Yerevan soil radioactivity: Radiological and geochemical assessment.

Spatial pattern of naturally occurring radionuclides (NOR): 226Ra, 232Th, 40K, and artificial 137Cs was studied using soil samples of the multipurpose geochemical survey of the city of Yerevan, capital of Armenia. High purity Ge detector-based gamma spectrometry system was used for the determination of radionuclides activity concentrations in urban soils. A combination of compositional data analysis, geochemical mapping and radiological assessment were applied to reveal potential factors of technologically enhanced natural radioactivity and excess lifetime cancer risk for Yerevan's population due to NOR and artificial 137Cs in the urban environment. Statistical methods with the geochemical mapping revealed the great contribution of soil-forming rocks to NOR distribution in urban soils. The spatial distribution of calculated radiological indices and dose rates levels follows the distribution patterns of NOR. The activity concentration of fallout radionuclide 137Cs was within the range typical for the studied altitudes. Above baseline activity of 137Cs was observed in the north-western and western part of the city that is in typical ranges of 137Cs content in soil derived from global radioactive fallout. Urban soils of Yerevan were found radiologically safe, however, igneous rock derived soils are a sink of NOR and the main environmental source of continuous exposure to the residents. Values of excess lifetime cancer risk were higher than mean global value.

AMPK-induced autophagy as a key regulator of cell migration.

Cell migration is a highly dynamic and energy-intensive process that ensures the correct targeting of cells during embryonic and postnatal development. In recent work, we highlighted the importance of macroautophagy/autophagy in regulating the dynamics of cell migration under baseline conditions and in response to a diverse set of molecular factors. Genetic suppression of autophagy-related genes induced longer stationary phases in migrating cells and cell stalling at the beginning of the migratory stream. We also showed that autophagy is required for recycling of the focal adhesion molecule PXN (paxillin), and is induced by energy levels of cells via AMPK activation. This recent study revealed the importance of autophagy in the maintenance of cell migration, and showed that the dynamic interplay between autophagy and energy levels is required to sustain neuronal migration and to cope with diverse micro-environmental factors.

Identification of spatial patterns, geochemical associations and assessment of origin-specific health risk of potentially toxic elements in soils of Armavir region, Armenia.

The study of soil potentially toxic elements (PTE) contents and establishment of the geochemical characterization of areas which have never been studied is of great concern. In 2019, soil survey of the Armavir region (Armenia) was conducted in order to investigate the spatial pattern of PTE, reveal PTE geochemical associations and assess the origin-specific health risks. The application of compositional data analysis and geospatial mapping allowed to identify two clusters of samples. The first cluster was spatially located on volcanic rocks and was represented by Fe, Co, Mn, Ti, Zn, Ba, Pb suggesting a natural origin of PTE in these areas. The second cluster was allocated on the alluvial, deluvial, and proluvial sediments and represented by As, Cu, Cr, Ni. Such combination of elements in the same group indicates the anthropogenic introduction of some quantities of PTE. The latter is confirmed by the presence of outliers and extreme values for As, Cu and Ni, as well as by the spatial colocation of Fe, Mn, Co, Pb, Zn outliers and extreme contents. The health risk assessment showed that for children the multi-elemental non-carcinogenic risk was detected, while for the adults the non-carcinogenic risk and carcinogenic risk were below the allowable level. The detailed study of the risk levels showed that in first cluster comparatively higher risk were observed for Pb, V, Ba, Zn while in the second cluster: Fe, Co, Mn, As, Cr, Cu, Ni. The results indicated the necessity of additional in-depth studies with special focus on bioavailability of PTE.

LRIG1-Mediated Inhibition of EGF Receptor Signaling Regulates Neural Precursor Cell Proliferation in the Neocortex.

Here, we ask how neural stem cells (NSCs) transition in the developing neocortex from a rapidly to a slowly proliferating state, a process required to maintain lifelong stem cell pools. We identify LRIG1, known to regulate receptor tyrosine kinase signaling in other cell types, as a negative regulator of cortical NSC proliferation. LRIG1 is expressed in murine cortical NSCs as they start to proliferate more slowly during embryogenesis and then peaks postnatally when they transition to give rise to a portion of adult NSCs. Constitutive or acute loss of Lrig1 in NSCs over this developmental time frame causes stem cell expansion due to increased proliferation. LRIG1 controls NSC proliferation by associating with and negatively regulating the epidermal growth factor receptor (EGFR). These data support a model in which LRIG1 dampens the stem cell response to EGFR ligands within the cortical environment to slow their proliferation as they transition to postnatal adult NSCs.

The dynamic interplay between ATP/ADP levels and autophagy sustain neuronal migration in vivo.

Cell migration is a dynamic process that entails extensive protein synthesis and recycling, structural remodeling, and considerable bioenergetic demand. Autophagy is one of the pathways that maintain cellular homeostasis. Time-lapse imaging of autophagosomes and ATP/ADP levels in migrating cells in the rostral migratory stream of mouse revealed that decreases in ATP levels force cells into the stationary phase and induce autophagy. Pharmacological or genetic impairments of autophagy in neuroblasts using either bafilomycin, inducible conditional mice, or CRISPR/Cas9 gene editing decreased cell migration due to the longer duration of the stationary phase. Autophagy is modulated in response to migration-promoting and inhibiting molecular cues and is required for the recycling of focal adhesions. Our results show that autophagy and energy consumption act in concert in migrating cells to dynamically regulate the pace and periodicity of the migratory and stationary phases to sustain neuronal migration.

Developmental Potential and Plasticity of Olfactory Epithelium Stem Cells Revealed by Heterotopic Grafting in the Adult Brain.

The neural stem cells (NSCs) residing in the olfactory epithelium (OE) regenerate damaged olfactory sensory neurons throughout adulthood. The accessibility and availability of these NSCs in living individuals, including humans, makes them a promising candidate for harvesting their potential for cell replacement therapies. However, this requires an in-depth understanding of their developmental potential after grafting. Here, we investigated the developmental potential and plasticity of mouse OE-derived NSCs after grafting into the adult subventricular zone (SVZ) neurogenic niche. Our results showed that OE-derived NSCs integrate and proliferate just like endogenous SVZ stem cells, migrate with similar dynamics as endogenous neuroblasts toward the olfactory bulb, and mature and acquire similar electrophysiological properties as endogenous adult-born bulbar interneurons. These results reveal the developmental potential and plasticity of OE-derived NSCs in vivo and show that they can respond to heterotopic neurogenic cues to adapt their phenotype and become functional neurons in ectopic brain regions.

Combination of compositional data analysis and machine learning approaches to identify sources and geochemical associations of potentially toxic elements in soil and assess the associated human health risk in a mining city.

Mining activities change the chemical composition of the environment and have negative reflection on people's health and there is no single measure to deal with adverse consequences of mining activities, as each case is specific and needs to be understood and mitigated in a unique way. In this study, the combination of compositional data analysis (CoDA), k-means algorithm, hierarchical cluster analysis applied to reveal the geochemical associations of potentially toxic elements (PTE) in soil of Alaverdi city (Armenia) (Ti, Fe, Ba, Mn, Co, V, Pb, Zn, Cu, Cr, Mo, As). Additionally, to assess PTE-induced health risk, two commonly used approaches were used. The obtained results show that the combination of CoDA and machine learning algorithms allow to identify and describe three geochemical associations of the studied elements: the natural, manmade and hybrid. Moreover, the revealed geochemical associations were linked to the natural pattern of distribution of the element concentrations including the influence of the natural mineralization of the parent rocks, as well as the emission from the copper smelter and urban management related activities. The health risk assessment using the US EPA method demonstrated that the observed contents of studied elements are posing a non-carcinogenic risk to children in the entire territory of the city. In the case of adults, the non-carcinogenic risk was identified in areas situated close to the copper smelter. The Summary pollution index (Zc) values were in line with the results of the US EPA method and indicated that the main residential part of the city was under the hazardous pollution level suggesting the possibility of increase in the overall incidence of diseases among frequently ill individuals, children with chronic diseases and functional disorders of vascular system. The obtained results indicated the need for further in-depth studies with special focus on the synergic effect of PTE.

Natural radioactivity in urban soils of mining centers in Armenia: Dose rate and risk assessment.

Soil radioactivity levels, dose rate and radiological health risk were assessed in metal mining centers of Armenia, at the towns of Kapan and Kajaran. Archive soil samples of the multipurpose soil surveys implemented in Kapan and Kajaran were used for estimation of total alpha and total beta activity levels using gas-less iMatic™ alpha/beta cօunting system (Canberra). Ten representative soil samples per town were randomly selected from different urban zones for naturally occurring radionuclide measurements (238U, 232Th, 40 K) using high purity germanium detector. Four radiological indices: radium equivalent activity, outdoor absorbed dose rate, annual effective dose equivalent and excess lifetime cancer risk were estimated based on naturally occurring radionuclide activity concentrations in soils. Results suggest that in Kapan the soil radioactivity, although enhanced by copper and gold-polymetallic mining, are not a significant risk factor to human health. In Kajaran, the soil radioactivity levels were above the background and world average values provided by UNSCEAR, but radionuclides originated in a natural geogenic source and not from mining activities. Generally, in this region no significant radiological risks were identified in relationship with molybdenum, copper, and gold-polymetallic ore mining.

Continuous impact of mining activities on soil heavy metals levels and human health.

Soils samples collected during different geochemical surveys of the city of Kajaran located near the biggest Cu-Mo mining area in Armenia were subjected to the multivariate geostatistical analysis and geochemical mapping in order to reveal soil heavy metals spatial distribution pattern and assess human health risk level under continuous impact of mining activities. In addition, human health risk assessment was done for the contents of Pb, Cu, Zn, Co, Mo, Mn, Ti, and Fe. The results of Principal Component Analysis and Cluster Analysis verify each other and were also complemented by the spatial distribution features of studied heavy metals indicating that two groups of elements have been generated. The first anthropogenically predominated group includes the main industrial elements Mo and Cu, and their accessories Pb and Zn while Ti, Mn, Fe and Co with the naturally predominant contents were observed in the second group. Moreover, the study reveals that the superposition of geogenic and anthropogenic components lead to the alteration of the shapes of areas with the high natural contents of heavy metals and formation of polluted areas with the intensive anomalies of elements. Health risk assessment showed that Mo was the only studied element which poses a non-carcinogenic risk to adult and children's health in some sampling sites during the whole period of investigations. Moreover, in all studied locations multi-elemental non-carcinogenic risk to children health from all studied heavy metals were detected. Special attention was given to the soils of kindergarten territories, and the results indicated that Hazard Index in kindergartens was >1 indicating an adverse health effect to children. The results obtained can serve as a basis for the development and implementation of risks reduction measures and systematic monitoring program planning.

Human health risk assessment and riskiest heavy metal origin identification in urban soils of Yerevan, Armenia.

The pollution of urban soils by heavy metals remains a topical issue because of the risks it represents to human health. Heavy metal pollution levels of Yerevan's soils were evaluated using Pollution index and Enrichment factor, while associated health risk was assessed by US EPA model. The heavy metals with significant amount of PI > 1 values were observed for V (100%), Cr (95.4%), Ni (92.5%), Cu (95.6%), Zn (92.9%), Hg (89.0%), Pb (99.9%), As (72.0%), and Ba (61.6% of samples). EF showed that Yerevan topsoils were significantly contaminated with Hg, and moderately contaminated with V, Ni, Cu, Zn, Cr, and As. Topsoils near the smelting plants of molybdenum concentrate have moderately to extremely high contamination levels for Mo. Topsoils were moderate to extremely highly contaminated with Pb, too. The high amounts of samples with heavy metal contents greater than Maximum Acceptable Concentrations were observed for Pb, Cr, Zn, Ni, and Cu. Pb and Cr exceeded corresponding Soil Screening Levels in 3.39% and 2.43% of samples, correspondingly. The risk assessment showed children's multi-elemental non-carcinogenic risk and low level of arsenic carcinogenic risk in the whole Yerevan. The riskiest element was Pb which high contents in 72 risky sites correlate only with the metals having a natural origin. Moreover, its main source is historically polluted soils and Pb supposed to be redistributed in the city environment linked to the sorption complexes of Fe and Mn oxides.

Heavy metals pollution levels and children health risk assessment of Yerevan kindergartens soils.

Children, the most vulnerable urban population group, are exceptionally sensitive to polluted environments, particularly urban soils, which can lead to adverse health effects upon exposure. In this study, the total concentrations of Ag, As, Ba, Cd, Co, Cr, Cu, Fe, Hg, Mn, Mo, Ni, Pb, Ti, V, and Zn were determined in 111 topsoil samples collected from kindergartens in Yerevan. The objectives of this study were to evaluate heavy metal pollution levels of kindergarten's soils in Yerevan, compare with national legal and international requirements on heavy metal contents in kindergarten soil, and assess related child health risk. Multivariate geostatistical analyses suggested that the concentrations of Ag, As, Ba, Cd, Cu, Hg, Mo, Pb, and Zn observed in the kindergarten's topsoil may have originated from anthropogenic sources, while Co, Cr, Fe, Mn, Ni, Ti, and V mostly come from natural sources. According to the Summary pollution index (Zc), 102 kindergartens belong to the low pollution level, 7 to the moderate and only 2 to the high level of pollution. Summary concentration index (SCI) showed that 109 kindergartens were in the allowable level, while 2 featured in the low level of pollution. The health risk assessment showed that in all kindergartens except for seven, non-carcinogenic risk for children was detected (HI>1), while carcinogenic risk from arsenic belongs to the very low (allowable) level. Cr and multi-element carcinogenic risk (RI) exceeded the safety level (1.0E- 06) in all kindergartens and showed that the potential of developing cancer, albeit small, does exist. Therefore, city's kindergartens require necessary remedial actions to eliminate or reduce soil pollution and heavy metal-induced health risks.

Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. [corrected].

As a result of brain injury, astrocytes become activated and start to proliferate in the vicinity of the injury site. Recently, we had demonstrated that these reactive astrocytes, or glia, can form self-renewing and multipotent neurospheres in vitro. In the present study, we demonstrate that it is only invasive injury, such as stab wounding or cerebral ischemia, and not noninvasive injury conditions, such as chronic amyloidosis or induced neuronal death, that can elicit this increase in plasticity. Furthermore, we find that Sonic hedgehog (SHH) is the signal that acts directly on the astrocytes and is necessary and sufficient to elicit the stem cell response both in vitro and in vivo. These findings provide a molecular basis for how cells with neural stem cell lineage emerge at sites of brain injury and imply that the high levels of SHH known to enter the brain from extraneural sources after invasive injury can trigger this response.

Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum.

Stroke induces the recruitment of neuronal precursors from the subventricular zone (SVZ) into the ischemic striatum. In injured areas, de-routed neuroblasts use blood vessels as a physical scaffold to their migration, in a process that resembles the constitutive migration seen in the rostral migratory stream (RMS). The molecular mechanism underlying injury-induced vasculature-mediated migration of neuroblasts in the post-stroke striatum remains, however, elusive. Using adult mice we now demonstrate that endothelial cells in the ischemic striatum produce brain-derived neurotrophic factor (BDNF), a neurotrophin that promotes the vasculature-mediated migration of neuronal precursors in the RMS, and that recruited neuroblasts maintain expression of p75NTR, a low-affinity receptor for BDNF. Reactive astrocytes, which are widespread throughout the damaged area, ensheath blood vessels and express TrkB, a high-affinity receptor for BDNF. Despite the absence of BDNF mRNA, we observed strong BDNF immunolabeling in astrocytes, suggesting that these glial cells trap extracellular BDNF. Importantly, this pattern of expression is reminiscent of the adult RMS, where TrkB-expressing astrocytes bind and sequester vasculature-derived BDNF, leading to the entry of migrating cells into the stationary phase. Real-time imaging of cell migration in acute brain slices revealed a direct role for BDNF in promoting the migration of neuroblasts to ischemic areas. We also demonstrated that cells migrating in the ischemic striatum display higher exploratory behavior and longer stationary periods than cells migrating in the RMS. Our findings suggest that the mechanisms involved in the injury-induced vasculature-mediated migration of neuroblasts recapitulate, at least partially, those observed during constitutive migration in the RMS.

Astrocytes control the development of the migration-promoting vasculature scaffold in the postnatal brain via VEGF signaling.

New neurons are constantly being generated in the postnatal subventricular zone. They have to migrate long distances via the rostral migratory stream (RMS) to reach their final destination in the olfactory bulb (OB). In adults, these neuronal precursors migrate in chains, ensheathed by astrocytic processes, and travel toward the OB along blood vessels (BVs) that topographically outline the RMS. The molecular and cellular mechanisms leading to the development of the RMS and the formation of the migration-promoting vasculature scaffold in the adult mice remain unclear. We now reveal that astrocytes orchestrate the formation and structural reorganization of the vasculature scaffold in the RMS and, during early developmental stages, the RMS contains only a few BVs oriented randomly with respect to the migrating neuroblasts. The first parallel BVs appeared at the outer border of the RMS, where vascular endothelial growth factor (VEGF)-expressing astrocytes are located. Gain-of-function and loss-of-function experiments revealed that astrocyte-derived VEGF plays a crucial role in the formation and growth of new BVs. Real-time videoimaging also showed that the migration of neuronal precursors in the developing RMS differs substantially from neuronal displacement in the adult migratory stream partially because of not yet fully developed vasculature scaffold. The downregulation of VEGF in vivo, specifically in the astrocytes of the developing RMS, affected the development of the vasculature scaffold and led to alterations in neuroblast migration. Altogether, our results demonstrate that astrocytes orchestrate the formation and growth of parallel BVs, crucial migration-promoting scaffolds in the adult migratory stream, via VEGF signaling.

Nicotinic receptors regulate the survival of newborn neurons in the adult olfactory bulb.

Cholinergic axons and nicotinic receptors are abundant in all layers of the olfactory bulb (OB), the main region of newborn neuron integration in the adult brain. Here, we report that the OB granule cell layer in mice lacking the predominant form of brain high-affinity nicotinic acetylcholine receptors (beta(2)(-/-) mice) displayed nearly 50% more newborn neurons and significantly fewer apoptotic cells than did beta(2)(+/+) mice. Conversely, in vivo chronic nicotine exposure significantly decreased the number of newborn granule cells in beta(2)(+/+) but not beta(2)(-/-) adult mice, confirming that the survival of newborn neurons can be controlled by the activation of beta(2)-containing nicotinic acetylcholine receptors. Unexpectedly, investigating the behavioral consequence of an increased number of granule cells in beta(2)(-/-) mice revealed that these animals have a less robust short-term olfactory memory than their wild-type counterparts. Taken together, these results provide evidence that high-affinity nicotinic receptors are involved in the maturation of adult OB local circuits. They also indicate that an increase in the number of granule cells does not necessarily correlate with better olfactory performance and further highlight the importance of cholinergic afferents for olfactory processing.