Jumps in current-voltage characteristics in disordered films

We argue that giant jumps of current at finite voltages observed in disordered samples of InO, TiN and YSi manifest a bistability caused by the overheating of electrons. One of the stable states is overheated and thus low-resistive, while the other, high-resistive state is heated much less by the same voltage. The bistability occurs provided that cooling of electrons is inefficient and the temperature dependence of the equilibrium resistance, R(T), is steep enough. We use experimental R(T) and assume phonon mechanism of the cooling taking into account its strong suppression by disorder. Our description of details of the I-V characteristics does not involve adjustable parameters and turns out to be in a quantitative agreement with the experiments. We propose experiments for more direct checks of this physical picture.Comment: Final version, as published; 4 pages, 3 figure

Unifying Parsimonious Tree Reconciliation

Evolution is a process that is influenced by various environmental factors, e.g. the interactions between different species, genes, and biogeographical properties. Hence, it is interesting to study the combined evolutionary history of multiple species, their genes, and the environment they live in. A common approach to address this research problem is to describe each individual evolution as a phylogenetic tree and construct a tree reconciliation which is parsimonious with respect to a given event model. Unfortunately, most of the previous approaches are designed only either for host-parasite systems, for gene tree/species tree reconciliation, or biogeography. Hence, a method is desirable, which addresses the general problem of mapping phylogenetic trees and covering all varieties of coevolving systems, including e.g., predator-prey and symbiotic relationships. To overcome this gap, we introduce a generalized cophylogenetic event model considering the combinatorial complete set of local coevolutionary events. We give a dynamic programming based heuristic for solving the maximum parsimony reconciliation problem in time O(n^2), for two phylogenies each with at most n leaves. Furthermore, we present an exact branch-and-bound algorithm which uses the results from the dynamic programming heuristic for discarding partial reconciliations. The approach has been implemented as a Java application which is freely available from http://pacosy.informatik.uni-leipzig.de/coresym.Comment: Peer-reviewed and presented as part of the 13th Workshop on Algorithms in Bioinformatics (WABI2013

Beyond representing orthology relations by trees

Reconstructing the evolutionary past of a family of genes is an important aspect of many genomic studies. To help with this, simple relations on a set of sequences called orthology relations may be employed. In addition to being interesting from a practical point of view they are also attractive from a theoretical perspective in that e.\,g.\,a characterization is known for when such a relation is representable by a certain type of phylogenetic tree. For an orthology relation inferred from real biological data it is however generally too much to hope for that it satisfies that characterization. Rather than trying to correct the data in some way or another which has its own drawbacks, as an alternative, we propose to represent an orthology relation $\delta$ in terms of a structure more general than a phylogenetic tree called a phylogenetic network. To compute such a network in the form of a level-1 representation for $\delta$, we formalize an orthology relation in terms of the novel concept of a symbolic 3- dissimilarity which is motivated by the biological concept of a ``cluster of orthologous groups'', or COG for short. For such maps which assign symbols rather that real values to elements, we introduce the novel {\sc Network-Popping} algorithm which has several attractive properties. In addition, we characterize an orthology relation $\delta$ on some set $X$ that has a level-1 representation in terms of eight natural properties for $\delta$ as well as in terms of level-1 representations of orthology relations on certain subsets of $X$

Reconciliation Revisited: Handling Multiple Optima when Reconciling with Duplication, Transfer, and Loss

Phylogenetic tree reconciliation is a powerful approach for inferring evolutionary events like gene duplication, horizontal gene transfer, and gene loss, which are fundamental to our understanding of molecular evolution. While duplication–loss (DL) reconciliation leads to a unique maximum-parsimony solution, duplication-transfer-loss (DTL) reconciliation yields a multitude of optimal solutions, making it difficult to infer the true evolutionary history of the gene family. This problem is further exacerbated by the fact that different event cost assignments yield different sets of optimal reconciliations. Here, we present an effective, efficient, and scalable method for dealing with these fundamental problems in DTL reconciliation. Our approach works by sampling the space of optimal reconciliations uniformly at random and aggregating the results. We show that even gene trees with only a few dozen genes often have millions of optimal reconciliations and present an algorithm to efficiently sample the space of optimal reconciliations uniformly at random in O(mn[superscript 2]) time per sample, where m and n denote the number of genes and species, respectively. We use these samples to understand how different optimal reconciliations vary in their node mappings and event assignments and to investigate the impact of varying event costs. We apply our method to a biological dataset of approximately 4700 gene trees from 100 taxa and observe that 93% of event assignments and 73% of mappings remain consistent across different multiple optima. Our analysis represents the first systematic investigation of the space of optimal DTL reconciliations and has many important implications for the study of gene family evolution.National Science Foundation (U.S.) (CAREER Award 0644282)National Institutes of Health (U.S.) (Grant RC2 HG005639)National Science Foundation (U.S.). Assembling the Tree of Life (Program) (Grant 0936234

Targeting of prion-infected lymphoid cells to the central nervous system accelerates prion infection

BACKGROUND: Prions, composed of a misfolded protein designated PrP(Sc), are infectious agents causing fatal neurodegenerative diseases. We have shown previously that, following induction of experimental autoimmune encephalomyelitis, prion-infected mice succumb to disease significantly earlier than controls, concomitant with the deposition of PrP(Sc) aggregates in inflamed white matter areas. In the present work, we asked whether prion disease acceleration by experimental autoimmune encephalomyelitis results from infiltration of viable prion-infected immune cells into the central nervous system. METHODS: C57Bl/6 J mice underwent intraperitoneal inoculation with scrapie brain homogenates and were later induced with experimental autoimmune encephalomyelitis by inoculation of MOG(35-55) in complete Freund's adjuvant supplemented with pertussis toxin. Spleen and lymph node cells from the co-induced animals were reactivated and subsequently injected into naïve mice as viable cells or as cell homogenates. Control groups were infected with viable and homogenized scrapie immune cells only with complete Freund's adjuvant. Prion disease incubation times as well as levels and sites of PrP(Sc) deposition were next evaluated. RESULTS: We first show that acceleration of prion disease by experimental autoimmune encephalomyelitis requires the presence of high levels of spleen PrP(Sc). Next, we present evidence that mice infected with activated prion-experimental autoimmune encephalomyelitis viable cells succumb to prion disease considerably faster than do mice infected with equivalent cell extracts or other controls, concomitant with the deposition of PrP(Sc) aggregates in white matter areas in brains and spinal cords. CONCLUSIONS: Our results indicate that inflammatory targeting of viable prion-infected immune cells to the central nervous system accelerates prion disease propagation. We also show that in the absence of such targeting it is the load of PrP(Sc) in the inoculum that determines the infectivity titers for subsequent transmissions. Both of these conclusions have important clinical implications as related to the risk of prion disease contamination of blood products

Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a systematic review and individual participant data meta-analysis

Background Ursodeoxycholic acid is commonly used to treat intrahepatic cholestasis of pregnancy, yet its largest trial detected minimal benefit for a composite outcome (stillbirth, preterm birth, and neonatal unit admission). We aimed to examine whether ursodeoxycholic acid affects specific adverse perinatal outcomes. Methods In this systematic review and individual participant data meta-analysis, we searched PubMed, Web of Science, Embase, MEDLINE, CINAHL, Global Health, MIDIRS, and Cochrane without language restrictions for relevant articles published between database inception, and Jan 1, 2020, using search terms referencing intrahepatic cholestasis of pregnancy, ursodeoxycholic acid, and perinatal outcomes. Eligible studies had 30 or more study participants and reported on at least one individual with intrahepatic cholestasis of pregnancy and bile acid concentrations of 40 μmol/L or more. We also included two unpublished cohort studies. Individual participant data were collected from the authors of selected studies. The primary outcome was the prevalence of stillbirth, for which we anticipated there would be insufficient data to achieve statistical power. Therefore, we included a composite of stillbirth and preterm birth as a main secondary outcome. A mixed-effects meta-analysis was done using multi-level modelling and adjusting for bile acid concentration, parity, and multifetal pregnancy. Individual participant data analyses were done for all studies and in different subgroups, which were produced by limiting analyses to randomised controlled trials only, singleton pregnancies only, or two-arm studies only. This study is registered with PROSPERO, CRD42019131495. Findings The authors of the 85 studies fulfilling our inclusion criteria were contacted. Individual participant data from 6974 women in 34 studies were included in the meta-analysis, of whom 4726 (67·8%) took ursodeoxycholic acid. Stillbirth occurred in 35 (0·7%) of 5097 fetuses among women with intrahepatic cholestasis of pregnancy treated with ursodeoxycholic acid and in 12 (0·6%) of 2038 fetuses among women with intrahepatic cholestasis of pregnancy not treated with ursodeoxycholic acid (adjusted odds ratio [aOR] 1·04, 95% CI 0·35–3·07; p=0·95). Ursodeoxycholic acid treatment also had no effect on the prevalence of stillbirth when considering only randomised controlled trials (aOR 0·29, 95% CI 0·04–2·42; p=0·25). Ursodeoxycholic acid treatment had no effect on the prevalence of the composite outcome in all studies (aOR 1·28, 95% CI 0·86–1·91; p=0·22), but was associated with a reduced composite outcome when considering only randomised controlled trials (0·60, 0·39–0·91; p=0·016). Interpretation Ursodeoxycholic acid treatment had no significant effect on the prevalence of stillbirth in women with intrahepatic cholestasis of pregnancy, but our analysis was probably limited by the low overall event rate. However, when considering only randomised controlled trials, ursodeoxycholic acid was associated with a reduction in stillbirth in combination with preterm birth, providing evidence for the clinical benefit of antenatal ursodeoxycholic acid treatment.Caroline Ovadia, Jenna Sajous, Paul T Seed, Kajol Patel, Nicholas J Williamson, George Attilakos, Francesco Azzaroli, Yannick Bacq, Linoy Batsry, Kelsey Broom, Romana Brun-Furrer, Laura Bull, Jenny Chambers, Yue Cui, Min Ding, Peter H Dixon, Maria C Estiú, Fergus W Gardiner, Victoria Geenes, Monika Grymowicz, Berrin Günaydin, William M Hague, Christian Haslinger, Yayi Hu, Ugo Indraccolo, Alexander Juusela, Stefan C Kane, Ayse Kebapcilar, Levent Kebapcilar, Katherine Kohari, Jūratė Kondrackienė, Maria P H Koster, Richard H Lee, Xiaohua Liu, Anna Locatelli, Rocio I R Macias, Riza Madazli, Agata Majewska, Kasia Maksym, Jessica A Marathe, Adam Morton, Martijn A Oudijk, Deniz Öztekin, Michael J Peek, Andrew H Shennan, Rachel M Tribe, Valeria Tripodi, Naciye Türk Özterlemez, Tharni Vasavan, L F Audris Wong, Yoav Yinon, Qianwen Zhang, Keren Zloto, Hanns-Ulrich Marschall, Jim Thornton, Lucy C Chappell, Catherine Williamso

Localization of preformed Cooper pairs in disordered superconductors

International audienceThe most profound effect of disorder on electronic systems is the localization of the electrons transforming an otherwise metallic system into an insulator. If the metal is also a superconductor then, at low temperatures, disorder can induce a pronounced transition from a superconducting into an insulating state. An outstanding question is whether the route to insulating behaviour proceeds through the direct localization of Cooper pairs or, alternatively, by a two-step process in which the Cooper pairing is first destroyed followed by the standard localization of single electrons. Here we address this question by studying the local superconducting gap of a highly disordered amorphous superconductor by means of scanning tunnelling spectroscopy. Our measurements reveal that, in the vicinity of the superconductor-insulator transition, the coherence peaks in the one-particle density of states disappear whereas the superconducting gap remains intact, indicating the presence of localized Cooper pairs. Our results provide the first direct evidence that the superconductor-insulator transition in some homogeneously disordered materials is driven by Cooper-pair localization

Reduction in Inter-Hemispheric Connectivity in Disorders of Consciousness

Clinical diagnosis of disorders of consciousness (DOC) caused by brain injury poses great challenges since patients are often behaviorally unresponsive. A promising new approach towards objective DOC diagnosis may be offered by the analysis of ultra-slow (<0.1 Hz) spontaneous brain activity fluctuations measured with functional magnetic resonance imaging (fMRI) during the resting-state. Previous work has shown reduced functional connectivity within the “default network”, a subset of regions known to be deactivated during engaging tasks, which correlated with the degree of consciousness impairment. However, it remains unclear whether the breakdown of connectivity is restricted to the “default network”, and to what degree changes in functional connectivity can be observed at the single subject level. Here, we analyzed resting-state inter-hemispheric connectivity in three homotopic regions of interest, which could reliably be identified based on distinct anatomical landmarks, and were part of the “Extrinsic” (externally oriented, task positive) network (pre- and postcentral gyrus, and intraparietal sulcus). Resting-state fMRI data were acquired for a group of 11 healthy subjects and 8 DOC patients. At the group level, our results indicate decreased inter-hemispheric functional connectivity in subjects with impaired awareness as compared to subjects with intact awareness. Individual connectivity scores significantly correlated with the degree of consciousness. Furthermore, a single-case statistic indicated a significant deviation from the healthy sample in 5/8 patients. Importantly, of the three patients whose connectivity indices were comparable to the healthy sample, one was diagnosed as locked-in. Taken together, our results further highlight the clinical potential of resting-state connectivity analysis and might guide the way towards a connectivity measure complementing existing DOC diagnosis

Orally Administrated Cinnamon Extract Reduces β-Amyloid Oligomerization and Corrects Cognitive Impairment in Alzheimer's Disease Animal Models

An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of β-amyloid polypeptide (Aβ) play a key role in Alzheimer's disease (AD) pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Aβ plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Aβ oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt), which markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Aβ oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Aβ species formation in AD through the utilization of a compound that is currently in use in human diet