Eliminating Cervical Cancer: Progress and Challenges for High-income Countries.

In 2020, the World Health Organization launched a major initiative to eliminate cervical cancer globally. The initiative is built around the three key pillars of human papillomavirus (HPV) vaccination, cervical screening and treatment, with associated intervention targets for the year 2030. The '90-70-90' targets specify that 90% of adolescent girls receive prophylactic HPV vaccination, 70% of adult women receive a minimum twice-in-a-lifetime cervical HPV test and 90% receive appropriate treatment for preinvasive or invasive disease. Modelling has shown that if these targets are met, the elimination of cervical cancer, defined as fewer than four cases per 100 000 women per annum, will be achieved within a century. Many high-income countries are well positioned to eliminate cervical cancer within the coming decades, but few have achieved '90-70-90' and many challenges must still be addressed to deliver these critical interventions effectively. This review considers the current status of cervical cancer control in relation to each of the three elimination pillars in high-income countries and discusses some of the developments that will assist countries in reaching these ambitious targets by 2030.

Increased expression of interleukin-6 gene in gastritis and gastric cancer.

Helicobacter pylori (H. pylori) induces an intense inflammatory response, mediated by proinflammatory cytokines, including interleukin (IL)-6 and its membrane receptor (IL-6R), which activates important signaling pathways in the development of gastric disease and cancer. We investigated the gene and protein expression of IL-6 and IL-6R and the influence of polymorphisms rs1800795, rs1800796, and rs1800797 on its gene expression together with H. pylori infection. Furthermore, an in-silico analysis was performed to support our results. Gastric biopsies were obtained from patients with gastric symptoms and patients with gastric cancer (GC) and were divided into groups (Control, Gastritis, and Cancer). H. pylori was detected by PCR. Real-time-qPCR was employed to determine gene expression, and western blot assay was used to analyze protein expression levels. PCR-RFLP was used to characterize IL-6 polymorphisms. Bioinformatics analyses were performed using the Gene Expression Omnibus (GEO) database and GEO2R to screen out differentially expressed genes (DEGs). H. pylori was detected in 43.3% of the samples. Statistically significant differences were found for IL-6 (P=0.0001) and IL-6R (P=0.0005) genes among the three groups, regardless of the presence of H. pylori. Among patients with H. pylori infection, the IL-6 and IL-6R gene and protein expressions were significantly increased, highlighting IL-6 gene overexpression in patients with GC. No statistically significant differences were found for the rs1800795, rs1800796, and rs1800797 polymorphisms compared to IL-6 gene expression. The results indicated that the IL-6 polymorphisms do not influence its expression, but IL-6 and IL-6R expression seems to be altered by the presence of H. pylori.

Retinal ganglion cell loss and gliosis in the retinofugal projection following intravitreal exposure to amyloid-beta.

Pathological accumulations of amyloid-beta (Aß) peptide are found in retina early in Alzheimer's disease, yet its effects on retinal neuronal structure remain unknown. To investigate this, we injected fibrillized Aß1-42 protein into the eye of adult C57BL/6 J mice and analyzed the retina, optic nerve (ON), and the superior colliculus (SC), the primary retinal target in mice. We found that retinal Aß exposure stimulated microglial activation and retinal ganglion cell (RGC) loss as early as 1-week post-injection. Pathology was not limited to the retina, but propagated into other areas of the central nervous system. Microgliosis spread throughout the retinal projection (retina, ON, and SC), with multiplex protein quantitation demonstrating an increase in endogenously produced Aß in the ON and SC corresponding to the injected retinas. Surprisingly, this pathology spread to the opposite side, with unilateral Aß eye injections driving increased Aß levels, neuroinflammation, and RGC death in the opposite, un-injected retinal projection. As Aß-mediated microglial activation has been shown to propagate Aß pathology, we also investigated the role of the Aß-binding microglial scavenger receptor CD36 in this pathology. Transgenic mice lacking the CD36 receptor were resistant to Aß-induced inflammation and RGC death up to 2 weeks following exposure. These results indicate that Aß pathology drives regional neuropathology in the retina and does not remain isolated to the affected eye, but spreads throughout the nervous system. Further, CD36 may serve as a promising target to prevent Aß-mediated inflammatory damage.

Increased expression of interleukin-6 gene in gastritis and gastric cancer

Helicobacter pylori (H. pylori) induces an intense inflammatory response, mediated by proinflammatory cytokines, including interleukin (IL)-6 and its membrane receptor (IL-6R), which activates important signaling pathways in the development of gastric disease and cancer. We investigated the gene and protein expression of IL-6 and IL-6R and the influence of polymorphisms rs1800795, rs1800796, and rs1800797 on its gene expression together with H. pylori infection. Furthermore, an in-silico analysis was performed to support our results. Gastric biopsies were obtained from patients with gastric symptoms and patients with gastric cancer (GC) and were divided into groups (Control, Gastritis, and Cancer). H. pylori was detected by PCR. Real-time-qPCR was employed to determine gene expression, and western blot assay was used to analyze protein expression levels. PCR-RFLP was used to characterize IL-6 polymorphisms. Bioinformatics analyses were performed using the Gene Expression Omnibus (GEO) database and GEO2R to screen out differentially expressed genes (DEGs). H. pylori was detected in 43.3% of the samples. Statistically significant differences were found for IL-6 (P=0.0001) and IL-6R (P=0.0005) genes among the three groups, regardless of the presence of H. pylori. Among patients with H. pylori infection, the IL-6 and IL-6R gene and protein expressions were significantly increased, highlighting IL-6 gene overexpression in patients with GC. No statistically significant differences were found for the rs1800795, rs1800796, and rs1800797 polymorphisms compared to IL-6 gene expression. The results indicated that the IL-6 polymorphisms do not influence its expression, but IL-6 and IL-6R expression seems to be altered by the presence of H. pylori.

Effect of breed as a risk factor for humeral condylar fracture in skeletally immature dogs.

OBJECTIVES: To investigate the effect of breed as a risk factor associated with humeral condylar fracture in skeletally immature dogs in the UK. MATERIALS AND METHODS: Retrospective study of dogs under 12 months of age that were presented with humeral condylar fracture to three specialist referral centres between 2015 and 2018. Data retrieved from medical records included breed, age, gender, neuter status, affected limb, fracture configuration and aetiology of the fracture. Breed population percentages were compared with those recorded by the UK Kennel Club. RESULTS: Of the 115 dogs with 118 fractures, French bulldogs (41%) and English springer spaniels (15%) were overrepresented: humeral condylar fractures were more commonly diagnosed in French bulldogs (odds ratio = 5.86) and English springer spaniels (odds ratio = 5.66) compared with mixed-breed dogs. Lateral condylar fractures occurred in 70% of cases, with medial condylar fractures and Y/T fractures accounting for 9% and 21%, respectively. Median age at the time of fracture was 4 months (range 2 to 10 months). CLINICAL SIGNIFICANCE: French bulldogs and English springer spaniels were identified as being at potentially increased risk of humeral condylar fracture in skeletally immature dogs.

Trabecula: A Random Generator of Computational Phantoms for Bone Marrow Dosimetry.

This study was motivated by the efforts to evaluate radiation risk for leukemia incidence in the Techa River cohort, where the main bone marrow dose contributors were Sr (bone-seeking beta emitters). Energy deposition in bone marrow targets was evaluated by simulating radiation particle transport using computational phantoms. The present paper describes the computer program Trabecula implementing an algorithm for parametric generation of computational phantoms, which serve as the basis for calculating bone marrow doses. Trabecula is a user-friendly tool that automatically converts analytical models into voxelized representations that are directly compatible as input to Monte Carlo N Particle code.

Karyotype, evolution and phylogenetic reconstruction in Micronycterinae bats with implications for the ancestral karyotype of Phyllostomidae.

BACKGROUND: The Micronycterinae form a subfamily of leaf-nosed bats (Phyllostomidae) that contains the genera Lampronycteris Sanborn, 1949, and Micronycteris Gray, 1866 (stricto sensu), and is characterized by marked karyotypic variability and discrepancies in the phylogenetic relationships suggested by the molecular versus morphological data. In the present study, we investigated the chromosomal evolution of the Micronycterinae using classical cytogenetics and multidirectional chromosome painting with whole-chromosomes probes of Phyllostomus hastatus and Carollia brevicauda. Our goal was to perform comparative chromosome mapping between the genera of this subfamily and explore the potential for using chromosomal rearrangements as phylogenetic markers. RESULTS: The Micronycterinae exhibit great inter- and intraspecific karyotype diversity, with large blocks of telomere-like sequences inserted within or adjacent to constitutive heterochromatin regions. The phylogenetic results generated from our chromosomal data revealed that the Micronycterinae hold a basal position in the phylogenetic tree of the Phyllostomidae. Molecular cytogenetic data confirmed that there is a low degree of karyotype similarity between Lampronycteris and Micronycteris specimens analyzed, indicating an absence of synapomorphic associations in Micronycterinae. CONCLUSIONS: We herein confirm that karyotypic variability is present in subfamily Micronycterinae. We further report intraspecific variation and describe a new cytotype in M. megalotis. The cytogenetic data show that this group typically has large blocks of interstitial telomeric sequences that do not appear to be correlated with chromosomal rearrangement events. Phylogenetic analysis using chromosome data recovered the basal position for Micronycterinae, but did not demonstrate that it is a monophyletic lineage, due to the absence of common chromosomal synapomorphy between the genera. These findings may be related to an increase in the rate of chromosomal evolution during the time period that separates Lampronycteris from Micronycteris.

Enhancements in the Techa River Dosimetry System: TRDS-2016D Code for Reconstruction of Deterministic Estimates of Dose From Environmental Exposures.

Waterborne releases to the Techa River from the Mayak plutonium facility in Russia during 1949-1956 resulted in significant doses to persons living downstream. The dosimetry system Techa River Dosimetry System-2016D has been developed, which provides individual doses of external and internal exposure for the members of the Techa River cohort and other persons who were exposed to releases of radioactive material to the Southern Urals. The results of computation of individual doses absorbed in red bone marrow and extraskeletal tissues for the Techa River cohort members (29,647 persons) are presented, which are based on residence histories on the contaminated Techa River and the East Urals Radioactive Trace, which was formed in 1957 as a result of the Kyshtym Accident. Available Sr body-burden measurements and available information on individual household locations have been used for refinement of individual dose estimates. Techa River Dosimetry System-2016D-based dose estimates will be used for verification of risk of low-dose-rate effects of ionizing radiation in the Techa River cohort.

Natural killer cell expression of Ki67 is associated with elevated serum IL-15, disease activity and nephritis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder whose pathology involves multiple immune cell types, including B and T lymphocytes as well as myeloid cells. While it is clear that autoantibody-producing B cells, as well as CD4+ T cell help, are key contributors to disease, little is known regarding the role of innate lymphoid cells such as natural killer (NK) cells in the pathogenesis of SLE. We have characterized the phenotype of NK cells by multi-color flow cytometry in a large cohort of SLE patients. While the overall percentage of NK cells was similar or slightly decreased compared to healthy controls, a subset of patients displayed a high frequency of NK cells expressing the proliferation marker, Ki67, which was not found in healthy donors. Although expression of Ki67 on NK cells correlated with Ki67 on other immune cell subsets, the frequency of Ki67 on NK cells was considerably higher. Increased frequencies of Ki67+ NK cells correlated strongly with clinical severity and active nephritis and was also related to low NK cell numbers, but not overall leukopenia. Proteomic and functional data indicate that the cytokine interleukin-15 promotes the induction of Ki67 on NK cells. These results suggest a role for NK cells in regulating the immune-mediated pathology of SLE as well as reveal a possible target for therapeutic intervention.

Nodes of Ranvier in Glaucoma.

Retinal ganglion cell axons of the DBA/2J mouse model of glaucoma, a model characterized by extensive neuroinflammation, preserve synaptic contacts with their subcortical targets for a time after onset of anterograde axonal transport deficits, axon terminal hypertrophy, and cytoskeletal alterations. Though retrograde axonal transport is still evident in these axons, it is unknown if they retain their ability to transmit visual information to the brain. Using a combination of in vivo multiunit electrophysiology, neuronal tract tracing, multichannel immunofluorescence, and transmission electron microscopy, we report that eye-brain signaling deficits precede transport loss and axonal degeneration in the DBA/2J retinal projection. These deficits are accompanied by node of Ranvier pathology - consisting of increased node length and redistribution of the voltage-gated sodium channel Nav1.6 that parallel changes seen early in multiple sclerosis (MS) axonopathy. Further, with age, axon caliber and neurofilament density increase without corresponding changes in myelin thickness. In contrast to these findings in DBA/2J mice, node pathologies were not observed in the induced microbead occlusion model of glaucoma - a model that lacks pre-existing inflammation. After one week of systemic treatment with fingolimod, an immunosuppressant therapy for relapsing-remitting MS, DBA/2J mice showed a substantial reduction in node pathology and mild effects on axon morphology. These data suggest that neurophysiological deficits in the DBA/2J may be due to defects in intact axons and targeting node pathology may be a promising intervention for some types of glaucoma.

Overcoming the dichotomy of implementing societal flood risk management while conserving instream fish habitat - A long-term study from a highly modified urban river.

Flood Risk Management (FRM) is often essential to reduce the risk of flooding to properties and infrastructure in urban landscapes, but typically degrades the habitats required by many aquatic animals for foraging, refuge and reproduction. This conflict between flood risk management and biodiversity is driven by conflicting directives, such as the EU Floods and Water Framework Directives, and has led to a requirement for synergistic solutions for FRM that integrate river restoration actions. Unfortunately, ecological monitoring and appraisal of combined FRM and river restoration works is inadequate. This paper uses a case study from the River Don in Northern England to evaluate the effects of the FRM and subsequent river restoration works on instream habitat and the associated fish assemblage over an 8-year period. Flood risk management created a homogeneous channel but did not negatively affect fish species composition or densities, specifically brown trout. Densities of adult brown trout were comparable pre and post-FRM, while densities of juvenile bullhead and brown trout increased dramatically post FRM. River restoration works created a heterogeneous channel but did not significantly improve species composition or brown trout density. Species composition post-river restoration works returned to that similar to pre-FRM over a short-term period, but with improved numbers of juvenile bullhead. Although habitat complexity increased after river restoration works, long-term changes in species composition and densities were marginal, probably because the river reset habitat complexity within the time framework of the study.

Whole-Genome Sequences of Variants of Bacillus anthracis Sterne and Their Toxin Gene Deletion Mutants.

Here, we report the draft genome sequences of three laboratory variants of Bacillus anthracis Sterne and their double (Δlef Δcya) and triple (Δpag Δlef Δcya) toxin gene deletion derivatives.

Monkey prefrontal neurons during Sternberg task performance: full contents of working memory or most recent item?

To explore the brain mechanisms underlying multi-item working memory, we monitored the activity of neurons in the dorsolateral prefrontal cortex while macaque monkeys performed spatial and chromatic versions of a Sternberg working-memory task. Each trial required holding three sequentially presented samples in working memory so as to identify a subsequent probe matching one of them. The monkeys were able to recall all three samples at levels well above chance, exhibiting modest load and recency effects. Prefrontal neurons signaled the identity of each sample during the delay period immediately following its presentation. However, as each new sample was presented, the representation of antecedent samples became weak and shifted to an anomalous code. A linear classifier operating on the basis of population activity during the final delay period was able to perform at approximately the level of the monkeys on trials requiring recall of the third sample but showed a falloff in performance on trials requiring recall of the first or second sample much steeper than observed in the monkeys. We conclude that delay-period activity in the prefrontal cortex robustly represented only the most recent item. The monkeys apparently based performance of this classic working-memory task on some storage mechanism in addition to the prefrontal delay-period firing rate. Possibilities include delay-period activity in areas outside the prefrontal cortex and changes within the prefrontal cortex not manifest at the level of the firing rate.NEW & NOTEWORTHY It has long been thought that items held in working memory are encoded by delay-period activity in the dorsolateral prefrontal cortex. Here we describe evidence contrary to that view. In monkeys performing a serial multi-item working memory task, dorsolateral prefrontal neurons encode almost exclusively the identity of the sample presented most recently. Information about earlier samples must be encoded outside the prefrontal cortex or represented within the prefrontal cortex in a cryptic code.

Mapping in-vivo optic nerve head strains caused by intraocular and intracranial pressures.

Although it is well documented that abnormal levels of either intraocular (IOP) or intracranial pressure (ICP) can lead to potentially blinding conditions, such as glaucoma and papilledema, little is known about how the pressures actually affect the eye. Even less is known about potential interplay between their effects, namely how the level of one pressure might alter the effects of the other. Our goal was to measure in-vivo the pressure-induced stretch and compression of the lamina cribrosa due to acute changes of IOP and ICP. The lamina cribrosa is a structure within the optic nerve head, in the back of the eye. It is important because it is in the lamina cribrosa that the pressure-induced deformations are believed to initiate damage to neural tissues leading to blindness. An eye of a rhesus macaque monkey was imaged in-vivo with optical coherence tomography while IOP and ICP were controlled through cannulas in the anterior chamber and lateral ventricle, respectively. The image volumes were analyzed with a newly developed digital image correlation technique. The effects of both pressures were highly localized, nonlinear and non-monotonic, with strong interactions. Pressure variations from the baseline normal levels caused substantial stretch and compression of the neural tissues in the posterior pole, sometimes exceeding 20%. Chronic exposure to such high levels of biomechanical insult would likely lead to neural tissue damage and loss of vision. Our results demonstrate the power of digital image correlation technique based on non-invasive imaging technologies to help understand how pressures induce biomechanical insults and lead to vision problems.

New insights into sex chromosome evolution in anole lizards (Reptilia, Dactyloidae).

Anoles are a clade of iguanian lizards that underwent an extensive radiation between 125 and 65 million years ago. Their karyotypes show wide variation in diploid number spanning from 26 (Anolis evermanni) to 44 (A. insolitus). This chromosomal variation involves their sex chromosomes, ranging from simple systems (XX/XY), with heterochromosomes represented by either micro- or macrochromosomes, to multiple systems (X1X1X2X2/X1X2Y). Here, for the first time, the homology relationships of sex chromosomes have been investigated in nine anole lizards at the whole chromosome level. Cross-species chromosome painting using sex chromosome paints from A. carolinensis, Ctenonotus pogus and Norops sagrei and gene mapping of X-linked genes demonstrated that the anole ancestral sex chromosome system constituted by microchromosomes is retained in all the species with the ancestral karyotype (2n = 36, 12 macro- and 24 microchromosomes). On the contrary, species with a derived karyotype, namely those belonging to genera Ctenonotus and Norops, show a series of rearrangements (fusions/fissions) involving autosomes/microchromosomes that led to the formation of their current sex chromosome systems. These results demonstrate that different autosomes were involved in translocations with sex chromosomes in closely related lineages of anole lizards and that several sequential microautosome/sex chromosome fusions lead to a remarkable increase in size of Norops sagrei sex chromosomes.

Donor-Derived Exosomes With Lung Self-Antigens in Human Lung Allograft Rejection.

The immunological role of exosomes in allograft rejection remains unknown. We sought to determine whether exosomes are induced during lung allograft rejection and to define the antigenic compositions of HLA, lung-associated self-antigens (SAgs) and microRNAs (miRNAs). Exosomes were isolated from sera and bronchoalveolar lavage fluid from 30 lung transplant recipients (LTxRs) who were stable or who had acute rejection (AR) or bronchiolitis obliterans syndrome (BOS). Exosomes were defined by flow cytometry for CD63 and western blotting for annexin V SAgs, collagen V (Col-V) and Kα1 tubulin were examined by electron microscopy; miRNAs were profiled by a miRNA array. Donor HLA and SAgs were detected on exosomes from LTxRs with AR and BOS but not from stable LTxRs. Exosomes expressing Col-V were isolated from sera from LTxRs 3 mo before AR and 6 mo before BOS diagnosis, suggesting that exosomes with SAgs may be a noninvasive rejection biomarker. Exosomes isolated from LTxRs with AR or BOS also contained immunoregulatory miRNAs. We concluded that exosomes expressing donor HLA, SAgs and immunoregulatory miRNAs are present in the circulation and local site after human lung transplantation and play an important role in the immune pathogenesis of acute allograft rejection and BOS.

Correlation between Cerebral Hemodynamic and Perfusion Pressure Changes in Non-Human Primates.

The mechanism that maintains a stable blood flow in the brain despite changes in cerebral perfusion pressure (CPP), and therefore guaranties a constant supply of oxygen and nutrients to the neurons, is known as cerebral autoregulation (CA). In a certain range of CPP, blood flow is mediated by a vasomotor adjustment in vascular resistance through dilation of blood vessels. CA is known to be impaired in diseases like traumatic brain injury, Parkinson's disease, stroke, hydrocephalus and others. If CA is impaired, blood flow and pressure changes are coupled and the oxygen supply might be unstable. Lassen's blood flow autoregulation curve describes this mechanism, where a plateau of stable blood flow in a specific range of CPP corresponds to intact autoregulation. Knowing the limits of this plateau and maintaining CPP within these limits can improve patient outcome. Since CPP is influenced by both intracranial pressure and arterial blood pressure, long term changes in either can lead to autoregulation impairment. Non-invasive methods for monitoring blood flow autoregulation are therefore needed. We propose to use Near infrared spectroscopy (NIRS) to fill this need. NIRS is an optical technique, which measures microvascular changes in cerebral hemoglobin concentration. We pe erformed experiments on non-human primates during exsanguination to demonstrate that the limits of blood flow autoregulation can be accessed with NIRS.

Enhanced Phosphorylation of Bax and Its Translocation into Mitochondria in the Brains of Individuals Affiliated with Alzheimer's Disease.

BACKGROUND: Despite increased neuronal death, senile plaques, and neurofibrillary tangles observed in patients suffering from Alzheimer's disease (AD), the detailed mechanism of cell death in AD is still poorly understood. METHOD: We hypothesized that p38 kinase activates and then phosphorylates Bax, leading to its translocation to mitochondria in AD brains compared to controls. The aim of this study was to investigate the role of p38 kinase in phosphorylation and sub-cellular localization of pro-apoptotic Bax in the frontal cortex of the brains from AD and control subjects. Increased oxidative stress in AD individuals compared to control was evaluated by measuring the levels of carbonylated proteins and oxidized peroxiredoxin, an antioxidant enzyme. The relative amounts of p38 kinase and phospho-Bax in mitochondria in AD brains and controls were determined by immunoblot analysis using the respective antibody against each protein following immunoprecipitation. RESULTS: Our results showed that the levels of oxidized peroxiredoxin-SO3 and carbonylated proteins are significantly elevated in AD brains compared to controls, demonstrating the increased oxidative stress. CONCLUSION: The amount of phospho-p38 kinase is increased in AD brains and the activated p38 kinase appears to phosphorylate Thr residue(s) of Bax, which leads to its mitochondrial translocation, contributing to apoptosis and ultimately, neurodegeneration.