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Spike fertility and associated traits are key factors in deciding the grain yield potential of wheat. Genome-wide association study (GWAS) interwoven with advanced post-GWAS analysis such as a genotype-phenotype network (geno-pheno network) for spike fertility, grain yield, and associated traits allow to identify of novel genomic regions and represents attractive targets for future marker-assisted wheat improvement programs. In this study, GWAS was performed on 200 diverse wheat genotypes using Breeders' 35K Axiom array that led to the identification of 255 significant marker-trait associations (MTAs) (–log10P ≥ 3) for 15 metric traits phenotyped over three consecutive years. MTAs detected on chromosomes 3A, 3D, 5B, and 6A were most promising for spike fertility, grain yield, and associated traits. Furthermore, the geno-pheno network prioritised 11 significant MTAs that can be utilised as a minimal marker system for improving spike fertility and yield traits. In total, 119 MTAs were linked to 81 candidate genes encoding different types of functional proteins involved in various key pathways that affect the studied traits either way. Twenty-two novel loci were identified in present GWAS, twelve of which overlapped by candidate genes. These results were further validated by the gene expression analysis, Knetminer, and protein modelling. MTAs identified from this study hold promise for improving yield and related traits in wheat for continued genetic gain and in rapidly evolving artificial intelligence (AI) tools to apply in the breeding program. [ABSTRACT FROM AUTHOR]

A 51-year-old lady with a background of rheumatoid arthritis presented to the foot and ankle clinic with pain and a typical history of Morton's neuroma. Examination revealed a palpable swelling over the right foot in the third intermetatarsal space. Following failed conservative management, the patient underwent excision of the neuroma. Histology revealed of necrotizing granulomas with peripheral palisading and no evidence of features specific to a neuroma. This has rarely been described previously and supports the concept of rheumatoid synovitis and nodules producing symptoms mimicking Morton's neuroma/metatarsalgia.Level of clinical evidence: 4

An 11-year-old girl presented with an extremely rare complication of Meckel's diverticulum. The patient presented with complaints of abdominal distension, abdominal pain, decreased appetite, and non-bilious vomiting for 20 days with a history of mass protruding per rectum. Examination revealed a distended abdomen and prolapsing bowel loops during rectal examination, resembling intussusception. Radiological findings indicated intestinal obstruction. Surgical exploration revealed Meckel's diverticulum invading the rectum, accompanied by dense inter-bowel adhesions. The patient underwent resection of Meckel’s diverticulum and repair of the rectal rent. This case highlights the rarity of Meckel's diverticulum fistulating into the rectum.

Purpose: To develop a nomogram in cases with mismatch between subjective and Topolyzer cylinder, and based on the magnitude of the mismatch, customize a treatment plan to attain good visual outcomes post-laser-assisted in situ keratomileusis (LASIK) surgery. Methods: The patients were evaluated preoperatively using corneal tomography with Pentacam. Five optimal corneal topography scans were obtained from the Topolyzer Vario were used for planning the LASIK treatment. For the nomogram purpose, the patients were divided into three categories based on the difference between the subjective cylinder and Topolyzer (corneal) cylinder. The first group (group 1) consisted of eyes of patients, where the difference was less than or equal to 0.4 D. The second group (group 2) consisted of eyes, where the difference was more than 0.4 D and the subjective cylinder was lesser than the Topolyzer cylinder. The third group (group 3) included eyes where the difference was more than 0.4 D but the subjective cylinder was greater than the Topolyzer cylinder. LASIK was performed with the WaveLight FS 200 femtosecond laser and WaveLight EX500 excimer laser. Assessment of astigmatism correction for the three groups was done using Aplins vector analysis. For comparison of proportions, Chi-square test was used. A P value less than 0.05 was considered statistically significant. Results: The UDVA was statistically significantly different when compared between groups 1 and 2 (P = 0.02). However, the corrected distance visual acuity (CDVA) was similar among all the three groups (P = 0.1). Group 3 showed an increase of residual cylinder by −0.25 D, which was significant at intermediate and near reading distances (P < 0.05). Group 3 showed significantly higher target-induced astigmatism (TIA) compared to groups 1 and 2 (P = 0.01). The mean surgically induced astigmatism (SIA) was the least in group 2, which was statistically significant (P < 0.01). Conclusion: The outcomes for distance vision using our nomogram postoperatively were excellent, but further refinement for improving the near vision outcomes is required.

Purpose: The purpose of this study was to identify and analyze the clinical and ocular surface risk factors influencing the progression of keratoconus (KC) using an artificial intelligence (AI) model. Methods: This was a prospective analysis in which 450 KC patients were included. We used the random forest (RF) classifier model from our previous study (which evaluated longitudinal changes in tomographic parameters to predict “progression” and “no progression”) to classify these patients. Clinical and ocular surface risk factors were determined through a questionnaire, which included presence of eye rubbing, duration of indoor activity, usage of lubricants and immunomodulator topical medications, duration of computer use, hormonal disturbances, use of hand sanitizers, immunoglobulin E (IgE), and vitamins D and B12 from blood investigations. An AI model was then built to assess whether these risk factors were linked to the future progression versus no progression of KC. The area under the curve (AUC) and other metrics were evaluated. Results: The tomographic AI model classified 322 eyes as progression and 128 eyes as no progression. Also, 76% of the cases that were classified as progression (from tomographic changes) were correctly predicted as progression and 67% of cases that were classified as no progression were predicted as no progression based on clinical risk factors at the first visit. IgE had the highest information gain, followed by presence of systemic allergies, vitamin D, and eye rubbing. The clinical risk factors AI model achieved an AUC of 0.812. Conclusion: This study demonstrated the importance of using AI for risk stratification and profiling of patients based on clinical risk factors, which could impact the progression in KC eyes and help manage them better.

Dry eye disease (DED) is a commonly occurring, multifactorial disease characterized by reduced tear film stability and hyperosmolarity at the ocular surface, leading to discomfort and visual compromise. DED is driven by chronic inflammation and its pathogenesis involves multiple ocular surface structures such as the cornea, conjunctiva, lacrimal glands, and meibomian glands. The tear film secretion and its composition are regulated by the ocular surface in orchestration with the environment and bodily cues. Thus, any dysregulation in ocular surface homeostasis causes an increase in tear break-up time (TBUT), osmolarity changes, and reduction in tear film volume, all of which are indicators of DED. Tear film abnormalities are perpetuated by underlying inflammatory signaling and secretion of inflammatory factors, leading to the recruitment of immune cells and clinical pathology. Tear-soluble factors such as cytokines and chemokines are the best surrogate markers of disease severity and can also drive the altered profile of ocular surface cells contributing to the disease. Soluble factors can thus help in disease classification and planning treatment strategies. Our analysis suggests increased levels of cytokines namely interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-9, IL-12, IL-17A, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α); chemokines (CCL2, CCL3, CCL4, CXCL8); MMP-9, FGF, VEGF-A; soluble receptors (sICAM-1, sTNFR1), neurotrophic factors (NGF, substance P, serotonin) and IL1RA and reduced levels of IL-7, IL-17F, CXCL1, CXCL10, EGF and lactoferrin in DED. Due to the non-invasive sample collection and ease of quantitively measuring soluble factors, tears are one of the best-studied biological samples to molecularly stratify DED patients and monitor their response to therapy. In this review, we evaluate and summarize the soluble factors profiles in DED patients from the studies conducted over the past decade and across various patient groups and etiologies. The use of biomarker testing in clinical settings will aid in the advancement of personalized medicine and represents the next step in managing DED.

Byline: S. Gupta, C. Kumar, N. Raghav Sir, Polymorphous low-grade adenocarcinoma (PLGA) is a malignancy arising predominantly from minor salivary glands. PLGAs account for 10% of all tumors of the [...]

Black Holes are not expected to form in the mass range of 60 M⊙ to 130 M⊙ because of the Pair-Instability Supernova (PISN). However, the recent observational evidence of GW190521 does not comply with the existing theory. Here, we have looked into the effects of Dark Matter (DM) in the progenitors of PISN in terms of luminosity, lifetime and temperature and have shown that in the presence of DM particles, the progenitors can overcome the PISN stage to collapse into a black hole (BH) as a remnant.

Elevated levels of cathepsins implicated in cancer, inflammation and number of degenerative diseases emphasize the investigation of potential inhibitors in search for novel chemotherapeutic agents with better efficacy. Along with other cathepsins, cathepsin L has emerged out as a potential drug target in these diseased conditions. In the present study, we have assayed the inhibitory potency of two structurally related series of substituted N-formylpyrazolines and N-benzoylpyrazolines as inhibitors to cathepsin L.SAR studies show that N-formylpyrazolines were better inhibitors than N-benzoylpyrazolines. The most potent inhibitors among the two series were nitro substituted compounds 1i and 2i with Ki values of ~6.4 × 10-10 and 5.7 × 10-9 M for cathepsin L, respectively. The inhibitory potential of the compounds have been found comparative to the specific inhibitor, leupeptin. Docking experiments showing interaction between N-formylpyrazolines, N-benzoylpyrazolines and cathepsin L active site also provided useful insights. [ABSTRACT FROM AUTHOR]

Spores of B acillus megaterium were immobilized on a sensor disk by entrapment method followed by addition of pretreated milk and fluorogenic substrate, i.e., diacetate fluorescein with a response time of about 20 ± 5 min with ≥0.25 μg/L detection limit. Fluorescence was measured semiquantitatively using microbiological plate reader at specific excitation and emission spectra, i.e., 485 and 535 nm, respectively. High fluorescence within 20 ± 5 min is an indication of spore germination with the release of enzyme and its action on fluorogenic substrate. However, decrease in fluorescence indicates that milk is positive for AFM1 at 0.25 ppb. Reliability of fluorescence-based assay has been checked by spiking AFM1 in milk, which shows that fluorescence is inversely proportional to AFM1 concentration. The developed assay was evaluated with real food matrix such as raw, pasteurized and dried milk ( n = 59), and it was compared with radioimmunoassay ( Charm assay) and enzyme-linked immunosorbent assay which showed correlation of 0.94 and 1.0, respectively. Fluorogenic assay based on spore germination principle on sensor disk has the potential for routine monitoring of AFM1 in dairy farm, reception dock and manufacturing unit of dairy industry. Practical Applications Fluorescence-based detection of AFM1 in milk using immobilized spores on a sensor disk have a response time of 20 ± 5 min with a detection limit of ≥0.25 ppb. High fluorescence within 20 ± 5 min specifies germination of spores with the release of marker enzyme and its action on fluorogenic substrate, whereas decrease in fluorescence shows the presence of AFM1 in milk at 0.25 ppb. The assay was validated with radioimmunoassay ( Charm assay) and enzyme-linked immunosorbent assay in real food matrix such as raw, pasteurized and dried milk. The assay has the potential for routine monitoring of AFM1 in dairy farm, reception dock and manufacturing unit of dairy industry. [ABSTRACT FROM AUTHOR]

A spore germination-based concept and its transformation into a field level prototype for monitoring aflatoxin M1(AFM1) in milk was developed. Initially, 15 strains ofBacillusspp. procured from different culture collection were screened for AFM1sensitivity using spot assay and marker strain showing inhibition at 0.5 ppb was selected based upon maximum zone of inhibition. The selected strainB. megaterium2949 was further screened for different enzymes activities and subsequently its spores were produced to an extent of 73.13% ± 3.197% in newly developed sporulation medium containing beef extract (0.0075% ± 0.0004%), yeast extract (0.015% ± 0.001%), peptone (0.0375% ± 0.0016%), and sodium chloride (0.0375% ± 0.0018%). A spore germination-based concept/ assay was optimized by immobilizing spores in eppendorf with pretreated milk (80°C/15 min) containing germinant and chromogenic substrate followed by incubation at 37°C. The appearance of sky blue color within real time of 45 min indicated spores germination and release of specific marker enzyme such as acetyl esterase and its specific action on chromogenic substrate which demonstrates absence of AFM1in milk. However, if there was no color change, presence of AFM1at 0.5 ppb MRL was denoted by Codex. The developed concept on AFM1detection was validated and a correlation of 0.97 was established with AOAC approved Charm 6602 and ELISA at Codex MRL with minimal false positive and negative results. The cost effective test has potential application in dairy farms, manufacturing, and R&D units for routine monitoring of AFM1in milk. [ABSTRACT FROM AUTHOR]

Salivary gland examination is an important part of oral examination, especially because of it′s involvement in most of the systemic diseases. Patients most commonly seek medical attention when the major salivary glands like parotid and submandibular gland become enlarged or painful. The various imaging modalities practiced to check the salivary gland disorders include conventional radiography, sialography, ultrasonography, computerized tomography, radionuclide imaging and magnetic resonance imaging. Sialography is one of the oldest imaging procedures and still most commonly practiced, as it is a chair side procedure, simple to perform, and cost effective. We report the role of sialography as an adjuvant in the diagnosis of bacterial sialadenitis and sialadenosis and as a diagnostic and therapeutic aid in a case of juvenile recurrent parotitis.

Cancer is a leading cause of death worldwide, surpassed only by heart disease. Despite improved diagnosis and treatment, cancer cells still evade normal physiological processes such as apoptosis, metabolism, angiogenesis, cell cycle, and epigenetics. To mitigate the numerous side effects linked to chemotherapy, leveraging natural products emerged as a promising alternative, either alone or in tandem with traditional agents. Cinnamaldehyde, an active ingredient of Cinnamomum cassia's stem bark has emerged as a molecule of research with diverse pharmacological properties. In the present study, we report an in silico potential of cinnamaldehyde (CM) potential as an anticancer agent across thirteen anti-cancer targets in comparison with chlorambucil (CB), docetaxel (DOC), melphalan (MP). Computational tools such as DFT, CHEM3D, molinspiration, vNNADMET, SWISS ADME, admetSAR, galaxyrefine, iGEMDOCK, and DS-Visualizer were employed. Additionally, anti-cathepsin B activity was assessed for cinnamaldehyde and the mentioned drugs and the results showed comparable inhibition at nano Molar concentrations. The results supported molecular docking using iGEMDOCK. Both in silico and experimental findings substantiate cinnamaldehyde as a promising drug for cancer treatment including metastasis and invasion where cathepsin B involvement is indicated., (© 2024 Wiley‐VCH GmbH.)

The escalating issue of obesity and related health conditions, including diabetes mellitus and coronary heart disease, necessitates the development of digestive enzyme inhibitors. Targeting pancreatic lipase to inhibit fatty acid generation to attain reduced lipid absorption is a promising approach for identifying effective agents. Orlistat, the only clinically approved pancreatic lipase inhibitor, is associated with gastrointestinal side effects like oily stools, spotting, and flatulence. Concurrently, α-amylase inhibitors can mitigate rapid spikes in blood sugar levels. With the growing significance of natural products in pharmaceutical research, cinnamaldehyde has been recognized as a potential enzyme inhibitor. This study explores the effects of cinnamaldehyde-derived hydrazone Schiff bases on lipase and α-amylase through in vitro experiments. The synthesized compounds exhibited IC 50 value for lipase in the same range ((0.41-12.58) × 10 -8  M) as exhibited by the commercial drug orlistat (5.76 × 10 -8  M). However, for α-amylase inhibition, the compounds (IC 50 value = 0.37-9.54 × 10 -9  M) were found effective inhibitors of acarbose (IC 50 value = 6.76 × 10 -6  M) and curcumin (IC 50 value = 467 × 10 -9  M). In silico DFT studies, molecular docking, drug likeliness, bioactivity score, ADME, and toxicity are also investigated for these compounds., Competing Interests: Declaration of competing interest The Authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Cysteine cathepsins play a crucial role in cancer, inflammation, and the regulation of degenerative processes such as apoptosis, making them significant targets in drug development. In this study, we designed, synthesized, and characterized sixteen novel bi-thiazole derivatives, confirmed by 1 H NMR, 13 C NMR, HRMS, and X-ray analysis, which demonstrated significant therapeutic potential as inhibitors of cathepsin B. The synthesized thiazoles showed % inhibition in the range of 59.11-77.32, out of which bis-methoxyphenyl derivative 8k showed the highest inhibition of 77.32 % with IC 50 and k i values of 1.04 nM and 0.52 nM, respectively. Methoxy-containing derivatives 8c, 8g, 8i, 8j, 8l, and 8o showed improved inhibition over methyl and chloro. In silico studies of the new bis-thiazole compounds at cathepsin B active sites supported the in vitro findings, indicating that the synthesized bis-thiazole esters are promising therapeutic candidates for conditions involving elevated cathepsin B levels., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sidhant Yadav reports was provided by Council for Scientific and Industrial Research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Double-headed warheads focusing on the pharmacological aspects as well as membrane permeability can contribute a lot to medicinal chemistry. Over the past few decades, a lot of research has been conducted on steroid-heterocycle conjugates as possible therapeutic agents against a variety of disorders. In the second half of the 20th century, successful research was conducted on cholesterol-based heterocyclic moieties. Keeping in view the biological significance of various triazoles, research on fusion with cholesterol has emerged. This review has been designed to explore the chemistry of cholesterol-based triazoles for the duration from 2010 to 2023 and their significance in medicinal chemistry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pepsin, a unique protease activity at acidic environment in the stomach, can cause chronic inflammation in surrounding tissues after becoming hyperactive lead to enlarged tonsils, vocal fold polyps, laryngopharyngeal cancers, and other diseases. Therefore, design and development of new effective pepsin inhibitors becomes significant. In the present work, we synthesized, and characterized thiophene-based chalcones as anti-pepsin agents. The synthesized chalcones exhibited significantly better pepsin inhibition than commercially available drugs omeprazole and pantoprazole. The in-vitro screening revealed that the synthesized compounds exhibited pepsin inhibition in the range of 53.19-91.14 % at 3 × 10 -8 M concentration showing promising results controlling elevated pepsin levels. Compound 3p was found the best inhibitor with an IC50 value 1.02 × 10 -9 M. Molecular docking studies executed show the decrease in energy of interaction between pepsin and the synthesized compounds 3(a-t) varies from -69.104 to -83.124 kcal/mol and the highest decreased interaction energy with compound 3p. DFT analyses were conducted to gain a deeper understanding of the structural parameters. Energy minimization and quantum chemical parameters computed using Avagadro and ORCA software indicated ΔE values in the range 9.593-10.246 eV as per DFT calculations. The results obtained from the in vitro studies were supported with in silico studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The present research focused on the tail-approach synthesis of novel extended thiazolotriazoles (8a-8j) and triazolothiadiazines (11a-11j) including aminotriazole intermediate 10. After successful synthesis, all the compounds were evaluated for their inhibition potential against cytosolic isoforms of human carbonic anhydrase (hCA I, II), tumor-linked transmembrane isoforms (hCA IX, XII), and cathepsin B. As per the inhibition data, the newly synthesized compounds showed poor inhibition against hCA I. Many of the compounds showed effective inhibition toward hCA IX and/or XII in low nanomolar concentration. Despite the strong to moderate inhibition of hCA II by these compounds, more than half of them demonstrated better inhibition against hCA IX and/or XII, comparatively. Further, insights of CA inhibition data of these extended analogs and their comparison with earlier reported thiazolotriazole and triazolothiadiazine derivatives might help in the rational design of novel potent and selective hCA IX and XII inhibitors. The novel compounds were also found to possess anti-cathepsin B potential at a low concentration of 10 -7  M. Broadly, compounds of series 11a-11j presented more effective inhibition against cathepsin B than their counterparts in series 8a-8j. Moreover, these in vitro results with respect to cathepsin B inhibition were also supported by the in silico insights obtained via molecular modeling studies., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

The design and synthesis of a library of 21 novel benzenesulfonamide-bearing 3-functionalized pyrazole-linked 1,2,3-triazole derivatives as dual inhibitors of cathepsin B and carbonic anhydrase enzymes are reported. The target 1,2,3-triazole-linked pyrazolic esters (16) were synthesized by the condensation of 1,2,3-triazolic diketo esters with 4-hydrazinobenzenesulfonamide hydrochloride, and these were further converted into the corresponding carboxylic acid (17) and carboxamide (18) analogs. The synthesized compounds were assayed in vitro for their inhibition potential against human carbonic anhydrase (hCA) isoforms I, II, IX, and XII. They were found to be potent inhibitors at the low nanomolar level against the cancer-related hCA IX and XII and to be selective towards the cytosolic isoform hCA I. The physiologically important isoform hCA II was potently inhibited by all the newly synthesized compounds showing K I values ranging between 0.8 and 561.5 nM. The ester derivative 16c having 4-fluorophenyl (K I  = 5.2 nM) was the most potent inhibitor of hCA IX, and carboxamide derivative 18b (K I  = 2.2 nM) having 4-methyl substituted phenyl was the most potent inhibitor of hCA XII. The newly synthesized compounds exhibited potent cathepsin B inhibition at 10 -7  M concentration. In general, the carboxamide derivatives (18) showed higher % inhibition as compared with the corresponding ester derivatives (16) and carboxylic acid derivatives (17) for cathepsin B. The interactions of the target compounds with the active sites of cathepsin B and CA were studied through molecular docking studies. Further, the in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of the target compounds were also studied., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Nowadays, the scientific community has focused on dealing with different kinds of diseases by exploring the chemistry of various heterocycles as novel drugs. In this connection, medicinal chemists identified carbonic anhydrases (CA) as one of the biologically active targets for curing various diseases. The widespread distribution of these enzymes and the high degree of homology shared by the different isoforms offer substantial challenges to discovering potential drugs. Medicinal and synthetic organic chemists have been continuously involved in developing CA inhibitors. This review explored the chemistry of different heterocycles as CA inhibitors using the last 11 years of published research work. It provides a pathway for young researchers to further explore the chemistry of a variety of synthetic as well as natural heterocycles as CA inhibitors., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

The emergence of cathepsins as a potential target for anticancer drugs has led to extensive research in the development of their inhibitors. In the present study, we designed, synthesized, and characterized several cinnamaldehyde schiff bases employing diverse hydrazines, as potential cathepsin B inhibitors. The parallel studies on cathepsin B isolated from liver and cerebrospinal fluid unveiled the significance of the synthesized compounds as cathepsin B inhibitors at nanomolar concentrations. The compound, 7 exhibited the highest inhibition of 83.48 % and 82.96 % with an IC 50 value of 0.06 nM and 0.09 nM for liver and cerebrospinal fluid respectively. The inhibitory potential of synthesized compounds has been extremely effective in comparison to previous reports. With the help of molecular docking studies using iGEMDOCK software, we found that the active site -CH 2 SH group is involved in the case of α-N-benzoyl-D, l-arginine-b-naphthylamide (BANA), curcumin 2, 3, 6, and 7. For toxicity prediction, ADMET studies were conducted and the synthesized compounds emerged to be non-toxic. The results obtained from the in vitro studies were supported with in silico studies. The synthesized cinnamaldehyde schiff bases can be considered promising drug candidates in conditions with elevated cathepsin B levels., Competing Interests: Declaration of competing interest The Authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tuberculosis is a communicable disease which affects humans particularly the lungs and is transmitted mainly through air. Despite two decades of intensive research aimed at understanding and combating tuberculosis, persistent biological uncertainties continue to hinder progress. Nowadays, heterocyclic compounds have proven themselves in effective treatment of tuberculosis because of their wide range of biological and pharmacological activities. Antituberculosis or antimycobacterial agents encompass a broad array of compounds utilized singly or in conjunction to combat Mycobacterium infections, spanning from tuberculosis to leprosy. Here, we summarize the synthesis of various heterocyclic compounds which includes the greener synthetic route as well as use of nano compounds as catalyst along with their anti TB activities., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Purpose: To evaluate diagnostic performance of ganglion cell inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) parameters measured with Cirrus high-definition optical coherence tomography (OCT) in patients with preperimetric glaucoma., Methods: In this multicenter cross-sectional study, 150 eyes of 83 patients with preperimetric glaucoma were compared with 200 eyes of age and sex matched healthy subjects. All patients had visual field testing and OCT scanning of GCIPL and RNFL in all quadrants. The independent Samples t -test was used to determine if a difference exists between the means of two independent groups on a continuous dependent variable. The area under the receiver operating characteristic (ROC) curve (AUC) of each parameter was calculated for discriminatory ability between normal controls and preperimetric glaucoma. The sensitivity and specificity were estimated by point coordinates on ROC curve., Results: The best parameters for distinguishing preperimetric glaucoma from healthy eyes were the combined average GCIPL + average RNFL, followed by average RNFL + GCIPL (inferotemporal), and average RNFL + GCIPL (minimum). The GCIPL parameters with the highest to lowest AUC (in decreasing order) were inferotemporal, followed by average, minimum, superior, inferior, superonasal, inferonasal, superotemporal, and quadrants. The RNFL parameters with the highest to lowest AUC (in decreasing order) were average, followed by nasal, temporal, superior, and inferior quadrants. The sensitivity of combined GCIPL + RNFL parameters ranged 85%-88% and the specificity ranged 76%-88%. The sensitivity for RNFL parameters ranged 80%-90% and the specificity ranged 64%-88%., Conclusion: GCIPL and RNFL have good discriminatory ability; the sensitivity and specificity increase when both parameters are combined for early detection of glaucoma., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Current Ophthalmology.)

Herein, we report the design and synthesis of a library of 28 new 1,2,3-triazole derivatives bearing carboxylic acid and ester moieties as dual inhibitors of carbonic anhydrase (CA) and cathepsin B enzymes. The synthesised compounds were assayed in vitro for their inhibition potential against four human CA (hCA) isoforms, I, II, IX and XII. The carboxylic acid derivatives displayed low micromolar inhibition against hCA II, IX and XII in contrast to the ester derivatives. Most of the target compounds showed poor inhibition against the hCA I isoform. 4-Fluorophenyl appended carboxylic acid derivative 6c was found to be the most potent inhibitor of hCA IX and hCA XII with a K I value of 0.7 μM for both the isoforms. The newly synthesised compounds showed dual inhibition towards CA as well as cathepsin B. The ester derivatives exhibited higher % inhibition at 10 -7  M concentration as compared with the corresponding carboxylic acid derivatives against cathepsin B. The results from in silico studies of the target compounds with the active site of cathepsin B were found in good correlation with the in vitro results. Moreover, two compounds, 5i and 6c, showed cytotoxic activity against A549 lung cancer cells, with IC 50 values lower than 100 μM., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Yamuna River water in Agra city of India is contaminated with toxic pollutants, including heavy metals that cause damage to the environment and human health. At present, the direct use of river water for drinking purposes and household activities lead to the direct exposure of society to the contaminants. In this study, Yamuna River water samples were collected from three different sites in Agra city during the monsoon, summer, and winter seasons. The physico-chemical parameters were estimated along with heavy metals. In physico-chemical parameter, the values found were mostly above the permissible limits. The results water samples contain high levels of cadmium, chromium, lead, and nickel above the desirable levels in most cases. The metagenomic analysis revealed that Proteobacteria, Bacteroidetes, Verrucomicrobia, Actinobacteria, and Planctobacteria were the most abundant phyla with a relative abundance of 61%, 9.34%, 5.23%, 4.64%, and 4.3%, respectively. The Comamonadaceae, the most abundant family consists of the genera involved in hydrogen oxidation, iron reduction, degraders of polycyclic aromatic hydrocarbons, and fermentation. The presence of Pseudomonas, Nitrosomonas sp., Thauera humireducens and Dechloromonas denitrificans (decomposition of sewage and organic matter) and Pseudomonas aeruginosa indicates the presence of heavy metal degrading bacteria in water sample. Functional prediction showed the presence of genes responsible for different metabolic pathways that could help developing new bioremediation strategies. The study concludes the status of water contamination, the presence of complex microbial community and suggests the futuristic use and their role in bioremediation., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Current sterility test performed for most biological products takes 14 days. We evaluated solid medium, containing 5% blood for use in the membrane filtration (MF) and direct inoculation (DI) sterility test. Representative microorganisms prepared in a sample matrix at approximately 0.1, 1, 10 and 100 colony forming units were tested for growth by compendial MF sterility test using fluid thioglycolate medium and tryptic soy broth and also on the Schaedler blood agar (SBA). Sterility test performed on SBA was significantly more sensitive and faster in detecting various microorganisms than the compendial method, particularly for sample matrix containing 0.01% thimerosal (p < 0.05). SBA detected all microorganisms within 7 days. To implement solid medium in the DI sterility test, multiple BA plates were inoculated with the sample. All representative microorganisms were detected within 5 days. The sterility test using solid medium required 3 different incubation conditions, 30-35 °C aerobically and anaerobically to detect bacteria, and at 20-25 °C aerobically to detect mold and yeast. To eliminate aerobic incubation of solid medium at 20-25 °C, we evaluated representative species of mold and yeast for their growth at 30-35 °C and 20-25 °C in the sterility test performed on solid medium. Penicillium chrysogenum could not be detected at 30-35 °C consistently within 7 days. Sterility test performed on solid medium without any additional technology could be completed in 7 days, as compared to the 14 days required for the current compendial method., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 International Alliance for Biological Standardization. All rights reserved.)

Background: Exploration of the multi-target approach considering both human carbonic anhydrase (hCA) IX and XII and cathepsin B is a promising strategy to target cancer. Methodology & Results:  22 novel 1,2,4-triazole derivatives were synthesized and evaluated for their inhibition efficacy against hCA I, II, IX, XII isoforms and cathepsin B. The compounds demonstrated effective inhibition against hCA IX and/or XII isoforms with considerable selectivity over off-target hCA I/II. All compounds presented significant anticathepsin B activities at a low concentration of 10 -7  M and in vitro results were also supported by the molecular modeling studies. Conclusion: Insights of present study can be utilized in the rational design of effective and selective hCA IX and XII inhibitors capable of inhibiting cathepsin B.

Enzymes are the biological macromolecules that have emerged as an important drug target as their upregulation/imbalance leads to various pathological conditions, such as inflammation, parasitic infection, Alzheimer's, cancer, and many others. Here, we designed and synthesized some morpholine tethered novel aurones and evaluated them as potential inhibitors for CTSB, α-amylase, lipase and activator for trypsin. All the newly synthesized compounds were fully characterized by various spectroscopic techniques ( 1 H NMR, 13 C NMR, HRMS) and the Z-configuration to them was assigned based on single crystal XRD data and 1 H NMR chemical shift values. Further, the hybrids were evaluated for their intracellular (cathepsin B) and extracellular (trypsin, lipase, amylase) enzyme inhibition potencies. The in-vitro inhibition screening against cathepsin B revealed that most of the synthesized compounds are good competitive inhibitors (% inhibition = 22.91-75.04), with 6q (% inhibition = 75.04) and 6r (% inhibition = 71.13) as the eminent inhibitors of the series. At the same time, they exhibited weak to moderate inhibition towards amylase (% inhibition = 7.22-22.48) and lipase (% inhibition = 16.29-54.83). A significant trypsin activation (% activation = 107.42-196.47) was observed even at the micromolar concentration of the compounds. Furthermore, the drug-modeling studies showed a good correlation between the in-vitro experimental results and the calculated binding affinity of the screened compounds with all the tested enzymes. These findings are expected to provide a new lead in drug development for different pathological disorders wherever these enzymes are involved., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Twenty-one novel extended analogs of acetazolamide were synthesized and screened in vitro for their inhibition efficacy against human carbonic anhydrase (hCA) isoforms I, II, IX, XII, and cathepsin B. The majority of the compounds were found to be effective inhibitors of tumor-associated hCA IX and XII, and poor inhibitors of cytosolic hCA I. Despite the strong to moderate inhibition potential possessed by these compounds toward another cytosolic isoform hCA II, some of them demonstrated better potency against hCA IX and/or XII isoforms as compared to hCA II. Four compounds (11f, 11g, 12c, and 12g) effectively inhibited hCA IX and/or XII isoforms with considerable selectivity over the off-targets hCA I and II. Interestingly, five compounds, including 11f, 11g, 12c, 12d, and 12g, inhibited hCA IX even better than the clinically used acetazolamide. Some of the novel synthesized compounds exhibited higher anti-cathepsin B potential than acetazolamide, with % inhibition of around 50%, at a concentration of 10 -7  M. Further, two compounds (12g and 12c) that showed effective and selective inhibition activity profiles against hCA IX and XII were additionally found to be effective inhibitors of cathepsin B., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

Supramolecular assemblies of perylene bisimide derivative (PBI-SAH) have been developed which show 'turn-on' detection of chlorpyrifos in aqueous media, apple residue and blood serum. Differently from the already reported fluorescent probes for the detection of CPF, PBI-SAH assemblies also show affinity for acetylcholinesterase (AChE) which endow the PBI-SAH molecules with mixed inhibitory potential to restrict the AChE catalysed hydrolysis of acetylthiocholine (ATCh) in MG-63 cell lines (in vitro) and in mice (in vivo). The molecular docking studies support the inhibitory activity of PBI-SAH assemblies and their potential to act as safe insecticide with high benefit to harm ratio. The insecticidal potential of PBI-SAH derivative has been examined against Spodoptera litura (S. litura) and these studies demonstrate its excellent insecticidal activity (100 % mortality in nineteen days). To the best of our knowledge, this is the first report regarding development of PBI-SAH assemblies which not only detect chlorpyrifos but also mimic AChE inhibitory activity of CPF to show promising aptitude as safe insecticide., (© 2023 Wiley-VCH GmbH.)

Background: Inhibition of human carbonic anhydrase (hCA) isoforms IX and XII with concurrent inhibition of cathepsin B is a promising approach for targeting cancers. Methods/results: 28 keto-bridged dual triazole-containing benzenesulfonamides were synthesized and tested, following the multitarget approach, for their efficacy as inhibitors of cathepsin B and hCA isoforms (I, II, IX, XII). The synthesized compounds showed excellent inhibition of CA isoforms (IX and XII) and cathepsin B. Compound 8i exhibited better and more selective inhibition of the cancer-associated isoform hCA IX as compared with acetazolamide (reference drug) and SLC-0111 (potent lead as carbonic anhydrase inhibitor). Molecular docking studies were also carried out. Conclusion: The present work gives important generalizations for the development of isoform-selective hCA inhibitors endowed with anti-cathepsin properties.

In the realm of enzymes, the Enzyme Immobilization technique can be extremely beneficial. More research into computational approaches could lead to a better understanding as well as lead us in the direction of a more environmentally friendly and greener path. In this study, molecular modelling techniques were used to collect information regarding the immobilization of Lysozyme (EC 3.2.1.17) on Dialdehyde Cellulose (CDA). Lysine, being the most nucleophilic, is most likely to interact with dialdehyde cellulose. Enzyme substrate interactions have been studied with and without the refinement of modified lysozyme molecules. A total of six CDA-modified lysine residues were selected for the study. The docking process for all modified lysozymes was carried out using four distinct docking programs: Autodock Vina, GOLD, Swissdock, and iGemdock. The binding affinity (-7.8 & -8.0 kcal mol -1 in case of non-refinement and -4.7 & -5.0 kcal mol -1 in case of refinement), calculated from Autodock vina, as well as the interaction similarity of Lys 116 immobilized lysozyme with its substrate, were found to be 75 % (W/o simulation) & 66.7 % (With simulation) identical with the reference case (unmodified lysozyme) if Lys 116 is bound to Dialdehyde Cellulose. The approach described here is utilized to identify amino acid residues that are used in the immobilization of lysozyme., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Polymers-based drug delivery systems constitute one of the highly explored thrust areas in the field of the medicinal and pharmaceutical industries. In the past years, the properties of polymers have been modified in context to their solubility, release kinetics, targeted action site, absorption, and therapeutic efficacy. Despite the availability of diverse synthetic polymers for the bioavailability enhancement of drugs, the use of natural polymers is still highly recommended due to their easy availability, accessibility, and non-toxicity. The aim of the review is to provide the available literature of the last five years on oral drug delivery systems based on four natural polymers i.e., cellulose, pectin, carrageenan, and alginate in a concise and tabulated manner. In this review, most of the information is in tabulated form to provide easy accessibility to the reader. The data related to active pharmaceutical ingredients and supported components in different formulations of the mentioned polymers have been made available., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Use of natural polymer in the development of Drug Delivery Systems (DDS) has greatly increased in recent past because of their biocompatible, non-allergic and biodegradable nature. Natural polymers are usually hydrophilic supports, so in order to be a carrier of a hydrophobic drug their nature needs to be changed. Each developed system behaves differently towards different drugs in terms of loading and sustained release of the drug as well. In the present work we report differential binding of piperine & curcumin with cetyltrimethylammonium bromide (CTAB) modified cellulose, alginate and pectin. Difference in interaction between the piperine and curcumin with supports has been visualized using in-vitro as well as in-silico studies. Initial results obtained after in-silico studies have been validated via time dependent anti-trypsin, serum protein binding, anti-cathepsin, anti-oxidant, and anti-α-amylase activities. FT-IR, SEM, fluorescence and Particle size have been used to characterize the piperine loaded on CTAB-modified polymeric supports., Competing Interests: Declaration of competing interest All the authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)