Exploring the interaction of myricetin with human alpha-2-macroglobulin: biophysical and in-silico analysis.

Myricetin (MYR) is a bioactive secondary metabolite found in plants that is recognized for its nutraceutical value and is an essential constituent of various foods and beverages. It is reported to exhibit a plethora of activities, including antioxidant, antimicrobial, antidiabetic, anticancer, and anti-inflammatory. Alpha-2-macroglobulin (α2M) is a major plasma anti-proteinase that can inhibit proteinases of both human and non-human origin, regardless of their specificity and catalytic mechanism. Here, we explored the interaction of MYR-α2M using various biochemical and biophysical techniques. It was found that the interaction of MYR brings subtle change in its anti-proteolytic potential and thereby alters its structure and function, as can be seen from absorbance and fluorescence spectroscopy. UV spectroscopy of α2M in presence of MYR indicated the occurrence of hyperchromism, suggesting complex formation. Fluorescence spectroscopy reveals that MYR reduces the fluorescence intensity of native α2M with a shift in the wavelength maxima. At 318.15 K, MYR binds to α2M with a binding constant of 2.4 × 103 M-1, which indicates significant binding. The ΔG value was found to be - 7.56 kcal mol-1 at 298.15 K, suggesting the interaction to be spontaneous and thermodynamically favorable. The secondary structure of α2M does not involve any major change as was confirmed by CD analysis. The molecular docking indicates that Asp-146, Ser-172, Glu-174, and Tyr-180 were the key residues involved in α2M-MYR complex formation. This study contributes to our understanding of the function and mechanism of protein and flavonoid binding by providing a molecular basis of the interaction between MYR and α2M.

Probing the binding of morin with alpha-2-macroglobulin using multi-spectroscopic and molecular docking approach : Interaction of morin with α2M.

Alpha-2-macroglobulin (α2M) is an essential antiproteinase that is widely distributed in human plasma. The present study was aimed at investigating the binding of a potential therapeutic dietary flavonol, morin, with human α2M using a multi-spectroscopic and molecular docking approach. Recently, flavonoid-protein interaction has gained significant attention, because a majority of dietary bioactive components interact with proteins, thereby altering their structure and function. The results of the activity assay exhibited a 48% reduction in the antiproteolytic potential of α2M upon interaction with morin. Fluorescence quenching tests unequivocally confirmed quenching in the fluorescence of α2M in the presence of morin, conforming complex formation and demonstrating that the binding mechanism involves a dynamic mode of interaction. Synchronous fluorescence spectra of α2M with morin showed perturbation in the microenvironment around tryptophan residues. Furthermore, structural changes were observed through CD and FT-IR, showing alterations in the secondary structure of α2M induced by morin. FRET further supports the results of the dynamic mode of quenching. Moderate interaction is shown by binding constant values using Stern-Volmer's fluorescence spectroscopy. Morin binds to α2M at 298 K with a binding constant of 2.7 × 104 M-1, indicating the strength of the association. The α2M-morin system was found to have negative ΔG values, which suggests that the binding process was spontaneous. Molecular docking also reveals the different amino acid residues involved in this binding process, revealing that the binding energy is -8.1 kcal/mol.

Percutaneous Image-guided Cryoneurolysis: Applications and Techniques.

The expansion and dissemination of interventional cryoneurolysis in recent years has been fueled by the integration of advanced imaging guidance, the evolution of our understanding of neuropathologic processes after exposure of nerves to cold, and opportunities for its use beyond pain management. The clinical translation of cryoneurolysis through interventional radiology requires consideration of many factors, including (a) the supply and composition of target nerves, (b) the value of diagnostic injection with imaging guidance for confirmation, (c) the integration of advanced imaging guidance that allows safe ablation, (d) the difference between neoplastic and nonneoplastic causes of pain, (e) the phenomenon of percutaneously induced neuroregeneration, (f) the potential to manage conditions other than pain, (g) the consideration of protocols, (h) the limitations of current technology, and (i) the potential complications and adverse effects. Cryoneurolysis has societal and legislative endorsement as an effective nonopioid option for pain palliation. The Centers for Medicare and Medicaid Services (CMS) approved three new category III Current Procedural Terminology (CPT) codes specifically for the cryoablation of nerves with advanced imaging guidance. Interventional radiologists who are aware of nerve-directed strategies see eligible patients in their daily practice and have opportunities to bundle procedures (eg, celiac plexus block at the time of a biliary drain for pancreatic cancer with low bile duct obstruction), offering an avenue to serve the patient, reduce opioid dependence, allow faster discharge, and establish name recognition of interventional radiologists. Also, the ability to use CT to target deep structures accurately and swiftly, often with only local anesthesia, compared with the usual monitored anesthesia care in a surgical setting, may provide another avenue to build a cryoneurolysis practice. ©RSNA, 2022.

Enhancement of maternal-neonatal bonding during the COVID-19 pandemic: A quality improvement initiative.

AIM: The COVID-19 pandemic adversely affected the essential care of newborns. In a tertiary care hospital in India, all COVID-19 suspect post-natal mothers awaiting COVID results were transferred to a ward shared with symptomatic COVID suspect female patients from other clinical specialities, due to shortage of space and functional health workforce. Babies born to COVID-19 suspect mothers were moved to a separate ward with a caretaker until their mothers tested negative. Due to shortage of beds and delay in receiving COVID results, mothers and babies were often discharged separately 2-3 days apart to their home. This deprived babies of their mother's milk and bonding. We, therefore, undertook a quality improvement (QI) initiative aiming to improve rooming-in of eligible COVID-19 suspect mother-newborn dyads from 0% to more than 90% over a period of 6 weeks. METHODS: A QI team was formed which ran multiple Plan-Do-Study-Act cycles. The results were reviewed at regular intervals and interventions were adopted, adapted or abandoned. These included advocacy, rearrangement of wards, counselling of mothers and caretakers regarding infection prevention practices and coordination between labour room, post-natal ward and nursery staff. RESULTS: An improvement in rooming-in from 0% to more than 90% was achieved. CONCLUSION: QI methodology is a systematic approach in addressing and solving unexpected unforeseen problems effectively.

The emergence of Covid-19: evolution from endemic to pandemic.

Human race has survived several outbreak of pandemics in the past and their impact was long lasting. Some of the recent pandemics have been caused by a viruses known as Coronaviruses (CoVs) which are diverse, complex, adaptable viruses that have a significant impact on human health and animal productivity. The novel coronavirus that emerged in Wuhan, China (SARS-CoV-2) in 2019 has quickly spread throughout the world. Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), have led to a global epidemic with high morbidity and mortality. Human pathogenic coronaviruses, SARS-CoV and SARS-CoV-2, bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidneys, and blood vessels. The efforts to contain the virus are undergoing throughout the world, given the many uncertainties regarding pathogen transmissibility and virulence. Thus, the ongoing studies to promote the understanding of HCoVs will help to avoid or/and minimize the impact of anticipated pandemics in future.

Cell Sources for Human In vitro Bone Models.

PURPOSE OF REVIEW: One aim in bone tissue engineering is to develop human cell-based, 3D in vitro bone models to study bone physiology and pathology. Due to the heterogeneity of cells among patients, patient's own cells are needed to be obtained, ideally, from one single cell source. This review attempts to identify the appropriate cell sources for development of such models. RECENT FINDINGS: Bone marrow and peripheral blood are considered as suitable sources for extraction of osteoblast/osteocyte and osteoclast progenitor cells. Recent studies on these cell sources have shown no significant differences between isolated progenitor cells. However, various parameters such as medium composition affect the cell's proliferation and differentiation potential which could make the peripheral blood-derived stem cells superior to the ones from bone marrow. Peripheral blood can be considered a suitable source for osteoblast/osteocyte and osteoclast progenitor cells, being less invasive for the patient. However, more investigations are needed focusing on extraction and differentiation of both cell types from the same donor sample of peripheral blood.

An overview of Covid-19 pandemic: immunology and pharmacology.

In this review, we present an elaborate account of coronavirus in context to Covid-19 focusing on its origin, genome, life cycle, and immunology with a basic understanding of the disease and its cause. Further, the transmission, prevention and advances in therapeutics have also been discussed anticipating the possible outcomes in the near future. Moreover, the recently emerged unconventional approaches to this viral disease like drug repurposing, plasma therapy, nasal spray, and other preventive measures worldwide are studied for a long-term impact and relevance. Hence, this account on coronavirus and the ongoing pandemic serves a purpose of spreading awareness and to pass on relevant knowledge for a better chance to combat such unfortunate health crisis in future.

Post-discharge Health Services Use for Patients with Serious Mental Illness Treated at an Emergency Department Versus a Dedicated Community Mental Health Center.

Emergency Medical Service (EMS) alternative destination programs may lead to improved care quality among those experiencing mental health crises but the association with cost and emergency department (ED) recidivism remains unexamined. We compare rates of post-discharge health services use and Medicaid spending among patients transported to an ED or community mental health center (CMHC) finding higher ED recidivism for patient treated in the ED, compared to those treated in a CMHC (68% vs 34%, p < 0.001). There were no differences in Medicaid spending or health services use post-discharge suggesting EMS-operated alternative destination programs may be cost-neutral for Medicaid programs.

Patient-Centered Values and Experiences with Emergency Department and Mental Health Crisis Care.

Little is known about what patients value in psychiatric crisis services or how they compare community-based services with those received in the emergency department. Three focus groups (n = 27) were held of participants who had received psychiatric crisis services in emergency departments or a community mental health center. Participants described care experiences and preferences. Focus groups were audio recorded, transcribed, and coded using a value-based lens. Themes included appreciation for feeling respected, basic comforts, and shared decision-making as foundations of quality care. Participants preferred the community mental health center. Research should address long-term outcomes to motivate change in psychiatric crisis care.

Two cases of female urethral reconstruction with acellular porcine urinary bladder matrix.

INTRODUCTION AND HYPOTHESIS: Female urethral reconstruction via the traditional routes can be limiting for various reasons. Current literature on the use of acellular biologic grafts derived from viscera for female urethral reconstruction is limited. We present two cases of women with complete loss of their posterior urethra presenting for urethral reconstruction. METHODS: Two cases of urethral reconstruction using acellular porcine urinary bladder matrix (UBM), along with labial fat pad transposition and biologic pubovaginal sling are presented. RESULTS: In both cases the UBM graft showed successful conversion to what appeared to be normal urethral mucosa. One woman showed significant improvement in continence and the other showed complete continence. CONCLUSIONS: Female urethral reconstruction using acellular porcine UBM is a viable option for patients who have lost a significant portion of their urethra. Both cases demonstrated transition of the graft into the posterior wall of the urethra with significant improvement in continence. Further studies are needed to confirm that acellular porcine UBM can transform to urethral mucosa in women requiring urethral reconstruction.

Role of miRNAs to control the progression of Chronic Myeloid Leukemia by their expression levels.

Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder distinguished by a specific genetic anomaly known as a reciprocal translocation between chromosomes 9 and 22. This translocation causes fusion between the BCR and ABL regions. Consequently, BCR::ABL oncoprotein is formed, which plays a significant role in driving CML progression. Imatinib, a tyrosine kinase inhibitor (TKI), became the first line of drugs against CML. However, with continuous treatment, patients developed resistance against it. Indeed, to address this challenge, microRNA-based therapy emerges as a promising approach. miRNAs are 20-25 nucleotides long and hold great significance in various cellular processes, including cell differentiation, proliferation, migration, and apoptosis. In several malignancies, it has been reported that miRNAs might help to promote or prevent tumourigenesis and abnormal expression because they could act as both oncogenes/tumor suppressors. Recently, because of their vital regulatory function in maintaining cell homeostasis, miRNAs might be used to control CML progression and in developing new therapies for TKI-resistant patients. They might also act as potential prognostic, diagnostic, and therapeutic biomarkers based on their expression profiles. Various annotation tools and microarray-based expression profiles can be used to predict dysregulated miRNAs and their target genes. The main purpose of this review is to provide brief insights into the role of dysregulated miRNAs in CML pathogenesis and to emphasize their clinical relevance, such as their significant potential as therapeutics against CML. Utilizing these miRNAs as a therapeutic approach by inhibition or amplification of their activity could unlock new doors for the therapy of CML.

Cancer detection and classification using a simplified binary state vector machine.

Cancer is an invasive and malignant growth of cells and is known to be one of the most fatal diseases. Its early detection is essential for decreasing the mortality rate and increasing the probability of survival. This study presents an efficient machine learning approach based on the state vector machine (SVM) to diagnose and classify tumors into malignant or benign cancer using the online lymphographic data. Further, two types of neural network architectures are also implemented to evaluate the performance of the proposed SVM-based approach. The optimal structures of the classifiers are obtained by varying the architecture, topology, learning rate, and kernel function and recording the results' accuracy. The classifiers are trained with the preprocessed data examples after noise removal and tested on the unknown cases to diagnose each example as positive or negative. Further, the positive cases are classified into different stages including metastases, malign lymph, and fibrosis. The results are evaluated against the feed-forward and generalized regression neural networks. It is found that the proposed SVM-based approach significantly improves the early detection and classification accuracy in comparison to the experienced physicians and the other machine learning approaches. The proposed approach is robust and can perform sub-class divisions for multipurpose tasks. Experimental results demonstrate that the two-class SVM gives the best results and can effectively be used for the classification of cancer. It has outperformed all other classifiers with an average accuracy of 94.90%.

Insight into the molecular interaction between the anticancer drug, enzalutamide and human alpha-2-macroglobulin: Biochemical and biophysical approach.

The drug pharmacokinetics is affected upon binding with proteins, thus making drug-protein interactions crucial. This study investigated the interaction between enzalutamide and human major antiproteinase alpha-2-macroglobulin (α2M) by using multi spectroscopic and calorimetric techniques. The spectroscopic techniques such as circular dichroism (CD), intrinsic fluorescence, and UV-visible absorption were used to determine the mechanism of enzalutamide-α2M interaction. Studies on the quenching of fluorescence at three different temperatures showed that the enzalutamide-α2M complex is formed through static quenching mechanism. The change in microenvironment around tyrosine residues in protein was detected through synchronised fluorescence. The secondary structure of α2M was slightly altered by enzalutamide according to far UV-CD spectral analysis. Changes in position of amide I band in FTIR spectra further confirm the secondary structural alteration in α2M. According to thermodynamic characteristics such as fluorescence quenching and isothermal titration calorimetry (ITC), hydrogen bonds and hydrophobic interactions were involved in the interaction machanism. The ITC reiterated the exothermic and spontaneous nature of the interaction. The lower proteinase inhibitory activity of the α2M-enzalutamide conjugate as reflects the disruption of the native α2M structure upon interaction with enzalutamide.

Control of Ph+ and additional chromosomal abnormalities in chronic myeloid leukemia by tyrosine kinase inhibitors.

Chronic myeloid leukemia (CML) is a type of blood cancer that is known to affect hematopoietic stem cells. The presence of the Philadelphia chromosome (Ph+) is the major characteristic of CML. A protein expressed by the Philadelphia chromosome shows elevated tyrosine kinase activity and is considered a tumorigenic factor. The first line of therapy that had been established for CML was "imatinib," a potent tyrosine kinase inhibitor. Various other second- and third-generation TKIs are taken into account in cases of imatinib failure/resistance. With the subsequent rise in the development of tyrosine kinase inhibitors, optimization in the treatment of CML and amplified total survival were observed throughout TKI dosage. As the disease progresses, additional chromosomal abnormalities (ACAs) have been reported, but their prognostic effect and impact on the response to treatment are still unknown. However, some substantial understandings have been achieved into the disease transformation mechanisms, including the role of somatic mutations, ACAs, and several different genomic mutations that occur during diagnosis or have evolved during treatment. The acquisition of ACAs impedes CML treatment. Due to additional chromosomal lesions, there are greater chances of future disease progression at the time of CML diagnosis beyond the Ph+ translocation. The synchronous appearance of two or more ACAs leads to lower survival and is classified as a poor prognostic group. The key objective of this review is to provide detailed insights into TKIs and their role in controlling Ph+ and ACAs, along with their response, treatment, overall persistence, and survival rate.

Development of serum substitute medium for bone tissue engineering.

In tissue engineering, cells are grown often on scaffolds and subjected to chemical/mechanical stimuli. Most such cultures still use fetal bovine serum (FBS) despite its known disadvantages including ethical concerns, safety issues, and variability in composition, which greatly influences the experimental outcomes. To overcome the disadvantages of using FBS, chemically defined serum substitute medium needs to be developed. Development of such medium depends on cell type and application-which makes it impossible to define one universal serum substitute medium for all cells in any application. Here, we developed a serum substitute medium for bone tissue engineering (BTE) in a step-by-step process. Essential components were added to the medium while human bone marrow mesenchymal stromal cells (hBMSCs, osteoblast progenitor cells) were cultured in two-dimensional and three-dimensional substrates. In a 3-week culture, the developed serum substitute medium worked equally well as FBS containing medium in term of cell attachment to the substrate, cell survival, osteoblast differentiation, and deposition of extracellular matrix. In the next step, the use of serum substitute medium was evaluated when culturing cells under mechanical loading in the form of shear stress. The outcomes showed that the application of shear stress is essential to improve extracellular matrix formation while using serum substitute medium. The developed serum substitute medium could pave the way in replacing FBS for BTE studies eliminating the use of controversial FBS and providing a better-defined chemical environment for BTE studies.

Deficit irrigation strategies (PRD, SDI) and titanium nanoparticles improve water use efficiency and flower quality in greenhouse-grown cut roses.

This study explored the use of deficit irrigation techniques for water management in the hydroponic greenhouse cultivation of cut roses. A factorial experiment was conducted using three irrigation treatments: full irrigation (FI), partial root drying (PRD), and sustained deficit irrigation (SDI), and three doses of titanium dioxide nanoparticle foliar application (0, 15, and 30 ppm) as stress alleviation. Results showed that drought stress increased biochemical parameters such as the plants' proline and total phenol content. Compared to SDI treatment, the PRD treatments have an increase in flower number by 40%. The PRD strategy has positive effects on drought tolerance by increasing osmotic and elastic adjustment. Therefore, higher relative water content and longer root length in PRD treatments were observed. Thus, Biomass water use efficiency significantly increased in PRD treatments compared to others. In the PRD treatment, yield WUE increases by 26% and 61% compared to FI and SDI, respectively. The results showed TiO2-NPs positively affected mitigating and even improving some traits in drought stress conditions. These results suggest the superiority of the PRD strategy, which improves growth characteristics and water use efficiency, leading to increased sustainability, reduced environmental impact of greenhouse toxic wastewater, and total profitability of the greenhouse.

Subacute invasive pulmonary aspergillosis in a nondiabetic immunocompetent female suffering from allergic broncho pulmonary aspergillosis.

A 55-year-old female presented with recent exacerbation of the chronic cough, dyspnea, and copious expectoration. The symptoms worsened during the winter months. In the past, she was misdiagnosed with pulmonary tuberculosis. A computed tomography scan revealed bronchiectasis changes, high attenuated mucus, and hypereosinophilia. The diagnosis of Allergic Bronchopulmonary Aspergillosis (ABPA) with subacute invasion was confirmed through bronchoscopy and fungal culture. Treatment with oral voriconazole significantly improved lung function and quality of life. This case highlights the importance of considering invasive pulmonary aspergillosis in patients with exacerbations of asthma and bronchiectasis. Early diagnosis and appropriate treatment are essential for improved outcomes in such cases.

Stroke in Pregnancy: A Case Report.

Reported here is a rare near-miss case of stroke in pregnancy presented to the Department of Obstetrics and Gynaecology. A 38 years gravida 8 was referred from a private hospital on 18 November 2022 with hemorrhagic stroke, a known case of chronic hypertension at 37 weeks of gestation with previous cesarean section and acute kidney injury. At a private hospital computed tomography head was done it showed intracerebral haemorrhage. On cesarean, intraoperatively it was a live female with thick meconium. The patient was kept in intensive care with a mechanical ventilator, antihypertensives, antibiotics, and analgesics. Serum creatinine was increasing daily. Suture was cut on the 7th postoperative and two times dialysis was done on the 8th and 9th postoperative days. Stroke in pregnancy is a rare diagnosis and it could have been prevented by regular antenatal visits and early referral antenatally along with a multidisciplinary approach. Keywords: case reports; hypertension; intracerebral haemorrhage; pregnancy; stroke.

Binding characteristics and conformational changes in alpha-2-macroglobulin by the dietary flavanone naringenin: biophysical and computational approach.

In the present study, we investigated the interaction of alpha-2-macroglobulin (α2M) with naringenin using multi-spectroscopic, molecular docking, and molecular simulation approaches to identify the functional changes and structural variations in the α2M structure. Our study suggests that naringenin compromised α2M anti-proteinase activity. The results of absorption spectroscopy and fluorescence measurement showed that naringenin-α2M formed a complex with a binding constant of (kb)∼104, indicative of moderate binding. The value of ΔG° in the binding indicates the process to be spontaneous and the major force responsible to be hydrophobic interaction. The findings of FRET reveal the binding distance between naringenin and the amino acids of α2M was 2.82 nm. The secondary structural analysis of α2M with naringenin using multi-spectroscopic methods like synchronous fluorescence, red-edge excitation shift (REES), FTIR, and CD spectra further confirmed the significant conformational alterations in the protein. Molecular docking approach reveals the interactions between naringenin and α2M to be hydrogen bonds, van der Waals forces, and pi interactions, which considerably favour and stabilise the binding. Molecular dynamics modelling simulations also supported the steady binding with the least RMSD deviations. Our study suggests that naringenin interacts with α2M to alter its confirmation and compromise its activity.Communicated by Ramaswamy H. Sarma.

Carotid Endarterectomy Versus Stenting for the Treatment of Patients With Carotid Artery Stenosis: An Updated Systematic Review and Meta-Analysis.

Carotid endarterectomy (CEA) is a surgical procedure that treats the narrowed carotid arteries, which may be narrowed by atherosclerosis. Stenting is the insertion of a wire mesh scaffold into the narrowed portion of the carotid artery to keep it open by preventing blood from clotting. Using the study done over 10 years back as a point of reference, this study will seek an update on an assessment comparing CEA and stenting in studies carried out between 2015 and to date. The PICOS (population, intervention, control, outcome, and study designs) criteria were used to construct a set of inclusion and exclusion guidelines. This meta-analysis and systematic review used two forms of investigative analysis; both quantitative and qualitative assessments. From the studies, stroke (95% CI: 0.51-0.71, P < 0.001), myocardial infarction (95% CI: 1.49-3.42, P = 0.001), and stroke or death analysis (95% CI: 0.53-0.77, P < 0.001) were noted to be significant. From the analysis, CEA was observed as having better treatment results in terms of stroke events and stroke or death incidences when compared to stenting. Carotid stenting was observed as having lower cases of myocardial infarctions when compared to endarterectomy.