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Background: Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) is associated with poor prognosis. Surfactant protein-D (SFTPD) and mannose-binding lectin (MBL) play a critical role in innate immunity and response to bacterial infections. We investigated serum levels and genetic variants of SFTPD and MBL in CF patients. Method: Thirty-five Caucasian patients homozygous for ΔF508del were genotyped for functional relevant polymorphisms within MBL2 (promoter−221 Y/X, codons 52, 54, and 57) and SFTPD genes (Met11Thr, Ala160Thr, and Ser270Thr). Serum levels of collectins, clinical characteristics, and PA status were correlated with genetic data. Results: Patients age, gender, and PA status did not affect MBL and SFTPD serum concentrations. MBL concentrations were correlated with MBL haplotypes. Patients with chronic Pseudomonas aeroginosa infection (PAC) and MBL insufficiency had a shorter interval between first PA infection and onset of PAC (0.01 vs. 4.6 years, p < 0.04) as well as a lower median age at transition to PAC (9.8 vs. 16.4 years, p < 0.03) compared to MBL sufficient patients with PAC. SFTPD serum level and FEV1% (Spearman r = −0.41, p < 0.03) showed a negative correlation irrespective of PA infection status. The hazard ratio to PA acquisition was increased in carriers of the SFTPD haplotype 11Thr-160Ala-270Ser compared to carriers of the common 11Met-160Thr-270Ser haplotype [HR 3.0 (95%CI: 1.1–8.6), p < 0.04]. Conclusion: MBL insufficiency leads to a shorter interval between first PA infection and onset of chronic infection. Susceptibility to PA acquisition is associated with SFTPD genetic variants with 11Thr-160Ala-270Ser as risk haplotype for early PA infection. This may be due to presence of threonine associated with oligomeric structure of SFTPD and binding ability to bacteria. [ABSTRACT FROM AUTHOR]

Many studies have been conducted to determine the composition of the glycoconjugates of the mucus-secreting cells of the fundic glands of the stomach. However, the chief cells of these glands have been largely ignored because they secrete mainly zymogens with a lower glycosylation. The aim of this work was to analyze the glycoconjugates of the gastric chief cells by a battery of 17 different lectins, recognizing Fucose, N-acetylgalactosamine, Galactose, N-acetylneuraminic acid, N-acetylglucosamine and Mannose containing oligosaccharides. Histochemical techniques were performed with several lectins and also combined with two pre-treatments; β-elimination, which removes O-linked oligosaccharides, and incubation with Peptide-N-Gycosidase F, which removes N-linked oligosaccharides. In addition, acid hydrolysis was performed before WGA histochemistry, and incubation with glucose oxidase before Con A labeling. Many lectins did not stain the chief cells. In addition, the presence of O-glycans in the apical cell membrane was demonstrated with the lectins AAL, HPA, MPA/MPL, PNA, RCA-I, and WGA. Some of these O-glycans were resistant to short-term β-elimination pre-treatments. Mannose-binding lectins stained the basal cytoplasm of the chief cells. The level of glycosylation of the chief cells was lower than that of the mucous cells. The presence of O-glycans in the apical cell membrane is consistent with the presence of mucins such as MUC1 in the apical membrane of chief cells. Moreover, Mannose-binding lectins revealed N-glycosylation in the basal cytoplasm. The knowledge of gastric chief cell glycoconjugates is relevant because of their potential involvement not only in in physiological but also in pathological processes, such as cancer. [ABSTRACT FROM AUTHOR]

Since early diagnosis of sepsis may assist clinicians in initiating timely, effective, and prognosis-improving antibiotic therapy, we developed an integrated microfluidic chip (IMC) for rapid isolation of both Gram-positive and Gram-negative bacteria from blood. The device comprised a membrane-based filtration module (90 min operating time), a bacteria-capturing module using a micro-mixer containing magnetic beads coated with "flexible neck" regions of mannose-binding lectin proteins for bacteria capture (20 min), and a miniature polymerase chain reaction (PCR) module for bacteria identification (90 min via TaqMan® probe technology). The filter separated all white blood cells and 99.5% of red blood cells from bacteria, which were captured at rates approaching 85%. The PCR assay's limit of detection was 5 colony-forming units (CFU) per reaction, and the entire process was completed in only 4 h. Since this is far less than that for culture-based approaches, this IMC may serve as a promising device for detection of sepsis. [ABSTRACT FROM AUTHOR]

The gene sequence encoding the mannose-binding homodimeric protein Allium sativum leaf agglutinin (ASAL) was introduced into maize inbred lines to achieve resistance against sap-sucking corn leaf aphids in transgenic lines. Maize transformants were generated after the co-cultivation of immature maize embryos with the Agrobacterium strain LB4404 harbouring a recombinant Ti-binary ASAL construct driven by the polyubiquitin promoter. The preliminary screening of maize transformants was performed via GUS histochemical analysis, and PCR and Southern blotting confirmed the insertion of the transgene and its stable integration in five transgenic maize lines. Transcript abundance was quantified by a quantitative real-time PCR assay, which revealed variable expression of the ASAL transgene among five transgenic maize lines. The highest mRNA expression of the ASAL gene was found in the A23 transgenic maize line, while the lowest expression was found in the AU1 transgenic maize line. In planta bioassays in the T1 progeny of the transgenic maize lines revealed high resistance against corn leaf aphids compared to the control non-transgenic line. The mortality of the infesting aphids (Rhopalosiphum maidi) was found to vary from 40 to 71% compared to that of the non-transgenic control maize line. [ABSTRACT FROM AUTHOR]

Eastern (Terrapene carolina carolina) and ornate (Terrapene ornata ornata) box turtles have robust plasma antibacterial activity, however, the mechanism behind this activity is unknown. We used sheep red blood cell (SRBC) hemolysis assays, mannan‐affinity chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE), and matrix‐assisted laser desorption ionization time‐of‐flight (MALDI‐TOF) to explore the mechanisms of complement activity in box turtles. Plasma from both species demonstrated volume, time, and temperature‐dependent SRBC hemolysis, with significantly greater hemolytic activity in ornate box turtle plasma. Hemolytic activity was highly attenuated following treatment with heat, EDTA, and salicylaldoxime in both species, but was unchanged after treatment with methylamine and ammonium hydroxide. Two abundant mannan‐binding proteins (presumed C‐type lectins) were identified in eastern box turtle plasma using SDS‐PAGE and MALDI‐TOF, but ornate box turtles did not express either protein. Eastern box turtles appear to rely on the lectin pathway of complement activation while ornate box turtles utilize the alternative pathway. This study provides further evidence that mechanisms underlying immune function are not always conserved between closely related species. This finding may have important implications for explaining species differences in susceptibility to emerging threats such as disease, toxicants, and climate change. Research Highlights: Box turtle plasma lyses sheep erythrocytes in a volume, time, and temperature‐dependent manner using the complement cascade.Eastern box turtles use the lectin pathway of complement activation while ornate box turtles use the alternative pathway. [ABSTRACT FROM AUTHOR]

DC-SIGN, a Ca(2+)-dependent transmembrane lectin, is found assembled in microdomains on the plasma membranes of dendritic cells. These microdomains bind a large variety of pathogens and facilitate their uptake for subsequent antigen presentation. In this study, DC-SIGN dynamics in microdomains were explored with several fluorescence microscopy methods and compared with dynamics for influenza hemagglutinin (HA), which is also found in plasma membrane microdomains. Fluorescence imaging indicated that DC-SIGN microdomains may contain other C-type lectins and that the DC-SIGN cytoplasmic region is not required for microdomain formation. Fluorescence recovery after photobleaching measurements showed that neither full-length nor cytoplasmically truncated DC-SIGN in microdomains appreciably exchanged with like molecules in other microdomains and the membrane surround, whereas HA in microdomains exchanged almost completely. Line-scan fluorescence correlation spectroscopy indicated an essentially undetectable lateral mobility for DC-SIGN but an appreciable mobility for HA within their respective domains. Single-particle tracking with defined-valency quantum dots confirmed that HA has significant mobility within microdomains, whereas DC-SIGN does not. By contrast, fluorescence recovery after photobleaching indicated that inner leaflet lipids are able to move through DC-SIGN microdomains. The surprising stability of DC-SIGN microdomains may reflect structural features that enhance pathogen uptake either by providing high-avidity platforms and/or by protecting against rapid microdomain endocytosis.

Bilateral, ANA-positive uveitis developed in a patient with primary total mannose binding lectin (MBL) deficiency during human herpes virus type 7 (HHV-7) reactivation from latently infected salivary glands. The diagnosis of uveitis was confirmed based on eye examination, findings of optical coherence tomography, and elevated serum antinuclear antibody titer (1:320). HHV-7 reactivation from persistence was verified by blood white cell polymerase chain reaction (PCR) and eye swab PCR. The patient was diagnosed with primary MBL deficiency based on the results of enzyme-linked immunosorbent assay and special genetic testing. The serum MBL level was zero, but all other studied characteristics were within respective reference ranges. We identified three pathologic polymorphisms (223 C/T, 230 G/A, and 239 A/G) in the MBL-2 gene, which indicated a genetic origin for the detected immunodeficiency. The results of these tests provided a rationale for administering a comprehensive treatment for suppression of the autoimmune process (rituximab and methotrexate), elimination of HHV-7 DNA from blood white cells and ocular smears (valganciclovir) and compensation of primary immunodeficiency by replacement therapy with intravenous infusion of solvent-detergent-treated fresh frozen plasma containing MBL. Our comprehensive approach to treatment led not only to a complete remission of uveitis, but also to compensation of other autoimmune, allergic and infectious symptoms and signs of the immunodeficiency. The data from this report expand our knowledge on the heterogeneity of clinical signs and symptoms of primary MBL deficiency in humans and provide pathways to studies on new potential pathogenetic mechanisms of autoimmune lesions in this genetic immune dysfunction which is one of the most common in the population. [ABSTRACT FROM AUTHOR]

Gram-negative bacteria that produce Extended-spectrum beta-lactamase (ESBL) and metallo beta-lactamase (MBL) show resistance to beta-lactam antibiotics. This study was to determine Beta-lactamases-producing Pseudomonas species in fish ponds. Pseudomonas species isolated from aquaculture water samples using Pseudomonas base agar were characterised biochemically. The detection of ESBL and MBL was made by double disc synergy and imipenem-EDTA combined disc methods, respectively. Antimicrobial susceptibility was by disc diffusion method. The 94 Pseudomonas species isolated comprised P. aeruginosa (62.8%), P. stutzeri (14.9%), P. putida (9.8%) and P. fluorescens (12.8%). P. aeruginosa 16 (16.3%) and P. stutzeri 4 (4.3%) produced ESBL, but 2 (10%) P. aeruginosa and 1 (5%) P. stutzeri produced MBL. Resistance of ESBL producers to trimethoprim was 55.5% and 7 (35.0%) were multidrug resistant. Detection of ESBL and MBL in Pseudomonas spp. from this study implies environmental health risk. Antibiotics misuse in aquaculture and discharge of untreated aquaculture wastewater into the environment should be discouraged. [ABSTRACT FROM AUTHOR]

The controls and patients were divided into three groups, a control group was healthy recurrent miscarriage women. The explained group was recurrent miscarriage women with RM. The unexplained group was recurrent miscarriage women with RM.The results showed genotypes CC, TT and allele C frequencies increased in patients (33.33%, 20.00% and 56.66%, respectively) than in control (13.33%, 13.33% and 50%, respectively) and this positive relation were insignificant (P= 0.39,0.62 and 0.796, respectively). On other hand, the genotype CT and allele T showed decreased frequencies in patients (46.66 and 43.33%, respectively) than in the control (73.33% and 50%, respectively). The genotype CC and C allele showed a higher frequency in patients (73.33% and 83.3%, respectively) than in the control (13.33% and 50%, respectively). While, the genotype GT, TT, and T allele showed decreased frequencies in patients(20.00%, 6.66% and 16.66%, respectively) than in the control (73.33%, 13.33% and 50%, respectively). [ABSTRACT FROM AUTHOR]

Drug-promoted cancers are increasingly recognized as a serious clinical problem in patients receiving BRAF inhibitory treatment. Here we report on a patient with BRAF mutant hairy cell leukemia and monoclonal B-cell lymphocytosis (MBL), who responded durably to BRAF/MEK inhibitors (BRAFi/MEKi) but experienced transformation of a RAS mutant MBL to chronic lymphocytic leukemia (CLL) with accelerated nodal progression. Hypothesizing that BRAFi triggered excessive MEK-ERK signaling in the MBL/CLL clone via the CRAF/RAS complex as previously described for BRAFi-induced cancers, BRAFi was discontinued inducing a rapid remission of the CLL on MEKi alone. Liquid biopsy monitoring showed a continuous increase of the MBL/CLL clone from the start of BRAFi/MEKi treatment followed by a rapid decline upon BRAFi withdrawal. Next-generation sequencing of a cohort of patients with MBL and monoclonal gammopathy of unclear significance (MGUS) revealed that almost one third of these cases harbored RAS mutations. In view of the population frequency of lymphatic pre-malignant conditions and the prevalence of RAS mutations in such cases, vigilant surveillance remains critical in patients treated with BRAF inhibitors. [ABSTRACT FROM AUTHOR]

Parasite-released extracellular vesicles (EVs) deliver signals to the host immune system that are critical to maintaining the long-term relationship between parasite and host. In the present study, total EVs (FhEVs) released in vitro by adults of the helminth parasite Fasciola hepatica were isolated using a recently described gravity flow method that protects their structural integrity. The FhEVs molecular cargo was defined using proteomic analysis and their surface topology characterised by glycan microarrays. The proteomic analysis identified 618 proteins, 121 of which contained putative N-linked glycosylation sites while 132 proteins contained putative O-linked glycosylation sites. Glycan arrays revealed surface-exposed glycans with a high affinity for mannose-binding lectins indicating the predominance of oligo mannose-rich glycoproteins, as well as other glycans with a high affinity for complex-type N-glycans. When added to bone-marrow derived dendritic cells isolated FhEV induced a novel phenotype that was categorised by the secretion of low levels of TNF, enhanced expression of cell surface markers (CD80, CD86, CD40, OX40L, and SIGNR1) and elevation of intracellular markers (SOCS1 and SOCS3). When FhEV-stimulated BMDCs were introduced into OT-II mice by adoptive transfer, IL-2 secretion from skin draining lymph nodes (sdLN) and spleen cells was inhibited in response to both specific and non-specific antigen stimulation. Immunisation of mice with a suspension of FhEV did not elicit significant immune responses; however, in the presence of alum, FhEVs induced a mixed Th1/Th2 immune response with high antigen specific antibody titres. Thus, we have demonstrated that FhEVs induce a unique phentotype in DC capable of suppressing IL-2 secretion from T-cells. Our studies add to the growing immuno-proteomic database that will be an important source for the discovery of future parasite vaccines and immunotherapeutic biologicals. Author summary: Parasite-released extracellular vesicles (EVs) deliver signals to the host immune system that are critical to maintaining the long-term relationship between parasite and host. This study isolated total EVs (FhEVs) released in vitro by the adult stages of the parasitic worm Fasciola hepatica using a gravity flow method that protects the structural integrity of the vesicles. Proteomic analysis identified 618 proteins, 121 of which contained putative N-linked glycosylation sites while 132 proteins contained putative O-linked glycosylation sites while glycan arrays revealed surface-exposed glycans were predominantly oligo mannose-rich glycoproteins, and glycans with a high affinity for complex-type N-glycans. Since the EV molecular cargo can influence host immune cells, FhEVs were added to bone-marrow derived dendritic cells, inducing a novel cell phenotype that when adoptive transferred into OT-II mice inhibited IL-2 secretion from skin draining lymph nodes (sdLN) and spleen cells. Immunisation of mice with FhEV did not elicit significant immune responses; however, in the presence of alum, FhEVs induced a mixed Th1/Th2 immune response with high antigen specific antibody titres. This studied sheds like on the biological activity of FhEVs and added to the growing immuno-proteomic database that will be an important source for the discovery of future therapeutics. [ABSTRACT FROM AUTHOR]

Objective: To explore the influence of photobiomodulation (PBMT) as an adjuvant to scaling and root planing (SRP) for treating periodontitis among gutka chewers. Materials and methods: Self-reported smokeless-tobacco (gutka) users were enrolled; and underwent SRP with (test group) and without (control group) PBMT. Full-mouth plaque index (P-I), bleeding upon probing (BUP), probing depth (P-D) clinical attachment loss (CAL), marginal bone loss (MBL) (on mesial and distal surfaces of the teeth), and number of missing teeth were recorded before treatment and at 3 and 6 months. Group comparisons were performed and p < 0.05 was referred significant. Results: In the control group, P-I (p < 0.013), BUP (p < 0.001), and P-D (p < 0.012) were high at baseline compared with 3 months follow-up. P-I, BUP, and P-D were higher in the test group, at baseline in comparison with the 3-month (p < 0.001) and 6-month (p < 0.01) follow-up. At 3 and 6 months, scores of P-I, BUP, and P-D were high in the control compared with the test group. No difference in CAL, and mesial and distal MBL was found among patients of both groups at 3 and 6 months. Conclusions: Among gutka chewers, SRP with PBMT is more efficient than SRP alone in the management of periodontitis. [ABSTRACT FROM AUTHOR]

In this study, using pathogenic and non-pathogenic bacteria, it was analyzed whether a polyclonal serum and a monoclonal antibody to A. culbertsoni mannose-binding protein (MBP) could inhibit its interaction. The association of the amoeba with E. coli O157:H7 was very strong at a level of over 100%, but the non-pathogenic E. coli strain was about five times lower at 22%. Pathogenic K. pnueumoniae also showed high association with amoeba by about 92% as compared with pathogenic E. coli O157:H7 and S. agalactiae. The polyclonal serum to MBP inhibited E. coli O157:H7 association to amoeba 2.5 times more than untreated E. coli O157:H7. Monoclonal antibody to MBP also inhibited bacterial association with amoeba but was not stronger than the polyclonal serum. Pathogenic E. coli O157:H7 showed about 88% invasion into amoeba and decreased about 22% as compared with associated E. coli O157:H7. Polyclonal serum to MBP inhibited about 55%, 50%, and 44% in E. coli O157:H7, K. pneumoniae and S. agalactiae, respectively. The invasion of K. pneumoniae and S. agalactiae was not high as polyclonal serum but was about 8% to 10% weaker than polyclonal serum. The pathogenic strains of K. pneumoniae and S. agalactiae showed less decrease in survival as shown at invasion than E. coli O157:H7 without antibody. This study provided the information that the pathogenic bacteria could be more interactive with A. culbertsoni trophozoites as a reservoir host than non-pathogenic E. coli, and the amoeba should interact with bacteria by the MBP lectin. [ABSTRACT FROM AUTHOR]

Objective: Mannose-binding lectin (MBL) is linked to risk of cardiovascular disease (CVD) in diabetes, but the nature of the association is unclear. We investigated the association between MBL and the risk of cardiovascular events (CVE) and all-cause mortality in type 2 diabetes.Research Design and Methods: In a cohort study of 7,588 patients with type 2 diabetes, we measured serum MBL in 7,305 patients and performed MBL expression genotyping in 3,043 patients. We grouped serum MBL and MBL expression genotypes into three categories: low, intermediate, and high. Outcomes were CVE (myocardial infarction, stroke, coronary revascularization, unstable angina, or cardiovascular death) and all-cause mortality. The association with outcomes was examined by spline and Cox regression analyses.Results: Serum MBL and CVE showed a U-shaped association. Compared with the intermediate serum MBL category, the adjusted hazard ratio (HR) for CVE was 1.82 (95% CI 1.34-2.46) for the low-MBL category and 1.48 (95% CI 1.14-1.92) for the high-MBL category. We found a similar U-shaped association for all-cause mortality, but with lower risk estimates. Compared with the intermediate MBL expression genotype, the adjusted HR for CVE was 1.40 (95% CI 0.87-2.25) for the low-expression genotype and 1.44 (95% CI 1.01-2.06) for the high-expression genotype. MBL expression genotype was not associated with all-cause mortality.Conclusions: Both serum MBL and MBL expression genotype showed a U-shaped association with CVE risk in individuals with type 2 diabetes. Our findings suggest that serum MBL is a risk factor for CVD in this population. [ABSTRACT FROM AUTHOR]

This study uses a recently developed trajectory model to trace eyewall updrafts in a high-resolution Hurricane Wilma (2005) prediction to their roots in the maritime boundary layer (MBL) in order to better understand their thermodynamics and how they interact with the swirling winds. Out of 97 020 four-hour backward trajectories seeded from the upper troposphere, the 45% of them originating from the MBL are stratified into five subsamples binned by peak vertical velocity wMAX. Of particular interest are the thermodynamic characteristics of parcels belonging to the wMAX-Extreme subsample (i.e., those with wMAX exceeding 20 m s-1 ) that ascend through Wilma’s strongest convective burst (CB) cores. A vertical momentum budget computed along a selected wMAX-Extreme trajectory confirms that the parcel possesses large positive buoyancy that more than compensates for negative hydrometeor loading to yield an uppertropospheric wMAX ; 30 m s-1 . Comparing all 1170 wMAX-Extreme trajectories with all 19 296 secondary circulation trajectories shows that the former tends to originate from the MBL where equivalent potential temperature θe and ocean surface heat and moisture fluxes are locally enhanced. The wMAX-Extreme parcels become further differentiated from the background ascent in terms of their (i) greater updraft width and smaller θe reduction while ascending into the midtroposphere, implying lower environmental entrainment rates, and (ii) less hydrometeor loading in the z 5 3–5-km layer. The Lagrangian analysis herein bridges two previous studies that focused separately on the importance of high SSTs and fusion latent heat release to the development of CBs, the latter of which may facilitate upper-level warm core development through their compensating subsidence. [ABSTRACT FROM AUTHOR]

Light, sound, and microwave are important tools for many interdisciplinary applications in a multi-physical environment, and they usually are inefficient to be detected simultaneously in the same physical platform. However, at the microscopic scale, these waves can unexpectedly interact with the same microstructure through resonant enhancement, making it a unique hybrid micro-system for new applications across multiple physical channels. Here we experimentally demonstrate an optomechanical microdevice based on Brillouin lasing operation in an optical microcavity as a sensitive unit to sense external light, sound, and microwave signals in the same platform. These waves can induce modulations to the microcavity Brillouin laser (MBL) in a resonance-enhanced manner through either the pressure forces including radiation pressure force or thermal absorption, allowing several novel applications such as broadband non-photovoltaic detection of light, sound-light wave mixing, and deep-subwavelength microwave imaging. These results pave the way towards on-chip integrable optomechanical solutions for sensing, free-space secure communication, and microwave imaging. [ABSTRACT FROM AUTHOR]

Epidemiological studies of monoclonal B-cell lymphocytosis (MBL) have been conducted in limited geographical regions. Little is known about the prevalence of MBL in Asia. We investigated the prevalence and immunophenotypic characteristics of MBL in Koreans who had idiopathic lymphocytosis (lymphocyte count >4.0×109/L) and were =40 years of age. A total of 105 leftover peripheral blood samples met these criteria among those from 73,727 healthy individuals who visited the Health Promotion Center, Samsung Medical Center, Korea, from June 2018 to August 2019. The samples were analyzed using eight-color flow cytometry with the following monoclonal antibodies: CD45, CD5, CD10, CD19, CD20, CD23, and kappa and lambda light chains. The overall prevalence of MBL in the study population was 2.9% (3/105); there was one case of chronic lymphocytic leukemia (CLL)-like MBL (CD5+CD23+), one case of atypical CLL-like MBL (CD5+CD23-), and one case of CD5-MBL with a lambda restriction pattern. This is the first study on the MBL prevalence in an East Asian population, and it reveals a relatively low prevalence of MBL in healthy Korean individuals with lymphocytosis. [ABSTRACT FROM AUTHOR]

Resistance to β‐lactam antibacterials is commonly associated with the production of the serine β‐lactamases (SBLs) and/or metallo‐β‐lactamases (MBLs). Although clinically useful inhibitors for the SBLs have been developed, no equivalent inhibitors are available for the MBLs, which can hydrolyze almost all β‐lactam antibiotics, including the so‐called "last resort" carbapenems. It is still a challenging task to develop a clinically useful inhibitor that should be broad‐spectrum targeting multiple clinically relevant MBL enzymes that differ in their active site features. This review provides a detailed description of interaction modes of substrates and small‐molecule inhibitors with various MBL enzymes and highlights the importance of metal‐ and "anchor residue"‐binding features to achieve broad‐spectrum MBL inhibition. Recently emerging active site interference strategies include metal ion deprivation, metal ion replacement, and cysteine modification as challenging, but worth experimenting directions for inhibitor development. The metalloenzyme selectivity, metal‐binding pharmacophore, and cellular permeability and accumulation should be properly considered in the further development of clinically useful inhibitors to combat MBL‐mediated antibacterial resistance. [ABSTRACT FROM AUTHOR]

N-Linked glycans are critical to the infection cycle of HIV, and most neutralizing antibodies target the high-mannose glycans found on the surface envelope glycoprotein-120 (gp120). Carbohydrate-binding proteins, particularly mannose-binding lectins, have also been shown to bind these glycans. Despite their therapeutic potency, their ability to cause lymphocyte proliferation limits their application. In this study, we report one such lectin named horcolin (Hordeum vulgare lectin), seen to lack mitogenicity owing to the divergence in the residues at its carbohydrate-binding sites, which makes it a promising candidate for exploration as an anti-HIV agent. Extensive isothermal titration calorimetry experiments reveal that the lectin was sensitive to the length and branching of mannooligosaccharides and thereby the total valency. Modeling and simulation studies demonstrate two distinct modes of binding, a monovalent binding to shorter saccharides and a bivalent mode for higher glycans, involving simultaneous interactions of multiple glycan arms with the primary carbohydrate-binding sites. This multivalent mode of binding was further strengthened by interactions of core mannosyl residues with a secondary conserved site on the protein, leading to an exponential increase in affinity. Finally, we confirmed the interaction of horcolin with recombinant gp120 and gp140 with high affinity and inhibition of HIV infection at nanomolar concentrations without mitogenicity [ABSTRACT FROM AUTHOR]

The complement system is a major humoral component of immunity and is essential for the fast elimination of pathogens invading the body. In addition to its indispensable role in innate immunity, the complement system is also involved in pathogen clearance during the effector phase of adaptive immunity. The fastest way of killing the invader is lysis by the membrane attack complex, which is formed by the terminal components of the complement cascade. Not all pathogens are lysed however and, if opsonized by a variety of molecules, they undergo phagocytosis and disposal inside immune cells. The most important complement‐derived opsonins are C1q, the first component of the classical pathway, MBL, the initiator of the lectin pathway and C3‐derived activation fragments, including C3b, iC3b and C3d, which all serve as ligands for their corresponding receptors. In this review, we discuss how complement receptors are utilized by various immune cells to tackle invading microbes, or by pathogens to evade host response. [ABSTRACT FROM AUTHOR]

The marine boundary layer (MBL) is the largest transport place and reaction vessel of atmospheric mercury (Hg). The transformations of atmospheric Hg in the MBL are crucial for the global transport and deposition of Hg. Herein, Hg isotopic compositions of total gaseous mercury (TGM) and particle-bound Hg (PBM) collected during three cruises to Chinese seas in summer and winter were measured to reveal the transformation processes of atmospheric Hg in the MBL. Unlike the observation results at inland sites, isotopic compositions of TGM in the MBL were affected not only by mixing continental emissions but also largely by the oxidation of Hg0 primarily derived by Br atoms. Δ199Hg values of TGM were significantly positively correlated with air temperature in summer, indicating that processes inducing positive mass-independent fractionation of odd isotopes in TGM could be more active at low temperatures, while the relative processes might be weak in winter. In contrast, the positive Δ199Hg and high ratios of Δ199Hg/Δ201Hg in PBM indicated that alternative oxidants other than Br or Cl atoms played a major role in the formation of Hg(II) in PBM, likely following the nuclear volume effect. Our results suggest the importance of local Hg environmental behaviors caused by an abundance of highly reactive species and provide new evidence for understanding the complicated transformations of atmospheric Hg in the MBL. [ABSTRACT FROM AUTHOR]

Background: Mannose-binding lectin (MBL) mediates the innate immune response either through direct opsonisation of microorganisms or through activation of the complement system. There are conflicting data whether MBL deficiency leads to increased susceptibility to infections or not. The aim of this study was to determine if low levels of mannose-binding lectin (MBL) predict sepsis development, sepsis severity and outcome from severe sepsis or septic shock. Method: Patients aged 18 years or more with documented sepsis within 24 h after admission to the intensive care unit were included if they had participated in a health survey and donated blood samples prior to the sepsis event. A subset of these patients had stored plasma also from the acute phase. Two matched referents free of known sepsis were selected for each case. Plasma levels MBL were determined in stored samples from health surveys (baseline) and from ICU admission (acute phase). The association between MBL and sepsis, sepsis severity and in-hospital mortality were determined with 1300 ng/mL as cut-off for low levels. Results: We identified 148 patients (61.5% women) with a first-time sepsis event 6.5 years (median with IQR 7.7) after participation in a health survey, of which 122 also had samples from the acute septic phase. Both high MBL levels in the acute phase (odds ratio [95% confidence interval]) (2.84 [1.20–6.26]), and an increase in MBL levels from baseline to the acute phase (3.76 [1.21–11.72]) were associated with increased risk for in-hospital death in women, but not in men (0.47 [0.11–2.06]). Baseline MBL levels did not predict future sepsis, sepsis severity or in-hospital mortality. Conclusions: An increase from baseline to the acute phase as well as high levels in the acute phase associated with an unfavourable outcome in women. [ABSTRACT FROM AUTHOR]

Delayed homing and engraftment of hematopoietic stem progenitor cells (HSPCs) or even failure to engraft at all is significant clinical problem after hematopoietic transplant. Therefore, in order to develop more efficient homing and engraftment facilitating strategies it is important to learn more about this process. Our team has postulated that myeloablative conditioning for transplantation induces in bone marrow (BM) microenvironment a state of sterile inflammation in which elements of innate immunity activated by radio- or chemotherapy conditioning for transplant play an important role. In frame with this claim we reported that a significant role in this process plays activation of complement cascade (ComC). Accordingly, mice that that lack a fifth component (C5) of ComC turned out to engraft poorly with normal syngeneic BM cells as compared to normal control animals. In extension of our previous studies we provide for first time evidence that mannan binding lectin (MBL) pathway is involved in activation of ComC in myeloablated transplant recipient BM and thus plays an important role in homing and engraftment of HSPCs. To support this MBL-KO mice show significant defect in hematopoietic reconstitution after hematopoietic transplantation. This correlates with a decrease in expression of stromal derived factor-1 (SDF-1) and impaired activation of Nlrp3 inflammasome in irradiated BM of these mice. [ABSTRACT FROM AUTHOR]

The crustacean haemolymph contains three main cell populations; however, it is not clear which mechanisms participate in the regulation of cells related to innate immunity. This work aimed to identify potential interleukin‐like receptors that could regulate cellular responses in Cherax quadricarinatus. By histochemical analysis with murine anti‐CD25 staining (targeting the α‐chain of the IL‐2 receptor), we identified that this antibody recognizes cytoplasmic granules in semigranular and granular haemocytes. In haemocytes stimulated with phorbol myristate acetate (PMA), increased fluorescence was observed in these cytoplasmic granules, whereas staining with a human IL‐2 antibody after stimulation with 1–10 ng/ml PMA revealed no overexpression of the receptor or oxidative burst in haemocytes. Two‐dimensional Western blot analysis of haemocyte lysates showed that anti‐CD25 identified a 27.4‐kDa protein with an isoelectric point (pI) of 7.7 and a 46‐kDa protein with a pI of 6.9. De novo sequencing of these proteins identified that they had 32% homology with a mannose‐binding lectin (MBL) from Pacifastacus leniusculus. Our results indicate that a mannose‐binding lectin‐like protein could exert a protective effect that prevents damage from other activated immune responses. [ABSTRACT FROM AUTHOR]

Background. Carbapenem resistance among Gram-negative isolates caused by the production of the metallo-β-lactamase (MBL) enzyme is being increasingly reported worldwide. One of the newly emerged metallo-β-lactamases is New Delhi metallo-β-lactamase. Data regarding its occurrence in hospital setting and percentage prevalence among different Gram-negative bacterial isolates are lacking in our part. This study has been undertaken for determining the presence of the bla NDM-1 gene among the clinical isolates of imipenem-resistant Gram-negative bacteria in a tertiary care center in Dharan, Nepal. Methods. A total of 75 imipenem-resistant Gram-negative isolates were studied. These were screened for metallo-β-lactamase (MBL) production by phenotypic assays such as double-disc synergy test (DDST) and combined disc diffusion test (CDDT). PCR was performed for the molecular detection of gene NDM-1. Ten-disc method was performed to detect the presence of ESBL, AmpC, carbapenamase, and K1 β-lactamase production. Results. Using the molecular method, bla NDM-1 was detected in 36% of the isolates. Phenotypically, double-disc synergy test (DDST) and combined disc diffusion test (CDST) detected MBL production in 38.7% and 37.3% of the isolates, respectively. Ten-disc method detected ESBL in 26.6% of the isolates, but none of the isolates was found to be AmpC, carbapenamase, and K1 β-lactamase producers. Conclusion. A high percentage of the NDM-1 producer was noted among imipenem-resistant GNB. Apart from performing only antimicrobial sensitivity test, phenotypic and molecular screening should be employed to find out the actual number of metallo-β-lactamase producers and the existence of the resistance gene. [ABSTRACT FROM AUTHOR]

Background: Prompt identification of carbapenemase-harboring organisms is valuable in informing therapeutic and infection-control measures. The modified carbapenem inactivation method (mCIM) and EDTA-modified carbapenem inactivation method (eCIM) are inexpensive and easy to interpret phenotypic tests endorsed by the Clinical and Laboratory Standards Institute (CLSI) for the detection of carbapenemase-harboring Enterobacterales. Only mCIM is endorsed by CLSI for detecting carbapenemase-harboring Pseudomonas aeruginosa. eCIM's ability to delineate serine and metallo-β-lactamases (MBL) could be advantageous in areas prevalent with carbapenemase-harboring P. aeruginosa. A recent assessment of mCIM/eCIM on MBL-harboring P. aeruginosa demonstrated high eCIM sensitivity for NDMs and VIMs but not for IMP-producers. Therefore, this study aimed to determine whether increasing EDTA concentrations would enhance eCIM sensitivity for a collection of IMP-harboring P. aeruginosa isolates. Twenty-six IMP-harboring P. aeruginosa isolates were utilized. For test validation, additional P. aeruginosa isolates harboring NDM (n = 3), VIM (n = 3), KPC (n = 8), wild-type (n = 1), and Enterobacterales isolates harboring IMP (n = 6) and NDM (n = 1) were assessed. The mCIM test was conducted as outlined by CLSI. Simultaneously, the eCIM test was performed with the standard 5 mM EDTA concentration and doubling EDTA concentrations: 10 mM, 20 mM, and 40 mM. Results: Concentration-dependent improvement was observed among the IMP-harboring P. aeruginosa with eCIM sensitivities at 0, 31, 85, and 100% respectively. Remaining Enterobacterales and P. aeruginosa responded concordantly with their genotype at the standard 5 mM eCIM concentration, with doubling EDTA concentrations providing no greater sensitivity. Conclusion: Combination of mCIM and an eCIM with a 40 mM EDTA concentration appropriately capture IMP-harboring P. aeruginosa without sacrificing test utility for other carbapenemase-harboring isolates. [ABSTRACT FROM AUTHOR]

Agaricus bisporus mannose-binding protein (Abmb) was discovered as part of the mushroom tyrosinase (PPO3) complex, but its function in the mushroom has remained obscure. The protein has a β-trefoil structure that is common for Ricin-B-like lectins. Indeed, its closest structural homologs are the hemagglutinin components of botulinum toxin (HA-33) and the Ricin-B-like lectin from Clitocybe nebularis (CNL), both of which bind galactose, and actinohivin, a recently discovered mannose-binding lectin from actinomycetes. Here we show that Abmb is evolutionarily related to them, which are lectins with a β-trefoil fold. We also show for the first time that Abmb can exhibit typical lectin agglutination activity but only when in the complex with mushroom tyrosinase. This is unexpected and unique because the two proteins are not evolutionarily related and have different activities. Lectin and tyrosinase major role in defense mechanism as well as Abmb and PPO3 gene regulation during the early stages of the development of mushroom fruiting bodies suggested that Abmb has likely a function in defense against bacterial infection and/or insect-induced damage. • Abmb is evolutionarily related to them, which are lectins with a β-trefoil fold. • For the first time that Abmb can exhibit typical lectin agglutination activity but only when in the complex with mushroom tyrosinase. • Lectin and tyrosinase major role in defense mechanism as well as Abmb and PPO3 gene regulation during the early stages of the development of mushroom fruiting bodies suggested that Abmb has likely a function in defense against bacterial infection and/or insect-induced damage. [ABSTRACT FROM AUTHOR]

C-type lectins that contain collagen-like domains are known as collectins. These proteins are present both in the circulation and in extravascular compartments and are central players of the innate immune system, contributing to first-line defenses against viral, bacterial, and fungal pathogens. The collectins mannose-binding lectin (MBL) and surfactant protein D (SP-D) are regulated by tissue fibroblasts at extravascular sites via an endocytic mechanism governed by urokinase plasminogen activator receptor-associated protein (uPARAP or Endo180), which is also a collagen receptor. Here, we investigated the molecular mechanisms that drive the uPARAP-mediated cellular uptake of MBL and SP-D. We found that the uptake depends on residues within a protruding loop in the fibronectin type-II (FNII) domain of uPARAP that are also critical for collagen uptake. Importantly, however, we also identified FNII domain residues having an exclusive role in collectin uptake. We noted that these residues are absent in the related collagen receptor, the mannose receptor (MR or CD206), which consistently does not interact with collectins. We also show that the second Ctype l-like domain (CTLD2) is critical for the uptake of SPD, but not MBL, indicating an additional level of complexity in the interactions between collectins and uPARAP. Finally, we demonstrate that the same molecular mechanisms enable uPARAP to engage MBL immobilized on the surface of pathogens, thereby expanding the potential biological implications of this interaction. Our study reveals molecular details of the receptor-mediated cellular regulation of collectins and offers critical clues for future investigations into collectin biology and pathology. [ABSTRACT FROM AUTHOR]

We employ the methods of machine learning to study the many-body localization (MBL) transition in a 1D random spin system. By using the raw energy spectrum without pre-processing as training data, it is shown that the MBL transition point is correctly predicted by the machine. The structure of the neural network reveals the nature of this dynamical phase transition that involves all energy levels, while the bandwidth of the spectrum and nearest level spacing are the two dominant patterns and the latter stands out to classify phases. We further use a comparative unsupervised learning method, i.e., principal component analysis, to confirm these results. [ABSTRACT FROM AUTHOR]

Mannose‐binding lectin (MBL) is an important component of the innate immunity, and it is responsible not only for opsonization of micro‐organisms, but also for efferocytosis. The aim of this study was to investigate whether MBL concentrations and lectin complement pathway activity are altered in non‐pregnant women with previous adverse pregnancy outcomes. Patients were divided into four groups on the basis of their history of pregnancy complications, including control patients who had uncomplicated pregnancies and term deliveries (control, n = 33), and three groups of patients with a history of pregnancy complications, including preterm labour (n = 29), recurrent miscarriage (n = 19) or unexplained intrauterine foetal death (IUFD; n = 17). All women enrolled in the study had an interval of three to six months following their previous pregnancy, and they agreed to have a blood sample taken. We found significantly higher MBL concentrations and functional activity of the lectin complement pathway in healthy controls who had previous uneventful term pregnancies (1341 ng/mL; activity 100% (IQR: 62%‐100%)), compared to women with the history of IUFD (684 ng/mL, P =.008; activity 8.5% (IQR: 0%‐97.8%), P =.011), recurrent miscarriage (524 ng/mL, P =.022; activity 44% (IQR: 4%‐83%), P =.011) or preterm labour (799 ng/mL, P =.022; activity 62.5% (IQR: 0%‐83%), P =.003). Our results suggest that inadequate function of the complement lectin pathway is associated with a higher risk of preterm labour, recurrent miscarriage and unexplained intrauterine foetal death. [ABSTRACT FROM AUTHOR]

This study compared piezoelectric (PE) and conventional drills (CD) for maxillary aesthetic zone implant insertion. This was a prospective split-mouth study. Implants were divided into two groups. Beds were prepared with CDs in group I and PE in group II. The implant stability quotient (ISQ) of the mechanical implant stability (MIS) was measured intraoperatively. The ISQ of the biological implant stability (BIS) was recorded at postoperative second and fourth months. Marginal bone loss (MBL) and bone density (BMD) were measured in the first and second years after prosthetic loading. The osteotomy time was also documented for both techniques. P values <0.05 were considered significant. Sixty implants in 30 patients were included. PE provided a significantly higher ISQ. All values were above 70 throughout the follow-up period. The mean of the ISQ for MIS was 63.78 ± 1.03 and 73.89 ± 1.05 in group I and group II, respectively (p = 0.003). PE needed significantly longer osteotomy time with a mean of 11.99 ± 0.839 min. The BIS quality had high stability in group II and medium stability in group I throughout the study period. Its values decreased in both groups. Group II had a lesser percentage of decrease. However, it was significant only at time intervals between intraoperative and two months' postoperative (p = 0.004). MBL and BMD demonstrated insignificant results. The implant site preparation with PE devices should be preferred to CDs whenever possible, because they seem to enhance implant stability and osseointegration, especially at the initial stages of healing. [ABSTRACT FROM AUTHOR]

Objectives: To clarify the spectrum of morphological and molecular subtypes of medulloblastoma (MBL), in addition to MYC and MYCN amplification statuses in a cohort of Saudi patients. The latter was correlated with patient outcome. Methods: We conducted a retrospective cohort study of 57 patients with MBL, diagnosed at the central laboratory of King Abdulaziz Medical City in Riyadh, Saudi Arabia, between 2006 and 2019. Molecular analysis for MYC and MYCN amplification was performed for the 19 most recently diagnosed patients. Results: Classic MBL was the most prevalent histologic subtype and MBL with extensive nodularity was the rarest. The non-WNT/non-SHH molecular subgroup was the most common while the WNT-activated was the least common. Among 19 patients analyzed, MYC and MYCN amplifications were discovered in 2 (10.5%) and 1 (5.3%) cases, respectively, using interphase fluorescence in-situ hybridization. The 2 MYC amplified cases belonged to the large cell/anaplastic subtype and had the worst outcomes. Conclusion: The MYC amplification corresponded with poor prognosis, the large cell/anaplastic variant of MBL, and the non-WNT/non-SHH molecular subtype. [ABSTRACT FROM AUTHOR]

Background: Increased levels of periodontal pathogens disrupt the homeostasis between the host and its microbiota and increase susceptibility to periodontal diseases. Periodontitis increases the serum concentration of mannose-binding lectin (MBL), which exacerbates local inflammatory processes. In animal studies, sirtuin 1 (SIRT1) was associated with protection against inflammation. This study analyzed the influence of non-surgical periodontal treatment on serum levels of MBL and SIRT1.Methods: Forty patients with periodontitis and 38 periodontally healthy individuals (aged 45 to 79 years) were included. Periodontitis patients received scaling and root planing using machine driven and hand instruments. Clinical parameters, inflammatory biomarkers, MBL, and SIRT1 levels were measured at baseline and at post-treatment.Results: For all patients, an inverse correlation was observed between serum concentrations of MBL and SIRT1 (r = -0.30; P = 0.006). Periodontal treatment reduced serum concentrations of MBL (1,099.35 ± 916.59 to 861.42 ± 724.82 ng/mL; P < 0.001) and C-reactive protein (6.05 ± 8.99 to 2.49 ± 2.89 mg/L; P = 0.009). By contrast, SIRT1 serum levels increased (1.06 ± 1.03 to 1.66 ± 1.64 ng/mL; P < 0.001) following periodontal treatment.Conclusions: Periodontal treatment was associated with decreased serum concentrations of MBL and CRP and increased serum levels of SIRT1. Prospective studies are needed to assess the impact of these biomarkers on pathophysiology of periodontitis. [ABSTRACT FROM AUTHOR]

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Bacteriocins are small peptides that can inhibit the growth of a diverse range of microbes. There is a need to identify bacteriocins that are effective against biofilms of resistant clinical strains. The present study focussed on the efficacy of purified nisin like bacteriocin-GAM217 against extended spectrum β-lactamase (ESBL) and metallo-beta-lactamase (MBL) producing clinical strains. Bacteriocin-GAM217 when combined with curcumin and cinnamaldehyde, synergistically enhanced antibacterial activity against planktonic and biofilm cultures of Staphylococcus epidermidis and Escherichia coli. Bacteriocin-GAM217 and phytochemical combinations inhibited biofilm formation by >80%, and disrupted the biofilm for selected ESBL and MBL producing clinical strains. The anti-adhesion assay showed that these combinatorial compounds significantly lowered the attachment of bacteria to Vero cells and that they elicited membrane permeability and rapid killing as viewed by confocal microscopy. This study demonstrates that bacteriocin-GAM217 in combination with phytochemicals can be a potential anti-biofilm agent and thus has potential for biomedical applications. [ABSTRACT FROM AUTHOR]

We investigated clinical associations of ficolins and mannose-binding lectin (MBL) in 157 patients suffering from acute myeloid leukaemia (AML). Concentrations of ficolin-1, ficolin-2, ficolin-3 and MBL (before chemotherapy) in serum were determined as were selected polymorphisms of the corresponding genes (FCN1, FCN2, FCN3 and MBL2). The control group (C) consisted of 267 healthy unrelated individuals. Median level of ficolin-1 in patients was lower (p < 0.000001) while median levels of ficolin-2, ficolin-3 and MBL were higher (p < 0.000001, p < 0.000001 and p = 0.0016, respectively) compared with controls. These findings were generally associated with AML itself, however the highest MBL levels predicted higher risk of severe hospital infections (accompanied with bacteremia and/or fungaemia) (p = 0.012) while the lowest ficolin-1 concentrations tended to be associated with prolonged (> 7 days) fever (p = 0.026). Genotyping indicated an association of G/G homozygosity (corresponding to FCN1 gene − 542 G > A polymorphism) with malignancy [p = 0.004, OR = 2.95, 95% CI (1.41–6.16)]. Based on ROC analysis, ficolin-1, -2 and -3 may be considered candidate supplementary biomarkers of AML. Their high potential to differentiate between patients from non-malignant controls but also from persons suffering from other haematological cancers (multiple myeloma and lymphoma) was demonstrated. [ABSTRACT FROM AUTHOR]

The North Pacific High (NPH) is a fundamental meteorological feature present during the boreal warm season. Marine boundary layer (MBL) clouds, which are persistent in this oceanic region, are influenced directly by the NPH. In this study, we combine 11 years of reanalysis and an unsupervised machine learning technique to examine the gamut of 850 hPa synoptic-scale circulation patterns. This approach reveals two distinguishable regimes – a dominant NPH setup and a land-falling cyclone – and in between a spectrum of large-scale patterns. We then use satellite retrievals to elucidate for the first time the explicit dependence of MBL cloud properties (namely cloud droplet number concentration, liquid water path, and shortwave cloud radiative effect – CRE SW) on 850 hPa circulation patterns over the northeast Pacific Ocean. We find that CRE SW spans from -146.8 to -115.5 Wm-2 , indicating that the range of observed MBL cloud properties must be accounted for in global and regional climate models. Our results demonstrate the value of combining reanalysis and satellite retrievals to help clarify the relationship between synoptic-scale dynamics and cloud physics. [ABSTRACT FROM AUTHOR]

Cell surfaces are often decorated with glycoconjugates that contain linear and more complex symmetrically and asymmetrically branched carbohydrates essential for cellular recognition and communication processes. Mannose is one of the fundamental building blocks of glycans in many biological membranes. Moreover, oligomannoses are commonly found on the surface of pathogens such as bacteria and viruses as both glycolipids and glycoproteins. However, their mechanism of action is not well understood, even though this is of great potential interest for translational medicine. Sequence-defined amphiphilic Janus glycodendrimers containing simple mono- and disaccharides that mimic glycolipids are known to self-assemble into glycodendrimersomes, which in turn resemble the surface of a cell by encoding carbohydrate activity via supramolecular multivalency. The synthetic challenge of preparing Janus glycodendrimers containing more complex linear and branched glycans has so far prevented access to more realistic cell mimics. However, the present work reports the use of an isothiocyanate-amine “click”-like reaction between isothiocyanate-containing sequence-defined amphiphilic Janus dendrimers and either linear or branched oligosaccharides containing up to six monosaccharide units attached to a hydrophobic amino-pentyl linker, a construct not expected to assemble into glycodendrimersomes. Unexpectedly, these oligoMan-containing dendrimers, which have their hydrophobic linker connected via a thiourea group to the amphiphilic part of Janus glycodendrimers, self-organize into nanoscale glycodendrimersomes. Specifically, the mannose-binding lectins that best agglutinate glycodendrimersomes are those displaying hexamannose. Lamellar “raft-like” nanomorphologies on the surface of glycodendrimersomes, self-organized from these sequence-defined glycans, endow these membrane mimics with high biological activity. [ABSTRACT FROM AUTHOR]

Objectives: The combination of cefepime and the novel β-lactam enhancer zidebactam (WCK 5222) is under development for the treatment of difficult-to-treat Gram-negative infections. Against MBL-producing pathogens, cefepime and zidebactam induce cell elongation and spheroplast formation, indicating PBP3 and PBP2 dysfunction, respectively, having a potent bactericidal effect as a combination. The objective of the present study was to determine the mechanistic basis of the bactericidal effect of cefepime/zidebactam on MBL-expressing pathogens.Methods: Pseudomonal PBP-binding affinities of cefepime, zidebactam and imipenem were assessed at different timepoints and also in the presence of purified VIM-1 using a Bocillin FL competition assay. The antibacterial activity of cefepime/zidebactam against three VIM-expressing Pseudomonas aeruginosa isolates was assessed by time-kill and neutropenic mouse lung/thigh infection studies.Results: Amidst cefepime-hydrolysing concentrations of VIM-1, substantial cefepime binding to target PBPs was observed. High-affinity binding of zidebactam to PBP2 remained unaltered in the presence of VIM-1; however, MBL addition significantly affected imipenem PBP2 binding. Furthermore, the rate of cefepime binding to the primary target PBP3 was found to be higher compared with the imipenem PBP2 binding rate. Finally, complementary PBP inhibition by cefepime/zidebactam resulted in enhanced bactericidal activity in time-kill and neutropenic mouse lung/thigh infection studies against VIM-6-, VIM-10- and VIM-11-expressing P. aeruginosa, thus revealing the mechanistic basis of β-lactam enhancer action.Conclusions: For the first time ever (to the best of our knowledge), this study demonstrates that in the presence of VIM-1 MBL, β-lactamase-labile cefepime and β-lactamase-stable zidebactam produce effective inhibition of respective target PBPs. For cefepime, this seems to be a result of a faster rate of PBP binding, which helps it overcome β-lactamase-mediated hydrolysis. [ABSTRACT FROM AUTHOR]

Many-body localization (MBL) describes a class of systems that do not approach thermal equilibrium under their intrinsic dynamics; MBL and conventional thermalizing systems form distinct dynamical phases of matter, separated by a phase transition at which equilibrium statistical mechanics breaks down. True many-body localization is known to occur only under certain stringent conditions for perfectly isolated one-dimensional systems, with Hamiltonians that have strictly short-range interactions and lack any continuous non-Abelian symmetries. However, in practice, even systems that are not strictly MBL can be nearly MBL, with equilibration rates that are far slower than their other intrinsic timescales; thus, anomalously slow relaxation occurs in a much broader class of systems than strict localization. In this review we address transport and dynamics in such nearly-MBL systems from a unified perspective. Our discussion covers various classes of such systems: (i) disordered and quasiperiodic systems on the thermal side of the MBL-thermal transition; (ii) systems that are strongly disordered, but obstructed from localizing because of symmetry, interaction range, or dimensionality; (iii) multiple-component systems, in which some components would in isolation be MBL but others are not; and finally (iv) driven systems whose dynamics lead to exponentially slow rates of heating to infinite temperature. A theme common to many of these problems is that they can be understood in terms of approximately localized degrees of freedom coupled to a heat bath (or baths) consisting of thermal degrees of freedom; however, this putative bath is itself nontrivial, being either small or very slowly relaxing. We discuss anomalous transport, diverging relaxation times, and other signatures of the proximity to MBL in these systems. We also survey recent theoretical and numerical methods that have been applied to study dynamics on either side of the MBL transition. [ABSTRACT FROM AUTHOR]

Mannose-binding lectin (MBL) deficiency is associated with recurrent infections, autoimmune and inflammatory skin disease, and vascular complications. MBL deficiency is not a recognized comorbidity in hidradenitis suppurativa (HS); the latter is associated with the group of autoinflammatory disorders. A 32-year-old woman presented with a history of recurrent painful, deep-seated abscesses and pustular lesions since the age of 13 years. Lesions were noted predominantly in HS distribution, i.e., submammary, inguinal, and perianal areas were affected. However, unusual locations (jawlines, neck) were also affected. The patient fulfilled the clinical criteria for HS but the presentation was atypical because lesions were noted in unusual locations, most lesions were in Hurley stage 1 (sparsity of sinus tracts and scarring), and most cultures from abscesses and pustular lesions were negative. The excruciating pain caused by constantly developing abscesses had a profound impact on the patient's quality of life. Laboratory workup showed an exceptionally low serum MBL level. Treatment was challenging with only a temporary, mild response to oral antibiotic therapy and no response to immunosuppressive and hormonal therapies. This atypical HS presentation may reflect an enhancement of proinflammatory mechanisms. Health care providers should be aware of this clinicopathologic presentation so that the establishment of HS diagnosis is not delayed and the patient receives appropriate counseling. [ABSTRACT FROM AUTHOR]

Objective: To explore the relationship between serum concentration of mannose binding lectin (MBL) and gene polymorphism of promoter region in schizophrenia and its role in immunopathology. Methods: From June 2018 to December 2018, 54 schizophrenics in our hospital were selected as the observation group, and 56 volunteers in our health examination center at the same period were selected as the normal control group. The polymorphism of H/L (-550bp G/C) and X/Y (-221bp C/G) promoter regions of MBL gene was analyzed by PCR-SSP, and the concentration of MBL in serum was detected by ELISA. Results: The serum MBL concentration in the observation group (1367.218± 1277.429) ng/ml was lower than that in the normal control group (1987.781± 976.748) ng/mL, the difference was statistically significant (P<0.05). The frequency of HY/HY genotype in the observation group was lower than the control group (P<0.05), and the frequency of HY/LY genotype was higher than the control group (P<0.05). The serum MBL concentration of HY/HY genotype in the observation group was significantly higher than HY/LX,LY/LX genotype (P<0.05). The serum MBL level of homozygous mutant in the promoter region of MBL gene in the observation group was no significant difference from that in the control group (P>0.05), but the difference of MBL level of MBL genotype heterozygotes was statistically significant (P<0.05). Conclusion: The low level of MBL in schizophrenics is related to the comprehensive regulation of each genotype in the promoter region of MBL gene. The low concentration of MBL is one of the molecular mechanisms for the retention or removal of CIC in schizophrenia. [ABSTRACT FROM AUTHOR]

Background and Objectives: Acinetobacter baumannii has been known as a major pathogen causing nosocomial infections. The aim of this study was to develop multiplex PCR for rapid and simultaneous detection of metallo-β-lactamase (MBL) genes in clinical isolates of A. baumannii. Materials and Methods: In this study, we used three sets of primers to amplify the MBL genes including blaOXA-48, blaOXA-23 and blaNDM. The multiplex PCR assay was optimized for rapid and simultaneous detection of MBL genes in A. baumannii strains recovered from clinical samples. Results: A. baumannii strains recovered from clinical samples were subjected to the study. The multiplex PCR produced 3 bands of 501 bp for blaOXA-23, 744 bp for blaOXA-48 and 623 bp for blaNDM genes. In addition to, no any cross-reactivity was observed in multiplex PCR. Conclusion: Based on obtained data, the multiplex PCR had a good specificity without any cross reactivity and it appears that the multiplex PCR is reliable assay for simultaneous detection of MBL genes in A. baumannii strains. [ABSTRACT FROM AUTHOR]

To successfully infect, Trypanosoma cruzi evades and modulates the host immune response. T. cruzi calreticulin (TcCalr) is a multifunctional, endoplasmic reticulum (ER)-resident chaperone that, translocated to the external microenvironment, mediates crucial host–parasite interactions. TcCalr binds and inactivates C1 and mannose-binding lectin (MBL)/ficolins, important pattern- recognition receptors (PRRs) of the complement system. Using an apoptotic mimicry strategy, the C1–TcCalr association facilitates the infection of target cells. T. cruzi infection also seems to confer protection against tumorigenesis. Thus, recombinant TcCalr has important antiangiogenic properties, detected in vitro , ex vivo , and in ovum , most likely contributing at least in part, to its antitumor properties. Consequently, TcCalr is useful for investigating key issues of host–parasite interactions and possible new immunological/pharmacological interventions in the areas of Chagas' disease and experimental cancer. TcCalr has essential roles in host–parasite interaction in Chagas' disease. TcCalr inhibits the classical and lectin pathways of the complement system by binding of their soluble PRRs such as C1, MBLs (mannose binding lectins), and ficolins. TcCalr binds C1, and this interaction is used as a strategy to infect the mammalian cell. TcCalr inhibits angiogenesis and interacts with tumor cells, modulating the expression of molecules that increase tumor immunogenicity. The combined experimental evidence reviewed herein is compatible with the possibility that Chagas' disease protects against concomitant tumors. [ABSTRACT FROM AUTHOR]

Background: Deposition of complement factors on Mycobacterium leprae may enhance phagocytosis. Such deposition may occur through the lectin pathway of complement. Three proteins of the lectin pathway are produced from the gene MASP1: Mannan-binding lectin-associated serine protease 1 (MASP-1) and MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44). Despite their obvious importance, the roles played by these proteins have never been investigated in leprosy disease. Methodology: We haplotyped five MASP1 polymorphisms by multiplex sequence-specific PCR (intronic rs7609662*G>A and rs13064994*C>T, exon 12 3'-untranslated rs72549262*C>G, rs1109452*C>T and rs850314*G>A) and measured MASP-1, MASP-3 and MAp44 serum levels in 196 leprosy patients (60%, lepromatous) and 193 controls. Principal findings: Lower MASP-3 and MAp44 levels were observed in patients, compared with controls (P = 0.0002 and P<0.0001, respectively) and in lepromatous, compared with non-lepromatous patients (P = 0.008 and P = 0.002, respectively). Higher MASP-3 levels were present in controls carrying variants/haplotypes associated with leprosy resistance (rs13064994*T, rs1109452_rs850314*CG within GT_CCG and rs850314*A: OR = 0.5–0.6, Pcorr = 0.01–0.04). Controls with rs1109452*T, included in susceptibility haplotypes (GT_GTG/GT_CTG: OR = 2.0, Pcorr = 0.03), had higher MASP-1 and lower MASP-3 levels (P≤0.009). Those with GC_CCG, presented increasing susceptibility (OR = 1.7, Pcorr = 0.006) and higher MAp44 levels (P = 0.015). MASP-3 expression decreased in patients, compared with controls carrying rs1109452_rs850314*CA or CG (P≤0.02), which may rely on exon 12 CpG methylation and/or miR-2861/miR-3181 mRNA binding. Conclusion: Polymorphisms regulating MASP-3/MAp44 availability in serum modulate leprosy susceptibility, underlining the importance of lectin pathway regulation against pathogens that exploit phagocytosis to parasitize host macrophages. Author summary: Since immemorial times, Mycobacterium leprae inflicts permanent injuries in human kind, within a wide symptomatic spectrum ranging from insensitive skin patches to disabling physical lesions. Innate resistance to this parasite is well recognized, but poorly understood. The complement system is one of the most important arms of the innate response, and several lines of evidence indicate that it may be usurped by the parasite to enhance its entrance into host cells. These include our recent work on genetic association of the disease with lectin pathway components and the complement receptor CR1, whose polymorphisms modulate susceptibility to infection and clinical presentation. Here, we add another pivotal piece in the leprosy parasite-host interaction puzzle: polymorphisms and serum levels of three different lectin pathway proteins, all encoded by the same gene, namely mannan-binding lectin-associated serine protease 1 (MASP1). We found lower levels of two of these proteins, MASP-3 and MAp44, in leprosy patients. Higher MASP-3/lower MASP-1 levels were associated with protective haplotypes, containing two side-by-side polymorphisms located in the exclusive untranslated region of MASP-3 exon 12, which may regulate exon splicing and/or translation efficiency. The associations revealed in this study reflect the pleiotropic nature of this gene. They further illustrate the complexity of the response mounted against the parasite, which places MASP1 products in the regulatory crossroad between the innate and adaptive arms of the immunological system, modulating leprosy susceptibility. [ABSTRACT FROM AUTHOR]

In this paper, we use exact matrix diagonalization to explore the many-body localization (MBL) transition of the Heisenberg Ising spin-1/2 chain with nearest neighbor couplings and disordered external fields. It demonstrates that the fidelity, magnetization and spin-spin space correlation can be used to characterize the many-body localization transition in this closed spin system which is also in agreement with previous analytical and numerical results. We test the properties for the middle third many-body eigenstates. It shows that for this model with random-field, the excited-state fidelity exhibits a pronounced drop at the transition and then gradually tends to be stable in the localized phase, the critical point and the final value of averaged fidelity are all size dependent. It demonstrates that disordered external fields drive the occurrence of the MBL transition. Moreover, we investigate the magnetization and spin-spin space correlation in this model to verify the conclusion we got and further explore the properties of ergodic phase and localized phase. [ABSTRACT FROM AUTHOR]

In the present study, for the discovery of uncharacterized glycan-binding receptors or lectin-like receptors in plants, we developed neoglycopolymers to which three types of N -glycopeptides are conjugated; the first with plant complex type N -glycan (M3FX), the second with high-mannose type N -glycan (M8), and the third with animal complex type N -glycan (NeuAc2Gal2GN2M3). Three types of Asn-oligosaccharide (Asn-M3FX, Asn-M8, or Asn-NeuAc2Gal2GN2M3) were prepared from storage glycoproteins of Ginkgo biloba seeds, Vigna angularis seeds, and egg yolk glycopeptides from actinase digests of each glycoproteins or glycopeptide. Neoglycopolymers were synthesized such that the α-amino groups of Asn-oligosaccharide were coupled to the carboxyl groups of poly-γ-L-glutamic acid (γ-L-PGA) with 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n -hydrate (DMT-MM). The resulting neoglycopolymers were purified through a combination of gel-filtration and reverse-phase HPLC. The incorporation of N -glycans into γ-L-PGA (mol%) was estimated through amino acid composition analysis after acid hydrolysis. The incorporation rates of Asn-M3FX, Asn-M8, and Asn-NeuAc2Gal2GN2M3 into γ-L-PGA were 15.4%, 8.6%, and 11.1%, indicating that nearly 890, 500, and 640 molecules of N -glycans were conjugated with γ-L-PGA, respectively. Furthermore, we confirmed that the neoglycopolymer carrying the multivalent high-mannose type N -glycans is a useful tool for rapid purification of mannose-binding protein, Concanavalin A, from jack bean extract. [ABSTRACT FROM AUTHOR]

Objectives: Elizabethkingia is an emerging life-threatening pathogen in both humans and animals. We describe the whole-genome analysis of an Elizabethkingia miricola strain isolated from a diseased frog in China and investigate the molecular mechanism of carbapenem resistance in this pathogen.Methods: WGS of E. miricola FL160902 was performed using single-molecule, real-time technology. A phylogenetic tree was generated by SNP analysis, comparing the genome of our strain with other E. miricola isolates of amphibian and human origins. Antimicrobial resistance genes and virulence-related genes were identified using the Comprehensive Antibiotic Resistance Database (CARD) and the Virulence Factor Database (VFDB). Two putative carbapenemase genes were expressed in Escherichia coli to evaluate their contribution to antimicrobial resistance.Results: The genome of E. miricola FL160902 consists of a 4 249 586 bp circular chromosome with 27 putative resistance genes and 38 predicted virulence-associated genes. Comparative genomic analysis demonstrated that the E. miricola strains of human and amphibian origins have similar virulence-associated gene profiles. In addition, all the amphibian isolates clustered together with one of the human isolates in the phylogenetic analysis. WGS revealed the presence of two novel MBL genes, designated blaBlaB-16 and blaGOB-19. Cloning of blaBlaB-16 and blaGOB-19 into E. coli DH5α resulted in increased MICs of most β-lactams, including imipenem, meropenem and ampicillin.Conclusions: We identified two chromosomal MBL gene variants, named blaBlaB-16 and blaGOB-19 in an amphibian E. miricola isolate, which was considered potentially zoonotic based on phylogenetic analysis and virulence-associated gene comparison. This study highlights the importance of E. miricola as a potential zoonotic pathogen and a reservoir of MDR genes. [ABSTRACT FROM AUTHOR]

Objective: To monitor the cytokine release patterns in the peri-implant crevicular fluid (PICF) and to investigate which factors affect the success rate of narrow diameter implants (NDI) during the first year. Material and methods: Mandibular implant overdentures (IOD) retained by 2 NDI were installed in 16 clinically atrophic edentulous patients. The following parameters were monitored during the first year: (i) peri-implant health parameters (plaque index (PI), calculus presence (CP), gingival index (GI), probing depth (PD) and bleeding on probing (BoP); (ii) cytokine concentrations in the PICF (TNF-α, IL-1β, IL-6, IL-10); (iii) implant stability quotient (ISQ); (iv) marginal bone level (MBL) and bone level change (BLC); (v) implant success. The insertion torque, bone type, mandibular atrophy, time since edentulism, and smoking habits were also recorded. All data were analyzed using multivariable multilevel mixed-effects regression models. Results: The variability in the TNF-α release patterns temporarily reduced at weeks (w) 8–12, while the IL-1β concentrations remained low until they peaked at w48 [p < 0.05; + 177.55 pg/μl (+ 96.13 − + 258.97)]. Conversely, IL-10 release decreased significantly at w48 [p < 0.05; − 456.24 pg/μl (− 644.41 − − 268.07)]. The PD and ISQ decreased significantly (p < 0.05) over the follow-up period, while the MBL was stable after w48 with a BLC of 0.12 ± 0.71 mm. The overall success rate was 81.3%, and was influenced by TNF-α, IL-1β, IL-10, PI, GI, PD, smoking, and time since edentulism. Conclusion: Pro- and anti-inflammatory cytokine release was balanced during the first 24 weeks. The GI, smoking, and time since edentulism are the most important factors determining the implant success. Clinical relevance: The study contributes to the understanding of the osseointegration process in a clinically atrophic population rehabilitated with IOD, and highlights the importance of monitoring clinical peri-implant health-related parameters, smoking habit, and time since edentulism to predict implant success rates. [ABSTRACT FROM AUTHOR]

Cardiovascular (CV) morbidity is the major cause of death in patients with Systemic Lupus Erythematosus (SLE). Previous studies on mannose-binding lectin (MBL) gene polymorphisms in SLE patients suggest that low levels of complement MBL are associated with cardiovascular disease (CVD). However, as large studies on MBL deficiency based on resulting MBL plasma concentrations are lacking, the aim of our study was to analyze the association of MBL concentrations with CVD in SLE patients. Plasma MBL levels SLE patients included in the Swiss SLE Cohort Study were quantified by ELISA. Five different CV organ manifestations were documented. Of 373 included patients (85.5% female) 62 patients had at least one CV manifestation. Patients with MBL deficiency (levels below 500 ng/ml or 1000 ng/ml) had no significantly increased frequency of CVD (19.4% vs. 15.2%, P = 0.3 or 17.7% vs. 15.7%, P = 0.7). After adjustment for traditional CV risk factors, MBL levels and positive antiphospholipid serology (APL+) a significant association of CVD with age, hypertension, disease duration and APL+ was demonstrated. In our study of a large cohort of patients with SLE, we could not confirm previous studies suggesting MBL deficiency to be associated with an increased risk for CVD. [ABSTRACT FROM AUTHOR]