Identification of robust cellular programs using reproducible LDA that impact sex-specific disease progression in different genotypes of a mouse model of AD.

The gene expression profiles of distinct cell types reflect complex genomic interactions among multiple simultaneous biological processes within each cell that can be altered by disease progression as well as genetic background. The identification of these active cellular programs is an open challenge in the analysis of single-cell RNA-seq data. Latent Dirichlet Allocation (LDA) is a generative method used to identify recurring patterns in counts data, commonly referred to as topics that can be used to interpret the state of each cell. However, LDA's interpretability is hindered by several key factors including the hyperparameter selection of the number of topics as well as the variability in topic definitions due to random initialization. We developed Topyfic, a Reproducible LDA (rLDA) package, to accurately infer the identity and activity of cellular programs in single-cell data, providing insights into the relative contributions of each program in individual cells. We apply Topyfic to brain single-cell and single-nucleus datasets of two 5xFAD mouse models of Alzheimer's disease crossed with C57BL6/J or CAST/EiJ mice to identify distinct cell types and states in different cell types such as microglia. We find that 8-month 5xFAD/Cast F1 males show higher level of microglial activation than matching 5xFAD/BL6 F1 males, whereas female mice show similar levels of microglial activation. We show that regulatory genes such as TFs, microRNA host genes, and chromatin regulatory genes alone capture cell types and cell states. Our study highlights how topic modeling with a limited vocabulary of regulatory genes can identify gene expression programs in single-cell data in order to quantify similar and divergent cell states in distinct genotypes.

COVID-19 and Vestibular Symptoms and Assessment: A Review.

BACKGROUND: The current pandemic of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality primarily associated with respiratory failure. However, it has also been reported that COVID-19 can evolve into a nervous system infection. The direct and indirect mechanisms of damage associated with SARS-CoV-2 neuropathogenesis could affect our sensory functionality, including hearing and balance. SUMMARY: In order to investigate a possible association between SARS-CoV-2 viral infection and possible damage to the vestibular system, this review describes the main findings related to diagnosing and evaluating otoneurological pathologies. KEY MESSAGES: The clinical evidence shows that SARS-CoV-2 causes acute damage to the vestibular system that would not leave significant sequelae. Recovery is similar to vestibular pathologies such as vestibular neuronitis and benign paroxysmal positional vertigo. Further basic science, clinical, and translational research is needed to verify and understand the short- and long-term effects of COVID-19 on vestibular function.

Longitudinal clinical phenotyping of post COVID condition in Mexican adults recovering from severe COVID-19: a prospective cohort study.

Introduction: Few studies have evaluated the presence of Post COVID-19 conditions (PCC) in people from Latin America, a region that has been heavily afflicted by the COVID-19 pandemic. In this study, we describe the frequency, co-occurrence, predictors, and duration of 23 symptoms in a cohort of Mexican patients with PCC. Methods: We prospectively enrolled and followed adult patients hospitalized for severe COVID-19 at a tertiary care centre in Mexico City. The incidence of PCC symptoms was determined using questionnaires. Unsupervised clustering of PCC symptom co-occurrence and Kaplan-Meier analyses of symptom persistence were performed. The effect of baseline clinical characteristics was evaluated using Cox regression models and reported with hazard ratios (HR). Results: We found that amongst 192 patients with PCC, respiratory problems were the most prevalent and commonly co-occurred with functional activity impairment. 56% had ≥5 persistent symptoms. Symptom persistence probability at 360 days 0.78. Prior SARS-CoV-2 vaccination and infection during the Delta variant wave were associated with a shorter duration of PCC. Male sex was associated with a shorter duration of functional activity impairment and respiratory symptoms. Hypertension and diabetes were associated with a longer duration of functional impairment. Previous vaccination accelerated PCC recovery. Discussion: In our cohort, PCC symptoms were frequent (particularly respiratory and neurocognitive ones) and persistent. Importantly, prior SARS-CoV-2 vaccination resulted in a shorter duration of PCC.

Systematic assessment of long-read RNA-seq methods for transcript identification and quantification.

The Long-read RNA-Seq Genome Annotation Assessment Project (LRGASP) Consortium was formed to evaluate the effectiveness of long-read approaches for transcriptome analysis. The consortium generated over 427 million long-read sequences from cDNA and direct RNA datasets, encompassing human, mouse, and manatee species, using different protocols and sequencing platforms. These data were utilized by developers to address challenges in transcript isoform detection and quantification, as well as de novo transcript isoform identification. The study revealed that libraries with longer, more accurate sequences produce more accurate transcripts than those with increased read depth, whereas greater read depth improved quantification accuracy. In well-annotated genomes, tools based on reference sequences demonstrated the best performance. When aiming to detect rare and novel transcripts or when using reference-free approaches, incorporating additional orthogonal data and replicate samples are advised. This collaborative study offers a benchmark for current practices and provides direction for future method development in transcriptome analysis.

The ENCODE Uniform Analysis Pipelines.

The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of the Homo sapiens and Mus musculus genomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community. The ENCODE project has engineered and distributed uniform processing pipelines in order to promote data provenance and reproducibility as well as allow interoperability between genomic resources and other consortia. All data files, reference genome versions, software versions, and parameters used by the pipelines are captured and available via the ENCODE Portal. The pipeline code, developed using Docker and Workflow Description Language (WDL; https://openwdl.org/) is publicly available in GitHub, with images available on Dockerhub (https://hub.docker.com), enabling access to a diverse range of biomedical researchers. ENCODE pipelines maintained and used by the DCC can be installed to run on personal computers, local HPC clusters, or in cloud computing environments via Cromwell. Access to the pipelines and data via the cloud allows small labs the ability to use the data or software without access to institutional compute clusters. Standardization of the computational methodologies for analysis and quality control leads to comparable results from different ENCODE collections - a prerequisite for successful integrative analyses.

The ENCODE4 long-read RNA-seq collection reveals distinct classes of transcript structure diversity.

The majority of mammalian genes encode multiple transcript isoforms that result from differential promoter use, changes in exonic splicing, and alternative 3' end choice. Detecting and quantifying transcript isoforms across tissues, cell types, and species has been extremely challenging because transcripts are much longer than the short reads normally used for RNA-seq. By contrast, long-read RNA-seq (LR-RNA-seq) gives the complete structure of most transcripts. We sequenced 264 LR-RNA-seq PacBio libraries totaling over 1 billion circular consensus reads (CCS) for 81 unique human and mouse samples. We detect at least one full-length transcript from 87.7% of annotated human protein coding genes and a total of 200,000 full-length transcripts, 40% of which have novel exon junction chains. To capture and compute on the three sources of transcript structure diversity, we introduce a gene and transcript annotation framework that uses triplets representing the transcript start site, exon junction chain, and transcript end site of each transcript. Using triplets in a simplex representation demonstrates how promoter selection, splice pattern, and 3' processing are deployed across human tissues, with nearly half of multi-transcript protein coding genes showing a clear bias toward one of the three diversity mechanisms. Evaluated across samples, the predominantly expressed transcript changes for 74% of protein coding genes. In evolution, the human and mouse transcriptomes are globally similar in types of transcript structure diversity, yet among individual orthologous gene pairs, more than half (57.8%) show substantial differences in mechanism of diversification in matching tissues. This initial large-scale survey of human and mouse long-read transcriptomes provides a foundation for further analyses of alternative transcript usage, and is complemented by short-read and microRNA data on the same samples and by epigenome data elsewhere in the ENCODE4 collection.

Self-limited epilepsy with autonomic seizures: A case report.

Self-limited epilepsy with autonomic seizures, formerly known as benign occipital epilepsy of childhood or Panayiotopoulos syndrome is a focal epilepsy that is part of the epileptic syndromes with onset during childhood. The objective of this report is to raise awareness about its importance and describe the clinical manifestations, timely diagnosis, and treatment. A pediatric patient admitted with gastrointestinal manifestations is presented. The autonomic manifestations must be considered as part of the clinical spectrum that includes this disease and the digestive and autonomic manifestations that mask the diagnosis, sometimes even in the absence of motor seizures themselves. Electroencephalographic confirmation was performed, avoiding cataloging it in other differential diagnoses.

The ENCODE Uniform Analysis Pipelines.

The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of the Homo sapiens and Mus musculus genomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community. The ENCODE project has engineered and distributed uniform processing pipelines in order to promote data provenance and reproducibility as well as allow interoperability between genomic resources and other consortia. All data files, reference genome versions, software versions, and parameters used by the pipelines are captured and available via the ENCODE Portal. The pipeline code, developed using Docker and Workflow Description Language (WDL; https://openwdl.org/) is publicly available in GitHub, with images available on Dockerhub (https://hub.docker.com), enabling access to a diverse range of biomedical researchers. ENCODE pipelines maintained and used by the DCC can be installed to run on personal computers, local HPC clusters, or in cloud computing environments via Cromwell. Access to the pipelines and data via the cloud allows small labs the ability to use the data or software without access to institutional compute clusters. Standardization of the computational methodologies for analysis and quality control leads to comparable results from different ENCODE collections - a prerequisite for successful integrative analyses.

The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models.

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × âˆ¼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Impact of the COVID-19 pandemic on the gingival health of children and adolescents with cerebral palsy / Impacto da pandemia do COVID-19 na saúde gengival de crianças e adolescentes com paralisia cerebral

Objective: to evaluate the impact of the COVID-19 pandemic on children and adolescents with cerebral palsy, comparing the gingival condition and the type of dental treatment before and after the interruption of dental care. Material and Methods: the retrospective longitudinal study consisted of 273 participants undergoing Dental Clinic of the AACD (Disabled Child Assistance Association), divided into three groups according to age: Group 1 (G1: 0 to 5 years and 11 months; n=137), Group 2 (G2: 6 to 11 years and 11 months; n=85) and Group 3 (G3: 12 to 17 years and 11 months; n=51). Sociodemographic, data, clinical pattern of cerebral palsy and use of medication were collected, evaluating the gingival condition by the gingival index and the type of dental treatment before the pandemic and during, nine months after the interruption of dental care. Chi-square, Fisher Exact and Kruskal-Wallis (α=5%) tests were used. Results: the groups were homogeneous in terms of sex (p=0.4581), race (p=0.1725), clinical pattern (p=0.3482) and use of antiepileptic drugs (p=0.3509). Regarding the gingival condition, in the period during the pandemic, there was a reduction in the number of participants with Gingival Index scores 0 and 1 and an increase in participants with scores 2 and 3 (p<0.05). As for the procedures performed, the three groups showed a reduction in preventive procedures (p<0.05) and an increase in surgical, periodontal and restorative procedures (p<0.05). Conclusion: it is concluded that the interruption of dental care for nine months during the COVID-19 pandemic in children and adolescents with cerebral palsy had a negative impact on oral health (AU)

Objetivo: avaliar o impacto da pandemia da COVID-19 em crianças e adolescentes com Paralisia Cerebral, comparando a condição gengival e o tipo de tratamento odontológico antes e após a interrupção dos atendimentos odontológicos. Material e Métodos: o estudo longitudinal retrospectivo foi composto por 273 participantes atendidos na Clínica odontológica da AACD (Associação de Assistência à Criança Deficiente), reunidos em três grupos segundo a faixa etária: Grupo 1 (G1: 0 a 5 anos e 11 meses; n=137), Grupo 2 (G2: 6 a 11 anos e 11 meses; n=85) e Grupo 3 (G3: 12 a 17 anos e 11 meses; n=51). Foram coletados dados sociodemográficos, padrão clínico da Paralisia Cerebral e o uso de medicação, avaliando a condição gengival pelo índice gengival e o tipo de tratamento odontológico antes e durante a pandemia, nove meses após a interrupção dos atendimentos. Foram empregados os testes Qui-quadrado, Exato de Fisher e Kruskal-Wallis (α=5%). Resultados: os grupos eram homogêneos quanto ao sexo (p=0,4581), raça (p=0,1725), padrão clínico (p=0,3482) e uso de drogas antiepiléticas (p=0,3509). Com relação à condição gengival, no período Durante Pandemia, observou-se redução no número de participantes com escores Índice Gengival 0 e 1 e aumento de participantes com escores 2 e 3 (p<0,05). Quanto aos procedimentos realizados, os três grupos apresentaram redução de procedimentos preventivos (p<0,05) e aumento dos procedimentos cirúrgicos, periodontal e restaurador (p<0,05). Conclusão: conclui-se que a interrupção do acompanhamento odontológico por nove meses na pandemia da COVID-19 em crianças e adolescentes com PC acarretou impacto negativo na saúde bucal (AU)

Tratamento de trauma por mordedura autoinflingida com laserterapia e bandagem elástica: relato de caso / Bite trauma treatment with laser therapy and elastic bandage: case report

Introdução: trauma de mordedura ou úlcera traumática é uma lesão aguda da mucosa oral que tem como etiologia um trauma mecânico ou irritação no tecido mole afetado. Objetivo: relatar um tratamento multidisciplinar de trauma por mordedura autoinflingida em lábio inferior. Relato do caso: paciente com 17 anos de idade, sexo masculino, paraplégico, ficou acamado devido às limitações neuromotoras e, de forma involuntária e reflexa, realizava a mordedura dos lábios. Essa movimentação traumatizava a região do lábio inferior causando a úlcera traumática, que não cicatrizava. Inicialmente foi instalado um protetor bucal de etil vinil acetato, mas o paciente não se adaptou. Então, foi realizado três sessões de laserterapia (fotobiomodulação), semanalmente e de forma pontual, ao longo da úlcera traumática, nas radiações vermelha e infravermelha (660nm; 808nm; 100mW; 2J/cm2 ­ Laser DUO MMO), aliado às bandagens elásticas (o método Therapy Taping®) para evitar a invaginação para cavidade bucal, afastando o lábio inferior dos dentes a fim de evitar o trauma da mucosa oral. Conclusão: a apresentação desse relato demonstrou algumas possibilidades de tratamento de uma lesão traumática, sendo o seu manejo ainda um grande desafio clínico na Odontologia e em especial para pacientes com deficiências motoras e ou cognitivas.

Introduction: bite trauma or traumatic ulcer is an acute injury of the oral mucosa whose etiology is mechanical trauma or irritation of the affected soft tissue. Objective: to report a multidisciplinary treatment of self-inflicted lower lip trauma. Case report: 17-year-old male patient, paraplegic, was bedridden due to neuromotor limitations and, involuntary and reflexive, bit the lips. This movement traumatized the region of the lower lip causing the traumatic ulcer, which did not heal. Initially, an ethyl vinyl acetate mouthguard was installed, but the patient did not adapt. Then, three sessions of laser therapy (photobiomodulation) was performed weekly and point, along the traumatic ulcer, in red and infrared radiation (660nm; 808nm; 100mW; 2J/cm2 ­ Laser DUO MMO), combined with elastic bandages (the Therapy Taping® method) to prevent invagination into the oral cavity, to move the lower lip away from his teeth in order to avoid trauma to the oral mucosa. Conclusion: the presentation of this report demonstrated some possibilities for the treatment of a traumatic injury, and its management is still a major clinical challenge in Dentistry, especially for patients with motor and/or cognitive impairments.

Sinais clínicos do transtorno do espectro autista (TEA) para auxiliar o odontopediatra no diagnóstico precoce / Clinical signs of Autistic Spectrum Disorder (ASD) to assist pediatric dentists in early diagnosis

Introdução: O Transtorno do Espectro Autista (TEA) é um distúrbio de desenvolvimento que interfere nas áreas de interação social e comportamental, podendo ser classificado em níveis leve, moderado e severo. Objetivo: Realizar uma revisão de literatura para identificar os sinais presentes em pacientes com esse transtorno, e assim auxiliar os cirurgiões dentistas, principalmente o odontopediatra, no diagnóstico precoce. Revisão de literatura: As primeiras manifestações do TEA aparecem antes dos 36 meses de idade. Um dos sinais clínicos relacionados à interação social são crianças que preferem ficar sozinhas, não participando de brincadeiras. Costumam ser observados sinais de comportamentos repetitivos e interesses restritos, que podem dificultar o convívio social. Atrasos na fala são, frequentemente, o principal sinal observado pelos pais. Alguns questionários de rastreamento de TEA podem ser aplicados pelos profissionais da saúde. Discussão: O cirurgião-dentista, especialmente o odontopediatra, deve estar atento ao desenvolvimento do paciente infantil, verificando a presença de atraso na fala, característica importante do espectro, bem como de desvios de comportamento incompatíveis com a idade ou procedimento odontológico. Na presença de algum sinal do espectro o profissional não deve hesitar em encaminhar para outros profissionais para melhor avaliação. Conclusão: O conhecimento desses sinais por parte dos profissionais de saúde, em especial o odontopediatra, é de fundamental importância para auxiliar no diagnóstico precoce, a fim de minimizar os sintomas e contribuir para o desenvolvimento e integração da criança com TEA na sociedade.

Introduction: Autism Spectrum Disorder (ASD) is a de-velopmental disorder that interferes in the behavioral and social interaction areas, and can be classified into mild, moderate, and severe levels. Aim: To conduct a literature review to identify the signs present in patients with ASD, and thus assist dentists, especially pediatric dentists, in early diagnosis. Literature review: The first manifestations of ASD appear before 36 months of age. One of the clinical signs related to social interaction are children who prefer to be alone, not participating in games. Signs of repetitive behaviors and restricted interests are usually observed, which can hinder social interaction. Speech delays are often the main sign observed by parents. Some ASD screening questionnaires can be applied by healthcare professionals. Discussion:The dentist, especially the pediatric dentist, must be attentive to the development of the patient, verifying the presence of speech delay, an important characteristic of the spectrum, as well as behavioral deviations incom-patible with age or dental procedure. In the presence of some signs of the spectrum, the professional should not hesitate to refer the patient to other professionals for further evaluation. Conclusion: Knowledge of these signs by health professionals, especially pediatric dentists, is of fundamental importance to assist in early diagnosis in order to minimize symptoms and contribute to the development and integration of children with ASD in society.

Etiology, risk factors, treatments and current status of Alzheimer's disease in Mexico.

Alzheimer's disease is a neurodegenerative disorder whose etiology continues to be discussed, to the point that there are different hypotheses that seek to clarify it, in addition to the fact that, given its multifactorial nature, there are different risk factors associated with its development. As regards diagnosis, advances in molecule detection techniques at femtomolar scales have allowed to distinguish between healthy and diseased subjects at relatively early stages, although there is still much to be done. Aducanumab is a monoclonal antibody targeted against Aß, whose marketing approval by the Food and Drug Administration has been questioned by the international medical community, given the controversial results in clinical trials. Approval of this antibody as a disease-modifying treatment for Alzheimer's disease opens the door to continue using this type of treatments, but with different therapeutic targets, such as, for example, tau protein. Finally, given the population tendency towards longevity, conditions such as Alzheimer's disease are gaining epidemiological importance, which is why it is imperative to analyze and link what is being done in the social, familiar, clinical and research fields and, most importantly, to find those areas of opportunity for the benefit of the patient.

La enfermedad de Alzheimer es un desorden neurodegenerativo cuya etiología aún se discute, al punto de que existen diferentes hipótesis que pretenden esclarecerla; además, dada su naturaleza multifactorial, existen diferentes factores de riesgo asociados a su desarrollo. Respecto al diagnóstico, los avances en las técnicas de detección de moléculas a escalas femtomolares han permitido discernir entre sujetos sanos y enfermos en estadios relativamente tempranos, aunque todavía hay mucho por hacer. Aducanumab es un anticuerpo monoclonal dirigido contra Aß, cuya aprobación por parte de la Food and Drug Administration para comercializarse ha sido cuestionada por la comunidad médica internacional, dados los resultados controversiales en los ensayos clínicos. La aprobación de este anticuerpo como tratamiento modificador de la enfermedad de Alzheimer abre la puerta para seguir utilizando este tipo de tratamientos, pero con blancos terapéuticos diferentes, como, por ejemplo, la proteína tau. Finalmente, dada la tendencia de la población hacia la longevidad, padecimientos como la enfermedad de Alzheimer están tomando importancia epidemiológica, por lo que resulta imperativo analizar y vincular lo que se está haciendo en los ámbitos social, familiar, clínico y de investigación y, sobre todo, encontrar esas áreas de oportunidad en beneficio del paciente.

Detection of periodontal disease activity based on histatin degradation in individuals with cerebral palsy.

Objectives: This proof-of-concept study aimed at evaluating the proteolytic profile of histatin 1 and 5 in saliva of adolescents with spastic cerebral palsy (CP) with gingivitis. Methods: This cross-sectional study included 24 individuals allocated into three groups: G1 (CP with gingivitis; n = 8), G2 (without CP and without gingivitis; n = 8), and G3 (without CP and with gingivitis; n = 8). The gingival index (GI) and simplified oral hygiene index (OHI-S) were evaluated. Whole saliva was collected and used to assess the rate and mode of histatin 1 and 5 at different times. The degradation products were visualized after cationic PAGE and the protein band densities (BDs) were compared with a protein standard. Fragmentation products were collected from the gel, pooled by group and characterized by mass spectrometry. BDs and gingival health parameters were analyzed by One-Way ANOVA or Kruskal Wallis tests, whereas poisson multilevel regression was used to the factors that influenced histatin degradation (α = 5%). Results: Groups G1 and G3 differed significantly on OHI-S, visible biofilm, oral calculus and GI (p < 0.001). Poisson Regression showed that: 1) CP and gingivitis influenced the degradation of histatin 1 and 5 (p < 0.05); 2) The degradation of histatin 5 was influenced by age and male sex (p < 0.05); and 3) GI influenced significantly the degradation of histatin 1 (p < 0.001). Unique histatin degradation peptides were identified in individuals with gingivitis. Conslusions: These data demonstrated that both the kinetics and pattern of histatins degradation differ according to the gingival health or disease conditions.

C5aR1 antagonism alters microglial polarization and mitigates disease progression in a mouse model of Alzheimer's disease.

Multiple studies have recognized the involvement of the complement cascade during Alzheimer's disease pathogenesis. However, the specific role of C5a-C5aR1 signaling in the progression of this neurodegenerative disease is still not clear. Furthermore, its potential as a therapeutic target to treat AD still remains to be elucidated. Canonically, generation of the anaphylatoxin C5a as the result of complement activation and interaction with its receptor C5aR1 triggers a potent inflammatory response. Previously, genetic ablation of C5aR1 in a mouse model of Alzheimer's disease exerted a protective effect by preventing cognitive deficits. Here, using PMX205, a potent, specific C5aR1 antagonist, in the Tg2576 mouse model of Alzheimer's disease we show a striking reduction in dystrophic neurites in parallel with the reduced amyloid load, rescue of the excessive pre-synaptic loss associated with AD cognitive impairment and the polarization of microglial gene expression towards a DAM-like phenotype that are consistent with the neuroprotective effects seen. These data support the beneficial effect of a pharmacological inhibition of C5aR1 as a promising therapeutic approach to treat Alzheimer's disease. Supportive of the safety of this treatment is the recent FDA-approval of another other C5a receptor 1 antagonist, Avacopan, as a treatment for autoimmune inflammatory diseases.

A potent virucidal activity of functionalized TiO2 nanoparticles adsorbed with flavonoids against SARS-CoV-2.

The coronavirus SARS-CoV-2 has caused a pandemic with > 550 millions of cases and > 6 millions of deaths worldwide. Medical management of COVID-19 relies on supportive care as no specific targeted therapies are available yet. Given its devastating effects on the economy and mental health, it is imperative to develop novel antivirals. An ideal candidate will be an agent that blocks the early events of viral attachment and cell entry, thereby preventing viral infection and spread. This work reports functionalized titanium dioxide (TiO2)-based nanoparticles adsorbed with flavonoids that block SARS-CoV-2 entry and fusion. Using molecular docking analysis, two flavonoids were chosen for their specific binding to critical regions of the SARS-CoV-2 spike glycoprotein that interacts with the host cell angiotensin-converting enzyme-2 (ACE-2) receptor. These flavonoids were adsorbed onto TiO2 functionalized nanoparticles (FTNP). This new nanoparticulate compound was assayed in vitro against two different coronaviruses; HCoV 229E and SARS-CoV-2, in both cases a clear antiviral effect was observed. Furthermore, using a reporter-based cell culture model, a potent antiviral activity is demonstrated. The adsorption of flavonoids to functionalized TiO2 nanoparticles induces a ~ threefold increase of that activity. These studies also indicate that FTNP interferes with the SARS-CoV-2 spike, impairing the cell fusion mechanism. KEY POINTS/HIGHLIGHTS: • Unique TiO2 nanoparticles displaying flavonoid showed potent anti-SARS-CoV-2 activity. • The nanoparticles precisely targeting SARS-CoV-2 were quantitatively verified by cell infectivity in vitro. • Flavonoids on nanoparticles impair the interactions between the spike glycoprotein and ACE-2 receptor.

Etiología, factores de riesgo, tratamientos y situación actual de la enfermedad de Alzheimer en México / Etiology, risk factors, treatments and current status of Alzheimer's disease in Mexico

Resumen La enfermedad de Alzheimer es un desorden neurodegenerativo cuya etiología aún se discute, al punto de que existen diferentes hipótesis que pretenden esclarecerla; además, dada su naturaleza multifactorial, existen diferentes factores de riesgo asociados a su desarrollo. Respecto al diagnóstico, los avances en las técnicas de detección de moléculas a escalas femtomolares han permitido discernir entre sujetos sanos y enfermos en estadios relativamente tempranos, aunque todavía hay mucho por hacer. Aducanumab es un anticuerpo monoclonal dirigido contra Aβ, cuya aprobación por parte de la Food and Drug Administration para comercializarse ha sido cuestionada por la comunidad médica internacional, dados los resultados controversiales en los ensayos clínicos. La aprobación de este anticuerpo como tratamiento modificador de la enfermedad de Alzheimer abre la puerta para seguir utilizando este tipo de tratamientos, pero con blancos terapéuticos diferentes, como, por ejemplo, la proteína tau. Finalmente, dada la tendencia de la población hacia la longevidad, padecimientos como la enfermedad de Alzheimer están tomando importancia epidemiológica, por lo que resulta imperativo analizar y vincular lo que se está haciendo en los ámbitos social, familiar, clínico y de investigación y, sobre todo, encontrar esas áreas de oportunidad en beneficio del paciente.

Abstract Alzheimer's disease is a neurodegenerative disorder whose etiology continues to be discussed, to the point that there are different hypotheses that seek to clarify it, in addition to the fact that, given its multifactorial nature, there are different risk factors associated with its development. As regards diagnosis, advances in molecule detection techniques at femtomolar scales have allowed to distinguish between healthy and diseased subjects at relatively early stages, although there is still much to be done. Aducanumab is a monoclonal antibody targeted against Aβ, whose marketing approval by the Food and Drug Administration has been questioned by the international medical community, given the controversial results in clinical trials. Approval of this antibody as a disease-modifying treatment for Alzheimer's disease opens the door to continue using this type of treatments, but with different therapeutic targets, such as, for example, tau protein. Finally, given the population tendency towards longevity, conditions such as Alzheimer's disease are gaining epidemiological importance, which is why it is imperative to analyze and link what is being done in the social, familiar, clinical and research fields and, most importantly, to find those areas of opportunity for the benefit of the patient.

Modulation of C5a-C5aR1 signaling alters the dynamics of AD progression.

BACKGROUND: The complement system is part of the innate immune system that clears pathogens and cellular debris. In the healthy brain, complement influences neurodevelopment and neurogenesis, synaptic pruning, clearance of neuronal blebs, recruitment of phagocytes, and protects from pathogens. However, excessive downstream complement activation that leads to generation of C5a, and C5a engagement with its receptor C5aR1, instigates a feed-forward loop of inflammation, injury, and neuronal death, making C5aR1 a potential therapeutic target for neuroinflammatory disorders. C5aR1 ablation in the Arctic (Arc) model of Alzheimer's disease protects against cognitive decline and neuronal injury without altering amyloid plaque accumulation. METHODS: To elucidate the effects of C5a-C5aR1 signaling on AD pathology, we crossed Arc mice with a C5a-overexpressing mouse (ArcC5a+) and tested hippocampal memory. RNA-seq was performed on hippocampus and cortex from Arc, ArcC5aR1KO, and ArcC5a+ mice at 2.7-10 months and age-matched controls to assess mechanisms involved in each system. Immunohistochemistry was used to probe for protein markers of microglia and astrocytes activation states. RESULTS: ArcC5a+ mice had accelerated cognitive decline compared to Arc. Deletion of C5ar1 delayed or prevented the expression of some, but not all, AD-associated genes in the hippocampus and a subset of pan-reactive and A1 reactive astrocyte genes, indicating a separation between genes induced by amyloid plaques alone and those influenced by C5a-C5aR1 signaling. Biological processes associated with AD and AD mouse models, including inflammatory signaling, microglial cell activation, and astrocyte migration, were delayed in the ArcC5aR1KO hippocampus. Interestingly, C5a overexpression also delayed the increase of some AD-, complement-, and astrocyte-associated genes, suggesting the possible involvement of neuroprotective C5aR2. However, these pathways were enhanced in older ArcC5a+ mice compared to Arc. Immunohistochemistry confirmed that C5a-C5aR1 modulation in Arc mice delayed the increase in CD11c-positive microglia, while not affecting other pan-reactive microglial or astrocyte markers. CONCLUSION: C5a-C5aR1 signaling in AD largely exerts its effects by enhancing microglial activation pathways that accelerate disease progression. While C5a may have neuroprotective effects via C5aR2, engagement of C5a with C5aR1 is detrimental in AD models. These data support specific pharmacological inhibition of C5aR1 as a potential therapeutic strategy to treat AD.

Implantación intraabdominal de un injerto renal con dos arterias renales en un receptor pediátrico de bajo peso. Primer caso reportado en el Paraguay / Intra-abdominal implantation of a kidney graft with two renal arteries in a low-weight pediatric recipient. First case reported in Paraguay

El trasplante renal de órganos provenientes de donantes adultos implantados en una cavidad anatómica estrecha en pacientes pediátricos de bajo peso, ofrece importantes desafíos médicos y quirúrgicos a ser considerados. En esta publicación reportamos el primer caso en el Paraguay de un riñón con dos arterias renales injertado a la aorta y vena cava inferior, dentro de la cavidad abdominal de un paciente pediátrico de 12 kilogramos de peso, evaluando las dificultades médicas, anatómicas y quirúrgicas enfrentadas, así como las opciones de tratamiento instituidas para llevar a cabo este procedimiento de manera exitosa

Kidney transplantation of organs from adult donors implanted into a narrow anatomical cavity in underweight pediatric patients offers significant medical and surgical challenges to be considered. In this publication we report the first case in Paraguay of a kidney with two renal arteries, grafted to the aorta and inferior vena cava within the abdominal cavity, on a 12 kilogram pediatric patient, evaluating the medical, anatomical and surgical conditions faced, as well as the treatment options instituted to successfully carry out this procedure