Recent weakening of seasonal temperature difference in East Asia beyond the historical range of variability since the 14th century

Seasonal differences of temperature are crucial components of the Earth's climate system.However,the relatively short observational record,especially for East Asia,has limited progress in understanding seasonal differences.In this study,we identify ten tree-ring chronologies separately correlated with local winter(December-February)temperatures and twelve different tree-ring chronologies separately correlated with summer(June-August)temperatures across East Asia.Using these discrete seasonal tree-ring chronologies,we develop two independent winter and summer temperature reconstructions covering the period 1376-1995 CE for East Asia,and compare them with model simulations.Our reconstructions show a more significant volcanic cooling and earlier onset of modern warming in summer than in winter.The reconstructed summer-minus-winter temperature decreased since as early as the late 19th century,which has driven the current state of seasonal temperature difference to out of the natural variability since the 1370s.Climate models could generally reproduce the variability and trends in seasonal reconstructions,but might largely underestimate seasonal differences due to the fact that seasonal expressions on external forcing and modes of internal variability are too small.Our study highlights the importance of using proxy-based seasonal reconstructions to evaluate the performance of climate models,and implies a substantial weakening of seasonal temperature differences in the future.

The role of high mobility group box 1(HMGB1)in the pathogenesis of kidney diseases

High mobility group box 1(HMGB1) is a nuclear protein that can bind to DNA and act as a co-factor for gene transcription. When released into extracellular fluid, it plays a proinflammatory role by acting as a damage-associated molecular pattern molecule(DAMP)(also known as an alarmin) to initiate innate immune responses by activating multiple cell surface receptors such as the receptor for advanced glycation end-products(RAGE) and toll-like receptors(TLRs), TLR2, TLR4 or TLR9. This proinflammatory role is now considered to be important in the pathogenesis of a wide range of kidney diseases whether they result from hemodynamic changes, renal tubular epithelial cell apoptosis, kidney tissue fibrosis or inflammation. This review summarizes our current understanding of the role of HMGB1 in kidney diseases and how the HMGB1-mediated signaling pathway may constitute a new strategy for the treatment of kidney diseases.

A 1556 year-long early summer moisture reconstruction for the Hexi Corridor, Northwestern China

We report a 1556 year-long tree-ring width chronology for the Hexi Corridor, in the arid Northwestern China,established by applying the signal-free regional curve standardization method to 416 juniper ring-width series. We found that drought in early summer(May–June) is the primary controlling factor for tree growth in this area. We then developed an early summer moisture(i.e., scPDSI) reconstruction from 455 CE to present. Our reconstruction captures multi-centennial scale moisture variations, showing two long-term dry periods during 800–950 CE and 1000–1200 CE, and two long-term wet periods during 1200–1450 CE and 1510–1620 CE. We found strong similarities between hydroclimatic changes in the Hexi Corridor and Qaidam Basin from interannual to centennial timescales; however, at multi-centennial(>300 years) timescales, hydroclimatic variations in the two regions showed significant regional differences. The Hexi Corridor witnessed a generally dry Medieval Climate Anomaly(MCA, here 800–1200 CE) and the drying 20 th century, whereas the Qaidam Basin experienced highprecipitation periods during the MCA and 20 th century. The different correlation pattern with Northern Hemisphere temperature suggest that the Qaidam Basin will receive more precipitation under global warming, whereas the Hexi Corridor will become dryer in the future.

Si-doping bone composite based on protein template- mediated assembly for enhancing bone regeneration

Bio-inspired hybrid materials that contain organic and inorganic networks interpenetration at the molecular level have been a particular focus of interest on designing novel nanoscale composites. Here we firstly synthesized a series of hybrid bone composites, silicon-hydroxyapatites/silk fibroin/collagen, based on a specific molecular assembled strategy. Results of material characterization confirmed that silicate had been successfully doped into nano-hydroxyapatite lattice. In vitro evaluation at the cellular level clearly showed that these Si-doped composites were capable of promoting the adhesion and proliferation of rat mesenchymal stem cells （rMSCs）, extremely enhancing osteoblastic differentiation of rMSCs compared with silicon-free composite. More interestingly, we found there was a critical point of silicon content in the composition on regulating multiple cell behaviors. In vivo animal evaluation further demonstrated that Si-doped composites enabled to significantly improve the repair of cranial bone defect. Consequently, our current work not only suggests fabricating a potential bone repair materials by integrating element-doping and molecular assembled strategy in one system, but also paves a new way for constructing multi-functional composite materials in the future.

Evaluation of multidecadal and longer-term temperature changes since 850 CE based on Northern Hemisphere proxy-based reconstructions and model simulations

The temperature variability over multidecadal and longer timescales(e.g., the cold epochs in the late 15 th, 17 th, and early 19 th centuries) is significant and dominant in the millennium-long, large-scale reconstructions and model simulations;however, their temporal patterns in the reconstructed and simulated temperature series are not well understood and require a detailed assessment and comparison. Here, we compare the reconstructed and simulated temperature series for the Northern Hemisphere(NH) at multidecadal and longer-term timescales(>30 years) by evaluating their covariance, climate sensitivity and amplitude of temperature changes. We found that covariances between different reconstructions or between reconstructions and simulations are generally high for the whole period of 850–1999 CE, due to their similar long-term temporal patterns. However,covariances between different reconstructions or between reconstructions and simulations steadily decline as time series extends further back in time, becoming particularly small during Medieval times. This is related to the large uncetainties in the reconstructions caused by the decreased number of proxy records and sample duplication during the pre-instrumental periods.Reconstructions based solely on tree-ring data show higher skill than multiproxy reconstructions in capturing the amplitude of volcanic cooling simulated by models. Meanwhile, climate models have a shorter recovery(i.e., lag) in response to the cooling caused by volcanic eruptions and solar activity minima, implying the lack of some important feedback mechanisms between external forcing and internal climate processes in climate models. Amplitudes of temperature variations in the latest published tree-ring reconstructions are comparable to those of the multiproxy reconstructions. We found that the temperature difference between the Medieval Climate Anomaly(950–1250 CE) and the Little Ice Age(1450–1850 CE) is generally larger in proxybased reconstructions than in model simulations, but the reason is unclear.

Zn/Sr dual ions-collagen co-assembly hydroxyapatite enhances bone regeneration through procedural osteo-immunomodulation and osteogenesis

The immune microenvironment induced by biomaterials played vital roles in bone regeneration.Hydroxyapatite(HA)and its ion-substituted derivates represent a large class of core inorganic materials for bone tissue engineering.Although ion substitution was proved to be a potent way to grant HA more biological functions,few studies focused on the immunomodulatory properties of ion-doped HA.Herein,to explore the potential osteoimmunomodulatory effects of ion-doped HA,zinc and strontium co-assembled into HA through a collagen template biomimetic way(ZnSr-Col-HA)was successfully achieved.It was found that ZnSr-Col-HA could induce a favorable osteo-immune microenvironment by stimulating macrophages.Furthermore,ZnSr-Col-HA demonstrated a procedural promoting effect on osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)in vitro.Specifically,the osteo-immune microenvironment acted as a dominant factor in promoting osteogenic gene expressions at the early stage through OSM signal pathway.Whereas the direct stimulating effects on BMSCs by Zn^(2+)/Sr^(2+) were more effectively at the later stage with Nfatc1/Maf and Wnt signals activated.In vivo study confirmed strong promoting effects of ZnSr-Col-HA on critical-sized cranial defect repair.The current study indicated that such a combined biomaterial design philosophy of dual ion-doping and biomimetic molecular co-assembly to endow HA applicable osteoimmunomodulatory characteristics might bring up a new cutting-edge concept for bone regeneration study.

Lineage reprogramming of fibroblasts into induced cardiac progenitor cells by CRISPR/Cas9-based transcriptional activators

Overexpression of exogenous lineage-determining factors succeeds in directly reprogramming fibroblasts to various cell types.Several studies have reported reprogramming of fibroblasts into induced cardiac progenitor cells(iCPCs).CRISPR/Cas9-mediated gene activation is a potential approach for cellular reprogramming due to its high precision and multiplexing capacity.Here we show lineage reprogramming to iCPCs through a dead Cas9(dCas9)-based transcription activation system.Targeted and robust activation of endogenous cardiac factors,including GATA4,HAND2,MEF2 C and TBX5(G,H,M and T;GHMT),can reprogram human fibroblasts toward iCPCs.The iCPCs show potentials to differentiate into cardiomyocytes,smooth muscle cells and endothelial cells in vitro.Addition of MEIS1 to GHMT induces cell cycle arrest in G2/M and facilitates cardiac reprogramming.Lineage reprogramming of human fibroblasts into iCPCs provides a promising cellular resource for disease modeling,drug discovery and individualized cardiac cell therapy.

Tree-ring-based winter temperature reconstruction for East Asia over the past 700 years

Almost all proxy-based temperature reconstructions for East Asia have hitherto been designed to resolve summer or annual temperature variability.Reconstruction for the winter temperature is still lacking.Here,we report an annually resolved,winter-season(December-February,DJF)temperature field reconstruction for East Asia covering the period 1300-2000 CE,based on 260 temperature-sensitive tree-ring records.The most striking feature of our new reconstruction is a significant longterm warming trend since the 14th century,which is associated with winter solar insolation at mid-latitudes of the Northern Hemisphere and the global anthropogenic impact.The amplitude of reconstructed winter temperature change over the study period was~4.7 times greater than that for summer temperature,and the rate of winter temperature increase was~6 times as much as that of summer temperature.The results from climate model simulations were consistent with the reconstruction,showing that the amplitude and rate of temperature change in winter were greater than those in summer.The reconstruction also suggests the possible influence of volcanic eruptions,anthropogenic activities and winter solar insolation on the winter temperature variations.Our result also suggests a long-term decrease in summer-to-winter temperature difference occurred in 1625(±24 years)CE.

Albumin-assembled copper-bismuth bimetallic sulfide bioactive nanosphere as an amplifier of oxidative stress for enhanced radio-chemodynamic combination therapy

The tumor microenvironment with overexpressed hydrogen peroxide(H_(2)O_(2))and reinforced antioxidative system(glutathione,GSH)becomes a double-edged sword for the accessibility of nano-therapy.Since reactive oxygen species(ROS)are easily quenched by the developed antioxidative network,ROS-based treatments such as chemodynamic therapy(CDT)and radiotherapy(RT)for killing cancer cells are severely attenuated.To overcome such limitations,a bioactive nanosphere system is developed to regulate intracellular oxidative stress for enhanced radio-chemodynamic combination therapy by using bovine serum albumin(BSA)based bioactive nanospheres that are BSA assembled with in situ generated copper-bismuth sulfide nanodots and diallyl trisulfide(DATS).The copper-bismuth sulfide nanodots react with H_(2)O_(2)to produce·OH and release Cu^(2+).Then,the Cu^(2+)further depletes GSH to generate Cu^(+)for more·OH generation in the way of Fenton-like reaction.Such a cascade reaction can initiate·OH generation and GSH consumption to realize CDT.The elevation of ROS triggered by the DATS from BBCD nanospheres further augments the breaking of redox balance for the increased oxidative stress in 4T1 cells.With the sensitization of increased oxidative stress and high Z element Bi,an enhanced radio-chemodynamic combination therapy is achieved.The current work provides an enhanced radio-chemodynamic combination treatment for the majority of solid tumors by using the co-assembled bioactive nanospheres as an amplifier of oxidative stress.