Predicting Kidney Transplantation Outcomes from Donor and Recipient Characteristics at Time Zero: Development of a Mobile Application for Nephrologists.

(1) Background: We report on the development of a predictive tool that can estimate kidney transplant survival at time zero. (2) Methods: This was an observational, retrospective study including 5078 transplants. Death-censored graft and patient survivals were calculated. (3) Results: Graft loss was associated with donor age (hazard ratio [HR], 1.021, 95% confidence interval [CI] 1.018-1.024, p < 0.001), uncontrolled donation after circulatory death (DCD) (HR 1.576, 95% CI 1.241-2.047, p < 0.001) and controlled DCD (HR 1.567, 95% CI 1.372-1.812, p < 0.001), panel reactive antibody percentage (HR 1.009, 95% CI 1.007-1.011, p < 0.001), and previous transplants (HR 1.494, 95% CI 1.367-1.634, p < 0.001). Patient survival was associated with recipient age (> 60 years, HR 5.507, 95% CI 4.524-6.704, p < 0.001 vs. < 40 years), donor age (HR 1.019, 95% CI 1.016-1.023, p < 0.001), dialysis vintage (HR 1.0000263, 95% CI 1.000225-1.000301, p < 0.01), and male sex (HR 1.229, 95% CI 1.135-1.332, p < 0.001). The C-statistics for graft and patient survival were 0.666 (95% CI: 0.646, 0.686) and 0.726 (95% CI: 0.710-0.742), respectively. (4) Conclusions: We developed a mobile app to estimate survival at time zero, which can guide decisions for organ allocation.

Type 1 diabetes in pediatrics during the COVID-19 pandemic: Time from symptom onset and forms of presentation at a referral hospital. / Diabetes tipo 1 en pediatría durante la pandemia por COVID-19: tiempo de evolución de síntomas y formas de presentación en un centro de referencia.

Introduction. The COVID-19 pandemic impacted on the health care of patients with type 1 diabetes mellitus (DM1). An increase in diabetic ketoacidosis (DKA) as a form of diagnosis was reported. Objectives. To assess whether there were changes in the time from symptom onset, the causes of hospitalization due to DM1, and the proportion of severe forms, and to describe SARS-CoV-2 infection in these patients. Population and methods. Cross-sectional study in patients younger than 19 years hospitalized due to DM1 from March 2018 to August 2019 (pre-pandemic) and from March 2020 to August 2021 (pandemic). Results. The assessment included 135 hospitalizations in the pre-pandemic period and 96 during the pandemic. The time from symptom onset during the pandemic in those with debut of diabetes was shorter than in the pre-pandemic period (18.8 ± 10.2 versus 52.1 ± 12.1 days, respectively; p < 0.001). Hospitalizations due to all forms of diabetes debut and debut with DKA were more common during the pandemic than before it (59.4% versus 39.3%; odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.3-3.8; p = 0.003 and 40.6% versus 20.7%; OR: 2.6; 95% CI: 1.4-5.2; p = 0.006, respectively). Severe forms of DKA did not change between both periods (48.1% versus 59.9%; p = 0.3). Only 6 patients developed SARS-CoV-2 infection; 3 were severe. Conclusion. During the pandemic, the time from symptom onset decreased and the frequency of hospitalizations due to debut of DM1 increased. The proportion of severe forms of DKA did not change.

Introducción. La pandemia por COVID-19 afectó la atención de pacientes con diabetes mellitus tipo 1 (DM1). Además, se reportó un aumento de cetoacidosis diabética (CAD) como forma de diagnóstico. Objetivos. Evaluar si durante la pandemia por COVID-19 se modificaron el tiempo de evolución de síntomas, las causas de hospitalización por DM1 y la proporción de formas graves, y describir la infección por SARS-CoV-2 en estos pacientes. Población y métodos. Estudio transversal que incluyó pacientes menores de 19 años hospitalizados por DM1 en un centro pediátrico de referencia de marzo de 2018 a agosto de 2019 (prepandemia) y de marzo de 2020 a agosto de 2021 (pandemia). Resultados. Se analizaron 231 internaciones, 135 prepandemia y 96 en pandemia. Los pacientes con debut diabético presentaron menor tiempo de evolución de síntomas en pandemia que en prepandemia (18,8 ± 10,2 vs. 52,1 ±12,1 días, respectivamente; p <0,001). Las hospitalizaciones por todas las formas de debut diabético y el debut con CAD fueron más frecuentes en pandemia que en prepandemia (59,4 % vs. 39,3 %; OR 2,3; IC95% 1,3-3,8; p = 0,003); y (40,6 % vs. 20,7 %; OR 2,6; IC95% 1,4-5,2; p = 0,006) respectivamente. La proporción de formas graves de CAD no se modificó entre ambos períodos (48,1 % vs. 59,9 %; p = 0,3). Solo 6 pacientes presentaron infección por SARS-CoV-2; 3 fueron formas graves. Conclusión. Durante la pandemia, disminuyó el tiempo de evolución de síntomas y aumentó la frecuencia de hospitalizaciones por debut de DM1, con mayor proporción de CAD. No se modificó la proporción de formas graves de CAD.

Metabolomics approach for phenolic compounds profiling of soursop (Annona muricata L.) fruit during postharvest storage.

INTRODUCTION: Soursop (Annona muricata L.) is a crop with medicinal properties and numerous bioactive compounds. Ripening is a complex process that regulates fruit quality and changes in metabolite content, such as flavonoids, polyphenols, and organic acids. OBJECTIVES: This study aimed to analyze the phenolic profiling of soursop fruit ripening. METHODS: The metabolic changes in different days of storage of soursop fruits were investigated using a semi-metabolomic approach based on ultra-performance liquid chromatography coupled to electrospray ionization quadrupole-time of flight mass spectrometry (UPLC-ESI-QTOF-MS). Further, multivariate analysis such as supervised partial least squares discriminant analysis (PLS-DA) was conducted to identify differential metabolites. RESULTS: A total of 68 metabolites were identified in soursop fruit during postharvest storage. A higher number of metabolites were identified in the Day zero (D0) compared to the Day one (D1), Day three (D3), and Day five (D5), belonging to flavonoids, other polyphenols, phenolic acids, and organic acids. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the pathways of flavone and flavonol biosynthesis, flavonoid biosynthesis, and biosynthesis of secondary metabolites were mostly enriched. Additionally, we included all the compounds and their postharvest storage in the public Phenolics profile database. CONCLUSIONS: Here, we show that the stage of ripening has a significant effect on the phenolic content, highlighting the point of cut (D0) and the onset of senescence (D5). The findings of this study provide new insights into the soursop fruit quality and may contribute to the identification of metabolic markers for its storage.

Treatment of infantile-onset Pompe disease in a rat model with muscle-directed AAV gene therapy.

OBJECTIVE: Pompe disease (PD) is caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA), leading to progressive glycogen accumulation and severe myopathy with progressive muscle weakness. In the Infantile-Onset PD (IOPD), death generally occurs <1 year of age. There is no cure for IOPD. Mouse models of PD do not completely reproduce human IOPD severity. Our main objective was to generate the first IOPD rat model to assess an innovative muscle-directed adeno-associated viral (AAV) vector-mediated gene therapy. METHODS: PD rats were generated by CRISPR/Cas9 technology. The novel highly myotropic bioengineered capsid AAVMYO3 and an optimized muscle-specific promoter in conjunction with a transcriptional cis-regulatory element were used to achieve robust Gaa expression in the entire muscular system. Several metabolic, molecular, histopathological, and functional parameters were measured. RESULTS: PD rats showed early-onset widespread glycogen accumulation, hepato- and cardiomegaly, decreased body and tissue weight, severe impaired muscle function and decreased survival, closely resembling human IOPD. Treatment with AAVMYO3-Gaa vectors resulted in widespread expression of Gaa in muscle throughout the body, normalizing glycogen storage pathology, restoring muscle mass and strength, counteracting cardiomegaly and normalizing survival rate. CONCLUSIONS: This gene therapy holds great potential to treat glycogen metabolism alterations in IOPD. Moreover, the AAV-mediated approach may be exploited for other inherited muscle diseases, which also are limited by the inefficient widespread delivery of therapeutic transgenes throughout the muscular system.

The Gap in Sustainable Food Services in Public Institutions: The Perceptions of Young Consumers from Public Universities in the Madrid Region (Spain).

The agri-food system needs to transition into a more balanced system that takes into account economic, social, and environmental factors. Young people are a key demographic group to consider as they are open to new trends of consumption, including sustainable buying practices. Public universities can play a significant role in promoting sustainable and healthy eating habits among students. In this paper, we focus on the perceptions of young people regarding sustainable food in the Madrid Region. We conducted a survey using a questionnaire-based approach among 1940 students in 2022. The results highlight that young consumers are highly concerned about food sustainability. They perceive sustainability as local and non-processed foods. However, this perception varies among young consumers, and we identified five different consumer profiles. Principal component analysis and cluster analysis provide insights into potential actions that universities can take to promote sustainable and healthy eating habits among students.

Arginine reprograms metabolism in liver cancer via RBM39.

Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in murine and patient hepatocellular carcinoma (HCC), despite reduced expression of arginine synthesis genes. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth.

Cell internalization kinetics and surface charge accessibility of surface-modified PAMAM dendrimers.

Surface-modified PAMAM dendrimers have important applications in drug delivery, yet a gap remains about the role that surface functionalization plays on their cell internalization capacity. We examined the cell internalization kinetics of PAMAM dendrimers that were surface-modified with acetyl, folate and poly(ethylene glycol), as model functional groups differing in size, charge, and chemical functionality. Dendrimers with 25% functionalization were internalized by HEK cells, but with slower rates and lower maximum uptakes than the native dendrimer between 1-6 h of incubation. Dendrimers with 50% functionalization exhibited negligible internalization capacities at all incubation times. Molecular dynamics simulations revealed that the solvent accessibility of the cationic surface charges is a key factor affecting cell internalization, unlike the total charge, functionality or size of surface-modified PAMAM dendrimers. These findings provide valuable insights to assist the design of PAMAM-based systems for drug delivery applications.

DPP9 Comes of Age: Highly Selective Inhibitors Promise New Therapeutic Opportunities.

Dipeptidyl peptidase-like protein 9 (DPP9) is emerging as a promising drug target for the treatment of hematological diseases. Two novel DPP9 inhibitors with nanomolar affinity and unprecedented selectivity to DPP9 over DPP8 have been discovered, paving the way for future progress in DPP9-mediated treatments.

Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions.

Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6' position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2'-N-acetyltransferase type Ia [AAC(2')-Ia], which reduces the antibiotic's potency. Designing formulations that combine an antimicrobial with an inhibitor of resistance is a recognized strategy to extend the useful life of existing antibiotics. We have recently found that several metal ions inhibit the enzymatic inactivation of numerous aminoglycosides mediated by the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib]. In particular, Ag+, which also enhances the effect of aminoglycosides by other mechanisms, is very effective in interfering with AAC(6')-Ib-mediated resistance to amikacin. Here we report that silver acetate is a potent inhibitor of AAC(2')-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of Escherichia coli carrying aac(2')-Ia. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the blaTEM-1 promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells.

Integrated gene expression profiles reveal a transcriptomic network underlying the thermogenic response in adipose tissue.

Obesity and type 2 diabetes are two closely related diseases representing a serious threat worldwide. An increase in metabolic rate through enhancement of non-shivering thermogenesis in adipose tissue may represent a potential therapeutic strategy. Nevertheless, a better understanding of thermogenesis transcriptional regulation is needed to allow the development of new effective treatments. Here, we aimed to characterize the specific transcriptomic response of white and brown adipose tissues after thermogenic induction. Using cold exposure to induce thermogenesis in mice, we identified mRNAs and miRNAs that were differentially expressed in several adipose depots. In addition, integration of transcriptomic data in regulatory networks of miRNAs and transcription factors allowed the identification of key nodes likely controlling metabolism and immune response. Moreover, we identified the putative role of the transcription factor PU.1 in the regulation of PPARγ-mediated thermogenic response of subcutaneous white adipose tissue. Therefore, the present study provides new insights into the molecular mechanisms that regulate non-shivering thermogenesis.

Beyond the classroom: The development of collective structural competency in pro-migrant activism.

Structural competency proposals have been developed as part of an effort to infuse clinical training with a structural focus. Framed in the context of medical education, the discussion on structural competency naturally emphasises the development of such competency in healthcare workers. In this article, we shift the focus to reflect on how the work of migrant community leaders may involve the development of structural competencies and what can be learned from this complementary perspective. We analysed the development of structural competency in an immigrant rights organisation in northern Chile. We conducted focus groups with migrant leaders and volunteers and used the tools proposed by the Structural Competency Working Group to facilitate dialogue. This allowed us to verify the development of structural competency and other collective competencies, including the capacity to create a protected space for circulating experiences and knowledge; coordinate a heterogeneous group of agents; have a socio-legal impact; and maintain autonomy concerning ideological production. This article introduces the concept of collective structural competency and reflects on the importance of expanding beyond the common medical-centred approach when considering structural competency.

Best practices during COVID-19 pandemic in solid organ transplant programs in Spain.

Clinical management of transplant patients abruptly changed during the first months of COVID-19 pandemic (March to May 2020). The new situation led to very significant challenges, such as new forms of relationship between healthcare providers and patients and other professionals, design of protocols to prevent disease transmission and treatment of infected patients, management of waiting lists and of transplant programs during state/city lockdown, relevant reduction of medical training and educational activities, halt or delays of ongoing research, etc. The two main objectives of the current report are: 1) to promote a project of best practices in transplantation taking advantage of the knowledge and experience acquired by professionals during the evolving situation of the COVID-19 pandemic, both in performing their usual care activity, as well as in the adjustments taken to adapt to the clinical context, and 2) to create a document that collects these best practices, thus allowing the creation of a useful compendium for the exchange of knowledge between different Transplant Units. The scientific committee and expert panel finally standardized 30 best practices, including for the pretransplant period (n = 9), peritransplant period (n = 7), postransplant period (n = 8) and training and communication (n = 6). Many aspects of hospitals and units networking, telematic approaches, patient care, value-based medicine, hospitalization, and outpatient visit strategies, training for novelties and communication skills were covered. Massive vaccination has greatly improved the outcomes of the pandemic, with a decrease in severe cases requiring intensive care and a reduction in mortality. However, suboptimal responses to vaccines have been observed in transplant recipients, and health care strategic plans are necessary in these vulnerable populations. The best practices contained in this expert panel report may aid to their broader implementation.

Insight into the Role of Active Site Protonation States and Water Molecules in the Catalytic Inhibition of DPP4 by Vildagliptin.

Vildagliptin (VIL) is an antidiabetic drug that inhibits dipeptidyl peptidase-4 (DPP4) through a covalent mechanism. The molecular bases for this inhibitory process have been addressed experimentally and computationally. Nevertheless, relevant issues remain unknown such as the roles of active site protonation states and conserved water molecules nearby the catalytic center. In this work, molecular dynamics simulations were applied to examine the structures of 12 noncovalent VIL-DPP4 complexes encompassing all possible protonation states of three noncatalytic residues (His126, Asp663, Asp709) that were inconclusively predicted by different computational tools. A catalytically competent complex structure was only achieved in the system with His126 in its ε-form and nonconventional neutral states for Asp663/Asp709. This complex suggested the involvement of one water molecule in the catalytic process of His740/Ser630 activation, which was confirmed by QM/MM simulations. Our findings support the suitability of a novel water-mediated mechanism in which His740/Ser630 activation occurs concertedly with the nucleophilic attack on VIL and the imidate protonation by Tyr547. Then, the restoration of His740/ Tyr547 protonation states occurs via a two-water hydrogen bonding network in a low-barrier process, thus describing the final step of the catalytic cycle for the first time. Additionally, two hydrolytic mechanisms were proposed based on the hydrogen bonding networks formed by water molecules and the catalytic residues along the inhibitory mechanism. These findings are valuable to unveil the molecular features of the covalent inhibition of DPP4 by VIL and support the future development of novel derivatives with improved structural or mechanistic profiles.

Manejo conservador de pseudoaneurisma de vena cava iatrogénico / Conservative management of iatrogenic vena cava pseudoaneurysm

Introducción: los pseudoaneurismas de vena cava infrarrenal (VCI) son una patología infrecuente, sin tratamiento estandarizado; la mayoría, secundarios a traumatismos abdominales. Presentan una mortalidad del 20-57 %. Su manejo debe ser individualizado, con opciones como conservador, quirúrgico o endovascular. Caso clínico: varón de 23 años con cardiopatía congénita compleja que ingresa por síncope extrahospitalario con posterior aleteo auricular e inestabilidad hemodinámica. Durante el procedimiento de ablación presenta shock hemorrágico. Precisa drogas vasoactivas y transfusión masiva. Tras su estabilización, se realiza angio TAC abdominal en el que se visualiza hematoma retroperitoneal dependiente de VCI sin hemorragia activa. Dada la comorbilidad del paciente y la estabilidad hemodinámica, se decide tratamiento conservador y control radiológico. En el angio TAC a los 15 días se visualiza pseudoaneurisma de VCI. Decide mantenerse actitud conservadora, retirar la anticoagulación y realizar revisiones periódicas. Se mantiene estable y se decide el alta, con vigilancia estrecha. En el control a los dos meses se objetiva completa resolución del pseudoaneurisma. Discusión: dada la complejidad de la patología, la estabilidad hemodinámica y las comorbilidades del paciente, se optó por manejo conservador, sin descartar otras opciones terapéuticas si presentaba empeoramiento clínico o radiológico. El tratamiento del pseudoaneurisma de VCI debe individualizarse, priorizando la clínica y la estabilidad del paciente y vigilando la evolución de la lesión con control radiológico estrecho.(AU)

Background: infrarenal cava vein (ICV) pseudoaneurysms are an infrequent pathology, without standardized treatment. Most secondary to abdominal trauma and may associate arterial injuries. Presenting a mortality of 20-57 %, which has not been reduced, despite advances in treatment. Iatrogenic IVC injuries can develop retroperitoneal hematomas and pseudoaneurysms. Its management must be individualized, with options such as conservative, surgical or endovascular. Case report: a 23-year-old male with complex congenital heart disease was admitted due to out-of-hospital syncope with subsequent atrial flutter and hemodynamic instability. During the ablation procedure, he presented hemorrhagic shock requiring doses of vasoactive drugs and massive transfusion. After stabilizing the patient, an abdominal angio-CT was performed, visualizing an IVC-dependent retroperitoneal hematoma with no signs of active bleeding. Given the patient's comorbidity and hemodynamic stability, conservative treatment and radiological control were implemented. CT angiography at 15 days shows IVC pseudoaneurysm. It was decided to maintain a conservative attitude, withdraw anticoagulation and periodic check-ups. Remaining stable, discharge is decided, with close monitoring. At the two months check-up, complete resolution of the pseudoaneurysm is observed. Discussion: given the complexity of the pathology, the patient's hemodynamic stability and comorbidities, conservative management was chosen, without ruling out other therapeutic options if presented with clinical or radiological worsening. The treatment of IVC pseudoaneurysm must be individualized, prioritizing the patient's symptoms and stability and monitoring the evolution of the lesion with close radiological control.(AU)

Molecularly imprinted nanoparticle-based assay (MINA) for microcystin-LR detection in water.

Microcystins (MCs) are highly toxic peptides produced by cyanobacteria during algal blooms. Microcystin-leucine-arginine (MC-LR) is the most toxic and common MC variant with major effects on human and animal health upon exposure. MC-LR detection has become critical to ensure water safety, therefore robust and reliable analytical methods are needed. This work reports the development of a simple and optimized Molecularly Imprinted Nanoparticle-Based Assay (MINA) for MC-LR detection in water. Molecularly Imprinted Nanoparticles (MINs) were prepared by solid-phase polymerization on glass beads conjugated to MC-LR through (3-aminopropyl) triethoxysilane (APTES) via amide bonding. APTES-modified glass beads were obtained under optimized conditions to maximize the density of surface amino groups available for MC-LR conjugation. Two quinary mixtures of acrylic monomers differing in charge, polarity, and functionality were selected from molecular docking calculations and used to obtain MINs for MC-LR recognition using N,N'-methylene-bis-acrylamide (BIS) as the crosslinking agent. MINs were immobilized by physical adsorption onto 96-well polystyrene microplate and evaluated as per their rebinding capacity toward the analyte by using a covalent conjugate between MC-LR and the enzyme horseradish peroxidase (HRP). Experimental conditions for the MINs immobilization protocol, HRP-MC-LR concentration, and composition of the blocking solution were set to maximize the colorimetric response of the MINs compared to non-treated wells. Optimized conditions were then applied to conduct competitive MINAs with the HRP-MC-LR conjugate and the free analyte, which confirmed the preferential binding of MC-LR to the immobilized MINs for analyte concentrations ranging from 1 × 10-5 nmol L-1 to 100 nmol L-1. The best competitive MINA showed a limit of detection of 2.49 × 10-4 nmol L-1 and coefficients of variation less than 10% (n = 6), which are auspicious for the use of MINs as analytical tools for MC-LR detection below the permissible limits issued by WHO for safe water consumption (1.00 nmol L-1). This assay also proved to be selective to the analyte in cross-reactivity studies with two analogous microcystins (MC-RR and MC-YR). Analyses of lagoon and drinking water samples enriched with MC-LR revealed strong matrix effects that reduce the MINA response to the analyte, thus suggesting the need for sample pretreatment methods in future development in this subject.

Down the membrane hole: Ion channels in protozoan parasites.

Parasitic diseases caused by protozoans are highly prevalent around the world, disproportionally affecting developing countries, where coinfection with other microorganisms is common. Control and treatment of parasitic infections are constrained by the lack of specific and effective drugs, plus the rapid emergence of resistance. Ion channels are main drug targets for numerous diseases, but their potential against protozoan parasites is still untapped. Ion channels are membrane proteins expressed in all types of cells, allowing for the flow of ions between compartments, and regulating cellular functions such as membrane potential, excitability, volume, signaling, and death. Channels and transporters reside at the interface between parasites and their hosts, controlling nutrient uptake, viability, replication, and infectivity. To understand how ion channels control protozoan parasites fate and to evaluate their suitability for therapeutics, we must deepen our knowledge of their structure, function, and modulation. However, methodological approaches commonly used in mammalian cells have proven difficult to apply in protozoans. This review focuses on ion channels described in protozoan parasites of clinical relevance, mainly apicomplexans and trypanosomatids, highlighting proteins for which molecular and functional evidence has been correlated with their physiological functions.

Drimane Sesquiterpene Alcohols with Activity against Candida Yeast Obtained by Biotransformation with Cladosporium antarcticum.

Fungal biotransformation is an attractive synthetic strategy to produce highly specific compounds with chemical functionality in regions of the carbon skeleton that are not easily activated by conventional organic chemistry methods. In this work, Cladosporium antarcticum isolated from sediments of Glacier Collins in Antarctica was used to obtain novel drimane sesquiterpenoids alcohols with activity against Candida yeast from drimendiol and epidrimendiol. These compounds were produced by the high-yield reduction of polygodial and isotadeonal with NaBH4 in methanol. Cladosporium antarcticum produced two major products from drimendiol, identified as 9α-hydroxydrimendiol (1, 41.4 mg, 19.4% yield) and 3ß-hydroxydrimendiol (2, 74.8 mg, 35% yield), whereas the biotransformation of epidrimendiol yielded only one product, 9ß-hydroxyepidrimendiol (3, 86.6 mg, 41.6% yield). The products were purified by column chromatography and their structure elucidated by NMR and MS. The antifungal activity of compounds 1-3 was analyzed against Candida albicans, C. krusei and C. parapsilosis, showing that compound 2 has a MIC lower than 15 µg/mL against the three-pathogenic yeast. In silico studies suggest that a possible mechanism of action for the novel compounds is the inhibition of the enzyme lanosterol 14α-demethylase, affecting the ergosterol synthesis.

Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist.

Lymphocystis disease virus-1 (LCDV-1) and several other Iridoviridae encode viral insulin/IGF-1 like peptides (VILPs) with high homology to human insulin and IGFs. Here we show that while single-chain (sc) and double-chain (dc) LCDV1-VILPs have very low affinity for the insulin receptor, scLCDV1-VILP has high affinity for IGF1R where it can antagonize human IGF-1 signaling, without altering insulin signaling. Consequently, scLCDV1-VILP inhibits IGF-1 induced cell proliferation and growth hormone/IGF-1 induced growth of mice in vivo. Cryo-electron microscopy reveals that scLCDV1-VILP engages IGF1R in a unique manner, inducing changes in IGF1R conformation that led to separation, rather than juxtaposition, of the transmembrane segments and hence inactivation of the receptor. Thus, scLCDV1-VILP is a natural peptide with specific antagonist properties on IGF1R signaling and may provide a new tool to guide development of hormonal analogues to treat cancers or metabolic disorders sensitive to IGF-1 without affecting glucose metabolism.

Evolución y protetización de las amputaciones mayores en pacientes con enfermedadarterial periférica de nuestro centro / Outcomes and prosthesis procedure of major amputations in patients with peripheral arterial disease in our center

Introducción: las amputaciones mayores han disminuido en los últimos años, hasta aproximadamente el 7 % de los pacientes con enfermedad arterial periférica crónica (EAPC). La protetización es un procedimiento complejo e importante para la calidad de vida de los pacientes. Las series publicadas comunican datos muy variables entre ellas. Objetivo: describir la evolución de los pacientes sometidos a una amputación mayor por EAPC en nuestro centro y su protetización en relación a su estado basal. Materiales y métodos: estudio descriptivo, retrospectivo y unicéntrico. Recogimos las amputaciones mayores realizadas por nuestro servicio entre 2013 y 2019. Realizamos una búsqueda del registro de pacientes protetizados. Se recogieron las variables sociodemográficas, clínicas, de la intervención, del posoperatorio y de la rehabilitación. Analizamos las variables cualitativas en forma de frecuencias absolutas y porcentajes, los datos cuantitativos mediante la media, la inferencia estadística con el χ2 y la supervivencia con análisis actuarial. Resultados: realizamos 282 amputaciones mayores, de las que el 65,95 % fue en hombres, con una edad media de 71,23 años. El 82,68 % fueron supracondíleas y el 17,32 %, infracondíleas. El 30,85 % tuvieron una amputación menor previa. El 51,06 % habían sido revascularizados previamente. Solo el 37,9 % contaba con una red social adecuada de apoyo. La mediana de supervivencia fue de 24 meses. La mortalidad al año fue del 35 %.El 29,32 % de los pacientes tenía una marcha independiente previa, el 21,22 % no deambulaba y el resto requería ayuda para la marcha. El 28 % (79) de los pacientes fue protetizado, con un uso medio de la prótesis de 15,34 horas al día. El estado de marcha previa se relacionó de manera significativa con la protetización, que consiguió el 49,9 % de los que tenían una marcha independiente frente al 1,69 % de los que no deambulaban (p < 0,001).

Introduction: a decrease in rate of mayor amputation has been reported over the last years; approximately 7 % of patients with chronic peripheral arterial disease (PAD). Implant a prosthesis is a complex and important procedure for the patients ́ quality of life. The journals shown different data between them. Objective: to describe the evolution of patients undergoing a major amputation due to PAD in our center andtheir prosthesis procedure in relation to their baseline status. Materials and methods: descriptive, retrospective and single center study. We collected all major amputations performed by our department between 2013 to 2019. We searched the registry of patients with prosthesis. Socio-demographic, clinical, intervention, postoperative and rehabilitation variables were collected. We analyzed the qualitative variables in the form of absolute frequencies and percentages, the quantitative data through the mean, the statistical inference with the chi2 and the survival with actuarial analysis. Results: we performed 282 major amputations, 65.95 % in men, with a mean age of 71.23 years. 82.68 % were above the knee and 17.32 % below the knee. 30.85 % had a previous minor amputation. 51.06 % had been previously revascularized. Only 37.9 % had an adequate social support. Median survival was 24 months. Mortality at one year was 35 %. 29.32 % of the patients had a previous independent walk, 21.22 % did not walk and the rest required assistance for walking. 28 % (79) of the patients received a prosthesis, with an average use of the prosthesis of 15.34 hours per day. Previous gait status was significantly related to wearing prosthesis, achieved by 49.9 % of those who walked independently versus 1.69 % of those who did not walk (p < 0.001). Of the rest of the factors analyzed, the following had a statistically significant relationship with prosthetic fitting: male gender (p < 0.028), younger than 70 years (p < 0.001),.(AU)