Screening of Multitarget Compounds against Acetaminophen Hepatic Toxicity Using In Silico, In Vitro, and In Vivo Approaches.

Combination therapy and multitarget drugs have recently attracted much attention as promising tools to fight against many challenging diseases and, thus, represent a new research focus area. The aim of the current project was to screen multitarget compounds and to study their individual and combined effects on acetaminophen-induced liver injury. In this study, 2 of the best hepatoprotective multitargeting compounds were selected from a pool of 40 major compounds present in Curcuma longa and Cinnamomum zeylanicum by using molecular docking, ADMET profiling, and Pfizer's rule of five. The two selected compounds, quercetin and curcumin, showed a high binding affinity for the CYP2E1 enzyme, MAPK, and TLR4 receptors that contribute to liver injury. The candidates caused the decreased viability of cancer cell lines (HepG2 and Huh7) but showed no effect on a normal cell line (Vero). Examination of biochemical parameters (ALT, AST, ALP, and bilirubin) showed the hepatoprotective effect of the candidate drugs in comparison with the control group, which was confirmed by histological findings. Taken together, quercetin and curcumin not only satisfied the drug-like assessment criterion and proved to be multitargeting by preventing liver damage but also showed anticancer activities.

Wind-noise reduction for infrasonic measurements using adaptive line enhancement.

Measurement quality and analysis capability of infrasonic signals are both affected by background wind-noise. Physical filters, i.e., barriers and pipe arrays, are traditionally employed to reduce such noise. However, limited efficacy, site dependence, cost, requirement of space, non-portability, and frequent maintenance are some of their major drawbacks. This work proposes an adaptive filtering-based adaptive line enhancer (ALE) noise cancellation scheme as an alternative. Two infrasonic sensors (Chaparral Physics 50A), are adjacently deployed. One sensor is fitted with a conventional four-armed non-porous hose array (physical filter), while the ALE scheme is applied to the second sensor, sans physical filter. In high wind-noise conditions, the ALE scheme seems to behave as a lowpass filter (cutoff at 0.2 Hz), with a maximum attenuation of 26 dB at 8 Hz, while the physical filter provides significant attenuation only above 4 Hz with a maximum attenuation of 17 dB at 8 Hz. Generally, at other frequencies, the ALE scheme provides up to 20 dB superior noise attenuation as compared to the physical filter. The ALE also provides up to 6 dB gain in the signal-to-noise ratio as compared to the physical filter, due to non-attenuation of the infrasonic signal.

Growth Inhibition of Common Enteric Pathogens in the Intestine of Broilers by Microbially Produced Dextran and Levan Exopolysaccharides.

Antibiotics are generally applied for treatment or as subtherapeutic agents to overcome diseases caused by pathogenic bacteria including Escherichia coli, Salmonella and Enterococcus species in poultry. However, due to their possible adverse effects on animal health and to maintain food safety, probiotics, prebiotics, and synbiotics have been proposed as alternatives to antibiotic growth promoters (AGPs) in poultry production. In this study, the effects of prebiotics on the augmentation of broiler's indigenous gut microbiology were studied. Day old 180 broilers chicks were divided into four treatment groups: G, L, C1, and C2. The groups G and L were fed with basal diet containing 3% dextran and 3% levan, respectively. Control groups were fed with basal diets without antibiotic (C1) and with antibiotics (C2). The experimental groups showed decreased mortality as compared to control groups. After 35 days, the chickens were euthanized and intestinal fluid was analyzed for enteric pathogens on chromogenic agar plates and by 16S rRNA gene sequencing. Inhibition of the growth of E. coli and Enterococcus was observed in groups G and L, respectively, whereas Salmonella was only present in group C1. Also, high populations of lactic acid bacteria were detected in the intestine of prebiotic fed birds as compared to controls. These results depict that dextran and levan have the potential to replace the use of antibiotics in poultry feed for inhibiting the growth of common enteric pathogens. To the best of our knowledge, this is the first study where effects of dextran and levan on intestinal microbiota of broilers have been reported.

Potential role of root membrane phosphatidic acid in superior agronomic performance of silage-corn cultivated in cool climate cropping systems.

The literature is replete with information describing the composition of the root lipidome in several plant species grown under various environmental conditions. However, it is unknown to what extent the root membrane lipidome vary between silage-corn genotypes, and how such variation could influence agronomic performances during field cultivation in cool climate. To address this issue, the root membrane lipidome and agronomic performance were assessed for five silage-corn genotypes (Fusion-RR, Yukon-R, A4177G3-RIB, DKC23-17RIB, DKC26-28RIB) cultivated under cool climatic conditions. Leaf area, plant height and biomass production were used as agronomic performance indicators. Varieties DKC26-28RIB and Yukon-R expressed significantly higher leaf area, plant height and biomass production compared to the other genotypes. A strong positive Spearman rank-order correlation (P = 0.001) was observed between biomass production and root phosphatidic acid (PA). The high correlation observed between PA and agronomic performance indicates PA could potentially be used as biomarker to assist in the selection of silage-corn genotypes with superior agronomic performance ideally suited for field cultivations in cool climatic conditions.

A State Optimization Model Based on Kalman Filtering and Robust Estimation Theory for Fusion of Multi-Source Information in Highly Non-linear Systems.

Consistent state estimation is a vital requirement in numerous real life applications from localization to multi-source information fusion. The Kalman filter and its variants have been successfully used for solving state estimation problems. Kalman filtering-based estimators are dependent upon system model assumptions. A deviation from defined assumptions may lead to divergence or failure of the system. In this work, we propose a Kalman filtering-based robust state estimation model using statistical estimation theory. Its primary intention is for multiple source information fusion, although it is applicable to most non-linear systems. First, we propose a robust state prediction model to maintain state constancy over time. Secondly, we derive an error covariance estimation model to accept deviations in the system error assumptions. Afterward, an optimal state is attained in an iterative process using system observations. A modified robust MM estimation model is executed within every iteration to minimize the impact of outlying observation and approximation errors by reducing their weights. For systems having a large number of observations, a subsampling process is introduced to intensify the optimized solution redundancy. Performance is evaluated for numerical simulation and real multi sensor data. Results show high precision and robustness of proposed scheme in state estimation.

Molecular investigation of foot-and-mouth disease virus circulating in Pakistan during 2014-17.

This study reports the molecular characterization of foot-and-mouth disease virus (FMDV) in the provinces of Punjab and Sindh, Pakistan during 2014-17. FMDV genome was detected in 42 and 41 out of 46 samples (epithelial tissue and saliva) by reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) and reverse transcriptase polymerase chain reaction (RT-PCR), respectively. Sequences of the complete VP1 coding region of the samples (n = 33) was achieved showing that 10, 4 and 19 samples belonged to serotype O, A and Asia1 respectively. Phylogenetic analysis of serotype O revealed that at least one novel sublineage within the ME-SA topotype is circulating in the region, named here as PAK-14. This sublineage showed similarity with the viruses circulating in Turkey and Pakistan during 2010 indicating that viruses circulating in these countries have common origin. Analysis of serotype A viruses revealed a new lineage is circulating in the region, reported here as A-PAK14 showing close identity with the strain prevalent in Pakistan during 2007. Circulation of these new linages in the region shows continuous evolution of the viruses. Two of the undisclosed serotype A sublineages within the Iran-05 lineage were also found circulating in the region. In addition, molecular investigation of the VP1 coding region sequences of serotype Asia1 strains revealed that they belong to Group-VII (Sindh-08). Interestingly some of the serotype Asia1 isolates (n = 6) showed 99.9% similarity (among themselves) although they were collected from different districts more than 100 Km apart from one another. This unusual conservation among serotype Asia1 over long distances can be explored by studying the role of wild animals, slaughter houses and milk collection centres in the spread the disease.

History of Gumboro (infectious bursal disease) in Pakistan.

Infectious Bursal Disease is the second important viral disease of poultry which affects the young growing pullets. The end fate appears in huge economic losses to poultry industry. Throughout the world, cheapest source of animal protein is chicken meat. It was initially reported in Europe; soon it spreads worldwide and causes drastic losses. In Pakistan, first of all this disease was reported in 1971. It is the first review to track the IBDV history in Pakistan. It provides comprehensive details of forty-six years researchers work in controlling this important disease. Different scientists worked to fill the gap areas to achieve the goal. Present review covers all the research aspects being explored in Pakistan since first report.

Differentiating Metastatic and Non-metastatic Tumor Cells from Their Translocation Profile through Solid-State Micropores.

Cancer treatment, care, and outcomes are much more effective if started at early stages of the disease. The presence of malignant cancer cells in human samples such as blood or biopsied tissue can be used to reduce overtreatment and underdiagnosis as well as for prognosis monitoring. Reliable quantification of metastatic tumor cells (MTCs) and non-metastatic tumor cells (NMTCs) from human samples can help in cancer staging as well. We report a simple, fast, and reliable approach to identify and quantify metastatic and non-metastatic cancer cells from whole biological samples in a point-of-care manner. The metastatic (MDA MB-231) and non-metastatic (MCF7) breast cancer cells were pushed through a solid-state micropore made in a 200 nm thin SiO2 membrane while measuring current across the micropore. The cells generated very distinctive translocation profiles. The translocation differences stemmed from their peculiar mechanophysical properties. The detection efficiency of the device for each type of tumor cells was ∼75%. MTCs showed faster translocation (36%) and 34% less pore blockage than NMTCs. The micropore approach is simple, exact, and quantitative for metastatic cell detection in a lab-on-a chip setting, without the need for any preprocessing of the sample.

Electromechanical transducer for rapid detection, discrimination and quantification of lung cancer cells.

Tumor cells are malignant derivatives of normal cells. There are characteristic differences in the mechanophysical properties of normal and tumor cells, and these differences stem from the changes that occur in the cell cytoskeleton during cancer progression. There is a need for viable whole blood processing techniques for rapid and reliable tumor cell detection that do not require tagging. Micropore biosensors have previously been used to differentiate tumor cells from normal cells and we have used a micropore-based electromechanical transducer to differentiate one type of tumor cells from the other types. This device generated electrical signals that were characteristic of the cell properties. Three non-small cell lung cancer (NSCLC) cell lines, NCl-H1155, A549 and NCI-H460, were successfully differentiated. NCI-H1155, due to their comparatively smaller size, were found to be the quickest in translocating through the micropore. Their translocation through a 15 µm micropore caused electrical pulses with an average translocation time of 101 ± 9.4 µs and an average peak amplitude of 3.71 ± 0.42 µA, whereas translocation of A549 and NCI-H460 caused pulses with average translocation times of 126 ± 17.9 µs and 148 ± 13.7 µs and average peak amplitudes of 4.58 ± 0.61 µA and 5.27 ± 0.66 µA, respectively. This transformation of the differences in cell properties into differences in the electrical profiles (i.e. the differences in peak amplitudes and translocation times) with this electromechanical transducer is a quantitative way to differentiate these lung cancer cells. The solid-state micropore device processed whole biological samples without any pre-processing requirements and is thus ideal for point-of-care applications.

Micro+nanotexturing of substrates to enhance ligand-assisted cancer cell isolation.

This paper presents a simple approach to create a two-tiered surface for superior cancer cell isolation. The idea is inspired by the interactions of cells with a nanotextured basement membrane. The texture mimicked the extracellular matrix and basement membrane for superior target cell adhesion. Prepared micro+nanotextured surfaces showed enhanced cell capture. Preparation of the two-tiered surface was done using micro- and nanotexturing and was easily reproducible. It has been shown before that the larger surface area of a nanotextured surface assists the cell's attachment through surface-anchored ligands. Taking it a step further, ligand functionalized two-level micro+nanotextured surfaces improved the sensitivity of the cancer cell isolation over simple flat nanotexturing. The isolation efficiency increased by 208% compared to the surface with a single-level nanotexture. The two-tiered surface was compatible with previously reported nanotextured devices used for cancer cell isolation. Micro-texture on the glass surface was created using simple sand gritting, followed by reactive ion etching (RIE) of the entire surface. The approach could create large surface areas within a short time while maintaining superior cell isolation efficiency.

Ischaemic Colitis from an Unusual Cause: Oral Contraceptives.

Ischaemic colitis is responsible for more than half of the presentations of gastrointestinal ischaemia and develops due to an interruption of intestinal blood flow. Risk factors include increasing age and conditions associated with decreased perfusion. Infrequently, ischaemic colitis may develop in young females prescribed oral contraceptives. Here, we present a case of ischaemic colitis secondary to oral contraceptives that resolved with medication discontinuation. LEARNING POINTS: Ischaemic colitis is due to insufficiency of intestinal blood flow and is responsible for half of the cases of gastrointestinal ischaemia.Oral contraceptives have an increased odd of 1.05 predisposing development of ischaemic colitis.Symptoms typically resolve with removal of the oral contraceptive.

Sirtuin insights: bridging the gap between cellular processes and therapeutic applications.

The greatest challenges that organisms face today are effective responses or detection of life-threatening environmental changes due to an obvious semblance of stress and metabolic fluctuations. These are associated with different pathological conditions among which cancer is most important. Sirtuins (SIRTs; NAD+-dependent enzymes) are versatile enzymes with diverse substrate preferences, cellular locations, crucial for cellular processes and pathological conditions. This article describes in detail the distinct roles of SIRT isoforms, unveiling their potential as either cancer promoters or suppressors and also explores how both natural and synthetic compounds influence the SIRT function, indicating promise for therapeutic applications. We also discussed the inhibitors/activators tailored to specific SIRTs, holding potential for diseases lacking effective treatments. It may uncover the lesser-studied SIRT isoforms (e.g., SIRT6, SIRT7) and their unique functions. This article also offers a comprehensive overview of SIRTs, linking them to a spectrum of diseases and highlighting their potential for targeted therapies, combination approaches, disease management, and personalized medicine. We aim to contribute to a transformative era in healthcare and innovative treatments by unraveling the intricate functions of SIRTs.

Exploration of gut microbial diversity of pheasants through pyrosequencing of 16S rRNA gene.

Despite the diversity of microbiota in birds is similar to that of other animals, there is a lack of research on the gut microbial diversity of nondomesticated bird species. This study aims to address this gap in knowledge by analyzing the bacterial communities present in the gut of two important game bird species, the Ring-necked pheasant (Phasianus colchicus) and the Green pheasant (Phasianus versicolor) to understand the gut microbial diversity of these species. The gut microbiome of 10 individual pheasants from two different species was studied using pooled fecal samples. We used 16S rRNA gene sequencing on the Ion S5 XL System next-generation sequencing with Mothur and SILVA Database for taxonomic division. An average of 141 different operational taxonomic units were detected in the gut microbiome. Analysis of microbial classification revealed the presence of 191 genera belonging to 12 different phyla in both pheasants. Alpha diversity indices revealed that P. colchicus exhibited most prevalence firmicutes with bacillus species microbial community than P. versicolor. Alpha diversity indices indicated that P. colchicus had a more diverse community and P. versicolor had a greater diversity of evolutionary lineages, while both species had similar levels of species richness and sample inclusiveness. These findings may have implications for the health and well-being of pheasants, serving as a reference for their bacterial diversity. Additionally, they provide a baseline for future research and conservation efforts aimed at improving the health and well-being of these and possibly other avian species.

A Novel Insight into the Identification of Potential SNP Markers for the Genomic Characterization of Buffalo Breeds in Pakistan.

Domestic buffaloes (Bubalus bubalis), known as water buffaloes, play a key role as versatile multipurpose agricultural animals in the Asiatic region. Pakistan, with the second-largest buffalo population in the world, holds a rich domestication history of buffaloes. The overall trends in buffalo production demand the genomic characterization of Pakistani buffalo breeds. To this end, the resequencing data of Pakistani breeds, along with buffalo breeds from 13 other countries, were retrieved from our previous study. This dataset, which contained 34,671,886 single-nucleotide polymorphisms (SNPs), was analyzed through a pipeline that was developed to compare possible allele differences among breeds at each SNP position. In contrast, other available tools only check for positional SNP differences for breed-specific markers. In total, 1918, 1549, 404, and 341 breed-specific markers were identified to characterize the Nili, Nili-Ravi, Azakheli, and Kundi breeds of Pakistani buffalo, respectively. Sufficient evidence in the form of phenotypic data, principal component analysis, admixture analysis, and linkage analysis showed that the Nili breed has maintained its distinct breed status despite sharing a close evolutionary relationship with the Nili-Ravi breed of buffalo. In this era of genome science, the conservation of these breeds and the further validation of the given selection markers in larger populations is a pressing need.

Nivolumab-induced exocrine pancreatic insufficiency.

Immune checkpoint inhibition is the standard-of-care for many advanced cancers. Side effects of therapy may prevent optimal treatment of the cancer. Management of side effects is dominated by recommendations derived from oncological, not gastroenterological practice. We report a patient who developed pancreatic insufficiency during checkpoint inhibitor therapy with a programmed cell death receptor 1 inhibitor, nivolumab, which if not diagnosed would have prevented ongoing treatment. This is a problem which affects approximately 1 in 100 patients treated with this agent but is rarely recognised. Gastroenterologists need to be aware of the spectrum of gastrointestinal disorders which occur after immunotherapy to treat cancer.

Host Defence Peptides: A Potent Alternative to Combat Antimicrobial Resistance in the Era of the COVID-19 Pandemic.

One of the greatest challenges facing the medical community today is the ever-increasing trajectory of antimicrobial resistance (AMR), which is being compounded by the decrease in our antimicrobial armamentarium. From their initial discovery to the current day, antibiotics have seen an exponential increase in their usage, from medical to agricultural use. Benefits aside, this has led to an exponential increase in AMR, with the fear that over 10 million lives are predicted to be lost by 2050, according to the World Health Organisation (WHO). As such, medical researchers are turning their focus to discovering novel alternatives to antimicrobials, one being Host Defence Peptides (HDPs). These small cationic peptides have shown great efficacy in being used as an antimicrobial therapy for currently resistant microbial variants. With the sudden emergence of the SARS-CoV-2 variant and the subsequent global pandemic, the great versatility and potential use of HDPs as an alternative to conventional antibiotics in treating as well as preventing the spread of COVID-19 has been reviewed. Thus, to allow the reader to have a full understanding of the multifaceted therapeutic use of HDPs, this literature review shall cover the association between COVID-19 and AMR whilst discussing and evaluating the use of HDPs as an answer to antimicrobial resistance (AMR).

Data set showing the development of a hyperspectral imaging technique using LA-ICP-MS to determine the spatial distribution of nutrients in soil cores.

This data in brief article represents the data set associated with a research article published in Geoderma [1]. The data set represents figures showing the spatial distribution of selected macro and micronutrients, and their quantification in different crop or nutrient management systems practiced in the boreal ecosystem. Spatial distribution of nutrients was measured by laser ablation inductively coupled plasma mass spectrometry (LA‒ICP‒MS), using the new techniques we developed to visualize nutrient distribution in intact soil cores representative of the root rhizosphere. This data article supports the findings published in the main article [1]. This work also demonstrates that LA-ICP-MS is a valuable technique to image the spatial distribution of macro and micronutrients in intact soil cores as affected by different crop management practices.

Development of a LAMP assay using a portable device for the real-time detection of cotton leaf curl disease in field conditions.

Cotton production is seriously affected by the prevalent cotton leaf curl disease (CLCuD) that originated from Nigeria (Africa) to various parts of Asia including Pakistan, India, China and Philippines. Due to CLCuD, Pakistan suffers heavy losses approximately 2 billion USD per annum. Numerous reports showed that CLCuD is associated with multiple species of begomoviruses, alphasatellites and a single species of betasatellite, that is 'Cotton leaf curl Multan betasatellite' (CLCuMuB). The most prevalent form of CLCuD is the combination of 'Cotton leaf curl Kokhran virus'-Burewala strain (CLCuKoV-Bur) and CLCuMuB. Thus, the availability of an in-field assay for the timely detection of CLCuD is important for the control and management of the disease. In this study, a robust method using the loop-mediated isothermal amplification (LAMP) assay was developed for the detection of CLCuD. Multiple sets of six primers were designed based on the conserved regions of CLCuKoV-Bur and CLCuMuB-ßC1 genes. The results showed that the primer set targeting the CLCuMuB-ßC1 gene performed best when the LAMP assay was performed at 58°C using 100 ng of total plant tissue DNA as a template in a 25 µl reaction volume. The limit of detection for the assay was as low as 22 copies of total purified DNA template per reaction. This assay was further adapted to perform as a colorimetric and real-time LAMP assay which proved to be advantageously applied for the rapid and early point-of-care detection of CLCuD in the field. Application of the assay could help to prevent the huge economic losses caused by the disease and contribute to the socio-economic development of underdeveloped countries.

Corn-Soybean Intercropping Improved the Nutritional Quality of Forage Cultivated on Podzols in Boreal Climate.

Intercropping systems could be a potential source of nutrient-rich forage production in cool climates on podzolic soils common in boreal ecosystems. In this study, we evaluated the effects of corn-soybean intercropping (IC) on the nutritional quality of forage. Two silage corn varieties were cultivated as monocropping (MC) or were intercropped with three forage soybean varieties using a randomized complete block design. IC significantly increased the crude protein (22%) and decreased the acid detergent (14%) and neutral detergent (6%) fibers. Forage net energy, total digestible nutrients, ash, dry matter intake, digestible dry matter and relative feed value were also significantly increased (p ≤ 0.05) in the IC treatments compared to corn MC. The macro and micro nutrients were higher in IC than corn MC. Intercropping increased the omega 3 fatty acid (FA) contents (67%) compared to corn MC. IC also increased the active microbial community in the plant root zone, which may contribute to the improvement in forage nutritional quality because the active soil microbial community composition showed significant correlations with soluble sugars, soluble proteins and potassium contents of the forage. These results demonstrate that corn-soybean IC could be a suitable cropping system to increase the nutritional quality of forage cultivated on podzols in boreal climates. The resultant forage has the potential to be a source of high-value animal feed for livestock production in cool climate regions of the world.

Heavy metals immobilization and improvement in maize (Zea mays L.) growth amended with biochar and compost.

Soil with heavy metals contamination, mainly lead (Pb), cadmium (Cd), and chromium (Cr) is a progressively worldwide alarming environmental problem. Recently, biochar has been used as a soil amendment to remediate contaminated soils, but little work has been done to compare with other organic amendments like compost. We investigated biochar and compost's comparative effect on Pb, Cd, and Cr immobilization in soil, photosynthesis, and growth of maize plants. Ten kg soil was placed in pots and were spiked with Pb, Cd, and Cr at concentrations 20, 10, 20 mg kg-1. The biochar and compost treatments included 0, 0.5, 1, 2, and 4% were separately applied to the soil. The crop from pots was harvested after 60 days. The results show that the highest reduction of AB-DTPA extractable Pb, Cd, and Cr in soil was 79%, 61% and 78% with 4% biochar, followed by 61%, 43% and 60% with 4% compost compared to the control, respectively. Similarly, the highest reduction in shoot Pb, Cd, and Cr concentration was 71%, 63% and 78%with 4% biochar, followed by 50%, 50% and 71% with 4% compost than the control, respectively. The maximum increase in shoot and dry root weight, total chlorophyll contents, and gas exchange characteristics were recorded with 4% biochar, followed by 4% compost than the control. The maximum increase in soil organic matter and total nitrogen (N) was recorded at 4% biochar application while available phosphorus and potassium in the soil at 4% compost application. It is concluded that both biochar and compost decreased heavy metals availability in the soil, reducing toxicity in the plant. However, biochar was most effective in reducing heavy metals content in soil and plant compared to compost. In the future, more low-cost, eco-friendly soil remediation methods should be developed for better soil health and plant productivity.