Enlargement of a self-assembled metal–organic rhomboid is achieved via the organic solid state. The solid-state synthesis of an elongated organic ligand was achieved by a template directed 2 + 2 ...photodimerization in a cocrystal. Initial cocrystals obtained of resorcinol template and reactant alkene afforded a 1:2 cocrystal with the alkene in a stacked yet photostable geometry. Cocrystallization performed in the presence of excess template resulted in a 3:2 cocrystal composed of novel discrete 10-component hydrogen-bonded “superassemblies” wherein the alkenes undergo a head-to-head 2 + 2 photodimerization. Isolation and reaction of elongated photoproduct with Cu(II) ions afforded a metal–organic rhomboid of nanoscale dimensions that hosts small molecules in the solid state as guests.
Research funding is an important factor for public science. Funding may affect which research topics get addressed, and what research outputs are produced. However, funding has often been studied ...simplistically, using top-down or system-led perspectives. Such approaches often restrict analysis to confined national funding landscapes or single funding organizations and instruments in isolation. This overlooks interlinkages, broader funding researchers might access, and trends of growing funding complexity. This paper instead frames a 'bottom-up' approach that analytically distinguishes between increasing levels of aggregation of funding instrument co-use. Funding of research outputs is selected as one way to test this approach, with levels traced via funding acknowledgements (FAs) in papers published 2009-18 by researchers affiliated to Denmark, the Netherlands or Norway, in two test research fields (Food Science, Renewable Energy Research). Three funding aggregation levels are delineated: at the bottom, 'funding configurations' of funding instruments co-used by individual researchers (from single-authored papers with two or more FAs); a middle, 'funding amalgamations' level, of instruments co-used by collaborating researchers (from multi-authored papers with two or more FAs); and a 'co-funding network' of instruments co-used across all researchers active in a research field (all papers with two or more FAs). All three levels are found to include heterogenous funding co-use from inside and outside the test countries. There is also co-funding variety in terms of instrument 'type' (public, private, university or non-profit) and 'origin' (domestic, foreign or supranational). Limitations of the approach are noted, as well as its applicability for future analyses not using paper FAs to address finer details of research funding dynamics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease Suntharalingham, Jenifer P., BSc; Buonocore, Federica, PhD; Duncan, Andrew J., PhD ...
Baillière's best practice and research in clinical endocrinology and metabolism/Baillière's best practice & research. Clinical endocrinology & metabolism,
08/2015, Letnik:
29, Številka:
4
Journal Article
Recenzirano
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DAX-1 (NR0B1) and SF-1 (NR5A1) are two nuclear receptor transcription factors that play a key role in human adrenal and reproductive development. Loss of DAX-1 function is classically associated with ...X-linked adrenal hypoplasia congenita. This condition typically affects boys and presents as primary adrenal insufficiency in early infancy or childhood, hypogonadotropic hypogonadism at puberty and impaired spermatogenesis. Late onset forms of this condition and variant phenotypes are increasingly recognized. In contrast, disruption of SF-1 only rarely causes adrenal insufficiency, usually in combination with testicular dysgenesis. Variants in SF-1/ NR5A1 more commonly cause a spectrum of reproductive phenotypes ranging from 46,XY DSD (partial testicular dysgenesis or reduced androgen production) and hypospadias to male factor infertility or primary ovarian insufficiency. Making a specific diagnosis of DAX-1 or SF-1 associated conditions is important for long-term monitoring of endocrine and reproductive function, appropriate genetic counselling for family members, and for providing appropriate informed support for young people.
Limit theorems for the zig-zag process Bierkens, Joris; Duncan, Andrew
Advances in applied probability,
09/2017, Letnik:
49, Številka:
3
Journal Article
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Markov chain Monte Carlo (MCMC) methods provide an essential tool in statistics for sampling from complex probability distributions. While the standard approach to MCMC involves constructing ...discrete-time reversible Markov chains whose transition kernel is obtained via the Metropolis–Hastings algorithm, there has been recent interest in alternative schemes based on piecewise deterministic Markov processes (PDMPs). One such approach is based on the zig-zag process, introduced in Bierkens and Roberts (2016), which proved to provide a highly scalable sampling scheme for sampling in the big data regime; see Bierkens et al. (2016). In this paper we study the performance of the zig-zag sampler, focusing on the one-dimensional case. In particular, we identify conditions under which a central limit theorem holds and characterise the asymptotic variance. Moreover, we study the influence of the switching rate on the diffusivity of the zig-zag process by identifying a diffusion limit as the switching rate tends to ∞. Based on our results we compare the performance of the zig-zag sampler to existing Monte Carlo methods, both analytically and through simulations.
The liver's unique chromosomal variations, including polyploidy and aneuploidy, influence hepatocyte identity and function. Among the most well-studied mammalian polyploid cells, hepatocytes exhibit ...a dynamic interplay between diploid and polyploid states. The ploidy state is dynamic as hepatocytes move through the "ploidy conveyor," undergoing ploidy reversal and re-polyploidization during proliferation. Both diploid and polyploid hepatocytes actively contribute to proliferation, with diploids demonstrating an enhanced proliferative capacity. This enhanced potential positions diploid hepatocytes as primary drivers of liver proliferation in multiple contexts, including homeostasis, regeneration and repopulation, compensatory proliferation following injury, and oncogenic proliferation. This review discusses the influence of ploidy variations on cellular activity. It presents a model for ploidy-associated hepatocyte proliferation, offering a deeper understanding of liver health and disease with the potential to uncover novel treatment approaches.
The liver contains a mixture of hepatocytes with diploid or polyploid (tetraploid, octaploid, etc.) nuclear content. Polyploid hepatocytes are commonly found in adult mammals, representing ~90% of ...the entire hepatic pool in rodents. The cellular and molecular mechanisms that regulate polyploidization have been well characterized; however, it is unclear whether diploid and polyploid hepatocytes function similarly in multiple contexts. Answering this question has been challenging because proliferating hepatocytes can increase or decrease ploidy, and animal models with healthy diploid‐only livers have not been available. Mice lacking E2f7 and E2f8 in the liver (liver‐specific E2f7/E2f8 knockout; LKO) were recently reported to have a polyploidization defect, but were otherwise healthy. Herein, livers from LKO mice were rigorously characterized, demonstrating a 20‐fold increase in diploid hepatocytes and maintenance of the diploid state even after extensive proliferation. Livers from LKO mice maintained normal function, but became highly tumorigenic when challenged with tumor‐promoting stimuli, suggesting that tumors in LKO mice were driven, at least in part, by diploid hepatocytes capable of rapid proliferation. Indeed, hepatocytes from LKO mice proliferate faster and out‐compete control hepatocytes, especially in competitive repopulation studies. In addition, diploid or polyploid hepatocytes from wild‐type (WT) mice were examined to eliminate potentially confounding effects associated with E2f7/E2f8 deficiency. WT diploid cells also showed a proliferative advantage, entering and progressing through the cell cycle faster than polyploid cells, both in vitro and during liver regeneration (LR). Diploid and polyploid hepatocytes responded similarly to hepatic mitogens, indicating that proliferation kinetics are unrelated to differential response to growth stimuli. Conclusion: Diploid hepatocytes proliferate faster than polyploids, suggesting that the polyploid state functions as a growth suppressor to restrict proliferation by the majority of hepatocytes.
Introduction
The diagnosis of psychogenic nonepileptic seizures (PNES) is a common clinical dilemma. We sought to assess the diagnostic value of four ictal signs commonly used in differentiating PNES ...from epileptic seizures (ES).
Methods
We retrospectively reviewed consecutive adult video-electroencephalogram (VEM) studies conducted at a single tertiary epilepsy center between May 2009 and August 2016. Each event was assessed by a blinded rater for the presence of four signs: fluctuating course, head shaking, hip thrusting, and back arching. The final diagnosis of PNES or ES was established for each event based on clinical and VEM characteristics. All ES were pooled regardless of focal or generalized onset. We analyzed the odds ratio of each sign in PNES in comparison to ES with adjustment for repeated measures using logistic regression. Additionally, we calculated the sensitivity, specificity, predictive values, and likelihood ratios of each sign to diagnose PNES.
Results
A total of 742 events from 140 VEM studies were assessed. Fluctuating course (odds ratio (OR) 37.37, 95% confidence interval (CI) 13.56–102.96, P < 0.0001), head shaking (OR 2.95, 95% CI 1.26–6.79, P = 0.012), and hip thrusting (OR 4.28, 95% CI 1.21–15.18, P = 0.02) were each significantly predictive of PNES. Fluctuating course had the highest sensitivity (76.16%). Back arching (OR 1.06, 95% CI 0.35–3.20, P = 0.92) was not significantly associated with PNES.
Conclusion
Fluctuating course, head shaking, and hip thrusting are semiological features significantly more common in PNES than ES. Fluctuating course is the most reliable sign. Back arching does not appear to differentiate PNES from ES.
Mononucleated and binucleated polyploid hepatocytes (4n, 8n, 16n and higher) are found in all mammalian species, but the functional significance of this conserved phenomenon remains unknown. ...Polyploidization occurs through failed cytokinesis, begins at weaning in rodents and increases with age. Previously, we demonstrated that the opposite event, ploidy reversal, also occurs in polyploid hepatocytes generated by artificial cell fusion. This raised the possibility that somatic 'reductive mitoses' can also happen in normal hepatocytes. Here we show that multipolar mitotic spindles form frequently in mouse polyploid hepatocytes and can result in one-step ploidy reversal to generate offspring with halved chromosome content. Proliferating hepatocytes produce a highly diverse population of daughter cells with multiple numerical chromosome imbalances as well as uniparental origins. Our findings support a dynamic model of hepatocyte polyploidization, ploidy reversal and aneuploidy, a phenomenon that we term the 'ploidy conveyor'. We propose that this mechanism evolved to generate genetic diversity and permits adaptation of hepatocytes to xenobiotic or nutritional injury.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Supervised deep learning is used to model the complex relationship between genomic sequence and regulatory function. Understanding how these models make predictions can provide biological insight ...into regulatory functions. Given the complexity of the sequence to regulatory function mapping (the cis-regulatory code), it has been suggested that the genome contains insufficient sequence variation to train models with suitable complexity. Data augmentation is a widely used approach to increase the data variation available for model training, however current data augmentation methods for genomic sequence data are limited.
Inspired by the success of comparative genomics, we show that augmenting genomic sequences with evolutionarily related sequences from other species, which we term phylogenetic augmentation, improves the performance of deep learning models trained on regulatory genomic sequences to predict high-throughput functional assay measurements. Additionally, we show that phylogenetic augmentation can rescue model performance when the training set is down-sampled and permits deep learning on a real-world small dataset, demonstrating that this approach improves data efficiency. Overall, this data augmentation method represents a solution for improving model performance that is applicable to many supervised deep-learning problems in genomics.
The open-source GitHub repository agduncan94/phylogenetic_augmentation_paper includes the code for rerunning the analyses here and recreating the figures.
In high doses zinc may cause copper deficiency, a diagnosis that is often missed resulting in anaemia, neutropenia and irreversible neurological symptoms. The aim of this study was to assess if zinc ...deficiency is erroneously diagnosed by misinterpretation of plasma zinc concentrations and whether copper deficiency is induced in patients prescribed zinc.
Casenotes of 70 patients prescribed zinc were scrutinised. Plasma concentrations of zinc, copper, C reactive protein and albumin were recorded from the laboratory database.
62% of patients were prescribed zinc at doses sufficient to cause copper deficiency. In 48% of the patients, plasma zinc concentrations were low as a probable result of hypoalbuminaemia or the systemic inflammatory response rather than deficiency. Awareness of copper deficiency was lacking; it was only documented as a possible side effect in one patient and plasma copper was measured in only two patients prescribed zinc. 9% of patients developed unexplained anaemia and 7% developed neurological symptoms typical of copper deficiency.
Zinc deficiency is frequently misdiagnosed on the basis of low plasma zinc concentrations. The potential risk of copper deficiency developing in patients prescribed high doses of zinc is apparently infrequently considered. It is probable that a significant minority of patients prescribed with high doses of zinc develop iatrogenic copper deficiency.
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