Engineering synthetic agonists for targeted activation of Notch signaling.

Notch signaling regulates cell fate decisions and has context-dependent tumorigenic or tumor suppressor functions. Although there are several classes of Notch inhibitors, the mechanical force requirement for Notch receptor activation has hindered attempts to generate soluble agonists. To address this problem, we engineered synthetic Notch agonist (SNAG) proteins by tethering affinity-matured Notch ligands to antibodies or cytokines that internalize their targets. This bispecific format enables SNAGs to 'pull' on mechanosensitive Notch receptors, triggering their activation in the presence of a desired biomarker. We successfully developed SNAGs targeting six independent surface markers, including the tumor antigens PDL1, CD19, and HER2, and the immunostimulatory receptor CD40. SNAGs targeting CD40 increase expansion of central memory γδ T cells from peripheral blood, highlighting their potential to improve the phenotype and yield of low-abundance T cell subsets. These insights have broad implications for the pharmacological activation of mechanoreceptors and will expand our ability to modulate Notch signaling in biotechnology.

Antioxidant, antibacterial, and molecular docking of methyl ferulate and oleic acid produced by Aspergillus pseudodeflectus AUMC 15761 utilizing wheat bran.

Secondary metabolites (SMs) are the primary source of therapeutics and lead chemicals in medicine. They have been especially important in the creation of effective cures for conditions such as cancer, malaria, bacterial and fungal infections, neurological and cardiovascular problems, and autoimmune illnesses. In the present study, Aspergillus pseudodeflectus AUMC 15761 was demonstrated to use wheat bran in solid state fermentation (SSF) at optimum conditions (pH 7.0 at 30 °C after 10 days of incubation and using sodium nitrate as a nitrogen source) to produce methyl ferulate and oleic acid with significant antioxidant and antibacterial properties. Gas chromatography-mass spectrometry (GC-MS) analysis of the crude methanol extract revealed eleven peaks that indicated the most common chemical components. Purification of methyl ferulate and oleic acid was carried out by column chromatography, and both compounds were identified by in-depth spectroscopic analysis, including 1D and 2D NMR and HR-ESI-MS. DPPH activity increased as the sample concentration increased. IC50 values of both compounds obtained were 73.213 ± 11.20 and 104.178 ± 9.53 µM, respectively. Also, the MIC value for methyl ferulate against Bacillus subtilis and Staphylococcus aureus was 0.31 mg/mL, while the corresponding MIC values for oleic acid were 1.25 mg/mL and 0.62 mg/mL for both bacterial strains, respectively. Molecular modeling calculations were carried out to reveal the binding mode of methyl ferulate and oleic acid within the binding site of the crucial proteins of Staphylococcus aureus. The docking results were found to be well correlated with the experimental data.

Effect of combined Kinesiotaping and resistive exercise on muscle strength and quality of life in breast cancer survivors: a randomized clinical trial.

BACKGROUND: Breast cancer (BC) and its treatment affect women's tissue architecture and physiology, which leads to impaired muscle strength and joint dysfunction, affecting quality of life (QOL). Most evidence has focused on exercises; however, due to the complexity and heterogeneity of patients' rehabilitation needs, further research is required to investigate more adjunctive methods to help optimal rehabilitation according to patients' needs, preferences, and effective interventions. METHODS: This study aimed to determine the effect of Kinesiotaping (KT) combined with resistive exercise on muscle strength and QOL in breast cancer survivors (BCS). Forty premenopausal BCS treated with chemotherapy postmastectomy participated in this study. Their age ranged from 40 to 55 years, and their body mass index (BMI) was 25-29.9 kg/m2. They were randomly distributed into two equal groups. The control group received resistive exercise two times/week for 12 weeks, while the study group received resistive exercise and KT applied to the lower limbs. Hip, knee, and ankle muscle strength were measured using a hand-held dynamometer, and QOL was evaluated using 36-Item Short Form (SF-36) before and after treatment. RESULTS: Both groups showed a significant increase (p = 0.0001) in the strength of hip flexors, knee extensors, flexors, ankle plantar flexors, and dorsiflexors, as well as SF-36 score after treatment. However, the study group showed a more significant increase in strength of hip flexors (p = 0.005), knee extensors (p = 0.01) and flexors (p = 0.02), ankle plantar flexors (p = 0.01), and dorsiflexors (p = 0.01), as well as SF-36 score (p = 0.006) than the control group. CONCLUSIONS: KT plus resistive exercise is more effective than exercise alone for improving muscle strength and QOL in BCS. So, the KT can be recommended as a non-invasive, adjunctive method added to the protocol therapy for BCS to help better outcomes during the rehabilitation period.

Tissue Inhibitor Of Metalloproteinase 3 As A Potential Staging Biomarker In Hepatocellular Carcinoma.

Objectives: To assessthe potential role of tissue inhibitor of metalloproteinase 3 as a staging marker of hepatocellular carcinoma. Method: The experimental study was conducted at Faculty of Pharmacy, Kafrelsheikh University, Egypt, from December 2020 to March 2022 after approval from the Faculty of Pharmacy, Kafrelsheikh University, Egypt, and comprised male albino rats. The subjects were divided into 4 groups. The control group was administrated a single intraperitoneal injection of normal saline, while the other groups were generated post-induction of hepatocellular carcinoma. The induction was done by injecting rats intraperitoneally with a single dose of 200mg/kg diethyl nitrosamine, followed by the administration of 0.05% phenobarbital sodium in drinking water daily. Rats were euthanised at 8, 16 and 24 weeks after the injection to obtain three groups related to the 3 stages of hepatocellular carcinoma. Serum was used for measuring the alpha protein level. Liver homogenates were used for the assessment of the hepatic tissue inhibitor of metalloproteinase 3 expression, B-cell lymphoma 2-associated X protein expression, and the hepatic content of matrix metalloproteinase -9 and cyclin D1. Data was analysed using Graph Prism 8. RESULTS: Of the 24 rats with weight range 120-130g, 6(25%) were in each of the 4 groups. The relative protein and messenger ribonucleic acid tissue inhibitor of metalloproteinase 3 expressions were significantly decreased in the intervention groups compared to the control group, with more decline as the hepatocellular carcinoma stage increased. The matrix metalloproteinase -9 and cyclin D1 concentrations and the relative hepatic protein Ki67 expression were significantly raised in the intervention groups compared to the control group (p<0.05). The relative expression of hepatic B-cell lymphoma 2-associated X protein was markedly decreased in the intervention groups compared to the control group (p<0.05). CONCLUSIONS: Tissue inhibitor of metalloproteinase 3 might be a promising diagnostic and staging biomarker in hepatocellular carcinoma.

Immune Response And Pathophysiological Features Of Klebsiella Pneumoniae In Mice.

Objectives: To assess the bacterial colonisation of mice organs and faeces infected with 3 strains of Klebsiella pneumoniae, to measure levels of tumour necrosisfactor-alpha, tumour necrosisfactor-beta and interleukin-6 in mice serum, and to evaluate immune response of mice infected with Klebsiella pneumoniae. Method: The animalstudy was conducted at Kafreslsheikh University, Egypt, in 2021, and comprised mice 5-7 weeks old who were infected with 3 strains of Klebsiella pneumoniae; K80uge+ (uri, kfu+, mrkD+; K68 gyrA+(gyrase A), mrkD+; and K84 uge+, kfu+, mrkD+". They were monitored for 14 days. The bacterial colonisation of mice livers, lungs, spleens and faeces were determined using culture on MacConkey agar. The percentage of neutrophils detected as cluster of differentiation 11b+ and cluster of differentiation 45+ in the mice serum was determined by flow cytometry. Levels of tumour necrosis factor-alpha and tumour necrosis factor-beta were measured using enzyme-linked immunosorbent assay. RESULTS: There were 4 sets of female mice [1 control and 3 infected groups for which 3 K. pneumoniae strains (K80 uge+, kfu+, mrkD+; K68 gyrA+, mrkD+; and K84 "uge+, kfu+, mrkD+)] weighing 13-24gm was used. Colonisation of mice organs and faeces was high after 24 hours then declined rapidly after 3 days, 10 days and 14 days in case of infection with capsulated and non-capsulated strains of bacteria. Livers, lungs and spleens showed maximum inflammation after 24 hours, then declined rapidly. Both cytokine production and organ inflammation increased after one day of infection. There was a significant correlation between the produced cytokines and histopathological changesin liver, lung and spleen. The neutrophils increase in case of infection with K84 and K80 was more than non-capsulated K68. CONCLUSIONS: Neutrophils were found to play an important role in the clearance and treatment of Klebsiella pneumoniae.

Synthesis, Physicochemical Characterization, Biological Assessment, and Molecular Docking Study of Some Metal Complexes of Alloxan and Ninhydrin as Alterdentate Ligands.

A series of transition metal complexes of alloxan monohydrate (H2L1) and ninhydrin (H2L2) have been prepared where metal ions are Fe(III), Co(II), Ni(II), Cu(II), Zr(IV), and Mo(VI). Different microanalytical techniques, spectroscopic methods, and magnetic studies were applied to assign the mode of bonding and elucidate the structure of complexes. All solid complexes are of 1:1 (M:L) stoichiometry and octahedral geometry except nickel (II) complexes exist in a tetrahedral geometry. FTIR spectral interpretation reveals that HL1 coordinates to the central metal ion in a bidentate ON pattern, whereas HL2 behaves as an alterdentate ligand through hydroxyl oxygen and carbonyl oxygen either C(1) = O or C(3) = O. The thermal behavior of some complexes was followed up to 700 °C by different techniques (TGA, DTA, and DSC) where decomposition stages progress in complicated mechanisms and are ended by the formation of metal oxide residue. Besides, biological screening involving antioxidant, antibacterial, and antifungal for ligands and some of their complexes was done. Moreover, four examined metal complexes displayed anticancer activity against hepatocellular carcinoma cells (HepG-2) but to different degrees. According to the IC50 values, Cu-ninhydrin complex, [Cu(HL2)(H2O)4].Cl has a better potency impact in comparison with cisplatin which was used as a reference control. This is in harmony with the molecular docking simulation outcomes that predicted a good binding propensity of the Cu-ninhydrin complex with hepatocellular carcinoma protein (2jrs). Therefore, the Cu-ninhydrin complex should be deemed as a potential chemotherapeutic agent for hepatocellular cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s10904-023-02661-5.

Comparative Real Life Egyptian Experience of the Combination of Sofosbuvir Plus Daclatasvir or Simeprevir for 12 Weeks in Naïve Cirrhotic Patients Infected with HCV Genotype 4.

BACKGROUND: Chronic infection with HCV is progressive worldwide health problem and the core reason for liver cirrhosis, portal hypertension, or hepatocellular carcinoma. HCV-G4 represents the most common threat to transplantation of the liver in Egypt. New interferon-free regimens have been started consuming direct-acting antiviral oral tablets for HCV cure. OBJECTIVES: In the current study, comparing the safety and efficacy of DAAs combination regimens including sofosbuvir with daclatasvir or sofosbuvir with simeprevir plus ribavirin for naïve cirrhotic Egyptian patients infected with HCV-G4 was our main goal. METHODS: We recruited 150 naïve cirrhotic HCV patients from the Tropical patients' clinic at Fayoum General Hospital. They were classified randomly into two groups, group one (n=75 patients) were administrated Sofosbuvir plus simeprevir (400 mg and 150 mg once daily respectively ) for twelve weeks, and group two (n=75 patients) were administrated Sofosbuvir plus Daclatasvir (400 mg and 60 mg once daily respectively) with ribavirin (1-1.2 gm daily weight-based) for twelve weeks. Clinical follow-up, laboratory investigations, and viral PCR were measured to detect treatment efficacy, safety, and any adverse events. RESULTS: Sustained virological response rates (SVR12) were 92%and 90.7% in the first and second groups, respectively. The major unfavorable events were fatigue, arthralgia, and weight loss without statistically meaningful differences between study groups. However, anemia and headache were significantly widespread in the second group (P=0.0161 and 0.0495, respectively). We observed four patients with photosensitivity in group I and not observed in the second group. CONCLUSION: The current study revealed that DAAs are safe and effective in the cure of naïve cirrhotic patients chronically infected by HCV-G4 with better results in those treated with sofosbuvir plus simeprevir regimen.

Pentoxifylline as an adjunctive in treatment of negative symptoms in chronic schizophrenia: A double-blind, randomized, placebo-controlled trial.

AIM: The aim of this study was to explore the effectiveness and safety of pentoxifylline as an adjuvant to risperidone in mitigating the negative symptoms in patients with chronic schizophrenia. METHODS: In this randomized, placebo-controlled study, eighty outpatients with chronic schizophrenia were given risperidone for 8 weeks along with either pentoxifylline or a placebo. The positive and negative syndrome scale (PANSS) was used to assess patients at the start of the trial, as well as at 2, 4, 6, and 8 weeks. Pre- and posttreatment serum levels of cAMP, TNF-α-, and IL-6 were measured. RESULTS: The pentoxifylline group revealed a significant effect for time-treatment interaction on PANSS-negative subscale scores (p < 0.001), PANSS general psychopathology subscale scores (p < 0.001), and PANSS total scores (p < 0.001), but not on PANSS-positive subscale scores (p = 0.169). Additionally, when compared to the placebo group, the pentoxifylline group demonstrated a statistically significant increase in cAMP serum level and a statistically significant decrease in TNF-α and IL-6 serum levels. CONCLUSION: Pentoxifylline adjunctive therapy with risperidone for 8 weeks was found to be promising in mitigating the negative symptoms in patients with chronic schizophrenia. TRIAL REGISTRATION NUMBER: NCT04094207.

Designing metal chelates of halogenated sulfonamide Schiff bases as potent nonplatinum anticancer drugs using spectroscopic, molecular docking and biological studies.

In this contribution, five Ni(II) complexes have been synthesized from sulfonamide-based Schiff bases (SB1-SB5) that comprise bromo or iodo substituents in the salicylidene moiety. The chemical structures of these compounds were extensively elucidated by different analytical and physicochemical studies. All ligands act as bidentate chelators with ON binding mode yielding octahedral, square planar, or tetrahedral geometries. The phenolic OH at δ 12.80 ppm in the free Schiff base SB2 vanishes in the 1H NMRspectrum of diamagnetic complex [Ni(SB2-H)2] favoring the OH deprotonation prior to the chelation with Ni(II) ion. The appearance of twin molecular ion peaks ([M - 1]+ and [M + 1]+) is due to the presence of bromine isotopes (79Br and 81Br) in the mass spectra of most cases. Also, the thermal decomposition stages of all complexes confirmed their high thermal stability and ended with the formation of NiO residue of mass 6.42% to 14.18%. Besides, antimicrobial activity and cytotoxicity of the ligands and some selected complexes were evaluated. Among the ligands, SB4 showed superior antimicrobial efficacy with MIC values of 0.46, 7.54, and 0.95 µM against B. subtilis, E. coli, and A. fumigatus strains, respectively. The consortium of different substituents as two bromine atoms either at positions 3 and/or 5 on the phenyl ring and a thiazole ring is one of the reasons behind the recorded optimal activity. Moreover, there is a good correlation between the cytotoxicity screening (IC50) and molecular docking simulation outcomes that predicted a strong binding of SB2 (16.0 µM), SB4 (18.8 µM), and SB5 (6.32 µM) to the breast cancer protein (3s7s). Additionally, [Ni(SB4-H)2] (4.33 µM) has nearly fourfold potency in comparison with cisplatin (19.0 µM) against breast carcinoma cells (MCF-7) and is highly recommended as a promising, potent, as well as low-cost non-platinum antiproliferative agent after further drug authorization processes.

Role of endoscopic ultrasound and cyst fluid tumor markers in diagnosis of pancreatic cystic lesions.

BACKGROUND: Pancreatic cystic lesions (PCLs) are common in clinical practice. The accurate classification and diagnosis of these lesions are crucial to avoid unnecessary treatment of benign lesions and missed opportunities for early treatment of potentially malignant lesions. AIM: To evaluate the role of cyst fluid analysis of different tumor markers such as cancer antigens [e.g., cancer antigen (CA)19-9, CA72-4], carcinoembryonic antigen (CEA), serine protease inhibitor Kazal-type 1 (SPINK1), interleukin 1 beta (IL1-ß), vascular endothelial growth factor A (VEGF-A), and prostaglandin E2 (PGE2)], amylase, and mucin stain in diagnosing pancreatic cysts and differentiating malignant from benign lesions. METHODS: This study included 76 patients diagnosed with PCLs using different imaging modalities. All patients underwent endoscopic ultrasound (EUS) and EUS-fine needle aspiration (EUS-FNA) for characterization and sampling of different PCLs. RESULTS: The mean age of studied patients was 47.4 ± 11.4 years, with a slight female predominance (59.2%). Mucin stain showed high statistical significance in predicting malignancy with a sensitivity of 87.1% and specificity of 95.56%. It also showed a positive predictive value and negative predictive value of 93.1% and 91.49%, respectively (P < 0.001). We found that positive mucin stain, cyst fluid glucose, SPINK1, amylase, and CEA levels had high statistical significance (P < 0.0001). In contrast, IL-1ß, CA 72-4, VEGF-A, VEGFR2, and PGE2 did not show any statistical significance. Univariate regression analysis for prediction of malignancy in PCLs showed a statistically significant positive correlation with mural nodules, lymph nodes, cyst diameter, mucin stain, and cyst fluid CEA. Meanwhile, logistic multivariable regression analysis proved that mural nodules, mucin stain, and SPINK1 were independent predictors of malignancy in cystic pancreatic lesions. CONCLUSION: EUS examination of cyst morphology with cytopathological analysis and cyst fluid analysis could improve the differentiation between malignant and benign pancreatic cysts. Also, CEA, glucose, and SPINK1 could be used as promising markers to predict malignant pancreatic cysts.

Value of pancreatic cyst fluid SPINK1 and glucose in differentiating potentially malignant cysts from those of benign nature: A prospective cohort study.

Background: Diagnosis of malignant pancreatic cystic lesions (PCLs) is challenging as there is no investigation that offers both high diagnostic sensitivity and specificity for a definite diagnosis. Accurate diagnosis of cyst type is vital in order to not miss opportunities for early treatment of potentially malignant lesions and to avoid unnecessary surgeries. Serine protease inhibitor Kazal type I (SPINK1) and glucose are promising cyst fluid markers for differentiation of mucinous from non-mucinous cysts. We aim to validate the value of SPINK1 and glucose in detecting potentially malignant PCLs. Methods: A prospective study was conducted on 80 patients presenting with PCLs. Endoscopic ultrasound (EUS) evaluation of detailed cyst morphology and EUS with fine needle aspiration (FNA) were done. Fluid analysis for carcinoembryonic antigen (CEA), glucose and SPINK1 and cytopathology were done. We compared these data with the final diagnosis based on cytopathological and postoperative histopathological examination. Results: Cyst fluid SPINK1 was significantly higher in malignant or potentially malignant cysts compared to benign cysts (0.91 vs 0.47 ng/ml; P = 0.001). Also, glucose was significantly lower in malignant or potentially malignant cysts compared to benign cysts (21.5 vs 68.5 mg/dl; P = 0.0001). Glucose and SPINK1 had the best sensitivity and specificity for differentiating mucinous from non-mucinous cysts with 84.78% and 73.53% (AUC 0.76; 95% CI [0.65-0.88]; cutoff value = 42 mg/dl), and 70.59% and 65.22% (AUC 0.72; 95% CI [0.64-0.86]; cutoff value = 0.58 ug/L) respectively. CEA level >192 ng/ml, high SPINK1 level and lymph node enlargement were the independent predictors of malignant cysts. Conclusion: Cyst fluid SPINK1 and glucose are promising diagnostic markers for the diagnosis of potentially malignant PCLs.

Restriction Checkpoint Controls Bradyzoite Development in Toxoplasma gondii.

Human toxoplasmosis is a life-threatening disease caused by the apicomplexan parasite Toxoplasma gondii. Rapid replication of the tachyzoite is associated with symptomatic disease, while suppressed division of the bradyzoite is responsible for chronic disease. Here, we identified the T. gondii cell cycle mechanism, the G1 restriction checkpoint (R-point), that operates the switch between parasite growth and differentiation. Apicomplexans lack conventional R-point regulators, suggesting adaptation of alternative factors. We showed that Cdk-related G1 kinase TgCrk2 forms alternative complexes with atypical cyclins (TgCycP1, TgCycP2, and TgCyc5) in the rapidly dividing developmentally incompetent RH and slower dividing developmentally competent ME49 tachyzoites and bradyzoites. Examination of cyclins verified the correlation of cyclin expression with growth dependence and development capacity of RH and ME49 strains. We demonstrated that rapidly dividing RH tachyzoites were dependent on TgCycP1 expression, which interfered with bradyzoite differentiation. Using the conditional knockdown model, we established that TgCycP2 regulated G1 duration in the developmentally competent ME49 tachyzoites but not in the developmentally incompetent RH tachyzoites. We tested the functions of TgCycP2 and TgCyc5 in alkaline induced and spontaneous bradyzoite differentiation (rat embryonic brain cells) models. Based on functional and global gene expression analyses, we determined that TgCycP2 also regulated bradyzoite replication, while signal-induced TgCyc5 was critical for efficient tissue cyst maturation. In conclusion, we identified the central machinery of the T. gondii restriction checkpoint comprised of TgCrk2 kinase and three atypical T. gondii cyclins and demonstrated the independent roles of TgCycP1, TgCycP2, and TgCyc5 in parasite growth and development. IMPORTANCE Toxoplasma gondii is a virulent and abundant human pathogen that puts millions of silently infected people at risk of reactivation of the chronic disease. Encysted bradyzoites formed during the chronic stage are resistant to current therapies. Therefore, insights into the mechanism of tissue cyst formation and reactivation are major areas of investigation. The fact that rapidly dividing parasites differentiate poorly strongly suggests that there is a threshold of replication rate that must be crossed to be considered for differentiation. We discovered a cell cycle mechanism that controls the T. gondii growth-rest switch involved in the conversion of dividing tachyzoites into largely quiescent bradyzoites. This switch operates the T. gondii restriction checkpoint using a set of atypical and parasite-specific regulators. Importantly, the novel T. gondii R-point network was not present in the parasite's human and animal hosts, offering a wealth of new and parasite-specific drug targets to explore in the future.

Iron Oxide Nanoparticles-Plant Insignia Synthesis with Favorable Biomedical Activities and Less Toxicity, in the "Era of the-Green": A Systematic Review.

In the era of favoring environment-friendly approaches for pharmaceutical synthesis, "green synthesis" is expanding. Green-based nanomedicine (NM), being less toxic and if having biomedical acceptable activities, thence, the chemical methods of synthesis are to be replaced by plants for reductive synthesis. Iron oxide nanoparticles (IONPs) exhibited remarkable anti-microbial and anti-cancer properties, besides being a drug delivery tool. However, owing to limitations related to the chemical synthetic method, plant-mediated green synthesis has been recognized as a promising alternative synthetic method. This systematic review (SR) is addressing plant-based IONPs green synthesis, characteristics, and toxicity studies as well as their potential biomedical applications. Furthermore, the plant-based green-synthesized IONPs in comparison to nanoparticles (NPs) synthesized via other conventional methods, characteristics, and efficacy or toxicity profiles would be mentioned (if available). Search strategy design utilized electronic databases including Science Direct, PubMed, and Google Scholar search. Selection criteria included recent clinical studies, available in the English language, published till PROSPERO registration. After screening articles obtained by first electronic database search, by title, abstract and applying the PICO criteria, the search results yielded a total of 453 articles. After further full text filtrations only 48 articles were included. In conclusion, the current SR emphasizes the perspective of the IONPs plant-mediated green synthesis advantage(s) when utilized in the biomedical pharmaceutical field, with less toxicity.

Host Resistance to Uromyces appendiculatus in Common Bean Genotypes.

Rust, induced by the fungus Uromyces appendiculatus, is one of the most serious bean diseases. The involved mechanisms in rust resistance were evaluated in 10 common bean genotypes during the 2019/2020 and 2020/2021 growing seasons. The disease parameters such as final rust severity (FRS%), area under the disease progress curve (AUDPC) and disease increase rate (r-value) were lower in the resistant genotypes than in highly susceptible genotypes. Biochemical compounds such as total phenols and the activity of antioxidant enzymes such as catalase, peroxidase and polyphenol oxidase were increased in the resistant genotypes compared to susceptible genotypes. In the resistance genotypes, the levels of oxidative stress markers such as hydrogen peroxide (H2O2) and superoxide (O2•-) increased dramatically after infection. The electrolyte leakage percentage (EL%), was found to be much greater in susceptible genotypes than resistant genotypes. The resistant gene SA14, which was found in genotypes Nebraska and Calypso at 800 bp, had an adequate level of resistance to bean rust with high grain yield potential. After infection, the transcriptions levels of 1,3-D-glucanases and phenylalanine ammonia lyase) were higher in the resistant genotypes than susceptible genotypes. In conclusion, the resistant genotypes successfully displayed desirable agronomic traits and promising expectations in breeding programs for improving management strategies of common bean rust disease. The resistance was mediated by antioxidant enzymes, phenolic compounds, and defense gene expressions, as well as the resistant gene SA14.

Identification of SARS-CoV-2 Spike Palmitoylation Inhibitors That Results in Release of Attenuated Virus with Reduced Infectivity.

The spike proteins of enveloped viruses are transmembrane glycoproteins that typically undergo post-translational attachment of palmitate on cysteine residues on the cytoplasmic facing tail of the protein. The role of spike protein palmitoylation in virus biogenesis and infectivity is being actively studied as a potential target of novel antivirals. Here, we report that palmitoylation of the first five cysteine residues of the C-terminal cysteine-rich domain of the SARS-CoV-2 S protein are indispensable for infection, and palmitoylation-deficient spike mutants are defective in membrane fusion. The DHHC9 palmitoyltransferase interacts with and palmitoylates the spike protein in the ER and Golgi and knockdown of DHHC9 results in reduced fusion and infection of SARS-CoV-2. Two bis-piperazine backbone-based DHHC9 inhibitors inhibit SARS-CoV-2 S protein palmitoylation and the resulting progeny virion particles released are defective in fusion and infection. This establishes these palmitoyltransferase inhibitors as potential new intervention strategies against SARS-CoV-2.

Role of serum cystatin C in the prediction of acute kidney injury following pediatric cardiac surgeries: A single center experience.

Intense contemporary research is directed towards validating novel biomarkers to predict acute kidney injury (AKI) in children undergoing cardiothoracic surgeries. We aimed to evaluate the role of cystatin C in early prediction of AKI following cardiac surgery in children with congenital heart disease. Prospective observational cohort study was conducted on 40 children with congenital heart disease undergoing cardiac surgery. 40 healthy children with matched age and sex were enrolled as a control group. Children were subjected to physical examination, routine blood tests, echocardiography, and measurement of plasma cystatin C level on different occasions. The median age of the patients was 3.65 years, a range from 1 to 5 years with no significant difference regarding the age and sex of cases and control groups. The mean serum cystatin C level in patients was 0.75 ±â€…0.15, 1.35 ±â€…0.34 and 1.21 ±â€…0.38 mg/dL (preoperative, at 6 h and at 24 h postoperative, respectively) with statistically significant difference P < .05. 30% of the patients developed postoperative AKI with significantly higher serum cystatin C at 6 hours postoperative >1.33 mg/dL compared to preoperative level p P < .05. Serum cystatin C level was positively correlated with cardiac bypass time, ischemic time and length of hospital stay at 6 hours postoperative. Serum cystatin C is a sensitive marker for early detection of AKI following cardiac surgery in children with congenital heart disease and it was positively correlated with cardiac bypass time, ischemic time and length of hospital stay.

Ultrasound detected synovitis, tenosynovitis and erosions in hand and wrist joints: a comparative study between rheumatoid and psoriatic arthritis.

OBJECTIVES: Musculoskeletal ultrasound (MSUS) has been introduced as a valuable simple imaging tool for arthritis. The objective was to assess the role of ultrasound (US) in the differential diagnosis between rheumatoid arthritis (RA) and psoriatic arthritis (PsA) at the wrist and hand joints and tendons. MATERIAL AND METHODS: Thirty-five patients (20 RA and 15 PsA) with symptomatic involvement of at least one of the hand and/or wrist joints for > 6 weeks were included. Bilateral wrists (distal radioulnar, radiocarpal and midcarpal joints), hands (1st-5th metacarpophalangeal [MCP], 2nd-5th proximal interphalangeal [PIP] and 1st-5th distal interphalangeal [DIP] joints), flexor tendons and extensor compartments at the level of the wrist joint were examined sonographically. Synovial hypertrophy, joint effusion, erosions and tenosynovitis were diagnosed according to Outcome Measures in Rheumatology definitions. The findings were correlated with clinical, laboratory and disease activity indices. RESULTS: Among 680 and 510 joints examined in RA and PsA respectively, certain US features such as synovitis and erosions at the DIP were exclusively detected in PsA (p < 0.001). Synovitis was frequently detected at the distal radioulnar joints (DRUJ) in RA in comparison to PsA patients (52.5% vs. 26.7% respectively, p = 0.029). Joint effusion was more frequently detected at radiocarpal and midcarpal joints in RA compared to PsA (p = 0.047, 0.039 respectively), whereas erosions were significantly more frequently detected at radiocarpal joints in RA versus PsA patients (45% vs. 20% respectively, p = 0.029). Tenosynovitis was significantly more frequently detected at the extensor tendons in RA and at the flexor tendons in PsA patients (p = 0.021, 0.022 respectively). CONCLUSIONS: There are significant differences in the musculoskeletal US findings of the hand and wrist that joints help to distinguish between RA and PsA.

Heavy Vacuum Gas Oil Upregulates the Rhamnosyltransferases and Quorum Sensing Cascades of Rhamnolipids Biosynthesis in Pseudomonas sp. AK6U.

We followed a comparative approach to investigate how heavy vacuum gas oil (HVGO) affects the expression of genes involved in biosurfactants biosynthesis and the composition of the rhamnolipid congeners in Pseudomonas sp. AK6U. HVGO stimulated biosurfactants production as indicated by the lower surface tension (26 mN/m) and higher yield (7.8 g/L) compared to a glucose culture (49.7 mN/m, 0.305 g/L). Quantitative real-time PCR showed that the biosurfactants production genes rhlA and rhlB were strongly upregulated in the HVGO culture during the early and late exponential growth phases. To the contrary, the rhamnose biosynthesis genes algC, rmlA and rmlC were downregulated in the HVGO culture. Genes of the quorum sensing systems which regulate biosurfactants biosynthesis exhibited a hierarchical expression profile. The lasI gene was strongly upregulated (20-fold) in the HVGO culture during the early log phase, whereas both rhlI and pqsE were upregulated during the late log phase. Rhamnolipid congener analysis using high-performance liquid chromatography-mass spectrometry revealed a much higher proportion (up to 69%) of the high-molecularweight homologue Rha-Rha-C10-C10 in the HVGO culture. The results shed light on the temporal and carbon source-mediated shifts in rhamonlipids' composition and regulation of biosynthesis which can be potentially exploited to produce different rhamnolipid formulations tailored for specific applications.

Long-term clinical outcomes in sustained responders with chronic hepatitis C after treatment with direct-acting antivirals.

OBJECTIVE: Little is known about how the achievement of sustained virological response (SVR) after treatment with direct-antiviral agents (DAAs) affects fibrosis and clinical outcomes in the long term. Our study aimed to evaluate the impact of achieving SVR on long-term changes in fibrosis and clinical outcomes in CHC patients treated with different DAAs-based regimens. METHODS: a prospective, 3-year follow-up study of 113 CHC patients who had achieved SVR after treatment with different DAAs-based regimens between January and June 2015 was conducted. The clinical outcomes of SVR on the biochemical profile, changes in fibrosis, ALBI score and grade and occurrence of liver-related events were analyzed. RESULTS: Overall, liver function parameters and serum alpha-fetoprotein level showed improvement from baseline to SVR12 and remained steady thereafter. Moreover, the ALBI score showed nonsignificant change at baseline to SVR12 (P = 0.2) but it was significantly better at 3-years follow-up than at SVR12 (P = 0.001). Regarding liver stiffness (LS) by transient elastography, a significant decrease in TE values was observed between baseline to SVR12 (P ≤ 0.0001) as well as between SVR12 to 3-years follow-up (P = 0.0005). Stratified by fibrosis stage, patients with advanced fibrosis and cirrhosis showed a more pronounced and significant improvement of LS during follow-up after SVR compared to patients with less advanced fibrosis stage. During the follow-up period, 3 (5.2%) cirrhotic patients developed liver-related events, including 2 (3.4%) patients with de novo HCC and one (1.7%) patient experienced ascites for the first time. CONCLUSION: This 3-year follow-up study provides evidence for the durability of SVR, improvement of liver function parameters and ALBI score and grade in patients with an advanced stage of fibrosis, in particular, and reduction of the clinical events after successful treatment with DAAs.

Serum anandamide level as a potential indicator for nonalcoholic fatty liver disease severity.

INTRODUCTION AND AIM: Nonalcoholic fatty liver disease (NAFLD) is a very common disease, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and is considered the hepatic expression of metabolic syndrome. Liver biopsy is currently considered the gold standard in diagnosis of NAFLD; however, it is an invasive technique and carries many risks. The serum anandamide level is recently discovered to play an important role as the potential indicator for NAFLD severity. The purpose of the study is to determine the association of endocannabinoid metabolite anandamide and NAFLD severity and to investigate its association with anthropometric and metabolic features in NAFLD patients. METHODOLOGY: A case-control study on 36 NAFLD biopsy-proven NAFLD patients and 15 healthy volunteers. They were subjected to full clinical history and examination, laboratory tests, abdominal ultrasound and serological testing of anadamide. RESULTS: The anadamide level was significantly higher among NAFLD subgroups (simple steatosis and NASH) vs. the normal group (1.1, 0.29 vs. 0.2 P value = 0.00085), with cutoff 0.58 in the NASH group (accuracy 89%; sensitivity 66% and specificity 100%) (P value < 0.01). CONCLUSION: Anandamide could be a specific serum marker for NASH and can be used to detect NAFLD severity.