was no additional external funding received for this study.