A pentavalent peptide vaccine elicits Aß and tau antibodies with prophylactic activity in an Alzheimer's disease mouse model.

Amyloid-ß (Aß) and hyperphosphorylated tau protein are targets for Alzheimer's Disease (AD) immunotherapies, which are generally focused on single epitopes within Aß or tau. However, due to the complexity of both Aß and tau in AD pathogenesis, a multipronged approach simultaneously targeting multiple epitopes of both proteins could overcome limitations of monotherapies. Herein, we propose an active AD immunotherapy based on a nanoparticle vaccine comprising two Aß peptides (1-14 and pyroglutamate pE3-14) and three tau peptides (centered on phosphorylated pT181, pT217 and pS396/404). These correspond to both soluble and aggregated targets and are displayed on the surface of immunogenic liposomes in an orientation that maintains reactivity with epitope-specific monoclonal antibodies. Intramuscular immunization of mice with individual epitopes resulted in minimally cross-reactive antibody induction, while simultaneous co-display of 5 antigens ("5-plex") induced antibodies against all epitopes without immune interference. Post-immune sera recognized plaques and neurofibrillary tangles from human AD brain tissue. Vaccine administration to 3xTg-AD mice using a prophylactic dosing schedule inhibited tau and amyloid pathologies and resulted in improved cognitive function. Immunization was well tolerated and did not induce antigen-specific cellular responses or persistent inflammatory responses in the peripheral or central nervous system. Antibody levels could be reversed by halting monthly vaccinations. Altogether, these results indicate that active immune therapies based on nanoparticle formulations of multiple Aß and tau epitopes warrant further study for treating early-stage AD.

Machine Learning Model in Obesity to Predict Weight Loss One Year after Bariatric Surgery: A Pilot Study.

Roux-en-Y gastric bypass (RYGB) is a treatment for severe obesity. However, many patients have insufficient total weight loss (TWL) after RYGB. Although multiple factors have been involved, their influence is incompletely known. The aim of this exploratory study was to evaluate the feasibility and reliability of the use of machine learning (ML) techniques to estimate the success in weight loss after RYGP, based on clinical, anthropometric and biochemical data, in order to identify morbidly obese patients with poor weight responses. We retrospectively analyzed 118 patients, who underwent RYGB at the Hospital Clínico Universitario of Valencia (Spain) between 2013 and 2017. We applied a ML approach using local linear embedding (LLE) as a tool for the evaluation and classification of the main parameters in conjunction with evolutionary algorithms for the optimization and adjustment of the parameter model. The variables associated with one-year postoperative %TWL were obstructive sleep apnea, osteoarthritis, insulin treatment, preoperative weight, insulin resistance index, apolipoprotein A, uric acid, complement component 3, and vitamin B12. The model correctly classified 71.4% of subjects with TWL < 30% although 36.4% with TWL ≥ 30% were incorrectly classified as "unsuccessful procedures". The ML-model processed moderate discriminatory precision in the validation set. Thus, in severe obesity, ML-models can be useful to assist in the selection of patients before bariatric surgery.

Pilot Trial on Ischemic Conditioning of the Gastric Conduit in Esophageal Cancer: Feasibility and Impact on Anastomotic Leakage (TIGOAL-I).

Objective: To evaluate the feasibility, safety, and effectiveness of gastric conditioning using preoperative arterial embolization (PAE) before McKeown esophagectomy at a tertiary university hospital. Background: Cervical anastomotic leakage (AL) is a common complication of esophagectomy. Limited clinical evidence suggests that gastric conditioning mitigates this risk. Methods: This pilot randomized clinical trial was conducted between April 2016 and October 2021 at a single-center tertiary hospital. Eligible patients with resectable malignant esophageal tumors, suitable for cervical esophagogastrostomy, were randomized into 2 groups: one receiving PAE and the other standard treatment. The primary endpoints were PAE-related complications and incidence of cervical AL. Results: The study enrolled 40 eligible patients. PAE-related morbidity was 10%, with no Clavien-Dindo grade III complications. Cervical AL rates were similar between the groups (35% vs 25%, P = 0.49), even when conduit necrosis was included (35% vs 35%, P = 1). However, AL severity, including conduit necrosis, was higher in the control group according to the Clavien-Dindo ≥IIIb (5% vs 30%, P = 0.029) and Comprehensive Complication Index (20.9 vs 33.7, P = 0.01). No significant differences were found in other postoperative complications, such as pneumonia or postoperative mortality. Conclusions: PAE is a feasible and safe method for gastric conditioning before McKeown minimally invasive esophagectomy and shows promise for preventing severe AL. However, further studies are required to confirm its efficacy.

Critical steps in the assembly process of the bacterial 50S ribosomal subunit.

During assembly, ribosomal particles in bacteria fold according to energy landscapes comprised of multiple parallel pathways. Cryo-electron microscopy studies have identified a critical maturation step that occurs during the late assembly stages of the 50S subunit in Bacillus subtilis. This step acts as a point of convergency for all the parallel assembly pathways of the subunit, where an assembly intermediate accumulates in a 'locked' state, causing maturation to pause. Assembly factors then act on this critical step to 'unlock' the last maturation steps involving the functional sites. Without these factors, the 50S subunit fails to complete its assembly, causing cells to die due to a lack of functional ribosomes to synthesize proteins. In this review, we analyze these findings in B. subtilis and examine other cryo-EM studies that have visualized assembly intermediates in different bacterial species, to determine if convergency points in the ribosome assembly process are a common theme among bacteria. There are still gaps in our knowledge, as these methodologies have not yet been applied to diverse species. However, identifying and characterizing these convergency points can reveal how different bacterial species implement unique mechanisms to regulate critical steps in the ribosome assembly process.

Adjuvanted nanoliposomes displaying six hemagglutinins and neuraminidases as an influenza virus vaccine.

Inclusion of defined quantities of the two major surface proteins of influenza virus, hemagglutinin (HA) and neuraminidase (NA), could benefit seasonal influenza vaccines. Recombinant HA and NA multimeric proteins derived from three influenza serotypes, H1N1, H3N2, and type B, are surface displayed on nanoliposomes co-loaded with immunostimulatory adjuvants, generating "hexaplex" particles that are used to immunize mice. Protective immune responses to hexaplex liposomes involve functional antibody elicitation against each included antigen, comparable to vaccination with monovalent antigen particles. When compared to contemporary recombinant or adjuvanted influenza virus vaccines, hexaplex liposomes perform favorably in many areas, including antibody production, T cell activation, protection from lethal virus challenge, and protection following passive sera transfer. Based on these results, hexaplex liposomes warrant further investigation as an adjuvanted recombinant influenza vaccine formulation.

Puromycin reveals a distinct conformation of neuronal ribosomes.

Puromycin is covalently added to the nascent chain of proteins by the peptidyl transferase activity of the ribosome and the dissociation of the puromycylated peptide typically follows this event. It was postulated that blocking the translocation of the ribosome with emetine could retain the puromycylated peptide on the ribosome, but evidence against this has recently been published [Hobson et al., Elife 9, e60048 (2020); and Enam et al., Elife 9, e60303 (2020)]. In neurons, puromycylated nascent chains remain in the ribosome even in the absence of emetine, yet direct evidence for this has been lacking. Using biochemistry and cryoelectron microscopy, we show that the puromycylated peptides remain in the ribosome exit channel in the large subunit in a subset of neuronal ribosomes stalled in the hybrid state. These results validate previous experiments to localize stalled polysomes in neurons and provide insight into how neuronal ribosomes are stalled. Moreover, in these hybrid-state neuronal ribosomes, anisomycin, which usually blocks puromycylation, competes poorly with puromycin in the puromycylation reaction, allowing a simple assay to determine the proportion of nascent chains that are stalled in this state. In early hippocampal neuronal cultures, over 50% of all nascent peptides are found in these stalled polysomes. These results provide insights into the stalling mechanisms of neuronal ribosomes and suggest that puromycylated peptides can be used to reveal subcellular sites of hybrid-state stalled ribosomes in neurons.

¿Están correctamente anticoagulados nuestros pacientes con fibrilación auricular no valvular? / Are our patients with non-valvular atrial fibrillation receiving appropriate anticoagulation therapy?

Resumen Introducción: La fibrilación auricular es uno de los problemas de salud más importantes en el mundo por su elevada prevalencia, morbilidad y mortalidad, y porque es una causa importante de los ingresos hospitalarios y la principal indicación de la anticoagulación en atención primaria. Objetivo: El objetivo de nuestro estudio era definir el porcentaje de pacientes tratados, en la fibrilación auricular no valvular con anticoagulantes orales y las características clínicas de estos pacientes, calculando los riesgos embolígenos y hemorrágicos en este tipo de pacientes y su adecuación terapéutica. Pacientes y método: Estudio descriptivo, transversal y retrospectivo, pacientes de un centro de salud, de tres cupos de Atención Primaria con diagnóstico de fibrilación auricular no valvular. Variables: datos demográficos, antecedentes personales (hipertensión arterial, diabetes mellitus, dislipidemia, alcoholismo, tabaquismo, cardiopatía isquémica, insuficiencia cardiaca, enfermedad cerebrovascular, insuficiencia renal, arteriopatía periférica y embolia sistémica), cálculo de las escalas CHA2DS2-VASc y HAS-BLED. Resultados: Se encontraron 99 pacientes con fibrilación auricular no valvular de un total de 4.626 pacientes (2,15%). Edad media 77 ± 10 años, 52,5% mujeres y 47,5% hombres. El 33% no toma ningún tratamiento anticoagulante, el 53% toma el acenocumarol y el resto (13%) un Nuevo anticoagulante oral (dabigatran, apixaban o rivaroxaban). El 97% de los pacientes presentan CHA2DS2-VASc ≥ 2 (alto riesgo embolígeno), de los cuales el 30% no está tomando ningún tratamiento anticoagulante. El 80% de los pacientes presentan HAS-BLED ≥ 3 (alto riesgo hemorrágico), de los cuales el 55% toma el acenocumarol, presentando el 25% una razón internacional normalizada fuera de rango terapéutico. Conclusiones: La fibrilación auricular no valvular es una de las principales causas del accidente vascular cerebral en nuestros pacientes. Se demuestra que el tratamiento anticoagulante en aquellos pacientes con alto riesgo embolígeno reduce los eventos cerebrovasculares en un 64% y la mortalidad en un 26%. En nuestro medio la mayoría de los pacientes diagnosticados con fibrilación auricular no valvular presentan ese riesgo, pero tenemos un 33% no anticoagulado y un 25% mal controlado con el acenocumarol (un total del 46% de los pacientes). Todo esto implica que casi el 50% de nuestros pacientes con fibrilación auricular no valvular presenten alto riesgo tromboembólico por falta de tratamiento o ineficacia de este.

Abstract Introduction: Atrial fibrillation is one of the most important health problems in the world due to its high prevalence, morbidity and mortality, and because it is a frequent cause of hospital admission and the main indicator for anticoagulation therapy in primary care. Objective: The motivation of our study was to define the percentage of patients with nonvalvular atrial fibrillation treated with oral anticoagulants and their clinical characteristics, calculating risks for embolisms and bleeding in this type of patients and their appropriate therapeutic approach. Patients and methods: Descriptive, cross-sectional, retrospective study in patients of a primary care centre with three primary care quotas with a diagnosis of non-valvular atrial fibrillation. Variables: demographic data, personal history (arterial hypertension, diabetes mellitus, dyslipidemia, alcohol addiction, smoking habit, ischemic heart disease, heart failure, cerebrovascular disease, kidney failure, peripheral artery disease and systemic embolism), CHA2DS2-VASc and HAS-BLED scores. Results: Out of 4,626 patients, 99 (2.15%) were found to have nonvalvular atrial fibrillation. Average age 77 ± 10 years, 52.5% women and 47.5% men. 33% are not receiving any anticoa- gulation therapy, 53% takes acenocoumarol and the rest (13%) a new oral blood-thinning drug (dabigatran, apixaban or rivaroxaban). 97% of patients present a CHA2DS2-VASc ≥2 risk (high for embolism), of which 30% are not receiving any anticoagulation therapy. 80% of patients present HAS-BLED ≥ 3 risk (high for bleeding), of which 55% is taking acenocoumarol, 25% showing international normalized ratio out of the therapeutic range. Conclusion: Nonvalvular atrial fibrillation is one of the main causes of cerebrovascular accidents in our patients. It is shown that anticoagulation therapy in patients with high risk of embolism reduces cerebrovascular accidents by 64% and mortality by 26%. In our field, most patients diagnoses with nonvalvular atrial fibrillation have this risk, but 33% are not taking anticoagulants and 25% are poorly controlled with acenocoumarol (a total of 46% of patients). All this implies that 50% of our patients with non-valvular atrial fibrillation develop a high risk for thromboembolic events due to lack or inadequacy of the treatment.

Equine leukoencephalomalacia (ELEM) due to fumonisins B1 and B2 in Argentina / Leucoencefalomalacia equina devida a fumonisinas B1 e B2 na Argentina

In August 2007 an outbreak of neurological disease and sudden death in Arabian horses occurred in a farm located in Coronel Rosales County, Buenos Aires Province, Argentina. The animals were on a pasture of native grasses and supplemented ad libitum with corn kernels and wheat bran. Three horses were observed having acute neurologic signs including blindness, four leg ataxia, hyperexcitability, aimless walking and circling, followed by death in two of them. Four other horses were found dead overnight without a history of neurologic signs. The morbidity, mortality and lethality rates were 11.6 percent, 10 percent and 85.7 percent, respectively. Grossly, the brain showed focal areas of hemorrhage, brown-yellow discoloration and softening of the sub-cortical white matter. The microscopic brain lesions consisted of extensive areas of malacia within the white matter of the cerebral hemispheres, brainstem and cerebellum, characterized by rarefaction of the white matter with cavitations filled with proteinaceous edema, multifocal hemorrhages and mild infiltration by neutrophils, and rare eosinophils. Swollen glial cells with abundant eosinophilic cytoplasm, distinct cell borders, intracytoplasmic deeply eosinophilic globules and eccentric, hyperchromatic, occasionally pyknotic nucleus were present throughout the areas of rarefaction hemorrhage, edema and necrosis. The feed supplements contained 12,490µg/kg of fumonisin B1 and 5,251µg/ kg of fumonisin B2. This is the first reported outbreak of ELEM associated with consumption of feed supplements containing high concentrations of fumonisins in Argentina.

Em agosto de 2007, ocorreu um surto de doença neurológica e morte súbita em cavalos árabes em uma propriedade localizada no município de Coronel Rosales, na província de Buenos Aires, Argentina. Os animais estavam em pasto nativo e eram suplementados ad libitum com grãos de milho e farelo de trigo. Três cavalos foram observados com sinais neurológicos agudos, incluindo cegueira, ataxia nas quatro pernas, hiperexcitabilidade, e andar sem rumo e em círculo, seguidos de morte em dois animais. Outros quatro cavalos foram encontrados mortos durante a noite sem histórico de distúrbios neurológicos. A mortalidade, morbidade e letalidade foram de 11,6 por cento, 10 por cento e 85,7 por cento, respectivamente. Macroscopicamente, o cérebro tinha áreas focais de hemorragia, coloração amarelada e amolecimento da substância branca sub-cortical. Microscopicamente, as lesões cerebrais consistiram de extensas áreas de malácia na substância branca dos hemisférios cerebrais, do tronco encefálico e do cerebelo. Estas lesões da substância branca se caracterizaram por rarefação, cavidades contendo fluido proteináceo (edema), hemorragias multifocais e moderado infiltrado por neutrófilos e raros eosinófilos. Células gliais tumefeitas com abundante citoplasma eosinifílico, limites celulares evidentes, globules citoplasmáticos eosinofílicos, e núcleo excéntrico, hipercromático e ocasionalmente picnótico foram observadas nas areas de rarefacção, edema, hemorragias e necrose. Os suplementos alimentares continham 12.490µg/kg de fumonisina B1 e 5.251µg/ kg de fumonisina B2. Este é o primeiro surto reportado na Argentina de leucoencefalomalácia equina associado ao consumo de suplementos alimentares contendo altas concentrações de fumonisinas.