Search

Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells. Reduced UPR expression is also seen in murine and human melanoma tumor specimens that responded to immune checkpoint therapy. Co-housing of Rnf5-/- and WT mice abolishes the anti-tumor immunity and tumor inhibition phenotype, whereas transfer of 11 bacterial strains, including B. rodentium, enriched in Rnf5-/- mice, establishes anti-tumor immunity and restricts melanoma growth in germ-free WT mice. Altered UPR signaling, exemplified in Rnf5-/- mice, coincides with altered gut microbiota composition and anti-tumor immunity to control melanoma growth.

The recalcitrance of biofilms to antimicrobials is a multi-factorial phenomenon, including genetic, physical, and physiological changes. Individually, they often cannot account for biofilm recalcitrance. However, their combination can increase the minimal inhibitory concentration of antibiotics needed to kill bacterial cells by three orders of magnitude, explaining bacterial survival under otherwise lethal drug treatment. The relative contributions of these factors depend on the specific antibiotics, bacterial strain, as well as environmental and growth conditions. An emerging population genetic property—increased biofilm genetic diversity—further enhances biofilm recalcitrance. Here, we develop a polygenic model of biofilm recalcitrance accounting for multiple phenotypic mechanisms proposed to explain biofilm recalcitrance. The model can be used to generate predictions about the emergence of resistance—its timing and population genetic consequences. We use the model to simulate various treatments and experimental setups. Our simulations predict that the evolution of resistance is impaired in biofilms at low antimicrobial concentrations while it is facilitated at higher concentrations. In scenarios that allow bacteria exchange between planktonic and biofilm compartments, the evolution of resistance is further facilitated compared to scenarios without exchange. We compare these predictions to published experimental observations.

Se fossemos localizar O Rei do Cagaço, 1977, dentro do universo cinematográfico de Edgard Navarro, ele faria parte, de forma mais geral, do chamado surto superoitista no Brasil, e do grande ciclo de filmes realizados em Super-8 na década de 70 que participaram de festivais da época, especificamente das chamadas Jornadas de Cinema da Bahia, e que possuíam, em geral, um forte teor provocativo ao mesmo tempo poético e político, e principalmente um sentido muito preciso de despojamento na flexibilização da linguagem possibilitada pela novidade da bitola.

RNF5 is a ubiquitin ligase regulating ER stress response. Here the authors show that Rnf5 deficiency potentiates immune response against melanoma via altered microbiota, and isolate bacterial strains that confer the same phenotype to wild type mice.

Urethral injuries occurring during pelvic trauma can cause a heavy morbidity and negative impact for the quality of life of a child.We present a case of a 7 years old boy with a complete posterior urethral disruption managed with a successful realignment by a unique modification of the “rendez vous” technique with the simultaneous performance of both antegrade flexible and a retrograde rigid cystoscopy.

ABSTRACT Estrogen, a major female sex steroid hormone, has been shown to promote the selection of mucoid Pseudomonas aeruginosa in the airways of patients with chronic respiratory diseases, including cystic fibrosis. This results in long-term persistence, poorer clinical outcomes, and limited therapeutic options. In this study, we demonstrate that at physiological concentrations, sex steroids, including testosterone and estriol, induce membrane stress responses in P. aeruginosa. This is characterized by increased virulence and consequent inflammation and release of proinflammatory outer membrane vesicles promoting in vivo persistence of the bacteria. The steroid-induced P. aeruginosa response correlates with the molecular polarity of the hormones and membrane fluidic properties of the bacteria. This novel mechanism of interaction between sex steroids and P. aeruginosa explicates the reported increased disease severity observed in females with cystic fibrosis and provides evidence for the therapeutic potential of the modulation of sex steroids to achieve better clinical outcomes in patients with hormone-responsive strains. IMPORTANCE Molecular mechanisms by which sex steroids interact with P. aeruginosa to modulate its virulence have yet to be reported. Our work provides the first characterization of a steroid-induced membrane stress mechanism promoting P. aeruginosa virulence, which includes the release of proinflammatory outer membrane vesicles, resulting in inflammation, host tissue damage, and reduced bacterial clearance. We further demonstrate that at nanomolar (physiological) concentrations, male and female sex steroids promote virulence in clinical strains of P. aeruginosa based on their dynamic membrane fluidic properties. This work provides, for the first-time, mechanistic insight to better understand and predict the P. aeruginosa related response to sex steroids and explain the interindividual patient variability observed in respiratory diseases such as cystic fibrosis that are complicated by gender differences and chronic P. aeruginosa infection.

The sciatic nerve and the piriformis muscle are closely related structures due to their anatomy, in which the nerve passes below the muscle in its normal path. For this reason, any anatomical changes can cause sciatic pain. Considering the importance of knowing the variations of these two structures, we aim to evaluate and describe the relationship of the sciatic nerve with the piriformis muscle in cadavers of human fetuses and of children up to one year of postnatal life. Eighty-seven individuals preserved by the Giacomini method, all belonging to the didactic collection of the Department of Anatomy of the Institute of Biomedical Sciences of the University of São Paulo (DA / ICB-USP), were dissected. Of the individuals studied, 70 had fetal ages ranging from 18 to 28 weeks of intrauterine life (IU) and 17 individuals from stillbirth to one year of postnatal life. Of the total, 40 were male and 47 female. 19 individuals presented variations: 14 with the sciatic nerve dividing before their arrival in the region of the piriformis muscle and 5 with a variation in the path of the sciatic nerve. No statistical correlations were found for the incidence of anatomical variations of the sciatic nerve with age, gender or antimere.

José Agripino de Paula e Maria Esther Stockler experimentaram gestos libertários no teatro, na dança e no cinema. Por trás do despojamento do filme Super-8 Céu sobre Água, haveria todo um saber cultivado na experiência estética ligada á contracultura e que colocaria aqui toda a sua fé criativa numa possibilidade de organicidade entre o ato de filmar e dançar como anti-espetáculo.

REST is a key component of the HDAC1 or 2, CoREST, LSD1, REST (HCLR) repressor complex. The primary function of the HCLR complex is to silence neuronal genes in non-neuronal cells. HCLR plays a role in regulating the expression of viral genes in productive infections as a donor of LDS1 for expression of α genes and as a repressor of genes expressed later in infection. In sensory neurons the HCLR complex is involved in the silencing of viral genome in the course of establishment of latency. The thesis of this article is that (a) sensory neurons evolved a mechanism to respond to the presence and suppress the transmission of infectious agents from the periphery to the CNS and (b) HSV evolved subservience to the HCLR with at least two objectives: to maintain a level of replication consistent with maximal person-to-person spread and to enable it to take advantage of neuronal innate immune responses to survive and be available for reactivation shielded from adaptive immune responses of the host.

Antecedentes: La culdotomía como vía de acceso para realizar esterilización tubaria aparece como una alternativa simple y segura. Objetivo: Evaluar esta técnica en mujeres que solicitan esterilización tubaria. Método: Esterilización tubaria por culdotomía en 75 multíparas. Resultados: El tiempo quirúrgico promedio fue 27,2 minutos. No hubo complicaciones durante la cirugía. En 5 casos (6,6%) la culdotomía se convirtió a laparotomía porque no se identificó una o ambas trompas. Conclusión: Técnica segura, de bajo costo y con buena satisfacción de usuariaBackground: Culdotomy as access way for tubal sterilization appear like a simple and safe alternative. Objective: To evaluate this technique in women who demand for tubal sterilization. Method: Tubal sterilization by culdotomy in 75 multiparous women. Results: The average surgical time was 27.2 minutes. There were no complications during the surgery. In 5 cases (6.6%) the culdotomy was converted to laparotomy because one or both tubes were not identified. Conclusion: Culdotomy is a safe technique, of low cost and with good user satisfaction

ABSTRACT Herpes simplex virus type 1 encodes three sets of genes, α, β, and γ, whose expression is sequentially ordered in a cascade fashion. The transactivators of α genes comprise virion protein 16 (VP16) and the cellular proteins octamer binding protein 1 (Oct1) and host factor 1 (HCF1). Efficient transition from α to β gene expression requires the α protein ICP0 (infected cell protein 0). Earlier studies have shown that this protein binds to CoREST and displaces HDAC1 from the CoREST/REST/lysine-specific demethylase 1 (LSD1) repressor complex. Ultimately, the components of the repressor complex are translocated at least in part into the cytoplasm. A key event in activation of α genes is the recruitment of LSD1 to demethylate histones bound to the α gene promoters. LSD1 is unstable in the absence of its partner, CoREST, and raises the question of whether both CoREST and REST are involved in the initiation of transcription of the α genes. Here we show that CoREST or REST small interfering RNAs (siRNAs) destabilize CoREST, REST, LSD1, and Sin3A, another component of the repressor complex. In cells transfected with REST or CoREST siRNA, the accumulation of α proteins and mRNAs is delayed in comparison to those of mock-transfected or control siRNA-transfected cells. The LSD1/CoREST/REST compressor complex is thus sequentially necessary and subsequently inimical for viral gene expression. IMPORTANCE Herpes simplex virus type 1 (HSV-1) is globally regulated at the following four checkpoints: (i) the activation of α (immediate-early) genes, (ii) the point of transition from α to β and γ gene expression, (iii) the silencing of viral genes for the establishment of the latent state, and (iv) the reactivation of viral genes on termination of latency. Earlier studies showed that the transition from α to β and γ gene expression involves the suppression of the HDAC1/lysine-specific demethylase 1 (LSD1)/CoREST/REST (HLCR) repressor complex. More recently, this laboratory reported evidence suggesting that in sensory neurons, HSV-1 hijacks the HLCR complex to silence itself for the establishment of latency. This report extends the observation that LSD1 is required for expression of the α genes to show that the HLCR complex is involved in this process. Thus, HSV-1 has evolved an intimate relationship with the HCLR complex to regulate its gene expression and, by extension, its fundamental interactions with its human host.

Abstract Background The genome of herpes simplex virus 1 encodes at least 84 transcripts from which proteins are translated and several additional RNAs whose status as mRNAs is unknown. These RNAs include latency-associated transcript, OriS1 and OriS2 RNAs and in case of α4 null mutant additional transcript that spans the junction between L and S component of the HSV-1 genome. Current data do not suggest that a peptide is translated from these RNAs. Results We describe here a novel RNA designated US5-1 that spans 4.5 kb of the unique-short (US) region. The RNA initiates in US5 and terminates in the α22 open reading frame. It is expressed antisense to US5, US4, US3 and ICP22 mRNAs. This transcript is expressed with γ2 kinetics and has a half-life of 80 minutes. Conclusion These results identify a novel transcript encoded within HSV-1 genome. Since no major hypothetical open-reading frames are present in this transcript it is feasible that this RNA exerts its function as a non-coding RNA.

Abstract Background Human papillomavirus (HPV) infection is known to be the most important etiologic factor of cervical cancer. There is no HPV specific therapy available for treatment of invasive squamous cell carcinoma of the cervix and its precursor lesions. The present study elucidates the potential to use herpes simplex virus (HSV) derived vectors for expression of antisense RNA to HPV -16 E7 oncogene. Results We have constructed replication competent, nonneuroinvasive HSV-1 vectors, deleted of the γ134.5 gene. The vectors express RNA antisense to the first 100 nucleotides of the HPV-16 E7 gene. We assayed the ability of the antisense E7 vectors R5225 (tk-) and R5226 (tk+), to produce antisense RNA, as well as the consequent effects on E7 mRNA and protein levels in HPV-16 positive CaSki cells. Anti-E7 RNA was expressed by both constructs in a dose-dependent manner. Expression of HPV-16 E7 mRNA was downregulated effectively in CaSki cells infected with the tk- recombinant R5225 or with R5226. The tk+ recombinant R5226 was effective in downregulating E7 protein expression. Conclusion We have shown that anti-E7 RNA expressed from an HSV vector could efficiently downregulate HPV-16 E7 mRNA and E7 protein expression in CaSki cells. We conclude that HSV vectors may become a useful tool for gene therapy of HPV infections.

Background The optimal time to commence anticoagulation in patients with atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA) is unclear, with guidelines differing in recommendations. A limitation of previous studies is the focus on clinically overt stroke, rather than radiologically obvious diffusion-weighted imaging ischaemic lesions. We aimed to quantify silent ischaemic lesions and haemorrhages on MRI at 1 month in patients commenced on early (5 mL, regardless of anticoagulation timing.Conclusion Commencing anticoagulation