פרסומים

The hydroclimatology, hydrometeorology, and hydrology of flash floods in the arid/semiarid southwestern United States are examined through empirical analyses of long-term, high-resolution rainfall and stream gauging observations, together with hydrological modeling analyses of the 19 August 2014 storm based on the Kinematic Runoff and Erosion Model (KINEROS2). The analyses presented here are centered on identifying the structure and evolution of flood-producing storms, as well as the interactions of space–time rainfall variability and basin characteristics in determining the upper-tail properties of rainfall and flood magnitudes over this region. This study focuses on four watersheds in Maricopa County, Arizona, with contrasting geomorphological properties. Flash floods over central Arizona are concentrated in both time and space, reflecting controls of the North American monsoon and complex terrain. Thunderstorm systems during the North American monsoon, as represented by the 19 August 2014 storm, are the dominant flood agents that determine the upper tail of flood frequency over central Arizona and that also shape the envelope curve of floods for watersheds smaller than 250 km2. Flood response for the 19 August 2014 storm is associated with storm elements of comparable spatial extent to the drainage area and slow movement for the three compact, headwater watersheds. Flood response for the elongated and relatively flat Skunk Creek highlights the importance of the spatial distribution of rainfall for transmission losses in arid/semiarid watersheds.

The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3-AXL-MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium. In contrast to protein S, the other TAM ligand, which was constitutively expressed postnatally, expression of GAS6 initiated only 3-4 wk after birth. Further analysis revealed that GAS6 expression was induced by the oral microbiota in a myeloid differentiation primary response gene 88 (MyD88)-dependent fashion. Mice lacking GAS6 presented higher levels of inflammatory cytokines, elevated frequencies of neutrophils, and up-regulated activity of enzymes, generating reactive nitrogen species. We also found an imbalance in Th17/Treg ratio known to control tissue homeostasis, as Gas6-deficient dendritic cells preferentially secreted IL-6 and induced Th17 cells. As a result of this immunological shift, a significant microbial dysbiosis was observed in Gas6-/- mice, because anaerobic bacteria largely expanded by using inflammatory byproducts for anaerobic respiration. Using chimeric mice, we found a critical role for GAS6 in epithelial cells in maintaining oral homeostasis, whereas its absence in hematopoietic cells synergized the level of dysbiosis. We thus propose GAS6 as a key immunological regulator of host-commensal interactions in the oral epithelium.

The geomorphic response of channels to base-level fall is an important factor in landscape evolution. To better understand the complex interactions between the factors controlling channel evolution in an emerging continental shelf setting, we use an extensive data set (high-resolution digital elevation models, aerial photographs, and Landsat imagery) of a newly incising, perennial segment of Nahal (Wadi) HaArava, Israel. This channel responds to the rapid and progressive lowering of its base-level, the Dead Sea ( \textgreater 30 m in \~35 years; \~0.5-1.3 m yr -1 ). Progressively evolving longitudinal profiles, channel width, sinuosity, and knickpoint retreat during the last few decades were documented or reconstructed. The results indicate that even under fast base-level fall, rapid delta progradation on top of the shelf and shelf edge can moderate channel mouth slopes and, therefore, largely inhibit channel incision and knickpoint propagation. This channel elongation stage ends when the delta reaches an extended accommodation within the receiving basin and fails to keep the channel mouth slopes as low as the channel bed slopes. Then, processes of incision, narrowing, and meandering begin to shape the channel and expand upstream. When the down-cutting channel encounters a more resistant stratum within the channel substrate, these processes are restricted to a downstream reach by formation of a retreating vertical knickpoint. When the knickpoint and the channel incise to a level below this stratum, a spatially continuous, diffusion-like evolution characterizes the channel’s response and source-to-sink transport can be implemented. These results emphasize the mouth slope and channel substrate resistance as the governing factors over long-term channel evolution, whereas flash floods have only local and short-lived impacts in a confined, continuously incising channel. The documented channel response applies to eustatic base-level fall under steepening basin bathymetry, rapid delta progradation, and lithologic variations in the channel substrate.

There are numerous heritable diseases associated with mutations in the LMNA gene. Most of these laminopathic diseases, including several muscular dystrophies, are autosomal dominant and have tissue-specific phenotypes. Our previous studies have shown that the globally expressed Emery-Dreifuss muscular dystrophy (EDMD)-linked lamin mutation, L535P, disrupts nuclear mechanical response specifically in muscle nuclei of C. elegans leading to atrophy of the body muscle cells and to reduced motility. Here we used RNA sequencing to analyze the global changes in gene expression caused by the L535P EDMD lamin mutation in order to gain better understanding of disease mechanisms and the correlation between transcription and phenotype. Our results show changes in key genes and biological pathways that can help explain the muscle specific phenotypes. In addition, the differential gene expression between wild-type and L535P mutant animals suggests that the pharynx function in the L535P mutant animals is affected by this lamin mutation. Moreover, these transcriptional changes were then correlated with reduced pharynx activity and abnormal pharynx muscle structure. Understanding disease mechanisms will potentially lead to new therapeutic approaches toward curing EDMD.

Clinical studies suggest that key genetic factors involved in stress resilience are related to the innate immune system. In the brain, this system includes microglia cells, which play a major role in stress responsiveness. Consistently, mice with deletion of the CX3CR1 gene (CX3CR1(-/-) mice), which in the brain is expressed exclusively by microglia, exhibit resilience to chronic stress. Here, we compared the emotional, cognitive, neurogenic and microglial responses to chronic unpredictable stress (CUS) between CX3CR1(-/-) and wild type (WT) mice. This was followed by hippocampal whole transcriptome (RNA-seq) analysis. We found that following CUS exposure, WT mice displayed reduced sucrose preference, impaired novel object recognition memory, and reduced neurogenesis, whereas CX3CR1(-/-) mice were completely resistant to these effects of CUS. CX3CR1(-/-) mice were also resilient to the memory-suppressive effect of a short period of unpredictable stress. Microglial somas were larger in CX3CR1(-/-) than in WT, but in both genotypes CUS induced a similar decline in hippocampal microglial density and processes length. RNA sequencing and pathway analysis revealed basal strain differences, particularly reduced expression of interferon (IFN)-regulated and MHC class I gene transcripts in CX3CR1(-/-) mice. Furthermore, while CUS exposure similarly altered neuronal gene transcripts (e.g. Arc, Npas4) in both strains, transcripts downstream of hippocampal estrogen receptor signaling (particularly Igf2 and Igfbp2) were altered only in CX3CR1(-/-) mice. These findings indicate that emotional and cognitive stress resilience involves CX3CR1-dependent basal and stress-induced alterations in hippocampal transcription, implicating inhibition of CX3CR1 signaling as a novel approach for promoting stress resilience.

Histone variants and their chaperones are key regulators of eukaryotic transcription, and are critical for normal development. The histone variant H3.3 has been shown to play important roles in pluripotency and differentiation, and although its genome-wide patterns have been investigated, little is known about the role of its dynamic turnover in transcriptional regulation. To elucidate the role of H3.3 dynamics in embryonic stem cell (ESC) biology, we generated mouse ESC lines carrying a single copy of a doxycycline (Dox)-inducible HA-tagged version of H3.3 and monitored the rate of H3.3 incorporation by ChIP-seq at varying time points following Dox induction, before and after RA-induced differentiation. Comparing H3.3 turnover profiles in ESCs and RA-treated cells, we identified a hyperdynamic H3.3-containing nucleosome at the −1 position in promoters of genes expressed in ESCs. This dynamic nucleosome is restricted and shifted downstream into the +1 position following differentiation. We suggest that histone turnover dynamics provides an additional mechanism involved in expression regulation, and that a hyperdynamic −1 nucleosome marks promoters in ESCs. Our data provide evidence for regional regulation of H3.3 turnover in ESC promoters, and calls for testing, in high resolution, the dynamic behavior of additional histone variants and other structural chromatin proteins.

Background: Mood disorders are dynamic disorders characterized by multimodal symptoms. Clinical assessment of symptoms is currently limited to relatively sparse, routine clinic visits, requiring retrospective recollection of symptoms present in the weeks preceding the visit. Novel advances in mobile tools now support ecological momentary assessment of mood, conducted frequently using mobile devices, outside the clinical setting. Such mood assessment may help circumvent problems associated with infrequent reporting and better characterize the dynamic presentation of mood symptoms, informing the delivery of novel treatment options. Objectives: The aim of our study was to validate the Immediate Mood Scaler (IMS), a newly developed, iPad-deliverable 22-item self-report tool designed to capture current mood states. Methods: A total of 110 individuals completed standardized questionnaires (Patient Health Questionnaire, 9-item [PHQ-9]; generalized anxiety disorder, 7-Item [GAD-7]; and rumina

Myeloid differentiation factor 88 (MyD88) recruits signaling proteins to the intracellular domain of receptors belonging to the toll-like/interleukin-1 (IL-1) receptor superfamily. Mice lacking MyD88 are highly susceptible to infectious diseases, but tend to resist experimentally induced autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE) and manifest diminished allograft rejection. We reasoned that inhibition of MyD88 should influence the cytokine profile of responding T cells by blocking costimulatory molecule expression by antigen-presenting cells (APCs) and by inhibiting T-cell responses to IL-18. We now report that inhibition of MyD88 in human APCs led to decreased IFNγ and IL-17 production and a shift to IL-4 production by responding T cells in a mixed lymphocyte reaction. Direct inhibition of Myd88 in mouse and human T cells also reduced their production of IFNγ in response to IL-12/IL-18 stimulation. Finally, systemic MyD88 antagonism significantly reduced the clinical manifestations of EAE in mice. Thus, MyD88 appears to be a key factor in determining T cell phenotype and represents a potential target for therapeutic intervention.

Intensity–duration–frequency (IDF) curves are widely used to quantify the probability of occurrence of rainfall extremes. The usual rain gauge-based approach provides accurate curves for a specific location, but uncertainties arise when ungauged regions are examined or catchment-scale information is required. Remote sensing rainfall records, e.g. from weather radars and satellites, are recently becoming available, providing high-resolution estimates at regional or even global scales; their uncertainty and implications on water resources applications urge to be investigated. This study compares IDF curves from radar and satellite (CMORPH) estimates over the eastern Mediterranean (covering Mediterranean, semiarid, and arid climates) and quantifies the uncertainty related to their limited record on varying climates. We show that radar identifies thicker-tailed distributions than satellite, in particular for short durations, and that the tail of the distributions depends on the spatial and temporal aggregation scales. The spatial correlation between radar IDF and satellite IDF is as high as 0.7 for 2–5-year return period and decreases with longer return periods, especially for short durations. The uncertainty related to the use of short records is important when the record length is comparable to the return period ( \~ 50, \~ 100, and \~ 150 % for Mediterranean, semiarid, and arid climates, respectively). The agreement between IDF curves derived from different sensors on Mediterranean and, to a good extent, semiarid climates, demonstrates the potential of remote sensing datasets and instils confidence on their quantitative use for ungauged areas of the Earth.

Hans Baron, Karl Popper, Leo Strauss and Erich Auerbach were among the many German-speaking Jewish intellectuals who fled Continental Europe with the rise of Nazism in the 1930s. Their scholarship, though not normally considered together, is studied here to demonstrate how, despite their different disciplines and distinctive modes of working, they responded polemically in the guise of traditional scholarship to their shared trauma. For each, the political calamity of European fascism was a profound intellectual crisis, requiring an intellectual response which Weinstein and Zakai now contextualize, ideologically and politically. They exemplify just how extensively, and sometimes how subtly, 1930s and 1940s scholarship was used not only to explain, but to fight the political evils that had infected modernity, victimizing so many. An original perspective on a popular area of research, this book draws upon a mass of secondary literature to provide an innovative and valuable contribution to twentieth-century intellectual history. – Publisher’s description

Several long noncoding RNAs (lncRNA) are abrogated in cancer but their precise contributions to oncogenesis are still emerging. Here we report that the lncRNA MALAT1 is upregulated in hepatocellular carcinoma and acts as a proto-oncogene through Wnt pathway activation and induction of the oncogenic splicing factor SRSF1. Induction of SRSF1 by MALAT1 modulates SRSF1 splicing targets, enhancing the production of antiapoptotic splicing isoforms and activating the mTOR pathway by modulating the alternative splicing of S6K1. Inhibition of SRSF1 expression or mTOR activity abolishes the oncogenic properties of MALAT1, suggesting that SRSF1 induction and mTOR activation are essential for MALAT1-induced transformation. Our results reveal a mechanism by which lncRNA MALAT1 acts as a proto-oncogene in hepatocellular carcinoma, modulating oncogenic alternative splicing through SRSF1 upregulation. Cancer Res; 77(5); 1155-67. ©2016 AACR.

Hematopoietic stem cells (HSCs) are rare cells that generate all the various types of blood and immune cells. High-quality transcriptome data have enabled the identification of significant genes for HSCs. However, most genes are expressed in various forms by alternative splicing (AS), extending transcriptome complexity. Here, we delineate AS to determine which isoforms are expressed in mouse HSCs. Our analysis of microarray and RNA-sequencing data includes differential expression of splicing factors that may regulate AS, and a complete map of splicing isoforms. Multiple types of isoforms for known HSC genes and unannotated splicing that may alter gene function are presented. Transcriptome-wide identification of genes and their respective isoforms in mouse HSCs will open another dimension for adult stem cells.

BACKGROUND & AIMS: Effective treatments are needed for hepatic steatosis characterized by accumulation of triglycerides in hepatocytes, which leads to hepatocellular carcinoma. MicroRNA 122 (MIR122) is expressed only in the liver, where it regulates lipid metabolism. We investigated the mechanism by which free fatty acids (FFAs) regulate MIR122 expression and the effect of MIR122 on triglyceride synthesis. METHODS: We analyzed MIR122 promoter activity and validated its target mRNAs by transfection of Luciferase reporter plasmids into Huh7, BNL-1ME, and HEK293 cultured cell lines. We measured levels of microRNAs and mRNAs by quantitative real-time PCR analysis of RNA extracted from plasma, liver, muscle, and adipose tissues of C57BL/6 mice given the FFA-inducer CL316243. MIR122 was inhibited using an inhibitor of MIR122. Metabolic profiles of mice were determined using metabolic chambers and by histologic analyses of liver tissues. We performed RNA sequence analyses to identify metabolic pathways involving MIR122. RESULTS: We validated human Agpat1 and Dgat1 mRNAs, involved in triglyceride synthesis, as targets of MIR122. FFAs increased MIR122 expression in livers of mice by activating the retinoic acid-related orphan receptor alpha, and induced secretion of MIR122 from liver to blood. Circulating MIR122 entered muscle and adipose tissues of mice, reducing mRNA levels of genes involved in triglyceride synthesis. Mice injected with an inhibitor of MIR122 and then given CL316243, accumulated triglycerides in liver and muscle tissues, and had reduced rates of beta-oxidation. There was a positive correlation between level of FFAs and level of MIR122 in plasma samples from 6 healthy individuals, collected before and during fasting. CONCLUSIONS: In biochemical and histologic studies of plasma, liver, muscle, and adipose tissues from mice, we found that FFAs increase hepatic expression and secretion of MIR122, which regulates energy storage vs expenditure in liver and peripheral tissues. Strategies to reduce triglyceride levels, by increasing MIR122, might be developed for treatment of metabolic syndrome.

Previous studies have indicated that obsessive-compulsive disorder (OCD) might have a reduced placebo response compared to other anxiety-related disorders including generalized anxiety disorder, panic disorder, post-traumatic stress disorder, and social anxiety disorder. No previous analysis has directly compared antidepressant and placebo responses between OCD and these conditions.