Genetic diversity of species Fowl aviadenovirus D and Fowl aviadenovirus E

Complete genomes of eight reference strains representing different serotypes within species Fowl aviadenovirus D (FAdV-D) and Fowl aviadenovirus E (FAdV-E) were sequenced. The sequenced genomes of FAdV-D and FAdV-E members comprise 43,287 to 44,336 bp, and have a gene organization identical to that of an earlier sequenced FAdV-D member (strain A-2A). Highest diversity was noticed in the hexon and fiber genes and ORF19. All genomes, sequenced in this study, contain one fiber gene. Phylogenetic analyses and G+C content support the division of the genus Aviadenovirus into the currently recognized species. Our data also suggest that the strain SR48 should be considered as FAdV-11 instead of FAdV-2 and similarly the strain HG as FAdV-8b. The present results complete the list of genome sequences of reference strains representing all serotypes in species FAdV-D and FAdV-E

CHL1 Is a Selective Organizer of the Presynaptic Machinery Chaperoning the SNARE Complex

Proteins constituting the presynaptic machinery of vesicle release undergo substantial conformational changes during the process of exocytosis. While changes in the conformation make proteins vulnerable to aggregation and degradation, little is known about synaptic chaperones which counteract these processes. We show that the cell adhesion molecule CHL1 directly interacts with and regulates the activity of the synaptic chaperones Hsc70, CSP and αSGT. CHL1, Hsc70, CSP and αSGT form predominantly CHL1/Hsc70/αSGT and CHL1/CSP complexes in synapses. Among the various complexes formed by CHL1, Hsc70, CSP and αSGT, SNAP25 and VAMP2 induce chaperone activity only in CHL1/Hsc70/αSGT and CHL1/CSP complexes, respectively, indicating a remarkable selectivity of a presynaptic chaperone activity for proteins of the exocytotic machinery. In mice with genetic ablation of CHL1, chaperone activity in synapses is reduced and the machinery for synaptic vesicle exocytosis and, in particular, the SNARE complex is unable to sustain prolonged synaptic activity. Thus, we reveal a novel role for a cell adhesion molecule in selective activation of the presynaptic chaperone machinery

Species Fowl aviadenovirus B Consists of a Single Serotype despite Genetic Distance of FAdV-5 Isolates

Fowl adenoviruses (FAdVs) are infectious agents, mainly of chickens, which cause economic losses to the poultry industry. Only a single serotype, namely FAdV-5, constitutes the species Fowl aviadenovirus B (FAdV-B); however, recently, phylogenetic analyses have identified divergent strains of the species, implicating a more complex scenario and possibly a novel serotype. Therefore, field isolates of the species were collected to investigate the contemporary diversification within FAdV-B, including traditional serotyping. Full genomes of fourteen FAdV-B strains were sequenced and four strains, possessing discriminatory mutations in the antigenic domains, were compared using virus cross-neutralization. Essentially, strains with identical antigenic signatures to that of the first described divergent strain were found in the complete new dataset. While chicken antiserum against FAdV-5 reference strain 340 could not neutralize any of the newly isolated viruses, low homologous/heterologous titer ratios were measured reciprocally. Although they argue against a new serotype, our results indicate the emergence of escape variants in FAdV-B. Charge-influencing amino acid substitutions accounted for only a few mutations between the strains; still, these enabled one-way cross-neutralization only. These findings underline the continued merit of the cross-neutralization test as the gold standard for serotyping, complementary to advancing sequence data, and provide a snapshot of the actual diversity and evolution of species FAdV-B

Efficacy and Safety of a Low-level Laser Device in the Treatment of Male and Female Pattern Hair Loss: A Multicenter, Randomized, Sham Device-controlled, Double-blind Study

Significance Male and female pattern hair loss are common, chronic dermatologic disorders with limited therapeutic options. In recent years, a number of commercial devices using low-level laser therapy have been promoted, but there have been little peer-reviewed data on their efficacy. Objective: To determine whether treatment with a low-level laser device, the US FDA-cleared HairMax Lasercomb®, increases terminal hair density in both men and women with pattern hair loss. Methods: Randomized, sham device-controlled, double-blind clinical trials were conducted at multiple institutional and private practices. A total of 146 male and 188 female subjects with pattern hair loss were screened. A total of 128 male and 141 female subjects were randomized to receive either a lasercomb (one of three models) or a sham device in concealed sealed packets, and were treated on the whole scalp three times a week for 26 weeks. Terminal hair density of the target area was evaluated at baseline and at 16- and 26-week follow-ups, and analyzed to determine whether the hypothesis formulated prior to data collection, that lasercomb treatment would increase terminal hair density, was correct. The site investigators and the subjects remained blinded to the type of device they dispensed/received throughout the study. The evaluator of masked digital photographs was blinded to which trial arm the subject belonged. Results: Seventy-eight, 63, 49, and 79 subjects were randomized in four trials of 9-beam lasercomb treatment in female subjects, 12-beam lasercomb treatment in female subjects, 7-beam lasercomb treatment in male subjects, and 9- and 12-beam lasercomb treatment in male subjects, compared with the sham device, respectively. Nineteen female and 25 male subjects were lost to follow-up. Among the remaining 122 female and 103 male subjects in the efficacy analysis, the mean terminal hair count at 26 weeks increased from baseline by 20.2, 20.6, 18.4, 20.9, and 25.7 per cm2 in 9-beam lasercomb-treated female subjects, 12-beam lasercomb-treated female subjects, 7-beam lasercomb-treated male subjects, and 9- and 12-beam lasercomb-treated male subjects, respectively, compared with 2.8 (p < 0.0001), 3.0 (p < 0.0001), 1.6 (p = 0.0017), 9.4 (p = 0.0249), and 9.4 (p = 0.0028) in sham-treated subjects (95 % confidence interval). The increase in terminal hair density was independent of the age and sex of the subject and the lasercomb model. Additionally, a higher percentage of lasercomb-treated subjects reported overall improvement of hair loss condition and thickness and fullness of hair in self-assessment, compared with sham-treated subjects. No serious adverse events were reported in any subject receiving the lasercomb in any of the four trials. Conclusions and relevance We observed a statistically significant difference in the increase in terminal hair density between lasercomb- and sham-treated subjects. No serious adverse events were reported. Our results suggest that low-level laser treatment may be an effective option to treat pattern hair loss in both men and women. Additional studies should be considered to determine the long-term effects of low-level laser treatment on hair growth and maintenance, and to optimize laser modality

A new Heterodontosaurus specimen elucidates the unique ventilatory macroevolution of ornithischian dinosaurs

Ornithischian dinosaurs were ecologically prominent herbivores of the Mesozoic Era that achieved a global distribution by the onset of the Cretaceous. The ornithischian body plan is aberrant relative to other ornithodiran clades, and crucial details of their early evolution remain obscure. We present a new, fully articulated skeleton of the early branching ornithischian Heterodontosaurus tucki. Phase-contrast enhanced synchrotron data of this new specimen reveal a suite of novel postcranial features unknown in any other ornithischian, with implications for the early evolution of the group. These features include a large, anteriorly projecting sternum; bizarre, paddle-shaped sternal ribs; and a full gastral basket – the first recovered in Ornithischia. These unusual anatomical traits provide key information on the evolution of the ornithischian body plan and suggest functional shifts in the ventilatory apparatus occurred close to the base of the clade. We complement these anatomical data with a quantitative analysis of ornithischian pelvic architecture, which allows us to make a specific, stepwise hypothesis for their ventilatory evolution

Aortic Dissection Type A in Alpine Skiers

Patients and Methods. 140 patients with aortic dissection type A were admitted for cardiac surgery. Seventy-seven patients experienced their dissection in the winter season (from November to April). We analyzed cases of ascending aortic dissection associated with alpine skiing. Results. In 17 patients we found skiing-related aortic dissections. Skiers were taller (180 (172-200) cm versus 175 (157-191) cm, = 0.008) and heavier (90 (68-125) kg versus 80 (45-110) kg, = 0.002) than nonskiers. An extension of aortic dissection into the aortic arch, the descending thoracic aorta, and the abdominal aorta was found in 91%, 74%, and 69%, respectively, with no significant difference between skiers and nonskiers. Skiers experienced RCA ostium dissection requiring CABG in 17.6% while this was true for 5% of nonskiers ( = 0.086). Hospital mortality of skiers was 6% versus 13% in nonskiers ( = 0.399). The skiers live at an altitude of 170 (0-853) m.a.s.l. and experience their dissection at 1602 (1185-3105; &lt; 0.001) m.a.s.l. In 82% symptom start was during recreational skiing without any trauma. Conclusion. Skiing associated aortic dissection type A is usually nontraumatic. The persons affected live at low altitudes and practice an outdoor sport at unusual high altitude at cold temperatures. Postoperative outcome is good

Lymphatic exosomes promote dendritic cell migration along guidance cues

Lymphatic endothelial cells (LECs) release extracellular chemokines to guide the migration of dendritic cells. In this study, we report that LECs also release basolateral exosome-rich endothelial vesicles (EEVs) that are secreted in greater numbers in the presence of inflammatory cytokines and accumulate in the perivascular stroma of small lymphatic vessels in human chronic inflammatory diseases. Proteomic analyses of EEV fractions identified >1,700 cargo proteins and revealed a dominant motility-promoting protein signature. In vitro and ex vivo EEV fractions augmented cellular protrusion formation in a CX3CL1/fractalkine-dependent fashion and enhanced the directional migratory response of human dendritic cells along guidance cues. We conclude that perilymphatic LEC exosomes enhance exploratory behavior and thus promote directional migration of CX3CR1-expressing cells in complex tissue environments.Peer reviewe

Oxygen atom transfer catalysis by dioxidomolybdenum(VI) complexes of pyridyl aminophenolate ligands

A series of new cationic dioxidomolybdenum(VI) complexes [MoO2(L-n)]PF6 (2-5) with the tripodal tetradentate pyridyl aminophenolate ligands HL2-HL5 have been synthesized and characterized. Ligands HL2-HL4 carry substituents in the 4-position of the phenolate ring, viz. Cl, Br and NO2, respectively, whereas the ligand HL5, N-(2-hydroxy-3,5-di-tert-butylbenzyl)-N,N-bis(2-pyridylmethyl)amine, is a derivative of 3,5-di-tert-butylsalicylaldehyde. X-ray crystal structures of complexes 2, 3 and 5 reveal that they have a distorted octahedral geometry with the bonding parameters around the metal centres being practically similar. Stoichiometric oxygen atom transfer (OAT) properties of 5 with PPh3 were investigated using UV-Vis, P-31 NMR and mass spectrometry. In CH2Cl2 solution, a dimeric Mo(V) complex [(mu-O){MoO(L-5)}(2)](PF6)(2) 6 was formed while in methanol solution an air-sensitive Mo(IV) complex [MoO (OCH3)(L-5)] 7 was obtained. The solid-state structure of the mu-oxo bridged dimer 6 was determined by X-ray diffraction. Complex 7 is unstable under ambient conditions and capable of reducing DMSO, thus showing reactivity analogous to that of DMSO reductases. Similarly, the OAT reactions of complexes 2-4 also resulted in the formation of dimeric Mo(V) and unsaturated monomeric Mo(IV) complexes that are analogous to complexes 6 and 7. Catalytic OAT at 25 degrees C could also be observed, using complexes 1-5 as catalysts for oxidation of PPh3 in deuterated dimethylsulfoxide (DMSO d(6)), which functioned both as a solvent and oxidant. All complexes were also tested as catalysts for sulfoxidation of methyl-p-tolylsulfide and epoxidation of various alkene substrates with tert-butyl hydroperoxide (TBHP) as an oxidant. Complex 1 did not exhibit any sulfoxidation activity under the conditions used, while 2-5 catalyzed the sulfoxidation of methyl-p-tolylsulfide. Only complexes 2 and 3, with ligands containing halide substituents, exhibited good to moderate activity for epoxidation of all alkene substrates studied, and, in general, good activity for all molybdenum(VI) catalysts was only exhibited when cis-cyclooctene was used as a substrate. No complex catalysed epoxidation of cis-cyclooctene when an aqueous solution of H2O2 was used as potential oxidant. (C) 2021 The Authors. Published by Elsevier Ltd

Development of novel methods for non-canonical myeloma protein analysis with an innovative adaptation of immunofixation electrophoresis, native top-down mass spectrometry, and middle-down de novo sequencing

OBJECTIVES: Multiple myeloma (MM) is a malignant plasma cell neoplasm, requiring the integration of clinical examination, laboratory and radiological investigations for diagnosis. Detection and isotypic identification of the monoclonal protein(s) and measurement of other relevant biomarkers in serum and urine are pivotal analyses. However, occasionally this approach fails to characterize complex protein signatures. Here we describe the development and application of next generation mass spectrometry (MS) techniques, and a novel adaptation of immunofixation, to interrogate non-canonical monoclonal immunoproteins. METHODS: Immunoprecipitation immunofixation (IP-IFE) was performed on a Sebia Hydrasys Scan2. Middle-down de novo sequencing and native MS were performed with multiple instruments (21T FT-ICR, Q Exactive HF, Orbitrap Fusion Lumos, and Orbitrap Eclipse). Post-acquisition data analysis was performed using Xcalibur Qual Browser, ProSight Lite, and TDValidator. RESULTS: We adapted a novel variation of immunofixation electrophoresis (IFE) with an antibody-specific immunosubtraction step, providing insight into the clonal signature of gamma-zone monoclonal immunoglobulin (M-protein) species. We developed and applied advanced mass spectrometric techniques such as middle-down de novo sequencing to attain in-depth characterization of the primary sequence of an M-protein. Quaternary structures of M-proteins were elucidated by native MS, revealing a previously unprecedented non-covalently associated hetero-tetrameric immunoglobulin. CONCLUSIONS: Next generation proteomic solutions offer great potential for characterizing complex protein structures and may eventually replace current electrophoretic approaches for the identification and quantification of M-proteins. They can also contribute to greater understanding of MM pathogenesis, enabling classification of patients into new subtypes, improved risk stratification and the potential to inform decisions on future personalized treatment modalities

Circulating levels of cell adhesion molecule L1 as a prognostic marker in gastrointestinal stromal tumor patients

<p>Abstract</p> <p>Background</p> <p>L1 cell adhesion molecule (CD171) is expressed in many malignant tumors and its expression correlates with unfavourable outcome. It thus represents a target for tumor diagnosis and therapy. An earlier study conducted by our group identified L1 expression levels in primary gastrointestinal stromal tumors (GIST) as a prognostic marker. The aim of the current study was to compare L1 serum levels of GIST patients with those of healthy controls and to determine whether levels of soluble L1 in sera could serve as a prognostic marker.</p> <p>Methods</p> <p>Using a sensitive enzyme-linked immunosorbent assay (ELISA), soluble L1 was measured in sera of 93 GIST patients und 151 healthy controls. Soluble L1 levels were then correlated with clinicopathological data.</p> <p>Results</p> <p>Median levels of soluble L1 were significantly higher (<it>p </it>< 0.001; Mann-Whitney U test) in sera of GIST patients compared to healthy individuals. Median soluble L1 levels were particularly elevated in patients with recurrence and relapse (<it>p </it>< 0.05; Mann Whitney U test).</p> <p>Conclusion</p> <p>These results suggest that high soluble L1 levels predict poor prognosis and may thus be a promising tumor marker that can contribute to individualise therapy.</p