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The identity of the earliest inhabitants of Xinjiang, in the heart of Inner Asia, and the languages that they spoke have long been debated and remain contentious1. Here we present genomic data from 5 individuals dating to around 3000–2800 bc from the Dzungarian Basin and 13 individuals dating to around 2100–1700 bc from the Tarim Basin, representing the earliest yet discovered human remains from North and South Xinjiang, respectively. We find that the Early Bronze Age Dzungarian individuals exhibit a predominantly Afanasievo ancestry with an additional local contribution, and the Early–Middle Bronze Age Tarim individuals contain only a local ancestry. The Tarim individuals from the site of Xiaohe further exhibit strong evidence of milk proteins in their dental calculus, indicating a reliance on dairy pastoralism at the site since its founding. Our results do not support previous hypotheses for the origin of the Tarim mummies, who were argued to be Proto-Tocharian-speaking pastoralists descended from the Afanasievo1,2 or to have originated among the Bactria–Margiana Archaeological Complex3 or Inner Asian Mountain Corridor cultures4. Instead, although Tocharian may have been plausibly introduced to the Dzungarian Basin by Afanasievo migrants during the Early Bronze Age, we find that the earliest Tarim Basin cultures appear to have arisen from a genetically isolated local population that adopted neighbouring pastoralist and agriculturalist practices, which allowed them to settle and thrive along the shifting riverine oases of the Taklamakan Desert., A genomic analysis of human remains from the Bronze Age provides insights into the origin of the Tarim Basin mummies from the Xinjiang region.

The Xinjiang region in northwest China is a historically important geographical passage between East and West Eurasia. By sequencing 201 ancient genomes from 39 archaeological sites, we clarify the complex demographic history of this region. Bronze Age Xinjiang populations are characterized by four major ancestries related to Early Bronze Age cultures from the central and eastern Steppe, Central Asian, and Tarim Basin regions. Admixtures between Middle and Late Bronze Age Steppe cultures continued during the Late Bronze and Iron Ages, along with an inflow of East and Central Asian ancestry. Historical era populations show similar admixed and diverse ancestries as those of present-day Xinjiang populations. These results document the influence that East and West Eurasian populations have had over time in the different regions of Xinjiang.

Background Notch signaling mediates the committed induced differentiation of ear sensory cells and promotes the formation of a precise arrangement of mosaics between hair cells and supporting cells. Embryonic stem cells (ESCs) are pluripotent stem cells which have the potential to differentiate into cell lines through three germ layers. Therefore, it is necessary to study the effects of regulating Notch receptors and ligand expression on the in vitro differentiation equilibrium of hair cells and supporting cells from ESCs.Methods and Results The temporal ex-pression pattern of Notch ligands and receptors during in vitro hair cell-like cell differentia-tion from human embryonic stem cells (hESCs) was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Subsequently, pAJ-U6-shRNA-CMV-Puro/GFP recombinant lentiviral vectors, encoding short hairpin RNAs, were used to silence JAG-1, JAG-2, and DLL-1, according to the temporal expression pattern of Notch ligands. Then the effect of each ligand on the in vitro differentiation of hair cells was examined by RT-PCR, immunofluorescence, and scanning electron microscopy (SEM).Conclusions Results showed that JAG-1 played an important role in regulating hESC differentiation to otic progenitors. The individual deletion of JAG-2 or DLL-1 had no significant effect on the differentiation of hair cell-like cells. Although the simultaneous inhibition of both DLL-1 and JAG-2 could increase the number of hair cell-like cells, it decreased the number of supporting cells.

The cold and warm intervals during the Plio-Pleistocene provide an opportunity to assess the response of the Asian summer monsoon (ASM) to different levels of global warming. In this study, the northern edge of the ASM, a sensitive indicator of the advance and retreat of the ASM rain belt, was analyzed using climate outputs from PMIP3 and PlioMIP1, for the Last Glacial Maximum (LGM, ∼21,000 yr BP), the preindustrial, the mid-Holocene (∼6,000 yr BP), and the mid-Pliocene (∼3.3–3.0 Ma), among which the global temperature increased sequentially. The results show that the northern edge of the ASM migrated northwestward by ∼200 km, ∼50 km, and ∼50 km with global warming from the LGM to preindustrial, from the preindustrial to mid-Holocene, and from the mid-Holocene to mid-Pliocene, respectively. These results are generally consistent with geological records. The simulations show that the western Pacific subtropical high (WPSH) intensified and expanded geographically, and the intertropical convergence zone (ITCZ) migrated northward over the Indian Ocean and was shifted southward over the western Pacific. This led to a northwestward shift of the Asian monsoonal rain belt, and consequently to wetter conditions in India and northern China. During the mid-Pliocene, pronounced warming substantially intensified the WPSH, leading to the suppression of moisture transport from the Indian Ocean to southern China and the Indo-China Peninsula. Our results suggest that if the planet returns to a Pliocene warm world, precipitation will increase in northern China, while southern China and the Indo-China Peninsula will experience more frequent droughts.

The ancient Loulan, situated on the west bank of Lake Lop Nur, Xinjiang, Northwest China, was an important town on the Silk Road connecting China to Europe. However, this once-prosperous kingdom has been a depopulated zone filled with wind-eroded mounds since approximately AD 500–600. A comprehensive understanding of the environmental setting of the flourishing Loulan civilization is a prerequisite for assessing environment–human interaction there. Here, we present our survey, chronology, and archaeobotany (the identification of plant remains) of vegetation use for architecture from eight ancient ruins of the Loulan kingdom to clarify the ecological landscape on the west bank of Lake Lop Nur and to assess paleoenvironmental conditions when the Loulan kingdom flourished. Our results suggest that Populus euphratica, tamarisk ( Tamarix Linn), and reed ( Phragmites Trin.) were most widely used as building materials in this period. Wood utilization for buildings depended entirely on indigenous vegetation rather than that of the mountains in the Loulan kingdom, even though the Loulan was a predominant transportation hub on the prosperous Silk Road. Our reconstruction indicates that the west bank of Lake Lop Nur was sufficiently wetter than present conditions to support riparian forest growth composed mainly of P. euphratica, tamarisk shrubs, and reed meadows, until approximately AD 500. These wetter conditions and flourishing civilization accompanied an increase in precipitation in arid central Asia. Conversely, combined evidence of both archeological and paleoclimatic records from the water sources of Lake Lop Nur and ancient oases suggest that abrupt decreased mountain precipitation could be considered a significant environmental factor in the decline of Loulan kingdom.

The 237 ancient mitochondrial genomes from Xinjiang reveal highly admixed populations from the Bronze Age to Historical Era., Xinjiang is a key region in northwestern China, connecting East and West Eurasian populations and cultures for thousands of years. To understand the genetic history of Xinjiang, we sequenced 237 complete ancient human mitochondrial genomes from the Bronze Age through Historical Era (41 archaeological sites). Overall, the Bronze Age Xinjiang populations show high diversity and regional genetic affinities with Steppe and northeastern Asian populations along with a deep ancient Siberian connection for the Tarim Basin Xiaohe individuals. In the Iron Age, in general, Steppe-related and northeastern Asian admixture intensified, with North and East Xinjiang populations showing more affinity with northeastern Asians and South Xinjiang populations showing more affinity with Central Asians. The genetic structure observed in the Historical Era of Xinjiang is similar to that in the Iron Age, demonstrating genetic continuity since the Iron Age with some additional genetic admixture with populations surrounding the Xinjiang region.

The Lop Nur region, as the junction of the Silk Roads, played an important role in ancient human migration between the East and the West, especially during the Han-Jin Dynasties (second century CE to fourth century CE). However, the scale and volume of human mobility in the region remain poorly understood. Here, we present a multi-approach (wood identification, strontium and oxygen isotopes of tooth enamel and historical documents) to investigate the extent of human mobility in the Lop Nur region. From a Han-Jin Dynasties cemetery, the appearance of nonlocal wood might suggest the existence of human migratory behaviors in the Lop Nur region. Furthermore, a piece of lacquerware with the possible origin of eastern China and a large-scale mural tomb likely belonged to a Kushan emigrant indicate the existence of long-distance connections across the Asia interior. Strontium and oxygen isotope data show a highly mobile population in the Lop Nur region, and the great isotopic variation suggests that these immigrants have diverse origins. In context with historical documents, we infer that the Lop Nur region was once the political, economic, and cultural meeting place of various societies, and also a communication corridor on the Silk Roads during the Han-Jin Dynasties.

As the junction of the Silk Roads, the Tarim Basin played a critical role in human migration and cultural interaction between the East and the West. Recently, population migration patterns have been increasingly reconstructed from strontium isotope ratios ( 87 Sr/ 86 Sr) in archaeological human skeletons, and further constraints on their provenance require a bioavailable 87 Sr/ 86 Sr map across the basin. Based on measurement data from 44 river samples in this study and 29 samples from published data, we generate the first map of bioavailable 87 Sr/ 86 Sr values across the Tarim Basin and the neighbouring area. From the baseline map, three geologically distinct regions can be identified: (1) the Yili Block, Tian Shan orogenic belt and northern Tarim Block with lower ratios (0.7105 ± 0.0007 (1σ), n = 25); (2) the southern Tarim Block with higher ratios (0.7118 ± 0.0008, n = 29); and (3) the eastern Pamir Block with diverse values (0.7110 ± 0.0009, n = 19). This map is a promising tool for recognizing the origins of immigrants in the Tarim Basin and may aid understanding of the migration patterns and cultural communication along the Silk Roads.

The hypothesis that climate change paced modern human dispersal is complicated by newly found fossil evidence from East Asia. Here we conduct a palynological analysis to a loessic Paleolithic site in Central China, spanning past 240 ka, to investigate the vegetation history and assess the impact of climate change to human activity intensity. Our results show that steppe was dominant during glacial periods and local forest was recovered during interglacial periods, pretty correlative to the quantity of stone artifacts. This correlation would suggest a coupling between human activity intensity and climate fluctuation in the study area. In addition, few stone artifacts continuously occurred in the later Last Glacial period, being tentatively attributed to improved adaption of local habitants or immigration of modern human.

To better constrain the tectonic evolution of Central Asia under the influence of the India-Asia collision, we performed combined magnetostratigraphy and anisotropy of magnetic susceptibility (AMS) analysis of the Baiyanghe section on the northern margin of the Hoxtolgay Basin (West Junggar Mt Range, northwestern China). The observed magnetostratigraphy shows a total of 14 pairs of normal and reversed geomagnetic polarity zones in the well-exposed ∼360 m thick section. In tandem with two ESR dating results, these zones can be reliably correlated with the geomagnetic polarity time scale (GPTS) from C3An.2r to C1n, and yield an age ranging from ∼7.0 Ma to ∼0.2 Ma. The long hiatus between the Mesozoic and the late Cenozoic, corresponding to the age of the basal conglomerates, suggests that uplift of the West Junggar Mt Range was initiated at least at ∼7.0 Ma ago. Furthermore, the onset of massive conglomerate deposits, as well as marked increases in sedimentation rate, k, T and Pj of AMS, occurred at ∼3.6 Ma. These notable changes are coeval with the peak deformation in Central Asia. Considering the depositional diachroneity of the Xiyu conglomerates and the predominantly dry climate in Central Asia since at least the late Cenozoic, we suggest that accelerated uplift of the West Junggar Mt Range at ∼3.6 Ma should be the main factor controlling these multiple changes within the Baiyanghe section. Another marked increase in conglomerate content, sedimentation rate and κ occurred at ∼1.1 Ma. The cause of this event deserves further investigation in the future.

The Ji'erzankale Necropolis, dating back to 2500 cal yr BP, is located in the Tashkurgan, Xinjiang Uyghur Autonomous Region of China. Abundant wooden objects were unearthed in 2013 and 2014, including plates, fire altars, hearth boards, hand drills, wooden sticks, arrow shafts, bowls, two pieces of konghou (musical instrument) and a harp, among other things. Species identification of 70 wooden objects from 25 tombs indicates that they were crafted from at least seven different trees, namely Juniperus sp. (4), Populus sp. (15), Betula sp. (28), Salix sp. (8), Lonicera sp. (8), Elaeagnus angustifolia (1), Fraxinus syriaca (2), and four unidentified types. Based on the ecological habitats of the different species, we inferred that woodland dominated by Betula , Populus and Salix , with some associated Lonicera and Elaeagnus angustifolia , developed on the floodplain of the Tashkurgan River, with Juniperus boscage on the shady slopes of the local mountains. This vegetation community suggests that an arid/semi-arid oasis environment was extant at that time. Comparing this result with the shrubs found in today's floodplain and montane desert environment, our findings indicate that the climate of the Tashkurgan River valley was relatively humid around 2500 years ago. This probably resulted from an increase in precipitation transported to the region by the mid-latitude westerlies.

Deciphering the long-term interaction among continental silicate weathering, global climate, and atmospheric CO2 concentrations is helpful in understanding the mechanisms of the Cenozoic climate change and accessing the future climatic and environmental response to anthropogenic carbon emissions. The Eocene, which is characterized by the Early Eocene Climatic Optimum (EECO) and the following global cooling, represents an ideal test case. Here we generate geochemical data of the Eocene lacustrine sediments from the Fushun Basin, northeast China, to explore the regional climatic response to the global climate change. The chemical index of alteration (CIA) and plagioclase index of alteration (PIA) consistently show a gradual, long-term decrease, indicating a climatic transition from warm and humid to relatively cold and arid during the Eocene in the Fushun Basin. This climatic trend is broadly coincident with the global cooling and decreasing CO2 concentration, implying that the regional climate is closely correlated with the global climate change over geological time scales. Additionally, the extreme silicate weathering and high lake productivity as reflected by relatively positive δ13C values of lacustrine organic matter are associated with the EECO. This consistency may demonstrate that enhanced continental weathering and lake productivity had served as effective sinks to lower atmospheric CO2 across the EECO. Collectively, our new geochemical data add supporting evidence for a long-term, close coupling among continental silicate weathering, climate, and global carbon cycle during the Eocene.

Sensorineural hearing loss and vestibular dysfunction have become the most common forms of sensory defects. Stem cell-based therapeutic strategies for curing hearing loss are being developed. Several attempts to develop hair cells by using chicken utricle stromal cells as feeder cells have resulted in phenotypic conversion of stem cells into inner ear hair-cell-like cells. Here, we induced the differentiation of human embryonic stem cells (hESCs) into otic epithelial progenitors (OEPs), and further induced the differentiation of OEPs into hair-cell-like cells using different substrates. Our results showed that OEPs cultured on the chicken utricle stromal cells with the induction medium could differentiate into hair-cell-like cells with stereociliary bundles. Co-culture with stromal cells, however, may be problematic for subsequent examination of the induced hair-cell-like cells. In order to avoid the interference from stromal cells, we cultured OEPs on laminin with different induction media and examined the effects of the induction medium on the differentiation potentials of OEPs into hair-cell-like cells. The results revealed that the culture of OEPs on laminin with the conditioned medium from chicken utricle stromal cells supplemented with EGF and all-trans retinoic acid (RA) could promote the organization of cells into epithelial clusters displaying hair-cell-like cells with stereociliary bundles. These cells also displayed the expected electrophysiological properties.

Today, the hydrological regime in East and South Asia is dominated by the monsoons, whilst central Asia is characterized as arid. Studies that have examined the onset of aridity and the intensification of the monsoons in Asia have generated significant debate, especially in respect to the timing of monsoon onset and how this relates to the potential causal mechanisms. The uplift of the Tibetan Plateau, the retreat of the Paratethys Sea, and the global cooling after the Eocene/Oligocene transition are all considered major drivers of Asian aridity and monsoonal intensification. However, little is known about each of these factor's contribution to the development of modern monsoon behaviour. Here, for the first time, we perform sensitivity simulations of a fully coupled ocean–atmosphere climate model (HadCM3) to investigate the effect of the Greenland and Antarctic ice-sheets formation, atmospheric carbon dioxide (CO2) variability, and Tibetan Plateau uplift on East Central Asian aridity and monsoon driven precipitation. We focus on three individual regions, the South Asian Monsoon, the East Asian Monsoon and the Arid East Central Asia and we present the annual precipitation cycle and the moisture availability over each region. Our results show that of the parameters investigated the primary control on Asian hydroclimate is the topography of the Tibetan Plateau. Furthermore, our results highlight that the significance of each forcing depends on the component of the hydrological region and factors studied, a factor that proxy interpretation need to take into consideration.

Chemical analysis reveals early ritual cannabis smoking in the eastern Pamirs by 2500 years ago., Cannabis is one of the oldest cultivated plants in East Asia, grown for grain and fiber as well as for recreational, medical, and ritual purposes. It is one of the most widely used psychoactive drugs in the world today, but little is known about its early psychoactive use or when plants under cultivation evolved the phenotypical trait of increased specialized compound production. The archaeological evidence for ritualized consumption of cannabis is limited and contentious. Here, we present some of the earliest directly dated and scientifically verified evidence for ritual cannabis smoking. This phytochemical analysis indicates that cannabis plants were burned in wooden braziers during mortuary ceremonies at the Jirzankal Cemetery (ca. 500 BCE) in the eastern Pamirs region. This suggests cannabis was smoked as part of ritual and/or religious activities in western China by at least 2500 years ago and that the cannabis plants produced high levels of psychoactive compounds.

Supplemental material, Supplement_1 for Oasis landscape of the ancient Loulan on the west bank of Lake Lop Nur, Northwest China, inferred from vegetation utilization for architecture by Kangkang Li, Xiaoguang Qin, Lei Zhang, Shuzhi Wang, Bing Xu, Guijin Mu, Yong Wu, Xiaohong Tian, Dong Wei, Zhaoyan Gu, Chunxue Wang, Jianping Zhang, Deke Xu, Zihua Tang, Yongchong Lin, Wen Li, Jiaqi Liu and Yinxin Jiao in The Holocene

The building of Tian Shan is often simplified to a Cenozoic reactivation of a Paleozoic fold belt. During the past decades extensive case studies have arrived at the conclusion that Tian Shan experienced diachronous uplift during the Cenozoic, however, understanding of the specific location and duration of the mountain building is still hindered by complex tectonic history of the orogenic belt. Considering the geochemical differences of various tectonic units within the mountains, we studied the chemical composition variability for the carbonate-free fine-grained samples collected from the longest terrestrial outcrop in the Kuche depression, southern Tian Shan, at a high resolution in order to better constrain the orogenic process. Our data show significant increases in mobile elements during the interval of 23–17 Ma, departing substantially from the stable long-term weathering trends and limited sedimentary sorting effects. We interpret the trend as provenance changes, which provide crucial evidence to support that the South Tian Shan experienced significant surface uplift during the early Miocene. This argument is supported by other studies conducted on both local and regional scales. Mineralogical analyses for the study section have shown that, since the early Neogene, a marked increase of detrital limeclasts derived from the South Tian Shan is accompanied by the decreases of the abundance of garnets derived from an ultrahigh-pressure metamorphic fold belt in the central Tian Shan. Moreover, low-temperature thermochronological results revealed that the central Tian Shan merely experienced pre-Neogene cooling, contrasting to the southern piedmont of the mountain where Neogene cooling dominated. Taken all together, we conclude that the uplift of the South Tian Shan initiated at ~ 23 Ma and the paleoelevation may exceed the height of the central Tian Shan at ~ 17 Ma.

The Paleocene-Eocene Thermal Maximum (PETM), a transient greenhouse climate interval associated with a huge release of carbon to the ocean-atmosphere system ~56 million years ago, provides a geological case study for the effect of rapid global warming on regional hydroclimate. Here we reconstruct carbon isotope discrimination (△) of C3 plants across the PETM in the Fushun and Nanyang Basins of China. The △ values present remarkable increase at both sites but with greater magnitude in the Fushun Basin during the PETM, which is explained as a response to regional precipitation. Quantitative estimate of mean annual precipitation based on the △ values suggests that East Asian continent generally became wetter with relatively more precipitation occurring at higher latitudes in response to the PETM warming. Our results support the prediction that continuous anthropogenic warming will lead to a wetter climate in East Asia with relatively more precipitation in higher-latitude lands.

It has been clearly established that the climate of Asia is significantly affected by high-elevation orogens such as the Tibetan Plateau, Mongolian Plateau and Tian-Shan. The East Asian Monsoon (EAM), one of the most prominent features of Asian climate, has been well studied in a modern context and its dynamics are generally well understood. However, specific features of the EAM are less studied and understood in a palaeoclimate context, largely because of associated uncertainties in palaeotopography for the Cenozoic era. Here, we investigate changes in the individual stages of the EAM in response to increasing topography over Central Asia. We perform a series of sensitivity experiments with different palaeogeographic elevations using a coupled ocean-atmosphere General Circulation Model (HadCM3), to investigate seasonal variability of the EAM, and investigate the emergent critical threshold in elevation where the patterns of atmospheric circulation and climate over Asia attains the characteristics observed in the modern climate system. Our results indicate that above an elevation threshold of 3000 m, EAM circulation follows the modern pattern, but below that threshold, EAM circulation and precipitation follow a distinctly different pattern, where the westerly jet does not propagate into the higher latitudes and monsoonal precipitation is limited to June and July. This shift in circulation pattern has important implications for the successful interpretation of proxy-based palaeoclimate and environmental reconstructions. In addition, our results emphasize the importance of the latitudinal position of high-elevation on the EAM circulation, by showing that low-elevation can produce modern-like EAM conditions, if located at different latitudes than modern.

As the northernmost part of the Indo-Eurasian collision belt, the Pamir-Tian Shan convergence zone (PTCZ) is a strategic location for understanding intracontinental deformation. Here we present a magnetostratigraphic investigation of a continuous section from the Baxbulak region, to better constrain regional tectonic history. Rock magnetic analyses indicate that hematite and magnetite are the main carriers of characteristic remanent magnetization. The resulting polarity sequence allows a distinct correlation to the geomagnetic polarity time scale, showing that the section spans the interval of 29.1–20.7 Ma. Rock magnetic results further suggest that paramagnetic and antiferromagnetic minerals dominantly contribute to anisotropy of magnetic susceptibility (AMS) of the sequence. Thus, the AMS would indicate the preferred orientations of the mineral grains that are sensitive to tectonic strain. At around 26 Ma, the grouped principal minimum perpendicular to the bedding diverts to a girdle distribution in a N-S direction, demonstrating the overprint of tectonic fabric to previous weakly deformed sedimentary fabric. This would be interpreted as a marked increase in tectonic strain, consistent with various evidence from the Pamir and the neighboring basin that show the Pamir began to migrate northward. Moreover, the coincident changes in distribution of AMS principal axes, in both direction and magnitude, are comparable to the regional counterclockwise rotations observed from paleomagnetic data, likely related to orogenesis.

The induction of inner ear hair cells from stem cells or progenitor cells in the inner ear proceeds through a committed inner ear sensory progenitor cell stage prior to hair cell differentiation. To increase the efficacy of inducing inner ear hair cell differentiation from the stem cells or progenitor cells, it is essential to identify comprehensive markers for the stem cells/progenitor cells from the inner ear, the committed inner ear sensory progenitor cells and the differentiating hair cells to optimize induction conditions. Here, we report that we efficiently isolated and expanded the stem cells or progenitor cells from postnatal mouse cochleae, and induced the generation of inner ear progenitor cells and subsequent differentiation of hair cells. We profiled the gene expression of the stem cells or progenitor cells, the inner ear progenitor cells, and hair cells using aRNA microarray analysis. The pathway and gene ontology (GO) analysis of differentially expressed genes was performed. Analysis of genes exclusively detected in one particular cellular population revealed 30, 38, and 31 genes specific for inner ear stem cells, inner ear progenitor cells, and hair cells, respectively. We further examined the expression of these genes in vivo and determined that Gdf10+Ccdc121, Tmprss9+Orm1, and Chrna9+Espnl are marker genes specific for inner ear stem cells, inner ear progenitor cells, and differentiating hair cells, respectively. The identification of these marker genes will likely help the effort to increase the efficacy of hair cell induction from the stem cells or progenitor cells.

The current clinical treatments for complications caused by hepatobiliary surgery still have some inevitable weakness. The aim of the study was to fabricate a tissue-engineered bile duct that utilized a novel bilayered polymer scaffold combined with human bone marrow-derived mesenchymal stem cells (hMSCs) for new treatment of biliary disease. The biocompatibility of polycaprolactone (PCL) (PCL)/poly(lactide-co-glycolide) (PLGA) scaffold with hMSCs was first examined, and the hMSC-PCL/PLGA constructs (MPPCs) prepared. The MPPCs and blank scaffolds were then transplanted into 18 pigs for evaluation its efficacy on bile duct repairing, respectively. In vitro, the PCL/PLGA scaffold was verified to support the adhesion, proliferation and matrix deposition of hMSCs. There was no sign of bile duct narrowing and cholestasis in all experimental animals. At 6 months, the MPPCs had a superior repairing effect on the bile duct injury, compared with the blank PCL/PLGA scaffolds. Therefore, the implanted scaffolds could not only support the biliary tract and allow free bile flow but also had direct or indirect positive effects on repair of injured bile duct. Copyright © 2015 John Wiley & Sons, Ltd.

The carbon isotope excursion (CIE) associated with the Paleocene–Eocene Thermal Maximum (PETM) has been recognized for the first time in the micritic carbonate, total organic carbon (TOC) and black carbon (BC) contained within the lacustrine sediments from the Nanyang Basin, central China. The remarkably large excursion ( ∼ − 6 ‰ ) in the δ13CTOC and δ13CBC values is possibly attributable to increased humidity and elevated pCO2 concentration. The ∼ − 4 ‰ CIE recorded in the δ13Ccalcite, reflecting the average isotope change of the watershed system, is consistent with that observed in planktonic foraminifera. This correspondence suggests that the true magnitude of the carbon isotope excursion in the ocean–atmosphere system is likely close to − 4 ‰ . The ∼10 m excursion onset in our multi-proxy δ13C records demonstrates that the large input of 13C-depleted carbon into the ocean–atmosphere system was not geologically instantaneous. Despite difference and somewhat smoothness in detailed pattern of the CIE due to localized controls on different substrates, inorganic and organic δ13C data generally depict a gradual excursion onset at least over timescales of thousands of years. In addition, continental temperature reconstruction, based on the distribution of membrane lipids of bacteria, suggests a warming of ∼4 °C prior to the PETM and ∼7 °C increase in temperature during the PETM. The temperature data are overall similar in pattern and trend to the δ13C change across the PETM. These observations, combined with pre-CIE warming, are in line with the idea that 13C-depleted carbon release operated as a positive feedback to temperature, suggesting supply from one or more large organic carbon reservoirs on Earth's surface.

Hindlimb unloading, as a simulation of microgravity, decreases the osteogenic potential of mesenchymal stem cells (MSCs) from hindlimb femur of rat. We simulated the microgravity by 28-day of hindlimb unloading for male Sprague-Dawley rat, and performed intramuscular injection of BMP-2 and FGF2 at a given interval during hindlimb unloading. Then, the bone marrow (BM) was collected from hindlimb femur of rat. MSCs were isolated from BM, cultured for four passages, and then induced for osteogenesis. The results revealed that the hindlimb unloading decreased the osteogenic potential of MSCs and also the expression of osteoblast gene marker mRNAs in cells induced by osteogenic conditions. Hindlimb unloading for 28 days resulted in the decrease of vinculin-containing focal adhesion in MSCs. During hindlimb unloading, the interval intramuscular injection of BMP-2 or FGF2 alone could increase the osteogenic potential of MSCs and the expression of osteoblast gene marker mRNA. However, the effect of BMP-2 or FGF2 injection alone was significantly lower than that of combination injection of both factors. The further examination showed that the intramuscular injection of BMP-2 promoted the expression of Runx2 mRNA and that the intramuscular injection of FGF2 increased the phosphorylation of ERK and Runx2. Nevertheless, the intramuscular injection of any factor could not increase the formation of vinculin-containing focal adhesions in MSCs. This suggests that BMP-2 should increase the expression of Runx2, and that the activation of Runx2 should be promoted by the FGF2 signaling pathway which activated ERK/Runx2. The activation of this signaling pathway should not lie on the formation of vinculin-containing focal adhesions.

Copolymer composite scaffolds and bioceramic/polymer composite scaffolds are two representative forms of composite scaffolds used for bone tissue engineering. Studies to compare biocompatibility and bone-repairing effects between these two scaffolds are significant for selecting or improving the scaffold for clinical application. We prepared two porous scaffolds comprising poly-lactic-acid/poly-glycolic-acid (PLGA) and poly-lactic-acid/nano-hydroxyapatite (nHAP/PLA) respectively, and examined their biocompatibility with human bone marrow-derived mesenchymal stem cells (hMSCs) through evaluating adhesion, proliferation and osteogenic differentiation potentials of hMSCs in the scaffold. Then, the PLGA scaffold with hMSCs (PM construct) and the nHAP/PLA scaffold with hMSCs (HPM construct) were transplanted into the rat calvarial defect areas to compare their effects on the bone reconstruction. The results showed that the nHAP/PLA scaffold was in favor of adhesion, matrix deposition and osteogenic differentiation of hMSCs. For in vivo transplantation, both HPM and PM constructs led to mineralization and osteogenesis in the defect area of rat. However, the area grafted with PM construct showed a better formation of mature bone than that with HPM construct. In addition, the evaluation of in vitro and in vivo degradation indicated that the degradation rate of nHAP/PLA scaffold was much lower than that of PLGA scaffold. It is inferred that the lower degradation of nHAP/PLA scaffold should result in its inferior bone reconstruction in rat calvaria. Therefore, the preparation of an ideal composite scaffold for bone tissue engineering should be taken into account of the balance between its biocompatibility, degradation rate, osteoconductivity and mechanical property.

A series of transient global warming events between 56 and 50 Ma are characterized by a pronounced negative carbon isotope excursion (CIE). However, the documents of these hyperthermals, such as Eocene Thermal Maximum 2 and H2 events, have come chiefly from marine sediments, and their expression in terrestrial organic carbon is still poorly constrained. Here we yield a high-resolution carbon isotope record of terrestrial organic material from the Fushun Basin, which displays four prominent CIEs with magnitudes larger than 2.5‰. Based on age constraint and comparisons with deep-sea records, our data provide the first evidence of the four hyperthermals in coal seams and suggest a global significance of these events. Moreover, the difference of CIE magnitudes between marine and terrestrial records shows a significant linear correlation with the marine carbonate CIE, implying that these events are likely attributable to recurring injections of 13C-depleted carbon from submarine methane hydrates and/or permafrost.

Monsoonal systems have gained dominance in East Eurasia since the latest Oligocene, evidenced by eolian deposits in North China. Consequently, the central Eurasia became a middle-latitude inland arid area, and in the Late Miocene finally formed a pattern like that of modern day. But the timing, extent, and forcing of the aridification remain poorly understood. Here we gathered palynological sequences from the continental interior and divide them into four chronological parts to reconstruct the development of the central Eurasian aridity during the Miocene. The oldest known aridification record shows the rise of xerophytes observed in the fluviolacustrine Jingou River section at the south margin of the Junggar Basin, suggesting a latest Oligocene drying. Compared with the well-dated records from the inland, the available palynological records reveal two stepwise expansions of arid conditions from the Junggar Basin to its adjacent regions, which occurred in late Middle Miocene and Late Miocene, respectively. The two major expansions are roughly synchronous with the development of North American steppe and call for a global forcing explanation. We discuss various possible explanations for the inland aridity expansions, including regional uplift, land-sea redistribution, global changes in CO2 concentration, and conclude that none of these are fully consistent with the available data. The most likely explanation for the northern mid-latitude drying is global cooling during the Miocene. For eastern Eurasia, cooling weakens monsoon circulation, and consequently drying conditions expand following retreat of the monsoonal rain belt, while in the west, cooling reduces water vapor pressure and therefore reduces the moisture mass transported into the continental interior.

The role of climate change on civilization evolution, varying from a driving force, to a supporting role or just background noise, is an often-debated issue. This paper presents the occupation history of prehistoric civilization in the hyperarid Tarim Basin as a case study to evaluate the influences of environmental change. The prehistorical relics in the Tarim Basin are centered at two periods: prior to 3000 BP and after 2700 BP, showing an apparent centurial gap in occupation. The gap is bridged by the relics from the Kunlun highland, 3000–2600 BP. Previous palaeoclimatic reconstructions show an anti-phased moisture changes between the southern Tarim and the Kunlun highland during the past 5000 years. Placing the timing of relics in the climatic context, the prehistoric relics only occur during relatively wet periods, both on the Kunlun highlands and in the southern basin. The pattern indicates that moisture change is an important explanation for relic distributions in southern Tarim. During the succession of relics from both the basin and the highland, cultural complexities increased gradually from 3800 BP to the historical period, without any significant absences or collapses. This implies that ancient cultures can develop, although the people migrated between the highland and the basin. The results show that in this case environmental pressures have little influence on civilization evolution, even in such a fragile habitat and during prehistoric periods. Caution is required in assessing the influences of environmental change on civilizations.

Archeological researches have proposed arguments for human mobility and long-distance trading over the Eurasia before the Silk Roads. Here we utilize biologically available strontium isotope analysis to assess the extent of pre-Silk Road population movements and cultural communications across the Asian interior. From an early Iron Age cemetery (ca. 2500 yr B.P.) on the eastern Pamir Plateau, mean 87Sr/86Sr ratios from 34 individuals display considerable isotopic variability, and 10 individuals are distinguished as migrants based on the local strontium isotope range of 0.710296–0.710572 defined by 12 ovicaprine bones. Comparison of the proportion (10/34) with the regional census data completed in 1909 A.D. (3% non-locals) suggests a highly migratory behavior on the plateau 2500 years ago. Furthermore, exotic mortuary objects, such as silk fabrics from eastern China and angular harp originated from the Near East, clearly demonstrate an interaction between different cultures on the plateau before the establishment of the Silk Road.

In this paper, we developed a two-step-induction method of generating functional hair cells from inner ear multipotent cells. Multipotent cells from the inner ear were established and induced initially into progenitor cells committed to the inner ear cell lineage on the poly-L-lysine substratum. Subsequently, the committed progenitor cells were cultured on the mitotically inactivated chicken utricle stromal cells and induced into hair-cell-like cells containing characteristic stereocilia bundles. The hair-cell-like cells exhibited rapid permeation of FM1-43FX. The whole-cell patch-clamp technique was used to measure the membrane currents of cells differentiated for 7 days on chicken utricle stromal cells and analyze the biophysical properties of the hair-cell-like cells by recording membrane properties of cells. The results suggested that the hair-cell-like cells derived from inner ear multipotent cells were functional following differentiation in an enabling environment.

Epac, exchange protein activated by cyclic adenosine monophosphate (cAMP), could regulate the trans-differentiation between adipogenesis and osteogenesis of human mesenchymal stem cells (hMSCs). Epac activated by 8-pCPT-2′- O -Me-cAMP, a cAMP analog preferentially activating Epac, resulted in the increase of adipogenic gene expression and the decrease of osteogenic gene expression. The pro-adipogenic and anti-osteogenic effect of 8-pCPT-2′- O -Me-cAMP was attributed to that 8-pCPT-2′- O -Me-cAMP led to the activation of protein kinase B (PKB) and cAMP response element-binding protein (CREB) as well as the inhibition of Ras homolog gene family member A (RhoA), focal adhesion kinase (FAK), extracellular-signal-regulated kinase (ERK) and runt-related transcription factor 2 (Runx2) activities. Inhibition of Epac by a dominant-negative form of Epac1 resulted in the decrease of phosphatidylinositol 3-kinase (PI3K), PKB and CREB activities as well as down-regulation of peroxisome proliferator activated receptor-γ (PPARγ) expression. Inhibition of PI3K by a specific inhibitor or inhibition of Arf and Rho GAP adapter protein 3 (ARAP3, a phosphatidylinositol (PtdIns)(3,4,5)P 3 binding protein) by ARAP3 siRNA led to the recovery of RhoA and FAK activities. RhoA-V14, a constitutively active form of RhoA, could activate the MEK/ERK/Runx2 signaling. Therefore, we conclude that PI3K activated by Epac leads to the activation of PKB/CREB signaling and the up-regulation of PPARγ expression, which in turn activate the transcription of adipogenic genes; whereas osteogenesis is driven by Rho/FAK/MEK/ERK/Runx2 signaling, which can be inhibited by Epac via PI3K. These results should be helpful to provide new targets for treatment of osteoporosis and related bone-wasting diseases.

Fluid shear stress (FSS) is an important biomechanical factor regulating the osteogenic differentiation of human mesenchymal stem cells (hMSCs) and is therefore widely used in bone tissue engineering. However, the mechanotransduction of FSS in hMSCs remains largely unknown. As β1 integrins are considered to be important mechanoreceptors in other cells, we suspect that β1 integrins should also be important for hMSCs to sense the stimulation of FSS. We used a perfusion culture system to produce FSS loading on hMSCs seeded in PLGA three-dimensional (3D) scaffolds and investigated the roles of β1 integrins, FAK and ERK1/2 in FSS-induced osteogenic differentiation of hMSCs. Our results showed that FSS not only markedly increased ALP activity and the expression of ALP, OCN, Runx2 and COLIα genes but also significantly enhanced the phosphorylation of ERK1/2, Runx2 and FAK. FSS-induced activation of ERK1/2 and FAK was inhibited by blockade of the connection between β1 integrins and ECM with RGDS peptide and integrins β1 monoclonal antibody. Our study also found that FSS could upregulate the expression level of β1 integrins and that this upregulation could be abolished by PD98059. Further investigation indicated that FSS-activated ERK1/2 led to the phosphorylation of IκBα and NFκB p65. The activation of NFκB p65 resulted in the upregulation of β1 integrin expression. Therefore, it could be inferred that β1 integrins should sense the stimulation of FSS and thus activate ERK1/2 through activating of FAK, and FSS-activated ERK1/2 feedback to upregulate the expression of β1 integrins through activating NFκB.

Evaluating how future climate changes may impact C3/C4 biomass in East Asia depends largely on the understanding of the relationship between past C3/C4 variations and Asian monsoon circulation. The glacial–interglacial variations in C3/C4 biomass have been readily ascribed to the summer monsoon. However, the internal processes governing the link of C3/C4 vegetation to the Asian monsoon have not been clearly described. Here we present isotopic results of pedogenic carbonate from northern China for the Holocene, the last and penultimate interglacial periods. Comparison of the observed and predicted δ18O values of modern soil carbonate from gravelly soils suggests that pedogenic carbonate forms mainly in warm, rainy season. Carbonate nodules from the Chinese loess demonstrate a distinct negative δ18O–δ13C relationship and a wider scatter of isotopic values in the southern Loess Plateau than in the northern part. By combining rainfall, δ18O of precipitation and the peak of C3 and C4 plant metabolism, we develop a conceptual model to explain the isotopic signatures of the carbonate nodules. Our model shows that a narrowly-focused season of monsoon precipitation at a specific site produces low δ18O values of soil water and simultaneously favors C4 over C3 plants. Our model further suggests that the scattered isotopic values of soil carbonate reflect a strong summer monsoon while the focused values indicate a weak summer monsoon. δ13C values of soil carbonate indicate a striking pattern of northward-increasing C4 vegetation for the last interglacial, while a flat spatial pattern is seen for the penultimate interglacial and the Holocene. It is inferred that the summer monsoon was stronger during the last interglacial than during the penultimate interglacial and the Holocene, leading to a northward displacement of C3 forest ecosystems into the southern Loess Plateau. In addition, an in-phase relationship between intra-nodule δ13C and δ18O values suggests a strong and possibly rapid response of C3/C4 biomass to the seasonality of Asian monsoon precipitation. In this context, if the last interglacial period (MIS 5) is taken as an analog for the projected near future, then C3 plants may be favored in the south while C4 plants may be efficient in the north.