Mushroom body-specific profiling of gene expression identifies regulators of long-term memory in Drosophila

Memory formation is achieved by genetically tightly controlled molecular pathways that result in a change of synaptic strength and synapse organization. While for short- term memory traces rapidly acting biochemical pathways are in place, the formation of long-lasting memories requires changes in the transcriptional program of a cell. Although many genes involved in learning and memory formation have been identified, little is known about the genetic mechanisms required for changing the transcriptional program during different phases of long-term memory formation. With Drosophila melanogaster as a model system we profiled transcriptomic changes in the mushroom body, a memory center in the fly brain, at distinct time intervals during long- term memory formation using the targeted DamID technique. We describe the gene expression profiles during these phases and tested 33 selected candidate genes for deficits in long-term memory formation using RNAi knockdown. We identified 10 genes that enhance or decrease memory when knocked-down in the mushroom body. For vajk-1 and hacd1, the two strongest hits, we gained further support for their crucial role in learning and forgetting. These findings show that profiling gene expression changes in specific cell-types harboring memory traces provides a powerful entry point to identify new genes involved in learning and memory. The presented transcriptomic data may further be used as resource to study genes acting at different memory phases

Flaring Up All Over -- Radio Activity in Rapidly-Rotating Late-Type M and L Dwarfs

We present Very Large Array observations of twelve late M and L dwarfs in the Solar neighborhood. The observed sources were chosen to cover a wide range of physical characteristics - spectral type, rotation, age, binarity, and X-ray and H\alpha activity - to determine the role of these properties in the production of radio emission, and hence magnetic fields. Three of the twelve sources, TVLM513-46546, 2MASS J0036159+182110, and BRI0021-0214, were observed to flare and also exhibit persistent emission, indicating that magnetic activity is not quenched at the bottom of the main sequence. The radio emission extends to spectral type L3.5, and there is no apparent decrease in the ratio of flaring luminosities to bolometric luminosities between M8-L3.5. Moreover, contrary to the significant drop in persistent H\alpha activity beyond spectral type M7, the persistent radio activity appears to steadily increase between M3-L3.5. Similarly, the radio emission from BRI0021-0214 violates the phenomenological relations between the radio and X-ray luminosities of coronally active stars, hinting that radio and X-ray activity are also uncorrelated at the bottom of the main sequence. The radio active sources that have measured rotational velocities are rapid rotators, Vsin(i)>30 km/sec, while the upper limits on radio activity in slowly-rotating late M dwarfs (Vsin(i)<10 km/sec) are lower than these detections. These observations provide tantalizing evidence that rapidly-rotating late M and L dwarfs are more likely to be radio active. This possible correlation is puzzling given that the observed radio emission requires sustained magnetic fields of 10-1000 G and densities of 10^12 cm^-3, indicating that the active sources should have slowed down considerably due to magnetic braking.Comment: Accepted to ApJ; Two new figures; Minor text revision

Memory phase-specific genes in the Mushroom Bodies identified using CrebB-target DamID.

The formation of long-term memories requires changes in the transcriptional program and de novo protein synthesis. One of the critical regulators for long-term memory (LTM) formation and maintenance is the transcription factor CREB. Genetic studies have dissected the requirement of CREB activity within memory circuits, however less is known about the genetic mechanisms acting downstream of CREB and how they may contribute defining LTM phases. To better understand the downstream mechanisms, we here used a targeted DamID approach (TaDa). We generated a CREB-Dam fusion protein using the fruit fly Drosophila melanogaster as model. Expressing CREB-Dam in the mushroom bodies (MBs), a brain center implicated in olfactory memory formation, we identified genes that are differentially expressed between paired and unpaired appetitive training paradigm. Of those genes we selected candidates for an RNAi screen in which we identified genes causing increased or decreased LTM

Regulators of Long-Term Memory Revealed by Mushroom Body-Specific Gene Expression Profiling in Drosophila melanogaster

Memory formation is achieved by genetically tightly controlled molecular pathways that result in a change of synaptic strength and synapse organization. While for short- term memory traces, rapidly acting biochemical pathways are in place, the formation of long-lasting memories requires changes in the transcriptional program of a cell. Although many genes involved in learning and memory formation have been identified, little is known about the genetic mechanisms required for changing the transcriptional program during different phases of long-term memory (LTM) formation. With Drosophila melanogaster as a model system, we profiled transcriptomic changes in the mushroom body—a memory center in the fly brain—at distinct time intervals during appetitive olfactory LTM formation using the targeted DamID technique. We describe the gene expression profiles during these phases and tested 33 selected candidate genes for deficits in LTM formation using RNAi knockdown. We identified 10 genes that enhance or decrease memory when knocked-down in the mushroom body. For vajk-1 and hacd1—the two strongest hits—we gained further support for their crucial role in appetitive learning and forgetting. These findings show that profiling gene expression changes in specific cell-types harboring memory traces provides a powerful entry point to identify new genes involved in learning and memory. The presented transcriptomic data may further be used as resource to study genes acting at different memory phases

Chronic Hepatitis C Treatment in Patients with Drug Injection History: Findings of the INTEGRATE Prospective, Observational Study.

INTRODUCTION: People who inject drugs represent an under-treated chronic hepatitis C virus (HCV)-infected patient population. METHODS: INTEGRATE was a prospective, observational study investigating the effectiveness, safety, and adherence in routine clinical practice to telaprevir in combination with peg-interferon and ribavirin (Peg-IFN/RBV) in patients with history of injecting drug use chronically infected with genotype 1 HCV. RESULTS: A total of 46 patients were enrolled and included in the intent-to-treat (ITT) population. Among heroin and/or cocaine users (n = 37; 80%), 22% reported use in the past month; 74% (34/46) of patients were on opioid substitution therapy in the pre-treatment phase, and 43% (20/46) discontinued HCV treatment prematurely. Sustained virologic response rate was 54% (25/46) in the ITT population and 74% (25/34) in the per protocol (evaluable-for-effectiveness) population. The main reason for failure in the ITT analysis was loss to follow-up (n = 8; 17%). Adverse events occurred in 91% (42/46) of patients. Mean patient-reported adherence to study drugs was >89% at Week 4, Week 12 and end of treatment. CONCLUSION: Despite a high rate of treatment discontinuation (including loss to follow-up), self-reported adherence to treatment was good and virologic cure rates were similar to those reported in large real-world cohorts. Our findings suggest that people with a history of injecting drug use should be considered for treatment of chronic HCV infection, and highlight the need for improvements in patient support to boost retention in care and, in turn, help to prevent reinfection and transmission. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT01980290. FUNDING: Janssen Pharmaceuticals

We know DAAs work, so now what?:Simplifying models of care to enhance the hepatitis C cascade

Globally, some 71 million people are chronically infected with hepatitis C virus (HCV). Marginalised populations, particularly people who inject drugs (PWID), have low testing, linkage-to-care and treatment rates for HCV. Several models of care (MoCs) and service delivery interventions have the potential to improve outcomes across the HCV cascade of care, but much of the relevant research was carried out when interferon-based treatment was the standard of care. Often it was not practical to scale up these earlier models and interventions because the clinical care needs of patients taking interferon-based regimens imposed too much of a financial and human resource burden on health systems. Despite the adoption of highly effective, all-oral direct-acting antiviral (DAA) therapies in recent years, approaches to HCV testing and treatment have evolved slowly and often remain rooted in earlier paradigms. The effectiveness of DAAs allows for simpler approaches and has encouraged countries where the drugs are widely available to set their sights on the ambitious World Health Organization (WHO) HCV elimination targets. Since a large proportion of chronically HCV-infected people are not currently accessing treatment, there is an urgent need to identify and implement existing simplified MoCs that speak to specific populations' needs. This article aims to: 1) review the evidence on MoCs for HCV; and 2) distil the findings into recommendations for how stakeholders can simplify the path taken by chronically HCV-infected individuals from testing to cure and subsequent care and monitoring

Erratum: Author Correction: System immunology-based identification of blood transcriptional modules correlating to antibody responses in sheep.

[This corrects the article DOI: 10.1038/s41541-018-0078-0.]

A powerful bursting radio source towards the Galactic Centre

Transient astronomical sources are typically powered by compact objects and usually signify highly explosive or dynamic events. While radio astronomy has an impressive record of obtaining high time resolution observations, usually it is achieved in quite narrow fields-of-view. Consequently, the dynamic radio sky is poorly sampled, in contrast to the situation in the X- and gamma-ray bands in which wide-field instruments routinely detect transient sources. Here we report a new transient source, GCRT J1745-3009, detected in 2002 during a moderately wide-field radio transient monitoring program of the Galactic center (GC) region at 0.33 GHz. The characteristics of its bursts are unlike those known for any other class of radio transient. If located in or near the GC, its brightness temperature (~10^16 K) and the implied energy density within GCRT J1745-3009 vastly exceeds that observed in most other classes of radio astronomical sources, and is consistent with coherent emission processes rarely observed. We conclude that GCRT J1745-3009 is the first member of a new class of radio transient sources, the first of possibly many new classes to be identified through current and upcoming radio surveys.Comment: 16 pages including 3 figures. Appears in Nature, 3 March 200

Survey on solar X-ray flares and associated coherent radio emissions

The radio emission during 201 X-ray selected solar flares was surveyed from 100 MHz to 4 GHz with the Phoenix-2 spectrometer of ETH Zurich. The selection includes all RHESSI flares larger than C5.0 jointly observed from launch until June 30, 2003. Detailed association rates of radio emission during X-ray flares are reported. In the decimeter wavelength range, type III bursts and the genuinely decimetric emissions (pulsations, continua, and narrowband spikes) were found equally frequently. Both occur predominantly in the peak phase of hard X-ray (HXR) emission, but are less in tune with HXRs than the high-frequency continuum exceeding 4 GHz, attributed to gyrosynchrotron radiation. In 10% of the HXR flares, an intense radiation of the above genuine decimetric types followed in the decay phase or later. Classic meter-wave type III bursts are associated in 33% of all HXR flares, but only in 4% they are the exclusive radio emission. Noise storms were the only radio emission in 5% of the HXR flares, some of them with extended duration. Despite the spatial association (same active region), the noise storm variations are found to be only loosely correlated in time with the X-ray flux. In a surprising 17% of the HXR flares, no coherent radio emission was found in the extremely broad band surveyed. The association but loose correlation between HXR and coherent radio emission is interpreted by multiple reconnection sites connected by common field lines.Comment: Solar Physics, in pres

Uranium isotope cycling on the highly productive Peruvian margin

Uranium isotopes (δ238U values) in ancient sedimentary rocks (shales, carbonate rocks) are widely used as a tool to reconstruct paleo-redox conditions, but the behaviour of U isotopes under modern non-sulfidic anoxic vs. oxic conditions remains poorly constrained. We present U concentration and isotope data for modern sediments from the Peruvian margin, a highly productive open ocean environment with a range of redox conditions. To investigate U in different host fractions of the sediment (reactive, silicate, and HNO3-soluble fraction), we conducted a series of sequential extractions. Detrital-corrected authigenic U isotope compositions (δ238Uauth) in sediments deposited beneath an oxic water column show little deviation from the dissolved seawater U source, while anoxically deposited sediments have δ238Uauth values that are up to 0.4‰ heavier compared to seawater δ238U. Under anoxic, non-euxinic conditions, the U isotope offset between sediment and seawater is larger compared with oxic, but significantly smaller when compared with euxinic conditions from the literature. The results from sequential extractions show that the reactive sediment fraction records more pronounced differences in δ238Ureactive than δ238Uauth values depending on the oxidation state of the overlying water column. Furthermore, we found a strong correlation between total organic carbon (TOC) and both U concentrations (Uauth) and δ238Uauth values (R2 = 0.70 and 0.94, respectively) at the persistently anoxic site that we examined. These correlations can be caused by several processes including U isotope fractionation during microbially-mediated U reduction at the sediment-water interface (diffusive U input), during sorption onto and/or incorporation into organic matter in the water column (particulate U input) and diagenetic redistribution of U, or a combination of these processes. Our data show that several factors can influence δ238U values including oxidation state of U, the presence or absence of hydrogen sulfide and organic matter. These findings add new constraints to the degree of U isotope fractionation associated with U incorporation into sediments in different low-oxygen environments, thus aiding in interpretation of ancient paleo-redox conditions from U isotope data