Huangkui Capsule in Combination with Leflunomide Improves Immunoglobulin A Nephropathy by Inhibiting the TGF-β1/Smad3 Signaling Pathway

OBJECTIVES: To investigate the efficacy and potential molecular mechanism of Huangkui capsule in combination with leflunomide (HKL) for the treatment of immunoglobulin A nephropathy (IgAN) METHODS: IgAN rat models were constructed by treating rats with bovine serum albumin, lipopolysaccharide, and tetrachloromethane. Th22 cells were isolated from the blood samples of patients with IgAN using a CD4+ T cell isolation kit. The expression levels of the components of the TGF-β1/Smad3 signaling pathway, namely, TGF-β1, Smad2, Smad3, Smad4, and Smad7, were detected using quantitative reverse transcription polymerase chain reaction. Cell proliferation was determined using the MTT assay, cell viability was determined using the WST 1 method, and the chemotaxis of Th22 cells was observed using the wound healing assay. Changes in the histology of the kidney tissues were analyzed using hematoxylin and eosin staining. RESULTS: Compared with IgAN rats, the rats subjected to HKL treatment showed good improvement in kidney injuries, and the combined drug treatment performed much better than the single-drug treatment. In addition, following HKL treatment, the viability, proliferation, and chemotaxis of Th22 cells dramatically decreased (*p<0.05, **p<0.01, and ***p<0.001). In addition, CCL20, CCL22, and CCL27 levels decreased and the expression of the key components of the TGF-β1/Smad3 signaling pathway was downregulated in IgAN rats and Th22 cells (*p<0.05, ***p<0.001). CONCLUSIONS: By targeting the TGF-β1/Smad3 signaling pathway, HKL treatment can improve kidney injury in IgAN rats as well as the excessive proliferation and metastasis of Th22 cells

ILT4 drives B7-H3 expression via PI3K/AKT/mTOR signalling and ILT4/B7-H3 co-expression correlates with poor prognosis in non-small cell lung cancer

AbstractImmunoglobulin-like transcript (ILT) 4 is critical for the inhibitory function of certain immune cells. We previously demonstrated that ILT4 is over-expressed in human non-small cell lung cancer (NSCLC) cells and is involved in tumour evasion via an unknown mechanism. In this report, we demonstrate that ILT4 increases the expression of the co-inhibitory molecule B7-H3 through PI3K/AKT/mTOR signalling. In primary human NSCLC tissues, a significant positive relationship is observed between ILT4 and B7-H3 expression. ILT4/B7-H3 co-expression is significantly associated with a reduction in T infiltrating lymphoid cells and lower overall survival. In summary, ILT4 increases B7-H3 expression and ILT4/B7-H3 co-expression may be involved in NSCLC progression

Initial Upper Paleolithic in North China: New data from Shuidonggou locality 9

The timing and dispersal of modern humans into Northeast Asia has been a subject of hot debate, fueled by increasing discoveries of previously unknown human species in the region, including the so-called Denisovans. In this debate, archaeological assemblages identified as Initial Upper Paleolithic (IUP) play a key role as they are often seen as possible markers for the dispersal of modern human culture across Eurasia. In North China, the presence of IUP blade assemblages is well-established at the Shuidonggou site complex (SDG), particularly at SDG locality 1 (SDG1). In this study, we present a preliminary analysis of another blade-dominated lithic assemblage from SDG locality 9 (SDG9). Applying a combination of typological and technological approaches, we demonstrate that, similar to SDG1, the lithic reduction patterns represented at SDG9 are centered on the use of the recurrent Levallois method to produce blades and elongated flakes, a technological feature that is characteristic of the IUP technology. However, the SDG9 assemblage also exhibits some differences to SDG1, including the dominant use of siliceous limestone as raw material, the absence of prismatic and sub-prismatic cores, and limited retouched pieces. These disparities indicate possible regional variation and diversities in IUP assemblages at SDG

Paleoenvironmental conditions at Madigou (MDG), a newly discovered Early Paleolithic site in the Nihewan Basin, North China

Paleoenvironmental reconstructions provide the context for human evolution and behavior. However, it is difficult to resolve relative proportions of specific habitats at a given place and time, how these may have changed over time, and the explicit nature of particular habitats for human adaptation. This paper examines the paleoenvironmental context of Early Pleistocene archaeological occurrences at Madigou (Hebei Province, North China), but with particular emphasis on the setting for early stone tool makers

Technological adaptations of early humans at the Lower Pleistocene Nihewan Basin, North China: the case of the bipolar technique

The Nihewan Basin in North China has proved to be a key area for the study of human evolution outside of Africa due to its continuous record of hominin occupation since the Early Pleistocene. Lower Paleolithic lithic assemblages at Nihewan are attributed to the East Asian Mode 1 techno-complex, which is often defined by the widespread use of freehand knapping techniques. However, our ongoing investigation of several early Pleistocene archaeological sites at Nihewan has revealed a higher prevalence of bipolar stone artifacts than previously considered, which may have been underestimated in the past due to the disparity of analytical techniques applied to Early Stone Age assemblages and the poor quality of the Nihewan Basin raw materials. This has constrained the identification of bipolar attributes and their differentiation from freehand knapping products. This study aims to investigate technological and economical differences between the two techniques based on experimental results of chert from the Nihewan Basin, creating a referential framework for the study of bipolar artifacts that we apply, to the Early Pleistocene assemblages of Xiaochangliang and Cenjiawan. Our results not only highlight morphological and technological differences between bipolar and freehand products but also demonstrate that both techniques share significant similarities in terms of dimensions and productivity. Overall, our results help to contextualize the technological flexibility of East Asian Mode 1assemblages in the Nihewan Basin, where early hominins employed alternative flaking techniques, often in the same assemblage, to overcome constrains imposed by the poor quality of most of the raw materials available.Peer reviewe

Stable Isotope Analysis of Mammalian Enamel From the Early Pleistocene Site of Madigou, Nihewan Basin: Implications for Reconstructing Hominin Paleoenvironmental Adaptations in North China

The reconstruction of environmental and climatic changes in the Pleistocene is an essential contribution to our understanding of human evolutionary and behavioral adaptations. Well preserved fluvio-lacustrine sediments at Nihewan basin have yielded a rich record of Early Pleistocene Paleolithic sites and mammalian fossils which provide a unique opportunity for exploring hominin behavior and paleoecology in North China. Taxonomic studies of mammalian fossils have provided important clues to the general environmental setting and landscapes of Early Pleistocene humans in the fluvio-lacustrine basin of Nihewan, but little is known about their isotopic signatures. In this paper, mammal teeth species at the Madigou archaeological site (ca. 1.2 Ma)were selected for bulk and sequential enamel stable isotope (C, O) analysis. Results show a variety of ecological environments, including grassland and sparse forest landscapes, and distinct patterns across taxa. C3-C4 mixed vegetation predominated, but C4 vegetation was also relevant at times. Madigou early humans likely experienced cold/warm or dry/wet fluctuations in this northern China basin. We hypothesize that the environmental fluctuations and diversified landscapes may have driven flexibility in various aspects of early human technological behaviors, and allowed hominins to face the environmental challenges of northern latitudes after the initial expansion from Africa into East Asia at the onset of the Middle Pleistocene Climate Transition.This research was supported by the Strategic Priority Research Program of Chinese Academy of Sciences (Gran No. XDB26000000), the National Natural Science Foundation of China (41872029, 41372032), and an ERC-Advanced Grant (Horizon 2020; BICAEHFID grant agreement No. 832980).Peer reviewe

Preliminary analysis on the distribution patterns of early human occupation influenced by environmental factors during Pleistocene in China

Although the population and distribution patterns of Pleistocene hominins are constrained by environmental factors, this pattern shows different characteristics over time with their more advanced adaptive capability. To identify the temporal and spatial patterns of Chinese Palaeolithic sites, this paper presents a preliminary statistical and spatial analysis on the distribution patterns of Palaeolithic sites in the region of modern China. The data used in this analysis include 2110 published Chinese Palaeolithic sites. For temporal analysis, the Monte-Carlo simulation was applied to model the temporal uncertainty of site counts. The Palaeolithic period was divided into 219 short time spans, then each site was assigned into those time spans randomly based on their start and end dates for 1000 times, after which a cumulative plot of Palaeolithic sites counts in China can be used for analyzing. For spatial analysis, all published Chinese Palaeolithic sites were reassigned into ten time spans, including 2.6~2.0 Ma, 2.0~1.2 Ma, 1.2~0.6 Ma, 600~300 ka, 300~130 ka, 130~73 ka, 73~57 ka, 57~29 ka, 29~11 ka and 11~10 ka. Kernel density estimation and k-means method were conducted for sites within each time span to recognize their spatial patterns. We also used boxplot to explore the range of elevation, distance to rivers, annual mean temperature and annual precipitation of the sites within different time spans. The result suggests that the total number and the range of Chinese Palaeolithic sites increased through time. Hominins gradually occupied habitats with diverse environmental conditions and they were able to adapt to those harsher ones in the northeast and northwest China. Particularly, 600 ka and 57 ka are two important transition points. Before 600 ka, the number of Palaeolithic sites remained at low levels, and the location of sites restricted in the monsoon region. During the period between 600 and 57 ka, the site number increased gradually, and their distribution expanded step by step. Since 57 ka, the number of sites rise significantly, and sites began to appear in harsh regions like the Tibetan Plateau and the non-monsoon region. It can be suggested that the change of temporal and spatial patterns over time indicates the development of hominin capability, which correlates to the current evidence of human fossils and stone tools in China, but more details need to be explored in the future. This study will contribute to research on the environmental adaptation, even the evolution and technical development influenced by environment of early hominins in China.Peer reviewe

Site formation processes at Cenjiawan (Nihewan Basin, North China): a case study on the structure of the Early Pleistocene archaeological record in lakeshore environments

Lakeshore environments offer an excellent opportunity to explore how early humans adapted to changing landscapes and environments. The Nihewan fluvio-lacustrine sequence in North China contains one of the densest concentrations of Early Pleistocene Palaeolithic sites outside of Africa. Among these, the Cenjiawan site, dated at 1.1 Ma, draws attention due to the large number of stone tool refits. We present here Cenjiawan's sedimentary context, artefact spatial patterns, size distribution and taphonomic features, which are complemented by an experimental programme to better understand archaeological debitage size patterns, thus enabling a detailed analysis of formation processes at the site. The Cenjiawan assemblage is also interpreted in the light of its geographical and geological context, where a synsedimentary fault induced a minor topographic relief across the lacustrine lakeshore. This resulted in a shallow-water setting in the down-thrown hanging wall of the fault compartment, and a fluvial environment in the uplifted footwall. Our results indicate that Cenjiawan, situated in the hanging wall of the fault, underwent minimal disturbance, constituting a remarkable example of optimal preservation of archaeological assemblages in Early Pleistocene lakeshore environments.This research was supported by the Strategic Priority Research Programme of the Chinese Academy of Sciences (Grant No. XDB26000000), the National Natural Science Foundation of China (41872029) and an ERC-Advanced Grant (Horizon 2020, BICAEHFID grant agreement No. 832980).Peer reviewe