Corrigendum: A Meta-Analysis of the Effect of Bacillus Calmette-Guérin Vaccination Against Bovine Tuberculosis:Is Perfect the Enemy of Good?

More than 50 million cattle are likely exposed to bovine tuberculosis (bTB) worldwide, highlighting an urgent need for bTB control strategies in low- and middle-income countries (LMICs) and other regions where the disease remains endemic and test-and-slaughter approaches are unfeasible. While Bacillus Calmette-Guérin (BCG) was first developed as a vaccine for use in cattle even before its widespread use in humans, its efficacy against bTB remains poorly understood. To address this important knowledge gap, we conducted a systematic review and meta-analysis to determine the direct efficacy of BCG against bTB challenge in cattle, and performed scenario analyses with transmission dynamic models incorporating direct and indirect vaccinal effects (“herd-immunity”) to assess potential impact on herd level disease control. The analysis shows a relative risk of infection of 0.75 (95% CI: 0.68, 0.82) in 1,902 vaccinates as compared with 1,667 controls, corresponding to a direct vaccine efficacy of 25% (95% CI: 18, 32). Importantly, scenario analyses considering both direct and indirect effects suggest that disease prevalence could be driven down close to Officially TB-Free (OTF) status (<0.1%), if BCG were introduced in the next 10-year time period in low to moderate (<15%) prevalence settings, and that 50–95% of cumulative cases may be averted over the next 50 years even in high (20–40%) disease burden settings with immediate implementation of BCG vaccination. Taken together, the analyses suggest that BCG vaccination may help accelerate control of bTB in endemic settings, particularly with early implementation in the face of dairy intensification in regions that currently lack effective bTB control programs

Potential Involvement of LOX-1 in Functional Consequences of Endothelial Senescence

Numerous studies have described the process of senescence associated with accumulation of oxidative damage, mutations and decline in proliferative potential. Although the changes observed in senescent cells are likely to result in significant phenotypic alterations, the studies on consequences of endothelial senescence, especially in relation to aging-associated diseases, are scarce. We have analyzed effects of senescence on the functions of endothelial cells relevant to the development of atherosclerosis including angiogenesis, adhesion, apoptosis and inflammation. In the course of progressing through the passages, human umbilical vein endothelial cells (HUVECs) displayed significant increase in size (+36% passage 12 vs. passage 4 , p<0.001) and reduction in both basal and VEGF-stimulated tube formation. The analysis of a scavenger receptor LOX-1, a key molecule implicated in atherogenesis, revealed a significant decline of its message (mRNA) and protein content in senescent endothelial cells (−33%) and in aortas of 50 wk (vs. 5 wk) old mice (all p<0.01). These effects were accompanied by a marked reduction of the basal expression of VCAM-1 and ICAM-1. Compared to early cultures, late passage HUVECs also exhibited nuclear translocation of NF-κB (p65) and reciprocal shifts in BAX and BCL2 protein content resulting in almost 2-fold increase in BAX/BCL2 ratio and 3-fold increase in apoptotic response to TNFα exposure (p<0.04). These changes in senescent endothelial cells are suggestive of aberrant responses to physiological stimuli resulting in a less permissive environment for tissue remodeling and progression of diseases requiring angiogenesis and cell adhesion in elderly, possibly, mediated by LOX-1

A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy

The Double homeobox 4 (DUX4) gene is an important regulator of early human development and its aberrant expression is causal for facioscapulohumeral muscular dystrophy (FSHD). The DUX4-full length (DUX4-fl) mRNA splice isoform encodes a transcriptional activator; however, DUX4 and its unique DNA binding preferences are specific to old-world primates. Regardless, the somatic cytotoxicity caused by DUX4 expression is conserved when expressed in cells and animals ranging from fly to mouse. Thus, viable animal models based on DUX4-fl expression have been difficult to generate due in large part to overt developmental toxicity of low DUX4-fl expression from leaky transgenes. We have overcome this obstacle and here we report the generation and initial characterization of a line of conditional floxed DUX4-fl transgenic mice, FLExDUX4, that is viable and fertile. In the absence of cre, these mice express a very low level of DUX4-fl mRNA from the transgene, resulting in mild phenotypes. However, when crossed with appropriate cre-driver lines of mice, the double transgenic offspring readily express DUX4-fl mRNA, protein, and target genes with the spatiotemporal pattern of nuclear cre expression dictated by the chosen system. When cre is expressed from the ACTA1 skeletal muscle-specific promoter, the double transgenic animals exhibit a developmental myopathy. When crossed with tamoxifen-inducible cre lines, DUX4-mediated pathology can be induced in adult animals. Thus, the appearance and progression of pathology can be controlled to provide readily screenable phenotypes useful for assessing therapeutic approaches targeting DUX4-fl mRNA and protein. Overall, the FLExDUX4 line of mice is quite versatile and will allow new investigations into mechanisms of DUX4-mediated pathophysiology as well as much-needed pre-clinical testing of DUX4-targeted FSHD interventions in vivo

Boundary layer flow of nanofluid over an exponentially stretching surface

The steady boundary layer flow of nanofluid over an exponential stretching surface is investigated analytically. The transport equations include the effects of Brownian motion parameter and thermophoresis parameter. The highly nonlinear coupled partial differential equations are simplified with the help of suitable similarity transformations. The reduced equations are then solved analytically with the help of homotopy analysis method (HAM). The convergence of HAM solutions are obtained by plotting h-curve. The expressions for velocity, temperature and nanoparticle volume fraction are computed for some values of the parameters namely, suction injection parameter α, Lewis number Le, the Brownian motion parameter Nb and thermophoresis parameter Nt

Procyanidins are potent inhibitors of LOX-1: a new player in the French Paradox

Lectin-like oxidized LDL receptor-1 (LOX-1) is an endothelial receptor for oxidized LDL (oxLDL) and plays multiple roles in the development of cardiovascular diseases. We screened more than 400 foodstuff extracts for identifying materials that inhibit oxLDL binding to LOX-1. Results showed that 52 extracts inhibited LOX-1 by more than 70% in cell-free assays. Subsequent cell-based assays revealed that a variety of foodstuffs known to be rich in procyanidins such as grape seed extracts and apple polyphenols, potently inhibited oxLDL uptake in Chinese hamster ovary (CHO) cells expressing LOX-1. Indeed, purified procyanidins significantly inhibited oxLDL binding to LOX-1 while other ingredients of apple polyphenols did not. Moreover, chronic administration of oligomeric procyanidins suppressed lipid accumulation in vascular wall in hypertensive rats fed with high fat diet. These results suggest that procyanidins are LOX-1 inhibitors and LOX-1 inhibition might be a possible underlying mechanism of the well-known vascular protective effects of red wine, the French Paradox

The second data release from the European Pulsar Timing Array III. Search for gravitational wave signals

We present the results of the search for an isotropic stochastic gravitational wave background (GWB) at nanohertz frequencies using the second data release of the European Pulsar Timing Array (EPTA) for 25 millisecond pulsars and a combination with the first data release of the Indian Pulsar Timing Array (InPTA). A robust GWB detection is conditioned upon resolving the Hellings-Downs angular pattern in the pairwise cross-correlation of the pulsar timing residuals. Additionally, the GWB is expected to yield the same (common) spectrum of temporal correlations across pulsars, which is used as a null hypothesis in the GWB search. Such a common-spectrum process has already been observed in pulsar timing data. We analysed (i) the full 24.7-year EPTA data set, (ii) its 10.3-year subset based on modern observing systems, (iii) the combination of the full data set with the first data release of the InPTA for ten commonly timed millisecond pulsars, and (iv) the combination of the 10.3-year subset with the InPTA data. These combinations allowed us to probe the contributions of instrumental noise and interstellar propagation effects. With the full data set, we find marginal evidence for a GWB, with a Bayes factor of four and a false alarm probability of 4%. With the 10.3-year subset, we report evidence for a GWB, with a Bayes factor of 60 and a false alarm probability of about 0.1% (≳3σ significance). The addition of the InPTA data yields results that are broadly consistent with the EPTA-only data sets, with the benefit of better noise modelling. Analyses were performed with different data processing pipelines to test the consistency of the results from independent software packages. The latest EPTA data from new generation observing systems show non-negligible evidence for the GWB. At the same time, the inferred spectrum is rather uncertain and in mild tension with the common signal measured in the full data set. However, if the spectral index is fixed at 13/3, the two data sets give a similar amplitude of (2.5 ± 0.7) × 10−15 at a reference frequency of 1 yr−1. Further investigation of these issues is required for reliable astrophysical interpretations of this signal. By continuing our detection efforts as part of the International Pulsar Timing Array (IPTA), we expect to be able to improve the measurement of spatial correlations and better characterise this signal in the coming years

The second data release from the European Pulsar Timing Array IV. Search for continuous gravitational wave signals

We present the results of a search for continuous gravitational wave signals (CGWs) in the second data release (DR2) of the European Pulsar Timing Array (EPTA) collaboration. The most significant candidate event from this search has a gravitational wave frequency of 4-5 nHz. Such a signal could be generated by a supermassive black hole binary (SMBHB) in the local Universe. We present the results of a follow-up analysis of this candidate using both Bayesian and frequentist methods. The Bayesian analysis gives a Bayes factor of 4 in favor of the presence of the CGW over a common uncorrelated noise process, while the frequentist analysis estimates the p-value of the candidate to be 1%, also assuming the presence of common uncorrelated red noise. However, comparing a model that includes both a CGW and a gravitational wave background (GWB) to a GWB only, the Bayes factor in favour of the CGW model is only 0.7. Therefore, we cannot conclusively determine the origin of the observed feature, but we cannot rule it out as a CGW source. We present results of simulations that demonstrate that data containing a weak gravitational wave background can be misinterpreted as data including a CGW and vice versa, providing two plausible explanations of the EPTA DR2 data. Further investigations combining data from all PTA collaborations will be needed to reveal the true origin of this feature.Comment: 12 figures, 15 pages, to be submitte

The second data release from the European Pulsar Timing Array: II. Customised pulsar noise models for spatially correlated gravitational waves

Aims. The nanohertz gravitational wave background (GWB) is expected to be an aggregate signal of an ensemble of gravitational waves emitted predominantly by a large population of coalescing supermassive black hole binaries in the centres of merging galaxies. Pulsar timing arrays (PTAs), which are ensembles of extremely stable pulsars at approximately kiloparsec distances precisely monitored for decades, are the most precise experiments capable of detecting this background. However, the subtle imprints that the GWB induces on pulsar timing data are obscured by many sources of noise that occur on various timescales. These must be carefully modelled and mitigated to increase the sensitivity to the background signal.Methods. In this paper, we present a novel technique to estimate the optimal number of frequency coefficients for modelling achromatic and chromatic noise, while selecting the preferred set of noise models to use for each pulsar. We also incorporated a new model to fit for scattering variations in the Bayesian pulsar timing package temponest. These customised noise models enable a more robust characterisation of single-pulsar noise. We developed a software package based on tempo2 to create realistic simulations of European Pulsar Timing Array (EPTA) datasets that allowed us to test the efficacy of our noise modelling algorithms.Results. Using these techniques, we present an in-depth analysis of the noise properties of 25 millisecond pulsars (MSPs) that form the second data release (DR2) of the EPTA and investigate the effect of incorporating low-frequency data from the Indian Pulsar Timing Array collaboration for a common sample of ten MSPs. We used two packages, enterprise and temponest, to estimate our noise models and compare them with those reported using EPTA DR1. We find that, while in some pulsars we can successfully disentangle chromatic from achromatic noise owing to the wider frequency coverage in DR2, in others the noise models evolve in a much more complicated way. We also find evidence of long-term scattering variations in PSR J1600-3053. Through our simulations, we identify intrinsic biases in our current noise analysis techniques and discuss their effect on GWB searches. The analysis and results discussed in this article directly help to improve the sensitivity to the GWB signal and they are already being used as part of global PTA efforts

The second data release from the European Pulsar Timing Array: IV. Implications for massive black holes, dark matter, and the early Universe

The European Pulsar Timing Array (EPTA) and Indian Pulsar Timing Array (InPTA) collaborations have measured a low-frequency common signal in the combination of their second and first data releases, respectively, with the correlation properties of a gravitational wave background (GWB). Such a signal may have its origin in a number of physical processes including a cosmic population of inspiralling supermassive black hole binaries (SMBHBs); inflation, phase transitions, cosmic strings, and tensor mode generation by the non-linear evolution of scalar perturbations in the early Universe; and oscillations of the Galactic potential in the presence of ultra-light dark matter (ULDM). At the current stage of emerging evidence, it is impossible to discriminate among the different origins. Therefore, for this paper, we consider each process separately, and investigated the implications of the signal under the hypothesis that it is generated by that specific process. We find that the signal is consistent with a cosmic population of inspiralling SMBHBs, and its relatively high amplitude can be used to place constraints on binary merger timescales and the SMBH-host galaxy scaling relations. If this origin is confirmed, this would be the first direct evidence that SMBHBs merge in nature, adding an important observational piece to the puzzle of structure formation and galaxy evolution. As for early Universe processes, the measurement would place tight constraints on the cosmic string tension and on the level of turbulence developed by first-order phase transitions. Other processes would require non-standard scenarios, such as a blue-tilted inflationary spectrum or an excess in the primordial spectrum of scalar perturbations at large wavenumbers. Finally, a ULDM origin of the detected signal is disfavoured, which leads to direct constraints on the abundance of ULDM in our Galaxy

Comparing recent PTA results on the nanohertz stochastic gravitational wave background

The Australian, Chinese, European, Indian, and North American pulsar timing array (PTA) collaborations recently reported, at varying levels, evidence for the presence of a nanohertz gravitational wave background (GWB). Given that each PTA made different choices in modeling their data, we perform a comparison of the GWB and individual pulsar noise parameters across the results reported from the PTAs that constitute the International Pulsar Timing Array (IPTA). We show that despite making different modeling choices, there is no significant difference in the GWB parameters that are measured by the different PTAs, agreeing within $1\sigma$. The pulsar noise parameters are also consistent between different PTAs for the majority of the pulsars included in these analyses. We bridge the differences in modeling choices by adopting a standardized noise model for all pulsars and PTAs, finding that under this model there is a reduction in the tension in the pulsar noise parameters. As part of this reanalysis, we "extended" each PTA's data set by adding extra pulsars that were not timed by that PTA. Under these extensions, we find better constraints on the GWB amplitude and a higher signal-to-noise ratio for the Hellings and Downs correlations. These extensions serve as a prelude to the benefits offered by a full combination of data across all pulsars in the IPTA, i.e., the IPTA's Data Release 3, which will involve not just adding in additional pulsars, but also including data from all three PTAs where any given pulsar is timed by more than as single PTA.Comment: 21 pages, 9 figures, submitted to Ap