Consensus Statements for Assessment and Management of Threatened Miscarriage in the First Trimester in Pakistan: A Three-Step Modified Delphi Approach.

BACKGROUND AND OBJECTIVE: It aimed to develop an expert consensus regarding the risk assessment, diagnosis, and threatened miscarriage management during the first trimester in Pakistan. METHODS: A three-step modified Delphi method was applied to develop the consensus. Eleven specialized obstetricians and gynecologists participated in its development. If 75% or higher agreement level was attained on each assertion, it was declared as a consensus. RESULTS: Age of 35 or above, previous history of two or more previous miscarriages, and direct strong trauma were considered to be threatened miscarriage risk factors. Infection was discussed and specified to include specific infectious diseases, like malaria, and COVID-19 as a risk factor. The experts agreed from the first time on considering endocrinological disorders, thrombophilia, and lifestyle variables as threatened miscarriage risk factors. They proposed adding a statement concerning acquired thrombophilia which was accepted unanimously. Finally, experts agreed on the importance of educating pregnant women about factors whose risk can be modified by modifying their behavior. As for diagnosis statements, it was agreed to be trifold: physical examination, imaging, and laboratory testing. Physical examination included abdominal and pelvic exams but focused more on vaginal examination with speculum to identify bleeding severity and etiology. The statements regarding the imaging approaches to diagnose threatened miscarriage in the first trimester achieved a consensus in most statements. TVS was recommended to check on uterine structural abnormalities, fetus viability focusing on heartbeat and crown-to-rump length, gestation sac size and emptiness, subchorionic hematoma, and ectopic pregnancy. Each was defined on how to identify and diagnose in separate statements. Statements about laboratory tests indicated the need for human chorionic gonadotropin hormone assessment whether serial or once is dependent on the ultrasound. Recommended hematologic investigations include complete blood count for anemia, Rh factor for potential bleeding risk and in special cases, thrombophilia assessment is undertaken. The first and foremost management aspect was follow-up while most management statements were controversial, and some were altogether removed with only some reaching agreement after discussion. CONCLUSION: These consensus statements aggregated the best available evidence and experts' opinion-supported statements to improve patient education, risk assessment, diagnosis, and evaluation as well as management of threatened miscarriage during the first trimester in Pakistan.

In silico molecular modeling and in vitro biological screening of novel benzimidazole-based piperazine derivatives as potential acetylcholinesterase and butyrylcholinesterase inhibitors.

New series of benzimidazole incorporating piperazine moieties in single molecular framework has been reported. The structures of the synthesized derivatives were assigned by 1H-NMR, 13C-NMR, and HR-MS techniques. The hybrid derivatives were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibition effect. All the synthesized analogs showed good to moderate inhibitory effect ranging from IC50 value 0.20 ± 0.01 µM to 0.50 ± 0.10 µM for acetylcholinesterase and from IC50 value 0.25 ± 0.01 µM to 0.70 ± 0.10 µM for butyrylcholinesterase except one that showed least potency with IC50 value 1.05 ± 0.1 µM and 1.20 ± 0.1 µM. The differences in inhibitory potential of synthesized compounds were due to the nature and position of substitution attached to the main ring. Additionally, molecular docking study was carried out for most active in order to explore the binding interactions established by ligand (active compounds) with the active residues of targeted AChE & BuChE enzyme.

Synthesis of modified Schiff base appended 1,2,4-triazole hybrids scaffolds: elucidating the in vitro and in silico α-amylase and α-glucosidase inhibitors potential.

The current study involves the synthesis of Schiff bases based on 1,2,4-triazoles skeleton and assessing their α-amylase and α-glucosidase profile. Furthermore, the precise structures of the synthesized derivatives were elucidated using various spectroscopic methods such as 1H-NMR, 13C-NMR and HREI-MS. Using glimepiride as the reference standard, the in vitro α-glucosidase and α-amylase inhibitory activities of the synthesized compounds were evaluated in order to determine their potential anti-diabetic properties. All analogues showed varied range of inhibitory activity having IC50 values ranging from 17.09 ± 0.72 to 45.34 ± 0.03 µM (α-amylase) and 16.35 ± 0.42 to 42.31 ± 0.09 µM (α-glucosidase), respectively. Specifically, the compounds 1, 7 and 8 were found to be significantly active with IC50 values of 17.09 ± 0.72, 19.73 ± 0.42, and 23.01 ± 0.04 µM (against α-amylase) and 16.35 ± 0.42, 18.55 ± 0.26, and 20.07 ± 0.02 µM (against α-glucosidase) respectively. The obtained results were compared with the Glimepiride reference drug having IC50 values of 13.02 ± 0.11 µM (for α-glucosidase) and 15.04 ± 0.02 µM (for α-amylase), respectively. The structure-activity relationship (SAR) studies were conducted based on differences in substituent patterns at varying position of aryl rings A and B may cause to alter the inhibitory activities of both α-amylase and α-glucosidase enzymes. Additionally, the molecular docking study was carried out to explore the binding interactions possessed by most active analogues with the active sites of targeted α-amylase and α-glucosidase enzymes.

Evaluating the impact of double dose vaccination on SARS-CoV-2 spread through optimal control analysis.

This paper presents a new nonlinear epidemic model for the spread of SARS-CoV-2 that incorporates the effect of double dose vaccination. The model is analyzed using qualitative, stability, and sensitivity analysis techniques to investigate the impact of vaccination on the spread of the virus. We derive the basic reproduction number and perform stability analysis of the disease-free and endemic equilibrium points. The model is also subjected to sensitivity analysis to identify the most influential model parameters affecting the disease dynamics. The values of the parameters are estimated with the help of the least square curve fitting tools. Finally, the model is simulated numerically to assess the effectiveness of various control strategies, including vaccination and quarantine, in reducing the spread of the virus. Optimal control techniques are employed to determine the optimal allocation of resources for implementing control measures. Our results suggest that increasing the vaccination coverage, adherence to quarantine measures, and resource allocation are effective strategies for controlling the epidemic. The study provides valuable insights into the dynamics of the pandemic and offers guidance for policymakers in formulating effective control measures.

Facile benzothiazole-triazole based thiazole derivatives as novel thymidine phosphorylase and α-glucosidase inhibitors: Experimental and computational approaches.

The present study reports the new thiazole (A-L) derivatives based on benzothiazole fused triazole which were synthesized and assessed against thymidine phosphorylase and α-glucosidase enzymes. Several compounds with the same basic structure but different substituents were found to have high activity against the targeted enzymes, while others with the same basic skeleton but different substituents were found to have medium to low activity among the members of tested series. These analogs showed a varied range of inhibition in both case thymidine phosphorylase and alpha glucosidase, A (IC50 = 7.20 ± 0.30 µM and IC50 = 1.30 ± 0.70 µM), B (IC50 = 8.80 ± 0.10 µM and IC50 = 2.10 ± 0.30 µM), C (IC50 = 8.90 ± 0.40 µM and IC50 = 3.20 ± 0.20 µM) and thiazole containing analogs such as G (IC50 = 11.10 ± 0.20 µM and IC50 = 7.80 ± 0.20 µM) and H (IC50 = 12.30 ± 0.30 µM and IC50 = 6.30 ± 0.20 µM). When compared with standard drugs 7-Deazaxanthine, 7DX (IC50 = 10.60 ± 0.50 µM) and acarbose (IC50 = 4.30 ± 0.30 µM) respectively. These analogs were also subjected to molecular docking studies which indicated the binding interaction of molecules with active sites of the enzyme and strengthen the drug profile of these compounds. ADMET studies also predict the drug-like properties of these compounds, with no violations of drug likeness rules.

Identification of novel benzothiazole-thiadiazole-based thiazolidinone derivative: in vitro and in silico approaches to develop promising anti-Alzheimer's agents.

Aim: The present study describes benzothiazole derived thiazolidinone based thiadiazole derivatives (1-16) as anti-Alzheimer agents. Materials & methods: Synthesis of benzothiazole derived thiazolidinone based thiadiazole derivatives was achieved using the benzothiazole bearing 2-amine moiety. These synthesized compounds were confirmed via spectroscopic techniques (1H NMR, 13C NMR and HREI-MS). These compounds were biologically evaluated for their anti-Alzheimer potential. Binding interactions with proteins and drug likeness of the analogs were explored through molecular docking and ADMET analysis, respectively. In the novel series, compound-3 emerged as the most potent inhibitor when compared with other derivatives of the series. Conclusion: The present study provides potent anti-Alzheimer's agents that can be further optimized to discover novel anti-Alzheimer's drugs.

[Box: see text].

Recent development and strategies towards target interactions: Synthesis, characterization and in silico analysis of benzimidazole based thiadiazole as potential anti-Alzheimer agents.

In the current research study, we aim to design and synthesize highly potent hybrid analogs of benzimidazole derived thiadiazole based Schiff base derivatives which can combat the cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase) accountable for developing Alzheimer's disease. In this context, we have synthesized 15 analogs of benzimidazole based thiadiazole derivatives, which were subsequently confirmed through spectroscopic techniques including 1H NMR, 13C NMR and HREI-MS. Biological investigation of all the analogs revealed their varied acetylcholinesterase inhibitory potency covering a range between 3.20 ± 0.10 µM to 20.50 ± 0.20 µM as well as butyrylcholinesterase inhibitory potential with a range of 4.30 ± 0.50 µM to 20.70 ± 0.50 µM when compared with the standard drug Donepezil having IC50 = 6.70 ± 0.20 µM for AChE and 7.90 ± 0.10 µM for BuChE. The promising inhibition by the analogs was evaluated in SAR analysis, where analog-1 (IC50 = 3.20 ± 0.10 µM for AChE and 4.30 ± 0.50 µM for BuChE), analog-4 (IC50 = 4.30 ± 0.30 µM for AChE and 5.50 ± 0.20 µM for BuChE) and analog-5 (IC50 = 4.10 ± 0.30 µM for AChE and 4.60 ± 0.40 µM for BuChE) were found as the lead candidates. Moreover, molecular docking and ADME analysis were conducted to explore the better binding interactions and drugs likeness respectively.

In vitro enzymatic, in silico ADME and molecular docking based analysis for the identification of novel bis-indole containing triazine-thiazole hybrids derivatives as promising urease inhibitors.

The current study details a sequence of sequential reactions for synthesizing bis-indole-based triazine bearing thiazole derivatives. Several steps were involved in the synthesis of bis-indole-based triazine bearing thiazole derivative. The synthetic reactions were monitored via thin-layer chromatography (TLC). Synthesized compounds were characterized using various spectroscopic techniques, including 1H NMR, 13C NMR, and HR-EIMS. The inhibitory activity against urease enzyme of these synthesized compounds was compared with that of thiourea, a standard drug (IC50 = 9.30 ± 0.20 µM). A range of inhibitory potencies were observed for the synthesized compounds, ranging from moderate to excellent, as follows (IC50 = 5.10 ± 0.40 µM to 29.80 ± 0.20 µM). Analyzing the structure-activity relationship (SAR) provided insight into the results, showing that different substituents had different effects on aromatic rings. Several compounds displayed outstanding inhibitory properties (among those tested were 1, 2, 4, 5, and 6 with IC50 = 6.30 ± 0.80, 5.10 ± 0.40, 5.90 ± 0.50, 8.20 ± 0.10, 8.90 ± 0.60 µM, respectively). Anti-urease evaluation of all the synthesized derivatives was conducted in which the selected compounds have shown remarkable potency compared with the standard drug thiourea (IC50 = 9.30 ± 0.20 µM). Molecular docking analysis was carried out for investigating the better binding sites and distance of the derivatives. Moreover, the drug-like properties were explored by the ADME attributes of the synthesized analogs.

Will advancement in technologies bring fear and damage human employment? Evidence from China's manufacturing industry.

Advancement in technologies such as robotic industries and artificial intelligence bring fear among human being that jobs will be substituted by robots. Base on the panel data of 28 China's manufacturing industries, this research analyzed the impact of technical progress bias on employment. First, we calculate the technical progress bias index of 28 industries base on the stochastic frontier model with transcendental logarithm function found 16 industries were toward the skilled labor while the remaining 12 industries were toward the unskilled labor. Second, the empirical results show that technical progress bias has a positive impact on the total manufacturing employment and significant positive effect on the unskilled labor, while no significant impact on skilled labor employment. Third, the threshold effect test proves that if taking industry value-added per capita or R&D capital stock as threshold variable, the threshold about the impact exist, making the impact on skilled labor was insignificant.

Synthesis, in vitro bio-evaluation and in silico molecular docking studies of thiadiazole-based Schiff base derivatives.

Aim: Recently, thiadiazole-containing drugs have gained greater clinical relevance and are being explored for the development of new antidiabetic, antiurease and antimicrobial agents that target drug resistance. Methods & results: The authors disclose the synthesis of N-(5-[4-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl)methanimine derivatives starting from 4-(trifluoromethyl)benzoic acid. All of the synthesized derivatives were evaluated for their biological potential in order to investigate the inhibitory activity against antidiabetic, antiurease and antibacterial profiles. Compounds 1, 2 and 9 showed excellent inhibitory activities due to the hydrogen bonding presence of -OH, -F and -CF3 substitutions attached with the phenyl ring. Conclusion: The present study provides potent antidiabetic, antiurease and antimicrobial agents that can be further optimized to discover novel antidiabetic, antiurease drugs.

The Synthesis, In Vitro Bio-Evaluation, and In Silico Molecular Docking Studies of Pyrazoline-Thiazole Hybrid Analogues as Promising Anti-α-Glucosidase and Anti-Urease Agents.

In the present work, a concise library of benzothiazole-derived pyrazoline-based thiazole (1-17) was designed and synthesized by employing a multistep reaction strategy. The newly synthesized compounds were screened for their α-glucosidase and urease inhibitory activities. The scaffolds (1-17) were characterized using a combination of several spectroscopic techniques, including FT-IR, 1H-NMR, 13C-NMR, and EI-MS. The majority of the synthesized compounds demonstrated a notable potency against α-glucosidase and urease enzymes. These analogues disclosed varying degrees of α-glucosidase and urease inhibitory activities, with their IC50 values ranging from 2.50 to 17.50 µM (α-glucosidase) and 14.30 to 41.50 (urease). Compounds 6, 7, 14, and 12, with IC50 values of 2.50, 3.20, 3.40, and 3.50 µM as compared to standard acarbose (IC50 = 5.30 µM), while the same compounds showed 14.30, 19.20, 21.80, and 22.30 comparable with thiourea (IC50 = 31.40 µM), respectively, showed excellent inhibitory activity. The structure-activity relationship revealed that the size and electron-donating or electron-withdrawing effects of substituents influenced the enzymatic activities such as α-glucosidase and urease. Compound 6 was a dual potent inhibitor against α-glucosidase and urease due to the presence of -CF3 electron-withdrawing functionality on the phenyl ring. To the best of our knowledge, these synthetic compounds were found to be the most potent dual inhibitors of α-glucosidase and urease with minimum IC50 values. Moreover, in silico studies on most active compounds, i.e., 6, 7, 14, and 12, were also performed to understand the binding interaction of most active compounds with active sites of α-glucosidase and urease enzymes.

Identification of Indazole-Based Thiadiazole-Bearing Thiazolidinone Hybrid Derivatives: Theoretical and Computational Approaches to Develop Promising Anti-Alzheimer's Candidates.

A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (1-17) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied range of inhibitory activities having IC50 values ranging from 0.86 ± 0.33 µM to 26.73 ± 0.84 µM (AChE) and 0.89 ± 0.12 µM to 27.08 ± 0.19 µM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC50 = 1.26 ± 0.18 µM for AChE) and (1.35 ± 0.37 µM for BuChE), respectively. Specifically, the derivatives 1-17, 1, 9, and 14 were found to be significantly active, with IC50 values of 0.86 ± 0.30, 0.92 ± 0.10, and 1.10 ± 0.37 µM (against AChE) and 0.89 ± 0.12, 0.98 ± 0.48 and 1.19 ± 0.42 µM (against BuChE), respectively.The structure-activity relationship (SAR) studies revealed that derivatives bearing para-CF3, ortho-OH, and para-F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as meta-Cl, -NO2, and para-chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using 1H-NMR, 13C-NMR, and (HR-MS) to confirm the precise structures of the synthesized compounds. Additionally, the molecular docking approach was carried out for most active compounds to explore the binding interactions established by most active compounds, with the active sites of targeted enzymes and obtained results supporting the experimental data.

Identification and Validation of Functional miRNAs and Their Main Targets in Sorghum bicolor.

MicroRNAs (miRNAs) are typically non-coding RNAs of 18-26 nucleotides (nts) that are produced endogenously and regulated post-transcriptionally through degradation or translational repression. Since miRNAs are evolutionarily conserved, their preservation is essential for important regulatory functions in plant development, growth, and responses to environmental stress. Sorghum bicolor (sbi) is a valuable food and fodder crop which is grown worldwide. A range of sbi miRNAs were identified so far as being connected to plant development and stress responses. Herein, we employed a variety of bioinformatics tools for miRNA profiling in sbi and a PCR-based platform for the validation of these miRNAs. In total, 74 new conserved sbi miRNAs from 52 miRNA families have been predicted. Using the psRNA Target method, 10613 different protein targets of these predicted miRNAs have been attained. These targets include 54 GO-terms which have substantial targets in the biological, molecular, and cellular processes. We particularly found that the sbi-miR1861c and sbi-miR5050 are involved to regulate sulphur compound biosynthetic process, while the significant spliceosomal complex is regulated by sbi-miR815b and sbi-miR7768b. Also, we report that the pre-ribosome, electron transport chain, cell communication, cellular respiration, protein localization, and photosynthesis are controlled by sbi-miR2907b, sbi-miR530, sbi-miR7749, sbi-miR1858a, sbi-mi7729a, and sbi-miR417, respectively. The identification and validation of these novel sbi miRNAs shall contribute a lot in improving the crop yield and ensure sustainable agriculture.

Investigation of novel bis-thiadiazole bearing schiff base derivatives as effective inhibitors of thymidine phosphorylase: Synthesis, in vitro bioactivity and molecular docking study.

Thymidine phosphorylase (TP) is an angiogenic enzyme. It is crucial for the development, invasion and metastasis of tumors as well as angiogenesis. In our current research, we examine how structurally changing bis-thiadiazole bearing bis-schiff bases affects their ability to inhibit TP. Through the oxidative cyclization of pyridine-based bis-thiosemicarbazone with iodine, a series of fourteen analogs of bis-thiadiazole-based bis-imines with pyridine moiety were developed. Newly synthesized scaffolds were assessed in vitro for their thymidine phosphorylase inhibitory potential and showed moderate to good inhibition profile. Eleven scaffolds such as 4a-4d,4f-4 h and 4j-4 m were discovered to be more effective than standard drug at inhibiting the thymidine phosphorylase enzyme with IC50 values of 1.16 ± 1.20, 1.77 ± 1.10, 2.48 ± 1.30, 12.54 ± 1.60, 14.63 ± 1.70, 15.53 ± 1.80, 17.47 ± 1.70, 18.98 ± 1.70, 19.53 ± 1.50, 22.73 ± 2.40 and 24.87 ± 2.80 respectively, while remaining three analogs such as 4n, 4i and 4ewere found to be more potent, but they were less potent than the standard drug. All analogs underwent SAR studies based on the pattern of substitutions around the aryl part of the bis-thiadiazole skeleton. The most active analogs in the synthesized series were then molecular docking study performed to investigate their interactions of active part of enzyme. The results showed that remarkable interactions were exhibited by these analogs with the targeted enzymes active sites. Furthermore, to confirm the structure of synthesized analogs by employing spectroscopic tools such as HREI-MS and NMR.

A machine learning-based Biding price optimization algorithm approach.

Trading companies of used product market are struggling to gain customers attentaion and to sell the products. The aim of this research is to develop a mechanism that can maximize the sale of products while considering profit implications. The literature review classifies the procurement mechanism. Given the limited-supply nature, that also includes unpredictable quality levels and a procurement mechanism that perceives the company offering prices to suppliers on a single-item basis. The academic literature has not covered such a mechanism. Techniques like those that improve the required bidding strategy are reviewed and considered fit to be included in the support tool as the procedures intention to maximize an objective function depending on the bidding price and contain the probability of winning the auction and the profit made from the proceeding, the motivation laid on the approach that predicts the probability. It is determined that this assembles a Response to Reverse Request for Quotation that meets the assumptions of a First-Price Sealed-Bid(FPSD) auction that potentially includes a hidden reservation price.

Does globalization and ecological footprint in OECD lead to national happiness.

This study examines the relationship between globalization, ecological footprint, innovation, and subjective wellbeing in the form of happiness, using a comprehensive assessment of OECD countries from 2008 to 2020. The study employs FGLS, Quantile, and Bootstrap Quantile regression estimation to investigate the quadratic effects of globalization, ecological footprint, and the moderating effect of innovation while controlling for renewable energy and population density. Happiness is a multidisciplinary subject, and this study focuses on the economic dimensions of happiness. The findings reveal a nonlinear relationship between ecological footprint and globalization, with negative effects on subjective wellbeing at high levels of ecological footprint and globalization. However, the moderating effect of innovation mitigates these adverse effects, indicating that innovation can help to offset the detrimental impacts of ecological footprint and globalization on subjective wellbeing. The study's implications are significant for policymakers promoting sustainable economic growth while enhancing subjective wellbeing. The findings highlight the importance of investing in innovation and sustainable development to promote subjective wellbeing in the face of increasing ecological footprint and globalization. Additionally, this research contributes to the multidisciplinary understanding of happiness and provides valuable insights for future research in this area.

Benzimidazole-Based Schiff Base Hybrid Scaffolds: A Promising Approach to Develop Multi-Target Drugs for Alzheimer's Disease.

A series of benzimidazole-based Schiff base derivatives (1-18) were synthesized and structurally elucidated through 1H NMR, 13C NMR and HREI-MS analysis. Subsequently, these synthetic derivatives were subjected to evaluation for their inhibitory capabilities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). All these derivatives showed significant inhibition against AChE with an IC50 value in the range of 123.9 ± 10.20 to 342.60 ± 10.60 µM and BuChE in the range of 131.30 ± 9.70 to 375.80 ± 12.80 µM in comparison with standard Donepezil, which has IC50 values of 243.76 ± 5.70 µM (AChE) and 276.60 ± 6.50 µM (BuChE), respectively. Compounds 3, 5 and 9 exhibited potent inhibition against both AChE and BuChE. Molecular docking studies were used to validate and establish the structure-activity relationship of the synthesized derivatives.

Imidazopyridine-Based Thiazole Derivatives as Potential Antidiabetic Agents: Synthesis, In Vitro Bioactivity, and In Silico Molecular Modeling Approach.

A new series of thiazole derivatives (4a-p) incorporating imidazopyridine moiety was synthesized and assessed for their in vitro potential α-glucosidase potency using acarbose as a reference drug. The obtained results suggested that compounds 4a (docking score = -13.45), 4g (docking score = -12.87), 4o (docking score = -12.15), and 4p (docking score = -11.25) remarkably showed superior activity against the targeted α-glucosidase enzyme, with IC50 values of 5.57 ± 3.45, 8.85 ± 2.18, 7.16 ± 1.40, and 10.48 ± 2.20, respectively. Upon further investigation of the binding mode of the interactions by the most active scaffolds with the α-glucosidase active sites, the docking analysis was accomplished in order to explore the active cavity of the α-glucosidase enzyme. The interpretation of the results showed clearly that scaffolds 4a and 4o emerged as the most potent α-glucosidase inhibitors, with promising excellent binding interactions with the active site of the α-glucosidase enzyme. Furthermore, utilizing a variety of spectroscopic methods, such as 1H-NMR, 13C-NMR, and HREI-MS, the precise structures of the synthesized scaffolds were determined.