RNA-mediated interaction of Cajal bodies and U2 snRNA genes

Cajal bodies (CBs) are nuclear structures involved in RNA metabolism that accumulate high concentrations of small nuclear ribonucleoproteins (snRNPs). Notably, CBs preferentially associate with specific genomic loci in interphase human cells, including several snRNA and histone gene clusters. To uncover functional elements involved in the interaction of genes and CBs, we analyzed the expression and subcellular localization of stably transfected artificial arrays of U2 snRNA genes. Although promoter substitution arrays colocalized with CBs, constructs containing intragenic deletions did not. Additional experiments identified factors within CBs that are important for association with the native U2 genes. Inhibition of nuclear export or targeted degradation of U2 snRNPs caused a marked decrease in the levels of U2 snRNA in CBs and strongly disrupted the interaction with U2 genes. Together, the results illustrate a specific requirement for both the snRNA transcripts as well as the presence of snRNPs (or snRNP proteins) within CBs. Our data thus provide significant insight into the mechanism of CB interaction with snRNA loci, strengthening the putative role for this nuclear suborganelle in snRNP biogenesis

Cholinergic suppression: A postsynaptic mechanism of long-term associative learning

Food avoidance learning in the mollusc Pleurobranchaea entails reduction in the responsiveness of key brain interneurons in the feeding neural circuitry, the paracerebral feeding command interneurons (PCNs), to the neurotransmitter acetylcholine (AcCho). Food stimuli applied to the oral veil of an untrained animal depolarize the PCNs and induce the feeding motor program (FMP). Atropine (a muscarinic cholinergic antagonist) reversibly blocks the food-induced depolarization of the PCNs, implicating AcCho as the neurotransmitter mediating food detection. AcCho applied directly to PCN somata depolarizes them, indicating that the PCN soma membrane contains AcCho receptors and induces the FMP in the isolated central nervous system preparation. The AcCho response of the PCNs is mediated by muscariniclike receptors, since comparable depolarization is induced by muscarinic agonists (acetyl-ß -methylcholine, oxotremorine, pilocarpine), but not nicotine, and blocked by muscarinic antagonists (atropine, trifluoperazine). The nicotinic antagonist hexamethonium, however, blocked the AcCho response in four of six cases. When specimens are trained to suppress feeding behavior using a conventional food-avoidance learning paradigm (conditionally paired food and shock), AcCho applied to PCNs in the same concentration as in untrained animals causes little or no depolarization and does not initiate the FMP. Increasing the concentration of AcCho 10-100 times, however, induces weak PCN depolarization in trained specimens, indicating that learning diminishes but does not fully abolish AcCho responsiveness of the PCNs. This study proposes a cellular mechanism of long-term associative learning -- namely, postsynaptic modulation of neurotransmitter responsiveness in central neurons that could apply also to mammalian species

Association of snRNA genes with coiled bodies is mediated by nascent snRNA transcripts

AbstractBackground: Coiled bodies are nuclear organelles that are highly enriched in small nuclear ribonucleoproteins (snRNPs) and certain basal transcription factors. Surprisingly, coiled bodies not only contain mature U snRNPs but also associate with specific chromosomal loci, including gene clusters that encode U snRNAs and histone messenger RNAs. The mechanism(s) by which coiled bodies associate with these genes is completely unknown.Results: Using stable cell lines, we show that artificial tandem arrays of human U1 and U2 snRNA genes colocalize with coiled bodies and that the frequency of the colocalization depends directly on the transcriptional activity of the array. Association of the genes with coiled bodies was abolished when the artificial U2 arrays contained promoter mutations that prevent transcription or when RNA polymerase II transcription was globally inhibited by α-amanitin. Remarkably, the association was also abolished when the U2 snRNA coding regions were replaced by heterologous sequences.Conclusions: The requirement for the U2 snRNA coding region indicates that association of snRNA genes with coiled bodies is mediated by the nascent U2 RNA itself, not by DNA or DNA-bound proteins. Our data provide the first evidence that association of genes with a nuclear organelle can be directed by an RNA and suggest an autogenous feedback regulation model

Multi-event assessment of typhoon-triggered landslide susceptibility in the Philippines

There is a clear need to improve and update landslide susceptibility models across the Philippines. This is challenging, as landslides in this region are frequently triggered by temporally and spatially disparate typhoon events, and it remains unclear whether such spatially and/or temporally distinct typhoon events cause similar landslide responses, i.e. whether the landslide susceptibility for one typhoon event is similar for another. Here, we use logistic regression to develop four landslide susceptibility models based on three typhoon-triggered landslide inventories for the 2009 Typhoon Parma (local name Typhoon Pepeng), the 2018 Typhoon Mangkhut (local name Typhoon Ompong), and the 2019 Typhoon Kammuri (local name Typhoon Tisoy)

The role of geomorphology, rainfall and soil moisture in the occurrence of landslides triggered by 2018 Typhoon Mangkhut in the Philippines

In 2018 Typhoon Mangkhut (locally known as Typhoon Ompong) triggered thousands of landslides in the Itogon region of the Philippines. A landslide inventory of the affected region is compiled for the first time, comprising 1101 landslides over a 570 km2 area. The inventory is used to study the geomorphological characteristics and land cover more prone to landsliding as well as the hydrometeorological conditions that led to widespread failure. The results showed that landslides mostly occurred on grassland and wooded slopes of clay superficial geology, predominantly facing eastsoutheast. Rainfall (Integrated Multi-satellitE Retrievals for Global Precipitation Measurement, IMERG GPM) associated with Typhoon Mangkhut is compared with 33 highintensity rainfall events that did not trigger regional landslide events in 2018. Results show that landslides occurred during high-intensity rainfall that coincided with the highest soil moisture values (estimated clays saturation point), according to Soil Moisture Active Passive level 4 (SMAP-L4) data. Our results demonstrate the potential of SMAP-L4 and GPM IMERG data for landslide hazard assessment and early warning where ground-based data are scarce. However, other rainfall events in the months leading up to Typhoon Mangkhut that had similar or higher rainfall intensities and also occurred when soils were saturated did not trigger widespread landsliding, highlighting the need for further research into the conditions that trigger landslides in typhoons

Observations and computational multi-phase modelling in tropical river settings show complex channel changes downstream from rainfall-triggered landslides

Alluvial river channels respond to changes in sediment supply by adjusting their geometry. Landslide sediment delivery and geomorphic response of river channels during floods are poorly understood and rarely examined in tropical settings. We investigate the impact of landslides on channel geomorphic changes during an extreme typhoon-induced flood event in the Philippines, specifically the complex geomorphic response of the Antamok River to Typhoon Mangkhut in September 2018, which triggered >500 landslides in the Ambalanga catchment. The catchment has a legacy of anthropogenic modifications, such as extensive small-scale (artisanal) mining and tailings storage facilities (TSFs) from large-scale mining activities. We use a novel mix of mapping and computational modelling approaches to test the hypothesis that landslide sediment delivery is a major control on channel geomorphic change. Pre- and post-event imagery show that the overall active channel area increased by 35.9% and the mean active channel width increased by 9.1 m. Spatially, we find no clear relationship between landslide sediment input or unit stream power and channel width geomorphic change, with longitudinal changes in active channel width complicated by TSFs. Multi-phase modelling using r.avaflow revealed how landslide sediment delivery and TSFs interacted with the flow to generate the observed patterns of channel change. The model simulated channel incision in the upper parts of the catchment (up to 0.78 m) and deposition in the TSFs (up to 1.73 m). Our findings demonstrate that well-established methods (e.g., stream power threshold) fail to fully explain channel width geomorphic changes, particularly for anthropogenically altered catchments. Integrating techniques, such as landslide mapping and multi-phase computational modelling improves understanding of sediment supply's role in channel width change during extreme events. Numerical simulations also demonstrate that conventional assumptions of increased erosion and deposition with rising flow discharge are inaccurate with large sediment input, highlighting instead the effectiveness of multi-phase models

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Lessons from non-canonical splicing

Recent improvements in experimental and computational techniques that are used to study the transcriptome have enabled an unprecedented view of RNA processing, revealing many previously unknown non-canonical splicing events. This includes cryptic events located far from the currently annotated exons and unconventional splicing mechanisms that have important roles in regulating gene expression. These non-canonical splicing events are a major source of newly emerging transcripts during evolution, especially when they involve sequences derived from transposable elements. They are therefore under precise regulation and quality control, which minimizes their potential to disrupt gene expression. We explain how non-canonical splicing can lead to aberrant transcripts that cause many diseases, and also how it can be exploited for new therapeutic strategies

Coiled Bodies Preferentially Associate with U4, U11, and U12 Small Nuclear RNA Genes in Interphase HeLa Cells but Not with U6 and U7 Genes

Coiled bodies (CBs) are nuclear organelles involved in the metabolism of small nuclear RNAs (snRNAs) and histone messages. Their structural morphology and molecular composition have been conserved from plants to animals. CBs preferentially and specifically associate with genes that encode U1, U2, and U3 snRNAs as well as the cell cycle–regulated histone loci. A common link among these previously identified CB-associated genes is that they are either clustered or tandemly repeated in the human genome. In an effort to identify additional loci that associate with CBs, we have isolated and mapped the chromosomal locations of genomic clones corresponding to bona fide U4, U6, U7, U11, and U12 snRNA loci. Unlike the clustered U1 and U2 genes, each of these loci encode a single gene, with the exception of the U4 clone, which contains two genes. We next examined the association of these snRNA genes with CBs and found that they colocalized less frequently than their multicopy counterparts. To differentiate a lower level of preferential association from random colocalization, we developed a theoretical model of random colocalization, which yielded expected values for χ(2) tests against the experimental data. Certain single-copy snRNA genes (U4, U11, and U12) but not controls were found to significantly (p < 0.000001) associate with CBs. Recent evidence indicates that the interactions between CBs and genes are mediated by nascent transcripts. Taken together, these new results suggest that CB association may be substantially augmented by the increased transcriptional capacity of clustered genes. Possible functional roles for the observed interactions of CBs with snRNA genes are discussed

Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group

OBJECTIVE: To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostaglandin E1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome (ARDS). DESIGN: Randomized, prospective, multicenter, double-blind, placebo-controlled, phase III clinical trial. SETTING: Forty-seven community and university-affiliated hospitals in the United States. PATIENTS: A total of 350 patients with ARDS were enrolled in this clinical trial. INTERVENTION: Patients were prospectively randomized in a 1:1 ratio to receive either liposomal prostaglandin E1 or placebo. The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 microg/kg/hr. The dose was increased every 12 hrs until the maximal dose (3.6 microg/kg/hr) was attained or intolerance to further increases developed. Patients received standard aggressive medical/surgical care during the infusion period. OUTCOME MEASURES: The primary outcome measure was the time it took to wean the patient from the ventilator. Secondary end points included time to improvement of the PaO2/FIO2 ratio (defined as first PaO2/FIO2 \u3e 300 mm Hg), day 28 mortality, ventilator dependence at day 8, changes in PaO2/FIO2, incidence of and time to development/resolution of organ failure other than ARDS. RESULTS: A total of 348 patients could be evaluated for efficacy. The distribution of variables at baseline describing gender, lung injury scores, Acute Physiology and Chronic Health Evaluation II scores, PaO2/FIO2, pulmonary compliance, and time from onset of ARDS or from institution of mechanical ventilation to the first dose of study drug was similar among patients in the liposomal prostaglandin E1 (n = 177) and the placebo (n = 171) treatment arms. There was no significant difference in the number of days to the discontinuation of ventilation in the liposomal prostaglandin E1 group compared with the placebo group (median number of days to off mechanical ventilation, 16.9 in patients receiving liposomal prostaglandin E1 and 19.6 in those administered placebo; p = .94). Similarly, mortality at day 28 was not significantly different in the two groups (day 28 mortality, 57 of 176 (32%) in the liposomal prostaglandin E1 group and 50 of 170 (29%) in patients receiving placebo; p = .55). In contrast, treatment with liposomal prostaglandin E1 was associated with a significantly shorter time to reach a PaO2/FIO2 ratio of \u3e300 mm Hg (median number of days to reaching a PaO2/FIO2 ratio \u3e300 mm Hg: 9.8 days in the liposomal prostaglandin E1 group and 13.7 days in patients receiving the placebo; p = .02). Among the subgroups examined, time to off mechanical ventilation was significantly reduced in patients who received at least 85% of a full dose (i.e., \u3e 45.9 microg/kg) of liposomal prostaglandin E1 (median number of days to discontinuation of ventilation, 10.3 in the liposomal prostaglandin E1 group and 16.3 days in patients receiving placebo; p = .05). The overall incidence of serious adverse events was not significantly different in the liposomal prostaglandin E1 (40%) or placebo-treated (37%) groups. Drug-related adverse events of all kinds were reported in 69% of the patients receiving liposomal prostaglandin E1 compared with 33% of the placebo group, with hypotension and hypoxia (occurring in 52% and 24% of the liposomal prostaglandin E1-treated patients, respectively, and 17% and 5% of the placebo-treated patients, respectively) being noted most frequently. CONCLUSIONS: In the intent-to-treat population of patients with ARDS, treatment with liposomal prostaglandin E1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival