Molecular and structural basis of oligopeptide recognition by the Ami transporter system in pneumococci.

ATP-binding cassette (ABC) transport systems are crucial for bacteria to ensure sufficient uptake of nutrients that are not produced de novo or improve the energy balance. The cell surface of the pathobiont Streptococcus pneumoniae (pneumococcus) is decorated with a substantial array of ABC transporters, critically influencing nasopharyngeal colonization and invasive infections. Given the auxotrophic nature of pneumococci for certain amino acids, the Ami ABC transporter system, orchestrating oligopeptide uptake, becomes indispensable in host compartments lacking amino acids. The system comprises five exposed Oligopeptide Binding Proteins (OBPs) and four proteins building the ABC transporter channel. Here, we present a structural analysis of all the OBPs in this system. Multiple crystallographic structures, capturing both open and closed conformations along with complexes involving chemically synthesized peptides, have been solved at high resolution providing insights into the molecular basis of their diverse peptide specificities. Mass spectrometry analysis of oligopeptides demonstrates the unexpected remarkable promiscuity of some of these proteins when expressed in Escherichia coli, displaying affinity for a wide range of peptides. Finally, a model is proposed for the complete Ami transport system in complex with its various OBPs. We further disclosed, through in silico modelling, some essential structural changes facilitating oligopeptide transport into the cellular cytoplasm. Thus, the structural analysis of the Ami system provides valuable insights into the mechanism and specificity of oligopeptide binding by the different OBPs, shedding light on the intricacies of the uptake mechanism and the in vivo implications for this human pathogen.

Pythium and Globisporangium species associated with cucumber rhizosphere causing damping-off and their effects on cucumber seed decay in Oman.

Pythium sensu lato (s.l.) is a pathogenic oomycete. The present study was conducted to isolate and identify Pythium s.l. species associated with the rhizosphere and roots of greenhouse-growing cucumbers showing damping-off symptoms in 10 Omani governorates (provinces). A total of 166 isolates were recovered from 276 rhizosphere soil and root samples and were identified based on the ribosomal DNA (rDNA) internal transcribed spacer (ITS) region and the cytochrome c oxidase subunit I (COX I) gene region. Pythium aphanidermatum, P. myriotylum, Globisporangium spinosum, Globisporangium sp.1 (isolates Kb003/PySyCu-1 and Kb004/PySyCu-2), and Globisporangium sp.2 (isolate Ib002R) were identified. Among these species, P. aphanidermatum was the most abundant species, represented by 143 isolates (86.1%), followed by G. spinosum with 18 isolates (10.8%), Globisporangium sp.1 and P. myriotylum each with 2 isolates (2.4%), and Globisporangium sp.2 with 1 isolate (0.6%). Pathogenicity tests were also conducted for 38 isolates, including P. aphanidermatum (25), P. myriotylum (2), Globisporangium sp.2 (1), G. spinosum (8), and Globisporangium sp.1 (2). Among the tested isolates, only Globisporangium sp.2 isolate was avirulent, and none of the seeds were rotted at the end of the treatment. However, the other species induced the symptoms of seed decay with the incidence ranged from 86.7 to 100%. Phylogenetic analyses were conducted based on 222 ITS and 53 COX I sequences, and confirmed morphological identification. In addition, the genetic diversity of 93 P. aphanidermatum isolates was assessed via the amplified fragment length polymorphism (AFLP) method. The analysis produced 93 genotypes and 449 polymorphic loci. Pythium aphanidermatum populations were found to have moderate levels of genetic diversity (H = 0.2) and a moderate Shannon information index (I = 0.3793). Analysis of molecular variance (FST = 0.1, P = 0.0) revealed a moderate level of genetic differentiation among P. aphanidermatum isolates between Oman governorates. The sensitivity of 15 P. aphanidermatum isolates was evaluated against hymexazol at different concentrations (10, 100, and 1000 ppm). The results revealed that P. aphanidermatum could grow well at concentrations of up to 100 ppm hymexazol. However, hymexazol at 1000 ppm retarded the growth of P. aphanidermatum. This study showed that P. aphanidermatum is the most prevalent species in greenhouses in Oman and exhibited a moderate level of genetic diversity. Most of the isolates exhibited differences in tolerance to hymexazol but showed no resistance.

Comparative Evaluation of Digital Cephalometric Tracing Applications on Mobile Devices and Manual Tracing.

BACKGROUND Cephalometric radiography evaluates facial skeleton development and aids in diagnosis and treatment phases (pre and post) in orthodontics. This study aimed to compare digital cephalometric tracing using a smartphone application (App), a tablet-based platform, and manual tracing in 30 orthodontic patients. MATERIAL AND METHODS Thirty orthodontic pretreatment, criteria based, lateral cephalometric radiographs were analyzed/grouped for Steiner analysis parameters (5 skeletal, 3 dentals, 1 soft tissue) by 3 tracing methods [manual - group (Gp M), smartphone (Android - OS9) - Gp S, tablet (Apple - IOS13) - Gp T) after mandatory standardization/calibration. Measurements include 5 angular (SNA, SNB, ANB, SNMPA, SNOP), 3 linear U1NA, L1NB, U1L1, and 1 soft tissue (S line) (millimeters and degrees). Inter-examiner rating was determined using Dahlberg's test. After normality distribution testing (Shapiro-Wilk), data were analyzed using one-way analysis of variance (ANOVA) for group differences. Homogeneity of variance was verified using the Levene test. Differences were determined on probability value of (p≤0.05). RESULTS The results showed that Steiner's analysis parameters were similar in all groups with homogenous variances. Highest differences in mean values were found for L1NB, U1L1, and S line measurement, with higher values being observed in Gp S tracings. However, these differences were not statistically significant (p≤0.05). All parameters, irrespective of being measured in either degrees or millimeters, had means comparable to each other. CONCLUSIONS Smartphone and tablet-based applications produced tracings that were comparable and reliable when compared to conventional manual tracings. Standardization of images, processing, printing, and calibration of devices is important to achieve good results.

Characterization of the root and canal anatomy of maxillary premolar teeth in an Iraqi subpopulation: a cone beam computed tomography study.

This study aims to evaluate the number of roots and root canal morphology types of maxillary premolars in relation to a patient's gender and age in an Iraqi population using two classification systems. Cone beam computed tomography (CBCT) scans of 1116 maxillary premolars from 385 patients were evaluated for the number of roots and root canal morphology types according to Vertucci's classification and Ahmed et al. classification systems. Differences in the number of roots and root canal morphology types with regard to tooth type, patients' gender and age groups were evaluated and the degree of bilateral symmetry was determined. Chi-squared test was used for statistical analysis. About 51.1% of the 1st premolars were double rooted. The majority (87.9%) of the 2nd premolars were single rooted. The three-rooted form presented in only 1.2% and 0.7% of the 1st and 2nd premolars, respectively. Vertucci Type IV (Ahmed et al. code 2MaxP B1P1) and Vertucci Type I (Ahmed et al. code 1MaxP1) were the most common canal morphology types in the 1st and 2nd premolars, respectively. Females showed a lower number of roots and a higher prevalence of Vertucci Type I configuration (P < 0.05). Younger age groups showed a higher prevalence of Vertucci Type I configuration (P < 0.05). Bilateral symmetry was seen in more than half of the maxillary premolars. There is a considerable variation in the number of roots and root canal configurations of maxillary premolars in the studied Iraqi population, with a significant difference by gender and age groups. Ahmed et al. classification provided more accurate presentation of the root and canal anatomy in maxillary premolars compared to Vertucci's classification.

ChatGPT as a psychotherapist for anxiety disorders: An empirical study with anxiety patients.

Purpose: this study aims to investigate the role of ChatGPT as a psychotherapist for anxiety disorders, examining its effectiveness, acceptability, and potential benefits among individuals with anxiety disorders. Methods: a quasi-experimental design was adopted, involving a 4-week intervention where participants used ChatGPT as a therapeutic tool. The study included outpatients aged above 18 years from public hospitals in Saudi Arabia. A total of 399 participants completed a survey questionnaire that focused on their experiences with AI-based psychotherapy (six items), perceptions of ChatGPT (four items), and its role in different therapy modalities for anxiety management (seven items). Measures were taken to ensure the validity and reliability of responses by using Cronbach's alpha reliability testing (> 0.7), including the use of a translated and verified questionnaire. Results: majority received prior therapy (89.6%), reporting severe anxiety symptoms (36.1%). ChatGPT was widely used and perceived as accurate by 91.2% of users. Concerns included privacy (67.2%) and ethics (64.9%). Statistically significant differences (p < .05) in perceptions of ChatGPT for anxiety disorders were observed. While urban residents generally rated ChatGPT more positively, females consistently reported higher levels of trustworthiness, effectiveness, and coherence in guidance compared to males. Conclusion: ChatGPT has the potential to complement traditional psychotherapeutic approaches and enhance access to quality mental health care.

Forgotten Biliary Plastic Stents: Complications, Management, and Clinical Outcomes.

Background and Objectives: Endoscopic biliary plastic stenting is a safe and effective temporary therapeutic modality used in various benign biliary disorders. Long-term indwelling stents for more than one year without retrieval are termed "forgotten biliary stents". In clinical practice, the forgotten stents are underestimated and the majority of data were obtained from case reports. The aim of this study was to determine the forgotten-biliary-plastic-stent-related complications, their management, and the patients' clinical outcomes. Materials and Methods: This retrospective study was performed at three hospitals during the period from January 2021 to December 2023. In total, 577 patients with biliary plastic stents-inserted for a variety of benign biliary conditions-were included. They were divided into two groups, as follows: group 1 included 527 patients who had biliary stents removed within 3 months, and group 2 included 50 patients with biliary stents retrieved after one year of their deployment. The stent-related complications (e.g., acute cholangitis, stent clogging, distal stent migration, new common bile duct (CBD) stone formation, and proximal stent migration) and the endoscopic management success rate were evaluated. Results: Irretrievable CBD stones were the main indication for biliary plastic stenting in both groups. The stent-related complications, number of endoscopic sessions, and hospital admissions were significantly higher in the patients with forgotten biliary stents than those with stent removal within 3 months. All the study patients were successfully managed endoscopically with uneventful outcomes. Conclusions: Based on this retrospective study, non-adherence to the endoscopists' instructions is the main reason for retained biliary stents for more than one year. The patients with forgotten stents had significantly higher complication rates, a higher number of endoscopic sessions, and a higher number of hospital admissions than those with stents that were retrieved in the scheduled time. All patients were managed endoscopically with a technical success rate of 100%, and with no complication-related mortality.

Bayesian network analysis of drug treatment strategies for thyroid associated ophthalmopathy.

BACKGROUND: The first line treatment for moderate to severe active thyroid associated ophthalmopathy is glucocorticoid pulse therapy, but for patients with contraindications to hormone therapy or hormone resistance, it is urgent to find a suitable treatment plan. AIMS: To find a reliable alternative to hormone pulse therapy for thyroid associated ophthalmopathy by comparing the efficacy with first-line treatment regimens. METHODS: Search PubMed, Ovid, Web of science, Cochrane library, and Clinical Trials.gov for randomized controlled trials on the treatment of thyroid associated ophthalmopathy published as of July 7, 2024. Quality evaluation and Bayesian network analysis were conducted using RevMan 5.3 software, STATA15.0 software, and ADDIS 1.16.8 software. RESULTS: A total of 666 patients were included in 11 studies and 8 interventions. Network analysis showed that the three interventions of mycophenolate mofetil combined with glucocorticoids, Teprotumumab and 99Tc-MDP were superior to glucocorticoid pulse therapy in improving clinical activity scores and proptosis. The regimen of glucocorticoids combined with statins can improve the quality of life score and diplopia score of patients. Neither methotrexate combined with glucocorticoids nor rituximab alone showed additional advantages when compared with glucocorticoid pulse therapy. CONCLUSION: Mycophenolate mofetil combined with glucocorticoid therapy is very beneficial for moderate to severe active thyroid associated ophthalmopathy. Mycophenolate mofetil may be a good choice when patients have contraindications to hormone use or hormone resistance. Teprotumumab is very promising and may be able to avoid patients undergoing orbital decompression surgery. The durability and safety of its long-term efficacy need to be further observed.

Are large language models a useful resource to address common patient concerns on hallux valgus? A readability analysis.

BACKGROUND: This study evaluates the accuracy and readability of Google, ChatGPT-3.5, and 4.0 (two versions of an artificial intelligence model) responses to common questions regarding bunion surgery. METHODS: A Google search of "bunionectomy" was performed, and the first ten questions under "People Also Ask" were recorded. ChatGPT-3.5 and 4.0 were asked these ten questions individually, and their answers were analyzed using the Flesch-Kincaid Reading Ease and Gunning-Fog Level algorithms. RESULTS: When compared to Google, ChatGPT-3.5 and 4.0 had a larger word count with 315 ± 39 words (p < .0001) and 294 ± 39 words (p < .0001), respectively. A significant difference was found between ChatGPT-3.5 and 4.0 compared to Google using Flesch-Kincaid Reading Ease (p < .0001). CONCLUSIONS: Our findings demonstrate that ChatGPT provided significantly lengthier responses than Google and there was a significant difference in reading ease. Both platforms exceeded the seventh to eighth-grade reading level of the U.S. LEVEL OF EVIDENCE: N/A.

Uterodilation effect of unripe fruit extract of Crataegus azarolus var. aronia L. on rat uterine smooth muscles.

Crataegus azarolus var. aronia L. (C. aronia) is one of the most important medicinal plants used widely in folk medicine for the prevention of several diseases due to its content of several bioactive compounds like phenolic acid, aromatic amines, proanthocyanidins and flavonoids. This study investigated the uterodilation effect of methanol extract (ME) of C. aronia unripe fruit on the uterine smooth muscle in rats. The mechanism of action underlying the plant's extract was also screened. The unripe fruits were cleaned and extracted in methanol. The extract (1.9-4 mg/ml) was tested on rat uterine relaxation in calcium-free Kreb's solution and potassium chloride-induced uterine contraction. The plant extract was also studied in the presence of antagonists in separate experiments to determine the role of various ion channels and hyperpolarizing agents. The plant extract showed an uterodilation effect on the uterus, in which the ME produced a considerable relaxant effect. The results confirmed that the induced dilation was mediated mainly by the nitric oxide pathway and the activation of potassium channels with a limited role of the prostaglandin pathway and calcium channel activation. This in-vitro study provides the first scientific evidence of the claimed effect of C. aronia on uterine relaxation.

Sodium carbonate modulated ultrashort mode-locked stretched pulses in an erbium-doped fiber laser.

In this paper, we propose a new, to the best of our knowledge, saturable absorber (SA) based on sodium carbonate (N a 2 C O 3) for producing an ultrafast mode-locked stretched pulse in a passively erbium-doped fiber laser at near-zero dispersion. The solid film of a N a 2 C O 3-SA was fabricated by the drop-casting method using polyvinyl alcohol as a host polymer. The modulation depth of the proposed SA, which was measured by a balanced twin detector technique, was 2.3% with saturation intensity of 181M W/c m 2. The mode-locking operation of the EDFL-based N a 2 C O 3-SA was observed at a pump power of 117 mW. A stable stretched pulse was generated by using the proposed N a 2 C O 3-SA. The laser can generate pulses with a repetition rate and duration of 1.87 MHz and 820 fs, respectively, within a bandwidth of 6.6 nm. The single pulse energy reaches up to 5 nJ, which is equivalent to the average output power of 9.3 mW. Finally, to the best of our knowledge, this is the first report on using the N a 2 C O 3-SA for generating a stretched-pulse mode-locked fiber laser.

New spiro-indeno[1,2-b]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights.

Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2-b]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton via cost-effective one-pot multicomponent [3 + 2] cycloaddition reaction. Absolute configuration was assigned by single crystal x-ray diffraction analysis and reaction mechanism was studied by Molecular Electron Density Theory. Initial MTT screening of the series against A549 cells and normal lung fibroblasts Wi-38 elected 6b as the study hit regarding potency (IC50 = 54 nM) and safety (SI = 6.64). In vitro CDK2 inhibition assay revealed that 6b (IC50 = 177 nM) was comparable to roscovitine (IC50 = 141 nM). Docking and molecular dynamic simulations suggested that 6b was stabilised into CDK2 cavity by hydrophobic interactions with key aminoacids.

Use of anti-viral therapies in hospitalised COVID-19 patients in the United Arab Emirates: a cost-effectiveness and health-care resource use analysis.

BACKGROUND: This study attempts to estimate the cost-effectiveness of the antiviral remdesivir, as recommended in the 2021 COVID treatment guidelines for the United Arab Emirates, compared to standard of care (SOC), but also favipiravir (FAVI), which was also recommended for the treatment of hospitalized COVID patients. METHODS: A cost-effectiveness model was built using published efficacy data for RDV, FAVI and SOC as well as local epidemiology data. The outcomes measured included hospital bed days averted, mortality, costs and cost per outcome over one year. One-way, probabilistic and scenario analyses were undertaken to reflect uncertainty in the estimates. RESULTS: When modelled over one year, the results indicated that treatment of adults in need of supplemental oxygen with RDV + SOC could result in 11,338 fewer general ward bed days, 7,003 fewer ICU days and 5,451 fewer ICU + MIV bed days compared to SOC alone and similar results when compared with FAVI + SOC. The model results also showed that there were 374 fewer deaths associated with the use of RDV + SOC compared to SOC alone. The model also estimates substantial potential cost-savings associated with RDV + SOC treatment compared with SOC alone (USD 3,454 per patient). The results of the one-way sensitivity analysis showed that the model was sensitive to estimates of length of stay and the cost of hospitalization. Despite this, the model predicted cost-savings in all scenarios versus all comparators. CONCLUSIONS: The model estimated that using RDV + SOC could result in substantial reductions in HCRU and cost savings regardless of the comparator. However, it should be noted that reliable clinical information on FAVI was limited therefore it is challenging to interpret these results. All the potential benefits modelled here for RDV + SOC can have implications not only for the health of the UAE population but for improving hospital capacity to deal with other conditions.

Work-related musculoskeletal symptoms among Saudi radiologists: a cross-sectional multi-centre study.

BACKGROUND: Musculoskeletal disorders are common health problems worldwide. Several factors cause these symptoms, including ergonomics and other individual considerations. Computer users are prone to repetitive strain injuries that increase the risk of developing musculoskeletal symptoms (MSS). Radiologists are susceptible to developing MSS because they work long hours analysing medical images on computers in an increasingly digitalised field. This study aimed to identify the prevalence of MSS among Saudi radiologists and the associated risk factors. METHODS: This study was a cross-sectional, non-interventional, self-administered online survey. The study was conducted on 814 Saudi radiologists from various regions in Saudi Arabia. The study's outcome was the presence of MSS in any body region that limited participation in routine activities over the previous 12 months. The results were descriptively examined using binary logistic regression analysis to estimate the odds ratio (OR) of participants who had disabling MSS in the previous 12 months. All university, public, and private radiologists received an online survey containing questions about work surroundings, workload (e.g., spent at a computer workstation), and demographic characteristics. RESULTS: The prevalence of MSS among the radiologists was 87.7%. Most of the participants (82%) were younger than 40 years of age. Radiography and computed tomography were the most common imaging modalities that caused MSS (53.4% and 26.8%, respectively). The most common symptoms were neck pain (59.3%) and lower back pain (57.1%). After adjustment, age, years of experience, and part-time employment were significantly associated with increased MSS (OR = .219, 95% CI = .057-.836; OR = .235, 95% CI = 087-.634; and OR = 2.673, 95% CI = 1.434-4.981, respectively). Women were more likely to report MSS than males (OR = 2.12, 95% CI = 1.327-3.377). CONCLUSIONS: MSS are common among Saudi radiologists, with neck pain and lower back pain being the most frequently reported symptoms. Gender, age, years of experience, type of imaging modality, and employment status were the most common associated risk factors for developing MSS. These findings are vital for the development of interventional plans to reduce the prevalence of musculoskeletal complaints in clinical radiologists.

Synthesis and SARs study of novel spiro-oxindoles as potent antiproliferative agents with CDK-2 inhibitory activities.

A series of 16 novel spirooxindole analogs 8a-p were designed and constructed via cost-effective single-step multicomponent [3+2] cycloaddition reaction of azomethine ylide (AY) generated in situ from substituted isatin (6a-d) with suitable amino acids (7a-c) and ethylene-engrafted pyrazole derivatives (5a,b). The potency of all compounds was assayed against a human breast cancer cell line (MCF-7) and a human liver cell line (HepG2). Spiro compound 8c was the most active member among the synthesized candidates, with exceptional cytotoxicity against the MCF-7 and HepG2 cell lines, with IC50 values of 0.189 ± 0.01 and 1.04 ± 0.21 µM, respectively. The candidate 8c exhibited more potent activity (10.10- and 2.27-fold) than the standard drug roscovitine (IC50 = 1.91 ± 0.17 µM (MCF-7) and 2.36 ± 0.21 µM (HepG2)). Compound 8c was investigated for epidermal growth factor receptor (EGFR) inhibition; it exhibited promising IC50 values of 96.6 nM compared with 67.3 nM for erlotinib. The IC50 value of 8c (34.98 nM) exhibited cyclin-dependent kinase 2 (CDK-2) inhibition, being more active than roscovitine the (IC50 = 140 nM) in targeting the CDK-2 kinase enzyme. Additionally, for apoptosis induction of compound 8c in MCF-7, it upregulated the expression levels of proapoptotic genes for P53, Bax, caspases-3, 8, and 9 at up to 6.18, 4.8, 9.8, 4.6, 11.3 fold-change, respectively, and downregualted the level of the antiapoptotic gene for Bcl-2 by 0.14-fold. Finally, a molecular docking study of the most active compound 8c highlighted a good binding affinity with Lys89 as the key amino acid for CDK-2 inhibition.

A Combined Experimental and Computational Study of Novel Benzotriazinone Carboxamides as Alpha-Glucosidase Inhibitors.

Diabetes is a chronic metabolic disorder of the endocrine system characterized by persistent hyperglycemia appears due to the deficiency or ineffective use of insulin. The glucose level of diabetic patients increases after every meal and medically recommended drugs are used to control hyperglycemia. Alpha-glucosidase inhibitors are used as antidiabetic medicine to delay the hydrolysis of complex carbohydrates. Acarbose, miglitol, and voglibose are commercial drugs but patients suffer side effects of flatulence, bloating, diarrhea, and loss of hunger. To explore a new antidiabetic drug, a series of benzotriazinone carboxamides was synthesized and their alpha-glucosidase inhibition potentials were measured using in vitro experiments. The compounds 14k and 14l were found to be strong inhibitors compared to the standard drug acarbose with IC50 values of 27.13 ± 0.12 and 32.14 ± 0.11 µM, respectively. In silico study of 14k and 14l was carried out using molecular docking to identify the type of interactions developed between these compounds and enzyme sites. Both potent compounds 14k and 14l exhibited effective docking scores by making their interactions with selected amino acid residues. Chemical hardness and orbital energy gap values were investigated using DFT studies and results depicted affinity of 14k and 14l towards biological molecules. All computational findings were found to be in good agreement with in vitro results.

Synthesis and Characterization of New Spirooxindoles Including Triazole and Benzimidazole Pharmacophores via [3+2] Cycloaddition Reaction: An MEDT Study of the Mechanism and Selectivity.

A new series of spirooxindoles based on benzimidazole, triazole, and isatin moieties were synthesized via a [3+2] cycloaddition reaction protocol in one step. The single X-ray crystal structure of the intermediate triazole-benzimidazole 4 was solved. The new chemical structures of these spirooxindole molecules have been achieved for the first time. The final synthesized chemical architecture has differently characterized electronic effects. An MEDT study of the key 32CA reaction between in situ generated azomethine ylide (AY) and chalcones explained the low reaction rates and the total selectivities observed. The supernucleophilic character of AY and the strong electrophilicity of chalcones favor these reactions through a highly polar two-stage one-step mechanism in which bond formation at the ß-conjugated carbon of the chalcones is more advanced. The present combined experimental and theoretical study reports the synthesis of new spirooxindoles with potential biological activities and fully characterizes the molecular mechanisms for their formation through the key 32CA reaction step.

Towards a Precise NMR Quantification of Acute Phase Inflammation Proteins from Human Serum.

Nuclear Magnetic Resonance (NMR) spectra of human serum and plasma show, besides metabolites and lipoproteins, two characteristic signals termed GlycA and B arising from the acetyl groups of glycoprotein glycans from acute phase proteins, which constitute good markers for inflammatory processes. Here, we report a comprehensive assignment of glycoprotein glycan NMR signals observed in human serum, showing that GlycA and GlycB signals originate from Neu5Ac and GlcNAc moieties from N-glycans, respectively. Diffusion-edited NMR experiments demonstrate that signal components can be associated with specific acute phase proteins. Conventionally determined concentrations of acute phase glycoproteins correlate well with distinct features in NMR spectra (R2 up to 0.9422, p-value <0.001), allowing the simultaneous quantification of several acute phase inflammation proteins. Overall, a proteo-metabolomics NMR signature of significant diagnostic potential is obtained within 10-20 min acquisition time. This is exemplified in serum samples from COVID-19 and cardiogenic shock patients showing significant changes in several acute phase proteins compared to healthy controls.

CTLA4-Ig mediated immunosuppression favors immunotolerance and restores graft in mouse airway transplants.

CTLA4-Ig is a potent costimulatory blocker that inhibits T cell activation during alloimmune inflammation and increases graft survival and function. CTLA4-Ig-mediated immunosuppression has been demonstrated to support transplant function in various clinical trials and preclinical settings, but its effects on the balance between regulatory T cells (Tregs) and effector T cells (Teffs), as well as complement activation, are less well investigated. In the present study, we proposed to investigate the effects of CTLA4-Ig mediated immunosuppression on the phase of immunotolerance and the subsequent graft microvascular and epithelial repair during the progression of subepithelial fibrosis in a mouse model of orthotopic trachea transplantation. Briefly, CTLA4-Ig treated allografts (2 mg/kg, I.P.), untreated allografts, and syngrafts were serially monitored for peripheral FOXP3+ Tregs, antibody-mediated complement activation (C3d and C4d), tissue oxygenation, donor-recipient microvascular blood flow, and subsequent tissue remodeling following transplantation. Our data demonstrate that CTLA4-Ig mediated immunosuppression significantly results in late increases in both peripheral CD4+/CD8+ FOXP3+ Tregs and serum IL-10, but prevents the microvascular deposition of IgG, complement factor C3d, and epithelial C4d respectively, which proportionally improved blood flow and tissue oxygenation in the graft and, thus, promotes graft repair. Also, it restored the airway lumen, epithelium, and prevented the progression of subepithelial collagen deposition up to 90 days after transplantation. This study demonstrates that CTLA4-Ig-mediated immunosuppression potentially modulates both effector response and a late surge of regulatory activity to preserve graft microvasculature and rescue allograft from sustained hypoxia and ischemia and thereby limits subepithelial fibrosis.

In-hospital mortality in SARS-CoV-2 stratified by gamma-glutamyl transferase levels.

BACKGROUND: This study investigates in-hospital mortality amongst patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its relation to serum levels of gamma-glutamyl transferase (GGT). METHODS: Patients were stratified according to serum levels of gamma-glutamyl transferase (GGT) (GGT<50 IU/L or GGT≥50 IU/L). RESULTS: A total of 802 participants were considered, amongst whom 486 had GGT<50 IU/L and a mean age of 48.1 (16.5) years, whilst 316 had GGT≥50 IU/L and a mean age of 53.8 (14.7) years. The chief sources of SARS-CoV-2 transmission were contact (366, 45.7%) and community (320, 40%). Most patients with GGT≥50 IU/L had either pneumonia (247, 78.2%) or acute respiratory distress syndrome (ARDS) (85, 26.9%), whilst those with GGT<50 IU/L had hypertension (141, 29%) or diabetes mellitus (DM) (147, 30.2%). Mortality was higher amongst patients with GGT≥50 IU/L (54, 17.1%) than amongst those with GGT<50 IU/L (29, 5.9%). More patients with GGT≥50 required high (83, 27.6%) or low (104, 34.6%) levels of oxygen, whereas most of those with GGT<50 had no requirement of oxygen (306, 71.2%). Multivariable logistic regression analysis indicated that GGT≥50 IU/L (odds ratio [OR]: 2.02, 95% confidence interval [CI]: 1.20-3.45, p=0.009), age (OR: 1.05, 95% CI: 1.03-1.07, p<0.001), hypertension (OR: 2.06, 95% CI: 1.19-3.63, p=0.011), methylprednisolone (OR: 2.96, 95% CI: 1.74-5.01, p<0.001) and fever (OR: 2.03, 95% CI: 1.15-3.68, p=0.016) were significant predictors of all-cause cumulative mortality. A Cox proportional hazards regression model (B = -0.68, SE =0.24, HR =0.51, p = 0.004) showed that patients with GGT<50 IU/L had a 0.51-times lower risk of all-cause cumulative mortality than patients with GGT≥50 IU/L. CONCLUSION: Higher levels of serum GGT were found to be an independent predictor of in-hospital mortality.

Dynamics study on the effect of memristive autapse distribution on Hopfield neural network.

As the shortest feedback loop of the nervous system, autapse plays an important role in the mode conversion of neurodynamics. In particular, memristive autapses can not only facilitate the adjustment of the dynamical behavior but also enhance the complexity of the nervous system, in view of the fact that the dynamics of the Hopfield neural network has not been investigated and studied in detail from the perspective of memristive autapse. Based on the traditional Hopfield neural network, this paper uses a locally active memristor to replace the ordinary resistive autapse so as to construct a 2 n-dimensional memristive autaptic Hopfield neural network model. The boundedness of the model is proved by introducing the Lyapunov function and the stability of the equilibrium point is analyzed by deriving the Jacobian matrix. In addition, four scenarios are established on a small Hopfield neural network with three neurons, and the influence of the distribution of memristive autapses on the dynamics of this small Hopfield neural network is described by numerical simulation tools. Finally, the Hopfield neural network model in these four situations is designed and implemented on field-programmable gate array by using the fourth-order Runge-Kutta method, which effectively verifies the numerical simulation results.