Host response during unresolved urinary tract infection alters female mammary tissue homeostasis through collagen deposition and TIMP1.

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells are absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue are mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolves the infection and restores mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlates with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, restores mammary tissue normal homeostasis, thus providing evidence for a link between the systemic host response during UTI and mammary gland alterations.

ß-Actin G342D as a Cause of NK Cell Deficiency Impairing Lytic Synapse Termination.

NK cell deficiency (NKD) occurs when an individual's major clinical immunodeficiency derives from abnormal NK cells and is associated with several genetic etiologies. Three categories of ß-actin-related diseases with over 60 ACTB (ß-actin) variants have previously been identified, none with a distinct NK cell phenotype. An individual with mild developmental delay, macrothrombocytopenia, and susceptibility to infections, molluscum contagiosum virus, and EBV-associated lymphoma had functional NKD for over a decade. A de novo ACTB variant encoding G342D ß-actin was identified and was consistent with the individual's developmental and platelet phenotype. This novel variant also was found to have direct impact in NK cells because its expression in the human NK cell line YTS (YTS-NKD) caused increased cell spreading in lytic immune synapses created on activating surfaces. YTS-NKD cells were able to degranulate and perform cytotoxicity, but they demonstrated defective serial killing because of prolonged conjugation to the killed target cell and thus were effectively unable to terminate lytic synapses. G342D ß-actin results in a novel, to our knowledge, mechanism of functional NKD via increased synaptic spreading and defective lytic synapse termination with resulting impaired serial killing, leading to overall reductions in NK cell cytotoxicity.

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells.

Patients with advanced prostate cancer (PCa) invariably develop resistance to anti-androgen therapy and taxane-based chemotherapy. Glucocorticoid receptor (GR) has been implicated in PCa therapy resistance; however, the mechanisms underlying GR-mediated chemoresistance remain unclear. Lens epithelium-derived growth factor p75 (LEDGF/p75, also known as PSIP1 and DFS70) is a glucocorticoid-induced transcription co-activator implicated in cancer chemoresistance. We investigated the contribution of the GR-LEDGF/p75 axis to docetaxel (DTX)-resistance in PCa cells. GR silencing in DTX-sensitive and -resistant PCa cells decreased LEDGF/p75 expression, and GR upregulation in enzalutamide-resistant cells correlated with increased LEDGF/p75 expression. ChIP-sequencing revealed GR binding sites in the LEDGF/p75 promoter. STRING protein-protein interaction analysis indicated that GR and LEDGF/p75 belong to the same transcriptional network, and immunochemical studies demonstrated their co-immunoprecipitation and co-localization in DTX-resistant cells. The GR modulators exicorilant and relacorilant increased the sensitivity of chemoresistant PCa cells to DTX-induced cell death, and this effect was more pronounced upon LEDGF/p75 silencing. RNA-sequencing of DTX-resistant cells with GR or LEDGF/p75 knockdown revealed a transcriptomic overlap targeting signaling pathways associated with cell survival and proliferation, cancer, and therapy resistance. These studies implicate the GR-LEDGF/p75 axis in PCa therapy resistance and provide a pre-clinical rationale for developing novel therapeutic strategies for advanced PCa.

Glucocorticoid Receptor and ß-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance.

Therapy resistance hinders the efficacy of anti-androgen therapies and taxane-based chemotherapy for advanced prostate cancer (PCa). Glucocorticoid receptor (GR) signaling mediates resistance to androgen receptor signaling inhibitors (ARSI) and has also been recently implicated in PCa resistance to docetaxel (DTX), suggesting a role in therapy cross-resistance. Like GR, ß-catenin is upregulated in metastatic and therapy-resistant tumors and is a crucial regulator of cancer stemness and ARSI resistance. ß-catenin interacts with AR to promote PCa progression. Given the structural and functional similarities between AR and GR, we hypothesized that ß-catenin also interacts with GR to influence PCa stemness and chemoresistance. As expected, we observed that treatment with the glucocorticoid dexamethasone promotednuclear accumulation of GR and active ß-catenin in PCa cells. Co-immunoprecipitation studies showed that GR and ß-catenin interact in DTX-resistant and DTX-sensitive PCa cells. Pharmacological co-inhibition of GR and ß-catenin, using the GR modulator CORT-108297 and the selective ß-catenin inhibitor MSAB, enhanced cytotoxicity in DTX-resistant PCa cells grown in adherent and spheroid cultures and decreased CD44+/CD24- cell populations in tumorspheres. These results indicate that GR and ß-catenin influence cell survival, stemness, and tumorsphere formation in DTX-resistant cells. Their co-inhibition could be a promising therapeutic strategy to overcome PCa therapy cross-resistance.

Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps.

The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor-binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-RBD and prevent viral entry into host cells ("receptor traps"). Here we determine cryo-EM structures of our receptor traps in complex with stabilized Spike ectodomain. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high-affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high-affinity (0.53-4.2 nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron and Delta pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.

The Nuclear Dense Fine Speckled (DFS) Immunofluorescence Pattern: Not All Roads Lead to DFS70/LEDGFp75.

The monospecific dense fine speckled (DFS) immunofluorescence assay (IFA) pattern is considered a potential marker to aid in exclusion of antinuclear antibody (ANA)-associated rheumatic diseases (AARD). This pattern is typically produced by autoantibodies against transcription co-activator DFS70/LEDGFp75, which are frequently found in healthy individuals and patients with miscellaneous inflammatory conditions. In AARD patients, these antibodies usually co-exist with disease-associated ANAs. Previous studies reported the occurrence of monospecific autoantibodies that generate a DFS-like or pseudo-DFS IFA pattern but do not react with DFS70/LEDGFp75. We characterized this pattern using confocal microscopy and immunoblotting. The target antigen associated with this pattern partially co-localized with DFS70/LEDGFp75 and its interacting partners H3K36me2, an active chromatin marker, and MLL, a transcription factor, in HEp-2 cells, suggesting a role in transcription. Immunoblotting did not reveal a common protein band immunoreactive with antibodies producing the pseudo-DFS pattern, suggesting they may recognize diverse proteins or conformational epitopes. Given the subjectivity of the HEp-2 IFA test, the awareness of pseudo-DFS autoantibodies reinforces recommendations for confirmatory testing when reporting patient antibodies producing a putative DFS pattern in a clinical setting. Future studies should focus on defining the potential diagnostic utility of the pseudo-DFS pattern and its associated antigen(s).

An ELF4 hypomorphic variant results in NK cell deficiency.

NK cell deficiencies (NKD) are a type of primary immune deficiency in which the major immunologic abnormality affects NK cell number, maturity, or function. Since NK cells contribute to immune defense against virally infected cells, patients with NKD experience higher susceptibility to chronic, recurrent, and fatal viral infections. An individual with recurrent viral infections and mild hypogammaglobulinemia was identified to have an X-linked damaging variant in the transcription factor gene ELF4. The variant does not decrease expression but disrupts ELF4 protein interactions and DNA binding, reducing transcriptional activation of target genes and selectively impairing ELF4 function. Corroborating previous murine models of ELF4 deficiency (Elf4-/-) and using a knockdown human NK cell line, we determined that ELF4 is necessary for normal NK cell development, terminal maturation, and function. Through characterization of the NK cells of the proband, expression of the proband's variant in Elf4-/- mouse hematopoietic precursor cells, and a human in vitro NK cell maturation model, we established this ELF4 variant as a potentially novel cause of NKD.

Relación entre el apoyo social percibido y la depresión en adultos mayores con asistencia en centro gerontológico / Relationship between perceived social support and depression in older people with attendance in a gerontological center

Objetivo: Evaluar la asociación entre el apoyo social percibido y el nivel de depresión en adultos mayores que asisten y participan en actividades de un centro gerontológico en el estado de Hidalgo, México. Metodología: Estudio no experimental cuantitativo, transversal y correlacional. Muestra de 71 adultos mayores que asisten a centros gerontológicos. Las variables de estudio fueron el apoyo social percibido y la depresión. Para la medición y obtención de datos se utilizaron los cuestionarios DUKE-UNC11, con una confiabilidad de 0,66 y una validez de 0,88, que evalúa cómo el adulto mayor percibe el apoyo social y la escala geriátrica de Yesavage, con una confiabilidad de 0,84 y una validez de 0,78, que identifica el grado de depresión del adulto mayor. Resultados: De los 71 adultos mayores, el 72,8% fueron mujeres y el 28,2% hombres. En la escolaridad, el 29,6% concluyeron la primaria, el 80,3% eran de religión católica, el 38% de los participantes están casados y el 62% de ellos se dedican al hogar. La edad que más prevaleció fue 75 años. El 42,3% de los adultos mayores presentan depresión leve, el 49,3 depresión moderada y el 8,5% depresión grave. Asimismo, un 67,6% tenía apoyo social normal y un 32,4% un apoyo social bajo. Se obtuvo una correlación inversa significativa entre el apoyo social y el nivel de depresión (r = –0,336; p < 0,01) Conclusión: A mayor apoyo social que reciban los adultos mayores menor será su grado de depresión (AU)

Objective: To evaluate the association between perceived social support and the depression level in older adults who attend and participate in activities at a gerontological center from Hidalgo state, Mexico. Methodology: Quantitative, descriptive, correlational non-experimental study. A sample of 71 older adults who attend gerontology centers. The study variables were perceived social support and depression. For the measurement and data collection, the questionnaires were used, DUKE-UNC11 with a reliability of 0.66 and validity of 0.88, which assesses how the older adults perceive social support and the Yesavage geriatric scale with a reliability of 0.84 and validity of 0.78 that identifies the degree of depression in the elderly. Results: Of the 71 older adults, 72.8% were female and 28.2% male. In schooling, 29.6% finished primary school, on the other hand, 80.3% are of the catholic religion, 38% of the participants are married and most of them dedicate themselves to the home, 62%. The age that most prevailed was 75 years. 42.3% of older adults are observed with mild depression, 49.3% moderate depression 8.5% severe depression. Likewise, 67.6% with normal social support and 32.4% low social support. A significant inverse correlation was obtained between social support and the level of depression (r = –0.336, p < 0.01). Conclusion:The more social support older adults receive, the lower their degree of depression (AU)

Structural consequences of sequence variation in mammalian prion ß2α2 loop segments.

Sequence variation in the ß2α2 loop, residues 165-175 of the mammalian prion protein (PrP), influences its structure. To better understand the consequences of sequence variation in this region of the protein, we biochemically and biophysically interrogate natural and artificial sequence variants of the ß2α2 loop of mammalian PrP. Using microcrystal electron diffraction (MicroED), we determine atomic resolution structures of segments encompassing residues 168-176 from the ß2α2 loop of PrP with sequences corresponding to human, mouse/cow, bank vole/hamster, rabbit/pig/guinea pig, and naked mole rat (elk-T174S) ß2α2 loops, as well as synthetic ß2α2 loop sequences. This collection of structures presents two dominant amyloid packing polymorphisms. In the first polymorph, denoted "clasped", side chains within a sheet form polar clasps by facing each other on the same strand, exemplified by the mouse/cow, human, and bank vole/hamster sequences. Because its stability is derived from within a strand and through polar ladders within a sheet, the sequence requirements for the mating strand are less restrictive. A second polymorph, denoted "interdigitated," has sidechains interdigitate across mating sheets, exemplified by the elk, naked mole rat (elk T174S), and rabbit sequences. The two types of packing present distinct networks of stabilizing hydrogen bonds. The identity of residue 174 appears to strongly influence the packing adopted in these peptides, but consideration of the overall sequence of a given segment is needed to understand the stability of its assemblies. Incorporation of these ß2α2 loop sequences into an 85 residue recombinant segment encoding wild-type bank vole PrP94-178 demonstrates that even single residue substitutions could impact fibril morphology as evaluated by negative stain electron microscopy. This is in line with recent findings supporting the accessibility of different structural geometries by varied mammalian prion sequences, and indicates that sequence-specific polymorphisms may be influenced by residues in the ß2α2 loop.

Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps.

The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-Spike-RBD and prevent viral entry into host cells ("receptor traps"). Here we determine cryo-EM structures of our receptor traps in complex with full length Spike. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high affinity (0.53 - 4.2nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron- and Delta-pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.

Detección de anticuerpos tipo igg contra borrelia burgdorferi, y factores asociados a la enfermedad de lyme en población canina, de los municipios honda-Tolima, la mesa y Chia-Cundinamarca. detección de anticuerpos tipo igg contra borrelia burgdorferi en población canina / Detection of IgG-type antibodies against Borrelia Burgdorferi, and factors associated with Lyme disease in the canine population, of the municipalities Honda-Tolima, La Mesa and Chia-Cundinamarca

Borrelia burgdorferi, is the spirochete responsible for causing Lyme disease in man and different animals. Objective. Detect specific IgG type antibodies against Borrelia burgdorferi, in canines using the immunofluorescence technique and its correlation with other factors associated with Lyme disease. Methods. Blood was taken for IgG detection against Borrelia burgdorferi sl; Peripheral blood smear of the canines and hemolymph of the ticks to search for spirochetes with Wright staining and finally classification of the ticks using morphometric keys. Results. In the serological test, on average 69.0% of the canines sampled gave positive results in the different titrations. Bacterial structures were spirally visualized both in the peripheral blood of the canines and in the hemolymph of the ticks. The vector found was classified as Rhipicephalus sanguineus, until now not reported in the scientific literature as a carrier of Borrelia, nor associated with the disease.

The LEDGF/p75 Integrase Binding Domain Interactome Contributes to the Survival, Clonogenicity, and Tumorsphere Formation of Docetaxel-Resistant Prostate Cancer Cells.

Patients with prostate cancer (PCa) receiving docetaxel chemotherapy invariably develop chemoresistance. The transcription co-activator lens epithelium-derived growth factor p75 (LEDGF/p75), also known as DFS70 and PSIP1, is upregulated in several human cancers, including PCa and promotes resistance to docetaxel and other drugs. The C-terminal region of LEDGF/p75 contains an integrase binding domain (IBD) that tethers nuclear proteins, including the HIV-1 integrase and transcription factors, to active chromatin to promote viral integration and transcription of cellular survival genes. Here, we investigated the contribution of the LEDGF/p75 IBD interactome to PCa chemoresistance. Quantitative immunoblotting revealed that LEDGF/p75 and its IBD-interacting partners are endogenously upregulated in docetaxel-resistant PCa cell lines compared to docetaxel-sensitive parental cells. Using specific human autoantibodies, we co-immunoprecipitated LEDGF/p75 with its endogenous IBD-interacting partners JPO2, menin, MLL, IWS1, ASK1, and PogZ, as well as transcription factors c-MYC and HRP2, in docetaxel-resistant cells, and confirmed their nuclear co-localization by confocal microscopy. Depletion of LEDGF/p75 and selected interacting partners robustly decreased the survival, clonogenicity, and tumorsphere formation capacity of docetaxel-resistant cells. These results implicate the LEDGF/p75 IBD interactome in PCa chemoresistance and could lead to novel therapeutic strategies targeting this protein complex for the treatment of docetaxel-resistant tumors.

CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.

The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.

CryoEM and AI reveal a structure of SARS-CoV-2 Nsp2, a multifunctional protein involved in key host processes.

The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis of those functions, remain unknown. Here, we report an atomic model for full-length Nsp2 obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. The resulting structure reveals a highly-conserved zinc ion-binding site, suggesting a role for Nsp2 in RNA binding. Mapping emerging mutations from variants of SARS-CoV-2 on the resulting structure shows potential host-Nsp2 interaction regions. Using structural analysis together with affinity tagged purification mass spectrometry experiments, we identify Nsp2 mutants that are unable to interact with the actin-nucleation-promoting WASH protein complex or with GIGYF2, an inhibitor of translation initiation and modulator of ribosome-associated quality control. Our work suggests a potential role of Nsp2 in linking viral transcription within the viral replication-transcription complexes (RTC) to the translation initiation of the viral message. Collectively, the structure reported here, combined with mutant interaction mapping, provides a foundation for functional studies of this evolutionary conserved coronavirus protein and may assist future drug design.

Sentinel cells enable genetic detection of SARS-CoV-2 Spike protein.

The COVID-19 pandemic has demonstrated the need for exploring different diagnostic and therapeutic modalities to tackle future viral threats. In this vein, we propose the idea of sentinel cells, cellular biosensors capable of detecting viral antigens and responding to them with customizable responses. Using SARS-CoV-2 as a test case, we developed a live cell sensor (SARSNotch) using a de novo-designed protein binder against the SARS-CoV-2 Spike protein. SARSNotch is capable of driving custom genetically-encoded payloads in immortalized cell lines or in primary T lymphocytes in response to purified SARS-CoV-2 Spike or in the presence of Spike-expressing cells. Furthermore, SARSNotch is functional in a cellular system used in directed evolution platforms for development of better binders or therapeutics. In keeping with the rapid dissemination of scientific knowledge that has characterized the incredible scientific response to the ongoing pandemic, we extend an open invitation for others to make use of and improve SARSNotch sentinel cells in the hopes of unlocking the potential of the next generation of smart antiviral therapeutics.

Análisis de la comunicación social en el Homeschooling: una revisión panorámica / Social communication analysis in Homeschooling: a scoping review

En el siglo XXI, las transformaciones al sistema social han generado alternativas educativas en las que el fonoaudiólogo adopta un papel importante, por ser un promotor de habilidades comunicativas. La educación en casa es una opción, sin embargo, existen controversias sobre su impacto en el desarrollo de habilidades sociales en los niños. Este artículo realiza una revisión panorámica de la literatura que explora la relación entre el Homeschooling y el desarrollo de la comunicación social. Se incluyen estudios publicados entre el 2000 y el 2020, en idioma español o inglés, con resumen y texto completo. Se excluyeron aquellos que incluían participantes con discapacidad cognitiva o trastornos del aprendizaje. En total de 328 artículos encontrados, sólo 9 cumplieron con los criterios de inclusión. Los documentos seleccionados se analizaron de acuerdo con los componentes de la comunicación social: interacción, cognición social y pragmática en comunicación verbal y no verbal. Existen discrepancias entre los resultados. Algunos autores afirman que las habilidades de comunicación social de los niños que aprenden en sus casas son mejores que las de los niños que van a la escuela, pero, en otros casos, estos solo cumplen con estándares esperados para su edad. Se identificó como determinante el papel de los padres o educadores. Sobre habilidades pragmáticas no se encontraron estudios. En conclusión, la limitación en el número de artículos y la heterogeneidad en las metodologías presentadas no permiten generalizar los resultados a la población. Es evidente la necesidad de realizar estudios en esta área, especialmente en este momento de confinamiento debido a la pandemia por el COVID-19.

In the 21st century, transformations to the social system have generated educational alternatives in which the speech language pathologist as a promoter of communicative skills takes an important role. Home education is an option, however, there are controversies about its impact on children's social skills development. This article is a scoping review that explores the relationship between Homeschooling and the social communication development. Studies published between 2000 and 2020, Spanish or English, with summary and full text are included. Those that included participants with cognitive disabilities or learning disorders were excluded. In total of 328 items found, only 9 met the inclusion criteria. The selected documents were analyzed according to the components of social communication: interaction, social and pragmatic cognition in verbal and nonverbal communication of children. There are discrepancies between the results. Some authors claim that social communication skills of children in homeschooling are better than those of children going to school, but in other cases, theymeet expected standards for their age. The role of parents or educators was identified as decisive. No studies were found in pragmatic skills. In conclusion, the limitation on the number of articles and heterogeneity in the methodologies presented does not allow the results to be generalized to the population. The need for studies in this area is evident, especially at this time of confinement due to the COVID-19 pandemic.

Twenty years of research on the DFS70/LEDGF autoantibody-autoantigen system: many lessons learned but still many questions.

The discovery and initial characterization 20 years ago of antinuclear autoantibodies (ANAs) presenting a dense fine speckled (DFS) nuclear pattern with strong staining of mitotic chromosomes, detected by indirect immunofluorescence assay in HEp-2 cells (HEp-2 IIFA test), has transformed our view on ANAs. Traditionally, ANAs have been considered as reporters of abnormal immunological events associated with the onset and progression of systemic autoimmune rheumatic diseases (SARD), also called ANA-associated rheumatic diseases (AARD), as well as clinical biomarkers for the differential diagnosis of these diseases. However, based on our current knowledge, it is not apparent that autoantibodies presenting the DFS IIF pattern fall into these categories. These antibodies invariably target a chromatin-associated protein designated as dense fine speckled protein of 70 kD (DFS70), also known as lens epithelium-derived growth factor protein of 75 kD (LEDGF/p75) and PC4 and SFRS1 Interacting protein 1 (PSIP1). This multi-functional protein, hereafter referred to as DFS70/LEDGF, plays important roles in the formation of transcription complexes in active chromatin, transcriptional activation of specific genes, regulation of mRNA splicing, DNA repair, and cellular survival against stress. Due to its multiple functions, it has emerged as a key protein contributing to several human pathologies, including acquired immunodeficiency syndrome (AIDS), leukemia, cancer, ocular diseases, and Rett syndrome. Unlike other ANAs, "monospecific" anti-DFS70/LEDGF autoantibodies (only detectable ANA in serum) are not associated with SARD and have been detected in healthy individuals and some patients with non-SARD inflammatory conditions. These observations have led to the hypotheses that these antibodies could be considered as negative biomarkers of SARD and might even play a protective or beneficial role. In spite of 20 years of research on this autoantibody-autoantigen system, its biological and clinical significance still remains enigmatic. Here we review the current state of knowledge of this system, focusing on the lessons learned and posing emerging questions that await further scrutiny as we continue our quest to unravel its significance and potential clinical and therapeutic utility.

Psychosocial Stress, Glucocorticoid Signaling, and Prostate Cancer Health Disparities in African American Men.

Recent advances in our understanding of racial disparities in prostate cancer (PCa) incidence and mortality that disproportionately affect African American (AA) men have provided important insights into the psychosocial, socioeconomic, environmental, and molecular contributors. There is, however, limited mechanistic knowledge of how the interplay between these determinants influences prostate tumor aggressiveness in AA men and other men of African ancestry. Growing evidence indicates that chronic psychosocial stress in AA populations leads to sustained glucocorticoid signaling through the glucocorticoid receptor (GR), with negative physiological and pathological consequences. Compelling evidence indicates that treatment of castration-resistant prostate cancer (CRPC) with anti-androgen therapy activates GR signaling. This enhanced GR signaling bypasses androgen receptor (AR) signaling and transcriptionally activates both AR-target genes and GR-target genes, resulting in increased prostate tumor resistance to anti-androgen therapy, chemotherapy, and radiotherapy. Given its enhanced signaling in AA men, GR-together with specific genetic drivers-may promote CRPC progression and exacerbate tumor aggressiveness in this population, potentially contributing to PCa mortality disparities. Ongoing and future CRPC clinical trials that combine standard of care therapies with GR modulators should assess racial differences in therapy response and clinical outcomes in order to improve PCa health disparities that continue to exist for AA men.

Factores asociados a infección por VIH en mujeres embarazadas, Municipio del Distrito Central, Honduras, 2016 / Associated factors to HIV infection among pregnant women, Municipio del Distrito Central, Honduras, 2016

La transmisión vertical del virus de inmunodeficiencia humana es la forma común en que el producto de la concepción puede contraer la infección, puede ocurrir durante el embarazo, el parto o la lactancia materna. Objetivo: determinar factores asociados a pacientes embarazadas positivas para virus de inmunodeficiencia humana, en la Región Metropolitana del Distrito Central, Honduras, 2016. Material y Métodos: estudio de casos y controles, relación 1:3. Se tomó el total de casos correspondientes al 2016 y se recolectaron controles de centros de salud de donde procedían los casos. Caso fue definido como: mujer embarazada con infección por virus de inmunodeficiencia humana captada por vigilancia pasiva; como control: paciente embarazada negativa para virus de inmunodeficiencia humana captada por vigilancia activa. Se recopiló información de la base de datos de la Región Sanitaria Metropolitana del Distrito Central, ficha epidemiológica e historia clínica perinatal. Los datos se analizaron con estadística descriptiva y de asociación, utilizando Microsoft Excel®2016, EpiInfo®7.2 y OpenEpi®. Resultados: se registraron 27 casos y 81 controles, con promedio de edad de 28.7 y 23.8 años respectivamente, es importante mencionar que no se encontraron datos consignados para todos los casos, ni para todos los controles. 17(70.8%) casos y 20(80%) controles tenían pareja estable. 5(81.5%) casos refirieron no utilizar métodos anticonceptivos después del parto y 18(66.7%) recibieron terapia antirretroviral. El riesgo de ser positiva para virus de inmunodeficiencia humana en mujeres embarazadas que no tenían pareja estable, fue mayor en comparación a las que tenían pareja estable (OR=3.9, IC95% 1.1-13.9), asimismo mayor riesgo entre las que las que tenían más de 3 gestaciones comparadas con las que tenían 3 o menos (OR=7.3, IC95% 2.0-27.2). Conclusión: los factores asociados estadísticamente a infección por virus de inmunodeficiencia humana fueron no tener pareja estable e historia obstétrica de más de tres gestaciones...(AU)