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Eosinophils were previously reported to play a role in intestinal inflammation and fibrosis. Whether this is as a bystander or as an active participant is still up for debate. Moreover, data describing a causal relationship between eosinophils and intestinal fibrosis are scarce. We here aimed to elucidate the role of eosinophils in the pathogenesis of intestinal inflammation and fibrosis. Therefore, we stimulated fibroblasts with (active) eosinophils or with Eosinophil Cationic Protein (ECP), and assessed fibroblast activation via flow cytometry and immunocytochemistry. We observed decreased fibroblast activation when fibroblasts were co-cultured with active eosinophils or after stimulation with ECP in comparison to monoculture conditions, but not in case of co-culturing with inactivated eosinophils. Furthermore, eosinophil depletion in a RAG−/− chronic DSS colitis model resulted in decreased inflammation, but increased development of fibrosis. In this model, we could show increased expression of the anti-inflammatory protein IL-10 and the pro-fibrotic factors IL-1β, FGF-21 and TGF-β3 in the eosinophil-depleted mice compared to the control mice. In conclusion, our in vitro data revealed an anti-fibrotic role for eosinophils. In line, in a chronic murine colitis model, we observed a pro-inflammatory, but an anti-fibrotic, role for eosinophils. Furthermore, we identified an increased presence of anti-inflammatory and pro-fibrotic cytokines in the eosinophil depleted group. [ABSTRACT FROM AUTHOR]

Background: The airway microbiome in severe asthma has not been characterised at species‐level by metagenomic sequencing, nor have the relationships between specific species and mucosal immune responses in 'type‐2 low', neutrophilic asthma been defined. We performed an integrated species‐level metagenomic data with inflammatory mediators to characterise prevalence of dominant potentially pathogenic organisms and host immune responses. Methods: Sputum and nasal lavage samples were analysed using long‐read metagenomic sequencing with Nanopore and qPCR in two cross‐sectional adult severe asthma cohorts, Wessex (n = 66) and Oxford (n = 30). We integrated species‐level data with clinical parameters and 39 selected airway proteins measured by immunoassay and O‐link. Results: The sputum microbiome in health and mild asthma displayed comparable microbial diversity. By contrast, 23% (19/81) of severe asthma microbiomes were dominated by a single respiratory pathogen, namely H. influenzae (n = 10), M. catarrhalis (n = 4), S. pneumoniae (n = 4) and P. aeruginosa (n = 1). Neutrophilic asthma was associated with H. influenzae, M. catarrhalis, S. pneumoniae and T. whipplei with elevated type‐1 cytokines and proteases; eosinophilic asthma with higher M. catarrhalis, but lower H. influenzae, and S. pneumoniae abundance. H. influenzae load correlated with Eosinophil Cationic Protein, elastase and IL‐10. R. mucilaginosa associated positively with IL‐6 and negatively with FGF. Bayesian network analysis also revealed close and distinct relationships of H. influenzae and M. catarrhalis with type‐1 airway inflammation. The microbiomes and cytokine milieu were distinct between upper and lower airways. Conclusions: This species‐level integrated analysis reveals central, but distinct associations between potentially pathogenic bacteria and airways inflammation in severe asthma. [ABSTRACT FROM AUTHOR]

Influenza poses a significant threat to global health, with the ability to cause severe epidemics and pandemics. The polymerase basic protein 2 (PB2) of the influenza virus plays a crucial role in the viral replication process, making the CAP-binding domain of PB2 an attractive target for antiviral drug development. This study aimed to identify and evaluate potential inhibitors of the influenza polymerase PB2 CAP-binding domain using computational drug discovery methods. We employed a comprehensive computational approach involving virtual screening, molecular docking, and 500 ns molecular dynamics (MD) simulations. Compounds were selected from the Diverse lib database and assessed for their binding affinity and stability in interaction with the PB2 CAP-binding domain. The study utilized the generalized amber force field (GAFF) for MD simulations to further evaluate the dynamic behaviour and stability of the interactions. Among the screened compounds, compounds 1, 3, and 4 showed promising binding affinities. Compound 4 demonstrated the highest binding stability and the most favourable free energy profile, indicating strong and consistent interaction with the target domain. Compound 3 displayed moderate stability with dynamic conformational changes, while Compound 1 maintained robust interactions throughout the simulations. Comparative analyses of these compounds against a control compound highlighted their potential efficacy. Compound 4 emerged as the most promising inhibitor, with substantial stability and strong binding affinity to the PB2 CAP-binding domain. These findings suggest that compound 4, along with compounds 1 and 3, holds the potential for further development into effective antiviral agents against influenza. Future studies should focus on experimental validation of these compounds and exploration of resistance mechanisms to enhance their therapeutic utility. [ABSTRACT FROM AUTHOR]

Background: Hirschsprung's disease (HSCR) is a congenital enteric nervous system (ENS) disorder. Genetics cannot explain most sporadic cases. To explore the relationship between pathogen infection, autoantibodies, innate immune, and HSCR. Methods: Pathogen microarray was conducted in the serum of the prospective neonatal abdominal distension (NAD) cohort, consisting of 56 children followed for at least 6 months until the final diagnosis of HSCR was determined or excluded. We conducted an autoantibody microarray in an HSCR cohort, which is comprised of diagnosed HSCR patients (HSCR) and healthy control subjects (HC). RNA‐seq of colon tissues from aganglionic and ganglionic segments of HSCR patients was performed. Results: Experimental results show that the serum lgM and lgG of enterovirus 71 (EV71) were significantly higher in HSCR than in the gastrointestinal dysfunction (GI) group, with a prediagnose value reaching area under the curve (AUC) over 0.76. We discovered that a group of autoantibodies were significantly higher in HSCR including neuronal pentraxin 1 (NPTX1), amyloid, neuron lysate, and myelin‐associated oligodendrocytic basic protein (MOBP) than that in the HC group. These four autoantibodies could distinguish HSCR from the HC group, with a combined AUC of over 0.90 using both serum IgG and IgM. Further analysis showed that wide activation of innate immune pathways, including toll‐like receptor (TLR) signaling pathway, neutrophil‐to‐lymphocyte ratio (NLR) signaling pathway, red cell distribution width to lymphocyte ratio (RLR) signaling pathway, and cyclic adenosine monophosphate (cAMP) signaling pathway in aganglionic compared to ganglionic segments of HSCR. Conclusion: This study suggested that virus‐triggered autoimmunity may contribute to HSCR through activation of innate immunity, which facilitates the diagnosis and prevention of HSCR. [ABSTRACT FROM AUTHOR]

Lactoferrin, lysozyme, and gelatin are three common basic proteins known for their ability to interact with acidic proteins (lactoglobulin, ovalbumin, casein, etc.) and form various supramolecular structures. Their basic nature makes them highly promising for interaction with other acidic proteins to form heteroprotein complex coacervation (HPCC) with a wide range of applications. This review extensively examines the structure, properties, and preparation methods of these basic proteins and delves into the internal and external factors influencing the formation of HPCC, including pH, ionic strength, mixing ratio, total protein concentration, temperature, and inherent protein properties. The applications of different HPCCs based on these three basic proteins are discussed, including the encapsulation of bioactive molecules, emulsion stabilization, protein separation and extraction, nanogel formation, and the development of formulas for infants. Furthermore, the challenges and issues that are encountered in the formation of heteroprotein complexes are addressed and summarized, shedding light on the complexities and considerations involved in utilizing HPCC technology in practical applications. By harnessing the basic proteins to interact with other proteins and to form complex coacervates, new opportunities arise for the development of functional food products with enhanced nutritional profiles and functional attributes. [ABSTRACT FROM AUTHOR]

Dinoflagellates are a remarkable group of protists, not only for their association with harmful algal blooms and coral reefs but also for their numerous characteristics deviating from the rules of eukaryotic biology. Genome research on dinoflagellates has lagged due to their immense genome sizes in most species (~ 1-250 Gbp). Nevertheless, the last decade marked a fruitful era of dinoflagellate genomics, with 27 genomes sequenced and many insights attained. This review aims to synthesize information from these genomes, along with other omic data, to reflect on where we are now in understanding dinoflagellates and where we are heading in the future. The most notable insights from the decade-long genomics work include: (1) dinoflagellate genomes have been expanded in multiple times independently, probably by a combination of rampant retroposition, accumulation of repetitive DNA, and genome duplication; (2) Symbiodiniacean genomes are highly divergent, but share about 3,445 core unigenes concentrated in 219 KEGG pathways; (3) Most dinoflagellate genes are encoded unidirectionally and are not intron-poor; (4) The dinoflagellate nucleus has undergone extreme evolutionary changes, including complete or nearly complete loss of nucleosome and histone H1, and acquisition of dinoflagellate viral nuclear protein (DVNP); (5) Major basic nuclear protein (MBNP), histone-like protein (HLP), and bacterial HU-like protein (HCc) belong to the same protein family, and MBNP can be the unifying name; (6) Dinoflagellate gene expression is regulated by poorly understood mechanisms, but microRNA and other epigenetic mechanisms are likely important; (7) Over 50% of dinoflagellate genes are "dark" and their functions remain to be deciphered using functional genetics; (8) Initial insights into the genomic basis of parasitism and mutualism have emerged. The review then highlights functionally unique and interesting genes. Future research needs to obtain a finished genome, tackle large genomes, characterize the unknown genes, and develop a quantitative molecular ecological model for addressing ecological questions. [ABSTRACT FROM AUTHOR]

The prothoracic gland (PG) is a major insect endocrine organ. It is the principal source of insect steroid hormones, and critical for key developmental events such as the molts, the establishment of critical weight (CW), pupation, and sexual maturation. However, little is known about the developmental processes that regulate PG morphology. In this study, we identified soul, which encodes a PG-specific basic helix-loop-helix (bHLH) transcription factor. We demonstrate that Tap, also a bHLH protein, dimerizes with Soul. Both are expressed in the developing PG. Interfering with either soul or tap function caused strikingly similar phenotypes, resulting in small and fragmented PGs, the abolishment of steroid hormone-producing gene expression, larval arrest, and a failure to undergo metamorphosis. Furthermore, both soul and tap showed expression peaks just prior to the CW checkpoint. Disrupting soul-or tap-function before, but not after, the CW checkpoint caused larval arrest, and perturbed highly similar gene cohorts, which were enriched for regulators and components of the steroid hormone biosynthesis pathway. Intriguingly, a chitin-based cuticle gene, Cpr49Ah, and a POU domain transcription factor gene, pdm3, are direct target genes of the Soul/Tap complex, and disruption of either phenocopied key aspects of soul/tap loss-of-function phenotypes. Taken together, our findings demonstrate that the Soul/Tap heterodimer resides at the top of a complex gene hierarchy that drives PG development, CW establishment, and steroid hormone production. [ABSTRACT FROM AUTHOR]

The prevalence of highly pathogenic avian influenza (HPAI) A(H5N1) viruses has increased in wild birds and poultry worldwide, and concomitant outbreaks in mammals have occurred. During 2023, outbreaks of HPAI H5N1 virus infections were reported in cats in South Korea. The H5N1 clade 2.3.4.4b viruses isolated from 2 cats harbored mutations in the polymerase basic protein 2 gene encoding single amino acid substitutions E627K or D701N, which are associated with virus adaptation in mammals. Hence, we analyzed the pathogenicity and transmission of the cat-derived H5N1 viruses in other mammals. Both isolates caused fatal infections in mice and ferrets. We observed contact infections between ferrets, confirming the viruses had high pathogenicity and transmission in mammals. Most HPAI H5N1 virus infections in humans have occurred through direct contact with poultry or a contaminated environment. Therefore, One Health surveillance of mammals, wild birds, and poultry is needed to prevent potential zoonotic threats. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR), the major mechanism by which various cancers develop specific resistance to therapeutic agents, has set up enormous obstacles to many forms of tumor chemotherapy. Traditional cocktail therapy administration, based on the combination of multiple drugs for anti-MDR chemotherapy, often suffers from inconsistent in vivo pharmacokinetic behaviors that cannot act synchronously on the lesions, leading to limited pharmacodynamic outcomes. Despite the emergence of nanomedicines, which has improved chemotherapeutic drugs' bioavailability and therapeutic effect on clinical application, these monotherapy-based nano-formulations still show poor progression in overcoming MDR. Herein, a "one stone and three birds" nanococktail integrated by a cocrystal@protein-anchoring strategy was purposed for triple-payload delivery, which paclitaxel-disulfiram cocrystal-like nanorods (NRs) were anchored with the basic protein drug Cytochrome c (Cyt C), followed by hyaluronic-acid modification. In particular, NRs were utilized as carrier-like particles to synchronously deliver biomacromolecule Cyt C into tumor cells and then promote cell apoptosis. Of note, on A549/Taxol drug-resistant tumor-bearing mice, the system with extraordinarily high encapsulation efficiency demonstrated prolonged in vivo circulation and increased tumor-targeting accumulation, significantly reversing tumor drug resistance and improving therapeutic efficacy. Our mechanistic study indicated that the system induced the apoptosis of Taxol-resistant tumor cells through the signal axis P-glycoprotein/Cyt C/caspase 3. Collectively, this nanococktail strategy offers a promising approach to improve the sensitivity of tumor cells to chemotherapeutic drugs and strengthen intractable drug-resistant oncotherapy. Cocrystal@protein-anchoring nanococktail (HA-HNRplex) triple-payload delivery platform used a "one stone and three birds" strategy to synchronously transport PTX, DSF and Cyt C for treating multidrug resistance cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

L -Glutamic acid (L -Glu) is a basic unit of proteins and also serves as an important neurotransmitter in the central nervous system. Its structural properties are critical for biological functions and selective receptor recognition. Although this molecule has been extensively studied, the low frequency vibrational behavior that is closely related to conformational changes and the intermolecular interactions between L -Glu and its receptors are still unclear. In this study, we acquired the fingerprint spectrum of L -Glu by using air plasma terahertz (THz) time-domain spectroscopy in the 0.5–18 THz range. The low frequency vibrational characteristics of L -Glu were investigated through density functional theory (DFT) calculations. The THz responses of the ligand binding domain of the NMDAR– L -Glu complex were studied by the ONIOM method, with a focus on discussing the normal modes and interactions of ligand L -Glu and water molecules. The results illustrate that THz spectroscopy exhibits a sensitive response to the influence of L -Glu on the structure of the NMDAR. The water molecules in proteins have various strong vibration modes in the THz band, showing specificity, diversity and complexity of vibrational behavior. There is potential for influencing and regulating the structural stability of the NMDAR– L -Glu complex through water molecules. [ABSTRACT FROM AUTHOR]

Enzyme‐modified electrodes are core components of electrochemical biosensors for diagnostic and environmental analytics and have promising applications in bioelectrocatalysis. Despite huge research efforts spanning decades, design of enzyme electrodes for superior performance remains challenging. Nanoporous gold (npAu) represents advanced electrode material due to high surface‐to‐volume ratio, tunable porosity, and intrinsic redox activity, yet its coupling with enzyme catalysis is complex. Here, the study reports a flexible‐modular approach to modify npAu with functional enzymes by combined material and protein engineering and use a tailored assortment of surface and in‐solution methodologies for characterization. Self‐assembled monolayer (SAM) of mercaptoethanesulfonic acid primes the npAu surface for electrostatic adsorption of the target enzyme (flavocytochrome P450 BM3; CYT102A1) that is specially equipped with a cationic protein module for directed binding to anionic surfaces. Modulation of the SAM surface charge is achieved by electrochemistry. The electrode‐adsorbed enzyme retains well the activity (33%) and selectivity (complete) from in‐solution. Electrochemically triggered nanoscale stirring in the internal porous network of npAu‐SAM enhances speed (2.5‐fold) and yield (3.0‐fold) of the enzyme immobilization. Biocatalytic reaction is fueled from the electrode via regeneration of its reduced coenzyme (NADPH). Collectively, the study presents a modular design of npAu‐based enzyme electrode that can support flexible bioelectrochemistry applications. [ABSTRACT FROM AUTHOR]

Secretory leukocyte protease inhibitor (SLPI) is an important cationic protein involved in innate airway immunityandhighlyexpressed inmucosal secretions, shownto target and inhibit neutrophil elastase (NE), cathepsinGand trypsinactivitytolimit proteolytic activity. Inaddition tothe potent anti-protease activity, SLPIhas beendemonstratedto exert a direct anti-inflammatory effect, which is mediated via increased inhibition and competitive binding of NF-kB, regulating immune responses through limiting transcription of pro-inflammatory gene targets. In muco-obstructive lung disorders, suchasChronicObstructivePulmonaryDisease(COPD)andCysticFibrosis (CF), there is an observed elevation in airway SLPI protein concentrations as a result of increased lung inflammation and disease progression. However, studies have identified COPD patients presenting with diminished SLPI concentrations. Furthermore, there is a decrease in SLPI concentrations through cleavage and subsequent inactivation by NE degradation in Pseudomonas aeruginosa infected people with CF (pwCF). These observations suggest reduced SLPI protein levels may contribute to the compromising of airway immunity indicating a potential role of decreased SLPI levels in the pathogenesis of muco-obstructive lung disease. The Beta Epithelial Na+ Channel transgenic (ENaC-Tg) mousemodel phenotype exhibits characteristics which replicate the pathological features observed in conditions such as COPD and CF, including mucus accumulation, alterations in airway morphology and increased pulmonary inflammation. To evaluate the effect of SLPI in muco-obstructive pulmonary disease, ENaC-Tg mice were crossed with SLPI knock-out (SLPI-/-) mice, generating a ENaC-Tg/SLPI-/- colony to further investigate the role of SLPI in chronic lung disease and determine the effect of its ablation on disease pathogenesis. [ABSTRACT FROM AUTHOR]

This study compared the safety and pharmacokinetics of a single oral dose of onradivir, an inhibitor of polymerase basic protein 2 in influenza A virus, in patients with hepatic impairment and healthy participants with normal hepatic function. Eight participants with mild hepatic impairment (Child‐Pugh A), eight participants with moderate hepatic impairment (Child‐Pugh B), and eight healthy matched controls were enrolled in this open‐label, parallel‐group clinical trial. After the administration of 600 mg of onradivir, pharmacokinetic parameters were calculated for each cohort and compared. Onradivir was generally well tolerated by all participants. No serious adverse events (AEs) and no deaths were reported during the study. Six patients with moderate hepatic impairment and three patients with mild hepatic impairment reported AEs, all of which were mild and quickly resolved. Compared with the normal liver function group, the maximum concentration, area under the curve from time zero to the last measurable concentration, and area under the curve from time zero to infinity were 103%, 68.5%, and 69.2% higher, respectively, in the mild hepatic impairment group. In the moderate hepatic impairment group, these increases were 101%, 197%, and 204%, respectively. Overall, there were clinically relevant differences in onradivir exposure between patients with mild or moderate hepatic impairment and normal controls. These data imply that onradivir dose adjustment is warranted in patients with mild or moderate hepatic impairment. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT05856513). [ABSTRACT FROM AUTHOR]

Summary: Background: Faecal biomarkers can be used to assess inflammatory bowel disease (IBD). Aim: To explore the performance of some promising biomarkers in diagnosing and predicting disease course in IBD. Methods: We included 65 patients with treatment‐naïve, new‐onset Crohn's disease (CD), 90 with ulcerative colitis (UC), 67 symptomatic controls (SC) and 41 healthy controls (HC) in this prospective observational study. We analysed faecal samples for calprotectin (FC), myeloperoxidase (MPO), human neutrophil lipocalin (HNL), eosinophil cationic protein ECP and eosinophil‐derived neurotoxin (EDN) and compared markers among groups. We assessed the diagnostic capability of biomarkers with receiver operating characteristic curves. Clinical disease course was determined for each patient with IBD and analysed the association with biomarkers by logistic regression. Results: All markers were elevated at inclusion in patients with IBD compared with HC (p < 0.001) and SC (p < 0.001). FC (AUC 0.85, 95% CI: 0.79–0.89) and MPO (AUC 0.85, 95% CI: 0.80–0.89) showed the highest diagnostic accuracy in distinguishing IBD from SC. The diagnostic ability of biomarkers differed between IBD subtypes with the highest performance for FC and MPO in CD. The diagnostic accuracy was further improved by combining FC and MPO (p = 0.02). Levels of FC, MPO and HNL at inclusion were predictive of an aggressive disease course with MPO showing the strongest association (p = 0.006). Conclusions: This study provides new insight into the diagnostic and prognostic capability of neutrophil and eosinophil biomarkers in IBD and suggests that MPO, alone or in combination with FC, may add to the diagnostic power of faecal biomarkers. [ABSTRACT FROM AUTHOR]

Objective: To explore the establishment and validation of a risk model for postoperative olfactory impairment in patients with chronic sinusitis with nasal polyps (CRSwNP) based on immunoinflammatory indexes. Methods: Retrospective analysis of 100 patients who attended CRSwNP in the Second Affiliated Hospital of Hainan Medical College from October 2020 to October 2022 all underwent nasal endoscopic surgery and were divided into no olfactory impairment group (44 cases) and olfactory impairment group (56 cases) according to the results of postoperative olfactory test, baseline data and routine examination indexes of the two groups were compared and analyzed, independent risk variables affecting olfactory impairment in CRSwNP patients were analyzed by Logistic multifactorial regression, and columnar graph prediction model was constructed and validated. Results: There were statistically significant differences in staging, lesion site, Lund-Mackay score, anterior olfactory fissure score, posterior olfactory fissure score, percentage of serum eosinophils, olfactory marker protein-positive cell count in the upper turbinate mucosa, and urea nitrogen between the two groups of CRSwNP patients (P<0.05) . IL-5, human eosinophil cationic protein (ECP) /peroxidase (MPO), tissue inhibitor of metalloproteinases 1 (TIMP1), chemokine 2 (CCL2), chemokine 3 (CCL3), chemokine 4 (CCL4), total immunoglobulin E (IgE) of tissue specimens, and total IgE of serum specimens in the olfactory impairment group were higher than those in the group without olfactory impairment, the differences were statistically significant (P<0.05) . The multifactorial logistic results were that staging, lesion site, Lund-Mackay score, anterior olfactory fissure score, posterior olfactory fissure score, IL-5, ECP/MPO, CCL4, and total IgE of tissue specimens were all independent risk factors affecting olfactory impairment in patients with CRSwNP；while olfactory marker protein-positive cell count in the upper turbinate mucosa was an independent protective factor for olfactory impairment in patients with CRSwNP. The results were validated by establishing a line graph model. The validation results of building the column line graph model suggested that the C-index of the training and validation sets were 0.858 and 0.825, respectively, and the area under the characteristic curve (AUC) of the subject patients were 0.853 and 0.815, respectively. Conclusion: A model to explore the risk of postoperative olfactory impairment in CRSwNP patients based on immunoinflammatory indexes has been established, the model with high predictive performance to help guide clinical decision making. [ABSTRACT FROM AUTHOR]

The role of Drosophila numb in regulating Notch signaling and neurogenesis has been extensively studied, with a particular focus on its effects on the peripheral nervous system (PNS). Previous studies based on a single loss-of-function allele of numb, numb1, showed an antineurogenic effect on the peripheral nervous system (PNS), which revealed that the wild-type numb suppresses Notch signaling. In the current study, we examined whether this phenotype is consistently observed in loss-of-function mutations of numb. Two more numb alleles, numbEY03840 and numbEY03852, were shown to have an antineurogenic phenotype in the PNS. We also found that introducing a wild-type numb genomic fragment into numb1 homozygotes rescued their antineurogenic phenotype. These results demonstrated that loss-of-function mutations of numb universally induce this phenotype. Many components of Notch signaling are encoded by maternal effect genes, but no maternal effect of numb was observed in this study. The antineurogenic phenotype of numb was found to be dependent on the Enhancer of split (E(spl)), a downstream gene of Notch signaling. We found that the combination of E(spl) homozygous and numb1 homozygous suppressed the neurogenic phenotype of the embryonic central nervous system (CNS) associated with the E(spl) mutation. In the E(spl) allele, genes encoding basic helix-loop-helix proteins, such as m5, m6, m7, and m8, remain. Thus, in the E(spl) allele, derepression of Notch activity by numb mutation can rescue the neurogenic phenotype by increasing the expression of the remaining genes in the E(spl) complex. We also uncovered a role for numb in regulating neuronal projections. Our results further support an important role for numb in the suppression of Notch signaling during embryonic nervous system development. [ABSTRACT FROM AUTHOR]

Bacteriocins are proteins secreted by many species of bacteria to inhibit other bacteria, thus eliminating competitors to gain resources. Bacteria from the Lactobacillus group are known for their applications as probiotics and food preservatives. They have earned a reputation for producing substances that inhibit the growth of other microorganisms, which include organic acids, diacetyl, and bacteriocins. Produced by the ribosomes, bacteriocins are cationic proteins that inhibit other bacteria coexisting within a shared ecological habitat. Due to their potential uses in a variety of applications large-scale production of Bacteriocins would be necessary. The study aimed to identify and characterize Lactobacillus bacteria that produce potent bacteriocins and to analyze the antimicrobial activity and stability of the isolated bacteriocin under various physical and biochemical conditions. A total of 50 samples including buffalo dung, cheese, and rhizospheric region of plants were screened to isolate 8 Lactobacillus Li-1, Li-2, Li-3, Li-4, Li-5, Li-6, Li-7, and Li-8, confirmed by gram staining and other biochemical tests. The cell free supernatant from the Li-3 strain showed higher inhibition of Escherichia coli and Staphylococcus aureus, as compared to the other isolated strains. Li-3 strain was further identified as Levilactobacillus brevis strain ABRIINW-K by 16S rRNA gene sequencing. The bacteriocin isolated from this strain is a thermostable peptide (~6kDa), which is characteristic of class II bacteriocins, with potent antibacterial activity against Lactobacillus rhamnosus, Escherichia coli, and Salmonella enterica. [ABSTRACT FROM AUTHOR]

Introduction: Allergic bronchopulmonary mycosis (ABPM) is a chronic airway disease characterized by the presence of fungi that trigger allergic reactions and airway obstruction. Here, we present a unique case of ABPM in which a patient experienced sudden respiratory failure due to mucus plug-induced airway obstruction. The patient's life was saved by venovenous extracorporeal membrane oxygenation (VV-ECMO) and bronchoscopic removal of the plug. This case emphasizes the clinical significance of mucus plug-induced airway obstruction in the differential diagnosis of respiratory failure in patients with ABPM. Case study: A 52-year-old female clerical worker with no smoking history, presented with dyspnea. CT scan revealed mucus plugs in both lungs. Despite treatment, the dyspnea progressed rapidly to respiratory failure, leading to VV-ECMO placement. Results: CT revealed bronchial wall thickening, obstruction, and extensive atelectasis. Bronchoscopy revealed extensive mucus plugs that were successfully removed within two days. The patient's respiratory status significantly improved. Follow-up CT revealed no recurrence. Fungal cultures identified Schizophyllum commune, confirming ABPM. Histological examination of the mucus plugs revealed aggregated eosinophils, eosinophil granules, and Charcot-Leyden crystals. Galectin-10 and major basic protein (MBP) staining supported these findings. Eosinophil extracellular traps (EETs) and eosinophil cell death (ETosis), which contribute to mucus plug formation, were identified by citrullinated histone H3 staining. Conclusion: Differentiating between asthma exacerbation and mucus plug-induced airway obstruction in patients with ABPM and those with acute respiratory failure is challenging. Prompt evaluation of mucous plugs and atelectasis using CT and timely decision to introduce ECMO and bronchoscopic mucous plug removal are required. [ABSTRACT FROM AUTHOR]

Characterization of inflammation in chronic rhinosinusitis with (CRSwNP) and without nasal polyps (CRSsNP) is an ongoing research process. To overcome limitations of current cytologic techniques, we investigated whether immunofluorescence multiplex image cytometry could quantify intact neutrophils, eosinophils, and other immune cells in solid upper airway mucosa. We used a four-channel immunofluorescence-microscopy technique for the simultaneous detection of the leukocyte marker CD45, the neutrophil marker myeloperoxidase, two eosinophil markers, i.e., major basic protein and eosinophil peroxidase, and DAPI (4′,6-diamidin-2-phenylindole), in formalin-fixed paraffin-embedded upper airway tissue samples of patients with CRSwNP and CRSsNP, as well as of patients free of CRS with inferior turbinate hypertrophy (controls). Image acquisition and analysis were performed with TissueFAXS and StrataQuest (TissueGnostics, Vienna, Austria), respectively. Positive and negative immunostaining were differentiated with a specific fluorescence signal/background signal ratio. Isotype controls were used as negative controls. In six controls, nine patients with CRSsNP, and 11 patients with CRSwNP, the median area scanned and median cell count per patient were 14.2 mm2 and 34,356, respectively. In CRSwNP, the number of eosinophils was three times higher (23%) than that of neutrophils (7%). Three times more immune cells were encountered in CRSwNP (33%) compared to CRSsNP (11%). In controls, inflammation was balanced between the epithelial layer and lamina propria, in contrast to CRS (three times more pronounced inflammation in the lamina propria). The quantification of intact neutrophils, eosinophils, and other immune cells in solid tissue with undisrupted architecture seems feasible with immunofluorescence multiplex image cytometry. [ABSTRACT FROM AUTHOR]

• The mediators of extracellular matrix deregulation downstream of Insulin-like growth factor II (IGF-II) were investigated. • Levels of pro-Lysyl Oxidase (ProLOX), its cleavage products LOX, and Lysyl oxidase propeptide (LOX-PP) as well as the enzymes that cleave ProLOX, Tolloid-like 1 (TLL1) isoforms and bone morphogenetic protein 1 (BMP1), increased in response to IGF-II. • LOX-PP levels were increased in human systemic sclerosis lung tissues and experimental murine lung fibrosis, and LOX-PP increased levels of markers of fibrosis by primary pulmonary fibroblasts. • The class E basic helix-loop-helix protein 40 (BHLHE40) regulates IGF-II-induced LOX-PP and TLL1 isoforms, and its deficiency increases matrix metalloprotease (MMP) 1, and restores MMP3 and cathepsin K levels repressed in response to IGF-II. • Our findings suggest that LOX-PP and BHLHE40 are new potential therapeutic targets in SSc-associated pulmonary fibrosis. Pulmonary fibrosis (PF) is a clinically severe and commonly fatal complication of Systemic Sclerosis (SSc). Our group has previously reported profibrotic roles for Insulin-like Growth Factor II (IGF-II) and Lysyl Oxidase (LOX) in SSc-PF. We sought to identify downstream regulatory mediators of IGF-II. In the present work, we show that SSc lung tissues have higher baseline levels of the total (N-glycosylated/unglycosylated) LOX-Propeptide (LOX-PP) than control lung tissues. LOX-PP-mediated changes were consistent with the extracellular matrix (ECM) deregulation implicated in SSc-PF progression. Furthermore, Tolloid-like 1 (TLL1) and Bone Morphogenetic Protein 1 (BMP1), enzymes that can cleave ProLOX to release LOX-PP, were increased in SSc lung fibrosis and the bleomycin (BLM)-induced murine lung fibrosis model, respectively. In addition, IGF-II regulated the levels of ProLOX, active LOX, LOX-PP, BMP1, and isoforms of TLL1. The Class E Basic Helix-Loop-Helix protein 40 (BHLHE40) transcription factor localized to the nucleus in response to IGF-II. BHLHE40 silencing downregulated TLL1 isoforms and LOX-PP, and restored features of ECM deregulation triggered by IGF-II. Our findings indicate that IGF-II, BHLHE40, and LOX-PP may serve as targets of therapeutic intervention to halt SSc-PF progression. [ABSTRACT FROM AUTHOR]

The experiment aimed to study the extraction of protein from fermented tea residue and its effect on the apparent nutrient metabolism rate of Wannan Sanhuang chickens. The raw material was fermented tea residue, and the alkaline solubilization and acid precipitation method was used to extract the tea protein, with the protein extraction rate as the evaluation index of the orthogonal experiment to determine the optimal extraction process. One hundred and twenty one-day-old Wannan Sanhuang chickens were selected and randomly divided into four groups, with three replicates per group, each containing 10 chickens. The control group was fed a basic diet, and the experimental groups were supplemented with 0.6%, 0.8%, and 1.0% tea protein in the basic diet, respectively. The pretest period was seven days, and the formal experimental period was 28 days. A metabolic experiment was conducted at the age of 31 days to analyze the apparent metabolizable rates of dietary dry matter (DM), crude protein (CP), crude fat (EE), calcium (Ca), and phosphorus (P). The results showed that the optimal extraction conditions for tea protein were a NaOH concentration of 0.15 mol/L, an extraction time of 80 minutes, an extraction temperature of 75 ℃, a liquid-to-material ratio of 50 mL/g. Under these process conditions, the extraction rate of tea protein from fermented tea residue was 51.09%. The apparent metabolizable rates of DM, CP, EE, Ca, and P in the Wannan Sanhuang chickens fed with 0.8% and 1.0% tea protein were significantly higher than those in the control group (P<0.05). The study indicates that the addition of 0.8% to 1.0% tea protein in the diet can improve the apparent nutrient metabolism rate in Wannan Sanhuang chickens. [ABSTRACT FROM AUTHOR]

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Inflammation and autoimmune responses contribute to the pathophysiology of Long COVID, and its affective and chronic fatigue syndrome symptoms, labeled "the physio‐affective phenome." To investigate whether Long COVID and its physio‐affective phenome are linked to autoimmunity to the tight junction proteins, zonulin and occludin (ZOOC), and immune reactivity to lipopolysaccharides (LPS), and whether the latter are associated with signs of human herpes virus‐6 (HHV‐6) reactivation, autoimmunity directed against oligodendrocyte and neuronal proteins, including myelin basic protein. IgA/IgM/IgG responses to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), HHV‐6, ZOOC, and neuronal proteins, C‐reactive protein (CRP), and advanced oxidation protein products (AOPPs), were measured in 90 Long COVID patients and 90 healthy controls. The physio‐affective phenome was conceptualized as a factor extracted from physical and affective symptom domains. Neural network identified IgA directed to LPS (IgA‐LPS), IgG‐ZOOC, IgG‐LPS, and IgA‐ZOOC as important variables associated with Long COVID diagnosis with an area under the ROC curve of 0.755. Partial Least Squares analysis showed that 40.9% of the variance in the physio‐affective phenome was explained by CRP, IgA‐myelin basic protein (MBP), and IgG‐MBP. A large part of the variances in both autoimmune responses to MBP (36.3%–39.7%) was explained by autoimmunity (IgA and IgG) directed to ZOOC. The latter was strongly associated with indicants of HHV‐6 reactivation, which in turn was associated with increased IgM‐SARS‐CoV‐2. Autoimmunity against components of the tight junctions and increased bacterial translocation may be involved in the pathophysiology of Long COVID's physio‐affective phenome. [ABSTRACT FROM AUTHOR]

Background: Sputum immunoglobulin G (Sp-IgG) has been discovered to induce cytolytic extracellular trap cell death in eosinophils, suggesting a potential autoimmune mechanism contributing to asthma. This study aimed to explore the potential origin of Sp-IgG and identify clinically relevant subtypes of Sp-IgG that may indicate autoimmune events in asthma. Methods: This study included 165 asthmatic patients and 38 healthy volunteers. We measured Sp-IgG and its five subtypes against eosinophil inflammatory proteins (Sp-IgGEPs), including eosinophil peroxidase, eosinophil major basic protein, eosinophilderived neurotoxin, eosinophil cationic protein, and Charcot-Leyden Crystal protein in varying asthma severity. Clinical andMendelian randomization (MR) analyses were conducted. A positive Sp-IgGEPs signature (Sp-IgGEPs+) was defined when any of the five Sp-IgGEPs values exceeded the predefined cutoff thresholds, calculated as the mean values of healthy controls plus twice the standard deviation. Results: The levels of Sp-IgG and Sp-IgGEPs were significantly elevated in moderate/severe asthma than those in mild asthma/healthy groups (all p < 0.05). Sp-IgG levels were positively correlated with airway eosinophil and Sp-IgGEPs. MR analysis showed causality between eosinophil and IgG (OR = 1.02, 95%CI = 1.00-1.04, p = 0.020), and elevated IgG was a risk factor for asthma (OR = 2.05, 95%CI = 1.00-4.17, p = 0.049). Subjects with Sp-IgGEPs+ exhibited worse disease severity and served as an independent risk factor contributing to severe asthma (adjusted-OR = 5.818, adjusted-95% CI = 2.193-15.431, adjusted-p < 0.001). Receiver operating characteristic curve analysis demonstrated that the combination of Sp-IgGEPs+ with non-allergic status, an ACT score < 15, and age = 45 years, effectively predicted severe asthma (AUC = 0.84, sensitivity = 86.20%, specificity = 67.80%). Conclusion: This study identifies a significant association between airway eosinophilic inflammation, Sp-IgG, and asthma severity. The Sp-IgGEPs panel potentially serves as the specific biomarker reflecting airway autoimmune events in asthma. [ABSTRACT FROM AUTHOR]

Eosinophil-mediated pathophysiology is tissue destructive and tissue altering with proinflammatory, prothrombotic, and profibrotic effects. The distinctive morphology of an eosinophil reveals a cytoplasm chockfull of unique granules, and the granule proteins have numerous toxic effects on cells, tissues, and organs. Eosinophils are not found in most human tissues, and eosinophil involvement in diseased tissues generally is identified by cell infiltration on histopathologic examination. However, eosinophils characteristically lose their structural integrity and deposit granules and granule proteins at sites of inflammation. Hence, their participation in tissue damage may be underrecognized or entirely overlooked. The eosinophil major basic protein 1 is a toxic granule protein and, when deposited, persists in tissues. Major basic protein 1 deposition can be regarded as a footprint of eosinophil activity. Analyses of numerous eosinophil-related diseases have demonstrated clear-cut evidence of major basic protein 1 deposition in affected tissues where eosinophils were not recognized by hematoxylin and eosin tissue staining and light microscopy. Eosinophil granule protein deposition, as exemplified by localization of major basic protein 1, especially when disproportionately greater than cellular infiltration, emerges as a biomarker of hidden eosinophil-related pathophysiology. Consequently, current assessments of recognized eosinophils may vastly underestimate their role in disease. [ABSTRACT FROM AUTHOR]

Inflammatory bowels diseases (IBD) are high risk conditions for colorectal cancer (CRC). The discovery of IBD and CRC noninvasive protein/peptide biomarkers using saliva and feces was the aim of this study involving 20 controls, 25 IBD (12 Crohn's Disease-CD), 37 CRC. By untargeted proteomic (LTQ-Orbitrap/MS), a total of 152 proteins were identified in saliva. Absent in controls, 73 proteins were present in both IBD and CRC, being mainly related to cell-adhesion, cadherin-binding and enzyme activity regulation (g-Profiler). Among the remaining 79 proteins, 14 were highly expressed in CD and 11 in CRC. These proteins clustered in DNA replication/expression and innate/adaptive immunity. In stool, endogenous peptides from 30 different proteins were identified, two being salivary and CD-associated: Basic Proline-rich Protein 1 (PRBs) and Acidic Proline-rich Phosphoprotein. Biological effects of the PRBs-related peptides GQ-15 and GG-17 found in CD stool were evaluated using CRC cell lines. These peptides induced cell proliferation and activated Erk1/2, Akt and p38 pathways. In conclusion, the salivary proteome unveiled DNA stability and immunity clusters shared between IBD and CRC. Salivary PRB-derived peptides, enriched in CD stool, stimulate CRC cell proliferation and the pro-oncogenic RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways suggesting a potential involvement of PRBs in IBD and cancer pathogenesis. [ABSTRACT FROM AUTHOR]

SUMMARY: The jasmonic acid (JA) signaling pathway plays an important role in promoting the biosynthesis of tanshinones. While individual transcription factors have been extensively studied in the context of tanshinones biosynthesis regulation, the influence of methyl jasmonate (MeJA)‐induced transcriptional complexes remains unexplored. This study elucidates the positive regulatory role of the basic helix–loop–helix protein SmMYC2 in tanshinones biosynthesis in Salvia miltiorrhiza. SmMYC2 not only binds to SmGGPPS1 promoters, activating their transcription, but also interacts with SmMYB36. This interaction enhances the transcriptional activity of SmMYC2 on SmGGPPS1, thereby promoting tanshinones biosynthesis. Furthermore, we identified three JA signaling repressors, SmJAZ3, SmJAZ4, and SmJAZ8, which interact with SmMYC2. These repressors hindered the transcriptional activity of SmMYC2 on SmGGPPS1 and disrupted the interaction between SmMYC2 and SmMYB36. MeJA treatment triggered the degradation of SmJAZ3 and SmJAZ4, allowing the SmMYC2–SmMYB36 complex to subsequently activate the expression of SmGGPPS1, whereas SmJAZ8 inhibited MeJA‐mediated degradation due to the absence of the LPIARR motif. These results demonstrate that the SmJAZ‐SmMYC2–SmMYB36 module dynamically regulates the JA‐mediated accumulation of tanshinones. Our results reveal a new regulatory network for the biosynthesis of tanshinones. This study provides valuable insight for future research on MeJA‐mediated modulation of tanshinones biosynthesis. Significance Statement: The results demonstrate that the SmJAZ‐SmMYC2–SmMYB36 module dynamically regulates the jasmonic acid‐mediated accumulation of tanshinones. [ABSTRACT FROM AUTHOR]

Dof transcription factor family in Cyperus esculentus genome was identified and analyzed using bioinformatics. The analysis results revealed that C.esculentus genome contains 29 Dof genes (CesDof), all of which are located in the nucleus according to subcellular localization prediction. CesDof proteinrs have a range of 124 to 512 amino acids, with most being basic proteins. Their secondary structure was mainly irregular curl. The promoter sequence of CesDof genes contains cis-acting elements that respond to light, drought, hormones, low temperature, and circadian rhythm. Codon preference analysis showed that CesDof genes' codon preference ends in T/A. Collinearity analysis revealed that C.esculentus had three pairs of collinear CesDof genes. Additionally, there were 15 pairs of collinear genes between C.esculentus and Arabidopsis thaliana. The genetic relationship between C.esculentus and Rhynchospora pubera was found to be the closest. Phylogenetic tree analysis revealed that 29 CesDof genes of C.esculentus can be classified into 4 subgroups. Additionally, 144 miRNAs were predicted to target these CesDof genes. Furthermore, protein interaction analysis indicated that 15 Dof proteins in C.esculentus had interactions. The qRT-PCR verification results of drought stress and salt stress treatment experiments showed that most CesDof genes were involved in drought stress and salt stress responses, and the gene expression trends under drought stress and salt stress conditions were consistent. These results lay a theoretical foundation for further studying the molecular functions of Dof gene family in C.esculentus and its molecular mechanisms in regulating the life activities of C.esculentus. [ABSTRACT FROM AUTHOR]

Gag-Pol protein is one of the important structural proteins of human immunodeficiency virus (HIV), comprising the basic scaffold proteins and functional enzymes required during the lifecycle of HIV. Currently, the inhibitors targeting different functional domains on Gag-Pol include capsid (CA) inhibitors, protease inhibitors, reverse transcriptase inhibitors, and integrase inhibitors. The CA inhibitors inhibit the maturation of CA or disrupt the assembly of CA, so as to affect the replication of HIV. The primary mechanism of protease inhibitors is to inhibit the protease from cleaving at the cleavage site CA-spacer peptide 1 (SP1). The reverse transcriptase inhibitors block the reverse transcription process of HIV by mimicking the reverse transcription substrates. The integrase inhibitors impact the activity of integrase by targeting the zinc-finger structure at the active center of integrase. This article summarizes the inhibitors targeting HIV Gag-Pol protein and their mechanisms, and reviews the approved dosages and usages of approved patent drugs, so as to provide the references for the future clinical combination therapies and the development of new inhibitors targeting HIV Gag-Pol protein. [ABSTRACT FROM AUTHOR]

The limited range of available flu treatments due to virus mutations and drug resistance have prompted the search for new therapies. RNA-dependent RNA polymerase (RdRp) is a heterotrimeric complex of three subunits, i.e., polymerase acidic protein (PA) and polymerase basic proteins 1 and 2 (PB1 and PB2). It is widely recognized as one of the most promising anti-flu targets because of its critical role in influenza infection and high amino acid conservation. In particular, the disruption of RdRp complex assembly through protein–protein interaction (PPI) inhibition has emerged as a valuable strategy for discovering a new therapy. Our group previously identified the 3-cyano-4,6-diphenyl-pyridine core as a privileged scaffold for developing PA–PB1 PPI inhibitors. Encouraged by these findings, we synthesized a small library of pyridine and pyrimidine derivatives decorated with a thio-N-(m-tolyl)acetamide side chain (compounds 2a–n) or several amino acid groups (compounds 3a–n) at the C2 position. Interestingly, derivative 2d, characterized by a pyrimidine core and a phenyl and 4-chloro phenyl ring at the C4 and C6 positions, respectively, showed an IC50 value of 90.1 μM in PA–PB1 ELISA, an EC50 value of 2.8 μM in PRA, and a favorable cytotoxic profile, emerging as a significant breakthrough in the pursuit of new PPI inhibitors. A molecular modeling study was also completed as part of this project, allowing us to clarify the biological profile of these compounds. [ABSTRACT FROM AUTHOR]

The efficacy of macrolides in the management of asthma has been studied but remains controversial. We conducted a systematic review and meta-analysis of macrolides in the management of adult patients with asthma. Randomized controlled trials of macrolides used in adult patients with asthma were searched for in MEDLINE, EMBASE, PsycINFO, Cochrane Library, CINAHL, and Igaku Chuo Zasshi databases to evaluate the efficacy and safety of macrolides. Seventeen reports with macrolide treatment durations ranging from 6 to 48 weeks were included. Macrolides did not reduce exacerbations requiring hospitalization, severe exacerbations, or rescue use of short-acting beta-2 agonist inhalers; improve lung function; decrease peripheral blood or sputum neutrophil counts; or decrease fractional exhaled nitric oxide compared to placebo. Macrolides statistically improved asthma control and quality of life but by less than the minimal clinically important difference. Peripheral blood eosinophil counts as well as serum and sputum eosinophilic cationic protein concentrations were significantly decreased with macrolides compared to placebo. The improvement of asthma symptoms and airway hyperresponsiveness varied by study. The safety profile of macrolides was comparable to that of placebo. Although macrolides have some useful clinical aspects, there is not sufficient evidence to recommend their use in the management of adult patients with asthma. [ABSTRACT FROM AUTHOR]

Copyright of Advances in Biochemistry / Postepy Biochemii is the property of Polish Biochemical Society / Acta Biochimica Polonica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Two‐dimensional electrophoresis (2DE) is a gel‐based protein separation method based on size and charge which is commonly used for the characterization of host cell proteins (HCPs) during drug development in biotech and pharmaceutical companies. HCPs are a heterogenous mixture of proteins produced by host cells during a biologics drug manufacturing process. Different gel electrophoresis methods including traditional 2D SDS‐PAGE with silver and SYPRO Ruby fluorescent dye staining as well as two‐dimensional difference gel electrophoresis (2D‐DIGE) were compared for their relative abilities to characterize HCPs. SYPRO Ruby was shown to be more sensitive than silver stain in the traditional 2D gels both with and without product protein present. Silver stain also displayed a significant preference for staining acidic proteins over basic ones while SYPRO Ruby was more consistent in imaging proteins across different isoelectric points. The non‐traditional method of 2D‐DIGE provides high resolution and reproducibility when comparing samples with similar protein profiles but was limited in imaging HCP spots due to its narrow dynamic range. Overall, 2DE is a powerful tool to separate and characterize HCPs and is optimized by choosing the best stain or method for each specific application. Using a combination of two or more different 2DE staining methods, when possible, provides the most comprehensive coverage to support the characterization of a complex mixture like HCPs. However, in instances where only one staining method can be used, SYPRO Ruby is shown to be the more reliable, more sensitive, and easier to use traditional staining method for most HCP‐based applications. [ABSTRACT FROM AUTHOR]

The human cationic antimicrobial protein (hCAP) corresponding to the overlapping sequences of 151–162 of hCAP named KR-12 peptide is the smallest portion of the only type of human Cathelicidin, which has been shown to be modifiable into a more effective antimicrobial. In this study, an in silico analysis, supported by potentiometric titration and isothermal titration calorimetry techniques, was performed to identify potential Cu(II) binding sites of KR-12. The analysis of the presented data at the given theoretical level (GFN2-xTB/ALPB) revealed which peptide chain fragments are involved in the most favourable KR-12–Cu(II) binding mode. Based on a quantum chemical approach, the most favourable coordination modes of Cu(II) to peptides are proposed together with the discussion of the chemical nature of the interactions. The presented results demonstrated that KR-12 interacts with metal ions mostly via the main chain's oxygen atoms; however, the two types of amino acids that are expected to be vital for the interaction of Cu(II) are D (aspartic acid) and R29 (arginine). It was demonstrated that in order to explain the complexity of the interaction process in peptide–metal ion systems, the use of theoretical methods is sometimes necessary to explain the details of the experimental results and provide an in-depth understanding of these dynamic systems. [ABSTRACT FROM AUTHOR]

Unfractionated heparin (UFH) and its low-molecular-weight fragments (LMWH) are widely used as anticoagulants for surgical procedures and extracorporeal blood purification therapies such as cardiovascular surgery and dialysis. The anticoagulant effect of heparin is essential for the optimal execution of extracorporeal blood circulation. However, at the end of these procedures, to avoid the risk of bleeding, it is necessary to neutralize it. Currently, the only antidote for heparin neutralization is protamine sulphate, a highly basic protein which constitutes a further source of serious side events and is ineffective in neutralizing LMWH. Furthermore, dialysis patients, due to the routine administration of heparin, often experience serious adverse effects, among which HIT (heparin-induced thrombocytopenia) is one of the most severe. For this reason, the finding of new heparin antagonists or alternative methods for heparin removal from blood is of great interest. Here, we describe the synthesis and characterization of a set of biocompatible macroporous cryogels based on poly(2-hydroxyethyl methacrylate) (pHEMA) and L-lysine with strong filtering capability and remarkable neutralization performance with regard to UFH and LMWH. These properties could enable the design and creation of a filtering device to rapidly reverse heparin, protecting patients from the harmful consequences of the anticoagulant. [ABSTRACT FROM AUTHOR]

TGF-β supergene family has a wide range of physiological functions including cell adhesion, motility, proliferation, apoptosis, and differentiation. We systematically analyzed and characterized the TGF-β gene superfamily from the whole blue whale (Balaenoptera musculus) genome, using comparative genomic and evolutionary analysis. We identified 30 TGF-β genes and were split into two subgroups, BMP-like and TGF-like. All TGF-β proteins demonstrating a basic nature, with the exception of BMP1, BMP2, BMP10, GDF2, MSTN, and NODAL modulator, had acidic characteristics. All the blue whale (B. musculus) TGF-β proteins, excluding BMP1, are thermostable based on aliphatic index. The instability index showed all proteins except the NODAL modulator was unstable. TGF-β proteins showed a hydrophilic character, with the exception of GDF1 and INHBC. Moreover, all the detected TGF-β genes showed evolutionary conserved nature. A segmental duplication was indicated by TGF-β gene family, and the Ka/Ks ratio showed that the duplicated gene pairs were subjected to selection pressure, indicating both purifying and positive selection pressure. Two possible recombination breakpoints were also predicted. This study provides insights into the genetic characterization and evolutionary aspects of the TGF-β superfamily in blue whales (B. musculus). [ABSTRACT FROM AUTHOR]

Although the cough reflex is one of the essential protective mechanisms in the respiratory tract, it is considered a considerable health problem in adults and children when it becomes chronic and hypersensitive. However, the need for biomarkers for chronic cough in children and adults is critical. The problem with cough is also a severe symptom in hypersensitivity children. Respiratory infections are a considerable challenge for pediatricians, especially in allergic children. The term cough hypersensitivity syndrome, although introduced in adults, was questioned for children. Eosinophil cationic protein (ECP) is a promising marker for chronic cough but still needs to be validated and proved in clinical settings. In this review article, we aimed to discuss the possible role of ECP in connection to IgE for chronic cough in children. [ABSTRACT FROM AUTHOR]

Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. Rises in the epithelial barrier permeability of airways alter tissue homeostasis and allow the penetration of allergens and other external agents. Different factors contribute to barrier impairment, such as eosinophilic infiltration and allergen protease action—eosinophilic cationic proteins' effects and allergens' proteolytic activity both contribute significantly to epithelial damage. In the airways, allergen proteases degrade the epithelial junctional proteins, allowing allergen penetration and its uptake by dendritic cells. This increase in allergen–immune system interaction induces the release of alarmins and the activation of type 2 inflammatory pathways, causing or worsening the main symptoms at the skin, bowel, and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic protease-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance, and progression. Moreover, we will explore potential clinical and radiological biomarkers of airway remodeling in allergic asthma patients. [ABSTRACT FROM AUTHOR]

Insects are the largest group of animals when it comes to the number and diversity of species. Yet, with the exception of Drosophila, no information is currently available on the primary structure of their sperm nuclear basic proteins (SNBPs). This paper represents the first attempt in this regard and provides information about six species of Neoptera: Poecillimon thessalicus, Graptosaltria nigrofuscata, Apis mellifera, Nasonia vitripennis, Parachauliodes continentalis, and Tribolium castaneum. The SNBPs of these species were characterized by acetic acid urea gel electrophoresis (AU-PAGE) and high-performance liquid chromatography fractionated. Protein sequencing was obtained using a combination of mass spectrometry sequencing, Edman N-terminal degradation sequencing and genome mining. While the SNBPs of several of these species exhibit a canonical arginine-rich protamine nature, a few of them exhibit a protamine-like composition. They appear to be the products of extensive cleavage processing from a precursor protein which are sometimes further processed by other post-translational modifications that are likely involved in the chromatin transitions observed during spermiogenesis in these organisms. [ABSTRACT FROM AUTHOR]

Sperm nuclear basic proteins (SNBPs) were isolated from extracted antheridia-rich male gametophytes raised from spores of the swordfern, Polystichum munitum. Electrophoretic (acetic acid-urea PAGE and SDS-PAGE) and chromatographic (rp-HPLC) characterization of the nuclear proteins exhibited the characteristics of the histone (H-type). In both types of gel electrophoresis, histones H1, H2A, and H2B showed an altered electrophoretic mobility corresponding to that which is routinely observed for the histones in other plants. Histones present during spermatogenesis of the fern P. munitum were compared with the few current SNBPs known to be present in higher and lower evolutionary plant clades. A transition from an early protamine (P-type) SNBPs in charophytes and bryophytes to the (H-type) SNBP observed here is reminiscent of similar reversions observed in the animal kingdom. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is the most prevalent form of non-infectious rhinitis and is characterized by an immune response mediated by immunoglobulin E (IgE). Aim: This study aims to compare the levels of biochemical markers and other parameters in individuals with AR, non-allergic rhinitis(n-AR), allergic rhinitis accompanied by symptoms of the lower respiratory tract(AR-SLRT), and healthy controls. Study Design: Case control study. Methods: Blood samples from the three study groups, AR (n = 22), n-AR (n=20), AR-SLRT group (n = 21), and the control group (n = 18), were analyzed to ascertain the levels of total IgE, specific IgE, periostin, pendrin, vitamin D, thyroid-stimulating hormone (TSH), free triiodothyronine (Ft3), free thyroxine (Ft4), anti-thyroid peroxidase (TPO), and eosinophilic cationic protein (ECP), as well as the leukocyte formula and hemogram. Results: The AR and n-AR groups had significantly higher hematocrit values in comparison to the control group(p< 0.05). Further, eosinophil counts were significantly higher in the AR and AR-SLRT groups than in the control group(p< 0.05). Total IgE levels were significantly higher in the AR-SLRT group than in the AR, n-AR, and control groups (p< 0.05). The AR group had higher total IgE values compared to the control group and the n-AR group(p< 0.05). The values of ECP, periostin, pendrin, Ft3, Ft4, TSH, anti-TPO, and vitamin D did not differ significantly between the groups(p 0.05). Conclusion: All the investigated groups did not differ in ECP, periostin, pendrin, Ft3, Ft4, TSH, anti-TPO, or vitamin D parameters. The groups with positive AR and AR-SLRT had higher eosinophil counts than the control group. The group with AR-SLRT had higher total IgE concentrations than the other groups. [ABSTRACT FROM AUTHOR]

Sinking particles are a critical conduit for the transport of surface microbes to the ocean's interior. Vertical connectivity of phylogenetic composition has been shown; however, the functional vertical connectivity of microbial communities has not yet been explored in detail. We investigated protein and taxa profiles of both free-living and particle-attached microbial communities from the surface to 3000 m depth using a combined metaproteomic and 16S rRNA amplicon sequencing approach. A clear compositional and functional vertical connectivity of microbial communities was observed throughout the water column with Oceanospirillales, Alteromonadales, and Rhodobacterales as key taxa. The surface-derived particle-associated microbes increased the expression of proteins involved in basic metabolism, organic matter processing, and environmental stress response in deep waters. This study highlights the functional vertical connectivity between surface and deep-sea microbial communities via sinking particles and reveals that a considerable proportion of the deep-sea microbes might originate from surface waters and have a major impact on the biogeochemical cycles in the deep sea. [ABSTRACT FROM AUTHOR]

Background: Schistosoma japonicum eggs lodge in the liver and induce a fibrotic granulomatous immune response in the liver of host. Galectin 3 (Gal-3) is a protein implicated in fibrosis in multiple organs. However, the pathology and molecular mechanisms promoting hepatic granuloma formation remain poorly understood. Methods: To investigate the effect of blocking galectin-receptor interactions by α-lactose on liver immunopathology in mice with S. japonicum infection, C57BL/6 mice were infected with S. japonicum and alpha (α)-lactose was intraperitoneally injected to block the interactions of galectins and their receptors. Results: Compared with S. japonicum-infected mice, there were significantly decreased Gal-3 mRNA and protein expression levels, decreased intensity of Gal-3 fluorescence in the liver, decreased serum ALT and AST levels, decreased egg numbers of S. japonicum in the liver section, attenuated hepatic and spleen pathology, and alleviated liver fibrosis accompanied with decreased protein expression levels of fibrosis markers [α-smooth muscle actin (α-SMA), collagen I, and collagen IV] in the liver of S. japonicum-infected mice blocked galectin-receptor interactions with hematoxylin-eosin staining, Masson's trichrome staining, immunohistochemistry, or Western blot analysis. Compared with S. japonicum-infected mice, blocking galectin-receptor interactions led to increased eosinophil infiltration and higher eosinophil cationic protein (ECP) expression in the liver, accompanied by increased mRNA levels of eosinophil granule proteins [ECP and eosinophil peroxidase (EPO)], IL-5, CCL11, and CCR3 in the liver and decreased mRNA levels of Gal-3 and M2 macrophage cytokines (TGF-β, IL-10, and IL-4) in the liver and spleen by using quantitative real-time reverse transcription-polymerase chain reaction. In addition, there were increased Beclin1 protein expression and protein expression ratio of LC3B-II/LC3B-I and decreased p62 protein expression and protein expression ratios of phospho-mTOR/mTOR and phospho-AKT/AKT by Western blot; increased double-labeled F4/80+/LC3B+ cells by immunofluorescence staining; increased M1 macrophage polarization in the liver of S. japonicum-infected mice blocked galectin-receptor interactions by flow cytometric analysis and immunofluorescence staining. Conclusions: Our data found that blockage of galectin-receptor interactions downregulated Gal-3, which in turn led to reduced liver functional damage, elevated liver eosinophil recruitment, promoted macrophage autophagy through the Akt/mTOR signaling pathway, and alleviated liver pathology and fibrosis. Therefore, Gal-3 plays a pivotal role during S. japonicum infection and could be a target of pharmacologic potential for liver fibrosis induced by S. japonicum infection. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is the primary cause of bronchiolitis-related hospitalizations among children under 5 years of age, with reinfection being common throughout life. Maternal vaccination has emerged as a promising strategy, delivering elevated antibody levels to newborns for immediate protection. However, limited research has explored the protective efficacy of maternal antibodies (matAbs) against secondary RSV infections in offspring. To address this gap, we employed a mouse model of maternal RSV vaccination and secondary infection of offspring to evaluate lung pathology following RSV reinfection in mice with varying levels of maternal antibody (matAb). Additionally, we aimed to investigate the potential causes of exacerbated lung inflammation in offspring with high matAb levels following secondary RSV exposure. Our findings revealed that offspring with elevated levels of maternal pre-F antibody demonstrated effective protection against lung pathology following the initial RSV infection. However, this protection was compromised upon reinfection, manifesting as heightened weight loss, exacerbated lung pathology, increased expression of RSV-A N genes, eosinophilia, enhanced IL-5, IL-13, MUC5AC, and eosinophils Major Basic Protein (MBP) production in lung tissue compared to offspring lacking matAbs. Importantly, these unexpected outcomes were not attributed to antibody-dependent enhancement (ADE) resulting from declining matAb levels over time. Notably, our findings showed a decline in secretory IgA (sIgA), mucosal IgA, and mucosal IgG levels in offspring with high matAb levels post-primary RSV challenge. We propose that this decline may be a critical factor contributing to the ineffective protection observed during secondary RSV exposure. Overall, these findings offer valuable insights intomaternal vaccination against RSV, contributing to a comprehensive understanding and mitigation of potential risks associated with maternal RSV vaccination. [ABSTRACT FROM AUTHOR]

As a versatile genome editing tool, the CRISPR-Cas9 system induces DNA double-strand breaks at targeted sites to activate mainly two DNA repair pathways: HDR which allows precise editing via recombination with a homologous template DNA, and NHEJ which connects two ends of the broken DNA, which is often accompanied by random insertions and deletions. Therefore, how to enhance HDR while suppressing NHEJ is a key to successful applications that require precise genome editing. Histones are small proteins with a lot of basic amino acids that generate electrostatic affinity to DNA. Since H2A.X is involved in DNA repair processes, we fused H2A.X to Cas9 and found that this fusion protein could improve the HDR/NHEJ ratio by suppressing NHEJ. As various post-translational modifications of H2A.X play roles in the regulation of DNA repair, we also fused H2A.X mimicry variants to replicate these post-translational modifications including phosphorylation, methylation, and acetylation. However, none of them were effective to improve the HDR/NHEJ ratio. We further fused other histone variants to Cas9 and found that H2A.1 suppressed NHEJ better than H2A.X. Thus, the fusion of histone variants to Cas9 is a promising option to enhance precise genome editing. [ABSTRACT FROM AUTHOR]

Objective: Although the role of brain-derived neurotrophic factor (BDNF) in allergic rhinitis and/or nasal polyps (NPs) development has been studied, the contribution of BDNF in non-allergic NPs has not been evaluated yet. This study was to investigate the possible role of BDNF in non-allergic NPs pathogenesis. Methods: The study was carried out at The Second Hospital of Shandong University from December 2020 to November 2021. The non-allergic NPs patients (n=26) and the control group (n=22) were included. Lund-Mackay CT scores, nasal endoscopy scores, and pulmonary function testing were evaluated before surgery. Tissue and serum levels of BDNF, eosinophil cationic protein (ECP), and cytokeratins 5 (CK5) were assessed between different groups. Result: The BDNF level in serum and tissue, CK5 count, and eosinophil infiltration in tissue were higher in non-allergic NPs. The eosinophils infiltration, ECP mRNA expression level, as well as BDNF mRNA level were increased in the BDNPigh subgroup compared with BDNFlow subgroup. Significantly negative correlations between BDNF count and the situation of airway obstruction were found in non-allergic NPs. Conclusion: BDNF may have both local and systemic effects in non-allergic NPs pathogenesis. BDNF may be a possible therapeutic target or an indicator for eosinophilic NPs management. [ABSTRACT FROM AUTHOR]

• A total number of 24 AAP and 14 CAT proteins in maize were identified. • Among all, 22 AAPs and 12 CATs were basic proteins localized in plasma membrane. • ZmAAPs and CATs showed significant structural variation. • Promoters of analyzed genes consist phytohormone and stress-related cis-elements. • Genes distributed in different chromosomes showed significant upregulation in drought. In maize, the amino acid permease (AAP) and the cationic amino acid transporters (CAT) play a significant role in amino nitrogen (N) uptake, transport, utilization, and homeostasis. Hence, genome-wide analysis of maize AAP and CAT resulted in 24 AAP (1-24) and 14 CAT (1-14) proteins in maize having significant variation in molecular weights. Most proteins are basic and localized in the plasma membrane. AAPs and CATs showed up to 7 and 14 introns respectively. All proteins showed multiple motifs, alpha-helices, transmembrane helices (except ZmAAP23), and coiled in nature. The ZmAAP and ZmCAT promoters consisted of phytohormone, plant growth and development, and stress-related cis -elements. All genes are distributed in different chromosomes. All the above properties are consistent with the same in Arabidopsis, which represent their functional similarities. Significantly higher transcription of some AAPs and CATs in vegetative and/or reproductive tissues reveal their great potential to source-sink transport and reuptake of leaked amino N from the rhizosphere. Interestingly, some members of the above-mentioned families are also upregulated during drought stress revealing their great role in drought tolerance or acclimatization during the stress. For increasing drought tolerance, these transporters might interact with the genes regulating the turgor pressure of the guard cells for increasing stomatal closure and reducing transpiration in leaves through controlling cellular osmotic homeostasis. [ABSTRACT FROM AUTHOR]

Phosphorylation of tyrosine is the basic mode of protein function and signal transduction in organisms. This process is regulated by protein tyrosine kinases (PTKs) and protein tyrosinases (PTPs). Immunoreceptor tyrosine-based inhibition motif (ITIM) has been considered as regulating the PTP activity through the interaction with the partner proteins in the cell signal pathway. The ITIM sequences need to be phosphorylated first to active the downstream signaling proteins. To explore potential regulatory mechanisms, the ITIM sequences of two transmembrane immunoglobulin proteins, myelin P0 protein-related protein (PZR) and programmed death 1 (PD-1), were analyzed to investigate their interaction with proteins involved in regulatory pathways. We discovered that phosphorylated ITIM sequences can selectively interact with the tyrosine phosphatase SHP2. Specifically, PZR-N-ITIM (pY) may be critical in the interaction between the ITIM and SH2 domains of SHP2, while PD1-C-ITSM (pY) may play a key role in the interaction between the ITIM and SH2 domains of SHP2. Quite a few proteins were identified containing the SH2 domain, exhibiting phosphorylation-mediated interaction with PZR-ITIM. In this study, 14 proteins with SH2 structural domains were identified by GO analysis on 339 proteins associated to the affinity pull-down of PZR-N-ITIM (pY). Through the SH2 domains, these proteins may interact with PZR-ITIM in a phosphorylation-dependent manner. [ABSTRACT FROM AUTHOR]

This article reports on a rare case of a patient with minimal change nephrotic syndrome, juvenile temporal arteritis (JTA), and eosinophilia. JTA is a rare disease characterized by localized vasculitis involving the temporal artery, and it is more commonly seen in younger male patients. Kimura's disease, another rare disease, often involves the internal organs, including the kidney, but the simultaneous development of JTA and nephrotic syndrome has not been reported before. The patient in this case study was a middle-aged woman, which is atypical for JTA. The authors suggest that further investigation is needed to determine if JTA is a manifestation of Kimura's disease. [Extracted from the article]

There is a need for the development of additional prognostic melanoma (e.g., head and neck melanoma) biomarkers to stratify melanoma patients and reliably identify high-risk subgroups with the aim of providing effective personalized therapy. Biomarkers play an important role in the diagnosis and prognostic classification of various types of cancer and may be indicators of biological or pathological processes or responses to exposure or intervention, providing a physician with the data helpful for future decision making with regard to patient management. The advent of novel treatments and modalities for treating various stages of the disease with a notable objective response-to-survival ratio gave us good reason, in this review, to emphasize non-histological serological biomarkers for the correction and improvement in the efficacy of treatment as well as the prognosis of survival in patients with head and neck melanoma. [ABSTRACT FROM AUTHOR]