AI-Assisted Generation and In-depth In-silico Evaluation of Potential Inhibitor Targeting Aurora Kinase A (AURKA): An Anticancer Discovery Exploiting Synthetic Lethality Approach.

Genetic alterations are lead causative agents behind the complex pathologies of cancers which render all treatments unarmed. Such alterations in oncogenes can be treated by direct inhibition by specific drugs while alteration in tumor suppressor genes mediating loss of function is challenging to treat. Identification of synthetic lethal partners to specific tumor suppressor genes and mediating their inhibition can be a potential approach to deal with loss of function mutations. Aurora kinase A (AURKA) has been established as an effective synthetic lethal partner of several tumor suppressor genes and is overexpressed in cancerous conditions, mediating adverse pathologies. The present AI-assisted study deals with the generation of novel inhibitor compounds against AURKA and the exhaustive evaluation of the best compound using molecular docking, molecular dynamic simulation, MM/PBSA, and QM/MMGBSA-based analysis. Out of the 200 novel compounds generated using features of ATP binding pocket of AURKA and previously reported inhibitor, compound 1 (4-{5-fluoro-6-[(1Z)-3-hydrazinyl-3-oxo-2-phenylprop-1-en-1-yl]pyridin-2-yl}benzoic acid) was identified as the most potent candidate with high negative binding energy of -10.4 kcal/mol in molecular docking analysis. The molecular dynamic simulation analysis of the AURKA-compound 1 complex and the apo-AURKA protein resulted in major conformational changes in the conserved DFG motif and loop 277-291 of AURKA in the AURKA-compound 1 complex thus inhibiting the entry of ATP to its binding site. The free energy landscape displayed a persistence of folded states of the enzyme in complex form. The MM/PBSA revealed effective Gibb's free energy of binding of -11 kcal/mol for compound 1 inhibiting AURKA. The QM/MMGBSA analysis resulted in a significantly high negative binding energy of -13.98 kcal/mol proving significant inhibition potential of compound 1 against AURKA. Therefore, further in-vitro investigation can provide a novel effective, and safe treatment against a wide range of cancers by targeting a well-established cancer target AURKA.

An automated ECG-based deep learning for the early-stage identification and classification of cardiovascular disease.

BACKGROUND: Heart disease represents the leading cause of death globally. Timely diagnosis and treatment can prevent cardiovascular issues. An Electrocardiograms (ECG) serves as a diagnostic tool for identifying heart difficulties. Cardiovascular Disease (CVD) often gets identified through ECGs. Deep learning (DL) garners attention in healthcare due to its potential in swiftly diagnosing ECG anomalies, crucial for patient monitoring. Conversely, automatic CVD detection from ECGs poses a challenging task, wherein rule-based diagnostic models usually achieve top-notch performance. These models encounter complications in supervision vast volumes of diverse data, demanding widespread analysis and medical capability to ensure precise CVD diagnosis. OBJECTIVE: This study aims to enhance cardiovascular disease diagnosis by combining symptom-based detection and ECG analysis. METHODS: To enhance these experiments, we built a novel automated prediction method based on a Feed Forward Neural Network (FFNN) model. The fundamental objective of our method is to develop the accuracy of ECG diagnosis. Our strategy employs chaos theory and destruction analysis to combine optimum deep learning features with a well-organized set of ECG properties. In addition, we use the constant-Q non-stationary Gabor transform (CQNGT) to convert one-dimensional ECG data into a two-dimensional picture. A pre-trained FFNN processes this image. To identify significant features from the FFNN output that correspond with the ECG data, we employ pairwise feature proximity. RESULTS: According to experimental findings, the suggested system, FFNN-CQNGT, surpasses other state-of-the-art systems in terms of precision of 94.89%, computational efficiency of 2.114 ms, accuracy of 95.55%, specificity of 93.77%, and sensitivity of 93.99% and MSE 40.32%. CONCLUSION: Contributing an automated ECG-based DL system based on FFNN-CQNGT for early-stage cardiovascular disease identification and classification holds great potential for both patient care and public health.

Rethinking Fistula Preservation in Anorectal Malformation Surgery: A Histopathological Perspective.

OBJECTIVE: This study aims to assess the histopathological characteristics of the fistulous tissue in males with anorectal malformation (ARM) to determine its suitability for use in constructing a neoanus. METHODS: This prospective observational study included male ARM patients with recto-urethral fistula. All other types were excluded. The tissue specimens comprised 0.5 to 2.0 cm of the most distal part of the rectal pouch and the fistulous tissue. Hematoxylin and eosin-stained sections were prepared. Histological features, viz. internal sphincter, anal grand and crypts, ganglion cells, presence of subepithelial fibrosis, thickened nerve trunks, and metaplasia, were evaluated. RESULTS: Of 65 patients of ARM admitted, 24 met the inclusion criteria. Gross and microscopic internal sphincter was not found in any sample. The anal mucosa was visualized in all samples; however, crypts were irregular and distorted architecture was seen in 4 (16.67%) samples. Urothelial metaplasia was identified in 10 (41.67%) samples. Adequate ganglion cells were seen only in 6 (25%) samples. Significant submucosal fibrosis was seen in all samples. Thickened nerve trunks were identified in 4 (16.67%) samples. CONCLUSIONS: All normal anal histological features could not be found together in the fistula tissue. With the absence of normal features, such as internal anal sphincter muscles, and the presence of abnormal histopathological features, such as subepithelial fibrosis, thickened nerve trunks, and metaplasia, there are high chances of abnormal bowel function like constipation if the fistulous tissue is used for neoanus construction. It may have an impact on the quality of life of patients.

Insights into the biodegradation of fipronil through soil microcosm-omics analyses of Pseudomonas sp. FIP_ A4.

Fipronil, a phenylpyrazole insecticide, is used to kill insects resistant to conventional insecticides. Though its regular and widespread use has substantially reduced agricultural losses, it has also caused its accumulation in various environmental niches. The biodegradation is an effective natural process that helps in reducing the amount of residual insecticides. This study deals with an in-depth investigation of fipronil degradation kinetics and pathways in Pseudomonas sp. FIP_A4 using multi-omics approaches. Soil-microcosm results revealed ∼87% degradation within 40 days. The whole genome of strain FIP_A4 comprises 4.09 Mbp with 64.6% GC content. Cytochrome P450 monooxygenase and enoyl-CoA hydratase-related protein, having 30% identity with dehalogenase detected in the genome, can mediate the initial degradation process. Proteome analysis revealed differential enzyme expression of dioxygenases, decarboxylase, and hydratase responsible for subsequent degradation. Metabolome analysis displayed fipronil metabolites in the presence of the bacterium, supporting the proposed degradation pathway. Molecular docking and dynamic simulation of each identified enzyme in complex with the specific metabolite disclosed adequate binding and high stability in the enzyme-metabolite complex. This study provides in-depth insight into genes and their encoded enzymes involved in the fipronil degradation and formation of different metabolites during pollutant degradation. The outcome of this study can contribute immensely to developing efficient technologies for the bioremediation of fipronil-contaminated soils.

Biodegradation of acetaminophen: Microcosm centric genomic-proteomic-metabolomics evidences.

Acetaminophen (APAP) is a frequently used, over-the-counter analgesic and antipyretic medication. Considering increase in global consumption, its ubiquity in environment with potential toxic impacts has become a cause of great concern. Hence, bioremediation of this emerging contaminant is of paramount significance. The present study incorporates a microcosm centric omics approach to gain in-depth insights into APAP degradation by Paracoccus sp. APAP_BH8. It can metabolize APAP (300 mg kg-1) within 16 days in soil microcosms. Genome analysis revealed potential genes capable of mediating degradation includes M20 aminoacylase family protein, guanidine deaminase, 4-hydroxybenzoate 3-monooxygenase, and 4-hydroxyphenylpyruvate dioxygenase. Whole proteome analysis showed differential expression of enzymes and bioinformatics provided evidence for stable binding of intermediates at the active site of considered enzymes. Metabolites identified were 4-aminophenol, hydroquinone, and 3-hydroxy-cis, cis-muconate. Therefore, Paracoccus sp. APAP_BH8 with versatile enzymatic and genetic attributes can be a promising candidate for formulating improved in situ APAP bioremediation strategies.

Analysis of the Efficacy of Elastography in Comparison with Dynamic Renal Nuclear Scintigraphy in the Evaluation of Unilateral Pelvi-Ureteric Junction Obstruction.

INTRODUCTION: In hydronephrosis due to pelviureteric junction obstruction (PUJO), an obstruction to urine flow may lead to increased pelvic pressure, which may cause interstitial fibrosis and renal impairment. Recently, there have been reports on renal pelvic assessment using ultrasound elastography (USE). This study was conducted to see if USE can evaluate PUJO and if it can be correlated to the findings of the dynamic renal nuclear scan. MATERIAL AND METHODS: In this observational study, only patients with unilateral PUJO underwent acoustic radiation force impulse (ARFI) elastography. A rectangular region of interest (ROI) measuring 5 × 10 mm was positioned on the cortex region of the upper, mid, and lower poles of the affected kidney. Three valid measurements were obtained, from which a mean value was calculated. A dynamic renal nuclear scan using Technetium-99m ethylene dicysteine (EC or TC99 m EC) was obtained and split renal function (SRF) was used for comparison. RESULTS: In the group of 20 patients, the mean age was 3.37 years. The mean SRF of the affected kidney was 26.65 %, and the corresponding USE value was 0.45 kpa. The Spearman's rho correlation coefficient for SRF and USE was 1 and 0.672, respectively (p = 0.001). Elastography was not feasible if SRF was less than 20 %. CONCLUSION: USE may be able to comment on the renal functional status of hydronephrosis. If USE is reported as non-feasible, it may suggest that renal function is grossly compromised. It may serve as an alternative diagnostic modality for renal functional evaluation. LEVEL OF EVIDENCE: Level II, Prospective Cohort Study.

Silver nanoparticle as an alternate to antibiotics in cattle semen during cryopreservation.

The proposed study was to determine if the silver nanoparticles can be used as potential antimicrobial agents and can replace the use of conventional antibiotics in semen without affecting the motility and fertility of semen. The silver nanoparticles prepared by chemical reduction method were confirmed by determination of the wavelength of surface plasmon resonance peak and further characterized using Zetasizer by determining their size, polydispersity index, and zeta potential. The nanoparticles were assessed for antibacterial activity and their concentration was optimized for use in semen extender for cryopreservation. Cryopreserved semen was further evaluated for seminal parameters, antioxidant parameter, and microbial load. Prepared silver NPs showed a plasmon resonance peak at 417 nm wavelength. NPs were found to possess antibacterial activity and were supplemented in semen extender @ 125 and 250 µg/ml for semen cryopreservation. There was a significant increase in pre and post-freezing motility and other seminal parameters. The microbial load of frozen-thawed semen of control and supplemented groups were well within the permissible limits. Lipid peroxidation levels were reduced in NPs supplemented groups, and reactive oxygen species (ROS) levels were significantly reduced in semen supplemented with 125 µg/ml NPs. Thus it can be conclude that silver NPs can be successfully used as a substitute for antibiotics in cattle bull semen cryopreservation with good antimicrobial activity and no adverse effects on sperm characteristics.

Synthesis of unsymmetrical ketones via dual catalysed cross-coupling of α,ß-unsaturated carboxylic acids with aryldiazonium salts.

A visible light-enabled synthesis of unsymmetrical ketones has been accomplished by the cross-coupling of α,ß-unsaturated carboxylic acids and aryldiazonium salts embracing a synergistic eosin Y and Co(OAc)2·4H2O catalysis. The reaction involves decarboxylative aerobic CC bond cleavage, and is endowed with the creation of new C-C and C-O bonds with good substrate scope.

Detection of the ß-lactoglobulin genotype in zebu cattle (Gangatiri) milk using high-resolution accurate mass spectroscopy.

We studied the genetic polymorphism of beta-lactoglobulin (ß-Lg) whey protein in Gangatiri zebu cows for this Research Communication. The polymorphic nature of milk protein fractions and their association with milk production traits, composition and quality has attracted several efforts in evaluating the allelic distribution of protein locus as a potential dairy trait marker. Genetic variants of ß-Lg have highly significant effects on casein number (B > A) and protein recovery (B > A) and also determine the yield of cheese dry matter (B > A). Molecular techniques of polyacrylamide gel electrophoresis and high-resolution accurate mass-spectroscopy were applied to characterize the ß-Lg protein obtained from the Gangatiri breed milk. Sequence analysis of ß-Lg showed the presence of variant B having UniProt database accession number P02754, coded on the PAEP gene. Our study can provide reference and guidance for the selection of superior milk (having ß-LgB) from this indigenous breed that could potentially give a good yield of ß-Lg for industrial applications.

Intensity of estrus expression - valuable obvious determinant of fertility in Bos indicus cows.

This study aimed to characterize estrus response and to establish relationships between intensity of estrus, preovulatory follicle (POF) size and estradiol (E2) concentrations on day of AI, luteal profiles and pregnancy outcome in lactating Hariana breed of cows. 200 cyclic cows were subjected to Ovsynch (n = 54) and Pre-OV treatment (n = 146). Ovsynch: Buserelin acetate (BA; 10 µg), Cloprostenol (500 µg) and BA (10 µg) were injected i.m. on day 0, 7 and 9, respectively, irrespective of treatment. Pre-OV: BA (10 µg) and Cloprostenol (500 µg) was also injected i.m. simultaneously 7 days prior to initiate Ovsynch. On the basis of estrus behavior, the cows were classified into three groups: weak, moderate and intense. Artificial insemination performed at 18-24 hours after 2nd BA of Ovsynch in both treatments. The average duration of estrus did not differ (p > 0.05) between Ovsynch and Pre-OV treatment. A positive correlation was observed between estrus response and POF size, concentration of E2 on day of AI and luteal profiles on day 12 post-AI. First service conception rate was higher in cows exhibited intense (45.46%) and moderate (42.56%) estrus response than weak (28.57%) estrus response. In conclusion, intensity of estrus expression could be considered as important determinant for deciding pregnancy outcomes in Bos indicus cows.

Fabrication of thin Molybdenum backed target using rolling method.

A successful attempt was made to fabricate a thin foil of natural Mo target on a thick Au backing with Indium in between to improve adhesion between the foils. Rolling at elevated temperature was considered to fabricate Mo foil while gold foil was fabricated employing conventional rolling technique. The heating of Mo foil under natural environment lead to the oxidation or carbonization on foil surface which was confirmed through Energy Dispersive X-ray Spectroscopy (EDS) measurements. Indium of thickness ∼86µg/cm2 was evaporated on Mo foil to improve adhesion between Mo and Au foils. The characterization of fabricated thin Mo foil was done using the Energy Dispersive X-ray Spectroscopy (EDS) and the Scanning Electron microscope (SEM) techniques. Thickness measurement of the target (Mo-Au) was done using Energy Dispersive X-ray Fluorescence (EDXRF) technique, in the measurements the thickness of the Mo foil and of gold backing are found out to be 1.3 mg/cm2 and 9 mg/cm2 respectively.

Proteomics-based milk whey proteome profiling of Indian Jersey crossbreed cows followed by chromosomal mapping.

BACKGROUND: Milk contains a massive class of minor proteins that are known for their various biological and molecular functions. Many whey proteins transfer the host defense mechanism to the human body. In this assay, electrophoresis followed by a high-resolution mass spectrometry-based proteomic approach has been applied to identify the whey proteome of Indian Jersey crossbreed bovines. RESULTS: Two search engines, MS Amanda and Sequest HT, have shown more than 29 minor proteins. Chromosomal mapping revealed that chromosomes 5 and 9 are expressing maximum proteins in the whey proteome. The principal component analysis, outlier plots, scree plots, score plots, and loading plots were generated to further assess the results. CONCLUSION: The majorly expressed ones are glycosylation-dependent cell adhesion molecule-1, ubiquitin, desmoglein, annexin, glycoprotein, arginase, histones, peroxiredoxin, vimentin, desmin, catenin, peripherin, and 70 kDa heat shock protein. © 2023 Society of Chemical Industry.

Microcosm-omics centric investigation reveals elevated bacterial degradation of imidacloprid.

Imidacloprid, a broad-spectrum insecticide, is widely used against aphids and other sucking insects. As a result, its toxic effect is becoming apparent in non-targeted organisms. In-situ bioremediation of residual insecticide from the environment utilizing efficient microbes would be helpful in reducing its load. In the present work, in-depth genomics, proteomics, bioinformatics, and metabolomics analyses were employed to reveal the potential of Sphingobacterium sp. InxBP1 for in-situ degradation of imidacloprid. The microcosm study revealed ∼79% degradation with first-order kinetics (k = 0.0726 day-1). Genes capable of mediating oxidative degradation of imidacloprid and subsequent decarboxylation of intermediates were identified in the bacterial genome. Proteome analysis demonstrated significant overexpression of the enzymes coded by these genes. Bioinformatic analysis revealed significant affinity and binding of the identified enzymes for their respective substrates (the degradation pathway intermediates). The nitronate monooxygenase (K7A41 01745), amidohydrolase (K7A41 03835 and K7A41 07535), FAD-dependent monooxygenase (K7A41 12,275), and ABC transporter enzymes (K7A41 05325, and K7A41 05605) were found to be effective in facilitating the transport and intracellular degradation of imidacloprid. The metabolomic study identified the pathway intermediates and validated the proposed mechanism and functional role of the identified enzymes in degradation. Thus, the present investigation provides an efficient imidacloprid degrading bacterial species as evidenced by its genetic attributes which can be utilized or further improved to develop technologies for in-situ remediation.

Management of non-functioning kidney due to pelvi-ureteric junction obstruction in pediatric age group: an observational study.

INTRODUCTION: A non-functional kidney (NFK) has been defined as one having paper-thin parenchyma, and split renal function (SRF) of < 10% on a nuclear scan. There are differences of opinion about nephrectomy or pyeloplasty in these patients. The present study was conducted to assess our management strategy of renal salvage for NFK. MATERIALS AND METHODS: It was a retrospective cohort study from January 2015 to July 2022, patients having SRF < 10% were included. These patients underwent ultrasound-guided percutaneous nephrostomy (PCN). A repeat nuclear scan was performed after 3 months. If SRF increased to > 10%, pyeloplasty was performed. RESULTS: Fifteen patients were managed. The mean age was 24.67 ± 23.61 months. Male to female ratio was 4:1. The initial mean SRF was 6.67 ± 2.85, which improved to 16.80 ± 4.69 after 3 months of placing the PCN (p < 0.001). The corresponding changes in the mean effective renal plasma flow (ERPF) were 60.13 ± 24.08 to 106.53 ± 24.61 (p < 0.001). There was no complaint after the placement of PCN. All patients underwent dismembered pyeloplasty. CONCLUSION: In NFK due to PUJO, expectant treatment in form of PCN followed by pyeloplasty appears to be the primary treatment modality, and nephrectomy may not be needed in any of them.

Multi-omics approach reveals elevated potential of bacteria for biodegradation of imidacloprid.

The residual imidacloprid, a widely used insecticide is causing serious environmental concerns. Knowledge of its biodegradation will help in assessing its residual mass in soil. In view of this, a soil microcosm-based study was performed to test the biodegradation potential of Agrobacterium sp. InxBP2. It achieved ∼88% degradation in 20 days and followed the pseudo-first-order kinetics (k = 0.0511 day-1 and t1/2=7 days). Whole genome sequencing of Agrobacterium sp. InxBP2 revealed a genome size of 5.44 Mbp with 5179 genes. Imidacloprid degrading genes at loci K7A42_07110 (ABC transporter substrate-binding protein), K7A42_07270 (amidohydrolase family protein), K7A42_07385 (ABC transporter ATP-binding protein), K7A42_16,845 (nitronate monooxygenase family protein), and K7A42_20,660 (FAD-dependent monooxygenase) having sequence and functional similarity with known counterparts were identified. Molecular docking of proteins encoded by identified genes with their respective degradation pathway intermediates exhibited significant binding energies (-6.56 to -4.14 kcal/mol). Molecular dynamic simulation discovered consistent interactions and binding depicting high stability of docked complexes. Proteome analysis revealed differential protein expression in imidacloprid treated versus untreated samples which corroborated with the in-silico findings. Further, the detection of metabolites proved the bacterial degradation of imidacloprid. Thus, results provided a mechanistic link between imidacloprid and associated degradative genes/enzymes of Agrobacterium sp. InxBP2. These findings will be of immense significance in carrying out the lifecycle analysis and formulating strategies for the bioremediation of soils contaminated with insecticides like imidacloprid.

Easy access to α-carbonyl sulfones using cross-coupling of α-aryl-α-diazoesters with sulfonyl hydrazides.

A facile synthesis of α-carbonyl sulfones has been accomplished by the cross-coupling of α-aryl-α-diazoesters with sulfonyl hydrazides in the presence of CuI and DBU. The reaction employs inexpensive and bench stable sulfonyl hydrazides as a sulfonyl source, and facilitates the migratory insertion with α-aryl-α-diazoesters under mild reaction conditions.

Intralesional steroid in the era of propranolol for infantile hemangioma-Do we need it?

INTRODUCTION: Despite its effectivity, there are reports of poor response to propranolol in the treatment of infantile hemangioma (IH). The literature is limited to the type of IH that fails to respond to propranolol. This study was conducted to analyze which types of hemangiomas respond poorly to propranolol and the effects of intralesional triamcinolone (IL TMC) in them. MATERIAL AND METHODS: In this prospective cohort study, IH was classified as superficial, deep, and mixed. The clinical details were recorded. Propranolol was started in the patients at a dose of 1 mg/kg/day and increased to 2-3 mg/kg/day. The response to the treatment was evaluated as excellent, good, poor, and no response. IL TMC was given in the non-responding group at a dose of 1-2 mg/kg at one-month interval for a total of six doses after stopping propranolol. RESULTS: Ninety-six patients (median age, 7 months; M/F = 2:1) were treated. Superficial hemangioma was present in 40 (41.7%), deep in 10 (10.4%), and mixed in 46 (47.9%) patients. The response was statistically better if initiated within four months of age. It was not influenced by the sex, number, site, or size. The response was statistically better in superficial hemangioma. IL TMC was administered in the 16 patients. The response was good or excellent in 10 patients. CONCLUSION: Propranolol will be used as a first-line drug for IH. All superficial IHs are likely to respond. There will be a possibility of non-responding mixed or deep IH. Use of IL TMC seems reasonable for IH not responding to propranolol.

Copper-Catalyzed Thiolation of Hydrazones with Sodium Sulfinates: A Straightforward Synthesis of Benzylic Thioethers.

A facile and sustainable protocol for the thiolation of hydrazones with sodium sulfinates has been developed in the presence of CuBr2 and DBU in DMF to afford diverse benzylic thioethers. Control experiments reveal a radical pathway involving a thiyl radical as a key intermediate.

Congenital anterior urethral valves and diverticula.

AIMS OF STUDY: Anterior urethral valves (AUVs) are rare congenital anomalies causing lower urinary tract obstruction in children. The present study highlights the clinical approach in identifying the condition and its treatment options. METHOD: Single centre, retrospective study of children. RESULT: Over a 16 year duration, 14 children were diagnosed with AUVs and diverticula with a mean age of 15 months. Clinical features included straining at micturation and a palpable penile swelling. Diagnosis was confirmed with voiding cystourethrogram and cystoscopy. An open surgical procedure was performed in 12 cases and endoscopic intervention done in one. On follow up 13 patients showed restoration of a normal voiding stream and normal renal function. One child died of chronic renal failure due to a delayed presentation, severe back-pressure changes, urinary ascites, and urosepsis. One patient developed a small urethrocutaneous fistula that healed spontaneously. CONCLUSION: AUV, though rare, should be recognizable due to the combination of a poor urinary stream and visible swelling in the ventral aspect of penis. Open surgical excision is the method of choice, and the outcome is excellent. LEVEL OF EVIDENCE: Level IV.