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The nanohertz stochastic gravitational wave background (SGWB), generated by unresolved supermassive black hole binaries (SMBHBs), provides a unique probe of their population and its cosmic evolution. In this work, we explore the potential of uncovering the SMBHB population and its redshift dependence by combining the SGWB signal and its anisotropies with galaxy distribution through cross-correlation analyses. Using a Fisher analysis technique, we show that the SGWB power spectrum alone can not provide any information on the evolutionary history of SMBHBs, whereas the inclusion of the angular power spectrum of the SGWB and its cross-correlation with the galaxy distribution substantially improves constraints on the redshift evolution parameters. Assuming pulsar timing array configurations achievable in the Square Kilometre Array era, we find that the combined use of isotropic and anisotropic SGWB signals, together with galaxy surveys, can provide valuable measurements of the redshift evolution of the SMBH–galaxy connection and the frequency distribution of SMBHBs. These results highlight the potential of joint gravitational wave–galaxy studies to address the long-standing open question of SMBH growth and evolution across cosmic time.

The isotropic stochastic gravitational-wave background (SGWB) generated by a population of supermassive black hole binaries (SMBHBs) provides a unique window into their cosmic evolution. In addition to the isotropic power spectrum, the anisotropic component of the signal carries additional information about the supermassive black holes (BHs) and host galaxy connection. The measurement of this signal is usually carried out by angular power spectra, which is only a sufficient measure for a Gaussian and statistically isotropic distribution of SMBHBs, where the statistical properties of a field remain unchanged across the sky. In contrast, the contribution from SMBHBs in nHz SGWB will be hosted by fewer massive galaxies, making the nHz background anisotropic and non-Gaussian. As a result, the performance of angular power spectra in extracting the underlying physics is limited. In this work, we propose a novel technique called multi-tracer correlated stacking, which enables the detection of anisotropies in the SGWB by stacking the signal from regions of the sky with tracers of BHs such as active galactic nuclei (AGN), quasars, bright galaxies, etc., that can be mapped up to high redshift. We demonstrate this technique on a simulated population of SMBHBs using an AGN catalog, which maps the underlying matter distribution approximately up to redshift z = 5. This stacking technique uniquely distinguishes between isotropic and anisotropic distributions of SGWB sources, surpassing the capabilities of angular power spectrum-based methods in detecting anisotropic signals. This highlights the effectiveness of this technique in detecting anisotropic SGWB signals, and in the future, this technique can play a crucial role in its discovery.

The stochastic gravitational wave background (SGWB) in the nanohertz (nHz) regime, detectable by pulsar timing arrays (PTAs), provides a promising probe of the cosmic population of supermassive black hole binaries (SMBHBs). These binaries are expected to retain significant eccentricity throughout their evolution. We present a new technique to model the nHz SGWB by incorporating eccentricity into a multiscale adaptive simulation framework. Using the time-domain eccentric waveform model ESIGMAHM, we generate realistic GW signals from astrophysical populations of SMBHBs. Unlike circular binaries, eccentric systems emit across multiple frequencies, introducing spectral correlations between frequency bins. These correlations provide a novel observational signature of the eccentricity distribution of the SMBHB population. In this work, we adopt simplified power-law models for the eccentricity distribution. While this does not capture the full complexity of galactic environments, it effectively highlights the key features of GW emission from eccentric binaries and their imprint on the SGWB. Our approach advances nHz GW signal modeling by incorporating eccentricity at small scales, enabling more realistic predictions and offering a new avenue for probing SMBHB astrophysics with future PTA observations.

Gravitational wave sources are standard sirens that provide an independent way to map the cosmic expansion history by combining with an independent redshift measurement, either from an electromagnetic counterpart for a bright siren or using different statistical techniques for dark sirens. In this analysis, we perform the first Blinded Mock Data Challenge (Blinded-MDC) to test the robustness in inferring the value of Hubble constant H0 for a dark siren technique which depends on astrophysical mass distribution of binary black holes (BBHs). We have considered different analysis setups for the Blinded-MDC to test both statistical and systematic uncertainties and demonstrate the capabilities in inferring H0 with detector sensitivity as per the fourth observation run of LIGO-Virgo-KAGRA. We find that when the astrophysical population of BBHs matches with the underlying assumption of the model, a cosmological pipeline can recover the injected parameters using the observed mass distribution. However, when the mock mass distribution of the astrophysical population depends slightly on redshift and one is ignorant about it in analyzing the data, it can cause a systematic discrepancy in the inferred value of H0 by about 1.5σ, above the statistical fluctuations due to noise and a limited number of events. In the future, elaborate studies will be required to mitigate systematic uncertainties due to unknown astrophysical complexities. This MDC framework sets the road map for inspecting the precision and accuracy of standard siren cosmology and provides the first insight into the robustness of the population-dependent cosmology inference in a blinded analysis setup.

LAMP diagnosis of malaria is simple and cost-effective with acceptable sensitivity and specificity as compared to standard diagnostic modules such as microscopy, RDTs and nested PCR, and thus its deployment for onsite screening of malaria in resource-limited regions is under consideration. However, the requirement of an electricity-operated dry bath and bulky read-out unit is still a major concern. In an effort to simplify this limitation, we have developed a portable LAMP device and fluorescence readout unit which can be used in the rapid point-of-care diagnosis of malaria. We have developed a point-of-care diagnostic LAMP device that is easy to operate by a mobile application, and the results can be quantified with a fluorescent readout unit. The diagnostic performance of the device was evaluated in 90 P . falciparum -infected clinical isolates stored at 4°C for 6-7 years and 10 freshly collected isolates from healthy volunteers. The LOD and quantitative ability of LAMP in estimating parasitemia levels were revealed with laboratory-grown P. falciparum strain (3D7). The LAMP assay performed in our device was exclusive for P. falciparum detection with sensitivity and specificity determined to be 98.89% and 100%, respectively, in clinical isolates. The LOD was documented to be 1 parasite/µl at the cut-off ADC value of 20. Parasite density estimated from ADC values showed concordance with microscopically determined parasite density of the cultured P. falciparum 3D7 strain. The LAMP assay performed in our device provides a possible portable platform for its deployment in the point-of-care diagnosis of malaria. Further validation of the quantitative ability of the assay with freshly collected or properly stored clinical samples of known parasitemia is necessary for field applicability.

The sphingolipid pool is key regulator of vital cellular functions in Plasmodium falciparum a causative agent for deadly malaria. Erythrocytes, the host for asexual stage of Plasmodium , are major reservoir for Sphingosine-1-phosphate (S1P). Erythrocyte possesses Sphingosine kinase (SphK) that catalyzed its biosynthesis from sphingosine (Sph). Since, Plasmodium lacks SphK homologous protein it can be envisaged that it co-opts sphingolipids from both intraerythrocytic as well as extracellular pools for its growth and development. Herein, by sphingosine-NBD probing, we report that infected erythrocytes imports Sph from extracellular pool, which is converted to S1P and thereby taken by P. falciparum . Next, by targeting of the SphK through specific inhibitor N,N-Dimethylsphingosine DMS, we show a reduction in erythrocyte endogenous S1P pool and SphK-phosphorylation that led to inhibition in growth and development of ring stage P. falciparum. Owing to the role of S1P in erythrocyte glycolysis we analyzed uptake of NBD-Glucose and production of lactate in DMS treated and untreated plasmodium. DMS treatment led to decreased glycolysis in Plasmodium . Interestingly the host free Plasmodium did not show any effect on glycolysis with DMS treatment indicating its host-mediated effect. Further to understand the in-vivo anti-plasmodial effects of exogenous and endogenous erythrocyte S1P level, Sphingosine-1-phosphate lyase (S1PL) inhibitor (THI), S1P and SphK-1 inhibitor (DMS), were used in Plasmodium berghei ANKA (PbA) mice model. DMS treatment led to reduction of endogenous S1P conferred significant decrease in parasite load, whereas the plasma level S1P modulated by (THI) and exogenous S1P have no effect on growth of Plasmodium . This suggested erythrocyte endogenous S1P pool is important for Plasmodium growth whereas the plasma level S1P has no effect. Altogether, this study provides insight on cellular processes regulated by S1P in  P. falciparum  and highlights the novel mechanistically distinct molecular target i.e. SphK-1.

Type-2 phosphatidic acid phosphatase (PAP2) a member of PAP2 superfamily mediates the conversion of phosphatidic acid (PA) to diacylglycerol (DAG) and thus plays a pivotal role in numerous cellular signaling processes in diverse organisms. An elevated level of intracellular PA is detrimental for the cell and induces cell death. In this study we identified and characterized a PAP2 homologue in Plasmodium falciparum, PfPAP2 and further elucidated its significance in regulation of PA homeostasis in parasite life cycle. PfPAP2 is expressed in the blood stage and harbors the canonical acid phosphatase domain (APD) with signature motifs. PfPAP2 catalyzes the dephosphorylation of PA to produce DAG and inorganic phosphate (Pi). Propranolol, a generic inhibitor of PAP2, inhibited the phosphatase activity of PfPAP2 by binding to the active site of APD domain as evident by in silico docking and confirmed by surface plasmon resonance (SPR) analysis. Inhibition of native PfPAP2 by propranolol led to rise in intracellular PA mediating disruption of intracellular PA homeostasis in parasites. The propranolol mediated inhibition of PfPAP2 directed early secretion of a micronemal Perforin like Protein, PfPLP1 leading to untimely permeabilization and host cell egress. The merozoites following premature egress were non-invasive and were attenuated to invade erythrocytes and cannot continue next cycle growth. This study demonstrates that disruption of PA homeostasis can cause growth retardation in malaria parasites, and thus its master regulator, PfPAP2, can serve as a very good molecular target for antimalarial chemotherapeutic interventions.

Clostridium perfringens epsilon toxin (Etx) is categorized as the third most lethal bioterrorism agent by the Centers for Disease Control and Prevention (CDC), with no therapeutic counter measures available for humans. Here, we have developed a high-affinity inhibitory compound by synthesizing and evaluating the structure activity relationship (SAR) of a library of diverse glycosides (numbered 1-12). SAR of glycoside-Etx heptamers revealed exceptionally strong H-bond interactions of glycoside-4 with a druggable pocket in the oligomerization and β-hairpin region of Etx. Analysis of its structure suggested that glycoside-4 might self-aggregate to form a robust micelle-like supra-molecular complex due to its linear side-chain architecture, which was authenticated by fluorescence spectroscopy. Further, this micelle hinders the Etx monomer-monomer interaction required for oligomerization, validated by both surface plasmon resonance (SPR) and immunoblotting. This phenomenon in turn leads to blockage of pore formation. Downstream evaluation revealed that glycoside-4 effectively blocked cell death of Etx-treated cultured primary cells and maintained cellular homeostasis via disrupting oligomerization, blocking pore formation, restoring calcium homeostasis, stabilizing the mitochondrial membrane and impairing high mobility group box 1 (HMGB1) translocation from nucleus to cytoplasm. Furthermore, a single dosage of glycoside-4 protected the Etx-challenged mice and restored normal function to multiple organs. This work reports for the first time a potent, nontoxic glycoside with strong ability to occlude toxin lethality, representing it as a bio-arm therapeutic against Etx-based biological threat.

Prevailing drug resistance in malaria imposes the major roadblock for the existing interventions necessitating the timely need to search for alternative therapies. Ants in Solenopsis spp, termed ’Fire ants’, are well known for their aggressive behavior, which leads to the release of toxic venom. Notably, the tribal natives of the malaria-laden densely forested Bastar region, Chhattisgarh, India, use fire ant sting-based therapy to cure malaria-like high fever. Inspired by this, we have collected the fire ants from the forest of Bastar and extracted peptide and alkaloid fractions from ant venom using HPLC and analyzed them by LC/MS-based applications. Evaluation of the anti-malarial efficacy of these peptide fractions demonstrated a significant reduction in the growth of Plasmodium falciparum (Pf 3D7) in vitro, whereas the alkaloid fraction showed a negligible effect. in vitro hemolytic activity confirmed the venom peptide fraction to be non-hemolytic. Additionally, the venom peptide fraction is purely non-toxic to HepG2 cells. Anti-malarial efficiency of the same in Plasmodium berghei ANKA infected mice models showed a drastic reduction in parasitemia representing promising anti-malarial activity. Overall, our study has unraveled the scientific rationale underlying fire ant sting therapy used as a tribal naturotherapy for curing malaria-like fever, thus, introducing a way forward to develop nature-inspired anti-malarial chemotherapeutics.

Post-translational modifications (PTMs) including phosphorylation and palmitoylation have emerged as crucial biomolecular events that govern many cellular processes including functioning of motility- and invasion-associated proteins during Plasmodium falciparum invasion. However, no study has ever focused on understanding the possibility of a crosstalk between these two molecular events and its direct impact on preinvasion- and invasion-associated protein–protein interaction (PPI) network-based molecular machinery. Here, we used an integrated in silico analysis to enrich two different catalogues of proteins: (i) the first group defines the cumulative pool of phosphorylated and palmitoylated proteins, and (ii) the second group represents a common set of proteins predicted to have both phosphorylation and palmitoylation. Subsequent PPI analysis identified an important protein cluster comprising myosin A tail interacting protein (MTIP) as one of the hub proteins of the glideosome motor complex in P. falciparum , predicted to have dual modification with the possibility of a crosstalk between the same. Our findings suggested that blocking palmitoylation led to reduced phosphorylation and blocking phosphorylation led to abrogated palmitoylation of MTIP. As a result of the crosstalk between these biomolecular events, MTIP’s interaction with myosin A was found to be abrogated. Next, the crosstalk between phosphorylation and palmitoylation was confirmed at a global proteome level by click chemistry and the phenotypic effect of this crosstalk was observed via synergistic inhibition in P. falciparum invasion using checkerboard assay and isobologram method. Overall, our findings revealed, for the first time, an interdependence between two PTM types, their possible crosstalk, and its direct impact on MTIP-mediated invasion via glideosome assembly protein myosin A in P. falciparum . These insights can be exploited for futuristic drug discovery platforms targeting parasite molecular machinery for developing novel antimalarial therapeutics.