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AbstractSince the SARS-CoV-2 epidemic, researchers have been working on figuring out ways to tackle multi-organ failure and hyperinflation, which are brought on by a cytokine storm. Angiotensin-converting enzyme 2 (ACE2), a SARS-CoV-2 spike glycoprotein’s cellular receptor, is involved in complicated molecular processes that result in hyperinflammation. Cordyceps militarisis one of the traditional Chinese medicines that is used as an immune booster, and it has exhibited efficacy in lowering blood glucose levels, seminal emissions, and infertility. In the current study, we explored the potential of Cordyceps militarissteroids as key agents in managing the anger of cytokine storm in Covid-19 using network ethnopharmacological techniques and structure-based drug designing approaches. The steroids present in Cordyceps militariswere initially screened against the targets involved in inflammatory pathways. The results revealed that out of 16 steroids, 5 may be effective against 17 inflammatory pathways by targeting 11 pathological proteins. Among the five steroids, beta-sitosterol, Cholest-5-en-3β-ol, 3β, and 7α-Dihydroxycholest-5-ene were found to interact with thrombin (F2), an important protein reported to reduce the severity of inflammatory mediators and Cholest-4-en-3-one was found to target Glucocorticoid receptor (NR3C1). The top docked steroid displayed key interactions with both targets, which retained key interactions throughout the 100 ns simulation period. These compounds were also shown high binding free energy scores in water swap studies. Based on obtained results the current study suggests the use of Cordyceps militarisas an add-on therapy that may reduce the progression of inflammatory co-morbidities among patients infected with SARS-CoV-2.Communicated by Ramaswamy H. Sarma

The European Commission proposed harmonised rules on artificial intelligence (AI) on the 21st of April 2021 (namely the EU AI Act). Following a consultative process with the European Council and many amendments, a General Approach of the EU AI Act was published on the 25th of November 2022. The EU Parliament approved the initial draft in May 2023. Trilogue meetings took place in June, July, September and October 2023, with the aim for the European Parliament, the Council of the European Union and the European Commission to adopt a final version early 2024. This is the first attempt to build a legally binding legal instrument on Artificial Intelligence in the European Union (EU). In a similar way as the General Data Protection Regulation (GDPR), the EU AI Act has an extraterritorial effect. It has, therefore, the potential to become a global gold standard for AI regulation. It may also contribute to developing a global consensus on AI Trustworthiness because AI providers must conduct conformity assessments for high-risk AI systems prior to entry into the EU market. As the AI Act contains limited guidelines on how to conduct conformity assessments and ex-post monitoring in practice, there is a need for consensus building on this topic. This paper aims at studying the governance structure proposed by the EU AI Act, as approved by the European Council in November 2022, and proposes tools to conduct conformity assessments of AI systems.

Aldehyde dehydrogenase 1A1 (ALDH1A1) is an isoenzyme that catalyzes the conversion of aldehydes to acids. However, the overexpression of ALDH1A1 in a variety of malignancies is the major cause of resistance to an anti-cancer drug, cyclophosphamide (CP). CP is a prodrug that is initially converted into 4-hydroxycyclophosphamide and its tautomer aldophosphamide, in the liver. These compounds permeate into the cell and are converted as active metabolites, i.e., phosphoramide mustard (PM), through spontaneous beta-elimination. On the other hand, the conversion of CP to PM is diverted at the level of aldophosphamide by converting it into inactive carboxyphosphamide using ALDH1A1, which ultimately leads to high drug inactivation and CP resistance. Hence, in combination with our earlier work on the target of resistance, i.e., ALDH1A1, we hereby report selective ALDH1A1 inhibitors. Herein, we selected a lead molecule from our previous virtual screening and implemented scaffold hopping analysis to identify a novel scaffold that can act as an ALDH1A1 inhibitor. This results in the identification of various novel scaffolds. Among these, on the basis of synthetic feasibility, the benzimidazole scaffold was selected for the design of novel ALDH1A1 inhibitors, followed by machine learning-assisted structure-based virtual screening. Finally, the five best compounds were selected and synthesized. All synthesized compounds were evaluated using in vitroenzymatic assay against ALDH1A1, ALDH2, and ALDH3A1. The results disclosed that three molecules A1, A2, and A3 showed significant selective ALDH1A1 inhibitory potential with an IC50value of 0.32 μM, 0.55 μM, and 1.63 μM, respectively, and none of the compounds exhibits potency towards the other two ALDH isoforms i.e.ALDH2 and ALDH3A1. Besides, the potent compounds (A1, A2, and A3) have been tested for in vitrocell line assay in combination with mafosfamide (analogue of CP) on two cell lines i.e.A549 and MIA-PaCa-2. All three compounds show significant potency to reverse mafosfamide resistance by inhibiting ALDH1A1 against these cell lines.

AbstractCytochrome P4501B1 is a ubiquitous family protein that is majorly overexpressed in tumors and is responsible for biotransformation-based inactivation of anti-cancer drugs. This inactivation marks the cause of resistance to chemotherapeutics. In the present study, integrated in-silicoapproaches were utilized to identify selective CYP1B1 inhibitors. To achieve this objective, we initially developed different machine learning models corresponding to two isoforms of the CYP1 family i.e. CYP1A1 and CYP1B1. Subsequently, small molecule databases including ChemBridge, Maybridge, and natural compound library were screened from the selected models of CYP1B1 and CYP1A1. The obtained CYP1B1 inhibitors were further subjected to molecular docking and ADMET analysis. The selectivity of the obtained hits for CYP1B1 over the other isoforms was also judged with molecular docking analysis. Finally, two hits were found to be the most stable which retained key interactions within the active site of CYP1B1 after the molecular dynamics simulations. Novel compound with CYP-D9 and CYP-14 IDs were found to be the most selective CYP1B1 inhibitors which may address the issue of resistance. Moreover, these compounds can be considered as safe agents for further cell-based and animal model studies. Communicated by Ramaswamy H. Sarma

Research shows that active pedagogies could play an important role in achieving more equitable outcomes for diverse groups of students in Science, Technology, Engineering, and Mathematics (STEM). Although flipped classes are a popular active methodology, there is a lack of high‐quality studies assessing their impact in ecologically valid settings and exploring how outcomes are related to gender and to prior education. This paper presents two modified replications of an experimental study investigating the impact of the flipped class approach on students' achievement in a large, first‐year class in an engineering bachelor's degree. We added a new strand, progressively flipped over 3 years, to eight parallel strands of a high‐stakes mandatory linear algebra course for engineers. The study followed a replicated‐between‐subjects design, with students in the flipped strand learning the same material as those in the other strands and taking the same final exam. Our results demonstrate that the flipped format did not have any significant impact on students' achievement compared to traditional lecturing. However, both replications in the flipped condition show a reduced attainment gap for women and students with less prior knowledge in mathematics. While the flipped class seems to have weaker effects on learning than other active methodologies, the evidence in this study indicates that it may have an impact on reducing the attainment gap between different groups of students. It may therefore be particularly interesting to consider in efforts to achieve more equitable outcomes for women and where students have heterogeneous educational backgrounds.

Following the COVID-19 pandemic, majority of paediatric cochlear implantees (CI) lost follow ups for rehabilitation and tele-therapy was initiated. Present study thus compared the outcome measures of paediatric CI users on tele-therapy versus conventional face to face therapy following COVID-19 pandemic.

The present study aimed to identify the differentially expressed genes (DEGs) and enriched pathways in docetaxel (DTX) resistant breast cancer cell lines by bioinformatics analysis. The microarray dataset GSE28784 was obtained from gene expression omnibus (GEO) database. The differentially expressed genes (DEGs), gene ontology (GO), and Kyoto Encyclopedia of gene and genome (KEGG) pathway analyses were performed with the help of GEO2R and DAVID tools. Furthermore, the protein–protein interaction (PPI) and hub-gene network of DEGs were constructed using STRING and Cytohubba tools. The prognostic values of hub genes were calculated with the help of the Kaplan–Meier plotter database. From the GEO2R analysis, 222 DEGs were identified of which 120 are upregulated and 102 are downregulated genes. In the PPIs network, five up-regulated genes including CCL2, SPARC, CYR61, F3, and MFGE8 were identified as hub genes. It was observed that low expression of six hub genes CXCL8, CYR61, F3, ICAM1, PLAT, and THBD were significantly correlated with poor overall survival of BC patients in survival analysis. miRNA analysis identified that hsa-mir-16-5p, hsa-mir-335-5p, hsa-mir-124-3p, hsa-mir-20a-5p, and hsa-mir-155-5p are the top 5 interactive miRNAs that are commonly interacting with more hub genes with degree score of greater than five. Additionally, drug-gene interaction analysis was performed to identify drugs which are could potentially elevate/lower the expression levels of hub genes. In summary, the gene-miRNAs-TFs network and subsequent correlation of candidate drugs with hub genes may improve individualized diagnosis and help select appropriate combination therapy for DTX-resistant BC in the future.

Tension is one of the most common problem found in people nowadays. With problems, the stress level increases and headaches are the most common problem faced during stress. The common headache found is tension type headache (TTH). The present study aims at studying the effect on TTH of various biofeedback technique like EMG and GSR on various modes like audio and visual the experiment was conducted on 90 people out of which 78 remained until the end (46 females and 32 males) were randomly assigned groups like EMGa, EMGav, GSRa, GSRav and the control group. The control group was only given the medication given by doctor. The session of the biofeedback therapy was conducted for over a time of 20 minutes in an isolated chamber. The therapy continued for over a period of 12 months. The results were taken after 1 month, 3 months, 6 months, and 12 months.

Introduction The onset and progression of chronic kidney disease (CKD) are strongly linked to a decrease in Klotho, which was once thought to have an anti-aging effect. The specific mechanism of this enzyme’s connection with CKD and its related co-morbidities has to be investigated further. Present study aimed to test Klotho levels in various phases of CKD and to study their correlation with cardiac morbidity.Methods Present study was single-center, observational, cross-sectional study conducted in all genders with age ≥18 years who presented with CKD stages G1-G5 ND. All cases underwent battery of investigations including estimation of serum Klotho & FGF 23 levels along with 2D echocardiography.Results Most study participants were found to be in CKD stage G2 (24%) followed by stages G4 and G5 (18% each). On cardiac evaluation, low LVEF was detected in 38% cases, diastolic dysfunction in 44% & LV hypertrophy in 48% cases. There was a negative correlation between serum Klotho levels and LVH (P= .009), LVEF (P= .015) or LV diastolic dysfunction (P= .005). Likewise, there was positive correlation between serum FGF 23 levels and LVH (P= .0001), LVEF (P= .0001) or LV diastolic dysfunction (P= .0001).Conclusions With our study, we want to emphasize the prognostic value of Klotho and FGF 23 in routine evaluation of CKD patients. Low serum Klotho & high FGF 23 levels were associated with low left ventricular ejection fraction (LVEF), left ventricular hypertrophy (LVH) and left ventricular dysfunction among CKD patients.

Most patients with Parkinson's disease are elderly with coexisting medical conditions as well as the complications of the disease and its treatment. Meticulous preoperative assessment, maintenance of drug therapy up to the time of anaesthesia and afterwards, avoiding known precipitating agents and intraoperative administration of L-DOPA if required, are key factors in the reduction of postoperative morbidity. This brief review focuses on the epidemiology, etiology, pathogenesis, pathophysiology, clinical features and anaesthetic management of Parkinson's disease. Keywords: Anaesthetic technique | Drugs., Indroduction Parkinsonism is the name given to a clinical syndrome comprising impairment of voluntary movement (hypokinesia), rigidity and tremor. Because of the characteristic stooped posture and chaplinesque shuffling, Parkinson's disease [...]

Molecular surfaces have comprehensive utility in the field of drug discovery. A deeper insight into different aspects of molecular surfaces is essential for the researchers to successfully identify a lead molecule with excellent pharmacokinetic profile. Therefore, the concept of molecular surfaces cannot be overlooked when designing a novel molecule. This is a better approach to correlate molecular surfaces with binding interaction, binding affinity, and their orientation, which in turn might produce information about the probable pharmacological potential. A profound knowledge of surface properties may provide more selective drugs in return, especially for the treatment of diseases where selectivity is the major issue associated with pathological conditions. This review sheds light on the various types of molecular surfaces, different visualization tools and their application in rationale drug designing. Moreover, this report also discloses the forthcoming perspectives of molecular surfaces that may create new ideas to deal with drug selectivity issues.

•Repeated use of oils for frying causes adverse health effects.•Reuse of frying oil need to be continuously monitored in the food establishments.•Rapid test kits to assess the quality of frying oil are required.•Tests kits are based on physical and chemical quality parameters for frying oils.

The current study reports optimization of hammer milling parameters to achieve crushed waste printed circuit boards (WPCBs) of − 16 BSS (British Standard Specification) sieve size. The WPCBs, having 22 wt% copper, have been crushed to − 16 BSS sieve size by means of a hammer mill. The result showed that initial milling takes place rapidly and then decreases gradually. Approximately 94% feed material is ground to − 16 BSS sieve size within 7 min, and further increase in the time does not affect the milling rate. It is also revealed that with the increasing feed rate, lower milling rate is experienced due to the distribution of impact energy among more pieces of WPCBs. Study of the size distribution of milled WPCBs (− 16 BSS sieve size) revealed that it follows the similar trend, and the crushed material is mostly concentrated in − 240 BSS and + 72 to − 52 BSS sieve size range. Further, 50–55% crushed fraction attains + 100 BSS sieve size, while the rest is smaller than this sieve size. Chemical analysis of the crushed material of various size fractions elucidated that a fraction above 100 BSS sieve size is copper rich (43 wt%), while − 100 BSS sieve size fraction has lesser copper because the nonmetals which account for majority concentration in WPCBs are milled to a finer size. Microscopic examinations of crushed fraction showed that copper has metallic luster and ruptured foil-type morphology. The fibrous structure of glass fiber and gray/black-colored polygon morphology of nonmetals were also visible.

Post-thrombotic syndrome secondary to iliofemoral deep venous thrombosis is a significant contributor to advanced chronic venous insufficiency. Iliac vein stenting is a standard procedure to treat iliocaval obstruction. In cases with obstruction extending across the groin, venous inflow for an iliac vein stent may be poor and compromise results of iliac vein stenting. Treatment options include extension of stents across the inguinal ligament that may have limitations in improving inflow only from only one vessel. Endovenectomy in this scenario becomes an attractive option with or without iliac vein stenting to provide outflow to the profunda vein, which otherwise is “axially transformed” in chronic iliofemoral deep venous thrombosis. We describe a technique of endovenectomy in combination with iliac vein stenting to establish a patent outflow tract for profunda and femoral veins. Accompanying also is a video demonstration of endovenectomy that will help viewers understand more technical aspects of the procedure.

Medial supracondylar spur from the humerus is a rare cause of neurovascular pain of the upper extremity. The spur typically entraps the brachial artery and median nerve, resulting in compression-related symptoms. In advance stages, compression could lead to endothelial damage and thrombotic occlusion of brachial artery. Spur is also associated with an anomalous higher insertion of the pronator teres muscle, which could result in multilevel entrapment of the brachial artery. We report a patient with acute upper limb ischemia secondary to brachial artery compression and distal embolization from a medial supracondylar spur and anomalous attachment of the pronator teres. The entrapped brachial artery and median nerve were released by resection of the spur and of the anomalous belly of the pronator teres with thrombectomy of brachial artery.

We describe a new technique of valve leaflet closure, reduction internal valvuloplasty (RIVAL), to treat primary deep vein valvular incompetence in patients with C6 venous disease.

Carotid-jugular arteriovenous fistula (C-J AVF) after inadvertent carotid puncture during internal jugular vein puncture is a rare entity. Previously, majority of reported cases of CJAVF were identified during inadvertent arterial puncture and managed as emergency. We report a delayed presentation of congestive cardiac failure following multiple attempts at securing an internal jugular venous access for dialysis 3 months prior to diagnosis. Carotid-jugular fistula was identified during workup and was successfully treated by endovascular technique with a covered stent.

An association between celiac disease (CD) and peripheral neuropathy (PN) has been reported.

Artificial intelligence (AI) applications can profoundly affect society. Recently, there has been extensive interest in studying how scientists design AI systems for general tasks. However, it remains an open question as to whether the AI systems developed in this way can work as expected in different regional contexts while simultaneously empowering local people. How can scientists co-create AI systems with local communities to address regional concerns? This article contributes new perspectives in this underexplored direction at the intersection of data science, AI, citizen science, and human-computer interaction. Through case studies, we discuss challenges in co-designing AI systems with local people, collecting and explaining community data using AI, and adapting AI systems to long-term social change. We also consolidate insights into bridging AI research and citizen needs, including evaluating the social impact of AI, curating community datasets for AI development, and building AI pipelines to explain data patterns to laypeople.

For precise job manufacturing, system should possess good dimensional accuracy and surface finish. In applications like drilling, punching, marking, boring, tapping work piece is positioned firstly and then cutting tool performs its action while motion axes are kept stationary. In traditional approach for such applications, manufacturer uses highly expensive CNC machine for programming job cycle and executing the same. Big scale manufacturer can afford such highly expensive machines but for small scale mechanical job manufacturing industry we have to think of low-cost solution that can deliver high class output. In this project we are trying to propose low-cost design which gives similar functionality as that of high-cost CNC machine. By applying this machine in industry, it can acquire the multi generation brief time. In order to perform some operation which requires continuous cutting over a pre-defined curve, CNC machines are used as the traditional machines in the industry. Installation of a CNC machine requires a high financial investment and a skilled labour to perform the different operations on the machine. Apart from that the maintenance cost of such machine are also high. In small scale industries where the operations are performed on small job pieces, the installation of such high-cost CNC machine is very difficult; hence this project work is taken up in which a low-cost CNC laser cutting machine is designed using the Arduino. This CNC laser cutting machine will be quite useful for small scale industries where the job size is not very large. Also, the machine does not require a highly skilled labour to perform operations.

B-cell proliferative disorders may display the pathogenic effects by increased cell numbers, increased concentration of the molecules produced by these cells or both. Most forms of renal disease associated with monoclonal gammaglobulinopathy results from deposition of monoclonal immunoglobulins or their subunits in different compartment of kidney. Renal monoclonal immunoglobulin deposition disease (MIDD) is defined by deposits of monoclonal light chain components in renal basement membrane, mesangium which often produces a nodular sclerosing glomerulopathy. Clinical features of renal MIDD include proteinuria with or without renal failure with dysproteinemias.

In the current study, the production of novel glutaminase free l-asparaginase from a new microbial source (Pseudomonas resinovoransIGS-131) is reported. Optimization of l-asparaginase production using conventional and statistical optimization techniques resulted in an enzyme yield of 37.63 IU/mL, which was 3.45-fold higher than the initial enzyme activity (i.e., 10.91 IU/mL). l-Asparaginase production from P. resinovoransIGS-131 was successfully carried out at the bioreactor level and investigations on the effect of agitation rates showed a maximum asparaginase yield of 38.88 IU/mL after 24 h fermentation at 400 rpm. The l-asparaginase gene from this source, showing 78% identity with a reported sequence in GenBank, was expressed in Escherichia colirosetta DE3. The molecular weight of the recombinant protein was determined as 35.6 kDa. Downstream processing of recombinant l-asparaginase resulted in a purified protein concentration of 62.53 mg/L, which showed good free radical scavenging activity of 62%. The current findings provide promising results for a process of l-asparaginase production from P. resinovoransIGS-131. Furthermore, the recombinant production of this enzyme could help in avoiding the complexity of down streaming processes associated with the purification of this enzyme from wild-type organisms.

Stable angina or angina pectoris is referred to as uneasiness/pain in the chest, resulting from coronary heart disease (CHD). Ivabradine Hydrochloride (IBH) is a recently approved drug to manage stable angina and heart failure symptoms. The approved IBH tablets exhibit some technical shortcomings i.e. short half-life (2 h), variable systemic absorption, and high first-pass metabolism (>50%). Therefore, utilizing a nanoformulation technique, we have designed a differentiated and innovative formulation of IBH. The IBH loaded polymeric nanoparticles (IBH-PNPs) are being developed for per-oral delivery by double emulsion method, using Poly lactic-co-glycolic acid (PLGA) as polymer, and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as a stabilizer. The pre-formulation studies performed are UV spectroscopy, FT-IR, and X-ray diffraction. The Box-Behnken design was exploited for formulation optimization. The optimized formulation was characterized for its particle size, zeta potential, morphology, entrapment efficiency, in-vitro release, stability studies, ex-vivo permeability, and in-vivo pharmacodynamics study. The optimized IBH-PNPs were found to be spherical (<200nm) and exhibited normal size distribution under transmission electron microscopy and atomic force microscopy respectively. The zeta potential and entrapment efficiency were found to be −43.75 mv and 60 ± 4.8% respectively. Developed IBH-PNPs analyzed for in-vitrodrug release where they exhibited biphasic release. The ex-vivodrug permeation study showed 1.85 folds increment in intestinal permeability as compared to IBH tablets. The in-vivoanti-anginal efficacy studies were performed using vasopressin-induced angina model in Wistar rats. Developed formulation was found to have a therapeutic effect for three days.

Steroids are perhaps one of the most widely used group of drugs in present day anaesthetic practice, sometimes with indication and sometimes without indications. Because of their diverse effects on various systems of the body, there has been renewed interest in the use of steroids in modern day anaesthetic practice. This paper focuses on the synthesis and functions of steroids and risks associated with their supplementation. This paper also highlights the recent trends, relevance, and consensus issues on the use of steroids as adjunct pharmacological agents in relation to anaesthetic practice and intensive care, along with emphasis on important clinical aspects of perioperative usefulness and supplementation.