Alteration of mesopontine cholinergic function by the lack of KCNQ4 subunit

The pedunculopontine nucleus (PPN), a structure known as a cholinergic member of the reticular activating system (RAS), is source and target of cholinergic neuromodulation and contributes to the regulation of the sleep-wakefulness cycle. The M-current is a voltage-gated potassium current modulated mainly by cholinergic signaling. KCNQ subunits ensemble into ion channels responsible for the M-current. In the central nervous system, KCNQ4 expression is restricted to certain brainstem structures such as the RAS nuclei. Here, we investigated the presence and functional significance of KCNQ4 in the PPN by behavioral studies and the gene and protein expressions and slice electrophysiology using a mouse model lacking KCNQ4 expression. We found that this mouse has alterations in the adaptation to changes in light-darkness cycles, representing the potential role of KCNQ4 in the regulation of the sleep-wakefulness cycle. As cholinergic neurons from the PPN participate in the regulation of this cycle, we investigated whether the cholinergic PPN might also possess functional KCNQ4 subunits. Although the M-current is an electrophysiological hallmark of cholinergic neurons, only a subpopulation of them had KCNQ4-dependent M-current. Interestingly, the absence of the KCNQ4 subunit altered the expression patterns of the other KCNQ subunits in the PPN. We also determined that, in wild-type animals, the cholinergic inputs of the PPN modulated the M-current, and these in turn can modulate the level of synchronization between neighboring PPN neurons. Taken together, the KCNQ4 subunit is present in a subpopulation of PPN cholinergic neurons, and it may contribute to the regulation of the sleep-wakefulness cycle.Fil: Bayasgalan, T.. University of Debrecen; HungríaFil: Stupniki, Sofia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Kovács, A.. University of Debrecen; HungríaFil: Csemer, A.. University of Debrecen; HungríaFil: Szentesi, P.. University of Debrecen; HungríaFil: Pocsai, K.. University of Debrecen; HungríaFil: Dionisio, Leonardo Raul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Spitzmaul, Guillermo Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Pal, B.. University of Debrecen; Hungrí

The egiin davaa prehistoric rupture, central mongolia: A large magnitude normal faulting earthquake on a reactivated fault with little cumulative slip located in a slowly deforming intraplate setting

The prehistoric Egiin Davaa earthquake rupture is well-preserved in late Quaternary deposits within the Hangay Mountains of central Mongolia. The rupture is expressed by a semicontinuous 80 km-long topographic scarp. Geomorphological reconstructions reveal a relatively constant scarp height of 4-4.5 m and a NW-directed slip vector. Previous researchers have suggested that the scarp's exceptional geomorphological preservation indicates that it may correspond to an earthquake that occurred in the region c. 500 years ago. However, we constrain the last rupture to have been at least 4 ka ago from morphological dating and < 7.4 ka ago based on radiocarbon dating from one of two palaeoseismic trenches. Our study shows that discrete earthquake ruptures, along with details such as the locations of partially infilled fissures, can be preserved for periods well in excess of 1000 years in the interior of Asia, providing an archive of fault movements that can be directly read from the Earth's surface over a timescale appropriate for the study of slowly deforming continental interiors. The Egiin Davaa rupture involved c. 8 m of slip which, along with the observations that it is largely unsegmented along its length and that the ratio of cumulative slip (c. 250 m) to fault length (c. 80 km) is small, suggests relatively recent reactivation of a pre-existing geological structure

Motion in the north Iceland volcanic rift zone accommodated by bookshelf faulting

Along mid-ocean ridges the extending crust is segmented1 on length scales of 10–1,000 km. Where rift segments are offset from one another, motion between segments is accommodated by transform faults that are oriented orthogonally to the main rift axis. Where segments overlap, non-transform offsets with a variety of geometries2 accommodate shear motions. Here we use micro-seismic data to analyse the geometries of faults at two overlapping rift segments exposed on land in north Iceland. Between the rift segments, we identify a series of faults that are aligned sub-parallel to the orientation of the main rift. These faults slip through left-lateral strike-slip motion. Yet, movement between the overlapping rift segments is through right-lateral motion. Together, these motions induce a clockwise rotation of the faults and intervening crustal blocks in a motion that is consistent with a bookshelf-faulting mechanism, named after its resemblance to a tilting row of books on a shelf3. The faults probably reactivated existing crustal weaknesses, such as dyke intrusions, that were originally oriented parallel to the main rift and have since rotated about 15° clockwise. Reactivation of pre-existing, rift-parallel weaknesses contrasts with typical mid-ocean ridge transform faults and is an important illustration of a non-transform offset accommodating shear motion between overlapping rift segments

Парагенез активных разломов и позднекайнозойское напряженное состояние земной коры центральной части Монголии

Active faults of the Hangay-Hentiy tectonic saddle region in Central Mongolia are studied by space images interpretation, relief analysis, structural methods and tectonic stress reconstruction. The study results show that faults activation during the Late Cenozoic stage was selective, and a cluster pattern of active faults is typical for the study region. Morphological and genetic types and the kinematics of faults in the Hangay-Hentiy saddle region are related the direction of the ancient inherited structural heterogeneities. Latitudinal and WNW trending faults are left lateral strike-slips with reverse or thrust component (Dzhargalantgol and North Burd faults). NW trending faults are reverse faults or thrusts with left lateral horizontal component. NNW trending faults have right lateral horizontal component. The horizontal component of the displacements, as a rule, exceeds the vertical one. Brittle deformations in fault zones do not conform with the Pliocene and, for the most part, Pleistocene topography. With some caution it may be concluded that the last phase of revitalization of strike slip and reverse movements along the faults commenced in the Late Pleistocene. NE trending disjunctives are normal faults distributed mainly within the Hangay uplift. Their features are more early activation within the Late Cenozoic and the lack of relation to large linear structures of the previous tectonic stages. According to the stress tensor reconstructions of the last phase of deformation in zones of active faults of the Hangay-Hentiy saddle using data on tectonic fractures and fault displacements, it is revealed that conditions of compression and strike-slip with NNE direction of the axis of maximum compression were dominant. Stress tensors of extensional type with NNW direction of minimum compression are reconstructed for the Orkhon graben. It is concluded that the activation of faults in Central Mongolia in the Pleistocene-Holocene, as well as modern seismicity were controlled mainly by additional horizontal compression in the SW direction, which was associated with convergence of the Indian subcontinent and Eurasia. The influence of the asthenosphere flow in the SE direction at the base lithosphere is an additional factor facilitating strike-slip deformation of the crust in the study area and a possible explanation of divergent movements in the Baikal Rift, as well as the SE movement of the Amur plate. The Eastern Hangay crust is deformed under extension associated with a dynamic impact of the local mantle anomaly on the lithosphere. The boundary between the Amur plate and the Mongolian block (according to [Zonenshain, Savostin, 1979]) is fragmentary expressed in the tectonic structure. It represents a rim part of the deformation zone, embracing the Mongolian block and the adjacent uplifts of the Mongolian Altai, Tuva and Eastern Sayan. Along the boundary, compressive and transpressive strain occurred in the Pleistocene-Holocene.В пределах Хангай-Хэнтейской тектонической седловины в центральной части Монголии выполнены исследования активных разломов с применением дешифрирования космических снимков, анализа рельефа, геолого-структурных данных и реконструкции тектонических палеонапряжений. Показано, что активизация разломов на позднекайнозойском этапе происходила селективно и для района характерен кластерный тип локализации комплекса активных разломов. Кинематика разломов Хангай-Хэнтейской седловины и их морфолого-генетический тип связаны с простиранием наследуемой ими древней структурной неоднородности. Разломы широтного и ЗСЗ простирания являются левосторонними сдвигами при обязательном наличии взбросовой или надвиговой компоненты (Джаргалантгольский и Северо-Бурдский разломы). Разломы СЗ простирания являются взбросами или надвигами с левосторонней, а при отклонении к северу – правосторонней компонентой горизонтальных смещений (Тухмийннуур-Уртынгольский, Орхон-Сангийндалайнуурский и Ховрийнгол-Шарлийнгийнгольский разломы). Горизонтальная составляющая смещений, как правило, превышает вертикальную. Разрывные деформации в зонах разломов не конформны плиоценовому и, по большей части, плейстоценовому рельефу. С определенной долей осторожности можно заключить, что начало последнего этапа активизации сдвиговых и взбросовых движений по разломам относится к позднему плейстоцену. Разломы СВ простирания – сбросы, распространенные главным образом в пределах Хангайского поднятия. Их особенностями является более ранняя активизация в пределах позднего кайнозоя и отсутствие связи с крупными линейными структурами предыдущих тектонических этапов. Реконструкции стресс-тензоров последнего этапа деформаций в зонах активных разломов Хангай-Хэнтейской седловины по тектонической трещиноватости и смещениям по разрывам указывают на преобладание условий сжатия и сдвига с ССВ направлением оси максимального сжатия. В пределах Орхонского грабена реконструированы тензоры типа растяжения с ССЗ направлением оси минимального сжатия. Сделан вывод о том, что активизация разломов центральной части Монголии на плейстоцен-голоценовом этапе, а также современная сейсмичность контролируются в основном дополнительным горизонтальным сжатием в СВ направлении, связанным с процессом конвергенции Индостана и Евразии. Дополнительным фактором, позволяющим реализоваться сдвиговым деформациям в земной коре территории исследований и объясняющим дивергентные движения в Байкальском рифте, а также ЮВ движение Амурской плиты, является воздействие на подошву литосферы астеносферного потока в ЮВ направлении. Земная кора Восточного Хангая деформируется в условиях растяжения, которое связано с динамическим воздействием на литосферу локальной аномалии разуплотненного мантийного вещества. Граница между Амурской плитой и Монгольским блоком (по [Zonenshain, Savostin, 1979]) в тектонической структуре выражена фрагментарно и представляет собой краевую часть зоны деформаций, охватывающей Монгольский блок и прилегающие к нему поднятия Монгольского Алтая, Тувинского нагорья, Восточного Саяна. Вдоль границы на плейстоцен-голоценовом этапе реализуются деформации сжатия и транспрессии

Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis

CCL17 is produced by conventional dendritic cells, signals through CCR4 on regulatory T (Treg) cells and drives atherosclerosis by suppressing Treg functions through yet undefined mechanisms. Here we show that conventional dendritic cells from CCL17-deficient mice display a pro-tolerogenic phenotype and transcriptome that is not phenocopied in mice lacking its cognate receptor CCR4. In the plasma of CCL17-deficient mice, CCL3 was the only decreased cytokine/chemokine. We found that CCL17 signaled through CCR8 as an alternate high-affinity receptor, which induced CCL3 expression and suppressed Treg functions in the absence of CCR4. Genetic ablation of CCL3 and CCR8 in CD4+ T cells reduced CCL3 secretion, boosted FoxP3+ Treg numbers and limited atherosclerosis. Conversely, CCL3 administration exacerbated atherosclerosis and restrained Treg differentiation. In symptomatic versus asymptomatic human carotid atheroma, CCL3 expression was increased, whereas FoxP3 expression was reduced. Together, we identified a non-canonical chemokine pathway whereby CCL17 interacts with CCR8 to yield a CCL3-dependent suppression of atheroprotective Treg cells. Doring, van der Vorst, Yan, Neideck et al. present a non-canonical chemokine pathway involving CCL17 signaling through CCR8, which induces CCL3 expression independent of CCR4 and suppresses the functions of atheroprotective Treg cells

Birth size and gestational age in opposite-sex twins as compared to same-sex twins: An individual-based pooled analysis of 21 cohorts

It is well established that boys are born heavier and longer than girls, but it remains unclear whether birth size in twins is affected by the sex of their co-twin. We conducted an individual-based pooled analysis of 21 twin cohorts in 15 countries derived from the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), including 67,850 dizygotic twin individuals. Linear regression analyses showed that boys having a co-twin sister were, on average, 31 g (95% CI 18 to 45) heavier and 0.16 cm (95% CI 0.045 to 0.274) longer than those with a co-twin brother. In girls, birth size was not associated (5 g birth weight; 95% CI -8 to -18 and -0.089 cm birth length; 95% CI -0.202 to 0.025) with the sex of the co-twin. Gestational age was slightly shorter in boy-boy pairs than in boy-girl and girl-girl pairs. When birth size was standardized by gestational age, the magnitude of the associations was attenuated in boys, particularly for birth weight. In conclusion, boys with a co-twin sister are heavier and longer at birth than those with a co-twin brother. However, these differences are modest and partly explained by a longer gestation in the presence of a co-twin sister

Genetic and environmental factors affecting birth size variation: a pooled individual-based analysis of secular trends and global geographical differences using 26 twin cohorts

Background: The genetic architecture of birth size may differ geographically and over time. We examined differences in the genetic and environmental contributions to birthweight, length and ponderal index (PI) across geographical-cultural regions (Europe, North America and Australia, and East Asia) and across birth cohorts, and how gestational age modifies these effects. Methods: Data from 26 twin cohorts in 16 countries including 57 613 monozygotic and dizygotic twin pairs were pooled. Genetic and environmental variations of birth size were estimated using genetic structural equation modelling. Results: The variance of birthweight and length was predominantly explained by shared environmental factors, whereas the variance of PI was explained both by shared and unique environmental factors. Genetic variance contributing to birth size was small. Adjusting for gestational age decreased the proportions of shared environmental variance and increased the propositions of unique environmental variance. Genetic variance was similar in the geographical-cultural regions, but shared environmental variance was smaller in East Asia than in Europe and North America and Australia. The total variance and shared environmental variance of birth length and PI were greater from the birth cohort 1990-99 onwards compared with the birth cohorts from 1970-79 to 1980-89. Conclusions: The contribution of genetic factors to birth size is smaller than that of shared environmental factors, which is partly explained by gestational age. Shared environmental variances of birth length and PI were greater in the latest birth cohorts and differed also across geographical-cultural regions. Shared environmental factors are important when explaining differences in the variation of birth size globally and over time

Association between birthweight and later body mass index: an individual-based pooled analysis of 27 twin cohorts participating in the CODATwins project

Background: There is evidence that birthweight is positively associated with body mass index (BMI) in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. We analysed the association between birthweight and BMI from infancy to adulthood within twin pairs, which provides insights into the role of genetic and environmental individual-specific factors. Methods: This study is based on the data from 27 twin cohorts in 17 countries. The pooled data included 78 642 twin individuals (20 635 monozygotic and 18 686 same-sex dizygotic twin pairs) with information on birthweight and a total of 214 930 BMI measurements at ages ranging from 1 to 49 years. The association between birthweight and BMI was analysed at both the individual and within-pair levels using linear regression analyses. Results: At the individual level, a 1-kg increase in birthweight was linearly associated with up to 0.9 kg/m 2 higher BMI ( P  < 0.001). Within twin pairs, regression coefficients were generally greater (up to 1.2 kg/m 2 per kg birthweight, P  < 0.001) than those from the individual-level analyses. Intra-pair associations between birthweight and later BMI were similar in both zygosity groups and sexes and were lower in adulthood. Conclusions: These findings indicate that environmental factors unique to each individual have an important role in the positive association between birthweight and later BMI, at least until young adulthood

Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994

Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886-1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.Peer reviewe

Associations between birth size and later height from infancy through adulthood: An individual based pooled analysis of 28 twin cohorts participating in the CODATwins project.

BACKGROUND: There is evidence that birth size is positively associated with height in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. AIM: To analyze the associations of birth weight, length and ponderal index with height from infancy through adulthood within mono- and dizygotic twin pairs, which provides insights into the role of genetic and environmental individual-specific factors. METHODS: This study is based on the data from 28 twin cohorts in 17 countries. The pooled data included 41,852 complete twin pairs (55% monozygotic and 45% same-sex dizygotic) with information on birth weight and a total of 112,409 paired height measurements at ages ranging from 1 to 69 years. Birth length was available for 19,881 complete twin pairs, with a total of 72,692 paired height measurements. The association between birth size and later height was analyzed at both the individual and within-pair level by linear regression analyses. RESULTS: Within twin pairs, regression coefficients showed that a 1-kg increase in birth weight and a 1-cm increase in birth length were associated with 1.14-4.25 cm and 0.18-0.90 cm taller height, respectively. The magnitude of the associations was generally greater within dizygotic than within monozygotic twin pairs, and this difference between zygosities was more pronounced for birth length. CONCLUSION: Both genetic and individual-specific environmental factors play a role in the association between birth size and later height from infancy to adulthood, with a larger role for genetics in the association with birth length than with birth weight