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Rexinoids are compounds that bind to the rexinoid X receptor (RXR) to modulate gene expression and have been proposed as a new class of therapeutics to treat Alzheimer's disease. Different rexinoids will initiate downstream effects that can be quite marked even though such compounds can be structurally similar and have comparable RXR binding affinities. RXR can both homo- and heterodimerize, and these protein-protein interactions and subsequent transactivating potential lead to differential gene expression, depending on the RXR dimeric partner, additional cofactors recruited, and downstream transcription factors that are up- or downregulated. Expression analysis was performed in the U87 human glioblastoma cell line treated with a panel of rexinoids, and our analysis demonstrated that rexinoids with similar RXR EC 50 values can have pronounced differences in differential gene expression. Rexinoid binding likely leads to distinctive RXR conformations that cause major downstream gene expression alterations via modulation of RXR interacting proteins. Yeast two-hybrid analysis of RXR bait with two RXR interacting partners demonstrates that rexinoids drive differential binding of RXR to distinctive protein partners. Physiochemical analysis of the rexinoids reveals that the molecules cluster similarly to their gene expression patterns. Thus, rexinoids with similar RXR binding affinities drive differential gene expression by stimulating additional binding patterns in RXR and its homo- and heteropartners, driven by the physicochemical characteristics of these molecules.

Background: Little is known about the aetiology of urethral discharge syndrome (UDS) and genital ulcer disease (GUD) in Brazil due to limited access to laboratory tests and treatment based mainly on the syndromic approach., Objectives: To update Brazilian treatment guidelines according to the current scenario, the first nationwide aetiological study for UDS and GUD was performed., Methods: Male participants with urethral discharge (UD) and/or genital ulcer (GU) reports were enrolled. Sample collection was performed by 12 sentinel sites located in the five Brazilian regions. Between 2018 and 2020, 1141 UD and 208 GU samples were collected in a Universal Transport Medium-RT (Copan). A multiplex quantitative PCR kit (Seegene) was used to detect UD: Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), M. hominis (MH), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV), Ureaplasma parvum (UP), U. urealyticum (UU) and another kit to detect GU: cytomegalovirus (CMV), Haemophilus ducreyi (HD), herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), lymphogranuloma venereum (LGV), Treponema pallidum (TP) and varicella-zoster virus (VZV)., Results: In UD samples, the frequency of pathogen detection was NG: 78.38%, CT: 25.6%, MG: 8.3%, UU: 10.4%, UP: 3.5%, MH: 3.5% and TV: 0.9%. Coinfection was assessed in 30.9% of samples, with 14.3% of NG/CT coinfection. The most frequent pathogen identified in GU was HSV2, present in 40.8% of the samples, followed by TP at 24.8%, LGV and CMV at 1%, and HSV1 at 0.4%. Coinfection of TP/HSV2 was detected in 4.4% of samples. VZV and HD were not detected. In 27.7% of the GU samples, no pathogen was detected., Conclusion: This study provided the acquisition of unprecedented data on the aetiology of UDS and GUD in Brazil, demonstrated the presence of a variety of pathogens in both sample types and reaffirmed the aetiologies known to be most prevalent globally., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Sphingomonadaceae are common membrane colonizers and biofilm formers. As part of our studies on long-term genetic changes in drinking water biofilm species, we report the draft genome sequence of Sphingomonas strain Sph5, isolated from a tap water filtration membrane. The isolate was determined as Sphingomonas paucimobilis through whole genome sequencing and de novo assembly., Competing Interests: The authors declare no conflict of interest.

The ability of bacteria to sense and respond to mechanical forces has important implications for pathogens during infection, as they experience wide fluid shear fluctuations in the host. However, little is known about how mechanical forces encountered in the infected host drive microbial pathogenesis. Herein, we combined mathematical modeling with hydrodynamic bacterial culture to profile transcriptomic and pathogenesis-related phenotypes of multidrug resistant S . Typhimurium (ST313 D23580) under different fluid shear conditions relevant to its transition from the intestinal tract to the bloodstream. We report that D23580 exhibited incremental changes in transcriptomic profiles that correlated with its pathogenic phenotypes in response to these progressive increases in fluid shear. This is the first demonstration that incremental changes in fluid shear forces alter stress responses and gene expression in any ST313 strain and offers mechanistic insight into how forces encountered by bacteria during infection might impact their disease-causing ability in unexpected ways.

The plant family Balsaminaceae comprises only two genera, and they are a study in contrasts. While Impatiens is an impressively prolific genus, with over 1,000 species and more being discovered each year, its sister genus, Hydrocera , has one solitary species, H. triflora . The two genera also differ in geographic distribution and habitat type ( Impatiens species are widely distributed in much of the Old World and N. America, while H. triflora is confined to wetlands specific to S. India, Sri Lanka, and SE Asia). Other contrasting features include plant habit, habitat, floral architecture, mode of seed dispersal, and a host of other traits. The family Balsaminaceae is therefore an excellent model for studying speciation and character evolution as well as understanding the proximal and evolutionary forces that have driven the two genera to adopt such contrasting evolutionary paths. Various species of the Impatiens genus are also commercially important in the ornamental flower industry and as sources of phytochemicals that are of medicinal and other commercial value. As a preliminary step towards studying the genomic basis of the contrasting features of the two genera, we have sequenced and assembled, de novo , the genome of an iconic Impatiens species from N. America, namely I. capensis , and report our findings here., Competing Interests: The authors declare that they have no competing interests., (© 2023 Gadagkar et al.)

Purpose: Mexico and Central America have the highest childhood cancer incidence in the West. Pediatric-specific oncology knowledge contributes to the disparity. We sought to (1) determine the self-identified treatment patterns and needs of Mexican pediatric radiation oncologists and (2) pilot a workshop to improve contouring accuracy., Materials and Methods: Partnering with local experts and the Sociedad Mexicana de Radioterapeutas (SOMERA), a 35-question survey was designed to ascertain pediatric radiotherapy capacity and distributed through the SOMERA listserv. The most challenging malignancies were selected for workshop. Participants received precontouring and postcontouring homework to assess improvement per the Dice metric. The Wilcoxon sign-rank test was used for comparative statistics., Results: Ninety-four radiation oncologists attempted and 79 completed the survey. Forty-four (76%) felt comfortable treating a pediatric patient, and 36 (62%) were familiar with national protocols for pediatric treatment. Most had access to nutrition, rehabilitation, endocrinology, and anesthesia; 14% had access to fertility services and 27% to neurocognitive support; 11% noted no support, and only one respondent had child-life support. The postsurvey contouring workshop was conducted for high-grade glioma, medulloblastoma, and Hodgkin lymphoma. Significant improvements were seen in all target volumes., Conclusion: We present the first national survey of Mexico's pediatric radiotherapy capacity and Latin American e-contouring educational intervention with preworkshop and postworkshop Dice metrics, noting statistically significant improvement in all target volumes. Participation improved compared with prior experience through SOMERA partnership and Continuing Medical Education incentivization.

Physical forces associated with spaceflight and spaceflight analogue culture regulate a wide range of physiological responses by both bacterial and mammalian cells that can impact infection. However, our mechanistic understanding of how these environments regulate host-pathogen interactions in humans is poorly understood. Using a spaceflight analogue low fluid shear culture system, we investigated the effect of Low Shear Modeled Microgravity (LSMMG) culture on the colonization of Salmonella Typhimurium in a 3-D biomimetic model of human colonic epithelium containing macrophages. RNA-seq profiling of stationary phase wild type and Δ hfq mutant bacteria alone indicated that LSMMG culture induced global changes in gene expression in both strains and that the RNA binding protein Hfq played a significant role in regulating the transcriptional response of the pathogen to LSMMG culture. However, a core set of genes important for adhesion, invasion, and motility were commonly induced in both strains. LSMMG culture enhanced the colonization (adherence, invasion and intracellular survival) of Salmonella in this advanced model of intestinal epithelium using a mechanism that was independent of Hfq. Although S . Typhimurium Δ hfq mutants are normally defective for invasion when grown as conventional shaking cultures, LSMMG conditions unexpectedly enabled high levels of colonization by an isogenic Δ hfq mutant. In response to infection with either the wild type or mutant, host cells upregulated transcripts involved in inflammation, tissue remodeling, and wound healing during intracellular survival. Interestingly, infection by the Δ hfq mutant led to fewer transcriptional differences between LSMMG- and control-infected host cells relative to infection with the wild type strain. This is the first study to investigate the effect of LSMMG culture on the interaction between S . Typhimurium and a 3-D model of human intestinal tissue. These findings advance our understanding of how physical forces can impact the early stages of human enteric salmonellosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barrila, Yang, Franco Meléndez, Yang, Buss, Davis, Aronow, Bean, Davis, Forsyth, Ott, Gangaraju, Kang, Hanratty, Nydam, Nauman, Kong, Steel and Nickerson.)

The research domain criteria (RDoC) is an innovative approach designed to explore dimensions of human behavior. The aim of this approach is to move beyond the limits of psychiatric categories in the hope of aligning the identification of psychological health and dysfunction with clinical neuroscience. Despite its contributions to adult psychopathology research, RDoC undervalues ontogenetic development, which circumscribes our understanding of the etiologies, trajectories, and maintaining mechanisms of psychopathology risk. In this paper, we argue that integrating temperament research into the RDoC framework will advance our understanding of the mechanistic origins of psychopathology beginning in infancy. In illustrating this approach, we propose the incorporation of core principles of temperament theories into a new "life span considerations" subsection as one option for infusing development into the RDoC matrix. In doing so, researchers and clinicians may ultimately have the tools necessary to support emotional development and reduce a young child's likelihood of psychological dysfunction beginning in the first years of life.

Resting-state electroencephalography (EEG) provides developmental neuroscientists a noninvasive view into the neural underpinnings of cognition and emotion. Recently, the psychometric properties of two widely used neural measures in early childhood-frontal alpha asymmetry and delta-beta coupling-have come under scrutiny. Despite their growing use, additional work examining how the psychometric properties of these neural signatures may change across infancy is needed. The current study examined the developmental stability, split-half reliability, and construct validity of infant frontal alpha asymmetry and delta-beta coupling. Infants provided resting-state EEG data at 8, 12, and 18 months of age (N = 213). Frontal alpha asymmetry and delta-beta coupling showed significant developmental change from 8 to 18 months. Reliability for alpha asymmetry, and alpha, delta, and beta power, individually, was generally good. In contrast, the reliability of delta-beta coupling scores was poor. Associations between frontal alpha asymmetry and approach tendencies generally emerged, whereas stronger (over-coupled) delta-beta coupling scores were associated with profiles of dysregulation and low inhibition. However, the individual associations varied across time and specific measures of interest. We discuss these findings with a developmental lens, highlighting the importance of repeated measures to better understand links between neural signatures and typical and atypical development., (© 2021 Wiley Periodicals LLC.)

Spaceflight uniquely alters the physiology of both human cells and microbial pathogens, stimulating cellular and molecular changes directly relevant to infectious disease. However, the influence of this environment on host-pathogen interactions remains poorly understood. Here we report our results from the STL-IMMUNE study flown aboard Space Shuttle mission STS-131, which investigated multi-omic responses (transcriptomic, proteomic) of human intestinal epithelial cells to infection with Salmonella Typhimurium when both host and pathogen were simultaneously exposed to spaceflight. To our knowledge, this was the first in-flight infection and dual RNA-seq analysis using human cells.