Acinetobacter baumannii clinical isolates resist complement-mediated lysis by inhibiting the complement cascade and improperly depositing MAC.

Acinetobacter baumannii is a gram-negative opportunistic bacterium that causes life-threatening infections in immunocompromised hosts. The World Health Organization (WHO) recognizes the high mortality and increasing antimicrobial resistance of A. baumannii and calls for new treatment options.

C4b-Binding Protein and Factor H Attenuate NLRP3 Inflammasome-Mediated Signalling Response during Group A Streptococci Infection in Human Cells.

Introduction: Streptococcus pyogenes (group A streptococcus; GAS) is a pathogen causing over half a million deaths annually worldwide. Human immune cells respond to GAS infection by activating the NLRP3 inflammasome leading to the release of pro-inflammatory cytokines that control infection. We investigated the role of C4b-binding protein (C4BP) and factor H (FH) in the inflammasome response to GAS, as they are recruited by GAS to prevent complement deposition and limit phagocytosis.

Machine learning based longitudinal virtual diagnostics at SwissFEL.

The bunch length in a linac driven Free Electron Laser (FEL) is a major parameter to be characterized to optimize the final accelerator performance. In linear machines, this observable is typically determined from the beam imaged on a screen located downstream of a Transverse Deflecting Structure (TDS) used to impinge a time dependent kick along the longitudinal coordinate of the beam. This measurement is typically performed during the machine setup and only sporadically to check the beam duration, but it cannot be continuously repeated because it is time consuming and invasive.

Recruitment of C4b-binding protein is not a complement evasion strategy employed by .

Complement offers a first line of defence against infection through the opsonization of microbial pathogens, recruitment of professional phagocytes to the infection site and the coordination of inflammatory responses required for the resolution of infection. is a successful pathogen that has developed multiple mechanisms to thwart host immune responses. Understanding the precise strategies employed by to bypass host immunity will be paramount for the development of vaccines and or immunotherapies designed to prevent or limit infection.

Tonsillectomy as Prevention of Tonsil and Base of Tongue Cancer: Systematic Review and Meta-analysis on the Immuno-Oncological Effect of One Among the Most Common Surgeries in the World.

Otorhinolaryngology tradition is that tonsillectomy (TE) is conducted among children and adolescents for obstructive sleep apnea secondary to adenotonsillar hypertrophy and in adults for chronic disease of the tonsils and adenoids (recurrent tonsillitis). Nevertheless, over the last 50 years, we have observed a decline in TE worldwide. As a result, there is an emerging concern of a correlated possible increased risk of tonsil cancer (TC) and other subtypes of oropharyngeal squamous cell carcinoma.

C4b-binding protein inhibits particulate- and crystalline-induced NLRP3 inflammasome activation.

Dysregulated NLRP3 inflammasome activation drives a wide variety of diseases, while endogenous inhibition of this pathway is poorly characterised. The serum protein C4b-binding protein (C4BP) is a well-established inhibitor of complement with emerging functions as an endogenously expressed inhibitor of the NLRP3 inflammasome signalling pathway. Here, we identified that C4BP purified from human plasma is an inhibitor of crystalline- (monosodium urate, MSU) and particulate-induced (silica) NLRP3 inflammasome activation.

Clinical Isolates of spp. Are Highly Serum Resistant Despite Efficient Recognition by the Complement System.

Gram-negative bacteria from the genus are responsible for life-threating hospital-related infections such as pneumonia, septicemia, and meningitis, especially in immunocompromised patients. Worryingly, have become multi- and extensively drug resistant (MDR/XDR) over the last few decades. The complement system is the first line of defense against microbes, thus it is highly important to increase our understanding of evasion mechanisms used by spp.

Serum Complement Activation by C4BP-IgM Fusion Protein Can Restore Susceptibility to Antibiotics in .

is the etiological agent of gonorrhea, the second most common bacterial sexually transmitted infection worldwide. Reproductive sequelae of gonorrhea include infertility, ectopic pregnancy and chronic pelvic pain. Most antibiotics currently in clinical use have been rendered ineffective due to the rapid spread of antimicrobial resistance among gonococci.

Nontypeable P5 Binds Human C4b-Binding Protein, Promoting Serum Resistance.

Nontypeable (NTHi) is a Gram-negative human pathogen that causes infections mainly in the upper and lower respiratory tract. The bacterium is associated with bronchitis and exacerbations in patients suffering from chronic obstructive pulmonary disease and frequently causes acute otitis media in preschool children. We have previously demonstrated that the binding of C4b binding protein (C4BP) is important for NTHi complement evasion.

Airborne vocal communication in adult neotropical otters (Lontra longicaudis).

Most aquatic mammals have complex social and communication systems. Interestingly, little is known about otters' vocal communication compared to other aquatic mammals. Here, for the first time, we acoustically describe vocalizations of the neotropical otter (Lontra longicaudis), a solitary and endangered New World otter species.

Can we still consider thyroid hyperfunction a protective condition for the onset of thyroid cancer?

Background: Thyroid cancer is the ninth most commonly diagnosed cancer in the world, and the most common endocrine carcinoma. It was originally believed to be a rare event in patients with thyroid hyperfunction and it was reported that hyperthyroidism had a protective role against thyroid neoplasms. However, in recent years, several studies have hypothesized that differentiated thyroid carcinomas and hyperthyroidism may coexist.

Antibacterial Fusion Proteins Enhance Killing.

is a human-specific commensal of the respiratory tract and an opportunistic pathogen. It is one of the leading cause of otitis media in children and of acute exacerbations in patients with chronic obstructive pulmonary disease, resulting in significant morbidity and economic burden. Vaccines and new immunotherapeutic strategies to treat this emerging pathogen are needed.

Laser-Driven Modulation of Electron Beams in a Dielectric Micro-Structure for X-Ray Free-Electron Lasers.

We describe an application of laser-driven modulation in a dielectric micro-structure for the electron beam in a free-electron laser (FEL). The energy modulation is transferred into longitudinal bunching via compression in a magnetic chicane before entering the undulator section of the FEL. The bunched electron beam comprises a series of enhanced current spikes separated by the wavelength of the modulating laser.

Generation and Characterization of Intense Ultralow-Emittance Electron Beams for Compact X-Ray Free-Electron Lasers.

The transverse emittance of the electron beam is a fundamental parameter in linac-based x-ray free-electron lasers (FELs). We present results of emittance measurements carried out at SwissFEL, a compact x-ray FEL facility at the Paul Scherrer Institute in Switzerland, including a description of the novel high-resolution measurement techniques and the optimization procedure. We obtained slice emittance values at the undulator entrance down to 200 nm for an electron beam with a charge of 200 pC and an rms duration of 30-40 fs.

C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infections.

Gonorrhea is a sexually transmitted infection with 87 million new cases per year globally. Increasing antibiotic resistance has severely limited treatment options. A mechanism that Neisseria gonorrhoeae uses to evade complement attack is binding of the complement inhibitor C4b-binding protein (C4BP).

The SwissFEL soft X-ray free-electron laser beamline: Athos.

The SwissFEL soft X-ray free-electron laser (FEL) beamline Athos will be ready for user operation in 2021. Its design includes a novel layout of alternating magnetic chicanes and short undulator segments. Together with the APPLE X architecture of undulators, the Athos branch can be operated in different modes producing FEL beams with unique characteristics ranging from attosecond pulse length to high-power modes.

Passive Linearization of the Magnetic Bunch Compression Using Self-Induced Fields.

In linac-driven free-electron lasers, colliders, and energy recovery linacs, a common way to compress the electron bunch to kiloampere level is based upon the implementation of a magnetic dispersive element that converts particle energy deviation into a path-length difference. Nonlinearities of such a process are usually compensated by enabling a high harmonic rf structure properly tuned in amplitude and phase. This approach is however not straightforward, e.

Interaction between Multimeric von Willebrand Factor and Complement: A Fresh Look to the Pathophysiology of Microvascular Thrombosis.

von Willebrand factor (VWF), a multimeric protein with a central role in hemostasis, has been shown to interact with complement components. However, results are contrasting and inconclusive. By studying 20 patients with congenital thrombotic thrombocytopenic purpura (cTTP) who cannot cleave VWF multimers because of genetic deficiency, we investigated the mechanism through which VWF modulates complement and its pathophysiological implications for human diseases.

Withdrawals/Retractions: Insights into the effects of complement factor H on the assembly and decay of the alternative pathway C3 proconvertase and C3 convertase.

VOLUME 291 (2016) PAGES 8214–8230 This article has been withdrawn by the authors. Lanes 1 and 7 of Fig. 4B were duplicated.

Insights into the Effects of Complement Factor H on the Assembly and Decay of the Alternative Pathway C3 Proconvertase and C3 Convertase.

The activated fragment of C3 (C3b) and factor B form the C3 proconvertase (C3bB), which is cleaved by factor D to C3 convertase (C3bBb). Older studies (Conrad, D. H.

Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome.

Background: Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronic nephropathy recently reclassified into immunoglobulin-associated MPGN (Ig-MPGN) and C3 glomerulopathy (C3G). In this study we aimed: (1) to evaluate the complement genetic and biochemical profile in patients with Ig-MPGN/C3G; (2) to investigate whether genetic variants and different patterns of complement activation (i.e.

Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome.

Background And Objectives: Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown.

Design, Setting, Participants, & Measurements: Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS.

Dynamics of complement activation in aHUS and how to monitor eculizumab therapy.

Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalities/anti-complement factor H antibodies, which paved the way to treatment with eculizumab. We studied 44 aHUS patients and their relatives to (1) test new assays of complement activation, (2) verify whether such abnormality occurs also in unaffected mutation carriers, and (3) search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a, or SC5b-9) was found in 47% to 64% of patients, irrespective of disease phase.

Insights into PARP Inhibitors' Selectivity Using Fluorescence Polarization and Surface Plasmon Resonance Binding Assays.

PARP inhibitors are an exciting new class of antineoplastic drugs that have been proven to be efficacious as single agents in cancer settings with inherent DNA repair defects, as well as in combination with DNA-damaging chemotherapeutics. Currently, they are designed to target the catalytic domain of PARP-1, the most studied member of the family, with a key role in the DNA-damage repair process. Because PARP inhibitors are substrate (NAD(+)) competitors, there is a need for a deeper understanding of their cross-reactivity.