FXN promoter silencing in the humanized mouse model of Friedreich Ataxia

Background - Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues. Methodology / Principal Findings - The humanized mouse model of Friedreich ataxia (YG8sR), which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R). We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse. Conclusions / Significance- Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues.This research was supported by grants from the National Institutes of Health (R01 NS072418), and the Muscular Dystrophy Association to S.I.B. Y.K.C. is supported by a postdoctoral research fellowship from the Million Dollar Bike Ride Grant Program of the Orphan Disease Center at University of Pennsylvania. T.T.H. was supported by the American College of Medical Genetics Foundation. A.C.P. and M.G.M. were supported by the SURE and OSCTR programs at OUHSC, respectively

Mixed RG Flows and Hydrodynamics at Finite Holographic Screen

We consider quark-gluon plasma with chemical potential and study renormalization group flows of transport coefficients in the framework of gauge/gravity duality. We first study them using the flow equations and compare the results with hydrodynamic results by calculating the Green functions on the arbitrary slice. Two results match exactly. Transport coefficients at arbitrary scale is ontained by calculating hydrodynamics Green functions. When either momentum or charge vanishes, transport coefficients decouple from each other.Comment: 22 pages, 6 figure

Explicit Stabilised Gradient Descent for Faster Strongly Convex Optimisation

This paper introduces the Runge-Kutta Chebyshev descent method (RKCD) for strongly convex optimisation problems. This new algorithm is based on explicit stabilised integrators for stiff differential equations, a powerful class of numerical schemes that avoid the severe step size restriction faced by standard explicit integrators. For optimising quadratic and strongly convex functions, this paper proves that RKCD nearly achieves the optimal convergence rate of the conjugate gradient algorithm, and the suboptimality of RKCD diminishes as the condition number of the quadratic function worsens. It is established that this optimal rate is obtained also for a partitioned variant of RKCD applied to perturbations of quadratic functions. In addition, numerical experiments on general strongly convex problems show that RKCD outperforms Nesterov's accelerated gradient descent

Disc reflection and a possible disc wind during a soft X-ray state in the neutron star low-mass X-ray binary 1RXS J180408.9-342058

1RXS J180408.9–342058 is a transient neutron star low-mass X-ray binary that exhibited a bright accretion outburst in 2015. We present $\textit{NuSTAR}$, $\textit{Swift}$, and $\textit{Chandra}$ observations obtained around the peak brightness of this outburst. The source was in a soft X-ray spectral state and displayed an X-ray luminosity of $L_\text{X}$ $\simeq$ (2–3) × 10$^{37}$($D$/5.8 kpc)$^2$ erg s$^{−1}$ (0.5–10 keV). The $\textit{NuSTAR}$ data reveal a broad Fe–K emission line that we model as relativistically broadened reflection to constrain the accretion geometry. We found that the accretion disc is viewed at an inclination of $i$ $\simeq$ 27$^{\circ}$–35$^{\circ}$ and extended close to the neutron star, down to $R_\text{in}$ $\simeq$ 5–7.5 gravitational radii ($\simeq$11–17 km). This inner disc radius suggests that the neutron star magnetic field strength is $B$ $\lesssim$ 2 × 10$^8$ G. We find a narrow absorption line in the $\textit{Chandra}$/HEG data at an energy of $\simeq$7.64 keV with a significance of $\simeq$4.8$\sigma$. This feature could correspond to blueshifted Fe $\small \text{XXVI}$ and arise from an accretion disc wind, which would imply an outflow velocity of $v_\text{out}$ $\simeq$0.086$c$ ($\simeq$25 800 km s$^{−1}$). However, this would be extreme for an X-ray binary and it is unclear if a disc wind should be visible at the low inclination angle that we infer from our reflection analysis. Finally, we discuss how the X-ray and optical properties of 1RXS J180408.9–342058 are consistent with a relatively small ($P_\text{orb}$ $\lesssim$ 3 h) binary orbit.ND is supported by an NWO/Vidi grant and an EU Marie Curie Intra-European fellowship under contract no. FP-PEOPLE-2013-IEF-627148. DA acknowledges support from the Royal Society. JCAMJ is supported by an Australian Research Council (ARC) Future Fellowship (FT140101082) and an ARC Discovery Grant (DP120102393). RW and AP are supported by an NWO/TOP grant, module 1, awarded to RW. COH is supported by an NSERC Discovery Grant. ATD is supported by an NWO/Veni grant. JWTH is supported by NWO/Vidi and ERC/starting (337062) grants

Impact of the Method of G6PD Deficiency Assessment on Genetic Association Studies of Malaria Susceptibility

BACKGROUND:Clinical association studies have yielded varied results regarding the impact of glucose-6-phosphate dehydrogenase (G6PD) deficiency upon susceptibility to malaria. Analyses have been complicated by varied methods used to diagnose G6PD deficiency. METHODOLOGY/PRINCIPAL FINDINGS:We compared the association between uncomplicated malaria incidence and G6PD deficiency in a cohort of 601 Ugandan children using two different diagnostic methods, enzyme activity and G6PD genotype (G202A, the predominant East African allele). Although roughly the same percentage of males were identified as deficient using enzyme activity (12%) and genotype (14%), nearly 30% of males who were enzymatically deficient were wild-type at G202A. The number of deficient females was three-fold higher with assessment by genotype (21%) compared to enzyme activity (7%). Heterozygous females accounted for the majority (46/54) of children with a mutant genotype but normal enzyme activity. G6PD deficiency, as determined by G6PD enzyme activity, conferred a 52% (relative risk [RR] 0.48, 95% CI 0.31-0.75) reduced risk of uncomplicated malaria in females. In contrast, when G6PD deficiency was defined based on genotype, the protective association for females was no longer seen (RR = 0.99, 95% CI 0.70-1.39). Notably, restricting the analysis to those females who were both genotypically and enzymatically deficient, the association of deficiency and protection from uncomplicated malaria was again demonstrated in females, but not in males (RR = 0.57, 95% CI 0.37-0.88 for females). CONCLUSIONS/SIGNIFICANCE:This study underscores the impact that the method of identifying G6PD deficient individuals has upon association studies of G6PD deficiency and uncomplicated malaria. We found that G6PD-deficient females were significantly protected against uncomplicated malaria, but this protection was only seen when G6PD deficiency is described using enzyme activity. These observations may help to explain the discrepancy in some published association studies involving G6PD deficiency and uncomplicated malaria

Atomic super-resolution tomography

We consider the problem of reconstructing a nanocrystal at atomic resolution from electron microscopy images taken at a few tilt angles. A popular reconstruction approach called discrete tomography confines the atom locations to a coarse spatial grid, which is inspired by the physical a priori knowledge that atoms in a crystalline solid tend to form regular lattices. Although this constraint has proven to be powerful for solving this very under-determined inverse problem in many cases, its key limitation is that, in practice, defects may occur that cause atoms to deviate from regular lattice positions. Here we propose a grid-free discrete tomography algorithm that allows for continuous deviations of the atom locations similar to super-resolution approaches for microscopy. The new formulation allows us to define atomic interaction potentials explicitly, which results in a both meaningful and powerful incorporation of the available physical a priori knowledge about the crystal's properties. In computational experiments, we compare the proposed grid-free method to established grid-based approaches and show that our approach can indeed recover the atom positions more accurately for common lattice defects

In Vivo Binding and Retention of CD4-Specific DARPin 57.2 in Macaques

The recently described Designed Ankyrin Repeat Protein (DARPin) technology can produce highly selective ligands to a variety of biological targets at a low production cost.To investigate the in vivo use of DARPins for future application to novel anti-HIV strategies, we identified potent CD4-specific DARPins that recognize rhesus CD4 and followed the fate of intravenously injected CD4-specific DARPin 57.2 in rhesus macaques. The human CD4-specific DARPin 57.2 bound macaque CD4(+) cells and exhibited potent inhibitory activity against SIV infection in vitro. DARPin 57.2 or the control E3_5 DARPin was injected into rhesus macaques and the fate of cell-free and cell-bound CD4-specific DARPin was evaluated. DARPin-bound CD4(+) cells were detected in the peripheral blood as early as 30 minutes after the injection, decreasing within 6 hours and being almost undetectable within 24 hours. The amount of DARPin bound was dependent on the amount of DARPin injected. CD4-specific DARPin was also detected on CD4(+) cells in the lymph nodes within 30 minutes, which persisted with similar kinetics to blood. More extensive analysis using blood revealed that DARPin 57.2 bound to all CD4(+) cell types (T cells, monocytes, dendritic cells) in vivo and in vitro with the amount of binding directly proportional to the amount of CD4 on the cell surface. Cell-free DARPins were also detected in the plasma, but were rapidly cleared from circulation.We demonstrated that the CD4-specific DARPin can rapidly and selectively bind its target cells in vivo, warranting further studies on possible clinical use of the DARPin technology

Partial ORF1ab Gene Target Failure with Omicron BA.2.12.1

Mutations in the genome of SARS-CoV-2 can affect the performance of molecular diagnostic assays. In some cases, such as S-gene target failure, the impact can serve as a unique indicator of a particular SARS-CoV-2 variant and provide a method for rapid detection. Here, we describe partial ORF1ab gene target failure (pOGTF) on the cobas SARS-CoV-2 assays, defined by a $2-thermocycle delay in detection of the ORF1ab gene compared to that of the E-gene. We demonstrate that pOGTF is 98.6% sensitive and 99.9% specific for SARS-CoV-2 lineage BA.2.12.1, an emerging variant in the United States with spike L452Q and S704L mutations that may affect transmission, infectivity, and/ or immune evasion. Increasing rates of pOGTF closely mirrored rates of BA.2.12.1 sequences uploaded to public databases, and, importantly, increasing local rates of pOGTF also mirrored increasing overall test positivity. Use of pOGTF as a proxy for BA.2.12.1 provides faster tracking of the variant than whole-genome sequencing and can benefit laboratories without sequencing capabilities

Plasmodium falciparum clearance with artemisinin-based combination therapy (ACT) in patients with glucose-6-phosphate dehydrogenase deficiency in Mali

URL : http://www.malariajournal.com/content/9/1/332Background: Artemisinin-based combination therapy (ACT) is currently the most effective medicine for the treatment of uncomplicated malaria. Artemisinin has previously been shown to increase the clearance of Plasmodium falciparum in malaria patients with haemoglobin E trait, but it did not increase parasite inhibition in an in vitro study using haemoglobin AS erythrocytes. The current study describes the efficacy of artemisinin derivatives on P. falciparum clearance in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD), a haemoglobin enzyme deficiency, not yet studied in the same context, but nonetheless is a common in malaria endemic areas, associated with host protection against uncomplicated and severe malaria. The impact of G6PD deficiency on parasite clearance with ACT treatment was compared between G6PD-deficient patients and G6PD-normal group. Methods: Blood samples from children and adults participants (1 to 70 years old) with uncomplicated P. falciparum malaria residing in Kambila, Mali were analysed. Study participants were randomly assigned to receive either artemether-lumefantrine (Coartem®) or artesunate plus mefloquine (Artequin™). A restriction-fragment length polymorphism analysis of PCR-amplified DNA samples was used to identify the (A-) allele of the gene mutation responsible for G6PD deficiency (G6PD*A-). 470 blood samples were thus analysed and of these, DNA was extracted from 315 samples using the QIAamp kit for PCR to identify the G6PD*A- gene. Results

How Work Impairments and Reduced Work Ability are Associated with Health Care Use in Workers with Musculoskeletal Disorders, Cardiovascular Disorders or Mental Disorders

__Abstract__ Purpose the aim of this study was to explore how work impairments and work ability are associated with health care use by workers with musculoskeletal disorders (MSD), cardiovascular disorders (CVD), or mental disorders (MD). Methods in this cross-sectional study, subjects with MSD (n = 2,074), CVD (n = 714), and MD (n = 443) were selected among health care workers in 12 Dutch organizations. Using an online questionnaire, data were collected on in