Zika virus infection of retinal cells and the developing mouse eye induces host responses that contrasts to the brain and dengue virus infection.

Zika virus (ZIKV) infection causes ocular and neurological pathologies with ZIKV-induction of developmental abnormalities following in utero infection a major concern. The study here has compared ZIKV and the related dengue virus (DENV) infection in the eye and brain. In vitro, both ZIKV and DENV could infect cell lines representing the retinal pigmented epithelium, endothelial cells, and Mueller cells, with distinct innate responses in each cell type. In a 1-day old mouse challenge model, both ZIKV and DENV infected the brain and eye by day 6 post-infection (pi). ZIKV was present at comparable levels in both tissues, with RNA increasing with time post-infection. DENV infected the brain, but RNA was detected in the eye of less than half of the mice challenged. NanoString analysis demonstrated comparable host responses in the brain for both viruses, including induction of mRNA for myosin light chain-2 (Mly2), and numerous antiviral and inflammatory genes. Notably, mRNA for multiple complement proteins were induced, but C2 and C4a were uniquely induced by ZIKV but not DENV. Consistent with the viral infection in the eye, DENV induced few responses while ZIKV induced substantial inflammatory and antiviral responses. Compared to the brain, ZIKV in the eye did not induce mRNAs such as C3, downregulated Retnla, and upregulated CSF-1. Morphologically, the ZIKV-infected retina demonstrated reduced formation of specific retinal layers. Thus, although ZIKV and DENV can both infect the eye and brain, there are distinct differences in host cell and tissue inflammatory responses that may be relevant to ZIKV replication and disease.

The Rat Genome Database (RGD) facilitates genomic and phenotypic data integration across multiple species for biomedical research.

Model organism research is essential for discovering the mechanisms of human diseases by defining biologically meaningful gene to disease relationships. The Rat Genome Database (RGD, ( https://rgd.mcw.edu )) is a cross-species knowledgebase and the premier online resource for rat genetic and physiologic data. This rich resource is enhanced by the inclusion and integration of comparative data for human and mouse, as well as other human disease models including chinchilla, dog, bonobo, pig, 13-lined ground squirrel, green monkey, and naked mole-rat. Functional information has been added to records via the assignment of annotations based on sequence similarity to human, rat, and mouse genes. RGD has also imported well-supported cross-species data from external resources. To enable use of these data, RGD has developed a robust infrastructure of standardized ontologies, data formats, and disease- and species-centric portals, complemented with a suite of innovative tools for discovery and analysis. Using examples of single-gene and polygenic human diseases, we illustrate how data from multiple species can help to identify or confirm a gene as involved in a disease and to identify model organisms that can be studied to understand the pathophysiology of a gene or pathway. The ultimate aim of this report is to demonstrate the utility of RGD not only as the core resource for the rat research community but also as a source of bioinformatic tools to support a wider audience, empowering the search for appropriate models for human afflictions.

Uterine transplantation: legal and regulatory implications in England.

Uterus transplantation (UTx) is fast evolving from an experimental to a clinical procedure, combining solid organ transplantation with assisted reproductive technology. The commencement of the first human uterus transplant trial in the United Kingdom leads us to examine and reflect upon the legal and regulatory aspects closely intertwined with UTx from the process of donation to potential implications for fertility treatment and the birth of the resultant child. As the world's first ephemeral transplant, the possibility of organ restitution requires consideration and is discussed herein. TWEETABLE ABSTRACT: Uterine transplantation warrants a closer look at the legal frameworks on fertility treatment and transplantation in England.

Uterine Transplantation: Scientific Impact Paper No. 65 April 2021.

A uterine transplant, or womb transplant, provides a potential treatment for women who cannot become pregnant or carry a pregnancy because they do not have a womb, or have a womb that is unable to maintain a pregnancy. This is estimated to affect one in 500 women. Options for those who wish to start a family include adoption and surrogacy, but these are associated with legal, cultural, ethical and religious implications that may not be appropriate for some women and their families. A womb transplant is undertaken when the woman is ready to start a family, and is removed following the completion of their family. Womb transplants have been performed all over the world, with more than 70 procedures carried out so far. At least 23 babies have been born as a result, demonstrating that womb transplants can work. While the procedure offers a different option to adoption and surrogacy, it is associated with significant risks, including multiple major surgeries and the need to take medications that help to dampen the immune system to prevent rejection of the womb. To date there has been a 30% risk of a transplant being unsuccessful. Although the number of transplants to date is still relatively small, the number being performed globally is growing, providing an opportunity to learn from the experience gained so far. This paper looks at the issues that have been encountered, which may arise at each step of the process, and proposes a framework for the future. However, long term follow-up of cases will be essential to draw reliable conclusions about any overall benefits of this procedure.

Mapping tree density at a global scale.

The global extent and distribution of forest trees is central to our understanding of the terrestrial biosphere. We provide the first spatially continuous map of forest tree density at a global scale. This map reveals that the global number of trees is approximately 3.04 trillion, an order of magnitude higher than the previous estimate. Of these trees, approximately 1.39 trillion exist in tropical and subtropical forests, with 0.74 trillion in boreal regions and 0.61 trillion in temperate regions. Biome-level trends in tree density demonstrate the importance of climate and topography in controlling local tree densities at finer scales, as well as the overwhelming effect of humans across most of the world. Based on our projected tree densities, we estimate that over 15 billion trees are cut down each year, and the global number of trees has fallen by approximately 46% since the start of human civilization.

The vaginal microbiome in uterine transplantation.

Women with congenital absolute uterine factor infertility (AUFI) often need vaginal restoration to optimise sexual function. Given their lack of procreative ability, little consideration has previously been given to the resultant vaginal microbiome (VM). Uterine transplantation (UTx) now offers the opportunity to restore these women's reproductive potential. The structure of the VM is associated with clinical and reproductive implications that are intricately intertwined with the process of UTx. Consideration of how vaginal restoration methods impact VM is now warranted and assessment of the VM in future UTx procedures is essential to understand the interrelation of the VM and clinical and reproductive outcomes. TWEETABLE ABSTRACT: The vaginal microbiome has numerous implications for clinical and reproductive outcomes in the context of uterine transplantation.

Deep inspirations attenuate postprandial airway inflammation in college-aged adults with elevated baseline exhaled nitric oxide: A pilot study.

Airway inflammation (assessed by exhaled nitric oxide (eNO)) increases after a single high-fat meal (HFM), yet this response may be modified by airway stretch and baseline eNO level.Purpose: The purpose of this study was to investigate whether deep inspirations (DIs) would attenuate airway inflammation post-HFM and whether this is modulated by baseline eNO level.Methods: A total of sixteen healthy college-aged participants completed a randomized cross-over study with 8 lower eNO (14.8 ± 2.0 ppb: 3 M/5F; age: 22.0 ± 2.2 yrs) and 8 higher eNO (29.3 ± 11.6 ppb 5 M/3F; age: 22.5 ± 2.6 yrs) participants. All participants completed a control (CON) condition (no DIs pre-HFM) and DI condition (60 DI's to total lung capacity immediately pre-HFM) after an overnight fast. The primary outcome was eNO. Participants had 20 minutes to consume the HFM (1 g fat/1 kg body weight) and eNO was performed at 2- and 4- hours post-HFM. To determine whether baseline eNO levels impacted the effect of DI's, a median split was performed on their baseline eNO level.Results: There was a significant increase in eNO as a main effect of time (p < 0.001). However when analyzing the potential effect of baseline eNO, there was no significant increase in eNO post-HFM in the higher eNO group in the DI condition (p = 0.54). DIs modified the eNO response to a HFM in the group with a higher baseline eNO value.Conclusions: These data display a possible bronchoprotective protect of DIs against postprandial airway inflammation in participants with higher initial eNO level.

Human uterine transplantation: a review of outcomes from the first 45 cases.

Uterine transplantation restores reproductive anatomy in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The number of cases being performed is increasing exponentially, with detailed outcomes from 45 cases, including nine live births, now available. In light of the data presented herein, including detailed surgical, immunosuppressive and obstetric outcomes, the feasibility of uterine transplantation is now difficult to refute. However, it is associated with significant risk with more than one-quarter of grafts removed because of complications, and one in ten donors suffering complications requiring surgical repair. TWEETABLE ABSTRACT: Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication.

Fungal-derived cues promote ocular autoimmunity through a Dectin-2/Card9-mediated mechanism.

Uveitis (intraocular inflammation) is a leading cause of loss of vision. Although its aetiology is largely speculative, it is thought to arise from complex genetic-environmental interactions that break immune tolerance to generate eye-specific autoreactive T cells. Experimental autoimmune uveitis (EAU), induced by immunization with the ocular antigen, interphotoreceptor retinoid binding protein (IRBP), in combination with mycobacteria-containing complete Freund's adjuvant (CFA), has many clinical and histopathological features of human posterior uveitis. Studies in EAU have focused on defining pathogenic CD4+ T cell effector responses, such as those of T helper type 17 (Th17) cells, but the innate receptor pathways precipitating development of autoreactive, eye-specific T cells remain poorly defined. In this study, we found that fungal-derived antigens possess autoimmune uveitis-promoting function akin to CFA in conventional EAU. The capacity of commensal fungi such as Candida albicans or Saccharomyces cerevisae to promote IRBP-triggered EAU was mediated by Card9. Because Card9 is an essential signalling molecule of a subgroup of C-type lectin receptors (CLRs) important in host defence, we evaluated further the proximal Card9-activating CLRs. Using single receptor-deficient mice we identified Dectin-2, but not Mincle or Dectin-1, as a predominant mediator of fungal-promoted uveitis. Conversely, Dectin-2 activation by α-mannan reproduced the uveitic phenotype of EAU sufficiently, in a process mediated by the Card9-coupled signalling axis and interleukin (IL)-17 production. Taken together, this report relates the potential of the Dectin-2/Card9-coupled pathway in ocular autoimmunity. Not only does it contribute to understanding of how innate immune receptors orchestrate T cell-mediated autoimmunity, it also reveals a previously unappreciated ability of fungal-derived signals to promote autoimmunity.

The mechanism producing initial transients on the clarinet.

In self-sustained instruments, starting transients are important timbral characteristics that help identify the instrument and the playing style. Often, the oscillation starts as a growing exponential. This study investigates the starting amplitude of this exponential for the clarinet. After a rapid tongue release, the reed quickly returns to its equilibrium position. The sudden change in aperture produces an abrupt change in both the airflow into the mouthpiece and the mouthpiece pressure. This perturbation travels along the bore and reflects at the open end. Returning to the mouthpiece with slight attenuation, the perturbation can be amplified by the reed acting as an active element-effectively a negative resistance. When the reed release time exceeds the time for sound to travel twice the bore length, the airflow and pressure wave into the bore via the aperture are superposed over their own returning reflection. Measurements of reed motion and mouthpiece pressures during reed release yield values that are used in a model to calculate waveforms showing similarities to those observed experimentally. The initial amplitude decreases with increasing reed release time, though not always monotonically. It can become very small in special cases due to synchronisation between the initial pulse and its reflection.

Influence of blood flow occlusion on the development of peripheral and central fatigue during small muscle mass handgrip exercise.

Critical power represents an important threshold for neuromuscular fatigue development and may, therefore, dictate intensities for which exercise tolerance is determined by the magnitude of fatigue accrued. Peripheral fatigue appears to be constant across O2 delivery conditions for large muscle mass exercise, but this consistency is equivocal for smaller muscle mass exercise. We sought to determine the influence of blood flow occlusion during handgrip exercise on neuromuscular fatigue development and to examine the relationship between neuromuscular fatigue development and W '. Blood flow occlusion influenced the development of both peripheral and central fatigue, thus providing further evidence that the magnitude of peripheral fatigue is not constant across O2 delivery conditions for small muscle mass exercise. W ' appears to be related to the magnitude of fatigue accrued during exercise, which may explain the reported consistency of intramuscular metabolic perturbations and work performed for severe-intensity exercise. The influence of the muscle metabolic milieu on peripheral and central fatigue is currently unclear. Moreover, the relationships between peripheral and central fatigue and the curvature constant (W ') have not been investigated. Six men (age: 25 ± 4 years, body mass: 82 ± 10 kg, height: 179 ± 4 cm) completed four constant power handgrip tests to exhaustion under conditions of control exercise (Con), blood flow occlusion exercise (Occ), Con with 5 min post-exercise blood flow occlusion (Con + Occ), and Occ with 5 min post-exercise blood flow occlusion (Occ + Occ). Neuromuscular fatigue measurements and W ' were obtained for each subject. Each trial resulted in significant peripheral and central fatigue. Significantly greater peripheral (79.7 ± 5.1% vs. 22.7 ± 6.0%) and central (42.6 ± 3.9% vs. 4.9 ± 2.0%) fatigue occurred for Occ than for Con. In addition, significantly greater peripheral (83.0 ± 4.2% vs. 69.0 ± 6.2%) and central (65.5 ± 14.6% vs. 18.6 ± 4.1%) fatigue occurred for Occ + Occ than for Con + Occ. W ' was significantly related to the magnitude of global (r = 0.91) and peripheral (r = 0.83) fatigue. The current findings demonstrate that blood flow occlusion exacerbated the development of both peripheral and central fatigue and that post-exercise blood flow occlusion prevented the recovery of both peripheral and central fatigue. Moreover, the current findings suggest that W ' may be determined by the magnitude of fatigue accrued during exercise.

Differential gene expression analysis in CCLE lesions provides new insights regarding the genetics basis of skin vs. systemic disease.

Lupus erythematosus is a heterogeneous autoimmune condition affecting multiple organs including skin, which remains poorly understood. To investigate pathogenetic processes relevant to cutaneous lupus as compared to systemic disease, we generated genome-wide expression data from lesional and non-lesional skin of chronic cutaneous LE (CCLE) patients. We reveal LE skin-associated transcriptional profiles and identify prominent functional pathways. A subset of CCLE differentially expressed genes (DEGs) was found to overlap with systemic lupus, including those linked to interferon and apoptosis. We identified 13 skin associated transcriptional "hot spots" that represent activated chromosomal regions. Seventeen CCLE DEGs (eight within "hot spots") were found to overlap with previously reported SLE-associated susceptibility loci. Additionally, we identify chromosomal regions not previously associated with lupus, potentially harboring distinct susceptibility loci for CCLE. This study suggests that overlapping as well as distinct genetic factors underlie disease pathogenesis in systemic and cutaneous lupus.

Genetic variation and coronary atherosclerosis in patients with systemic lupus erythematosus.

Coronary artery disease is the major cause of mortality in patients with systemic lupus erythematosus (SLE). Increased cardiovascular risk in SLE is not explained by traditional risk factors. We examined the hypothesis that genetic variation contributes to the presence of coronary atherosclerosis in patients with SLE. The genotypes of single-nucleotide polymorphisms (SNP) in 152 candidate genes linked with autoimmune or cardiovascular risk were determined in 125 patients with SLE. Coronary artery calcium (CAC), a measure of coronary atherosclerosis, was detected in 32 patients (26%) by electron-beam computed tomography. Polymorphism in 20 of the candidate genes (ADAM33, ADIPOQ, CCL5, CCR7, CDKN2B, CSF1, IL4, IL12A, IL23R, INS, IRF5, MIF, MS4A1, PTGS1, PTPN22, RETN, SELE, TNFSF4, TNFRSF11B, and VCAM1) were nominally associated with the presence of CAC (p-values = 0.001-0.047 after adjustment for age, sex and race). Some of these are known susceptibility genes for SLE and others have been implicated in cardiovascular disease in other populations. No association withstood false discovery rate adjustment. Replication studies in additional cohorts of patients with SLE may be informative.

Psychological assessment tool for patients diagnosed with absolute uterine factor infertility and planning to undergo uterine transplantation.

Uterine transplantation (UTn) has been proposed as a treatment option for women diagnosed with absolute uterine factor infertility (AUFI) and who are willing to bear their own child. AUFI renders a woman 'unconditionally infertile'. For AUFI women in general, UTn may offer a way to re-discover their own femininity through the restoration of fertility. Thus, when faced with a patient who may undergo UTn, the 'holistic approach' takes on an extra meaning. This is because the psychological element is two-sided for these patients. On one side lies the psychology of infertility, and on the other and equally important, is the substantially higher prevalence of psychiatric disorders in transplant candidates and recipients than in the general population. However, the psychology of a potential recipient of a uterine graft in order to bring about fertility has not been adequately explored or reviewed scientifically. We have presented here an outline of the areas which should be included in a psychological assessment for patients wishing to undergo UTn.

Amino acid restriction, aging, and longevity: an update.

Various so-called dietary restriction paradigms have shown promise for extending health and life. All such paradigms rely on ad libitum (hereafter ad lib) feeding, something virtually never employed in animals whose long-term health we value, either as a control or, except for food restriction itself, for both control and treatment arms of the experiment. Even though the mechanism(s) remain only vaguely understood, compared to ad lib-fed animals a host of dietary manipulations, including calorie restriction, low protein, methionine, branched-chain amino acids, and even low isoleucine have demonstrable health benefits in laboratory species in a standard laboratory environment. The remaining challenge is to determine whether these health benefits remain in more realistic environments and how they interact with other health enhancing treatments such as exercise or emerging geroprotective drugs. Here we review the current state of the field of amino acid restriction on longevity of animal models and evaluate its translational potential.

Uterine transplantation: what else needs to be done before it can become a reality?

Uterine transplantation may be a possible treatment option in the future for absolute uterine infertility. We describe three important areas of research that we feel are important in order to move closer to a successful and, crucially, safe transplant in the human setting. With closer collaboration among the various international teams working on this project, the first human uterine transplant should be possible in the next few years.