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We carry out an in-depth analysis of the capability of the upcoming space-based gravitational wave mission eLISA in addressing the Hubble tension, with a primary focus on observations at intermediate redshifts ($3, Comment: To appear in JCAP, 30 pages, 12 sets of figures, 7 tables

Reasonable parametrizations of the current Hubble data set of the expansion rate of our homogeneous and isotropic universe, after suitable smoothing of these data, strongly suggests that the area of the apparent horizon increases irrespective of whether the spatial curvature of the metric is open, flat or closed. Put in another way, any sign of the spatial curvature appears consistent with the second law of thermodynamics., Comment: 9 pages, 7 sets of figures, Version published in MNRAS

Two types of distance measurement are important in cosmological observations, the angular diameter distance $d_A$ and the luminosity distance $d_L$. In the present work, we carried out an assessment of the theoretical relation between these two distance measurements, namely the cosmic distance duality relation, from type Ia supernovae (SN-Ia) data, the Cosmic Chronometer (CC) Hubble parameter data, and baryon acoustic oscillation (BAO) data using Gaussian Process. The luminosity distance curve and the angular diameter distance curve are extracted from the SN-Ia data and the combination of BAO and CC data respectively using the Gaussian Process. The distance duality relation is checked by a non-parametric reconstruction using the reconstructed $H$, $d_L$, and the volume-averaged distance $D_v$. We compare the results obtained for different choices of the covariance function employed in the Gaussian Process. It is observed that the theoretical distance duality relation is in well agreement with the present analysis in 2$\sigma$ for the overlapping redshift domain $0 \leq z \leq 2$ of the reconstruction., Comment: 10 pages, 8 sets of figures, accepted for publication in MNRAS

The cosmic curvature density parameter has been constrained in the present work independent of any background cosmological model. The reconstruction is performed adopting the non-parametric Gaussian Processes (GP). The constraints on $\Omega_{k0}$ are obtained via a Markov Chain Monte Carlo (MCMC) analysis. Late-time cosmological probes viz., the Supernova (SN) distance modulus data, the Cosmic Chronometer (CC) and the radial Baryon Acoustic Oscillations ($r$BAO) measurements of the Hubble data have been utilized for this purpose. The results are further combined with the data from redshift space distortions (RSD) which studies the growth of large scale structure in the universe. The only \textit{a priori} assumption is that the universe is homogeneous and isotropic, described by the FLRW metric. Results indicate that a spatially flat universe is well consistent in 2$\sigma$ within the domain of reconstruction $0, Comment: 16 pages, 8 sets of figures, Accepted for publication in Phys. Rev. D

Background and Purpose: A recombinant engineered variant of APC (activated protein C), 3K3A-APC, lacks anticoagulant properties ( Methods: Tenecteplase-mediated lysis of thrombin generated plasma clots of human normal pooled plasma was monitored in the presence of varying doses of 3K3A-APC. The effects on fibrinolysis by tenecteplase and alteplase were compared. Results: The presence of 3K3A-APC shortened the time for clot lysis induced by tenecteplase at very low levels but not at higher therapeutic concentrations of tenecteplase. Comparisons of alteplase-mediated clot lysis to tenecteplase clot lysis showed that both thrombolytic agents behaved similarly in the presence of 3K3A-APC. Conclusions: These results indicate that 3K3A-APC does not interfere with tenecteplase’s clot lysis function.

The gut microbiome is a malleable microbial community that can remodel in response to various factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic D,L-α-peptides that remodeled the Western diet (WD) gut microbiome toward the low-fat-diet microbiome state. Daily oral administration of the peptides in WD-fed LDLr-/- mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including interleukin-6, tumor necrosis factor-α and interleukin-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.

In this work, we explore the possibility of using artificial neural networks to impose constraints on teleparallel gravity and its $f(T)$ extensions. We use the available Hubble parameter observations from cosmic chronometers and baryon acoustic oscillations from different galaxy surveys. We discuss the procedure for training a network model to reconstruct the Hubble diagram. Further, we describe the procedure to obtain $H'(z)$, the first order derivative of $H(z)$, using artificial neural networks which is a novel approach to this method of reconstruction. These analyses are complemented with further studies on the impact of two priors which we put on $H_0$ to assess their impact on the analysis, which are the local measurements by the SH0ES team ($H_0^{\text{R20}} = 73.2 \pm 1.3$ km Mpc$^{-1}$ s$^{-1}$) and the updated TRGB calibration from the Carnegie Supernova Project ($H_0^{\text{TRGB}} = 69.8 \pm 1.9$ km Mpc$^{-1}$ s$^{-1}$), respectively. Additionally, we investigate the validity of the concordance model, through some cosmological null tests with these reconstructed data sets. Finally, we reconstruct the allowed $f(T)$ functions for different combinations of the observational Hubble data sets. Results show that the $\Lambda$CDM model lies comfortably included at the 1$\sigma$ confidence level for all the examined cases., Comment: 19 pages, 11 sets of figures, version accepted in JCAP

The possibility of a non-gravitational interaction between the dark matter and the dark energy has been reconstructed using some recent datasets. The crucial aspect is that the interaction is not parametrized at the outset, but rather reconstructed directly from the data in a non-parametric way. The Cosmic Chronometer Hubble data, the Pantheon Supernova compilation of CANDELS and CLASH Multy-Cycle Treasury programs obtained by the HST, and the Baryon Acoustic Oscillation Hubble data have been considered in this work. The widely accepted Gaussian Process is used for the reconstruction. The results clearly indicate that a no interaction scenario is quite a possibility. Also, the interaction, if any, is not really significant at the present epoch. The direction of the flow of energy is clearly from the dark energy to the dark matter which is consistent with the thermodynamic requirement., Comment: 19 pages, 12 sets of figures, Accepted for publication in Phys. Rev. D

The cosmic deceleration parameter $q$ has been reconstructed in a non-parametric way using various combinations of recent observational datasets. The Pantheon compilation of the Supernova (SN) distance modulus data, the Cosmic Chronometer (CC) measurements of the Hubble parameter including the full systematics and the Baryon Acoustic Oscillation (BAO) data have been considered in this work. The redshift $z_t$, where the transition from a past decelerated to a late-time accelerated phase of evolution occurs, is estimated from the reconstructed $q$. The possible effect of a non-zero spatial curvature from the Planck 2020 estimate is checked. The outcome of including different $H_0$ measurements from recent Planck 2020 and Riess 2021 probes having a maximum discrepancy at the $4.2\sigma$ level, is investigated. Results indicate that the transition from a past decelerated phase to the late-time accelerated phase occurs within the redshift range $0.51$, the reconstructed $q$ is observed to have a non-monotonic evolution in case of the combined CC and SN data. On introducing the BAO data, the reconstructed $q$ shows an oscillating behaviour for $z\gtrsim1$. To investigate the effect of matter perturbations, the growth rate data from the Redshift-Space Distortions (RSD) are utilized in reconstructing $q$. Using the $\mathcal{O}m(z)$ diagnostic, we draw inferences on the validity of $\Lambda$CDM as a consistency check. The $\Lambda$CDM model is well consistent and included at the 2$\sigma$ level in the domain of all the reconstructions., Comment: Thoroughly revised, including a change in title. Version accepted by Physics of the Dark Universe

The cosmological jerk parameter $j$ is reconstructed in a non-parametric way from observational data independent of a fiducial cosmological model. From this kinematical quantity, the equation of state parameter for composite matter distribution is also found out. The result shows that there is a deviation from the $\Lambda$CDM model close to $z=1.5$, at the $3\sigma$ confidence level., Comment: 16 pages, 7 figures

Exact solutions are studied in the context of modified Brans-Dicke theory. The non-linearity of the modified Brans-Dicke field equations is treated with the Euler-Duarte-Moreira method of integrability of anharmonic oscillator equation. While some solutions show a forever accelerating nature, in some cases there is a signature flip in the evolution of deceleration parameter in recent past. Importance of these latter models are studied in the context of late-time acceleration of the universe. Constraints on the model parameters are obtained from Markov Chain Monte Carlo (MCMC) analysis using the Supernova distance modulus data, observational measurements of Hubble parameter, Baryon acoustic oscillation data, and the CMB Shift parameter data., Comment: 12 pages, 10 figures, to appear in The European Physical Journal C (Particles and Fields)

Although the functional specificity and catalytic versatility of enzymes have been exploited in numerous settings, controlling the spatial and temporal activity of enzymes remains challenging. Here we describe an approach for programming the function of streptokinase (SK), a protein that is clinically used as a blood "clot buster" therapeutic. We show that the fibrinolytic activity resulting from the binding of SK to the plasma proenzyme plasminogen (Pg) can be effectively regulated (turned "OFF" and "ON") by installing an intrasteric regulatory feature using a DNA-linked protease inhibitor modification. We describe the design rationale, synthetic approach, and functional characterization of two generations of intrasterically regulated SK-Pg constructs and demonstrate dose-dependent and sequence-specific temporal control in fibrinolytic activity in response to short predesignated DNA inputs. The studies described establish the feasibility of a new enzyme-programming approach and serves as a step toward advancing a new generation of programmable enzyme therapeutics.

The catalytic subunit (Pol) of herpes simplex virus 1 (HSV-1) DNA polymerase has been extensively studied both as a model for other family B DNA polymerases and for its differences from these enzymes as an antiviral target. Among the activities of HSV-1 Pol is an intrinsic RNase H activity that cleaves RNA from RNA-DNA hybrids. There has long been a controversy regarding whether this activity is due to the 3′-to-5′ exonuclease of Pol or whether it is a separate activity, possibly acting on 5′ RNA termini. To investigate this issue, we compared wild-type HSV-1 Pol and a 3′-to-5′ exonuclease-deficient mutant, D368A Pol, for DNA polymerase activity, 3′-to-5′ exonuclease activity, and RNase H activity in vitro . Additionally, we assessed the RNase H activity using differentially end-labeled templates with 5′ or 3′ RNA termini. The mutant enzyme was at most modestly impaired for DNA polymerase activity but was drastically impaired for 3′-to-5′ exonuclease activity, with no activity detected even at high enzyme-to-DNA substrate ratios. Importantly, the mutant showed no detectable ability to excise RNA with either a 3′ or 5′ terminus, while the wild-type HSV-1 Pol was able to cleave RNA from the annealed RNA-DNA hairpin template, but only detectably with a 3′ RNA terminus in a 3′-to-5′ direction and at a rate lower than that of the exonuclease activity. These results suggest that HSV-1 Pol does not have an RNase H separable from its 3′-to-5′ exonuclease activity and that this activity prefers DNA degradation over degradation of RNA from RNA-DNA hybrids. IMPORTANCE Herpes simplex virus 1 (HSV-1) is a member of the Herpesviridae family of DNA viruses, several of which cause morbidity and mortality in humans. Although the HSV-1 DNA polymerase has been studied for decades and is a crucial target for antivirals against HSV-1 infection, several of its functions remain to be elucidated. A hypothesis suggesting the existence of a 5′-to-3′ RNase H activity intrinsic to this enzyme that could remove RNA primers from Okazaki fragments has been particularly controversial. In this study, we were unable to identify RNase H activity of HSV-1 DNA polymerase on RNA-DNA hybrids with 5′ RNA termini. We detected RNase H activity on hybrids with 3′ termini, but this was due to the 3′-to-5′ exonuclease. Thus, HSV-1 is unlikely to use this method to remove RNA primers during DNA replication but may use pathways similar to those used in eukaryotic Okazaki fragment maturation.

The present work deals with holographic dark energy models with Hubble horizon as the infra-red cut-off. The interaction rate between dark energy and dark matter has been reconstructed with three different choices of the interaction term. It is shown that the coupling parameter of the interaction term should evolve with redshift to allow the successful transition from decelerated to accelerated phase of expansion. Constraints on the model parameters are obtained from Markov Chain Monte Carlo (MCMC) analysis using the supernova distance modulus data and observational measurements of the Hubble parameter. Results show that the model with the coupling parameter increasing with redshift (z) or equivalently decreasing with the evolution, are ruled out. On the other hand, coupling parameters, increasing or slowly varying with the evolution, are consistent with the observed evolution scenario. A Bayesian evidence calculation has been carried out for statistical selection of the reconstructed models. Though the kinematical parameters are well behaved for these models, the physical variables which determine the nature of the components in the matter sector, are not at all realistic. We have concluded that the existence of spatial curvature is essential for this particular type of dark energy models., 16 pages, 7 figures. Accepted for publication in EPJ Plus

Dpo4 and Dbh are from two closely related Sulfolobus species and are well studied archaeal homologues of pol IV, an error prone Y-family polymerase from Escherichia coli. Despite sharing 54% amino acid identity, these polymerases display distinct mutagenic and translesion specificities. Structurally, Dpo4 and Dbh adopt different conformations because of the difference in relative orientation of their N-terminal catalytic and C-terminal DNA binding domains. Using chimeric constructs of these two polymerases, we have previously demonstrated that the interdomain linker is a major determinant of polymerase conformation, base-substitution fidelity, and abasic-site translesion synthesis. Here we find that the interdomain linker also affects the single-base deletion frequency and the mispair extension efficiency of these polymerases. Exchanging just three amino acids in the linkers of Dbh and Dpo4 is sufficient to change the fidelity by up to 30-fold, predominantly by altering the rate of correct (but not incorrect) nucleotide incorporation. Additionally, from a 2.4 Å resolution crystal structure, we have found that the three linker amino acids from Dpo4 are sufficient to allow Dbh to adopt the standard conformation of Dpo4. Thus, a small region of the interdomain linker, located more than 11 Å away from the catalytic residues, determines the fidelity of these Y-family polymerases, by controlling the alignment of substrates at the active site.

Polymerases belonging to the DinB class of the Y-family translesion synthesis DNA polymerases have a preference for accurately and efficiently bypassing damaged guanosines. These DinB polymerases also generate single-base (� 1) deletions at high frequencies with most occurring on repetitive ‘deletion hotspot’ sequences. Human DNA polymerase kappa (hPoli), the eukaryotic DinB homologue, displays an unusual efficiency for to extend from mispaired primer termini, either by extending directly from the mispair or by primer-template misalignment. This latter property explains how hPoli creates single-base deletions in non-repetitive sequences, but does not address how deletions occur in repetitive deletion hotspots. Here, we show that hPoli uses a classical Streisinger template-slippage mechanism to generate � 1 deletions in repetitive sequences, as do the bacterial and archaeal homologues. After the first nucleotide is added by template slippage, however, hPoli can efficiently realign the primer-template duplex before continuing DNA synthesis. Strand realignment results in a base-substitution mutation, minimizing generation of more deleterious frameshift mutations. On non-repetitive sequences, we find that nucleotide misincorporation is slower if the incoming nucleotide can correctly basepair with the nucleotide immediately 5 0 to the templating base, thereby competing against the mispairing with the templating base.

PolC is the C-family replicative polymerase in low G+C content Gram-positive bacteria. To date several structures of C-family polymerases have been reported, including a high resolution crystal structure of a ternary complex of PolC with DNA and incoming deoxynucleoside triphosphate (dNTP). However, kinetic information needed to understand the enzymatic mechanism of C-family polymerases is limited. For this study we have performed a detailed steady-state and pre-steady-state kinetic characterization of correct dNTP incorporation by PolC from the Gram-positive pathogen Staphylococcus aureus, using a construct lacking both the non-conserved N-terminal domain and the 3'-5' exonuclease domain (Sau-PolC-ΔNΔExo). We find that Sau-PolC-ΔNΔExo has a very fast catalytic rate (k(pol) 330 s(-1)) but also dissociates from DNA rapidly (k(off) ∼150 s(-1)), which explains the low processivity of PolC in the absence of sliding clamp processivity factor. Although Sau-PolC-ΔNΔExo follows the overall enzymatic pathway defined for other polymerases, some significant differences exist. The most striking feature is that the nucleotidyl transfer reaction for Sau-PolC-ΔNΔExo is reversible and is in equilibrium with dNTP binding. Simulation of the reaction pathway suggests that rate of pyrophosphate release, or a conformational change required for pyrophosphate release, is much slower than rate of bond formation. The significance of these findings is discussed in the context of previous data showing that binding of the β-clamp processivity factor stimulates the intrinsic nucleotide incorporation rate of the C-family polymerases, in addition to increasing processivity.

The fundamental constants in Nature play a crucial role in the understanding of physical phenomena. Hence, it is of paramount importance to measure them with exquisite precision and to examine whether they present any variability across cosmic time, as a means to test the standard model of Cosmology, as well as fundamental physics. We revisit a consistency test of the speed of light variability proposed by Cai {\it et al.} using the latest cosmological observations, viz., Pantheon compilation of Type Ia Supernova luminosity distances (SN), cosmic chronometers from differential galaxy ages (CC), and measurements of both radial and transverse modes of baryonic acoustic oscillations ($r$-BAO and $a$-BAO) respectively. Such a test has the advantage of being independent of any assumption on the cosmic curvature - which can be degenerated with some variable speed of light models - as well as any dark energy model. We deploy the well-known Gaussian Processes to reconstruct cosmic distances and ages in the $01$ when the $a$-BAO data are included for some priors and reconstruction kernel cases. Still, we ascribe no statistical significance to this result for the incompleteness of this data set at such higher redshifts.