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The production of high-quality noodles relies on using premium-quality wheat flour. There is growing interest in using nonthermal technologies (NTTs), like ultrasound, high hydrostatic pressure (HHP), and plasma techniques, to enhance the nutritional properties of wheat flour starch and protein, specifically its digestibility. This review compiles the impact of these nonthermal technologies on wheat flour characteristics for optimal noodle preparation. Ultrasound applications can modify protein networks and starch granules in wheat flour, resulting in improved consistency and texture of noodles. High hydrostatic pressure (HHP) treatments have been observed to effectively alter protein specificity, thereby forming desirable textural attributes such as hardness and firmness. Consequently, this process significantly contributes to the overall improvement in the quality of the noodles. Additionally, HHP treatments promote gelatinization within structures, improving noodle digestibility. On the other hand, plasma treatment modifies the structure and properties of gluten, enhancing dough rheology and stability and improving the texture, nutrition, and sensory attributes of noodles. The modifications induced by ultrasound HHP and plasma treatments in gluten structure enzymatic potential, starch granules, and protein functionality collectively enhance noodle characteristics. Furthermore, the modifications efficiently improve digestibility and increase nutrient availability during digestion, thereby increasing the overall nutritional value of noodles., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare. This article does not contain studies involving human or animal subjects., (Copyright © 2024 Elsevier B.V. All rights reserved.)

SARS-CoV-2 variants of concern (VOC) have been associated with increased viral transmission and disease severity. We investigated the mechanisms of pathogenesis caused by variants using a host blood transcriptome profiling approach. We analysed transcriptional signatures of COVID-19 patients comparing those infected with wildtype (wt), alpha, delta or omicron strains seeking insights into infection in Asymptomatic cases.Comparison of transcriptional profiles of Symptomatic and Asymptomatic COVID-19 cases showed increased differentially regulated gene (DEGs) of inflammatory, apoptosis and blood coagulation pathways, with decreased T cell and Interferon stimulated genes (ISG) activation. Between SARS-CoV-2 strains, an increasing number of DEGs occurred in comparisons between wt and alpha (196), delta (1425) or, omicron (2313) infections. COVID-19 cases with alpha or, delta variants demonstrated suppression transcripts of innate immune pathways. EGR1 and CXCL8 were highly upregulated in those infected with VOC; heme biosynthetic pathway genes (ALAS2, HBB, HBG1, HBD9) and ISGs were downregulated. Delta and omicron infections upregulated ribosomal pathways, reflecting increased viral RNA translation. Asymptomatic COVID-19 cases infected with delta infections showed increased cytokines and ISGs expression. Overall, increased inflammation, with reduced host heme synthesis was associated with infections caused by VOC infections, with raised type I interferon in cases with less severe disease., (© 2024. The Author(s).)

Background: There is a dire need for the establishment of active dengue surveillance to continuously detect cases, circulating serotypes, and determine the disease burden of dengue fever (DF) in the country and region. Predicting dengue PCR results using machine learning (ML) models represents a significant advancement in pre-emptive healthcare measures. This study outlines the comprehensive process of data preprocessing, model selection, and the underlying mechanisms of each algorithm employed to accurately predict dengue PCR outcomes. Methods: We analyzed data from 300 suspected dengue patients in Islamabad and Rawalpindi, Pakistan, from August to October 2023. NS1 antigen ELISA, IgM and IgG antibody tests, and serotype-specific real-time polymerase chain reaction (RT-PCR) were used to detect the dengue virus (DENV). Representative PCR-positive samples were sequenced by Sanger sequencing to confirm the circulation of various dengue serotypes. Demographic information, serological test results, and hematological parameters were used as inputs to the ML models, with the dengue PCR result serving as the output to be predicted. The models used were logistic regression, XGBoost, LightGBM, random forest, support vector machine (SVM), and CatBoost. Results: Of the 300 patients, 184 (61.33%) were PCR positive. Among the total positive cases detected by PCR, 9 (4.89%), 171 (92.93%), and 4 (2.17%) were infected with serotypes 1, 2, and 3, respectively. A total of 147 (79.89%) males and 37 (20.11%) females were infected, with a mean age of 33 ± 16 years. In addition, the mean platelet and leukocyte counts and the hematocrit percentages were 75,447%, 4189.02%, and 46.05%, respectively. The SVM was the best-performing ML model for predicting RT-PCR results, with 71.4% accuracy, 97.4% recall, and 71.6% precision. Hyperparameter tuning improved the recall to 100%. Conclusion: Our study documents three circulating serotypes in the capital territory of Pakistan and highlights that the SVM outperformed other models, potentially serving as a valuable tool in clinical settings to aid in the rapid diagnosis of DF., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Ariba Qaiser et al.)

Gamma-aminobutyric acid (GABA), a non-protein amino acid primarily biosynthesized in cereals, is vital to the human neurological system. As the primary neurotransmitter, it promotes relaxation, inhibits depression and sleeplessness, and regulates synaptic transmission and neuronal development. GABA also protects the liver, kidneys, and intestines, reduces blood pressure, and fights cancer and inflammation. Colorimetric and enzyme-based procedures, biosensors, and High-Performance Liquid Chromatography primarily detect GABA. GABA content is enriched by treatments, like germination and fermentation, suitable and economical methods on industrial scales. Moreover, ultrasonication, abiotic stress, heat, and relative humidity are also utilized for GABA enrichment. With advancing technology and knowledge of the nutrients concerning human health, target-specific nutrition utilizing sustainable ingredients needs exploration. Conclusively, the current article delves into the latest developments in GABA enrichment and detection techniques and GABA's potential health benefits. Further studies are required to understand and refine enrichment procedures to develop GABA-enriched foods with health-promoting qualities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Linezolid-resistant Enterococcus faecium (LRE) is a global priority pathogen. Thirteen LRE were reported from clinical specimens between November 2021 and April 2023 at two laboratories in Karachi, Pakistan. We aimed to investigate the strain types and genes associated with linezolid resistance among these isolates. Whole genome sequencing (WGS) was performed and analyzed by multilocus sequence typing (MLST). The presence of linezolid resistance genes was identified using ResFinder v4.1.11 and the LRE-finder tool., Results: Twelve isolates belonged to clonal complex 17 (CC17); ST80 (n = 10), ST612 (n = 1) and ST1380 (n = 1). Six isolates showed the presence of optrA gene and G2576T mutations in the 23S rRNA gene, while six showed poxtA and cfr(D) genes. One isolate showed the combination of optrA, cfr(D) and poxtA genes., Conclusion: Our findings show the circulation of CC17 sequence types with a known outbreak potential and we identified molecular mechanisms of resistance that were not previously reported from Pakistan., (© 2024. The Author(s).)

CAR T-cell therapy is a promising immunotherapy, providing successful results for cancer patients who are unresponsive to standard and traditional therapeutic approaches. However, there are limiting factors which create a hurdle in the therapy performing its role optimally. CAR T cells get exhausted, produce active antitumor responses, and might even produce toxic reactions. Specifically, in the case of solid tumors, chimeric antigen receptor T (CAR-T) cells fail to produce the desired outcomes. Then, the need to use supplementary agents such as immune system modifying immunomodulatory agents comes into play. A series of the literature was studied to evaluate the role of immunomodulators including a phytochemical, Food and Drug Administration (FDA)-approved targeted drugs, and ILs in support of their achievements in boosting the efficiency of CAR-T cell therapy. Some of the most promising out of them are reported in this article. It is expected that by using the right combinations of immunotherapy, immunomodulators, and traditional cancer treatments, the best possible cancer defying results may be produced in the future., (© 2024. The Author(s).)

Globally, 50% of people consume rice ( Oryza sativa ), which is among the most abundant and extensively ingested cereal grains. Rice bran is a by-product of the cereal industry and is also considered a beneficial waste product of the rice processing industry. Rice bran oil (RBO) is created from rice bran (20-25 wt% in rice bran), which is the outermost layer of the rice kernel; has a lipid content of up to 25%; and is a considerable source of a plethora of bioactive components. The main components of RBO include high levels of fiber and phytochemicals, including vitamins, oryzanols, fatty acids, and phenolic compounds, which are beneficial to human health and well-being. This article summarizes the stabilization and extraction processes of rice bran oil from rice bran using different techniques (including solvent extraction, microwaving, ohmic heating, supercritical fluid extraction, and ultrasonication). Some studies have elaborated the various biological activities linked with RBO, such as antioxidant, anti-platelet, analgesic, anti-inflammatory, anti-thrombotic, anti-mutagenic, aphrodisiac, anti-depressant, anti-emetic, fibrinolytic, and cytotoxic activities. Due to the broad spectrum of biological activities and economic benefits of RBO, the current review article focuses on the extraction process of RBO, its bioactive components, and the potential health benefits of RBO. Furthermore, the limitations of existing studies are highlighted, and suggestions are provided for future applications of RBO as a functional food ingredient.

The texture properties after cooking for 12 min were selected to optimize the sheeting parameters, and the results were verified using the comprehensive quality of dried noodles. The distribution of water, characteristics of gluten protein, and interaction between gluten network and starch were analyzed to clarify the mechanism of the quality of dried noodles. Results showed that the optimal folding angle was 45°, under this condition, the largest anti-extension displacement perpendicular to the rolling direction and the smallest cooking loss were obtained. The hardness and smoothness of cooked noodles increased by about 14% to 17%. Further, the transverse relaxation time of strongly bound water significantly decreased, while the relative content and binding strength increased. The hydrogen bonds and α-helix contents increased by about 68.8% and 53.1%, respectively. Folding and sheeting enhanced the combination of starch granules and gluten network causing, decreased in the average length and porosity of the gluten network. It is depicted from the results that the method of optimizing the sheeting process based on the texture of dried noodles cooked for 12 min was feasible. And the 45° folding and sheeting could help to improve the quality of dried noodles., (© 2024 Wiley Periodicals LLC.)

Objectives: The study aimed to assess the effectiveness of anxiety reduction protocol using auditory distraction in alleviating dental anxiety among patients undergoing tooth extraction., Materials and Methods: A randomized controlled trial was conducted at the Oral Surgery Department at Islamabad Dental Hospital from July to December 2022, involving 50 patients scheduled for tooth extraction. Participants were randomly divided into two groups: an interventional group, exposed to auditory distraction, and a noninterventional group, without exposure to auditory distraction before the dental extraction. Dental anxiety was measured using the modified dental anxiety scale (MDAS) questionnaire, which scores anxiety levels on a range from 5 (not anxious) to 25 (extremely anxious). Anxiety levels were assessed in the waiting room and just before extraction, and the results were compared across both groups to evaluate the effectiveness of auditory distraction in reducing dental anxiety., Results: The sample size of 50 was randomly and equally allocated to the interventional and noninterventional groups. The study population consisted of 28 (56%) female and 22 (44%) male participants. No significant difference was observed between the anxiety scores of interventional and noninterventional groups at baseline. A significant reduction in anxiety scores was observed in the intervention group during postintervention assessment, while no significant difference was seen in the noninterventional group's anxiety scores., Conclusions: The study supports the efficacy of anxiety reduction protocol using auditory distraction as a practical tool for reducing dental anxiety among patients undergoing tooth extraction., (© 2024 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

The nexus between food production (FP), energy consumption (EC), institutional quality (IQ), and ecological degradation (ED) has important implications for environmental sustainability. Nevertheless, environmental degradation caused by FP is widely ignored, especially in Pakistan. To fill this void, we investigated the impact of energy use, FP, and IQ on Pakistan's environmental degradation between 1990 and 2021. We also explore the moderating influence of IQ on ED. To evaluate this influence, we use the autoregressive distributed lag (ARDL) method for cointegration and the fully modified ordinary least-squares method for robustness estimation. Our empirical results demonstrate that, whereas FP and EC contribute to pollution, IQ reduces the pace of environmental degradation. Furthermore, the presence of a strong IQ mitigates the harmful ecological effects of FP and EC. Moreover, the results revealed that unbiased domestic IQ is crucial to boosting energy and agricultural efficiency while reducing CO 2 emissions. Our findings might be considered while public policies to reduce carbon emissions and increase FP in a healthy environment are being developed. Integr Environ Assess Manag 2024;20:518-532. © 2023 (SETAC)., (© 2023 (SETAC).)

Background: Many elite genes have been identified from the available cotton genomic data, providing various genetic resources for gene-driven breeding. However, backbone cultivar-driven breeding is the most widely applied strategy. Revealing the genetic basis of cultivar-driven strategy's restriction is crucial for transition of cotton breeding strategy., Result: CRI12 is a backbone cultivar in cultivar-driven breeding. Here we sequence the pedigree of CRI12 using Nanopore long-read sequencing. We construct a graphical pedigree genome using the high-quality CRI12 genome and 13,138 structural variations within 20 different pedigree members. We find that low hereditary stability of elite segments in backbone cultivars is a drawback of cultivar-driven strategy. We also identify 623 functional segments in CRI12 for multiple agronomic traits in presence and absence variation-based genome-wide association study on three cohorts. We demonstrate that 25 deleterious segments are responsible for the geographical divergence of cotton in pathogen resistance. We also characterize an elite pathogen-resistant gene (GhKHCP) utilized in modern cotton breeding. In addition, we identify 386 pedigree fingerprint segments by comparing the segments of the CRI12 pedigree with those of a large cotton population., Conclusion: We characterize the genetic patterns of functional segments in the pedigree of CRI12 using graphical genome method, revealing restrictions of cultivar-driven strategies in cotton breeding. These findings provide theoretical support for transitioning from cultivar-driven to gene-driven strategy in cotton breeding., (© 2023. The Author(s).)

The Belt and Road Initiative (BRI) has boosted economic development while harming the ecology. It is vital to track its CO 2 emissions to guide the BRI toward a green future and low carbon. Our research contributes to these goals in two ways. First, this research examines the spatial-temporal effects of institutional quality (IQ) and renewable and non-renewable energy consumption on CO 2 emissions for 75 BRI countries from 1990 to 2019. Second, geographical implications are considered when assessing the factors that affect CO 2 emissions on a regional scale. Several diagnostic methods are used to determine the significant spatial impacts, and spatial panel models (SPMs) are used to analyze the phenomenon's spillover and direct consequences. The empirical findings demonstrate that increased IQ and renewable energy (RNC) harm the country's CO 2 emissions. These negative consequences spread geographically to adjacent countries of the impacted country. Moreover, non-renewable energy (NC) positively affects the CO 2 of the impacted nation and its neighbors. Hence, the objective of reducing CO 2 emissions compels BRI to establish an effective plan to reduce non-renewable energy, enhance IQ, resolve internal and external disputes, and foster religious and ethnic harmony in BRI-affected nations. Positive direct and negative spatial impacts of economic expansion highlight the zero-sum game of nations, so high CO 2 -emitting countries should exercise caution when implementing economic policies., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Changing morbidity and mortality due to COVID-19 across the pandemic has been linked with factors such as the emergence of SARS-CoV-2 variants and vaccination. Mutations in the Spike glycoprotein enhanced viral transmission and virulence. We investigated whether SARS-CoV-2 mutation rates and entropy were associated COVID-19 in Pakistan, before and after the introduction of vaccinations. We analyzed 1,705 SARS-CoV-2 genomes using the Augur phylogenetic pipeline. Substitution rates and entropy across the genome, and in the Spike glycoprotein were compared between 2020, 2021 and 2022 (as periods A, B and C). Mortality was greatest in B whilst cases were highest during C. In period A, G clades were predominant, and substitution rate was 5.25 × 10 -4 per site per year. In B, Delta variants dominated, and substitution rates increased to 9.74 × 10 -4 . In C, Omicron variants led to substitution rates of 5.02 × 10 -4 . Genome-wide entropy was the highest during B particularly, at Spike E484K and K417N. During C, genome-wide mutations increased whilst entropy was reduced. Enhanced SARS-CoV-2 genome substitution rates were associated with a period when more virulent SARS-CoV-2 variants were prevalent. Reduced substitution rates and stabilization of genome entropy was subsequently evident when vaccinations were introduced. Whole genome entropy analysis can help predict virus evolution to guide public health interventions., (© 2023. The Author(s).)

Background: COVID-19 waves caused by specific SARS-CoV-2 variants have occurred globally at different times. We focused on Omicron variants to understand the genomic diversity and phylogenetic relatedness of SARS-CoV-2 strains in various regions of Pakistan., Methods: We studied 276,525 COVID-19 cases and 1,031 genomes sequenced from December 2021 to August 2022. Sequences were analyzed and visualized using phylogenetic trees., Results: The highest case numbers and deaths were recorded in Sindh and Punjab, the most populous provinces in Pakistan. Omicron variants comprised 93% of all genomes, with BA.2 (32.6%) and BA.5 (38.4%) predominating. The first Omicron wave was associated with the sequential identification of BA.1 in Sindh, then Islamabad Capital Territory, Punjab, Khyber Pakhtunkhwa (KP), Azad Jammu Kashmir (AJK), Gilgit-Baltistan (GB) and Balochistan. Phylogenetic analysis revealed Sindh to be the source of BA.1 and BA.2 introductions into Punjab and Balochistan during early 2022. BA.4 was first introduced in AJK and BA.5 in Punjab. Most recent common ancestor (MRCA) analysis revealed relatedness between the earliest BA.1 genome from Sindh with Balochistan, AJK, Punjab and ICT, and that of first BA.1 from Punjab with strains from KPK and GB., Conclusions: Phylogenetic analysis provides insights into the introduction and transmission dynamics of the Omicron variant in Pakistan, identifying Sindh as a hotspot for viral dissemination. Such data linked with public health efforts can help limit surges of new infections., (© 2023. The Author(s).)

Background: Enteric fever is an acute systemic infectious disease associated with substantial morbidity and mortality in low- and middle-income countries (LMIC), with a global burden of 14.3 million cases. Cases of enteric fever or paratyphoid fever, caused by Salmonella enterica serovar Paratyphi A (S. Para A) have been found to rise in many endemic and non-endemic countries. Drug resistance is relatively uncommon in S. Para A. Here we report a case of paratyphoid fever caused by ceftriaxone resistant S. Para A from Pakistan., Case Presentation: A 29-year-old female presented with a history of fever, headache, and shivering. Her blood culture revealed a S. Para A isolate (S7), which was resistant to ceftriaxone, cefixime, ampicillin and ciprofloxacin. She was prescribed oral Azithromycin for 10 days, which resulted in resolution of her symptoms. Two other isolates of S. Para A (S1 and S4), resistant to fluoroquinolone were also selected for comparison. DST and whole genome sequencing was performed for all three isolates. Sequence analysis was performed for identification of drug resistance and phylogeny. Whole Genome Sequencing (WGS) of S7 revealed the presence of plasmids, IncX4 and IncFIB(K). blaCTX-M-15 and qnrS1 genes were found on IncFIB(K). The gyrA S83F mutation conferring fluoroquinolone resistance was also found present. Multi-locus sequence typing (MLST) showed the S7 isolate to belong to ST129. S1 and S4 had the gyrA S83Y and S83F mutations respectively., Conclusions: We highlight the occurrence of plasmid-mediated ceftriaxone resistant strain of S. Para A. This is of significance as ceftriaxone is commonly used to treat paratyphoid fever and resistance in S. Para A is not known. Continuous epidemiological surveillance is required to monitor the transmission and spread of antimicrobial resistance (AMR) among Typhoidal Salmonellae. This will guide treatment options and preventive measures including the need for vaccination against S. Para A in the region., (© 2023. The Author(s).)

The nexus between food security (FS), institutional quality (IQ), human capital (HC), and environmental deterioration (ED) has important implications for ecological sustainability. Yet, environmental deterioration resulting from food security activities is a widely ignored topic, particularly in BRI countries. To address this gap, we examined the influence of food security, human capital and institutional quality on the environmental deterioration of BRI countries from 1984 to 2019. Furthermore, it investigates the moderating effect of institutional quality and human capital on ED. The empirical findings revealed that food security increases ED. The research also revealed that HC and IQ lower the ED. Furthermore, food security promotes ecological sustainability through the HC channel. Additionally, institutional quality decreases the negative environmental implications of food security. Based on these results, BRI nations should enhance ecological sustainability by investing in HC and using food resources efficiently., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: To understand the magnitude of risk of health events, such as cardiovascular diseases (CVD), related to poor oral health, both relative and absolute risk measures should be reported. Our aim was to investigate the extent to which absolute and relative measures of risk are reported in longitudinal studies that assess the association between oral health indicators (OHIs) and CVD., Methods: A systematic search of longitudinal studies investigating the association of any OHI with CVD was carried out using the Embase, Medline and Cochrane library databases. The search covered each database from its inception date to August 2021. Data about reporting relative and absolute risks of the relationship between CVD and OHI from the abstract were extracted. If the relative risk for OHIs and CVD was reported in the abstract, then the underlying absolute risks were searched from the full text, and it was assessed whether it was similarly adjusted for confounding than was the relative risk in the abstract., Results: One hundred-six articles were included. From these, 85 (80%) studies reported the association of OHIs and CVD with one or more relative risks in the abstract. Of those 85 studies, the underlying absolute risks were accessible or calculable from the abstract or full text of 60 studies. However, of these 60 studies, in only 10 (12%), the underlying absolute risks were similarly adjusted, as were the relative risks in the abstract. The absolute risks of CVD by OHIs were rarely reported without corresponding relative risks in the abstract (n = 2, 2%). Median absolute risk difference in the CVD risk between exposure levels to which the first relative risk in the abstract referred was 1.8% (interquartile range 0.6-4.6, n = 63)., Conclusions: Focusing on relative risks over absolute risks was a common practice in literature. Reporting similarly adjusted underlying absolute risks of relative risks was rare in most studies, despite those being helpful for comprehending the magnitude of CVD-risk increase related to poor oral health. Current reporting practices could lead to an overinterpretation of risk increase of CVD related to poor oral health., (© 2022 The Authors. Community Dentistry and Oral Epidemiology published by John Wiley & Sons Ltd.)

Expanding food production to commensurate with population growth has often come at a cost resulting from environmental problems. Industries generate pollutants that destroy the environment and negatively affect the level of food security. These trends threaten the sustainability of food systems and undermine the capacity to meet food security needs. Against this backdrop, this study examines how the green environment influences food security in Africa. To further articulate the novelty and contributions of the research to the extant literature, the study also examines the interaction effect of the green environment and social protection on food security. The study engaged panel data consisting of 37 African countries listed in the International Development Association (IDA) of the World Bank. The data was sourced from Food and Agricultural Organisation (FAO), Country Policy and Institutional Assessment (CPIA) and the World Development Indicators (WDI) for the period 2005 to 2019 and applied the system Generalised Method of Moments (SGMM). The result shows that a green environment and social protection are statistically significant and positively determine the level of food security in Africa. In addition, the result shows that a green environment and social protection interaction positively and significantly influence food security. The implication is that a 1% increase in the drive for a green environment may improve the level of food security by 0.8%. Also, increases in the level of social protection intervention may increase food security by 1.2%. The interaction between social protection and food security can increase food security by 0.96%. In summary, it is found that African countries under study have moderate social protection coverage and policy for environmental management and sustainability required to drive food security. The discussions of the findings and policy implications of the study are underscored in the paper., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Nitrate is the primary type of nitrogen available to plants, which is absorbed and transported by nitrate transporter 2 (NRT2) at low nitrate conditions., Methods: Genome-wide identification of NRT2 genes in G. hirsutum was performed. Gene expression patterns were revealed using RNA-seq and qRT-PCR. Gene functions were characterized using overexpression in A. thaliana and silencing in G. hirsutum . Protein interactions were verified by yeast two-hybrid and luciferase complementation imaging (LCI) assays., Results: We identified 14, 14, seven, and seven NRT2 proteins in G. hirsutum , G. barbadense , G. raimondii , and G. arboreum . Most NRT2 proteins were predicted in the plasma membrane. The NRT2 genes were classified into four distinct groups through evolutionary relationships, with members of the same group similar in conserved motifs and gene structure. The promoter regions of NRT2 genes included many elements related to growth regulation, phytohormones, and abiotic stresses. Tissue expression pattern results revealed that most GhNRT2 genes were specifically expressed in roots. Under low nitrate conditions, GhNRT2 genes exhibited different expression levels, with GhNRT2.1e being the most up-regulated. Arabidopsis plants overexpressing GhNRT2.1e exhibited increased biomass, nitrogen and nitrate accumulation, nitrogen uptake and utilization efficiency, nitrogen-metabolizing enzyme activity, and amino acid content under low nitrate conditions. In addition, GhNRT2.1e -silenced plants exhibited suppressed nitrate uptake and accumulation, hampered plant growth, affected nitrogen metabolism processes, and reduced tolerance to low nitrate. The results showed that GhNRT2.1e could promote nitrate uptake and transport under low nitrate conditions, thus effectively increasing nitrogen use efficiency (NUE). We found that GhNRT2.1e interacts with GhNAR2.1 by yeast two-hybrid and LCI assays., Discussion: Our research lays the foundation to increase NUE and cultivate new cotton varieties with efficient nitrogen use., Competing Interests: The authors declare that they have no competing interests., (© 2023 Zhang et al.)

Objective: Postinfectious irritable bowel syndrome (IBS) is a known entity. We evaluated the incidence of post-COVID-19 IBS in patients discharged from the hospital and analyzed its correlation with the clinical and laboratory parameters, and treatment during the hospital stay., Methods: Three hundred three COVID-19 hospitalized patients without prior history of IBS were prospectively followed after their discharge and were evaluated as per Rome-IV criteria for IBS., Results: One hundred seventy-eight patients were males (58.7%). The age range was 17-95 years (mean ± SD, 55.9 ± 15.8). A total of 194 (64%) had mild COVID-19, 74 (24.4%) had moderate COVID-19, whereas 35 (11.6%) had severe COVID-19 infection. Sixteen (5.3%) patients had concomitant GI symptoms during COVID-19 infection. IBS symptoms were found to be present in 32 (10.6%) patients, out of which 17 (53.13%) had diarrhea-predominant, 10 (31.25%) had constipation-predominant, and five (15.62%) had mixed-type IBS. Post-COVID-19 IBS was more common in the female sex (P < 0.001), concomitant GI symptoms with COVID-19 (P < 0.001), oxygen requirement (P = 0.015), deranged liver function tests at the time of admission (P = 0.002), high procalcitonin (P = 0.013), high C-reactive protein levels (P = 0.035); whereas negative correlation was found with remdesivir treatment (P = 0.047). After performing regression analysis, female sex (P < 0.001), oxygen requirement during hospital stay (P = 0.016), GI symptoms during COVID-19 infection (P < 0.001), and high procalcitonin levels (P = 0.017) were independently associated with post-COVID-19 IBS., Conclusion: GI symptoms during active COVID-19 infection increase the chances of developing post-COVID-19 IBS. The risk of developing post-COVID-19 IBS increases in female patients, those requiring oxygen and having high procalcitonin levels during COVID-19 infection., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Biofouling on surfaces, caused by the assimilation of proteins, peptides, lipids and microorganisms, leads to contamination, deterioration and failure of biomedical devices and causes implants rejection. To address these issues, various antifouling strategies have been extensively studied, including polyethylene glycol-based polymer brushes. Conducting polymers-based biointerfaces have emerged as advanced surfaces for interfacing biological tissues and organs with electronics. Antifouling of such biointerfaces is a challenge. In this study, we fabricated electrospun fibre mats from sulphonated polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (sSEBS), infused with conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) (sSEBS-PEDOT), to produce a conductive (2.06 ± 0.1 S/cm), highly porous, fibre mat that can be used as a biointerface in bioelectronic applications. To afford antifouling, here the poly(oligo (ethylene glycol) methyl ether methacrylate) (POEGMA) brushes were grafted onto the sSEBS-PEDOT conducting fibre mats via surface-initiated atom transfer radical polymerization technique (SI-ATRP). For that, a copolymer of EDOT and an EDOT derivative with SI-ATRP initiating sites, 3,4-ethylenedioxythiophene) methyl 2-bromopropanoate (EDOTBr), was firstly electropolymerized on the sSEBS-PEDOT fibre mat to provide sSEBS-PEDOT/P(EDOT-co-EDOTBr). The POEGMA brushes were grafted from the sSEBS-PEDOT/P(EDOT-co-EDOTBr) and the polymerization kinetics confirmed the successful growth of the brushes. Fibre mats with 10-mers and 30-mers POEGMA brushes were studied for antifouling using a BCA protein assay. The mats with 30-mers grafted brushes exhibited excellent antifouling efficiency, ~82% of proteins repelled, compared to the pristine sSEBS-PEDOT fibre mat. The grafted fibre mats exhibited cell viability >80%, comparable to the standard cell culture plate controls. Such conducting, porous biointerfaces with POEGMA grafted brushes are suitable for applications in various biomedical devices, including biosensors, liquid biopsy, wound healing substrates and drug delivery systems.

Resistance associated mutations have been reported to alter the growth of Mycobacterium tuberculosis (MTB) isolates under drug pressure. However, there is little information on the growth characteristics of bedaquiline (BDQ) resistant isolates in the presence of BDQ. To further understand the role of rv0678, we aimed to study whether the presence of rv0678 variants in BDQ resistant isolates alters the killing effect of BDQ. We, therefore, selected BDQ resistant clinical MTB isolates with (n = 6) and without (n = 3) variants in rv0678 gene. Using time kill assays, growth inhibition; taken as the relative change in log average colony forming unit (CFU)/ml at selected time points (24-96 h), was studied at Minimum Inhibitory Concentrations (MICs): 0x, 1x, 2.5x, 5x, 7.5x, 10x for these isolates. Growth inhibition was then analyzed using Kruskal Wallis and Kolmogorov Smirnov tests in PRISM vr.9. During the 24-96 h lag phase isolates with and without variants in rv0678 showed a similar growth inhibition pattern. No difference was noted in growth inhibition between BDQ resistant isolates and H37Rv. These findings suggest that role of alternate mechanisms in contributing to BDQ tolerance needs to be explored., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective Our objective is to assess the diagnostic accuracy of contrast-enhanced magnetic resonance imaging (MRI) in identifying the depth of myometrial invasion and cervical stromal involvement in endometrial carcinoma (EC) along with nodal status and its correlation with surgical and histopathological (HP) findings. Materials and methods We performed a retrospective study on female patients at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. Patients with endometrial carcinoma (CA) were searched from the electronic record system, and a total of 188 patients fulfilling the study criteria were selected. All the patients were evaluated using a 1.5T MRI and underwent a hysterectomy. The outcome of preoperative MRI was correlated with histopathology results, keeping pathology as the gold standard. Results A total of 188 patients were included in the study, with a mean age of 56.67 ± 12.47 years. Of the patients, 72 (38.3%) were diagnosed with stage 1a. The second common stage was 1b, seen in 43 (22.9%) patients. It was found that the staging of endometrial CA on MRI and HP were significantly correlated for myometrial invasion (stage 1a and 1b), cervical stromal involvement (stage 2b), serosal and adnexal (stage 3a), vaginal (stage 3b), and nodal (stage 3c) involvement as shown by their p-values of <0.01. However, in cases of parametrial invasion (stage 3b), bladder involvement, and rectal involvement (stage 4), MRI showed decreased sensitivity as shown by their p-values of 0.833, 0.87, and 0.9, respectively. Conclusion Preoperative MRI can predict local disease and low-risk patients accurately, thereby helping in proper surgical planning and avoiding more extensive surgery such as lymphadenectomy in these patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Gul et al.)

Internet of Things (IoT)-backed smart shopping carts are generating an extensive amount of data in shopping markets around the world. This data can be cleaned and utilized for setting business goals and strategies. Artificial intelligence (AI) methods are used to efficiently extract meaningful patterns or insights from such huge amounts of data or big data. One such technique is Association Rule Mining (ARM) which is used to extract strategic information from the data. The crucial step in ARM is Frequent Itemsets Mining (FIM) followed by association rule generation. The FIM process starts by tuning the support threshold parameter from the user to produce the number of required frequent patterns. To perform the FIM process, the user applies hit and trial methods to rerun the aforesaid routine in order to receive the required number of patterns. The research community has shifted its focus towards the development of top-K most frequent patterns not using the support threshold parameter tuned by the user. Top-K most frequent patterns mining is considered a harder task than user-tuned support-threshold-based FIM. One of the reasons why top-K most frequent patterns mining techniques are computationally intensive is the fact that they produce a large number of candidate itemsets. These methods also do not use any explicit pruning mechanism apart from the internally auto-maintained support threshold parameter. Therefore, we propose an efficient TKIFIs Miner algorithm that uses depth-first search strategy for top-K identical frequent patterns mining. The TKIFIs Miner uses specialized one- and two-itemsets-based pruning techniques for topmost patterns mining. Comparative analysis is performed on special benchmark datasets, for example, Retail with 16,469 items, T40I10D100K and T10I4D100K with 1000 items each, etc. The evaluation results have proven that the TKIFIs Miner is at the top of the line, compared to recently available topmost patterns mining methods not using the support threshold parameter.

In this research, we debate the critical challenges posed by the COVID-19 pandemic such as food scarcity, by examining the influence of consumption values on consumers' willingness to consume genetically modified (GM) food in the presence of consumer food attitudes, animosity, and ethnocentrism, which could be the one possible option to deal with the food scarcity problem. The proposed relationship could help to understand the complex societal problem of food scarcity and import dependency in the food sector before and after the crisis. Therefore, based on the theory of consumption values, we investigated government actions, consumer attitudes, and their willingness to consume GM food through 1340 valid USA responses and 1065 Chinese responses. We observed that COVID-19 doubled the number of malnourished people in 2020 relative to 2019, while consumption values, to some extent, changed consumer food attitudes and were inclined toward other food alternatives such as GM food regardless of governmental support for GM food in both USA and China. Moreover, this research enables governments, policymakers, market practitioners, and other stakeholders to use the COVID-19 crisis as an opportunity to negotiate with other countries to share their food technology along with imports.

Electrochemical techniques offer great opportunities for the capture of chemical and biological entities from complex mixtures and their subsequent release into clean buffers for analysis. Such methods are clean, robust, rapid, and compatible with a wide range of biological fluids. Here, we designed an electrochemically addressable system, based on a conducting terpolymer [P(EDOT -co- EDOTSAc -co- EDOTEG)] coated onto a carbon cloth substrate, to selectively capture and release biological entities using a simple electrochemical redox process. The conducting terpolymer composition was optimized and the terpolymer-coated carbon cloth was extensively characterized using electrochemical analysis, Raman and Fourier transform-infrared spectroscopy, water contact angle analysis, and scanning electron microscopy. The conductive terpolymer possesses a derivative of EDOT with an acetylthiomethyl moiety (EDOTSAc), which is converted into a "free" thiol that then undergoes reversible oxidation/reduction cycles at +1.0 V and -0.8 V (vs Ag/AgCl), respectively. That redox process enables electrochemical capture and on-demand release. We first demonstrated the successful electrochemical capture/release of a fluorescently labeled IgG antibody. The same capture/release procedure was then applied to release extracellular vesicles (EVs), originating from both MCF7 and SKBR3 breast cancer cell line bioreactors. EVs were captured using the substrate-conjugated HER2 antibody which was purified from commercially available trastuzumab. Capture and release of breast cancer EVs using a trastuzumab-derived HER2 antibody has not been reported before (to the best of our knowledge). A rapid (2 min) release at a low potential (-0.8 V) achieved a high release efficiency (>70%) of the captured, HER2 +ve , SKBR3 EVs. The developed system and the electrochemical method are efficient and straightforward and have vast potential for the isolation and concentration of various biological targets from large volumes of biological and other (e.g., environmental) samples.

Coronary vessel disease (CVD) is a class of diseases that impacts the blood vessels and heart and is one of the leading causes of disability and death. CVD includes cerebrovascular disease and coronary heart disease, both illnesses of the vessels transporting the oxygenated blood to the brain or heart. Colchicine is an inexpensive and old drug with strong anti-inflammatory effects. Numerous randomized control trials (RCTs) have demonstrated the effectiveness of low-dose colchicine for the prevention of severe cardiovascular events without showing any signs of serious adverse effects within the regime of treatment. In the current meta-analysis, we aim to assess the efficacy and safety of colchicine for secondary cardiovascular outcome prevention among patients with clinically proven CVD. The current meta-analysis was carried out using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. PUBMED, Cochrane, and EMBASE databases were used to search for RCTs comparing colchicine and placebos for the prevention of secondary cardiovascular outcomes. The primary efficacy endpoint was mortality due to cardiovascular disease, stroke, urgent coronary revascularization, and myocardial infarction. Secondary efficacy outcomes included death due to all-cause mortality. Seven RCTs were reviewed, with a pooled sample size of 12114, out of which 6099 were randomized to the colchicine group, and 6015 were randomized to the control group. The decrease in cardiovascular events, including myocardial infarction, stroke, urgent coronary revascularization, and cardiac-related death, was significantly lower in patients randomized to colchicine (p-value<0.05). The incidence of safety outcomes did not vary significantly different between groups (p>0.05). In patients with CVD, compared to standard medical therapy, colchicine significantly decreases the risk of cardiovascular events such as cardiovascular-related death, myocardial infarction, stroke, and urgent coronary revascularizations., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Sattar et al.)

Objective: The current study aimed to investigate the association of temporomandibular disorders (TMD)-related pain with the presence of migraine or tension-type headaches (TTH) over a follow-up period of 11 years., Methods: Data sets from Finnish national health surveys, the Health 2000 Survey (baseline), and the Health 2011 Survey (follow-up) were utilized. Study participants are undergoing clinical TMD examination at baseline and answering questions related to the presence of migraine and TTH at follow-up were included in the study (n = 530). For analyses, the study sample was divided into two data sets: One with those excluded suffering from migraine at baseline (Data set I, n = 345), and the other excluding those having TTH at baseline (Data set II, n = 464)., Results: Based on logistic regression modelling, no consistent association between TMD-related pain and the presence of migraine was observed, although jTMD associated with elevated estimates for migraine. However, participants with muscle-related TMD pain (mTMD) at baseline had markedly higher odds for having TTH at follow-up than participants without mTMD at baseline (OR 2.1, 95% CI 1.2-3.8). Joint-related TMD pain (jTMD) at baseline was inversely associated with the presence of TTH at follow-up (OR 0.4, 95% CI 0.1-1.3)., Conclusion: Contrasting patterns of the associations of TMD-related pain with different severe headaches point towards a more thorough and systematic research approach are needed to understand the mechanisms behind these associations., (© 2021 The Authors. Community Dentistry and Oral Epidemiology published by John Wiley & Sons Ltd.)

Rice is pivotal pyramid of about half of the world population. Bearing small genome size and worldwide utmost food crop rice has been known as ideal cereal crop for genome research. Currently, decreasing water table and soil fatigue are big challenges and intense consequences in changing climate. Whole sequenced genome of rice sized 389 Mb of which 95% is covered with excellent mapping order. Sequenced rice genome helps in molecular biology and transcriptomics of cereals as it provides whole genome sequence of indica and japonica sub species. Through rice genome sequencing and functional genomics, QTLs or genes, genetic variability and halophyte blocks for agronomic characters were identified which have proved much more useful in molecular breeding and direct selection. There are different numbers of genes or QTLs identified for yield related traits i.e., 6 QTLs/genes for plant architecture, 6 for panicle characteristics, 4 for grain number, 1 gene/QTL for tiller, HGW, grain filling and shattering. QTLS/genes for grain quality, biotic stresses and for abiotic stresses are 7, 23 and 13 respectively. Low yield, inferior quality and susceptibility to biotic and abiotic stresses of a crop is due to narrow genetic background of new evolving rice verities. Wild rice provides genetic resources for improvement of these characters, molecular and genomics tool at different stages can overcome these stresses and improve yield and quality of rice crop., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

To find new potential tyrosinase inhibitors, a diverse range of 2-arylchromone-4-thione derivatives ( 2a - 2p ) were designed and synthesized by employing a multistep strategy, and the newly synthesized compounds, for the first time, were screened in vitro for their tyrosinase inhibitory activity. In this context, the newly synthesized compounds ( 2a - 2p ) were characterized using a combination of several spectroscopic techniques including Fourier transform infrared, UV-vis, 1 H NMR, and 13 C NMR spectroscopies and electron ionization-mass spectrometry. All the target compounds were potent against tyrosinase as compared to the standard inhibitor kojic acid (half-maximal inhibitory concentration (IC 50 ) = 12.6 ± 0.6 μM). The compounds ( 2a - 2p ) produced IC 50 values in the range from 1.12 ± 0.04 to 5.68 ± 0.13 μM. Among the synthesized 4-thioflavones and 4-thioflavonols, the compound 2n exhibited excellent tyrosinase inhibitory activity with the lowest IC 50 of 1.12 ± 0.04 μM that could be recommended as potential lead candidates to cure tyrosinase-mediated hyperpigmentation in the future. A kinetic study of compound 2n revealed that compound 2n inhibited tyrosinase in a competitive mode. Furthermore, the nontoxic performance of the most beneficial compounds ranging from 1 to 25 g/mL was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test method for A375 human melanoma cells for the highly efficient target compounds ( 2m , 2n , 2o , and 2p ). Moreover, a molecular modeling study was performed against tyrosinase enzyme (2Y9X) to check the binding interactions of the synthesized compounds ( 2a - 2p ) against the target protein. Furthermore, quantitative structure-activity relationship studies were conducted based on an antityrosinase assay. The value of the correlation coefficient ( R 2 ) 0.9997 shows that there was a good correlation between ( 2a - 2p ) structures and selected properties. The geometry optimization of all complexes was performed by using Gaussian 09. Additionally, a drug-likeness research was used to establish the potent analogues' positive action as a new antityrosinase agent ( 2n , 2o , and 2p )., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Aim To analyze the histopathological outcome of stereotactic biopsies of newly developed suspicious calcifications at lumpectomy scar site in patients with breast conservation surgery (BCS) to determine the incidence of malignancy and the association of mammographic appearance of recurrent microcalcification and their distribution. We also determined the association of disease recurrence with the presence of calcifications in original tumor and lumpectomy resection margins with the risk of recurrence. Materials and methods This study is a retrospective review of mammograms of patients with breast cancer from 2010 to 2021 who underwent stereotactic biopsy of newly developed suspicious calcifications at scar site appreciated on annual follow-up mammogram after breast conservation surgery (BCS) with no mass on correlative ultrasound. The radiological and pathological features of the patients' primary tumor and new calcifications were obtained from the hospital's electronic patient record system. Results A total of 84 patients with breast cancer developed suspicious microcalcifications at the lumpectomy scar site detected on follow-up mammograms after BCS, and 28.6% showed malignant histopathological outcomes. All malignant cases demonstrated pleomorphic morphology. All amorphous (9.5%) and coarse heterogeneous (54.8%) calcifications were benign. The distribution pattern of recurrent malignant calcifications was grouped in 9.5%, regional in 2.4%, linear in 9.5%, and segmental in 7.1%. Calcifications in primary tumors were found in 20.2% of cases. Positive margins were found in 7.1% of these malignant cases. Statistically, there was a strong association between calcification morphology, calcification distribution, presence of calcifications on baseline mammogram, and tumor resection margins. The presence of calcifications in primary tumors and positive resection margins were identified as significant independent risk factors of malignant recurrent calcifications in the logistic regression model and marginal statistical significance in the multivariable logistic regression (MLR) model. Conclusion The interval development of pleomorphic calcifications after BCS with either linear or segmental pattern, positive resection margins, and associated calcifications in primary tumors was related to the increase in the risk of recurrence. Although amorphous and coarse heterogeneous morphology with grouped distribution showed benign outcomes, stereotactic biopsy is recommended to exclude disease recurrence in this high-risk patient population., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Aleem et al.)

Background: Upland cotton provides the most natural fiber in the world. During fiber development, the quality and yield of fiber were influenced by gene transcription. Revealing sequence features related to transcription has a profound impact on cotton molecular breeding. We applied convolutional neural networks to predict gene expression status based on the sequences of gene transcription start regions. After that, a gradient-based interpretation and an N-adjusted kernel transformation were implemented to extract sequence features contributing to transcription., Results: Our models had approximate 80% accuracies, and the area under the receiver operating characteristic curve reached over 0.85. Gradient-based interpretation revealed 5' untranslated region contributed to gene transcription. Furthermore, 6 DOF binding motifs and 4 transcription activator binding motifs were obtained by N-adjusted kernel-motif transformation from models in three developmental stages. Apart from 10 general motifs, 3 DOF5.1 genes were also detected. In silico analysis about these motifs' binding proteins implied their potential functions in fiber formation. Besides, we also found some novel motifs in plants as important sequence features for transcription., Conclusions: In conclusion, the N-adjusted kernel transformation method could interpret convolutional neural networks and reveal important sequence features related to transcription during fiber development. Potential functions of motifs interpreted from convolutional neural networks could be validated by further wet-lab experiments and applied in cotton molecular breeding., (© 2022. The Author(s).)

Objectives: To determine the main characteristics, reasons and patterns of road traffic injuries (RTIs) in a tertiary care public hospital of Karachi., Methods: It was a hospital based cross sectional study conducted in a public tertiary care hospital emergency department with a sample size 425 selected conveniently. Participants included the consenting victims or caretaking attendants of road traffic injuries (RTIs) from 25 th May to 28 th June in 2019. A structured questionnaire was developed after literature review and was translated into "Urdu" language. The questionnaire collected detailed information on socio-demographic characteristics, possible reasons of RTI's such as condition of vehicle, over speeding and breaking traffic rules. Data was analyzed by using software SPSS version 20., Results: Almost half of RTI victims (43.1%) belonged to the age group 18-29. Majority of the victims were males (86.6%). The most common vehicle involved was motorbike (87.50%) followed by Rickshaw (6.8%) and Car (2.4%). Majority of RTIs occurred on main road (75.30%). The most common sites of injuries were lower limb (64%), upper limb (37.60%) and head (32.2%). The severe injuries were significantly more likely to happen in events in which direct collision with other vehicle/thing was involved, road conditions were wet and pedestrian were crossing the road., Conclusion: Motorbikes were involved in majority of RTIs. Main reasons of RTIs included irresponsible road behaviors including over-speeding, careless road crossing, breaking the signal and riding on wet roads which lead to moderate to severe injuries in almost two thirds of participants., (Copyright: © Pakistan Journal of Medical Sciences.)

The effect of quality institutions on growth-environmental nexus is a generally ignored topic, especially in South Asia economies affiliated with the belt and road initiatives (BRIs). To fill this gap, we have examined the effect of BRI policy, economic freedom (EF), and institutional quality (IQ) on growth-environmental nexus in the South Asian region from 1984 to 2019. We have used CO 2 emission as a proxy for the environment in this study. To prevent variable bias, we also included energy consumption (EN) and trade openness (TO) as key factors in the model. To solve the problem of cross-sectional dependence, we have used the second-generational unit root test. The results of unit root tests indicate that the variable IQ is stationary at the level and other variables are stationary at the first difference. Furthermore, all of the variables are cointegrated, according to the panel cointegration test. Thus, we have used the panel autoregressive distributed lag (ARDL) method to estimate the long-run (LR) and short-run (SR) impact of response factors on economic growth. Furthermore, this research utilized the Granger causality test among the selected variables to inquire into the causalities. The basic findings are as follows: (i) A significantly positive interaction variable (CO 2 IQ) among CO 2 and IQ suggests that effective and fair political institutions are critical for increasing economic development and decreasing CO 2 emissions simultaneously. (ii) Economic growth is invigorated by energy consumption, trade, economic freedom, and institutional quality. (iii) Since 2013, more significant economic growth has been stimulated by BRI policy in BRI-associated countries; thus, both the SR and LR results are significantly positive. Hence, it is essential to improve the quality of institutions to reduce carbon emissions during economic growth., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This review comprises the inorganic compounds particularly metal coordinated complexes, as drugs play a relevant role in medicinal chemistry. It has been observed that copper complexes are potentially attractive as medicinal importance. In this review, the most remarkable achievements of copper complexes undertaken over the past few decades as antimicrobial, antioxidant, enzyme inhibition activity, and anti-cancer agents are discussed. This work was motivated by the observation that no comprehensive surveys of the diversity of biological activities of copper complexes were available in the literature., Competing Interests: Disclosure statement No potential conflict of interest was reported by the authors., (© TÜBİTAK.)

Objectives: Association of temporomandibular disorders (TMD)-related pain with severe headaches (migraine and tension-type headaches [TTH]) was studied over a follow-up period of 11 years., Materials and Methods: The data used was from two nationally representative health surveys in Finland-the Health 2000 Survey (baseline) and the Health 2011 Survey (follow-up) (Bioresource Research Impact Factor [BRIF] 8901)-conducted by the Finnish Institute for Health and Welfare (THL). The primary dataset of the current study included a subset of the population undergoing a clinical oral examination, including TMD examination, at baseline, and answering the questions related to severe headaches, both at baseline and at follow-up (n = 530). From the primary dataset, two datasets were created to study the onset of migraine (dataset 1) and TTH (dataset 2) separately. Dataset 1 included participants healthy of migraine, but not other headaches, at baseline (n = 345), and dataset 2 participants healthy of TTH and other headaches, except migraine, at baseline (n = 464). Bayesian logistic regression models with weakly informative priors were utilized to assess the association of muscle-related TMD pain (mTMD) at baseline and temporomandibular joint-related TMD pain (jTMD) at baseline with the presence of migraine and TTH at follow-up., Results: Neither of the baseline TMD-related pain variables were associated with the presence of migraine at follow-up (posterior effect estimates-0.12, 95% credible interval [CI] -0.49-0.24, and 0.11, 95% CI -0.38-0.59, for mTMD and jTMD, respectively), whereas mTMD at baseline (posterior effect estimate 0.36, 95% CI 0.02-0.69), but not jTMD at baseline (posterior effect estimate -0.32, 95% CI -0.94-0.25), was associated with the presence of TTH at follow-up. Bayesian sensitivity analyses revealed that the estimates of the regression models were stable, demonstrating sufficient validity and consistency of the estimates., Conclusion: These results indicate that diverse mechanisms may exist behind the associations of TMD-related painful conditions with different types of severe headaches., Clinical Relevance: TMD-related pain is a frequent comorbidity of severe primary headaches. Therapy of severe primary headaches may thus benefit significantly with the incorporation of a multi-disciplinary clinical team., (© 2021. The Author(s).)

Understanding key host protective mechanisms against SARS-CoV-2 infection can help improve treatment modalities for COVID-19. We used a blood transcriptome approach to study biomarkers associated with differing severity of COVID-19, comparing severe and mild Symptomatic disease with Asymptomatic COVID-19 and uninfected Controls. There was suppression of antigen presentation but upregulation of inflammatory and viral mRNA translation associated pathways in Symptomatic as compared with Asymptomatic cases. In severe COVID-19, CD177 a neutrophil marker, was upregulated while interferon stimulated genes (ISGs) were downregulated. Asymptomatic COVID-19 cases displayed upregulation of ISGs and humoral response genes with downregulation of ICAM3 and TLR8. Compared across the COVID-19 disease spectrum, we found type I interferon (IFN) responses to be significantly upregulated (IFNAR2, IRF2BP1, IRF4, MAVS, SAMHD1, TRIM1), or downregulated (SOCS3, IRF2BP2, IRF2BPL) in Asymptomatic as compared with mild and severe COVID-19, with the dysregulation of an increasing number of ISGs associated with progressive disease. These data suggest that initial early responses against SARS-CoV-2 may be effectively controlled by ISGs. Therefore, we hypothesize that treatment with type I interferons in the early stage of COVID-19 may limit disease progression by limiting SARS-CoV-2 in the host., (© 2021. The Author(s).)

To explore new scaffolds as tyrosinase enzyme inhibitors remain an interesting goal in the drug discovery and development. In due course and our approach to synthesize bioactive compounds, a series of varyingly substituted 3-hydroxyflavone derivatives ( 1-23 ) were synthesized in one-pot reaction and screened for in vitro against mushroom tyrosinase enzyme. The structures of newly synthesized compounds were unambiguously corroborated by usual spectroscopic techniques (FTIR, UV-Vis, 1 H-, 13 C-NMR) and mass spectrometry (EI-MS). The structure of compound 15 was also characterized by X-ray diffraction analysis. Furthermore, the synthesized compounds ( 1-23 ) were evaluated for their antimicrobial potential. Biological studies exhibit pretty good activity against most of the bacterial-fungal strains and their activity is comparable to those of commercially available antibiotics i.e. Cefixime and Clotrimazole. Amongst the series, the compounds 2, 4, 5, 6, 7, 10, 11, 14 and 22 exhibited excellent inhibitory activity against tyrosinase, even better than standard compound. Remarkably, the compound 2 (IC 50 = 0.280 ± 0.010 μg/ml) was found almost sixfold and derivative 5 (IC 50 = 0.230 ± 0.020 μg/ml) about sevenfold more active as compared to standard Kojic acid (IC 50 =1.79 ± 0.6 μg/ml). Moreover, these synthetic compounds ( 1-23 ) displayed good to moderate activities against tested bacterial and fungal strains. Their emission behavior was also investigated in order to know their potential as fluorescent probes. The molecular modelling simulations were also performed to explore their binding interactions with active sites of the tyrosinase enzyme. Limited structure-activity relationship was established to design and develop new tyrosinase inhibitors by employing 2-arylchromone as a structural core in the future. Communicated by Ramaswamy H. Sarma.

Background: Cotton is the world's richest source of natural fiber. Meanwhile cotton plant is top ranked stress sensitive plant thereby affecting its yield and fiber quality. But, in climate change scenario, fiber yield and quality are being affected due to environmental stresses, especially heat, drought and salinity. Present study is aimed to identify cotton genotype harboring prominently expressed stress responsive genes., Methods: Four cotton genotypes (IUB-13, IUB-222, IUB-09 and MM-58) were evaluated under drought and salinity stress for yield traits and expression of different stress responsive genes (GhWRKY3, GhDREB2 and GhRDR6)., Results: Pronounced expression of GhWRKY3, GhDREB2and GhRDR6 was observed in cotton variety IUB-13 in stress condition (drought and salinity) as compared to control followed by IUB-222 which revealed that these genotypes might possess substantial potential to cope with environmental hazards encountered in growing season CONCLUSION: Utilization of cotton genotypes i.e., IUB-13 and IUB-222 in cotton breeding program can be very much fruitful for developing cotton genotypes adoptable to climate change., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The excelling role of organic chemistry in the medicinal field continues to be one of the main leads in the drug development process. Particularly, this industry requires organic chemists to discover small molecular structures with powerful pharmacological potential. Herein, a diverse range of chalcone (1-11) and aurone (12-22) derivatives was designed and synthesized and for the first time, and both motifs were evaluated as potent inhibitors of alkaline phosphatases (APs). Structural identification of the target compounds (1-22) was accomplished using common spectroscopic techniques. The effect of the nature and position of the substituent was interestingly observed and justified based on the detailed structure-activity relationship (SAR) of the target compounds against AP. It was concluded from the obtained results that all the newly synthesized compounds exhibit high inhibitory potential against the AP enzyme. Among them, compounds 12 (IC 50 = 2.163 ± 0.048 μM), 15 (IC 50 = 2.146 ± 0.056 μM), 16 (IC 50 = 2.132 ± 0.034 μM), 18 (IC 50 = 1.154 ± 0.043 μM), 20 (IC 50 = 1.055 ± 0.029 μM) and 21 (IC 50 = 2.326 ± 0.059 μM) exhibited excellent inhibitory activity against AP, and even better/more active than KH 2 PO 4 (standard) (IC 50 = 2.80 ± 0.065 μM). Remarkably, compound 20 (IC 50 = 1.055 ± 0.029 μM) may serve as a lead structure to design more potent inhibitors of alkaline phosphatase. To the best of our knowledge, these synthetic compounds are the most potent AP inhibitors with minimum IC 50 values reported to date. Furthermore, a molecular modeling study was performed against the AP enzyme (1EW2) to check the binding interaction of the synthesized compounds 1-22 against the target protein. The Lineweaver-Burk plots demonstrated that most potential derivative 20 inhibited h-IAP via a non-competitive pathway. Finally, molecular dynamic (MD) simulations were performed to evaluate the dynamic behavior, stability of the protein-ligand complex, and binding affinity of the compounds, resulting in the identification of compound 20 as a potential inhibitor of AP. Accordingly, excellent correlation was observed between the experimental and theoretical results. The pharmacological studies revealed that the synthesized analogs 1-22 obey Lipinski's rule. The assessment of the ADMET parameters showed that these compounds possess considerable lead-like characteristics with low toxicity and can serve as templates in drug design., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: We investigated the genome diversity of SARS-CoV-2 associated with the early COVID-19 period to investigate evolution of the virus in Pakistan., Materials and Methods: We studied ninety SARS-CoV-2 strains isolated between March and October 2020. Whole genome sequences from our laboratory and available genomes were used to investigate phylogeny, genetic variantion and mutation rates of SARS-CoV-2 strains in Pakistan. Site specific entropy analysis compared mutation rates between strains isolated before and after June 2020., Results: In March, strains belonging to L, S, V and GH clades were observed but by October, only L and GH strains were present. The highest diversity of clades was present in Sindh and Islamabad Capital Territory and the least in Punjab province. Initial introductions of SARS-CoV-2 GH (B.1.255, B.1) and S (A) clades were associated with overseas travelers. Additionally, GH (B.1.255, B.1, B.1.160, B.1.36), L (B, B.6, B.4), V (B.4) and S (A) clades were transmitted locally. SARS-CoV-2 genomes clustered with global strains except for ten which matched Pakistani isolates. RNA substitution rates were estimated at 5.86 x10-4. The most frequent mutations were 5' UTR 241C > T, Spike glycoprotein D614G, RNA dependent RNA polymerase (RdRp) P4715L and Orf3a Q57H. Strains up until June 2020 exhibited an overall higher mean and site-specific entropy as compared with sequences after June. Relative entropy was higher across GH as compared with GR and L clades. More sites were under selection pressure in GH strains but this was not significant for any particular site., Conclusions: The higher entropy and diversity observed in early pandemic as compared with later strains suggests increasing stability of the genomes in subsequent COVID-19 waves. This would likely lead to the selection of site-specific changes that are advantageous to the virus, as has been currently observed through the pandemic., Competing Interests: The authors have declared that no competing interests exist.

Reproduction comes at a cost, including accelerated death. Previous studies of the interconnections between reproduction, lifespan, and fat metabolism in C. elegans were predominantly performed in low-reproduction conditions. To understand how increased reproduction affects lifespan and fat metabolism, we examined mated worms; we find that a Δ9 desaturase, FAT-7, is significantly up-regulated. Dietary supplementation of oleic acid (OA), the immediate downstream product of FAT-7 activity, restores fat storage and completely rescues mating-induced death, while other fatty acids cannot. OA-mediated lifespan restoration is also observed in C. elegans mutants suffering increased death from short-term mating, and in mated C. remanei females, indicating a conserved role of oleic acid in post-mating lifespan regulation. Our results suggest that increased reproduction can be uncoupled from the costs of reproduction from somatic longevity regulation if provided with the limiting lipid, oleic acid., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Choi, Shi, Ashraf, Sohrabi and Murphy.)

Circular RNAs (circRNAs) are a class of endogenous noncoding RNA, which were previously considered as a byproduct of RNA splicing error. Numerous studies have demonstrated the altered expression of circRNAs in organ tissues during pathological conditions and their involvements in disease pathogenesis and progression, including cancers. In colorectal cancer (CRC), multiple circRNAs have been identified and characterized as "oncogenic", given their involvements in the downregulation of tumor suppressor genes and induction of tumor initiation, progression, invasion, and metastasis. Additionally, other circRNAs have been identified in CRC and characterized as "tumor suppressive" based on their ability of inhibiting the expression of oncogenic genes and suppressing tumor growth and proliferation. circRNAs could serve as potential diagnostic and prognostic biomarkers, and therapeutic targets or vectors to be utilized in cancer therapies. This review briefly describes the dynamic changes of the tumor microenvironment inducing immunosuppression and tumorigenesis, and outlines the biogenesis and characteristics of circRNAs and recent findings indicating their roles and functions in the CRC tumor microenvironment. It also discusses strategies and technologies, which could be employed in the future to overcome current cancer therapy challenges associated with circRNAs., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The present study describes the discovery of novel inhibitors of mushroom tyrosinase enzyme. For that purpose, a series of varyingly substituted 2-phenylchromone analogues 1-28 were synthesized and characterized in detail by various spectroscopic techniques (UV-Vis, FTIR, 1 H NMR, 13 C NMR) and mass spectrometry. All the derivatives (1-28) were screened in vitro for their inhibitory potential against mushroom tyrosinase enzyme. Interestingly, all the synthetic compounds displayed good to excellent inhibitory activity with IC 50 values ranging from 0.093 ± 0.003 μg/ml to 23.58 ± 0.94 μg/ml for brominated 3-hydroxy-2-phenylchromones and 0.22 ± 0.017 μg/ml to 22.22 ± 1.1 μg/ml for brominated 2-phenylchromones against tyrosinase in comparison to the standard kojic acid (IC 50  = 1.79 ± 0.64 μg/ml). Remarkably, the bromine atoms attached on ring A attribute to increases the inhibitory potential of 2-phenylchromone moiety and anti-tyrosinase assay demonstrated that compound 10 (IC 50  = 0.093 ± 0.003 µg/ml) was found almost nineteenfold, 11 (IC 50  = 0.126 ± 0.015 µg/ml) fourteenfold and 26 (IC 50  = 0.22 ± 0.017 µg/ml) about eightfold more active than the positive control. Notably, among the already literature reported tyrosinase inhibitors, these analogues have been found the most active inhibitors of mushroom tyrosinase with the lowest possible IC 50 values. To design and develop novel tyrosinase inhibitors using 2-phenylchromone as a structural motif in the future, a limited structure-activity relationship was established. Moreover, in silico studies were carried out to rationalize the binding mode of interactions of all the targeted compounds (1-28) with the active site of enzymes. The experimental and theoretical results are in parallel with one another. In addition, molecular description was performed with the drug-likeness and bioactivity scores. Computational analysis predicted that few compounds are in a linear correlation with Lipinski's RO5 indicating superb drug-likeness and bioactivity score for drug targets., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Congenital megaprepuce (CMP) is a malformation consisting of redundant inner foreskin, normal penile shaft, and severe phimosis. The excess inner prepuce pushes the penile shaft deeper causing the appearance of a buried penis. We describe a novel surgical technique using dartos fascial flaps to reconstruct the prepuce giving excellent cosmetic and functional results. Patients and Methods: Penile reconstruction was performed by a single surgeon in 07 cases of CMP between January 2018 and December 2019. In all cases, the described surgical technique was used. Following surgery, cosmetic and functional outcomes were reviewed as well as the incidence of complications. The patients' ages ranged from 15 to 27 months (mean = 19). Mean hospital stay was 9 hours (range = 7-12). Operating time was between 50 and 85 minutes. Results: Postoperative appearance of the penis was satisfactory for all the parents in our group. Swelling of the penile shaft was seen in all of our patients but settled within one week of surgery. Scrotal hematoma was seen in only one of our patients, but that also did not need any intervention and settled spontaneously. During the follow-up period (mean = 14.5 months, range 6-24) no patient underwent revision surgery. In all our patients, the final appearance was of a circumcised penis. The final similarity to a normal circumcised penis was excellent in all of our patients. Correction of penoscrotal transposition was done in all patients achieving an elongated penile shaft and almost invisible postoperative scarring. Conclusion: Our modified surgical procedure to correct CMP is a safe and simple technique, providing good cosmetic results with the appearance of a standard circumcised penis. This also provides a good functional outcome with complication rate quite low. This technique is also easy to reproduce and teach compared with other complex procedures.