Investigating dynamics, etiology, pathology, and therapeutic interventions of Caligus clemensi and Vibrio alginolyticus co-infection in farmed marine fish.

This study investigated a disease outbreak characterized by caligid copepod infestations and subsequent secondary bacterial infections in European seabass (Dicentrarchus labrax) and flathead grey mullet (Mugil cephalus) cultivated at a private facility in the Deeba Triangle region of Egypt. Moribund fish displayed brown spots on the skin, tongue, and gills, along with lethargy and excess mucus. The fish suffered severe infections, exhibiting external hemorrhages, ulcers, and ascites. The fish had pale, enlarged livers with hemorrhaging. Comprehensive parasitological, bacteriological, molecular, immunity and histopathological analyses were conducted to identify the etiological agents and pathological changes. Caligid copepod infestation was observed in wet mounts from the buccal and branchial cavities of all examined fish, and the caligids were identified as Caligus clemensi through COI gene sequencing and phylogenetic analysis. Vibrio alginolyticus was confirmed as a secondary bacterial infection through biochemical tests, recA gene sequencing, and phylogenetic analyses. Antibiotic susceptibility testing revealed resistance to ß-lactams, aminoglycosides, and trimethoprim-sulfamethoxazole in V. alginolyticus isolates. Upregulation of the inflammatory marker IL-1ß in gill and skin tissues indicated a robust cell-mediated immune response against the pathogens. Histopathological examination revealed severe tissue damage, hyperplasia, hemorrhage, and congestion in the gills, along with hepatocellular degeneration and steatosis in the liver, providing initial insights into this outbreak. A comprehensive therapeutic regimen was implemented, comprising prolonged hydrogen peroxide immersion baths, followed by the application of the nature-identical plant-based compound Lice-less and probiotic Sanolife Pro-W supplementation. This integrated approach effectively eliminated C. clemensi infestations, controlled secondary bacterial infections, and restored fish health, reducing morbidity and mortality rates to minimal levels.

Efficient genetic code expansion without host genome modifications.

Supplementing translation with noncanonical amino acids (ncAAs) can yield protein sequences with new-to-nature functions but existing ncAA incorporation strategies suffer from low efficiency and context dependence. We uncover codon usage as a previously unrecognized contributor to efficient genetic code expansion using non-native codons. Relying only on conventional Escherichia coli strains with native ribosomes, we develop a plasmid-based codon compression strategy that minimizes context dependence and improves ncAA incorporation at quadruplet codons. We confirm that this strategy is compatible with all known genetic code expansion resources, which allowed us to identify 12 mutually orthogonal transfer RNA (tRNA)-synthetase pairs. Enabled by these findings, we evolved and optimized five tRNA-synthetase pairs to incorporate a broad repertoire of ncAAs at orthogonal quadruplet codons. Lastly, we extend these resources to an in vivo biosynthesis platform that can readily create >100 new-to-nature peptide macrocycles bearing up to three unique ncAAs. Our approach will accelerate innovations in multiplexed genetic code expansion and the discovery of chemically diverse biomolecules.

Impacts of circulating cytokine levels and gene polymorphism predisposition on type 1 diabetes mellitus.

PURPOSE: A wide range of cytokines has been demonstrated to be involved in the etiology of type 1 diabetes mellitus (T1DM). Gene polymorphisms may potentially contribute to a hereditary predisposition toward circulating cytokine levels as (high, intermediate, or low) since they can affect cytokine production or function. The aim of this study was to investigate the roles of cytokine levels and the association of single-nucleotide polymorphisms (SNPs) within cytokine genes with T1DM in Saudi children. METHODS: Totals of 91 well-characterized T1DM patients and 91 T1DM-free control subjects were enrolled in this study. RESULTS: The levels of 3 circulating cytokines (transforming growth factor [TGF]-ß1, interleukin [IL]-10, and IL-6) and 6 SNPs in 3 cytokine genes (TGF-ß1 [rs1800470 and rs1800471], IL-10 [rs1800896, rs1800871, and rs1800872], and IL-6 [rs1800795]) that contribute to genetic susceptibility were measured by enzyme-linked immunosorbent assay and polymerase chain reaction with sequence-specific primers. Our fn dings show that TGF-ß1 serum levels were signifcantly lower in the children with T1DM than in the control participants. The TGF-ß1 genotypes with a high-production phenotype were signifcantly less frequent and those with a lowproduction phenotype were signifcantly more frequent in the children with T1DM compared to the control participants. respectively. Furthermore, the IL-6 genotype frequency with low level of IL-6 production were signifcantly increased in the T1DM group compared to the control group. Moreover, our data demonstrated no appreciable diferences in circulating serum level or genotype and phenotype of IL- 10 between the patients and controls. CONCLUSION: This kind of measurement, which considers the prediction of T1DM, may be useful in assessing the severity of T1DM and susceptibility to T1DM among Saudi children.

Effects of Transjugular Intrahepatic Portosystemic Shunt on Renal and Pulmonary Function in Hepatic Decompensation with and without Hepatorenal and Hepatopulmonary Syndromes: A Review.

Cirrhosis is often characterized by decreased liver function, ranging from a compensated, typically asymptomatic phase to a decompensated phase characterized by the appearance of ascites or variceal bleeding, and ultimately hepatorenal syndrome (HRS) or hepatopulmonary syndrome (HPS). The latter two complications are associated with a poor prognosis and limited treatment efficacy. In cases of ascites or variceal bleeding resistant to medical therapy, transjugular intrahepatic portosystemic shunt (TIPS) is effective and safe. Shunting blood by TIPS diverts portal blood to the systemic circulation, potentially increasing systemic blood volume and benefiting renal function. However, TIPS could also divert nitric oxide to the systemic circulation, potentially worsening systemic hypotension and perfusion, which could be detrimental to renal function. Available evidence indicates that TIPS often improves renal function in patients with portal hypertension, with or without HRS. No studies have shown persistently decreased renal function after TIPS. However, these data are insufficient to support a recommendation for the use of TIPS specifically for HRS. In patients without pre-existing HPS, TIPS does not appear to significantly affect pulmonary gas exchange. Results of TIPS in HPS have been inconsistent; some studies have shown improvement, but effects were transient. No studies have shown a persistent decline in pulmonary function after TIPS. The evidence supports the need for large randomized controlled trials to investigate the beneficial effects of TIPS for HRS. Similar pulmonary function data are less clear regarding TIPS for HPS. The aim of the current report was to review the literature regarding the effects of TIPS on renal and pulmonary function in hepatic decompensation, with or without the development of HRS or HPS.

Limb-girdle muscular dystrophy in pregnancy: a narrative review.

Limb-girdle muscular dystrophy (LGMD) poses unique challenges for women during pregnancy, necessitating comprehensive care and tailored management strategies. The present narrative review aims to examine the unique challenges and management strategies required for women with LGMD during pregnancy. With over 30 genetic subtypes identified and the potential for additional discoveries through advanced diagnostic techniques, preconception counseling plays a crucial role in informing prospective parents about reproductive risks and available options. Baseline assessments, including cardiac and pulmonary evaluations, are essential to guide antenatal care, alongside genetic testing for precise diagnosis and counseling. Optimizing maternal health through respiratory exercises, cardiac monitoring, and individualized exercise and nutrition plans is paramount to avoid potential complications. During pregnancy, close monitoring of maternal and fetal well-being is important, with collaborative care between obstetricians and specialists. An individualized approach to delivery mode considering factors such as muscle strength, pelvic size, and fetal presentation is crucial. While vaginal delivery has been proven to be possible, the need for an emergency cesarean delivery should always be kept in mind. Regional anesthesia is preferred, with proactive planning for potential respiratory support. Bupivacaine has been shown to be effective with epidural catheters that may be used for prolonged relief with opioids like morphine and fentanyl, while also evaluating the patients' respiratory function. Postpartum considerations include pain management, mobility support, breastfeeding assistance, and emotional support. Early mobilization and tailored physiotherapy regimens may promote optimal recovery, while comprehensive breastfeeding guidance is needed to address challenges related to muscle weakness. Access to mental health resources and support networks is essential to helping individuals cope with the emotional demands of parenthood alongside managing LGMD. By addressing the unique needs of pregnant individuals with LGMD, healthcare providers can optimize maternal and fetal outcomes while supporting individuals in their journey to parenthood.

Genome-wide CRISPR/Cas9 library screen identifies C16orf62 as a host dependency factor for porcine deltacoronavirus infection.

Porcine deltacoronavirus (PDCoV) is an emerging pathogen that can cause severe diarrhoea and high mortality in suckling piglets. Moreover, evidence of PDCoV infection in humans has raised concerns regarding potential public health risks. To identify potential therapeutic targets for PDCoV, we performed a genome-wide CRISPR/Cas9 library screening to find key host factors important to PDCoV infection. Several host genes in this screen were enriched, including ANPEP, which encodes the PDCoV receptor aminopeptidase N (APN). Furthermore, we discovered C16orf62, also known as the VPS35 endosomal protein sorting factor like (VPS35L), as an important host factor required for PDCoV infection. C16orf62 is an important component of the multiprotein retriever complex involved in protein recycling in the endosomal compartment and its gene knockout led to a remarkable decrease in the binding and internalization of PDCoV into host cells. While we did not find evidence for direct interaction between C16orf62 and the viral s (spike) protein, C16orf62 gene knockout was shown to downregulate APN expression at the cell surface. This study marks the first instance of a genome-wide CRISPR/Cas9-based screen tailored for PDCoV, revealing C16orf62 as a host factor required for PDCoV replication. These insights may provide promising avenues for the development of antiviral drugs against PDCoV infection.

Dietary biogenic selenium nanoparticles improve growth and immune-antioxidant indices without inducing inflammatory responses in Nile tilapia.

The present study evaluated the use of green-synthesized selenium nanoparticles (SeNPs), using the microalgae Pediastrum boryanum as a diet additive in aquaculture to improve the growth performance, health, and immune response of Nile tilapia. Nile tilapia were fed different concentrations of green SeNPs (79.26 nm) as follows: 0, 0.75, and 1.5 mg/kg of SeNPs for 8 weeks. Following the trial, growth performance, biochemical indices, antioxidant and pro-inflammatory cytokine-related genes, and tissue histological examinations were performed. The study showed that SeNPs significantly improved (P < 0.05) growth performance and innate immune parameters (P < 0.001, IgM, and lysozyme) at both supplemented doses compared with the control. The protein profile and liver function enzymes were normal compared with those in the control group (P > 0.05). Serum malondialdehyde and superoxide dismutase levels were not significantly changed, while reduced glutathione and catalase were significantly enhanced (P < 0.01, P < 0.05) in the SeNPs 1.5 mg/kg compared to the control group. No inflammatory response was detected upon SeNP supplementation, as indicated by the absence of changes in the expression of pro-inflammatory cytokine genes. The earlier assays' results were histopathologically evidenced, where hepatic and splenic tissue architectures in SeNPs groups did not reveal any deviation from the control group. Our findings indicate that green selenium nanoparticles can potentially improve the growth and immunological response of Nile tilapia, offering opportunities for incorporating health benefits into functional foods and nutraceuticals, which corresponds to the increasing consumer interest in eco-friendly, environmentally sustainable dietary supplements.

Developing PRISM: A Pragmatic Institutional Survey and Bench Marking Tool to Measure Digital Research Maturity of Cancer Centers.

BACKGROUND: Multicenter precision oncology real-world evidence requires a substantial long-term investment by hospitals to prepare their data and align on common Clinical Research processes and medical definitions. Our team has developed a self-assessment framework to support hospitals and hospital networks to measure their digital maturity and better plan and coordinate those investments. From that framework, we developed PRISM for Cancer Outcomes: PR: agmatic I: nstitutional S: urvey and benchM: arking. OBJECTIVES: The primary objective was to develop PRISM as a tool for self-assessment of digital maturity in oncology hospitals and research networks; a secondary objective was to create an initial benchmarking cohort of >25 hospitals using the tool as input for future development. METHODS: PRISM is a 25-question semiquantitative self-assessment survey developed iteratively from expert knowledge in oncology real-world study delivery. It covers four digital maturity dimensions: (1) Precision oncology, (2) Clinical digital data, (3) Routine outcomes, and (4) Information governance and delivery. These reflect the four main data types and critical enablers for precision oncology research from routine electronic health records. RESULTS: During piloting with 26 hospitals from 19 European countries, PRISM was found to be easy to use and its semiquantitative questions to be understood in a wide diversity of hospitals. Results within the initial benchmarking cohort aligned well with internal perspectives. We found statistically significant differences in digital maturity, with Precision oncology being the most mature dimension, and Information governance and delivery the least mature. CONCLUSION: PRISM is a light footprint benchmarking tool to support the planning of large-scale real-world research networks. It can be used to (i) help an individual hospital identify areas most in need of investment and improvement, (ii) help a network of hospitals identify sources of best practice and expertise, and (iii) help research networks plan research. With further testing, policymakers could use PRISM to better plan digital investments around the Cancer Mission and European Digital Health Space.

Cellular therapies for idiopathic pulmonary fibrosis: current progress and future prospects.

Idiopathic pulmonary fibrosis (IPF) is an interstitial, fibrotic lung disease characterized by progressive damage. Lung tissues with IPF are replaced by fibrotic tissues with increased collagen deposition, modified extracellular matrix, all which overall damages the alveoli. These changes eventually impede the gas exchange function of the alveoli, and eventually leads to fatal respiratory failure of the lung. Investigations have been conducted to further understand IPF's pathogenesis, and significant progress in understanding its development has been made. Additionally, two therapeutic treatments, Nintedanib and Pirfenidone, have been approved and are currently used in medical applications. Moreover, cell-based treatments have recently come to the forefront of developing disease therapeutics and are the focus of many current studies. Furthermore, a sizable body of research encompassing basic, pre-clinical, and even clinical trials have all been amassed in recent years and hold a great potential for more widespread applications in patient care. Herein, this article reviews the progress in understanding the pathogenesis and pathophysiology of IPF. Additionally, different cell types used in IPF therapy were reviewed, including alveolar epithelial cells (AECs), circulating endothelial progenitors (EPCs), mixed lung epithelial cells, different types of stem cells, and endogenous lung tissue-specific stem cells. Finally, we discussed the contemporary trials that employ or explore cell-based therapy for IPF.

Awareness of insomnia caused by coffee consumption among adults in Jazan, Saudi Arabia.

The Kingdom of Saudi Arabia is the second largest country in the Arabian Peninsula and ranks 61st out of 150 countries in terms of coffee consumption. Excessive coffee consumption is associated with the risk of adverse health outcomes. This study aimed to assess awareness of the effects of coffee consumption and its relationship with insomnia among the adult population in Jazan, Saudi Arabia. A cross-sectional study was conducted with 431 adults in the Jazan region. A self-administered questionnaire was distributed to the participants using an online survey. Data were analyzed using Statistical Program for the Social Sciences, Version 24.0. Of 431 participants, 377 (87.5%) consumed coffee. Females and married women consumed more coffee than their counterparts (91.3%, P < .01; 92.8%, P < .05; respectively), while students consumed coffee (85.2%) less than both the employed and unemployed (P < .05). The proportion of consumption increased from underweight (79.7%) to normal weight (88.5%), and as high as 91.3% among overweight/obese (P < .05). More than one-third of the participants (35.5%) preferred drinking coffee at coffee shops. The most preferred coffee was Arabic coffee (40%), and the major reason for drinking coffee was to change their mood (29.7%). More than half of the participants (54.5%) reported that coffee caused insomnia (P < .01). Awareness-raising initiatives for the negative effects of excessive coffee consumption are important. Longitudinal studies are required in the next stage of research to identify trends such as the motivations and profiles of Saudi coffee drinkers.

Effects of α-sitosterol on growth, hematobiochemical profiles, immune-antioxidant resilience, histopathological features and expression of immune apoptotic genes of Nile tilapia, Oreochromis niloticus, challenged with Candida albicans.

In this study, the effect of the Streptomyces misakiensis metabolite (α- sitosterol, 0, 20, 40, 60, and 80 mg/kg) dietary supplementation on growth performance, antioxidant-immune stability and Candida albicans resistance of Nile tilapia was evaluated. The results revealed that the incorporation of α-sitosterol at doses of 60 and 80 mg/kg into the diet significantly improved the growth rate of Nile tilapia. The fish received 80 mg/kg showed an increased level of high-density lipoprotein, total protein, globulin, and albumin, and significantly reduced levels of indicators of hepato-renal damage, glucose, triglycerides, low-density lipoprotein, and total cholesterol. Dietary α-sitosterol induced a considerable increase in hepatopancreas glutathione peroxidase, superoxide dismutase and catalase activities and a significant drop in malondialdehyde levels. Supplementing the diet with 80 mg/kg of α-sitosterol increased nitric oxide, complement-3, nitro blue tetrazolium levels, lysozyme, and phagocytic activities. In particular, supplementing with α-sitosterol at 60-80 mg/kg of diet significantly enhanced the expression of pro/anti-inflammatory markers (il1b, il10, tgfb, ifng, tnfa and il8) after the C. albicans challenge. Also, there was a decrease in cumulative mortality percent, pro-apoptotic markers (casp3, bax and hsp70) and an increase in anti-apoptotic indicators (bcl2). Interestingly, following the C. albicans challenge, fish that received 0 and 20 mg α-sitosterol/kg exhibited significant inflammation in the hepatopancreas, spleen, and intestine. On the other hand, inflammation could be alleviated by feeding 60-80 mg α-sitosterol/kg. Due to these findings, α-sitosterol could be an innovative option to enhance growth, general physiological status, immune service, and antifungal resistance of Nile tilapia against C. albicans.

Plants' molecular behavior to heavy metals: from criticality to toxicity.

The contamination of soil and water with high levels of heavy metals (HMs) has emerged as a significant obstacle to agricultural productivity and overall crop quality. Certain HMs, although serving as essential micronutrients, are required in smaller quantities for plant growth. However, when present in higher concentrations, they become very toxic. Several studies have shown that to balance out the harmful effects of HMs, complex systems are needed at the molecular, physiological, biochemical, cellular, tissue, and whole plant levels. This could lead to more crops being grown. Our review focused on HMs' resources, occurrences, and agricultural implications. This review will also look at how plants react to HMs and how they affect seed performance as well as the benefits that HMs provide for plants. Furthermore, the review examines HMs' transport genes in plants and their molecular, biochemical, and metabolic responses to HMs. We have also examined the obstacles and potential for HMs in plants and their management strategies.

Hepato-renal protective impact of nanocapsulated Petroselinum crispum and Anethum graveolens essential oils added in fermented milk against some food additives via antioxidant and anti-inflammatory effects: In silico and in vivo studies.

The study assessed the efficacy of parsley and dill essential oils (EOs) nanocapsules incorporated into fermented milk in hepato-renal protection against specific food additives. A molecular docking assay was conducted between parsley and dill EOs bioactive molecules and inflammatory cytokines. Freeze-dried parsley and dill EOs nanocapsules were developed, characterized for their morphological structure, particle size, zeta potential, polydispersity index and encapsulation efficiency and assessed in fast green dye and sodium benzoate (SB) combination-treated rats. The docking results revealed that the primary constituents of parsley and dill EOs (apiol, myristicin, α-pinene, (-)-carvone, and d-limonene) interacted with the active sites of TNF-α, IL-1ß and TGF-1ß cytokines with hydrophobic and hydrogen bond interactions. D-limonene had the highest binding affinity (6.4 kcal/mol) for the TNF-α. Apiol and myristicin had the highest binding affinity (5.1, 5.0, 5.0 and 5.0 kcal/mol, respectively) for the IL-1ß and TGF-ß1 receptors. Biochemically and histopathologically, the excessive co-administration of fast green and SB revealed adverse effects on the liver and the kidney. Whereas the treatment with parsley and dill EOs nanocapsules afford hepato-renal protective effects as manifested by suppression the elevated liver and kidney functions. Parsley and dill EOs nanocapsules showed a significant reduction of the liver (64.08 and 80.5 pg/g, respectively) and kidney (59.3 and 83.6 pg/g, respectively) ROS. Moreover, parsley and dill EOs nanocapsules down-regulated the liver and the kidney inflammatory cytokines (IL-6, TNF-α, IL-1ß and TGF-1ß) and lipid peroxidation and up-regulated the antioxidant enzymes. In conclusion, the data suggest a potential hepato-renal protective effects of parsley and dill EOs nanocapsules.

Does dutasteride reduce the bleeding in transurethral resection of the prostate in patients on antiplatelet drugs?

Background: The aim of this study was to assess the effect of a 4-week dutasteride treatment on reducing the intraoperative and postoperative bleeding, as well as the amount and duration of irrigation required to clear the urine after transurethral resection of the prostate (TURP) ≥50 g in men receiving the antiplatelet drug (APD). Materials and methods: This double-blind randomized clinical trial included patients with a prostate size ≥50 g who were indicated for TURP and were already receiving APD. The study was conducted in the Urology Department of Cairo University over a 12-month period. Routine preoperative laboratory investigations were performed in all patients. Moreover, baseline prostate size, serum prostate-specific antigen level, and International Prostate Symptom Score were estimated. The patients were randomly divided into 2 equal groups (groups A and B). Group A, the dutasteride group, received dutasteride (0.5 mg) once daily for 4 weeks. Group B, the placebo group, received a placebo capsule once daily for 4 weeks. Both groups underwent bipolar TURP. Fifteen patients were excluded from the study; 9 patients from group A and 6 patients from group B, either due to drug intolerability or loss follow-up. Results: The mean blood loss was insignificant between the 2 groups immediately after and 24 hours after surgery (Δ hemoglobin: 1.41 ± 0.63 g/dL vs. 1.48 ± 0.54 g/dL, 2.12 ± 0.70 g/dL vs. 2.31 ± 0.78 g/dL, respectively, p = 0.631, p = 0.333; Δ hematocrit: 2.97% ± 1.51% vs. 3.16% ± 1.36%, 4.96% ± 1.87% vs. 5.73% ± 4.39%, respectively, p = 0.610, p = 0.380). However, there were significant differences in duration of indwelling urethral catheter (5.10 ± 0.55 days vs. 5.80 ± 1.79 days, p = 0.048), duration of bladder irrigation (13.60 ± 2.85 hours vs. 16.33 ± 6.62 hours, p = 0.044), and the amount of saline used for bladder irrigation (11.03 ± 2.30 L vs. 13.87 ± 6.13 L, p = 0.046) between group A and group B. respectively. Conclusions: Treatment with dutasteride for 4 weeks before TURP in men receiving APD did not significantly reduce intraoperative or postoperative bleeding after TURP but could significantly reduce the duration of indwelling catheter placement, as well as the duration and amount of saline irrigation.

Overview of Nanocosmetics with Emphasis on those Incorporating Natural Extracts.

The cosmetic industry is rapidly rising worldwide. To overcome certain deficiencies of conventional cosmetics, nanomaterials have been introduced to formulations of nails, lips, hair, and skin for treating/alleviating hyperpigmentation, hair loss, acne, dandruff, wrinkles, photoaging, etc. Innovative nanocarrier materials applied in the cosmetic sector for carrying the active ingredients include niosomes, fullerenes, liposomes, carbon nanotubes, and nanoemulsions. These exhibit several advantages, such as elevated stability, augmented skin penetration, specific site targeting, and sustained release of active contents. Nevertheless, continuous exposure to nanomaterials in cosmetics may pose some health hazards. This review features the different new nanocarriers applied for delivering cosmetics, their positive impacts and shortcomings, currently marketed nanocosmetic formulations, and their possible toxic effects. The role of natural ingredients, including vegetable oils, seed oils, essential oils, fats, and plant extracts, in the formulation of nanocosmetics is also reviewed. This review also discusses the current trend of green cosmetics and cosmetic regulations in selected countries.

Rare anatomical variants encountered during laparoscopic cholecystectomy in low resource conditions and the convenient concept of the safe zone of dissection: a prospective observational study at a single center.

Purpose: The severity of surrounding adhesions, anomalous anatomy, and technical issues are the main factors that complicate cholecystectomy. This study focused on determining the types and frequency of laparoscopic anatomical variations found during laparoscopic cholecystectomy in our limited-resources condition and on defining the safe zone of dissection. Methods: This prospective study was conducted at a single center in Aden, Yemen from 2012 to 2019. A total of 375 patients, comprising 355 females (94.7%) and 20 males (5.3%), presented with symptomatic gallbladders and underwent standard four-port laparoscopic cholecystectomy. The regional laparoscopic variations were evaluated and recorded. Results: Of the 375 patients, 26 (6.9%) had laparoscopic anatomical variations, of whom 19 (73.1%) had vascular variations and seven (26.9%) had ductal variations. The anatomical variations included the following: double cystic artery of separated origin, seven cases (26.9%); Moynihan's hump, six (23.1%); double cystic artery of single origin, four (15.4%); thin long cystic duct, four (15.4%); subvesical duct, three (11.5%); and cystic artery hocking the cystic duct, two (7.7%). Conclusion: Biliary anatomical variations can be expected in any dissected zone. Most of the detected variants were associated with the cystic artery. An overlooked accessory cysto-biliary communication can cause complicated biliary leakage. A surgeon's skills and knowledge of laparoscopic anatomical variants are essential for performing a safe laparoscopic cholecystectomy.

Theoretical study of the antioxidant mechanism and structure-activity relationships of 1,3,4-oxadiazol-2-ylthieno[2,3-d]pyrimidin-4-amine derivatives: a computational approach.

A theoretical thermodynamic study was conducted to investigate the antioxidant activity and mechanism of 1,3,4-oxadiazol-2-ylthieno[2,3-d]pyrimidin-4-amine derivatives (OTP) using a Density Functional Theory (DFT) approach. The study assessed how solvent environments influence the antioxidant properties of these derivatives. With the increasing prevalence of diseases linked to oxidative stress, such as cancer and cardiovascular diseases, antioxidants are crucial in mitigating the damage caused by free radicals. Previous research has demonstrated the remarkable scavenging abilities of 1,3,4-oxadiazole derivatives, prompting this investigation into their potential using computational methods. DFT calculations were employed to analyze key parameters, including bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), and electron transfer enthalpy (ETE), to delineate the antioxidant mechanisms of these compounds. Our findings indicate that specific electron-donating groups such as amine on the phenyl rings significantly enhance the antioxidant activities of these derivatives. The study also integrates global and local reactivity descriptors, such as Fukui functions and HOMO-LUMO energies, to predict the stability and reactivity of these molecules, providing insights into their potential as effective synthetic antioxidants in pharmaceutical applications.

S-Alkylated quinazolin-4(3H)-ones as dual EGFR/VEGFR-2 kinases inhibitors: design, synthesis, anticancer evaluation and docking study.

Dual targeting by a single molecule has emerged as a promising strategy for fighting cancer. In this study, a new set of 2-thioquinazolin-4(3H)-ones as potential anti-cancer surrogates endowed with dual EGFR/VEGFR-2 kinases inhibitory activities were synthesized. The anti-tumor potency of the newly synthesized candidates 4-27 was evaluated against a panel of four cancer cell lines. The prepared candidates 4-27 showed comparable activity to that of the standard drug sorafenib. For instance, compound 4 (IC50 = 1.50-5.86 µM) and compound 20 (IC50 = 4.42-6.39 µM) displayed superior potencies against all cell lines compared to sorafenib (IC50 = 5.47-7.26 µM). Dual EGFR/VEGFR-2 inhibitory activities of the most active analogues (4, 11, and 20) were investigated. Compound 4 showed comparable EGFR/VEGFR-2 inhibitory activity to the used control drugs. Flow cytometric analysis indicates that the most potent analogue 4 stopped the cell cycle at the G1 phase and induced 46.53% total apoptosis in HCT-116 cells that was much more powerful than the untreated cells with 2.15% apoptosis. Molecular docking and dynamic simulations of 4, 11, and 20 with EGFR and VEGFR-2 were performed to examine the binding mode and interaction within the enzyme binding pockets.

BRCA1/2 mutations and outcomes among Middle Eastern patients with early-onset breast cancer in Oman.

BACKGROUND: High prevalence of early-onset breast cancer (EOBC) has been reported in Middle Eastern populations. For example, in Oman more than 50% of patients with breast cancer (BC) are under age 45 at diagnosis. Causes for this high incidence are unknown. Germline BRCA gene mutations have been associated with EOBC, however, prevalence of these mutations and how they relate to EOBC in Oman has not been assessed. PATIENTS AND METHODS: Clinical data were collected for patients with BC treated at Royal Hospital, Oman between 2010 and 2022. Germline BRCA1/2 gene mutations were identified using sequencing and MLPA. Correlation and Kaplan-Meier survival analyses were performed to test relationships among clinico-pathological features, gene mutations, and outcomes. RESULTS: Total of 1336 Middle Eastern patients with BC were included; 611 were aged <45 at diagnosis (45.7%). No significant correlation was found between BRCA1/2 mutation status and EOBC (P = .229), and the majority of EOBC cases had no family history of BC. EOBC tumors did, however, differ in clinicopathological features; EOBCs were significantly larger (P < .0001), of higher grade (P < .0001), and included more HER2-enriched, and triple negative subtypes (P = .018) compared with later onset cases. Accordingly, survival analyses revealed that EOBC had significantly worse disease-free survival (P = .002). BRCA gene variants showed a distinct range of mutations including, in BRCA2, 3 previously unreported mutations and 4 potential founder recurrent mutations. CONCLUSION: Our findings showed that germline BRCA1/2 mutations were not over-represented in EOBC cases in Oman, and therefore are unlikely to be responsible for high EOBC rates.

Assessing the antiviral activity of antimicrobial peptides Caerin1.1 against PRRSV in Vitro and in Vivo.

The Porcine reproductive and respiratory syndrome (PRRS) causes severe financial losses to the global swine industry. Due to continuous virus evolution, the protection against the PRRS provided by current vaccines is limited. In order to find new antiviral strategies, this study investigated the antiviral potential of antimicrobial peptides (AMPs) against PRRSV. Given the diversity of PRRSV strains and the limited effectiveness of existing vaccines in controlling PRRSV, this study evaluated the inhibitory effects of KLAK, Cecropin B, Piscidin1, and Caerin1.1 on 3 strains of PRRSV (lineage 5 classical strain, lineage 8 highly pathogenic strain, and lineage 1 NADC30-like strain). Caerin1.1 exhibited significant dose-dependent antiviral activity, with an effective concentration (EC50) of 7.5 µM. Caerin1.1 effectively inhibited PRRSV replication when added before or in early infection but showed reduced effectiveness when added in late infection, indicating its potential involvement in targeting early transcription mechanisms of viral RNA polymerase and significantly upregulating cytokine gene expression. In the NADC30 strain-based animal infection model, Caerin1.1 treatment significantly reduced lung viral loads and inflammation in the lungs of PRRSV-infected pigs, with a mortality rate of 0 % (0/5) in the treated group compared to 66.67 % (4/6) in the untreated group, indicating a reduction in the mortality rate. Additionally, compared with the untreated group, the Caerin1.1-treated group showed significant improvements, such as lighter fever, more daily weight gain, less clinical symptoms, less viral load in blood, and less virus oral shedding (P < 0.05). These findings reveal the potential of antimicrobial peptides as PRRSV therapeutic agents and suggest that Caerin1.1 is a promising candidate for a novel anti-PRRSV drug.