Project description:Transposable elements (TEs) compose about 40% of the murine genome. Retrotransposition of active TEs such as LINE-1 (L1) tremendously impacts genetic diversification and genome stability. Therefore, transcription and transposition activities of retrotransposons are tightly controlled. Here, we show that the Krüppel-like zinc finger protein Zfp281 directly binds and suppresses a subset of retrotransposons, including the active young L1 repeat elements, in mouse embryonic stem (ES) cells. In addition, we find that Zfp281-regulated L1s are highly enriched for 5-hydroxymethylcytosine (5hmC) and H3K4me3. The COMPASS-like H3K4 methyltransferase Mll2 is the major H3K4me3 methylase at the Zfp281-regulated L1s and required for their proper expression. Our studies also reveal that Zfp281 functions partially through recruiting the L1 regulators DNA hydroxymethylase Tet1 and Sin3A, and restricting Mll2 at these active L1s, leading to their balanced expression. In summary, our data indicate an instrumental role of Zfp281 in suppressing the young active L1s in mouse ES cells.
Project description:Host-defense peptides (HDPs) are vital components of innate immunity in all vertebrates. While their antibacterial activity toward bacterial cells was the original focus for research, their ability to modulate immune and inflammatory processes has emerged as one of their major functions in the host and as a promising approach from which to develop novel therapeutics targeting inflammation and innate immunity. In this review, with particular emphasis on the cathelicidin family of peptides, the roles of natural HDPs are examined in managing immune activation, cellular recruitment, cytokine responses, and inflammation in response to infection, as well as their contribution(s) to various inflammatory disorders and autoimmune diseases. Furthermore, we discuss current efforts to develop synthetic HDPs as therapeutics aimed at restoring balance to immune responses that are dysregulated and contribute to disease pathologies.
Project description:The current definition of prediabetes is controversial and subject to continuous debate. Nonetheless, prediabetes is a risk factor for type 2 diabetes, is highly prevalent and is associated with diabetic complications and mortality. Thereby, it has the potential to become a huge strain on healthcare systems in the future, necessitating action from legislators and healthcare providers. But how do we best reduce its associated burden on health? As a compromise between differing opinions in the literature and among the authors of this article, we suggest stratifying individuals with prediabetes according to estimated risk and only offering individual-level preventive interventions to those at high risk. At the same time, we argue to identify those with prediabetes and already established diabetes-related complications and treat them as we would treat individuals with established type 2 diabetes.
Project description:Background and objectivesEnglish and Welsh laws require "contemporaneous" consent to sexual relations, often precluding "non-capacituos" people living with advanced dementia from these human interactions.Research design and methodsThe views of people living with dementia, carers, professionals, and over-55s were explored on implications of current laws on sexuality in dementia. Thirty-five participants from England were recruited through purposive selective sampling. Audio-taped semistructured interviews were transcribed and thematically analyzed with each stakeholder group coded separately.ResultsCommon themes across stakeholders were (i) law reform needed due to their hammer-like effect ignoring the individual; (ii) dissonant theme of needing the law for protection; (iii) negative impact of denied intimacy on individuals and partners; (iv) support for Advance Decisions on Intimacy with caveats; (v) less support for involvement of Court of Protection and Powers of Attorney; (vi) call for review of capacity concept with support for an assent model. People living with dementia described shame and stigma associated with policing of their sexuality and perception of being singled out for protection and intrusion into their lives. For informal carers (mostly wives), the theme of "what about me" emerged, demonstrating that for the long-term partnered, this is a couple's issue.Discussion and implicationsPractical implications of this study include need to address ageism and ableism; human rights education for society and professionals; starting point of presumed capacity for sexual relations with consensus on how and when this should be rebutted; and care homes' certification requirements should incorporate assessment of the relationship health of their residents.
Project description:To evaluate factors affecting the outcomes of short-term Mono-J insertion for 6 h following ureteroscopic stone removal. Patients treated with a Mono-J for 6 h after ureterorenoscopy and stone removal were analysed. FaST 1 and 2 (Fast Track Stent Studies), two consecutive single academic centre studies, were conducted between August 2014 and April 2018. In each study, we randomized patients with renal or ureteral calculi to two groups before ureterorenoscopy. FaST 1 compared a Mono-J insertion for 6 h versus Double-J insertion for 3-5 days after ureterorenoscopy. FaST 2 compared a Mono-J insertion to a tubeless procedure in the same clinical setting. All patients were pre-stented for 3-5 days before URS. The study endpoint was stent-related symptoms as assessed by a validated questionnaire (USSQ). Results were stratified by clinical parameters, stone characteristics and operation details. 108 of 156 initially randomized patients undergoing ureterorenoscopy were included. USSQ scores covering the time 3-5 weeks after stone removal showed a significantly reduced urinary symptoms and pain index compared to the scores before ureterorenoscopy. USSQ results before and after stone removal did not correlate with stone size or operation time and did not differ significantly depending on stone localization, the treating endourologist, or ureterorenoscopic device used (p > 0.05). Six patients (5%) required reintervention. Following secondary ureterorenoscopy and ureteral drainage with a Mono-J for 6 h, quality of life is independent of stone size and localization, operation time, the treating endourologist, and the URS device used.
Project description:Singlet fission is a process that splits collective excitations, or excitons, into two with unity efficiency. This exciton splitting process, unique to molecular photophysics, has the potential to considerably improve the efficiency of optoelectronic devices through more efficient light harvesting. While the first step of singlet fission has been characterized in great detail, subsequent steps critical to achieving overall highly-efficient singlet-to-triplet conversion are only just beginning to become well understood. One of the most elementary suggestions, which has yet to be tested, is that an appropriately balanced coupling is necessary to ensure overall highly efficient singlet fission; that is, the coupling needs to be strong enough so that the first step is fast and efficient, yet weak enough to ensure the independent behavior of the resultant triplets. In this work, we show how high overall singlet-to-triplet conversion efficiencies can be achieved in singlet fission by ensuring that the triplets comprising the triplet pair behave as independently as possible. We show that side chain sterics govern local packing in amorphous pentacene derivative nanoparticles, and that this in turn controls both the rate at which triplet pairs form and the rate at which they decay. We show how compact side chains and stronger couplings promote a triplet pair that effectively couples to the ground state, whereas bulkier side chains promote a triplet pair that appears more like two independent and long-lived triplet excitations. Our results show that the triplet pair is not emissive, that its decay is best viewed as internal conversion rather than triplet-triplet annihilation, and perhaps most critically that, in contrast to a number of recent suggestions, the triplets comprising the initially formed triplet pair cannot be considered independently. This work represents a significant step toward better understanding intermediates in singlet fission, and how molecular packing and couplings govern overall triplet yields.
Project description:RationaleThe last decade has seen a dramatic increase in the application of serial sampling of human dentine in archaeology. Rapid development in the field has provided many improvements in the methodology, in terms of both time resolution as well as the ability to integrate more isotope systems in the analysis. This study provides a comparison of two common sampling approaches, allowing researchers to select the most suitable approach for addressing specific research questions.MethodsTwo common approaches for sequential sampling of human dentine (micro-punches and micro-slices) are compared in terms of viability and efficacy. Using archaeological deciduous second molars and permanent first molars, this study demonstrates how the two approaches capture aspects of the weaning process in different ways. In addition, different aspects related to the extraction protocols, such as the thickness of the central slide and the solubilisation step, are also evaluated.ResultsWhile both approaches show similar intra-tooth isotopic patterns, the micro-punches approach is preferable for research that requires a very fine temporal resolution, while the micro-slices approach is best for research where δ34 S values are needed, or when the samples are poorly preserved. In addition, the solubilisation step has a large effect on collagen yield, and, to a lesser extent, on isotopic compositions. Therefore, it is important to ensure that only samples that have undergone the same pre-treatment protocol are directly compared.ConclusionsWe present the pros and cons of the two micro-sampling approaches and offer possible mitigation strategies to address some of the most important issues related to each approach.
Project description:The transcription factor Grainyhead-like 2 (GRHL2) is a critical transcription factor for epithelial tissues that has been reported to promote cancer growth in some and suppress aspects of cancer progression in other studies. We investigated its role in different breast cancer subtypes. In breast cancer patients, GRHL2 expression was increased in all subtypes and inversely correlated with overall survival in basal-like breast cancer patients. In a large cell line panel, GRHL2 was expressed in luminal and basal A cells, but low or absent in basal B cells. The intersection of ChIP-Seq analysis in 3 luminal and 3 basal A cell lines identified conserved GRHL2 binding sites for both subtypes. A pathway analysis of ChIP-seq data revealed cell-cell junction regulation and epithelial migration as well as epithelial proliferation, as candidate GRHL2-regulated processes and further analysis of hub genes in these pathways showed similar regulatory networks in both subtypes. However, GRHL2 deletion in a luminal cell line caused cell cycle arrest while this was less prominent in a basal A cell line. Conversely, GRHL2 loss triggered enhanced migration in the basal A cells but failed to do so in the luminal cell line. ChIP-Seq and ChIP-qPCR demonstrated GRHL2 binding to CLDN4 and OVOL2 in both subtypes but not to other GRHL2 targets controlling cell-cell adhesion that were previously identified in other cell types, including CDH1 and ZEB1. Nevertheless, E-cadherin protein expression was decreased upon GRHL2 deletion especially in the luminal line and, in agreement with its selectively enhanced migration, only the basal A cell line showed concomitant induction of vimentin and N-cadherin. To address how the balance between growth reduction and aspects of EMT upon loss of GRHL2 affected in vivo behavior, we used a mouse basal A orthotopic transplantation model in which the GRHL2 gene was silenced. This resulted in reduced primary tumor growth and a reduction in number and size of lung colonies, indicating that growth suppression was the predominant consequence of GRHL2 loss. Altogether, these findings point to largely common but also distinct roles for GRHL2 in luminal and basal breast cancers with respect to growth and motility and indicate that, in agreement with its negative association with patient survival, growth suppression is the dominant response to GRHL2 loss.
Project description:The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells by interacting with membrane-bound angiotensin-converting enzyme 2 (ACE2), a vital element in the renin-angiotensin system (RAS), which regulates blood pressure, fluid balance, and cardiovascular functions. We herein evaluate existing evidence for the molecular alterations within the RAS pathway (e.g., ACE2 and angiotensin II) during SARS-CoV-2 infection and subsequent Coronavirus Disease 2019 (COVID-19). This includes reports regarding potential effect of RAS blockade (e.g., ACE inhibitors and angiotensin II receptor blockers) on ACE2 expression and clinical outcomes in patients with co-morbidities commonly treated with these agents. The collective evidence suggests a dual role for ACE2 in COVID-19, depending on the stage of infection and the coexisting diseases in individual patients. This information is further discussed with respect to potential therapeutic strategies targeting RAS for COVID-19 treatment.
Project description:Purpose The identification of abnormalities that are relatively rare within otherwise normal anatomy is a major challenge for deep learning in the semantic segmentation of medical images. The small number of samples of the minority classes in the training data makes the learning of optimal classification challenging, while the more frequently occurring samples of the majority class hamper the generalization of the classification boundary between infrequently occurring target objects and classes. In this paper, we developed a novel generative multi-adversarial network, called Ensemble-GAN, for mitigating this class imbalance problem in the semantic segmentation of abdominal images.Method The Ensemble-GAN framework is composed of a single-generator and a multi-discriminator variant for handling the class imbalance problem to provide a better generalization than existing approaches. The ensemble model aggregates the estimates of multiple models by training from different initializations and losses from various subsets of the training data. The single generator network analyzes the input image as a condition to predict a corresponding semantic segmentation image by use of feedback from the ensemble of discriminator networks. To evaluate the framework, we trained our framework on two public datasets, with different imbalance ratios and imaging modalities: the Chaos 2019 and the LiTS 2017.Result In terms of the F1 score, the accuracies of the semantic segmentation of healthy spleen, liver, and left and right kidneys were 0.93, 0.96, 0.90 and 0.94, respectively. The overall F1 scores for simultaneous segmentation of the lesions and liver were 0.83 and 0.94, respectively.Conclusion The proposed Ensemble-GAN framework demonstrated outstanding performance in the semantic segmentation of medical images in comparison with other approaches on popular abdominal imaging benchmarks. The Ensemble-GAN has the potential to segment abdominal images more accurately than human experts.