Quantitative Proteomics in Translational Absorption, Distribution, Metabolism, and Excretion and Precision Medicine.

A reliable translation of in vitro and preclinical data on drug absorption, distribution, metabolism, and excretion (ADME) to humans is important for safe and effective drug development. Precision medicine that is expected to provide the right clinical dose for the right patient at the right time requires a comprehensive understanding of population factors affecting drug disposition and response. Characterization of drug-metabolizing enzymes and transporters for the protein abundance and their interindividual as well as differential tissue and cross-species variabilities is important for translational ADME and precision medicine. This review first provides a brief overview of quantitative proteomics principles including liquid chromatography-tandem mass spectrometry tools, data acquisition approaches, proteomics sample preparation techniques, and quality controls for ensuring rigor and reproducibility in protein quantification data. Then, potential applications of quantitative proteomics in the translation of in vitro and preclinical data as well as prediction of interindividual variability are discussed in detail with tabulated examples. The applications of quantitative proteomics data in physiologically based pharmacokinetic modeling for ADME prediction are discussed with representative case examples. Finally, various considerations for reliable quantitative proteomics analysis for translational ADME and precision medicine and the future directions are discussed. SIGNIFICANCE STATEMENT: Quantitative proteomics analysis of drug-metabolizing enzymes and transporters in humans and preclinical species provides key physiological information that assists in the translation of in vitro and preclinical data to humans. This review provides the principles and applications of quantitative proteomics in characterizing in vitro, ex vivo, and preclinical models for translational research and interindividual variability prediction. Integration of these data into physiologically based pharmacokinetic modeling is proving to be critical for safe, effective, timely, and cost-effective drug development.

USP11 modulates mitotic progression and senescence by regulating the p53-p21 axis through MDM2 deubiquitination.

USP11 is overexpressed in colorectal cancer (CRC) and breast cancer tissues compared to normal tissues, suggesting a role in promoting cell proliferation and inhibiting cell death. In this study, we observed that depleting USP11 inhibits cell proliferation and delays cell cycle progression. This depletion leads to increased p53 protein levels due to an extended half-life, resulting in elevated p21 mRNA levels in a p53-dependent manner. The rise in p53 protein upon USP11 depletion is linked to a reduced half-life of MDM2, a known E3 ligase for p53, via enhanced polyubiquitination of MDM2. These findings indicate that USP11 might act as a deubiquitinase for MDM2, regulating the MDM2-p53-p21 axis. Additionally, USP11 depletion promotes the induction of senescent cells in a manner dependent on its deubiquitinase activity. Our findings provide insights into the physiological significance of high USP11 expression in primary tumors and its reduction in senescent cells, highlighting its potential as a therapeutic target.

A review on endophytic fungi: a potent reservoir of bioactive metabolites with special emphasis on blight disease management.

Phytopathogenic microorganisms have caused blight diseases that present significant challenges to global agriculture. These diseases result in substantial crop losses and have a significant economic impact. Due to the limitations of conventional chemical treatments in effectively and sustainably managing these diseases, there is an increasing interest in exploring alternative and environmentally friendly approaches for disease control. Using endophytic fungi as biocontrol agents has become a promising strategy in recent years. Endophytic fungi live inside plant tissues, forming mutually beneficial relationships, and have been discovered to produce a wide range of bioactive metabolites. These metabolites demonstrate significant potential for fighting blight diseases and provide a plentiful source of new biopesticides. In this review, we delve into the potential of endophytic fungi as a means of biocontrol against blight diseases. We specifically highlight their significance as a source of biologically active compounds. The review explores different mechanisms used by endophytic fungi to suppress phytopathogens. These mechanisms include competing for nutrients, producing antifungal compounds, and triggering plant defense responses. Furthermore, this review discusses the challenges of using endophytic fungi as biocontrol agents in commercial applications. It emphasizes the importance of conducting thorough research to enhance their effectiveness and stability in real-world environments. Therefore, bioactive metabolites from endophytic fungi have considerable potential for sustainable and eco-friendly blight disease control. Additional research on endophytes and their metabolites will promote biotechnology solutions.

Do probiotic interventions improve female unexplained infertility? A critical commentary.

Disruption of women's gut and cervicovaginal microbiota has been associated with multiple gynaecological diseases such as endometriosis, polycystic ovary syndrome, non-cyclic pelvic pain and infertility. Female infertility affects 12.6% of women worldwide; its aetiology is complex and multifactorial and can be underpinned by uterine pathologies, systemic diseases and age. In addition, a new perspective has emerged on the role of the gut and vaginal microbiomes in reproductive health. Research shows that the administration of precisely selected probiotics, often in combination with prior antibiotic treatment, may facilitate the restoration of symbiotic microbiota to increase successful conception and assisted reproductive technology outcomes. However, clarity on this issue from fuller research is currently hampered by a lack of consistency and harmonization in clinical studies: various lactobacilli and bifidobacteria species have been delivered through both the oral and vaginal routes, in different dosages, for different treatment durations. This commentary explores the intricate relationship between the microbiota in the cervicovaginal area and gut of women, exploring their potential contribution to infertility. It highlights ongoing research on the use of probiotic formulations in improving pregnancy outcomes, critically examining the divergent findings in these studies, which complicate a conclusive assessment of the efficacy of these interventions.

In Silico Identification and Characterization of Rare Cold Inducible 2 (RCI2) Gene Family in Cotton.

RCI2/PMP3s are involved in biotic and abiotic stresses and have an influence on the regulation of many genes. RCI2/PMP3 genes, which particularly encode small membrane proteins of the PMP3 family, are involved in abiotic stress responses in plants. In this work, in silico studies were used to investigate RCI2's potential function in stress tolerance and organogenesis. We conducted an extensive study of the RCI2 gene family and revealed 36 RCI2 genes from cotton species that were distributed over 36 chromosomes of the cotton genome. Functional and phylogenetic examination of the RCI2/PMP3 gene family has been studied in Arabidopsis, but in cotton, the RCI2/PMP3 genes have not yet been studied. Phylogenetic and sequencing studies revealed that cotton RCI2s are conserved, with most of them categorized into six distinct clades. A chromosome distribution and localization study indicated that cotton RCI2 genes were distributed unevenly on 36 chromosomes with segmental duplications, suggesting that the cotton RCI2 family is evolutionarily conserved. Many cis-elements related to stress responsiveness, development, and hormone responsiveness were detected in the promoter regions of the cotton RCI2. Moreover, the 36 cotton RCI2s revealed tissue-specific expression patterns in the development of cotton performed by transcriptome analysis. Gene structure analysis indicated that nearly all RCI2 genes have two exons and one intron. All of the cotton RCI2 genes were highly sensitive to drought, abscisic acid, salt, and cold treatments, demonstrating that they may be employed as genetic objects to produce stress-resistant plants.

Untargeted metabolomics, optimization of microwave-assisted extraction using Box-Behnken design and evaluation of antioxidant, and antidiabetic activities of sugarcane bagasse.

INTRODUCTION: The fruit wastes, in particular agricultural wastes, are considered potential and inexpensive sources of bioactive compounds. OBJECTIVE: The current study was aimed at the preparation of an optimized extract of sugarcane bagasse using microwave-assisted extraction (MAE) technology and comparative evaluation of chemical composition, antioxidant, and antidiabetic activities with extract prepared through maceration technique. METHODOLOGY: Box-Behnken Design (BDD) with response surface methodology was applied to observe interactions of three independent variables (ethanol concentrations [%], microwave power [W], and extraction time [min]) on the dependent variables (total phenolic content [TPC] and antioxidant status via 2,2-diphenyl-1-picrylhydrazyl [DPPH] to establish optimal extraction conditions. The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) analysis was applied for untargeted metabolite profiling, and in vitro assays were used for evaluation of the antidiabetic and antioxidant potential of the extract. Moreover, an in silico study was used to predict the interaction of five dominant compounds from the UHPLC-Q-TOF-MS profile against the dipeptidyl peptidase-IV (DPP-IV) enzyme. RESULTS: The optimal conditions for the extraction were established at 60% (v/v) ethanol, 500 W microwave power, and 5 min time with TPC 12.83 ± 0.66 mg GAE/g d.w. and DPPH 45.09 ± 0.07%. The UHPLC-Q-TOF-MS analysis revealed the presence of a total of 106 compounds in the extract. Moreover, the extract prepared through MAE technology presented higher TPC and DPPH findings than the extract prepared through maceration. Similarly, the extract was also found with good antidiabetic activity by inhibiting the DPP-IV enzyme which was also rectified theoretically by a molecular docking study. CONCLUSION: The current study presents a sustainable and an optimized approach for the preparation of sugarcane bagasse extract with functional phytoconstituents and higher antidiabetic and antioxidant activities.

Evaluation of the antifungal properties of nanoliposomes containing rhinacanthin-C isolated from the leaves of Rhinacanthus nasutus.

Fungal infections represent a challenging threat to the human health. Microsporum gypseum and Trichophyton rubrum are pathogenic fungi causing various topical mycoses in humans. The globally emerging issue of resistance to fungi demands the development of novel therapeutic strategies. In this context, the application of nanoliposomes as vehicles for carrying active therapeutic agents can be a suitable alternative. In this study, rhinacanthin-C was isolated from Rhinacanthus naustus and encapsulated in nano-liposomal formulations, which were prepared by the modified ethanol injection method. The two best formulations composed of soybean phosphatidylcholine (SPC), cholesterol (CHL), and tween 80 (T80) in a molar ratio of 1:1:0 (F1) and 1:1:0.5 (F2) were proceeded for experimentation. The physical characteristics and antifungal activities were performed and compared with solutions of rhinacanthin-C. The rhinacanthin-C encapsulating efficiencies in F1 and F2 were 94.69 ± 1.20% and 84.94 ± 1.32%, respectively. The particle sizes were found to be about 221.4 ± 13.76 nm (F1) and 115.8 ± 23.33 nm (F2), and zeta potential values of -38.16 mV (F1) and -40.98 mV (F2). Similarly, the stability studies of rhinacanthin-C in liposomes demonstrated that rhinacanthin-C in both formulations was more stable in mediums with pH of 4.0 and 6.6 than pure rhinacanthin-C when stored at the same conditions. Rhinacanthin-C in F1 was slightly more stable than F2 when stored in mediums with a pH of 10.0 after three months of storage. However, rhinacanthin-C in both formulations was less stable than pure rhinacanthin-C in a basic medium of pH 10.0. The antifungal potential was evaluated against M. gypsum and T. rubrum. The findings revealed a comparatively higher zone of inhibition for F1. In the MIC study, SPC: CHL: T80 showed higher inhibition against M. gypseum and a slightly higher inhibition against T. rubrum compared to free rhinacanthin-C solution. Moreover, rhinacanthin-C showed significant interaction against 14α-demethylase in in silico study. Overall, this study demonstrates that nanoliposomes containing rhinacanthin-C can improve the stability and antifungal potential of rhinacanthin-C with sustained and prolonged duration of action and could be a promising vehicle for delivery of active ingredients for targeting various fungal infections.

Gestational diabetes mellitus as a risk factor for future Type-2 diabetes mellitus: An experience from a tertiary care diabetes hospital, Karachi - Pakistan.

Objective: To evaluate the history of gestational diabetes mellitus and other risk factors in women presenting with Type-2 diabetes mellitus at a tertiary care hospital. Methods: This cross-sectional study was carried out at Baqai Institute of Diabetology & Endocrinology (BIDE), Baqai Medical University (BMU), Karachi-Pakistan from July 2019 to May 2022. Women with Type-2 diabetes mellitus (T2DM) visiting outpatient department of BIDE with a previous history of GDM were recruited. Details were obtained on pre-designed questionnaire after taking informed written consent. Results: A total of 378 women who had a prior history of GDM were included. Mean age (years) was 43.53±10.17. Mostly women were obese (BMI = 30.53±6.08) and have sedentary lifestyle. Mean HbA1c (%) was 9.08±2.24. This study found family history of T2DM and hypertension were common risk factors in women with GDM history. Mostly, women were diagnosed as GDM during 2nd trimester 153(42%) and was mainly seen in multiparous women (occur in 4th and above pregnancy). We found hypertension as common complication during pregnancy. Around 46% women developed T2DM within one year of GDM diagnosis, and 29.6% between one to five years. Conclusion: Majority of women with GDM developed T2DM within five years of diagnosis. The potential associated risk factors were age, family history of diabetes, insulin use during pregnancy, trimester of GDM diagnosis, and hypertension during pregnancy. Awareness and life style modifications along with regular post-partum follow up with screening for T2DM should be part of GDM management to prevent or delay the occurrence of this serious complication.

Multi-functional regulation of cGAS by the nuclear localization signal2 (NLS2) motif: Nuclear localization, enzyme activity and protein degradation.

Cyclic GMP-AMP synthase (cGAS), which recognizes double-stranded DNA (dsDNA) and activates the innate immune system, is mainly localized in the cytosol, but also shows nuclear localization. Here, we sought to determine the role of nuclear cGAS by mutating known nuclear localization signal (NLS) motifs in cGAS and assessing its functionality by monitoring phosphorylation of the downstream target, interferon regulatory factor-3 (IRF3). Interestingly, NLS2-mutated cGAS failed to promote phosphorylation of IRF3, reflecting the loss of its ability to produce cyclic GMP-AMP (cGAMP). We further found that insertion of an NLS from SV40 large T antigen could not restore this loss of activity, indicating that this loss was attributable to the mutation of NLS2 itself, but not dependent on the inability of cGAS to enter the nucleus. NLS2-mutant cGAS protein also showed decreased stability dependent on polyubiquitination, an effect that was independent of both its loss of catalytic function and its inability to enter into the nucleus. Collectively, these findings indicate that the NLS2 motif of cGAS is not only involved in regulating the subcellular localization of cGAS protein but also influences its stability and enzymatic activity through independent mechanisms, highlighting the novel roles of NLS2 in regulating the intracellular functions of cGAS.

Relevance of Human Aldoketoreductases and Microbial ß-Glucuronidases in Testosterone Disposition.

Testosterone exhibits high variability in pharmacokinetics and glucuronidation after oral administration. Although testosterone metabolism has been studied for decades, the impact of UGT2B17 gene deletion and the role of gut bacterial ß-glucuronidases on its disposition are not well characterized. We first performed an exploratory study to investigate the effect of UGT2B17 gene deletion on the global liver proteome, which revealed significant increases in proteins from multiple biological pathways. The most upregulated liver proteins were aldoketoreductases [AKR1D1, AKR1C4, AKR7A3, AKR1A1, and 7-dehydrocholesterol reductase (DHCR7)] and alcohol or aldehyde dehydrogenases (ADH6, ADH1C, ALDH1A1, ALDH9A1, and ALDH5A). In vitro assays revealed that AKR1D1 and AKR1C4 inactivate testosterone to 5ß-dihydrotestosterone (5ß-DHT) and 3α,5ß-tetrahydrotestosterone (3α,5ß-THT), respectively. These metabolites also appeared in human hepatocytes treated with testosterone and in human serum collected after oral testosterone dosing in men. Our data also suggest that 5ß-DHT and 3α, 5ß-THT are then eliminated through glucuronidation by UGT2B7 in UGT2B17 deletion individuals. Second, we evaluated the potential reactivation of testosterone glucuronide (TG) after its secretion into the intestinal lumen. Incubation of TG with purified gut microbial ß-glucuronidase enzymes and with human fecal extracts confirmed testosterone reactivation into testosterone by gut bacterial enzymes. Both testosterone metabolic switching and variable testosterone activation by gut microbial enzymes are important mechanisms for explaining the disposition of orally administered testosterone and appear essential to unraveling the molecular mechanisms underlying UGT2B17-associated pathophysiological conditions. SIGNIFICANCE STATEMENT: This study investigated the association of UGT2B17 gene deletion and gut bacterial ß-glucuronidases with testosterone disposition in vitro. The experiments revealed upregulation of AKR1D1 and AKR1C4 in UGT2B17 deletion individuals, and the role of these enzymes to inactivate testosterone to 5ß-dihydrotestosterone and 3α, 5ß-tetrahydrotestosterone, respectively. Key gut bacterial species responsible for testosterone glucuronide activation were identified. These data are important for explaining the disposition of exogenously administered testosterone and appear essential to unraveling the molecular mechanisms underlying UGT2B17-associated pathophysiological conditions.

Functional characterization of transcriptional activator gene SIARRI in tomato reveals its role in fruit growth and ripening.

Auxins regulate several characteristics of plant development and growth. Here, we characterized a new transcriptional activator SIARRI which binds specific DNA sequences and was revealed in Arabidopsis (ARR1). SIARRI acts as a two-component response regulator and its Arabidopsis homologous gene is AT3G16857. It belongs to the subfamily of type-B response regulators in the cytokinin signaling pathway. The study aimed to characterize the transgenic Micro-Tom plants by the overexpression of Solanum lycopersicum two-component response regulator ARR1. Overexpression of SIARRI results in a pleiotropic phenotype during fruit development and ripening. This study indicates that SIARRI is a primary regulator of leaf morphology and fruit development. Moreover, overexpressed plants showed variations in growth related to auxin as well as shorter hypocotyl elongation, enlarged leaf vascularization, and decreased apical dominance. The qRT-PCR investigation revealed that expression was downregulated at the breaker stage and high at Br+6 at various stages of fruit growth and ripening. In contrast to the fruit color, lycopene and ß-carotene concentrations in red-yellow overexpression line fruits were reduced significantly, and also slightly reduced in some red fruits. The quantity of ß-carotene in the transgenic fruits was lower than that of lycopene. This study showed that this gene might be a new transcriptional activator in fruit development and ripening. Furthermore, this study will provide new insights into tomato fruit ripening.

Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling.

Rats are extensively used as a preclinical model for assessing drug pharmacokinetics (PK) and tissue distribution; however, successful translation of the rat data requires information on the differences in drug metabolism and transport mechanisms between rats and humans. To partly fill this knowledge gap, we quantified clinically relevant drug-metabolizing enzymes and transporters (DMETs) in the liver and different intestinal segments of Sprague-Dawley rats. The levels of DMET proteins in rats were quantified using the global proteomics-based total protein approach (TPA) and targeted proteomics. The abundance of the major DMET proteins was largely comparable using quantitative global and targeted proteomics. However, global proteomics-based TPA was able to detect and quantify a comprehensive list of 66 DMET proteins in the liver and 37 DMET proteins in the intestinal segments of SD rats without the need for peptide standards. Cytochrome P450 (Cyp) and UDP-glycosyltransferase (Ugt) enzymes were mainly detected in the liver with the abundance ranging from 8 to 6502 and 74 to 2558 pmol/g tissue. P-gp abundance was higher in the intestine (124.1 pmol/g) as compared to that in the liver (26.6 pmol/g) using the targeted analysis. Breast cancer resistance protein (Bcrp) was most abundant in the intestinal segments, whereas organic anion transporting polypeptides (Oatp) 1a1, 1a4, 1b2, and 2a1 and multidrug resistance proteins (Mrp) 2 and 6 were predominantly detected in the liver. To demonstrate the utility of these data, we modeled digoxin PK by integrating protein abundance of P-gp and Cyp3a2 into a physiologically based PK (PBPK) model constructed using PK-Sim software. The model was able to reliably predict the systemic as well as tissue concentrations of digoxin in rats. These findings suggest that proteomics-informed PBPK models in preclinical species can allow mechanistic PK predictions in animal models including tissue drug concentrations.

Predilation Ballooning in High Thrombus Laden STEMIs: An Independent Predictor of Slow Flow/No-Reflow in Patients Undergoing Emergent Percutaneous Coronary Revascularization.

Background: Distal embolization due to microthrombus fragments formed during predilation ballooning is considered one of the possible mechanisms of slow flow/no-reflow (SF/NR). Therefore, this study aimed to compare the incidence of intraprocedure SF/NR during the primary percutaneous coronary intervention (PCI) in patients with high thrombus burden (≥4 grade) with and without predilation ballooning for culprit lesion preparation. Methodology. This prospective descriptive cross-sectional study included patients with a high thrombus burden (≥4 grades) who underwent primary PCI. Propensity-matched cohorts of patients with and without predilation ballooning in a 1 : 1 ratio were compared for the incidence of intraprocedure SF/NR. Results: A total of 765 patients with high thrombus burden undergoing primary PCI were included in this study. The mean age was 55.75 ± 11.54 years, and 78.6% (601) were males. Predilation ballooning was conducted in 346 (45.2%) patients. The incidence of intraprocedure SF/NR was significantly higher (41.3% vs. 27.4%; p < 0.001) in patients with predilation ballooning than in those without preballooning, respectively. The incidence of intraprocedure SF/NR also remained significantly higher for the predilation ballooning cohort with an incidence rate of 41.3% as against 30.1% (p=0.002) for the propensity-matched cohort of patients without predilation ballooning with a relative risk of 1.64 (95% CI: 1.20 to 2.24). Moreover, the in-hospital mortality rate remained higher but insignificant, among patients with and without predilation ballooning (8.1% vs. 4.9%; p=0.090). Conclusion: In conclusion, predilation ballooning can be associated with an increased risk of incidence of intraprocedure SF/NR during primary PCI in patients with high thrombus burden.

Hybrid FSK-FDM Scheme for Data Rate Enhancement in Dual-Function Radar and Communication.

In this paper, we present a hybrid frequency shift keying and frequency division multiplexing (i.e., FSK-FDM) approach for information embedding in dual-function radar and communication (DFRC) design to achieve an improved communication data rate. Since most of the existing works focus on merely two-bit transmission in each pulse repetition interval (PRI) using different amplitude modulation (AM)- and phased modulation (PM)-based techniques, this paper proposes a new technique that doubles the data rate by using a hybrid FSK-FDM technique. Note that the AM-based techniques are used when the communication receiver resides in the side lobe region of the radar. In contrast, the PM-based techniques perform better if the communication receiver is in the main lobe region. However, the proposed design facilitates the delivery of information bits to the communication receivers with an improved bit rate (BR) and bit error rate (BER) regardless of their locations in the radar's main lobe or side lobe regions. That is, the proposed scheme enables information encoding according to the transmitted waveforms and frequencies using FSK modulation. Next, the modulated symbols are added together to achieve a double data rate using the FDM technique. Finally, each transmitted composite symbol contains multiple FSK-modulated symbols, resulting in an increased data rate for the communication receiver. Numerous simulation results are presented to validate the effectiveness of the proposed technique.

Evaluating the Aphrodisiac Potential of Mirabilis jalapa L. Root Extract: Phytochemical Profiling and In Silico, In Vitro, and In Vivo Assessments in Normal Male Rats.

The traditional use of Mirabilis jalapa L. roots to enhance male sexual performance prompted us to assess the in silico, in vitro, and in vivo aphrodisiac activities of its hydroethanolic extract using normal male rats. Spectroscopic characterization indicated the presence of ß-D-glucopyranoside, methyl-1,9-benzyl-2,6-dichloro-9H-purine, and Bis-(2-ethylhexyl)-phthalate; these compounds have a significant inhibitory effect on the phosphodiesterase-5 (PDE-5) enzyme in silico evaluation and minerals (including zinc, cadmium, and magnesium). Other phytochemical analyses revealed the presence of phenolic compounds and flavonoids. These phytochemicals and minerals may contribute to the aphrodisiac activities of the extract. Additionally, the in vivo study revealed that the administration of M. jalapa root extract (300 mg/kg) significantly enhanced (p < 0.01, p < 0.03) mount, intromission, and ejaculation frequencies while significantly (p < 0.05) decreasing the mount and intromission latencies, as well as the post-ejaculatory interval time, in comparison with the standard drugs sildenafil and ginseng, resulting in enhanced erection and sexual performance in the rats. Furthermore, the extract significantly (p < 0.05) increased penile reflexes and also elevated the levels of testosterone and luteinizing hormones. Extract (300 mg/kg) significantly (p < 0.05) inhibited the PDE-5 enzyme in an in vitro study. Concludingly, the comprehensive findings of this study suggest that a standardized herbal extract derived from M. jalapa roots alleviates erectile dysfunction and premature ejaculation in male rats. M. jalapa root extract proved to be an alternative treatment for erectile dysfunction and premature ejaculation.

Ultraviolet-B radiation in relation to agriculture in the context of climate change: a review.

Over the past few decades, the amount of ultraviolet-B radiation (UV-B) reaching the earth's surface has been altered due to climate change and stratospheric ozone dynamics. This narrow but highly biologically active spectrum of light (280-320 nm) can affect plant growth and development. Depletion of ozone and climate change are interlinked in a very complicated manner, i.e., significantly contributing to each other. The interaction of climate change, ozone depletion, and changes in UV-B radiation negatively affects the growth, development, and yield of plants. Furthermore, this interaction will become more complex in the coming years. The ozone layer reduction is paving a path for UV-B radiation to impact the surface of the earth and interfere with the plant's normal life by negatively affecting the plant's morphology and physiology. The nature and degree of the future response of the agricultural ecosystem to the decreasing or increasing UV-B radiation in the background of climate change and ozone dynamics are still unclear. In this regard, this review aims to elucidate the effects of enhanced UV-B radiation reaching the earth's surface due to the depletion of the ozone layer on plants' physiology and the performance of major cereals.

Association of Hepcidin levels in Type 2 Diabetes Mellitus treated with metformin or combined anti-diabetic agents in Pakistani population.

Objective: To evaluate the impact of hepcidin and ferritin in pathogenesis and prognosis of type 2 diabetes mellitus subjects taking only metformin or combined anti-glycaemic agents. METHODS: The observational case-control study was conducted at the Department of Physiology, Baqai Medical University, Karachi, from August 2019 to October 2020, and comprised subjects from both genders who categorised into equal groups as non-diabetic controls, newly-diagnosed type 2 diabetes mellitus patients without any treatment, type 2 diabetes mellitus patients with exposure to metformin only, type 2 diabetes mellitus patients taking oral hypoglycaemic agents along with metformin, type 2 diabetes mellitus patients taking only insulin, and type 2 diabetes mellitus patients taking insulin and oral hypoglycaemic agents. Fasting plasma glucose was determined using glucose oxidase-peroxidase method, glycated haemoglobin by high performance liquid chromatography, high-density lipoprotein and low-density lipoprotein by direct methods, cholesterol by cholesterol oxidase phenol 4-amino antipyrine peroxidase and triglycerides by glycerol phosphate oxidase-phenol 4-amino antipyrine peroxidase method. Serum levels of ferritin, insulin and hepcidin were evaluated using Enzyme-linked immunosorbent assay. Insulin resistance was assessed using homeostasis model assessment for insulin resistance. Data was analysed using SPSS 21. RESULTS: Of the 300 subjects, there were 50(16.66%) in each of the 6 groups. Overall, there were 144(48%) males and 155(51.66%) females. The mean age was significantly lower in the control group 34.72±7.87 compared to all the diabetic groups (p<0.05), and the same was the case with respect to all the parameters (p<0.05) except high-density lipoprotein (p>0.05). Besides, hepcidin level was significantly higher in the control group (p<0.05). Ferritin levels were significantly increased in newly-diagnosed T2DM subjects compared to the controls (p<0.05) while all other groups showed decreased ferritin levels (p<0.05). Hepcidin gave inverse correlation with glycated haemoglobin only in diabetics taking only metformin (r = -0.27, p=0.05). CONCLUSIONS: Anti-diabetes drugs not only addressed type 2 diabetes mellitus, but also reduced levels of ferritin and hepcidin that are found to play a role in diabetes development.

Alternating Direction Method of Multipliers-Based Constant Modulus Waveform Design for Dual-Function Radar-Communication Systems.

In this paper, we design constant modulus waveforms for dual-function radar-communication (DFRC) systems based on a multi-input multi-output (MIMO) configuration of sensors for a far-field scenario. At first, we formulate a non-convex optimization problem subject to waveform synthesis for minimizing the interference power while maintaining a constant modulus constraint. Next, we solve this non-convex problem, iteratively, using the alternating direction method of multipliers (ADMM) algorithm. Importantly, the designed waveforms approximate a desired beampattern in terms of a high-gain radar beam and a slightly high gain communication beam while maintaining a desired low sidelobe level. The designed waveforms ensure an improved detection probability and an improved bit error rate (BER) for radar and communications parts, respectively. Finally, we demonstrate the effectiveness of the proposed method through simulation results.

A detailed biochemical characterization, toxicological assessment and molecular docking studies of Launaea fragilis: An important medicinal xero-halophyte.

Launaea fragilis (Asso) Pau (Family: Asteraceae) is a wild medicinal plant that has been used in the folklore as a potential treatment for numerous ailments such as skin diseases, diarrhea, infected wounds, inflammation, child fever and hepatic pain. This study explored the chemical constitution, in-vivo toxicity, antimicrobial, antioxidant, and enzyme inhibition potential of ethanolic extract of L. fragilis (EELF). Additionally, in-silico docking studies of predominant compounds were performed against in-vitro tested enzymes. Similarly, in-silico ADMET properties of the compounds were performed to determine their pharmacokinetics, physicochemical properties, and toxicity profiles. The EELF was found rich in TFC (73.45 ± 0.25 mg QE/g) and TPC (109.02 ± 0.23 mg GAE/g). GC-MS profiling of EELF indicated the presence of a total of 47 compounds mainly fatty acids and essential oil. EELF showed no toxicity or growth retardation in chicks up to 300 mg/kg with no effect on the biochemistry and hematology of the chicks. EELF gave promising antioxidant activity through the CUPRAC method with an IC50 value of 13.14 ± 0.18 µg/ml. The highest inhibition activity against tyrosinase followed by acetylcholinesterase and α-Glucosidase was detected. Similarly, the antimicrobial study revealed the extract with good antibacterial and antiviral activity. A good docking score was observed in the in silico computational study of the predominant compounds. The findings revealed L. fragilis as a biocompatible, potent therapeutic alternative and suggest isolation and further in vivo pharmacological studies.

Change in pulmonary function tests and their relation to the serum levels of ceruloplasmin, copper and superoxide dismutase in patients suffering from Type-1 and Type-2 diabetes.

Objective: To correlate the serum levels of ceruloplasmin (Cp), copper (Cu), and superoxide dismutase (SOD) with pulmonary function tests (PFTs) in non-diabetics (controls) and patients suffering from Type-1 and Type- 2 diabetes. Methods: The comparative cross-sectional study of 348 participants was performed at the Baqai Institute of Diabetes and Endocrinology (BIDE) - Karachi, Pakistan, from February 2019 to September 2020. Individuals having diabetes-related complications, asthma, chronic obstructive pulmonary disease, chest infection, pregnant women and smokers were excluded. A total of 348 participants were included into three groups after signing informed consent. The control group had 107 non-diabetic participants, with an age range of 6 to 60 years. The diagnosed T1D group (n=107) had an age range of 6 to 25 years. While diagnosed T2D group (n=134) had an age range of 26 to 60 years. During the fasting state, anthropometric parameters, blood pressure, spirometry, and a venous blood sample (5ml) were collected to measure serum Cp, serum Cu, serum SOD, and HbA1c levels by using commercially available kits. The SPSS, version 21, was used for data analysis. Results: The reduced FVC (p-value <0.001), FEV1 (p-value <0.001), and PEFR (p-value <0.001) were found in both groups of diabetes. However, the lower levels of serum Cu (p-value <0.001), SOD (p-value <0.001), and significantly increased values of FEV1/ FVC (p-value <0.001) and Cp levels (p-value 0.030) were found only in T2D group as compared to T1D and controls. The study found no significant correlation of PFTs and serum Cp, Cu, and SOD levels in patients suffering from T1D and T2D. Conclusion: Hyperglycemia leads to more non-enzymatic glycosylation of tissue proteins that reflects reduced PFTs and increased Cp; particularly in T2D, which may alter lung tissue's physiology. Moreover, the study showed no correlation of PFTs with the Cp, Cu, and SOD in patients suffering from T1D and T2D.