BLK positively regulates TLR/IL-1R signaling by catalyzing TOLLIP phosphorylation.

TLR/IL-1R signaling plays a critical role in sensing various harmful foreign pathogens and mounting efficient innate and adaptive immune responses, and it is tightly controlled by intracellular regulators at multiple levels. In particular, TOLLIP forms a constitutive complex with IRAK1 and sequesters it in the cytosol to maintain the kinase in an inactive conformation under unstimulated conditions. However, the underlying mechanisms by which IRAK1 dissociates from TOLLIP to activate TLR/IL-1R signaling remain obscure. Herein, we show that BLK positively regulates TLR/IL-1R-mediated inflammatory response. BLK-deficient mice produce less inflammatory cytokines and are more resistant to death upon IL-1ß challenge. Mechanistically, BLK is preassociated with IL1R1 and IL1RAcP in resting cells. IL-1ß stimulation induces heterodimerization of IL1R1 and IL1RAcP, which further triggers BLK autophosphorylation at Y309. Activated BLK directly phosphorylates TOLLIP at Y76/86/152 and further promotes TOLLIP dissociation from IRAK1, thereby facilitating TLR/IL-1R-mediated signal transduction. Overall, these findings highlight the importance of BLK as an active regulatory component in TLR/IL-1R signaling.

Tyrosine phosphorylation of IRF3 by BLK facilitates its sufficient activation and innate antiviral response.

Viral infection triggers the activation of transcription factor IRF3, and its activity is precisely regulated for robust antiviral immune response and effective pathogen clearance. However, how full activation of IRF3 is achieved has not been well defined. Herein, we identified BLK as a key kinase that positively modulates IRF3-dependent signaling cascades and executes a pre-eminent antiviral effect. BLK deficiency attenuates RNA or DNA virus-induced ISRE activation, interferon production and the cellular antiviral response in human and murine cells, whereas overexpression of BLK has the opposite effects. BLK-deficient mice exhibit lower serum cytokine levels and higher lethality after VSV infection. Moreover, BLK deficiency impairs the secretion of downstream antiviral cytokines and promotes Senecavirus A (SVA) proliferation, thereby supporting SVA-induced oncolysis in an in vivo xenograft tumor model. Mechanistically, viral infection triggers BLK autophosphorylation at tyrosine 309. Subsequently, activated BLK directly binds and phosphorylates IRF3 at tyrosine 107, which further promotes TBK1-induced IRF3 S386 and S396 phosphorylation, facilitating sufficient IRF3 activation and downstream antiviral response. Collectively, our findings suggest that targeting BLK enhances viral clearance via specifically regulating IRF3 phosphorylation by a previously undefined mechanism.

Mechanisms of Cancer-killing by Quercetin; A Review on Cell Death Mechanisms.

Cancer drug resistance has always been a serious issue regarding cancer research and therapy. Different cancers undergo different mutations, which may cause suppression of tumor suppressor genes, inhibition of apoptosis, stimulation of drug resistance mediators, and exhaustion of the immune system. The modulation of pro-death and survival-related mediators is an intriguing strategy for cancer therapy. Several nature-derived molecules, e.g., quercetin, have shown interesting properties against cancer through the modulation of apoptosis and autophagy mediators. Such molecules, e.g., quercetin, have been shown to stimulate apoptosis and other types of cell death pathways in cancers via the modulation of ROS metabolism. Quercetin may affect immune system function and trigger the expression and activity of tumor suppressor genes. Furthermore, it may suppress certain multidrug resistance mechanisms in cancer cells. This paper aims to review the effects of quercetin on various cell death mechanisms such as apoptosis, autophagic cell death, senescence, ferroptosis, and others.

Magnetic response of Arsenic pollution in a slag covered soil profile close to an abandoned tungsten mine, southern China.

Previous studies indicated serious soil arsenic (As) pollution of large spatial extent related to tungsten mining. We performed systematic analyses of magnetic parameters and As contents of a slag covered soil profile close to the abandoned tungsten mine in southern China, in order to discuss the feasibility of using sensitive, non-destructive, and cost-effective magnetic methods for monitoring the soil arsenic content in such arsenic pollution areas. The results indicate that arsenic sulfide entered from slags into the underlying soil and changed to iron arsenate and moveable arsenic ion. The arsenic ions were transported from the upper to the lower part of the soil profile, leading to more serious arsenic pollution at lower levels of the section. Pedogenesis and oxidation of the entered iron and arsenic sulfide resulted in coexistence of magnetite/maghemite and hematite, with different contributions at depths of 125-195 cm, 60-125 cm, and 0-60 cm. The arsenic content is significant positively correlated with the hematite concentration given by the magnetic parameter HIRM and negatively correlated with the S-300 ratio that measures the relative contributions of magnetite(+maghemite) and hematite. The S-300 ratio is effective for semi-quantification of soil arsenic content, and may be also used for soil arsenic pollution assessment and monitoring in similar settings of tungsten mining.

Potential effects of exploiting the Yunfu pyrite mine (southern China) on soil: evidence from analyzing trace elements in surface soil.

Trace element contamination caused by mining is a serious environmental problem. The potential effects of exploiting the Yunfu pyrite mine (southern China) on soil were investigated by determining trace elements in 56 surface soil samples from the vicinity of the Yunfu pyrite mine. The samples were acid dissolved and measured by an inductively coupled plasma mass spectrometry (ICP-MS). Principal component analysis and hierarchical cluster analysis were used to identify factors influencing the trace element contents and possible sources of the trace elements. The degree of trace element pollution was determined using the geological accumulation index Igeo. Monte Carlo simulations were used to assess the health risks posed. The results show that (1) six factors (parent material, mining activities, ore composition, rainfall, terrain, and other inputs) strongly affected the trace element contents of the soil samples. (2) There were three groups of trace elements, according to their possible sources. One group (Cs, Ga, Ge, Hf, Nb, Rb, Ta, Th, Ti, U, and Zr) mainly originated in parent rocks. Another group (Cr, Ni, Sr, and V) was mainly supplied by industrial plants and traffic emissions. The third group (Ba, Co, Cu, Mn, Pb, and Zn) was mainly supplied through pyrite ore exploitation processes. (3) Some samples were slightly to moderately polluted with Cs, Ga, Ge, Nb, Rb, Ta, and Ti. Most samples were moderately to highly polluted with Ba, Co, Cu, Mn, Pb, and Zn. (4) Trace elements in soil pose strong non-carcinogenic and carcinogenic health risks to people (particularly children) living near the Yunfu pyrite mine.

Hominin occupation of the Chinese Loess Plateau since about 2.1 million years ago.

Considerable attention has been paid to dating the earliest appearance of hominins outside Africa. The earliest skeletal and artefactual evidence for the genus Homo in Asia currently comes from Dmanisi, Georgia, and is dated to approximately 1.77-1.85 million years ago (Ma)1. Two incisors that may belong to Homo erectus come from Yuanmou, south China, and are dated to 1.7 Ma2; the next-oldest evidence is an H. erectus cranium from Lantian (Gongwangling)-which has recently been dated to 1.63 Ma3-and the earliest hominin fossils from the Sangiran dome in Java, which are dated to about 1.5-1.6 Ma4. Artefacts from Majuangou III5 and Shangshazui6 in the Nihewan basin, north China, have also been dated to 1.6-1.7 Ma. Here we report an Early Pleistocene and largely continuous artefact sequence from Shangchen, which is a newly discovered Palaeolithic locality of the southern Chinese Loess Plateau, near Gongwangling in Lantian county. The site contains 17 artefact layers that extend from palaeosol S15-dated to approximately 1.26 Ma-to loess L28, which we date to about 2.12 Ma. This discovery implies that hominins left Africa earlier than indicated by the evidence from Dmanisi.

Screening and identification of the tumor-associated antigen CK10, a novel potential liver cancer marker.

Hepatocellular carcinoma (HCC) is a malignancy that is associated with high mortality rates in Asia. These tumors are highly invasive and their etiology is frequently unknown. Thus, most patients are diagnosed in the middle and late stages of the disease, and thus do not have sufficient time for therapy. Therefore, it is essential to study the early diagnosis and treatment of HCC; in this regard, the study of tumor-associated antigens has received much attention. Here, antigens from the human primary HCC cell line, QGY-7703, were used to immunize mice in order to prepare monoclonal antibodies. The specific antigen recognized by antibody 11C3 was purified from total protein lysates of QGY-7703 by immunoaffinity chromatography. The validity of the candidate antigen as a new HCC-associated marker was tested using SDS/PAGE, western blot, HPLC-ESI-MS/MS, and RT-qPCR. Our results showed that the levels of CK10 in HCC-derived cell lines were significantly higher than those in normal liver cells. Thus, we suggest that CK10 may be involved in the formation and development of HCC, and may be a therapeutically targetable tumor-associated antigen.

New dating of the Homo erectus cranium from Lantian (Gongwangling), China.

The Homo erectus cranium from Gongwangling, Lantian County, Shaanxi Province is the oldest fossil hominin specimen from North China. It was found in 1964 in a layer below the Jaramillo subchron and was attributed to loess (L) L15 in the Chinese loess-palaeosol sequence, with an estimated age of ca. 1.15 Ma (millions of years ago). Here, we demonstrate that there is a stratigraphical hiatus in the Gongwangling section immediately below loess 15, and the cranium in fact lies in palaeosol (S) S22 or S23, the age of which is ca. 1.54-1.65 Ma. Closely spaced palaeomagnetic sampling at two sections at Gongwangling and one at Jiacun, 10 km to the north, indicate that the fossil layer at Gongwangling and a similar fossil horizon at Jiacun were deposited shortly before a short period of normal polarity above the Olduvai subchron. This is attributed to the Gilsa Event that has been dated elsewhere to ca. 1.62 Ma. Our investigations thus demonstrate that the Gongwangling cranium is slightly older than ca. 1.62 Ma, probably ca. 1.63 Ma, and significantly older than previously supposed. This re-dating now makes Gongwangling the second oldest site outside Africa (after Dmanisi) with cranial remains, and causes substantial re-adjustment in the early fossil hominin record in Eurasia.

Identification of small non-coding RNAs in the planarian Dugesia japonica via deep sequencing.

Freshwater planarian flatworm possesses an extraordinary ability to regenerate lost body parts after amputation; it is perfect organism model in regeneration and stem cell biology. Recently, small RNAs have been an increasing concern and studied in many aspects, including regeneration and stem cell biology, among others. In the current study, the large-scale cloning and sequencing of sRNAs from the intact and regenerative planarian Dugesia japonica are reported. Sequence analysis shows that sRNAs between 18nt and 40nt are mainly microRNAs and piRNAs. In addition, 209 conserved miRNAs and 12 novel miRNAs are identified. Especially, a better screening target method, negative-correlation relationship of miRNAs and mRNA, is adopted to improve target prediction accuracy. Similar to miRNAs, a diverse population of piRNAs and changes in the two samples are also listed. The present study is the first to report on the important role of sRNAs during planarian Dugesia japonica regeneration.

Differential expression of microRNA patterns in planarian normal and regenerative tissues.

MicroRNAs (miRNAs) are ~22-nt small non-coding RNAs that regulate the expression of specific target genes in many eukaryotes. miRNAs have been shown to play important roles in stem cell maintenance, cell fate determination, and differentiation. Planarians are capable of regenerating entire body plans from tiny fragments; this regenerative capacity is facilitated by a population of pluripotent stem cells known as neoblasts. Planarians have been a classic model system for the study of many aspects of stem cell biology. However, very limited knowledge on miRNA involved in this regulatory mechanism exists. This study profiles the expression of miRNAs in the normal and regenerative tissues of planarians using miRCURY LNA array technology. Thirteen miRNAs showed significant differences in expression between these two tissues. To further confirm our results, we examined the expression of two miRNAs by qRT-PCR. Results show that some known miRNAs may play key roles in the regulatory mechanisms of regeneration. Our findings can be utilized in future research on miRNA function.

Modular design, expression and characterization of novel bifunctional mutants of fibrolase with combined platelet aggregation-inhibition and fibrinolytic activity.

Fibrolase is a non-hemorrhagic zinc metalloproteinase found in southern copperhead snake (Agkistrodon contortrix contortrix) venom that acts directly on fibrin clots and does not require plasminogen or any other blood-borne intermediate for activity. Chimeras of fibrolase with RGD peptides conferring antiplatelet activity have been synthesized covalently, but we describe a simpler, cheaper and less toxic method, using site-directed mutagensis. Fibrolase variants that constitute the arginine-glycine-aspartic acid (Arg-Gly-Asp, RGD) motif were constructed using site-directed mutagenesis. Chimeric genes of fibrolase were expressed in Escherichia coli to obtain the bifunctional chimeric molecule of fibrolase that can inhibit platelet aggregation. After refolding and purification, platelet-targeted thrombolysis and antiplatelet aggregation of the target chimeric protein were determined. The mutant RGD-F2, using the GPRGDWRMLG peptide to replace the TSVSHD sequence between sites 69 and 72, not only had almost the same catalytic ability as wild-type fibrolase but also a strong ability to inhibit platelet aggregation.

Transcriptome profiling and digital gene expression by deep-sequencing in normal/regenerative tissues of planarian Dugesia japonica.

Planarians exhibit an extraordinary ability to regenerate lost body parts which is attributed to an abundance of pluripotent somatic stem cells called neoblasts. In this article, we report a transcriptome sequence of a Planaria subspecies Dugesia japonica derived by high-throughput sequencing. In addition, we researched transcriptome changes during different periods of regeneration by using a tag-based digital gene expression (DGE) system. Consequently, 11,913,548 transcriptome sequencing reads were obtained. Finally, these reads were eventually assembled into 37,218 unique unigenes. These assembled unigenes were annotated with various methods. Transcriptome changes during planarian regeneration were investigated by using a tag-based DGE system. We obtained a sequencing depth of more than 3.5million tags per sample and identified a large number of differentially expressed genes at various stages of regeneration. The results provide a fairly comprehensive molecular biology background to the research on planarian development, particularly with regard to its regeneration progress.

A new assessment method for urbanization environmental impact: urban environment entropy model and its application.

The thermodynamic law is one of the most widely used scientific principles. The comparability between the environmental impact of urbanization and the thermodynamic entropy was systematically analyzed. Consequently, the concept "Urban Environment Entropy" was brought forward and the "Urban Environment Entropy" model was established for urbanization environmental impact assessment in this study. The model was then utilized in a case study for the assessment of river water quality in the Pearl River Delta Economic Zone. The results indicated that the assessing results of the model are consistent to that of the equalized synthetic pollution index method. Therefore, it can be concluded that the Urban Environment Entropy model has high reliability and can be applied widely in urbanization environmental assessment research using many different environmental parameters.

Assessing impact of urbanization on river water quality in the Pearl River Delta Economic Zone, China.

The Pearl River Delta Economic Zone is one of the most developed regions in China. It has been undergoing a rapid urbanization since the reformation and opening of China in 1978. This process plays a significant impact on the urban environment, particularly river water quality. The main goal of this present study is to assess the impact of urban activities especially urbanization on river water quality for the study area. Some Landsat TM images from 2000 were used to map the areas for different pollution levels of urban river sections for the study area. In addition, an improved equalized synthetic pollution index method was utilized to assess the field analytical results. The results indicate that there is a positive correlation between the rapidity of urbanization and the pollution levels of urban river water. Compared to the rural river water, urban river water was polluted more seriously. During the urban development process, urbanization and urban activities had a significant negative impact on the river water quality.

River water quality and pollution sources in the Pearl River Delta, China.

Some physicochemical parameters were determined for thirty field water samples collected from different water channels in the Pearl River Delta Economic Zone river system. The analytical results were compared with the environmental quality standards for surface water. Using the SPSS software, statistical analyses were performed to determine the main pollutants of the river water. The main purpose of the present research is to investigate the river water quality and to determine the main pollutants and pollution sources. Furthermore, the research provides some approaches for protecting and improving river water quality. The results indicate that the predominant pollutants are ammonium, phosphorus, and organic compounds. The wastewater discharged from households in urban and rural areas, industrial facilities, and non-point sources from agricultural areas are the main sources of pollution in river water in the Pearl River Delta Economic Zone.

Water pollution and degradation in Pearl River Delta, South China.

The Pearl River Delta Economic Zone is the most dynamic economic area in South China. One of the major problems in the region is the sustainable utilization of the water resources. On the basis of analysis of the water environment status and pollution sources, it is suggested that domestic sewage is the primary cause of pollution. Two new concepts "degradation coefficient" and "degradation volume" of water resources, due to pollution, which may be used to assess macroscopically the carrying capacity of the water resources and sustainability of the water environment, are proposed by the authors. The results calculated indicate that the volumes of degraded water resources will be up to 204, 352, and 537 million m3 in 2002, 2010, and 2020. It is suggested that water for daily consumption and domestic sewage must be controlled more effectively and there should be cross-regional coordination in tackling problems of water environment.