Search Results (42)

Human Interleukin-6 (hIL-6) is a pro inflammatory cytokine that binds to its receptor, IL-6Rα followed by binding to gp130 and subsequent dimerization to form a hexamer signaling complex. As a critical inflammation mediator, hIL-6 is associated with a diverse range of diseases and monoclonal antibodies in clinical use that either target IL-6Rα or hIL-6 to inhibit signaling. Here, we perform high-throughput structure-based computational screening using ensemble docking for small-molecule antagonists for which the target conformations were taken from 600 ns long molecular dynamics simulations of the apo protein. Prior knowledge of the contact sites from binary complex studies and experimental work was incorporated into the docking studies. The top 20 scoring ligands from the in silico studies after post analysis were subjected to in vitro functional assays. Among these compounds, the ligand with the second-highest calculated binding affinity experimentally showed an ~84% inhibitory effect on IL6-induced STAT3 reporter activity at 10 μM concentration. This finding may pave the way for designing small-molecule inhibitors of hIL-6 of therapeutic significance. Full article

Both hepatitis B virus (HBV), an hepadnavirus with a DNA genome, and hepatitis A virus (HAV), a picornavirus, require the TRAMP-like host ZCCHC14-TENT4 complex for efficient replication. However, whereas HBV requires the nucleotidyltransferase activity of TENT4 to extend and stabilize the 3′ poly(A) tails of mRNA transcribed from its genome, the role played by TENT4 in HAV replication is uncertain. HAV proteins are synthesized directly from its genomic RNA, which possesses a 3′ poly(A) tail, with its length and composition presumably maintained by 3D^pol-catalyzed RNA transcription during its replicative cycle. Using nanopore long-read sequencing of RNA from infected cells, we confirm here that the length of the HAV 3′ poly(A) tail is not altered by treating infected cells with RG7834, a small molecule TENT4 inhibitor with potent anti-HAV activity. Despite this, TENT4 catalytic activity is essential for HAV replication. Surprisingly, nanopore sequencing revealed a low abundance of HAV subgenomic RNAs (hsRNAs) that extend from the 5′ end of the genome to a site within the 5′ untranslated RNA (5′UTR) immediately downstream of a stem-loop to which the ZCCHC14-TENT4 complex is recruited. These hsRNAs are polyadenylated, and their abundance is sharply reduced by RG7834 treatment, implying they are likely products of TENT4. Similar subgenomic RNAs were not identified in poliovirus-infected cells. hsRNAs are present not only in HAV-infected cell culture but also in the liver of HAV-infected mice, where they represent 1–3% of all HAV transcripts, suggesting their physiological relevance. However, transfecting exogenous hsRNA into TENT4-depleted cells failed to rescue HAV replication, leaving the functional role of hsRNA unresolved. These findings reveal a novel picornaviral subgenomic RNA species while highlighting mechanistic differences in the manner in which HAV and HBV exploit the host ZCCHC4-TENT4 complex for their replication. Full article

Cyclacenes with the general formula C_4nH_2n are cyclic analogs of acenes. Acenes are well-known for their high reactivity, which increases with the number of fused benzene rings. The cyclic strain, absence of a Clar sextet, and diradical or polyradical nature are expected to render cyclacenes highly reactive under ambient conditions. Their primary decomposition pathway is anticipated to involve dimerization or polymerization. We explore the reaction pathway of the [_π4_s + _π4_s] dimerization of [n]-cyclacenes for 6 ≤ n ≤ 20 by density functional theory (DFT) using spin-unrestricted and thermally-assisted-occupation (TAO) formalisms. Computational analysis predicts a stepwise reaction mechanism that starts with the formation of a van der Waals complex and proceeds through a transition state to an intermediate with a single new C–C bond and two unsaturated valences. A subsequent second transition state results in the formation of the dimerization product. However, for smaller cyclacenes (n < 10), neither the van der Waals complex nor the first transition state is involved, and the intermediate is formed without a barrier. The largest [20]-cyclacene investigated exhibits the highest barriers for these processes. However, with a barrier as low as 3.9 kcal/mol at the UB3LYP-D3(BJ)/6-31G(d) level of theory, dimerization is anticipated to occur very rapidly. Full article

Background: Takotsubo Syndrome (TTS) is a transient left ventricular systolic dysfunction typically characterized by anteroseptal-apical dyskinetic ballooning of the left ventricle with a hyperkinetic base, without significant obstructive coronary artery disease. The interplay between systemic inflammation and hemodynamic stress in sepsis exacerbates susceptibility to TTS. We aim to investigate the characteristics and factors associated with TTS in critically ill patients with sepsis admitted to the intensive care unit. Methods: A retrospective cohort study was conducted on 361 patients admitted to the medical ICU at a tertiary care hospital in New York City. All patients underwent transthoracic echocardiography (TTE) within 72 h of sepsis diagnosis. Patients were divided into TTS and non-TTS groups. Clinical data, comorbidities, and hemodynamic parameters were extracted from electronic medical records and analysed using multivariate logistic regression to determine independent predictors of TTS. Results: Among 361 patients, 24 (6.65%) were diagnosed with TTS. Female sex (OR 3.145, 95% CI 1.099–9.003, p = 0.033) and higher shock index (OR 4.454, 95% CI 1.426–13.910, p = 0.010) were significant predictors of TTS. Individuals with ≥ 25 kg/m² had a lower odds of developing TTS as compared to their obese counterparts (OR 0.889, 95% CI 0.815–0.969, p = 0.007). Conclusions: The findings highlight that Female sex, higher shock index and a BMI < 25 kg/m² emerge as possible predictors for development of TTS in patients with sepsis. Further research is needed to unravel the mechanisms behind the “obesity paradox” in TTS and optimize clinical strategies for high-risk patients. Full article

This study investigates the enhancement of organic light-emitting diode (OLED) performance through the integration of titanium dioxide (TiO₂) nanocomposites within a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT/PSS) matrix. The nanocomposite films were prepared using a controlled dispersion of TiO₂ belts into the PEDOT/PSS solution, followed by their incorporation into the OLED hole-injection layer (HIL). Our results demonstrate a significant improvement in device efficiency, attributed to the optimized charge carrier mobility and reduced recombination losses, which were achieved by the presence of TiO₂. The nanocomposite hybrid layer enhances light emission efficiency due to its role in modifying surface roughness, promoting better film uniformity, and improving hole injection. The incorporation of TiO₂ nanobelts into PEDOT/PSS led to significant efficiency enhancements, yielding a 39% increase in PE_max, a 37% improvement in CE_max, and a remarkable 72% rise in EQE_max compared to the undoped counterpart. This research provides insight into the potential of TiO₂ nanocomposites in advancing OLED technology for next-generation display and lighting applications. Full article

Background: Accurate delineation of lesions in acute ischemic stroke is important for determining the extent of tissue damage and the identification of potentially salvageable brain tissues. Automatic segmentation on CT images is challenging due to the poor contrast-to-noise ratio. Quantitative CT perfusion images improve the estimation of the perfusion deficit regions; however, they are limited by a poor signal-to-noise ratio. The study aims to investigate the potential of deep learning (DL) algorithms for the improved segmentation of ischemic lesions. Methods: This study proposes a novel DL architecture, DenseResU-NetCTPSS, for stroke segmentation using multiparametric CT perfusion images. The proposed network is benchmarked against state-of-the-art DL models. Its performance is assessed using the ISLES-2018 challenge dataset, a widely recognized dataset for stroke segmentation in CT images. The proposed network was evaluated on both training and test datasets. Results: The final optimized network takes three image sequences, namely CT, cerebral blood volume (CBV), and time to max (Tmax), as input to perform segmentation. The network achieved a dice score of 0.65 ± 0.19 and 0.45 ± 0.32 on the training and testing datasets. The model demonstrated a notable improvement over existing state-of-the-art DL models. Conclusions: The optimized model combines CT, CBV, and T_max images, enabling automatic lesion identification with reasonable accuracy and aiding radiologists in faster, more objective assessments. Full article

The gas (or plastron) trapped between micro/nano-scale surface textures, such as that on superhydrophobic surfaces, is crucial for many engineering applications, including drag reduction, heat and mass transfer enhancement, anti-biofouling, anti-icing, and self-cleaning. However, the longevity of the plastron is significantly affected by gas diffusion, a process where gas molecules slowly diffuse into the ambient liquid. In this work, we demonstrated that plastron longevity could be extended using a gas-soluble and gas-permeable polydimethylsiloxane (PDMS) surface. We performed experiments for PDMS surfaces consisting of micro-posts and micro-holes. We measured the plastron longevity in undersaturated liquids by an optical method. Our results showed that the plastron longevity increased with increasing the thickness of the PDMS surface, suggesting that gas initially dissolved between polymer chains was transferred to the liquid, delaying the wetting transition. Numerical simulations confirmed that a thicker PDMS material released more gas across the PDMS–liquid interface, resulting in a higher gas concentration near the plastron. Furthermore, we found that plastron longevity increased with increasing pressure differences across the PDMS material, indicating that the plastron was replenished by the gas injected through the PDMS. With increasing pressure, the mass flux caused by gas injection surpassed the mass flux caused by the diffusion of gas from plastron to liquid. Overall, our results provide new solutions for extending plastron longevity and will have significant impacts on engineering applications where a stable plastron is desired. Full article

Groundwater contamination with sub-lethal dissolved contaminants poses significant health risks globally, especially in rural India, where access to safe drinking water remains a critical challenge. This study explores the hydrogeochemical characterization and associated health risks of groundwater from shallow aquifers in the Marginal Ganga Alluvial Plain (MGAP) of northern India. The groundwater chemistry is dominated by Ca-Mg-CO₃ and Ca-Mg-Cl types, where there is dominance of silicate weathering and the ion-exchange processes are responsible for this solute composition in the groundwater. All the ionic species are within the permissible limits of the World Health Organization, except fluoride (F⁻) and nitrate (NO₃⁻). Geochemical analysis using bivariate relationships and saturation plots attributes the occurrence of F⁻ to geogenic sources, primarily the chemical weathering of granite-granodiorite, while NO₃⁻ contaminants are linked to anthropogenic inputs, such as nitrogen-rich fertilizers, in the absence of a large-scale urban environment. Multivariate statistical analyses, including hierarchical cluster analysis and factor analysis, confirm the predominance of geogenic controls, with NO₃⁻-enriched samples derived from anthropogenic factors. The spatial distribution and probability predictions of F⁻ and NO₃⁻ were generated using a non-parametric co-kriging technique approach, aiding in the delineation of contamination hotspots. The integration of the USEPA human health risk assessment methodology with the urbanization index has revealed critical findings, identifying approximately 23% of the study area as being at high risk. This comprehensive approach, which synergizes geospatial analysis and statistical methods, proves to be highly effective in delineating priority zones for health intervention. The results highlight the pressing need for targeted mitigation measures and the implementation of sustainable groundwater management practices at regional, national, and global levels. Full article

Different cropping systems and nutrient management techniques impact the microbiological characteristics of soil and nutrient availability for plants. This study assessed four cropping systems—rice–wheat, cotton–wheat, pearl millet–wheat, and pearl millet–mustard in Hisar district, Haryana, using 80 soil samples (20 from each system) collected in April 2022 after the Rabi crop harvest. The cotton–wheat system had the highest accessible nitrogen (N) at 155.9 kg ha⁻¹, while both the cotton–wheat (59.3 kg ha⁻¹) and rice–wheat (54.0 kg ha⁻¹) systems had higher available sulfur (S) levels compared to pearl millet–wheat (41.2 kg ha⁻¹). Pearl millet–wheat also showed 12.4% higher potassium (K) levels than rice–wheat. The rice–wheat system exhibited the highest phosphorus (P) concentration at 54.3 kg ha⁻¹ and greater DTPA-extractable micronutrients. Soils from the rice–wheat system had higher DTPA-extractable micronutrients (Zn, Fe, Mn, Cu) and superior microbial biomass nitrogen (MBN, 54.7 mg kg⁻¹), urease (37.9 µg NH₄⁺-N g⁻¹ h⁻¹), and alkaline phosphatase activity (APA, 269.7 µg PNP g⁻¹ h⁻¹) compared to other systems. Canonical discriminant functions explained 88.1% of the variability among cropping systems, while principal component analysis identified available P, DTPA-extractable Zn, and Cu as key soil quality indicators, accounting for 66.9% of the variance. These insights can inform policymakers on promoting effective cropping systems and sustainable soil health in northwestern India. Full article

Functionally Graded Metamaterials (FGMMs) constitute an innovative class of materials within the realm of additive manufacturing (AM), attracting substantial attention from material science and research communities. These materials, characterized by unique designs and gradient properties, are not commonly found in nature but are deliberately engineered through the arrangement of subwavelength structures. The distinct attributes of such materials have propelled them into significant prominence across various industries, including automotive, aerospace, medical, electronics, and agriculture. This review paper aims to present a comprehensive overview of a range of techniques applied in the fabrication, design, theoretical models, and simulation methods related to these materials. It delves into the assessment of such material’s performance, specifically focusing on mechanical, thermal, and electromagnetic properties. Moreover, this review addresses advancements, challenges, and potential solutions in the field. Ultimately, it delivers valuable insights to researchers, practitioners, and stakeholders, enhancing their understanding of FGMMs and their significance in the broader context. Full article

Information on the long-term effects of the addition of organics and fertilizers to wheat under the pearl millet–wheat cropping system with semi-arid conditions in north-western India is still lacking. The present research was conducted in an ongoing field experiment initiated during Rabi 1995 at the Research Farm of Chaudhary Charan Singh at Haryana Agricultural University, Hisar. After 25 years, the impacts of nutrient management practices on soil fertility and wheat productivity were evaluated. The experiment comprised a total of eight treatment combinations viz. half and full doses of recommended fertilizers (N and P), organic manures (FYM: farmyard manure, POM: poultry manure, and PRM: press mud) alone and in combination with NP fertilizers. The conjoint application of organic manure and chemical fertilizers resulted in a positive influx of nutrients via increasing total organic carbon (TOC), available N, P, K, and S, which ranged from 0.46 to 1.42%, 122.70 to 194.70, 15.66 to 74.92, 340.5 to 761.2, and 15.26 to 54.63 kg ha⁻¹ in surface soil (0–15 cm), respectively. Carbon fractions and crop yield were significantly improved by adopting integrated nutrient management (INM). The TOC showed a positive and significant correlation with C fractions (r > 0.92) and with soil-available N, P, K, and S (r > 0.77) content. The data also revealed a strong relationship between TOC and soil-available (0–15 cm) nutrients i.e., available N (R²= 0.769), available P (R² = 0.881), available K (R² = 0.758), and available S (R² = 0.914), respectively. Thus, practices that increased TOC were also beneficial in enhancing the availability of the nutrients in the soil. A positive and highly significant correlation was also found among wheat yield, nutrient (NPKS) content, and uptake. A polynomial relationship between grain yield and grain N (R² = 0.962), P (R² = 0.946), and K (R² = 0.967) content, and between straw yield and straw N (R² = 0.830), P (R² = 0.541) and K (R² = 0.976) content was obtained. Integrated use of PRM_7.5 followed by FYM₁₅ and POM₅ coupled with NP fertilizers proved best, which could be beneficial for obtaining nutritious and highest wheat yield (grain: 6.01 t ha⁻¹ and straw: 7.70 t ha⁻¹) coupled with improved fertility within a sustained manner under the pearl millet–wheat sequence in prevailing semi-arid conditions of the North Indian state of Haryana. Full article

Malaria parasites increase their host erythrocyte’s permeability to obtain essential nutrients from plasma and facilitate intracellular growth. In the human Plasmodium falciparum pathogen, this increase is mediated by the plasmodial surface anion channel (PSAC) and has been linked to CLAG3, a protein integral to the host erythrocyte membrane and encoded by a member of the conserved clag multigene family. Whether paralogs encoded by other clag genes also insert at the host membrane is unknown; their contributions to PSAC formation and other roles served are also unexplored. Here, we generated transfectant lines carrying epitope-tagged versions of each CLAG. Each paralog is colocalized with CLAG3, with concordant trafficking via merozoite rhoptries to the host erythrocyte membrane of newly invaded erythrocytes. Each also exists within infected cells in at least two forms: an alkaline-extractable soluble form and a form integral to the host membrane. Like CLAG3, CLAG2 has a variant region cleaved by extracellular proteases, but CLAG8 and CLAG9 are protease resistant. Paralog knockout lines, generated through CRISPR/Cas9 transfection, exhibited uncompromised growth in PGIM, a modified medium with higher physiological nutrient levels; this finding is in marked contrast to a recently reported CLAG3 knockout parasite. CLAG2 and CLAG8 knockout lines exhibited compensatory increases in the transcription of the remaining clags and associated rhoph genes, yielding increased PSAC-mediated uptake for specific solutes. We also report on the distinct transport properties of these knockout lines. Similar membrane topologies at the host membrane are consistent with each CLAG paralog contributing to PSAC, but other roles require further examination. Full article

This general review paper presents a condensed view of recent inventions in the Additive Manufacturing (AM) field. It outlines factors affecting the development and commercialization of inventions via research collaboration and discusses breakthroughs in materials and AM technologies and their integration with emerging technologies. The paper explores the impact of AM across various sectors, including the aerospace, automotive, healthcare, food, and construction industries, since the 1970s. It also addresses challenges and future directions, such as hybrid manufacturing and bio-printing, along with socio-economic and environmental implications. This collaborative study provides a concise understanding of the latest inventions in AM, offering valuable insights for researchers, practitioners, and decision makers in diverse industries and institutions. Full article

In this paper, we report the effect of metal oxide (Fe₂O₃) loading in different weight ratios (0.5%, 1%, 2%, and 4%) on the structural and electrical parameters, viz., the complex dielectric constant, electric modulus spectra, and the AC conductivity, of polymeric composites of PVDF/PMMA (30/70 weight ratio) blend. The structural and geometric measurements have been analyzed with the help of peak location, peak intensity, and peak shape obtained from XRD as well as from FTIR spectra. The electrical properties have been investigated using an impedance analyzer in the frequency range 100 Hz to 1 MHz. The real parts of the complex permittivity and the dielectric loss tangent of these materials are found to be frequency independent in the range from 20 KHz to 1 MHz, but they increase with the increase in the concentration of nano-Fe₂O₃. The conductivity also increases with an increased loading of Fe₂O₃ in PVDF/PMMA polymer blends. The electric modulus spectra were used to analyze the relaxation processes associated with the Maxwell–Wagner–Sillars mechanism and chain segmental motion in the polymer mix. Full article