The BRAFV600E Mutation Is Not a Risk Factor for More Aggressive Tumor Behavior in Radiogenic and Sporadic Papillary Thyroid Carcinoma at a Young Age

Histopathological changes in the fusion oncogene-driven papillary thyroid carcinomas (PTCs) from children and adolescents exposed to Chernobyl fallout have been extensively studied. However, characteristics of the radiogenic BRAFV600E-positive PTCs, whose proportion is growing with time, are not well described yet. We analyzed the relationship between the BRAFV600E status (determined immunohistochemically with the VE1 antibody) and the clinicopathological features of 247 radiogenic and 138 sporadic PTCs from young Ukrainian patients aged ≤28 years. The frequency of BRAFV600E was increasing with patient age, consistently remaining lower in radiogenic PTCs. In both etiopathogenic groups, the BRAFV600E-positive PTCs more frequently had a dominant papillary growth pattern, smaller tumor size, higher Ki67 labeling index, and a frequency of the major indicators of tumor invasiveness that is lower than or equal to that of the BRAFV600E-negative tumors. Comparison of the BRAFV600E-positive PTCs across the groups found a virtual absence of differences. In contrast, the BRAFV600E-negative radiogenic PTCs displayed less frequent dominant papillary and more frequent solid growth patterns, lower Ki67 labeling index, and higher invasiveness than the BRAFV600E-negative sporadic tumors. Thus, BRAFV600E is not associated with a more aggressive course of PTC in young patients regardless of etiology. The major clinicopathological differences between the radiogenic and sporadic PTCs are observed among the BRAFV600E-negative tumors.

Host Restriction Factors Modulating HIV Latency and Replication in Myeloid Cells

In addition to CD4+ T lymphocytes, myeloid cells, and, particularly, differentiated macrophages, are targets of the human immunodeficiency virus type-1 (HIV-1) infection via interaction of gp120Env with CD4 and CCR5 or CXCR4. Both T cells and macrophages support virus replication although with substantial differences. In contrast to activated CD4+ T lymphocytes, HIV-1 replication in macrophages occurs in nondividing cells and it is characterized by virtual absence of cytopathicity both in vitro and in vivo. These general features should be considered in evaluating the role of cell-associated restriction factors aiming at preventing of curtailing virus replication in macrophages and T cells particularly in the context of designing strategies to tackle the viral reservoir in infected individuals receiving combination antiretroviral therapy. In this regard, we will here also discuss a model of reversible HIV-1 latency in primary human macrophages and the role of host factor determining restriction or reactivation of virus replication in myeloid cells.

Exotic facies episodes of a carbonate platform: implications for middle and late Cambrian ecosystems and impact of bioturbation in the Alborz Basin, Iran

The sedimentological and ichnological data of the Mila Group in the Alborz Basin, northern Iran indicate that the appearance of exotic facies and resurgence of microbialites resulted from the development of extraordinary palaeoceanographic conditions with widespread environmental stress and enhanced precipitation of CaCO3. Inhospitable environmental conditions in the Mila Group platform led to a considerable reduction in ichnodiversity, bioturbation intensity, depth and size of burrows, which led to periods of dominating calcimicrobe ecology. The development of exotic, or anachronistic facies started around the Cambrian Stage 4-Wuliuan boundary, probably simultaneous with the SPICE event whereas the Furongian exotic facies period probably took place simultaneous with the HERB event. Biotic and physico-chemical changes in the ocean during these events may have led as well to the virtual absence of the mixed layer and infaunal ecospace utilisation in the deposits of the Mila Group. Nevertheless, the local presence of metazoan-microbial build-ups that established between the two suggested exotic facies developments indicates that these periods started at the Cambrian Stage 4-Wuliuan boundary interval, but a fluctuation of abnormal palaeoceanographic conditions and ambient normal marine conditions took place during the Miaolingian and Furongian in the Alborz Basin as a representative of northern Gondwanan margin.

In Vivo Renin Activity Imaging in the Kidney of Progeroid Ercc1 Mutant Mice

Changes in the renin–angiotensin system, known for its critical role in the regulation of blood pressure and sodium homeostasis, may contribute to aging and age-related diseases. While the renin–angiotensin system is suppressed during aging, little is known about its regulation and activity within tissues. However, this knowledge is required to successively treat or prevent renal disease in the elderly. Ercc1 is involved in important DNA repair pathways, and when mutated causes accelerated aging phenotypes in humans and mice. In this study, we hypothesized that unrepaired DNA damage contributes to accelerated kidney failure. We tested the use of the renin-activatable near-infrared fluorescent probe ReninSense680™ in progeroid Ercc1d/− mice and compared renin activity levels in vivo to wild-type mice. First, we validated the specificity of the probe by detecting increased intrarenal activity after losartan treatment and the virtual absence of fluorescence in renin knock-out mice. Second, age-related kidney pathology, tubular anisokaryosis, glomerulosclerosis and increased apoptosis were confirmed in the kidneys of 24-week-old Ercc1d/− mice, while initial renal development was normal. Next, we examined the in vivo renin activity in these Ercc1d/− mice. Interestingly, increased intrarenal renin activity was detected by ReninSense in Ercc1d/− compared to WT mice, while their plasma renin concentrations were lower. Hence, this study demonstrates that intrarenal RAS activity does not necessarily run in parallel with circulating renin in the aging mouse. In addition, our study supports the use of this probe for longitudinal imaging of altered RAS signaling in aging.

Stretching of the retinal pigment epithelium contributes to zebrafish optic cup morphogenesis

The vertebrate eye-primordium consists of a pseudostratified neuroepithelium, the optic vesicle (OV), in which cells acquire neural retina or retinal pigment epithelium (RPE) fates. As these fates arise, the OV assumes a cup-shape, influenced by mechanical forces generated within the neural retina. Whether the RPE passively adapts to retinal changes or actively contributes to OV morphogenesis remains unexplored. We generated a zebrafish Tg(E1-bhlhe40:GFP) line to track RPE morphogenesis and interrogate its participation in OV folding. We show that, in virtual absence of proliferation, RPE cells stretch and flatten, thereby matching the retinal curvature and promoting OV folding. Localized interference with the RPE cytoskeleton disrupts tissue stretching and OV folding. Thus, extreme RPE flattening and accelerated differentiation are efficient solutions adopted by fast-developing species to enable timely optic cup formation. This mechanism differs in amniotes, in which proliferation drives RPE expansion with a much-reduced need of cell flattening.

Hematopoiesis Remains Permissive to Bone Marrow Transplantation After Expansion of Progenitors and Resumption of Blood Cell Production

The immense regenerative power of hematopoietic tissue stems from the activation of the immature stem cells and the progenitor cells. After partial damage, hematopoiesis is reconstituted through a period of intense regeneration when blood cell production originates from erythro-myeloid progenitors in the virtual absence of stem cells. Since the damaged hematopoiesis can also be reconstituted from transplanted hematopoietic cells, we asked whether this also leads to the transient state when activated progenitors initially execute blood cell production. We first showed that the early reconstitution of hematopoiesis from transplanted cells gives rise to extended populations of developmentally advanced but altered progenitor cells, similar to those previously identified in the bone marrow regenerating from endogenous cells. We then identified the cells that give rise to these progenitors after transplantation as LSK CD48– cells. In the submyeloablative irradiated host mice, the transplanted LSK CD48– cells preferably colonized the spleen. Unlike the endogenous hematopoiesis reconstituting cells, the transplanted whole bone marrow cells and sorted LSK CD48– cells had greater potential to differentiate to B-lymphopoiesis. Separate transplantation of the CD150– and CD150+ subsets of LSK CD48– cells suggested that CD150– cells had a greater preference to B-lymphopoiesis than CD150+ cells. In the intensively regenerating hematopoiesis, the CD71/Sca-1 plot of immature murine hematopoietic cells revealed that the expanded populations of altered myeloid progenitors were highly variable in the different places of hematopoietic tissues. This high variability is likely caused by the heterogeneity of the hematopoiesis supporting stroma. Lastly, we demonstrate that during the period when active hematopoiesis resumes from transplanted cells, the hematopoietic tissues still remain highly permissive for further engraftment of transplanted cells, particularly the stem cells. Thus, these results provide a rationale for the transplantation of the hematopoietic stem cells in successive doses that could be used to boost the transplantation outcome.

Spinal Cord Injury Significantly Alters the Properties of Reticulospinal Neurons: I. Biophysical Properties, Firing Patterns, Excitability, and Synaptic Inputs

Following spinal cord injury (SCI) for larval lampreys, descending axons of reticulospinal (RS) neurons regenerate, and locomotor function gradually recovers. In the present study, the electrophysiological properties of uninjured (left)-injured (right) pairs of large, identified RS neurons were compared following rostral, right spinal cord hemi-transections (HTs). First, changes in firing patterns of injured RS neurons began in as little as 2–3 days following injury, these changes were maximal at ~2–3 weeks (wks), and by 12–16 wks normal firing patterns were restored for the majority of neurons. Second, at ~2–3 wks following spinal cord HTs, injured RS neurons displayed several significant changes in properties compared to uninjured neurons: (a) more hyperpolarized VREST; (b) longer membrane time constant and larger membrane capacitance; (c) increased voltage and current thresholds for action potentials (APs); (d) larger amplitudes and durations for APs; (e) higher slope for the repolarizing phase of APs; (f) virtual absence of some afterpotential components, including the slow afterhyperpolarization (sAHP); (g) altered, injury-type firing patterns; and (h) reduced average and peak firing (spiking) frequencies during applied depolarizing currents. These altered properties, referred to as the “injury phenotype”, reduced excitability and spiking frequencies of injured RS neurons compared to uninjured neurons. Third, artificially injecting a current to add a sAHP waveform following APs for injured neurons or removing the sAHP following APs for uninjured neurons did not convert these neurons to normal firing patterns or injury-type firing patterns, respectively. Fourth, trigeminal sensory-evoked synaptic responses recorded from uninjured and injured pairs of RS neurons were not significantly different. Following SCI, injured lamprey RS neurons displayed several dramatic changes in their biophysical properties that are expected to reduce calcium influx and provide supportive intracellular conditions for axonal regeneration.

Criminal records: problems of classification

Problems of criminal records classification have been studied. The article considers classification of criminal records according to the main criteria: intended purpose, degree of centralization and functional (target) purpose. Criminal records develop and operate within various state bodies of Ukraine, therefore records can be classified by intended purpose as follows: records of the Ministry of Internal Affairs of Ukraine; State Tax Service of Ukraine; State Customs Service of Ukraine; Security Service of Ukraine; State Bureau of Investigation of National Anti-Corruption Bureau; General Prosecutor’s Office, etc.All of them are aimed at facilitating investigation of criminal offenses. At the same time, criminal records of the Ministry of Internal Affairs of Ukraine, in turn include records of: the National Police of Ukraine, functioning in the department of information and analytical support; State Border Guard Service of Ukraine; State Migration Service of Ukraine; Main service center of MIA of Ukraine; Expert Service of the Ministry of Internal Affairs of Ukraine. It has been proved that according to the degree of centralization, records should be divided into central, regional and local; but at the same time, the virtual absence of records in the expert service at the local level is stressed, which is confirmed by results of studying case files of criminal proceedings and interviews of investigators. According to the view of authors, criminal record keeping of objects at the local level in the general classification should be left for further consideration, but responsibility for its formation and functioning should be assigned to the city departments of technical and forensic support of police. Classification of criminal records by functional (target) purpose into search and reference ones is substantiated. At the same time, it is noted that reference and support records in the form of collections have lost their meaning today and cannot make up the system of criminal records. In view of the authors, they can be characterized as information databases formed and operating in cyberspace and that can be both freely available and owned by enterprises, institutions, organizations and individuals. In practice, this type of record keeping practically non-existent which is evidenced by studying work results of investigative police departments and expert service.

EVALUATING COMPOSITIONAL FIDELITY AND SOURCES OF MORTALITY OF SHORELINE FISH CARCASSES IN A FRESHWATER LAKE COMMUNITY IN WESTERN CANADA

ABSTRACT Taxonomic comparisons of death assemblages with extant communities continue to provide insight for ecological studies but whether demographic aspects such as age structure, sex ratio, and causes of mortality are accurately captured by the former remains little studied. At a 110 ha dystropic lake in western Canada, seasonal shoreline accumulations of fish carcasses were collected annually for 12 years (N=4499) during 95 full lake-circuits and analyzed for taxa, body size frequencies, sex ratio relative to live-captures and sources of mortality. Rank order of the four fish species (Gasterosteus aculeatus, Oncorhynchus clarki, O. keta, Salvelinus malma) was similar for live-captures and carcasses. Of the dominant species (G. aculeatus), modal adult body length (∼80 mm SL) was the same for carcasses and live-captures and shifted by about 10% over 30 years with parallel trends between the groups for both sexes. Age-specific body size was about 5% larger (P<0.001) in carcasses than live-captures. Carcasses were significantly female-biased (2:1) each year relative to a population sex ratio of 1:1 in the lake. There was a complete absence of juvenile fish (<30 mm) among carcasses but these constituted 70% of the live population. Estimated relative contributions to mortality for the carcasses include starvation (<1%), parasitism (3%), senescence (4%) and lethal injuries from predator attack (70–80%). If these carcasses are representative of a fossil series in freshwater lake sediments, then several demographic parameters including age-specific body size, age-class frequencies and sex ratio depart substantially from the live population. As well, the virtual absence of avian piscivores in the carcass assemblage, the major source of predation on the fish population, warrants additional attention in paleoecological studies.