Freeze-in, glaciation, and UV sensitivity from light mediators

Dark matter (DM) freeze-in through a light mediator is an appealing model with excellent detection prospects at current and future experiments. Light mediator freeze-in is UV-insensitive insofar as most DM is produced at late times, and thus the DM abundance does not depend on the unknown early evolution of our universe. However the final DM yield retains a dependence on the initial DM population, which is usually assumed to be exactly zero. We point out that in models with light mediators, the final DM yield will also depend on the initial conditions assumed for the light mediator population. We describe a class of scenarios we call "glaciation" where DM freezing in from the SM encounters a pre-existing thermal bath of mediators, and study the dependence of the final DM yield on the initial temperature of this dark radiation bath. To compute DM scattering rates in this cosmology, we derive for the first time an exact integral expression for the Boltzmann collision term describing interactions between two species at different temperatures. We quantify the dependence of the DM yield on the initial dark temperature and find that it can be sizeable in regions near the traditional (zero initial abundance) freeze-in curve. We generalize the freeze-in curve to a glaciation band, which can extend as much as an order of magnitude below the traditional freeze-in direct detection target, and point out that the DM phase space distribution as well as the yield can be strongly dependent on initial conditions.Comment: 31 pages, 5 figure

Stochastic Gravitational Waves from Early Structure Formation

Early matter-dominated eras (EMDEs) are a natural feature arising in many models of the early universe and can generate a stochastic gravitational wave background (SGWB) during the transition from an EMDE to the radiation-dominated universe required by the time of Big Bang Nucleosynthesis. While there are calculations of the SGWB generated in the linear regime, no detailed study has been made of the nonlinear regime. We perform the first comprehensive calculation of GW production in the nonlinear regime, using a hybrid $N$-body and lattice simulation to study GW production from both a metastable matter species and the radiation produced in its decay. We find that nonlinearities significantly enhance GW production up to frequencies at least as large as the inverse light-crossing time of the largest halos that form prior to reheating. The resulting SGWB is within future observational reach for curvature perturbations as small as those probed in the cosmic microwave background, depending on the reheating temperature. Out-of-equilibrium dynamics could further boost the induced SGWB, while a fully relativistic gravitational treatment is required to resolve the spectrum at even higher frequencies.Comment: 7+10 pages, 3+2 figure

Principles of Carbon Catabolite Repression in the Rice Blast Fungus: Tps1, Nmr1-3, and a MATE–Family Pump Regulate Glucose Metabolism during Infection

Understanding the genetic pathways that regulate how pathogenic fungi respond to their environment is paramount to developing effective mitigation strategies against disease. Carbon catabolite repression (CCR) is a global regulatory mechanism found in a wide range of microbial organisms that ensures the preferential utilization of glucose over less favourable carbon sources, but little is known about the components of CCR in filamentous fungi. Here we report three new mediators of CCR in the devastating rice blast fungus Magnaporthe oryzae: the sugar sensor Tps1, the Nmr1-3 inhibitor proteins, and the multidrug and toxin extrusion (MATE)–family pump, Mdt1. Using simple plate tests coupled with transcriptional analysis, we show that Tps1, in response to glucose-6-phosphate sensing, triggers CCR via the inactivation of Nmr1-3. In addition, by dissecting the CCR pathway using Agrobacterium tumefaciens-mediated mutagenesis, we also show that Mdt1 is an additional and previously unknown regulator of glucose metabolism. Mdt1 regulates glucose assimilation downstream of Tps1 and is necessary for nutrient utilization, sporulation, and pathogenicity. This is the first functional characterization of a MATE–family protein in filamentous fungi and the first description of a MATE protein in genetic regulation or plant pathogenicity. Perturbing CCR in Δtps1 and MDT1 disruption strains thus results in physiological defects that impact pathogenesis, possibly through the early expression of cell wall–degrading enzymes. Taken together, the importance of discovering three new regulators of carbon metabolism lies in understanding how M. oryzae and other pathogenic fungi respond to nutrient availability and control development during infection

Plant defense suppression is mediated by a fungal sirtuin during rice infection by \u3ci\u3eMagnaporthe oryzae\u3c/i\u3e

Crop destruction by the hemibiotrophic rice pathogen Magnaporthe oryzae requires plant defense suppression to facilitate extensive biotrophic growth in host cells before the onset of necrosis. How this is achieved at the genetic level is not well understood. Here, we report that a M. oryzae sirtuin, MoSir2, plays an essential role in rice defense suppression and colonization by controlling superoxide dismutase (SOD) gene expression. Loss of MoSir2 function in Δsir2 strains did not affect appressorial function, but biotrophic growth in rice cells was attenuated. Compared to wild type, Δsir2 strains failed to neutralize plant-derived reactive oxygen species (ROS) and elicited robust defense responses in rice epidermal cells that included elevated pathogenesis-related gene expression and granular depositions. Deletion of a SOD-encoding gene under MoSir2 control generated Δsod1 deletion strains that mimicked Δsir2 for impaired rice defense suppression, confirming SOD activity as a downstream output of MoSir2. In addition, comparative protein acetylation studies and forward genetic analyses identified a JmjC domain-containing protein as a likely target of MoSir2, and a Δsir2 Δjmjc double mutant was restored for MoSOD1 expression and defense suppression in rice epidermal cells. Together, this work reveals MoSir2 and MoJmjC as novel regulators of early rice cell infection

Towards Defining Nutrient Conditions Encountered by the Rice Blast Fungus during Host Infection

Fungal diseases cause enormous crop losses, but defining the nutrient conditions encountered by the pathogen remains elusive. Here, we generated a mutant strain of the devastating rice pathogen Magnaporthe oryzae impaired for de novo methionine biosynthesis. The resulting methionine-requiring strain grew strongly on synthetic minimal media supplemented with methionine, aspartate or complex mixtures of partially digested proteins, but could not establish disease in rice leaves. Live-cell-imaging showed the mutant could produce normal appressoria and enter host cells but failed to develop, indicating the availability or accessibility of aspartate and methionine is limited in the plant. This is the first report to demonstrate the utility of combining biochemical genetics, plate growth tests and live-cell-imaging to indicate what nutrients might not be readily available to the fungal pathogen in rice host cells

Exploring challenges in Giardia cyst visualisation by common microscopy methods

Giardia spp. is an intestinal parasite responsible for worldwide disease outbreaks. Guiding researchers and practitioners to choose among current methods for microscopy detection of the infectious forms may be directly beneficial to public health and the environment. This study provides an overall comparison of brightfield (BF), fluorescence and darkfield (DF) microscopies for detecting Giardia duodenalis and Giardia muris cysts, by illustrating micrographs of such protocols applied to purified samples, as well as discussing advantages and constraints based on secondary information and collected data. BF analysis included Lugol's iodine staining. In fluorescence microscopy, samples were processed by immunofluorescence assay (IFA) with DAPI and by standalone DAPI dye. Cyst suspensions were also analysed by DF microscopy using a recently developed low-cost system. The three techniques enabled detecting Giardia spp. cysts, although they did not provide species identification by morphology. The overview of each method points out some relevant aspects to consider when selecting common optical microscopy techniques, and includes challenges and advantages regarding each of them. HIGHLIGHTS Comparisons of BF, DF, standalone DAPI and IFA-combined are provided.; BF and DF may be alternatives for low-cost detection of Giardia cysts.; Combinations of at least two diagnostic methods are recommended to minimise inherent errors.

Characterization of the High-Albedo NEA 3691 Bede

Characterization of NEAs provides important inputs to models for atmospheric entry, risk assessment and mitigation. Diameter is a key parameter because diameter translates to kinetic energy in atmospheric entry. Diameters can be derived from the absolute magnitude, H(PA=0deg), and from thermal modeling of observed IR fluxes. For both methods, the albedo (pv) is important - high pv surfaces have cooler temperatures, larger diameters for a given Hmag, and shallower phase curves (larger slope parameter G). Thermal model parameters are coupled, however, so that a higher thermal inertia also results in a cooler surface temperature. Multiple parameters contribute to constraining the diameter. Observations made at multiple observing geometries can contribute to understanding the relationships between and potentially breaking some of the degeneracies between parameters. We present data and analyses on NEA 3691 Bede with the aim of best constraining the diameter and pv from a combination of thermal modeling and light curve analyses. We employ our UKIRT+Michelle mid-IR photometric observations of 3691 Bede's thermal emission at 2 phase angles (27&43 deg 2015-03-19 & 04-13), in addition to WISE data (33deg 2010-05-27, Mainzer+2011). Observing geometries differ by solar phase angles and by moderate changes in heliocentric distance (e.g., further distances produce somewhat cooler surface temperatures). With the NEATM model and for a constant IR beaming parameter (eta=constant), there is a family of solutions for (diameter, pv, G, eta) where G is the slope parameter from the H-G Relation. NEATM models employing Pravec+2012's choice of G=0.43, produce D=1.8 km and pv0.4, given that G=0.43 is assumed from studies of main belt asteroids (Warner+2009). We present an analysis of the light curve of 3691 Bede to constrain G from observations. We also investigate fitting thermophysical models (TPM, Rozitis+11) to constrain the coupled parameters of thermal inertia (Gamma) and surface roughness, which in turn affect diameter and pv. Surface composition can be related to pv. This study focuses on understanding and characterizing the dependency of parameters with the aim of constraining diameter, pv and thermal inertia for 3691 Bede

Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center

The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, and molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers have been recruited to participate in cognitive, neuropsychologic, imaging, fluid biomarkers, genomic and multi-omic studies. Tissue and longitudinal data collected to foster, facilitate, and support research on dementia and aging. The Genetics and high throughput -omics core (GHTO) have collected of more than 26,000 biological samples from 6,625 Knight-ADRC participants. Samples available include longitudinal DNA, RNA, non-fasted plasma, cerebrospinal fluid pellets, and peripheral blood mononuclear cells. The GHTO has performed deep molecular profiling (genomic, transcriptomic, epigenomic, proteomic, and metabolomic) from large number of brain (n = 2,117), CSF (n = 2,012) and blood/plasma (n = 8,265) samples with the goal of identifying novel risk and protective variants, identify novel molecular biomarkers and causal and druggable targets. Overall, the resources available at GHTO support the increase of our understanding of Alzheimer Disease

Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria.

A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963 (1), which demonstrates potent cellular activity against Pf 3D7 (EC50 = 0.006 μM) and achieves artemisinin-like kill kinetics in vitro with a parasite clearance time of \u3c24 h. A single dose of 30 mg/kg is fully curative in the Pf-humanized severe combined immunodeficient mouse model. INE963 (1) also exhibits a high barrier to resistance in drug selection studies and a long half-life (T1/2) across species. These properties suggest the significant potential for INE963 (1) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963 (1) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials

Susceptibility and Response of Human Blood Monocyte Subsets to Primary Dengue Virus Infection

Human blood monocytes play a central role in dengue infections and form the majority of virus infected cells in the blood. Human blood monocytes are heterogeneous and divided into CD16− and CD16+ subsets. Monocyte subsets play distinct roles during disease, but it is not currently known if monocyte subsets differentially contribute to dengue protection and pathogenesis. Here, we compared the susceptibility and response of the human CD16− and CD16+ blood monocyte subsets to primary dengue virus in vitro. We found that both monocyte subsets were equally susceptible to dengue virus (DENV2 NGC), and capable of supporting the initial production of new infective virus particles. Both monocyte subsets produced anti-viral factors, including IFN-α, CXCL10 and TRAIL. However, CD16+ monocytes were the major producers of inflammatory cytokines and chemokines in response to dengue virus, including IL-1β, TNF-α, IL-6, CCL2, 3 and 4. The susceptibility of both monocyte subsets to infection was increased after IL-4 treatment, but this increase was more profound for the CD16+ monocyte subset, particularly at early time points after virus exposure. These findings reveal the differential role that monocyte subsets might play during dengue disease