Spectrum of APC and MUTYH germ‐line mutations in Russian patients with colorectal malignancies

Distribution of cancer‐predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ‐line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with 2 known mutational hotspots (p.E1309Dfs*4 [n = 5] and p.Q1062fs* [n = 3]), while 6/26 (23%) mutations were novel (p.K73Nfs*6, p.S254Hfs*12, p.S1072Kfs*9, p.E1547Kfs*11, p.L1564X and p.C1263Wfs*22). Biallelic mutations in MUTYH gene were detected in 3/12 (25%) remaining subjects with polyposis and in 6/90 (6.7%) patients with colorectal cancer (CRC) carrying KRAS p.G12C substitution, but not in 231 early‐onset CRC cases negative for KRAS p.G12C allele. In addition to known European founder alleles p.Y179C and p.G396D, this study revealed a recurrent character of MUTYH p.R245H germ‐line mutation. Besides that, 3 novel pathogenic MUTYH alleles (p.L111P, p.R245S and p.Q293X) were found. Targeted next‐generation sequencing of 7 APC/MUTYH mutation‐negative DNA samples identified novel potentially pathogenic POLD1 variant (p.L460R) in 1 patient and known low‐penetrant cancer‐associated allele CHEK2 p.I157T in 3 patients. The analysis of 1120 healthy subjects revealed 15 heterozygous carriers of recurrent MUTYH mutations, thus the expected incidence of MUTYH‐associated polyposis in Russia is likely to be 1:23 000.     

Running,jumping, hunting,and scavenging: Functional analysis of vertebral mobility and backbone properties in carnivorans

Carnivorans are well-known for their exceptional backbone mobility, which enables them to excel in fast running and long jumping, leading to them being among the most successful predators amongst terrestrial mammals. This study presents the first large-scale analysis of mobility throughout the presacral region of the vertebral column in carnivorans. The study covers representatives of 6 families, 24 genera and 34 species. We utilized a previously developed osteometry-based method to calculate available range of motion, quantifying all three directions of intervertebral mobility: sagittal bending (SB), lateral bending (LB), and axial rotation (AR). We observed a strong phylogenetic signal in the structural basis of the vertebral column (vertebral and joint formulae, length proportions of the backbone modules) and an insignificant phylogenetic signal in most characteristics of intervertebral mobility. This indicates that within the existing structure (stabilization of which occurred rather early in different phylogenetic lineages), intervertebral mobility in carnivorans is quite flexible. Our findings reveal that hyenas and canids, which use their jaws to seize prey, are characterized by a noticeably elongated cervical region and significantly higher SB and LB mobility of the cervical joints compared to other carnivorans. In representatives of other carnivoran families, the cervical region is very short, but the flexibility of the neck (both SB and LB) is significantly higher than that of short-necked odd-toed and even-toed ungulates. The lumbar region of the backbone in carnivorans is dorsomobile in the sagittal plane, being on average ~23° more mobile than in artiodactyls and ~38° more mobile than in perissodactyls. However, despite the general dorsomobility, only some representatives of Canidae, Felidae, and Viverridae are superior in lumbar flexibility to the most dorsomobile ungulates. The most dorsomobile artiodactyls are equal or even superior to carnivorans in their ability to engage in dorsal extension during galloping. In contrast, carnivorans are far superior to ungulates in their ability to engage ventral flexion. The cumulative SB in the lumbar region in carnivorans largely depends on the mode of running and hunting. Thus, adaptation to prolonged and enduring pursuit of prey in hyenas is accompanied by markedly reduced SB flexibility in the lumbar region. A more dorsostable run is also a characteristic of the Ursidae, and the peculiar maned wolf. Representatives of Felidae and Canidae have significantly more available SB mobility in the lumbar region. However, they fully engage it only occasionally at key moments of the hunt associated with the direct capture of the prey or when running in a straight line at maximum speed.     

Investigation of endovenous laser ablation of varicose veins in vitro using 1.885-μm laser radiation

This paper presents the results of endovenous laser ablation (EVLA) of varicose veins in vitro using radiation of a solid-state laser based on the crystal LiYF₄:Tm, with a wavelength of 1.885 μm and power output of around 3 W. An experimental series with saline solution and red blood cell (RBC) suspension in the venous lumen was performed to identify the impact of a heated carbonized layer precipitated on the fiber end face versus the efficiency of EVLA. Results of these experiments confirmed that the presence of a heated carbonized layer on the fiber end face increases the efficiency of EVLA.     

Compartmentalization of bone morphogenetic proteins and their antagonists in lymphoid progenitors and supporting microenvironments and functional implications

Bone morphogenetic protein (BMP) signalling regulates lymphopoiesis in bone marrow and thymus via the interaction of haemato-lymphoid progenitors with the stroma microenvironment. Despite increasing functional evidence for the role of BMP signalling in lymphopoiesis, little is known of the spatial distribution of BMP/BMP antagonists in the thymus and of how BMP signals exert specific functions in developing lymphocytes. We analysed expression of BMP/BMP antagonists in the thymus and bone marrow and determined the topology of BMP/BMP antagonist expression using lacZ reporter mice. Bmp4, Bmp7, Gremlin and Twisted gastrulation (Twsg1) are all expressed in the thymus and expression was clearly different for each gene investigated. Expression was seen both in cortical and medullary regions suggesting that BMP signals regulate all stages of T-cell development. Two genes in particular, Bmp7 and Twsg1, were dynamically expressed in developing T and B lymphocytes. Their conditional ablation in all haematopoietic cells surprisingly did not affect the steady state of B-cell and T-cell development. This indicates that both lymphoid cell-derived BMP7 and TWSG1 are dispensable for normal lymphopoiesis and that bone-marrow stroma-derived TWSG1 is responsible for the lymphoid defects observed in Twsg1 null mice. In summary our data demonstrate a complex network of lymphoid and stroma derived BMP signals involved in the orchestration of lymphopoiesis in both bone marrow and thymus.     

Thermo-Optical Studies of Laser Ceramics

A cycle of works on manufacturing and studying laser and magnetooptical ceramics with a focus on their thermo-optical characteristics performed by the research team is analyzed. Original results that have not been published before such as measurements of the Verdet constant in the Zr:TAG, Re:MgAl₂O₄, and ZnAl₂O₄ ceramics are also presented.     

Effects of L-Selectin Stimulation of the Expression of Chemokine Receptor CXCR4 on NK Cells of Healthy Donors and Tumor Patients

We studied the effects of fucoidan (L-selectin ligand) on the expression and SDF-1-induced internalization of CXCR4 receptor on human NK cells of healthy donors and tumor patients. Fucoidan stimulated the expression of surface CXCR4 due to mobilization of the intracellular pool. The effect of fucoidan on CXCR4 expression in cancer patients was low. It was hypothesized that L-selectin-dependent migration of circulating NK cells along the SDF-1 chemokine gradient is reduced in cancer patients.     

How the even-toed ungulate vertebral column works: Comparison of intervertebral mobility in 33 genera

In this study, we used a previously developed osteometry-based method to calculate available range of motion in presacral intervertebral joints in artiodactyls. We have quantified all three directions of intervertebral mobility: sagittal bending (SB), lateral bending (LB), and axial rotation (AR). This research covers 10 extant families of artiodactyls from 33 genera and 39 species. The cervical region in artiodactyls is the most mobile region of the presacral vertebral column in SB and LB. Mobility is unevenly distributed throughout the joints of the neck. The posterior neck joints (C4–C7) are significantly more mobile (on average by 2.5–3.5°) to anterior joints (C2–C4) and to the neck–thorax joint (C7–T1) in SB and LB. An increase in the relative length of the cervical region in artiodactyls is accompanied by an increase in the bending amplitudes (SB: Pearson r = 0.781; LB: r = 0.884). Animals with the most mobile necks (representative of Giraffidae and Camelidae) are 2–3 times more mobile in SB and LB compared to species with the least mobile necks. The thoracic region in artiodactyls, as in other mammals, is characterized by the greatest amplitudes of AR due to the tangential orientation of the zygapophyseal articular facets. The lowest AR values in the thoracic region are typical for the heaviest artiodactyls—Hippopotamidae. The highest AR values are typical for such agile runners as cervids, musk deer, pronghorn, as well as large and small antelopes. SB mobility in the posterior part of the thoracic region can be used by artiodactyls during galloping. The highest values of SB aROM in the posterior part of the thoracic region are typical for small animals with high SB mobility in the lumbar region. The lumbar region in mammals is adapted for efficient SB. Both the cumulative and average SB values in the lumbar region showed correspondence to the running type employed by an artiodactyl. The greatest SB amplitudes in the lumbar region are typical for small animals, which use saltatorial and saltatorial–cursorial running. An increase in body size also corresponds to a decrease in lumbar SB amplitudes. The lowest SB amplitudes are typical for species using the so-called mediportal running. Adaptation to endurance galloping in open landscapes is accompanied by a decrease in lumbar SB amplitudes in artiodactyls. The consistency of the approach used and the wide coverage of the studied species make it possible to significantly expand and generalize the knowledge of the biomechanics of the vertebral column in artiodactyls.