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We present a new method, called "forced-spectrum fitting", for physically-based spectral modelling of radio sources during deconvolution. This improves upon current common deconvolution fitting methods, which often produce inaccurate spectra. Our method uses any pre-existing spectral index map to assign spectral indices to each model component cleaned during the multi-frequency deconvolution of WSClean, where the pre-determined spectrum is fitted. The component magnitude is evaluated by performing a modified weighted linear least-squares fit. We test this method on a simulated LOFAR-HBA observation of the 3C196 QSO and a real LOFAR-HBA observation of the 4C+55.16 FRI galaxy. We compare the results from the forced-spectrum fitting with traditional joined-channel deconvolution using polynomial fitting. Because no prior spectral information was available for 4C+55.16, we demonstrate a method for extracting spectral indices in the observed frequency band using "clustering". The models generated by the forced-spectrum fitting are used to improve the calibration of the datasets. The final residuals are comparable to existing multi-frequency deconvolution methods, but the output model agrees with the provided spectral index map, embedding correct spectral information. While forced-spectrum fitting does not solve the determination of the spectral information itself, it enables the construction of accurate multi-frequency models that can be used for wide-band calibration and subtraction., Comment: 17 pages, 9 figures, 5 tables. Accepted for publication in MNRAS

The redshifted 21-cm signal from neutral hydrogen is a direct probe of the physics of the early universe and has been an important science driver of many present and upcoming radio interferometers. In this study, we use a single night of observations with the New Extension in Nan\c{c}ay Upgrading LOFAR (NenuFAR) to place upper limits on the 21-cm power spectrum from the Cosmic Dawn at a redshift of $z$ = 20.3. NenuFAR is a new low-frequency radio interferometer, operating in the 10-85 MHz frequency range, currently under construction at the Nan\c{c}ay Radio Observatory in France. It is a phased array instrument with a very dense uv-coverage at short baselines, making it one of the most sensitive instruments for 21-cm cosmology analyses at these frequencies. Our analysis adopts the foreground subtraction approach, in which sky sources are modeled and subtracted through calibration, and residual foregrounds are subsequently removed using Gaussian process regression (GPR). The final power spectra are constructed from the gridded residual data cubes in the uv-plane. Signal injection tests are performed at each step of the analysis pipeline, and the relevant pipeline settings are optimized to ensure minimal signal loss, and any signal suppression is accounted for through a bias correction on our final upper limits. We obtain a best 2$\sigma$ upper limit of $2.4\times 10^7$ $\text{mK}^{2}$ at $z$ = 20.3 and $k$ = 0.041 $h\,\text{cMpc}^{-1}$. We see a strong excess power in the data, making our upper limits two orders of magnitude higher than the thermal noise limit. We investigate the origin and nature of this excess power and discuss further improvements in the analysis pipeline, which can potentially mitigate it and consequently allow us to reach the thermal noise sensitivity when multiple nights of observations are processed in the future., Comment: 27 pages, 21 figures, and 6 tables; accepted for publication in Astronomy and Astrophysics (A&A)

Measurement of the redshifted 21-cm signal of neutral hydrogen from the Cosmic Dawn (CD) and Epoch of Reionisation (EoR) promises to unveil a wealth of information about the astrophysical processes during the first billion years of evolution of the universe. The AARTFAAC Cosmic Explorer (ACE) utilises the AARTFAAC wide-field imager of LOFAR to measure the power spectrum of the intensity fluctuations of the redshifted 21-cm signal from the CD at z~18. The RFI from various sources contaminates the observed data and it is crucial to exclude the RFI-affected data in the analysis for reliable detection. In this work, we investigate the impact of non-ground-based transient RFI using cross-power spectra and cross-coherence metrics to assess the correlation of RFI over time and investigate the level of impact of transient RFI on the ACE 21-cm power spectrum estimation. We detected moving sky-based transient RFI sources that cross the field of view within a few minutes and appear to be mainly from aeroplane communication beacons at the location of the LOFAR core in the 72-75 MHz band, by inspecting filtered images. This transient RFI is mostly uncorrelated over time and is only expected to dominate over the thermal noise for an extremely deep integration time of 3000 hours or more with a hypothetical instrument that is sky temperature dominated at 75 MHz. We find no visible correlation over different k-modes in Fourier space in the presence of noise for realistic thermal noise scenarios. We conclude that the sky-based transient RFI from aeroplanes, satellites and meteorites at present does not pose a significant concern for the ACE analyses at the current level of sensitivity and after integrating over the available 500 hours of observed data. However, it is crucial to mitigate or filter such transient RFI for more sensitive experiments aiming for significantly deeper integration., Comment: 13 pages, 9 figures, and 3 tables; accepted for publication in Astronomy and Astrophysics (A&A)

Featured Application: Electrical and electronic devices that experience long-term vibrations. Electrical boards, also called printed circuit boards, constitute the basis of most electronic devices. These boards are mainly fabricated of thin copper films bonded to fiber epoxy laminates, such as FR4. Being the most important functional component of these devices, they sometimes undergo mechanical stresses such as shock and vibration during transport and operation that can induce electrical failure and malfunction; hence, studies addressing the effects of vibrations on their electrical properties have important applications. In this paper, small cantilever samples made of bare copper bonded to FR4 with three isolated rectangular zones were studied to analyze, for the first time, variations in electrical properties such as sheet resistance and resistivity before and after 200 k, 500 k, and 800 k vibration cycles at three different temperatures (25, 35, and 45 °C). A significant rise in resistance equivalent to 1657% of the initial value was observed from 0 to 800 k vibration cycles. These changes were accompanied by a 95% decrease in conductivity, from 4.1 × 107 to 2.3 × 106 S/m, whereas very little change in the electrical properties was observed due to temperature rise. Surface analysis by ESEM showed cracks ~1 µm in width and several millimeters in length with a crack density of ~8 cracks per mm after 800 k cycles. The surface composition (100% copper) was not altered even upon a high number of vibration cycles, and static drop contact angle measurements of 117–119 degrees indicated an increase in the hydrophobicity of the surface attributed to increased surface roughness and the accumulation of very small air bubbles on the cracks.

Detecting the 21-cm signal from the Epoch of Reionisation (EoR) is challenging due to the strong astrophysical foregrounds, ionospheric effects, radio frequency interference and instrumental effects. Understanding and calibrating these effects are crucial for the detection. In this work, we introduce a newly developed direction-dependent (DD) calibration algorithm DDECAL and compare its performance with an existing algorithm, SAGECAL, in the context of the LOFAR-EoR 21-cm power spectrum experiment. In our data set, the North Celestial Pole (NCP) and its flanking fields were observed simultaneously. We analyse the NCP and one of its flanking fields. The NCP field is calibrated by the standard pipeline, using SAGECAL with an extensive sky model and 122 directions, and the flanking field is calibrated by DDECAL and SAGECAL with a simpler sky model and 22 directions. Additionally, two strategies are used for subtracting Cassiopeia A and Cygnus A. The results show that DDECAL performs better at subtracting sources in the primary beam region due to the application of a beam model, while SAGECAL performs better at subtracting Cassiopeia A and Cygnus A. This indicates that including a beam model during DD calibration significantly improves the performance. The benefit is obvious in the primary beam region. We also compare the 21-cm power spectra on two different fields. The results show that the flanking field produces better upper limits compared to the NCP in this particular observation. Despite the minor differences between DDECAL and SAGECAL due to the beam application, we find that the two algorithms yield comparable 21-cm power spectra on the LOFAR-EoR data after foreground removal. Hence, the current LOFAR-EoR 21-cm power spectrum limits are not likely to depend on the DD calibration method., Comment: 28 pages, 14 figures, accepted for publication in A&A

The dimensions of intrinsically disordered proteins (IDPs) are sensitive to small energetic-entropic differences between intramolecular and protein-solvent interactions. This is commonly observed on modulating solvent composition and temperature. However, the inherently heterogeneous conformational landscape of IDPs is also expected to be influenced by mutations that can (de)stabilize pockets of local and even global structure, native and non-native, and hence the average dimensions. Here, we show experimental evidence for the remarkably tunable landscape of IDPs by employing the DNA-binding domain of CytR, a high-sequence-complexity IDP, as a model system. CytR exhibits a range of structure and compactness upon introducing specific mutations that modulate microscopic terms, including main-chain entropy, hydrophobicity, and electrostatics. The degree of secondary structure, as monitored by far-UV circular dichroism (CD), is strongly correlated to average ensemble dimensions for 14 different mutants of CytR and is consistent with the Uversky-Fink relation. Our experiments highlight how average ensemble dimensions can be controlled via mutations even in the disordered regime, the prevalence of non-native interactions and provide testable controls for molecular simulations.

BackgroundThere is little information on the incidence of AIDS-defining events which have been reported in the literature to be associated with immune reconstitution inflammatory syndrome (IRIS) after combined antiretroviral therapy (cART) initiation. These events include tuberculosis, mycobacterium avium complex (MAC), cytomegalovirus (CMV) retinitis, progressive multifocal leukoencephalopathy (PML), herpes simplex virus (HSV), Kaposi sarcoma, non-Hodgkin lymphoma (NHL), cryptococcosis and candidiasis.MethodsWe identified individuals in the HIV-CAUSAL Collaboration, which includes data from six European countries and the US, who were HIV-positive between 1996 and 2013, antiretroviral therapy naive, aged at least 18 years, had CD4 cell count and HIV-RNA measurements and had been AIDS-free for at least 1 month between those measurements and the start of follow-up. For each AIDS-defining event, we estimated the hazard ratio for no cART versus less than 3 and at least 3 months since cART initiation, adjusting for time-varying CD4 cell count and HIV-RNA via inverse probability weighting.ResultsOut of 96 562 eligible individuals (78% men) with median (interquantile range) follow-up of 31 [13,65] months, 55 144 initiated cART. The number of cases varied between 898 for tuberculosis and 113 for PML. Compared with non-cART initiation, the hazard ratio (95% confidence intervals) up to 3 months after cART initiation were 1.21 (0.90-1.63) for tuberculosis, 2.61 (1.05-6.49) for MAC, 1.17 (0.34-4.08) for CMV retinitis, 1.18 (0.62-2.26) for PML, 1.21 (0.83-1.75) for HSV, 1.18 (0.87-1.58) for Kaposi sarcoma, 1.56 (0.82-2.95) for NHL, 1.11 (0.56-2.18) for cryptococcosis and 0.77 (0.40-1.49) for candidiasis.ConclusionWith the potential exception of mycobacterial infections, unmasking IRIS does not appear to be a common complication of cART initiation in high-income countries.

BackgroundRNA-protein interactions stabilize many viruses and also the nucleoprotein cores of enveloped animal viruses (e.g. retroviruses). The nucleoprotein particles are frequently pleomorphic and generally unstable due to the lack of strong protein-protein interactions in their capsids. Principles governing their structures are unknown because crystals of such nucleoprotein particles that diffract to high resolution have not previously been produced. Cowpea chlorotic mottle virions (CCMV) are typical of particles stabilized by RNA-protein interactions and it has been found that crystals that diffract beyond 4.5 A resolution are difficult to grow. However, we report here the purification of CCMV with an exceptionally mild procedure and the growth of crystals that diffract X-rays to 3.2 A resolution.ResultsThe 3.2 A X-ray structure of native CCMV, an icosahedral (T = 3) RNA plant virus, shows novel quaternary structure interactions based on interwoven carboxyterminal polypeptides that extend from canonical capsid beta-barrel subunits. Additional particle stability is provided by intercapsomere contacts between metal ion mediated carboxyl cages and by protein interactions with regions of ordered RNA. The structure of a metal-free, swollen form of the virus was determined by cryo-electron microscopy and image reconstruction. Modeling of this structure with the X-ray coordinates of the native subunits shows that the 29 A radial expansion is due to electrostatic repulsion at the carboxyl cages and is stopped short of complete disassembly by preservation of interwoven carboxyl termini and protein-RNA contacts.ConclusionsThe CCMV capsid displays quaternary structural interactions that are unique compared with previously determined RNA virus structures. The loosely coupled hexamer and pentamer morphological units readily explain their versatile reassembly properties and the pH and metal ion dependent polymorphism observed in the virions. Association of capsomeres through

BackgroundRNA-protein interactions stabilize many viruses and also the nucleoprotein cores of enveloped animal viruses (e.g. retroviruses). The nucleoprotein particles are frequently pleomorphic and generally unstable due to the lack of strong protein-protein interactions in their capsids. Principles governing their structures are unknown because crystals of such nucleoprotein particles that diffract to high resolution have not previously been produced. Cowpea chlorotic mottle virions (CCMV) are typical of particles stabilized by RNA-protein interactions and it has been found that crystals that diffract beyond 4.5 A resolution are difficult to grow. However, we report here the purification of CCMV with an exceptionally mild procedure and the growth of crystals that diffract X-rays to 3.2 A resolution.ResultsThe 3.2 A X-ray structure of native CCMV, an icosahedral (T = 3) RNA plant virus, shows novel quaternary structure interactions based on interwoven carboxyterminal polypeptides that extend from canonical capsid beta-barrel subunits. Additional particle stability is provided by intercapsomere contacts between metal ion mediated carboxyl cages and by protein interactions with regions of ordered RNA. The structure of a metal-free, swollen form of the virus was determined by cryo-electron microscopy and image reconstruction. Modeling of this structure with the X-ray coordinates of the native subunits shows that the 29 A radial expansion is due to electrostatic repulsion at the carboxyl cages and is stopped short of complete disassembly by preservation of interwoven carboxyl termini and protein-RNA contacts.ConclusionsThe CCMV capsid displays quaternary structural interactions that are unique compared with previously determined RNA virus structures. The loosely coupled hexamer and pentamer morphological units readily explain their versatile reassembly properties and the pH and metal ion dependent polymorphism observed in the virions. Association of capsomeres through

Crystallographic and molecular biological studies of T = 3 nodaviruses (180 identical subunits in the particle) and T = 4 tetraviruses (240 identical subunits in the particle) have revealed similarity in both the architecture of the particles and the strategy for maturation. The comparative studies provide a novel opportunity to examine an apparent evolution of particle size, from smaller (T = 3) to larger (T = 4), with both particles based on similar subunits. The BBV and FHV nodavirus structures are refined at 2.8 A and 3 A respectively, while the N omega V structure is at 6 A resolution. Nevertheless, the detailed comparisons of the noda and tetravirus X-ray electron density maps show that the same type of switching in subunit twofold contacts is used in the T = 3 and T = 4 capsids, although differences must exist between quasi and icosahedral threefold contacts in the T = 4 particle that have not yet been detected. The analyses of primary and tertiary structures of noda and tetraviruses show that N omega V subunits undergo a post assembly cleavage like that observed in nodaviruses and that the cleaved 76 C-terminal residues remain associated with the particle.

Crystallographic and molecular biological studies of T = 3 nodaviruses (180 identical subunits in the particle) and T = 4 tetraviruses (240 identical subunits in the particle) have revealed similarity in both the architecture of the particles and the strategy for maturation. The comparative studies provide a novel opportunity to examine an apparent evolution of particle size, from smaller (T = 3) to larger (T = 4), with both particles based on similar subunits. The BBV and FHV nodavirus structures are refined at 2.8 A and 3 A respectively, while the N omega V structure is at 6 A resolution. Nevertheless, the detailed comparisons of the noda and tetravirus X-ray electron density maps show that the same type of switching in subunit twofold contacts is used in the T = 3 and T = 4 capsids, although differences must exist between quasi and icosahedral threefold contacts in the T = 4 particle that have not yet been detected. The analyses of primary and tertiary structures of noda and tetraviruses show that N omega V subunits undergo a post assembly cleavage like that observed in nodaviruses and that the cleaved 76 C-terminal residues remain associated with the particle.

Crystals of cowpea chlorotic mottle virus (CCMV) that diffract X-rays to 3.1 A resolution were grown in a succinate-PEG solution buffered at pH 3.3. The crystals are in space group P2(1)2(1)2(1) with unit cell dimensions of a = 381.26 A, b = 381.26 A, and c = 408.59 A. Four particles occupy the unit cell, placing a single virion in the crystallographic asymmetric unit. Diffraction intensities measured from 196 films collected at the Cornell High Energy Synchrotron Source accounted for 55% of the theoretically possible data to 3.2 A. Unit cell dimensions and rotation function analyses of the X-ray data revealed that the particles were organized in a pseudo-tetragonal relationship with the pseudo-fourfold axis along the crystal c axis. Analysis of electron micrographs of two-dimensional crystals of CCMV revealed a remarkable similarity between these and planes of particles perpendicular to the crystallographic c axis in the three-dimensional crystal.

Crystals of cowpea chlorotic mottle virus (CCMV) that diffract X-rays to 3.1 A resolution were grown in a succinate-PEG solution buffered at pH 3.3. The crystals are in space group P2(1)2(1)2(1) with unit cell dimensions of a = 381.26 A, b = 381.26 A, and c = 408.59 A. Four particles occupy the unit cell, placing a single virion in the crystallographic asymmetric unit. Diffraction intensities measured from 196 films collected at the Cornell High Energy Synchrotron Source accounted for 55% of the theoretically possible data to 3.2 A. Unit cell dimensions and rotation function analyses of the X-ray data revealed that the particles were organized in a pseudo-tetragonal relationship with the pseudo-fourfold axis along the crystal c axis. Analysis of electron micrographs of two-dimensional crystals of CCMV revealed a remarkable similarity between these and planes of particles perpendicular to the crystallographic c axis in the three-dimensional crystal.

Silencing of the FMR1 gene leads to fragile X syndrome, the most common cause of inherited intellectual disability. To study the epigenetic modifications of the FMR1 gene during silencing in time, we used fibroblasts and induced pluripotent stem cells (iPSCs) of an unmethylated full mutation (uFM) individual with normal intelligence. The uFM fibroblast line carried an unmethylated FMR1 promoter region and expressed normal to slightly increased FMR1 mRNA levels. The FMR1 expression in the uFM line corresponds with the increased H3 acetylation and H3K4 methylation in combination with a reduced H3K9 methylation. After reprogramming, the FMR1 promoter region was methylated in all uFM iPSC clones. Two clones were analyzed further and showed a lack of FMR1 expression, whereas the presence of specific histone modifications also indicated a repressed FMR1 promoter. In conclusion, these findings demonstrate that the standard reprogramming procedure leads to epigenetic silencing of the fully mutated FMR1 gene.

Recurrent outbreaks of novel zoonotic coronavirus (CoV) diseases in recent years have highlighted the importance of developing therapeutics with broad-spectrum activity against CoVs. Because all CoVs use −1 programmed ribosomal frameshifting (−1 PRF) to control expression of key viral proteins, the frameshift signal in viral mRNA that stimulates −1 PRF provides a promising potential target for such therapeutics. To test the viability of this strategy, we explored whether small-molecule inhibitors of −1 PRF in SARS-CoV-2 also inhibited −1 PRF in a range of bat CoVs—the most likely source of future zoonoses. Six inhibitors identified in new and previous screens against SARS-CoV-2 were evaluated against the frameshift signals from a panel of representative bat CoVs as well as MERS-CoV. Some drugs had strong activity against subsets of these CoV-derived frameshift signals, while having limited to no effect on −1 PRF caused by frameshift signals from other viruses used as negative controls. Notably, the serine protease inhibitor nafamostat suppressed −1 PRF significantly for multiple CoV-derived frameshift signals. These results suggest it is possible to find small-molecule ligands that inhibit −1 PRF specifically in a broad spectrum of CoVs, establishing frameshift signals as a viable target for developing pan-coronaviral therapeutics.