p53 mutations in human aggressive and nonaggressive basal and squamous cell carcinomas.

PURPOSE: The purpose is to investigate whether aggressive basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) differ from nonaggressive BCC and SCC with respect to the p53 mutation spectrum and whether specific mutations can serve as prognostic indicators of tumor aggressiveness. EXPERIMENTAL DESIGN: We analyzed 342 tissues from patients with aggressive and nonaggressive BCCs and SCCs for p53 mutations by single-strand conformation polymorphism and nucleotide sequencing. RESULTS: p53 mutations were detected in 33 of 50 aggressive BCCs (66%), 37 of 98 nonaggressive BCCs (38%), 28 of 80 aggressive SCCs (35%), 28 of 56 nonaggressive SCCs (50%), and 3 of 29 samples of sun-exposed skin (10%). About 71% of the p53 mutations detected in aggressive and nonaggressive BCCs and SCCs were UV signature mutations. The frequency of CC to TT mutations in aggressive (36%) and nonaggressive SCCs (39%) was 2-fold higher than in aggressive (18%) and nonaggressive (14%) BCCs. In contrast, aggressive BCCs had a higher frequency (24%) of transversions than nonaggressive BCCs (8%) and aggressive (14%) and nonaggressive (11%) SCCs did. CONCLUSIONS: Our results indicate that UV radiation is responsible for the induction of p53 mutations and perhaps for the initiation of both aggressive and nonaggressive BCCs and SCCs. Although some differences in p53 mutation frequency, types of mutation, and hot spots were seen between aggressive and nonaggressive BCCs and SCCs, these factors do not constitute as clear-cut diagnostic or prognostic indicators of tumor aggressiveness. Tumor aggressiveness may be attributable to other genetic changes or events that occur during tumor progression.     

Preparation and Study of Composite Materials of the NiAl-Cr-Mo-Nanoparticles (ZrO2, MgAl2O4) System

Materials based on the NiAl-Cr-Mo system with zirconium oxide or aluminum-magnesium spinel nanoparticle small additions were obtained by spark plasma sintering. Thermodynamic modeling was carried out to predict the phase formation in the NiAl-Cr-Mo system and its change depending on temperature, considering the presence of a small amount of carbon in the system. The phase composition and microstructure of materials were studied. NiAl (B2) and CrMo phases were found in the sintered samples. Bending strength measurements at different temperatures shows that nanoparticles of insoluble additives lead to an increase in bending strength, especially at high temperatures. A fractographic analysis of the sample’s fractures shows their hybrid nature and intercrystalline fracture, which is confirmed by the clearly visible matrix grains similar to cleavage. The maximum strength at 700 °C (475 MPa) was found for material with the addition of 0.1 wt.% zirconium oxide nanoparticles. In the study of internal friction, typical peaks of a nickel-aluminum alloy were found in the temperature ranges of 150–200 °C and 350–400 °C.     

The differentiated roles of health in the transition from work to retirement – conceptual and methodological challenges and avenues for future research

ObjectivesThe aim of this discussion paper is to (i) identify the differentiated roles of health in the work–retirement transition, and, with respect to these, (ii) highlight topics related to conceptual and methodological problems and challenges in research, and (iii) present avenues for future research.MethodsThis discussion paper summarizes an OMEGA-NET working group discussion ongoing from November 2018 to September 2021 with face-to-face and online meetings as well as a written online discourse.Results‘Health’ and ‘retirement’ are ambiguous concepts. With respect to both, in retirement research, the choice of concept and indicator influences the findings. In addition, the impact of health on retirement is not necessarily a direct one, but can be influenced by further factors such as the ability, motivation and opportunity to work. The strong overall association of poor health with retiring early (path 1) bears the risk of masking distinct and deviating mechanisms in subgroups. In fact, there is evidence that also good health may lead to early retirement (path 2), while both poor health (path 3) and good health (path 4) may also make people retire later.ConclusionsAn increased awareness of the differentiated roles that health may have in the work–retirement transition as outlined in this discussion paper may support research to address questions relevant for policy and practice and increase the impact of research. Recommendations for occupational health and social research are given.     

Characteristics and Sonophotocatalytic Activity of Natural Sphalerite under Ultrasonic (1.7 MHz) and UVA LED (365 nm) Irradiation

Naturally occurring sono- and photoactive minerals, which are abundant on Earth, represent an attractive alternative to the synthesized sonophotocatalysts as cost-effective materials for water and wastewater treatment. This study focuses on characterizing and evaluating the sonophotocatalytic activity of natural sphalerite (NatS) from Dovatka deposit (Siberia) under high-frequency ultrasonic (US, 1.7 MHz) and ultraviolet light-emitting diodes (UVA LED, 365 nm) irradiation towards degradation of 4-chlorophenol as a model organic pollutant. Since raw natural sphalerite did not exhibit a measurable photocatalytic activity, it was calcined at 500, 900 and 1200 °C. The natural sphalerite after calcination at 900 °C (NatS*) was found to be the most effective for sonophotocatalytic degradation of 4-chlorophenol, attaining the highest efficiency (55%, 1 h exposure) in the following row: UV < US ≈ UV/US ≈ US/NatS* < UV/NatS* < UV/US/NatS*. Addition of 1 mM H₂O₂ increased the removal to 74% by UV/US/NatS*/H₂O₂ process. An additive effect between UV/NatS* and US/NatS* processes was observed in the sonophotocatalytic system as well as in the H₂O₂-assisted system. We assume that the sonophotocatalytic hybrid process, which is based on the simultaneous use of high-frequency ultrasound, UVA light, calcined natural sphalerite and H₂O₂, could provide a basis of an environmentally safe and cost-effective method of elimination of organic pollutants from aqueous media.     

【In Press】Lyme Borrelia as the etiological factor in three cases of primary inflammatory choriocapillaropathies

Letter to the editor     

Metagenomic Analysis of Ampelographic Collections of Dagestan Revealed the Presence of Two Novel Grapevine Viruses

In this study, we analyzed the virome of 73 grape samples from two Dagestan ampelographic collections in Russia using high-throughput sequencing of total RNAs. Fourteen viruses and four viroids were identified, with one to eleven of them detected in each plant. For the first time in Russia, we identified grapevine leafroll-associated virus 7 and grapevine Kizil Sapak virus. A total of 206 genomes of viruses and viroids were obtained, and their phylogenetic analysis was carried out. The de novo assembly and tblastx analysis allowed us to obtain contigs of a novel (+) ssRNA genome of a plant virus from the genus Umbravirus, which was tentatively named grapevine umbra-like virus (GULV), as well as contigs of a novel dsDNA pararetrovirus from the genus Caulimovirus, which was tentatively named grapevine pararetrovirus (GPRV). Complete genomes of these viruses were obtained and used for Sequence Demarcation Tool (SDT) analysis and phylogeny studies. GULV and GPRV were detected in 16 and 33 germplasm samples from the Dagestan collections, respectively.     

Stroke-prone salt-sensitive spontaneously hypertensive rats show higher susceptibility to spreading depolarization (SD) and altered hemodynamic responses to SD

Spreading depolarization (SD) occurs in a plethora of clinical conditions including migraine aura, delayed ischemia after subarachnoid hemorrhage and malignant hemispheric stroke. It describes waves of near-breakdown of ion homeostasis, particularly Na⁺ homeostasis in brain gray matter. SD induces tone alterations in resistance vessels, causing either hyperperfusion in healthy tissue; or hypoperfusion (inverse hemodynamic response = spreading ischemia) in tissue at risk. Observations from mice with genetic dysfunction of the ATP1A2-encoded α₂-isoform of Na⁺/K⁺-ATPase (α₂NaKA) suggest a mechanistic link between (1) SD, (2) vascular dysfunction, and (3) salt-sensitive hypertension via α₂NaKA. Thus, α₂NaKA-dysfunctional mice are more susceptible to SD and show a shift toward more inverse hemodynamic responses. α₂NaKA-dysfunctional patients suffer from familial hemiplegic migraine type 2, a Mendelian model disease of SD. α₂NaKA-dysfunctional mice are also a genetic model of salt-sensitive hypertension. To determine whether SD thresholds and hemodynamic responses are also altered in other genetic models of salt-sensitive hypertension, we examined these variables in stroke-prone spontaneously hypertensive rats (SHRsp). Compared with Wistar Kyoto control rats, we found in SHRsp that electrical SD threshold was significantly reduced, propagation speed was increased, and inverse hemodynamic responses were prolonged. These results may have relevance to both migraine with aura and stroke.     

Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors

Type 1 interferon-producing cells (IPCs), also known as plasmacytoid dendritic cell (DC) precursors, represent the key effectors in antiviral innate immunity and triggers for adaptive immune responses. IPCs play important roles in the pathogenesis of systemic lupus erythematosus (SLE) and in modulating immune responses after hematopoietic stem cell transplantation. Understanding IPC development from hematopoietic progenitor cells (HPCs) may provide critical information in controlling viral infection, autoimmune SLE, and graft-versus-host disease. FLT3-ligand (FLT3-L) represents a key IPC differentiation factor from HPCs. Although hematopoietic cytokines such as interleukin-3 (IL-3), IL-7, stem cell factor (SCF), macrophage-colony-stimulating factor (M-CSF), and granulocyte M-CSF (GM-CSF) promote the expansion of CD34+ HPCs in FLT3-L culture, they strongly inhibit HPC differentiation into IPCs. Here we show that thrombopoietin (TPO) cooperates with FLT3-L, inducing CD34+ HPCs to undergo a 400-fold expansion in cell numbers and to generate more than 6 x 10(6) IPCs per 10(6) CD34+ HPCs within 30 days in culture. IPCs derived from HPCs in FLT3-L/TPO cultures display blood IPC phenotype and have the capacity to produce large amounts of interferon-alpha (IFN-alpha) and to differentiate into mature DCs. This culture system, combined with the use of adult peripheral blood CD34+ HPCs purified from G-CSF-mobilized donors, permits the generation of more than 10(9) IPCs from a single blood donor.     

In vivo identification of genes that modify ether-a-go-go-related gene activity in Caenorhabditis elegans may also affect human cardiac arrhythmia

Human ether-a-go-go-related gene (HERG) encodes the pore-forming subunit of I(Kr), a cardiac K(+) channel. Although many commonly used drugs block I(Kr), in certain individuals, this action evokes a paradoxical life-threatening cardiac rhythm disturbance, known as the acquired long QT syndrome (aLQTS). Although aLQTS has become the leading cause of drug withdrawal by the U.S. Food and Drug Administration, DNA sequencing in aLQTS patients has revealed HERG mutations only in rare cases, suggesting that unknown HERG modulators are often responsible. By using the worm Caenorhabditis elegans, we have developed in vivo behavioral assays that identify candidate modulators of unc-103, the worm HERG orthologue. By using RNA-interference methods, we have shown that worm homologues of two HERG-interacting proteins, Hyperkinetic and K channel regulator 1 (KCR1), modify unc-103 function. Examination of the human KCR1 sequence in patients with drug-induced cardiac repolarization defects revealed a sequence variation (the substitution of isoleucine 447 by valine, I447V) that occurs at a reduced frequency (1.1%) relative to a matched control population (7.0%), suggesting that I447V may be an allele for reduced aLQTS susceptibility. This clinical result is supported by in vitro studies of HERG dofetilide sensitivity by using coexpression of HERG with wild-type and I447V KCR1 cDNAs. Our studies demonstrate the feasibility of using C. elegans to assay and potentially identify aLQTS candidate genes.