Comprehensive analyses of prognostic biomarkers and immune infiltrates among histone lysine demethylases (KDMs) in hepatocellular carcinoma.

BACKGROUND: Histone lysine demethylases (KDMs) are closely related to the occurrence and development of different tumors through epigenetic mechanisms. However, the prognosis and immune infiltration of KDMs in hepatocellular carcinoma (HCC) remain undefined. METHODS: In the current study, we analyzed the expression of KDMs on HCC patients using the Oncomine, GEPIA, UALCAN, Kaplan-Meier Plotter, cBioPortal, GeneMANIA, STRING, Metascape, GSEA, and TIMER databases. Finally, we investigated KDM expression in HCC by qRT-PCR, Western blotting, and IHC. RESULTS: We found that KDM3A/3B/5A/5B and KDM6A were upregulated in HCC patients, while KDM6B and KDM8 were downregulated. The high expressions of KDM1A/2B/3B/5B/5C were markedly related to tumor stages and grades of HCC patients. The abnormal expression of KDM1A/1B/3A/4A/5A/5C/6A/6B/7A and KDM8 were associated with HCC patients' prognosis. Also, we found that HCC tissues presented higher expression levels of KDM1A/2A/5A/5B and lower expression levels of KDM6B. The function of KDMs was primarily related to the histone demethylase activity and cell cycle, p53 signaling pathway, pathways in cancer, transcriptional mis-regulation in cancer, viral carcinogenesis, and FoxO signaling pathway. Furthermore, we indicated that the pathways most involved were the mitotic spindle and DNA repair. Additionally, we found that the expression of KDM1A/1B/3A/4A/5B/5C and KDM6A were significantly correlated with HCC immune infiltration. CONCLUSIONS: Overall, our current results indicated that KDM1A/1B/3A/4A/5B/5C and KDM6A could be novel prognostic biomarkers and provide insights into potential immunotherapy targets to HCC patients.

miR-182-5p attenuates Schistosoma japonicum-induced hepatic fibrosis by targeting tristetraprolin.

Egg granuloma formation in the liver is the main pathological lesion caused by Schistosoma japonicum infection, which generally results in liver fibrosis and may lead to death in advanced patients. MicroRNAs (miRNAs) regulate the process of liver fibrosis, but the putative function of miRNAs in liver fibrosis induced by S. japonicum infection is largely unclear. Here, we detect a new miRNA, miR-182-5p, which shows significantly decreased expression in mouse livers after stimulation by soluble egg antigen (SEA) of S. japonicum or S. japonicum infection. Knockdown or overexpression of miR-182-5p in vitro causes the increased or decreased expression of tristetraprolin (TTP), an important immunosuppressive protein in the process of liver fibrosis. Furthermore, knockdown of miR-182-5p in vivo upregulates TTP expression and significantly alleviates S. japonicum-induced hepatic fibrosis. Our data demonstrate that downregulation of miR-182-5p increases the expression of TTP in mouse livers following schistosome infection, which leads to destabilization of inflammatory factor mRNAs and attenuates liver fibrosis. Our results uncover fine-tuning of liver inflammatory reactions related to liver fibrosis caused by S. japonicum infection and provide new insights into the regulation of schistosomiasis-induced hepatic fibrosis.

Prohibitin 1 (PHB1) controls growth and development and regulates proliferation and apoptosis in Schistosoma japonicum.

Schistosomiasis is a zoonotic parasitic disease caused by the trematode blood flukes of the genus Schistosoma. The prodigious egg output of females is the main cause of the disease in definitive hosts, while the female worm relies on continuous pairing with the male worm to fuel the growth and maturation of the reproductive organs and egg production. Prohibitin, which contains the functionally interdependent PHB1 and PHB2 subunits in human and some other species, has been proposed to participate in the cell proliferation and apoptosis regulation in mammals. However, little is known about the function of PHB homolog in the growth and reproductive development of schistosomes. Here, we reported the Phb1 gene that was structurally and evolutionarily conserved in Schistosoma japonicum when compared with that of other species from Caenorhabditis elegans to human. Real-time PCR detected that SjPhb1 was highly transcribed in the vitellaria of female worms. SjPhb1 knockdown achieved through the dsRNA-mediated RNAi in vivo resulted in retarded growth, decreased pairing, and fecundity in adult worms, as well as attenuated pathogenicity or virulence of worms to their hosts. Cell proliferation and apoptosis examination found decreased cell proliferation and increased cell apoptosis in SjPhb1 dsRNA-treated worms. Therefore, our study provides the first characterization of S. japonicum PHB1 and reveals its fundamental role in the regulation of growth and development of S. japonicum by specific dsRNA-mediated RNAi in vivo. Our findings prompt for a promising molecular of schistosomes that can be targeted to effectively retard the growth and development of the schistosomes.

Upregulation of KSRP by miR-27b attenuates schistosomiasis-induced hepatic fibrosis by targeting TGF-ß1.

Hepatic stellate cells (HSCs) are the main effectors for various types of hepatic fibrosis, including Schistosome-induced hepatic fibrosis. Multiple inflammatory cytokines/chemokines, such as transforming growth factor-ß1 (TGF-ß1), activate HSCs, and contribute to the development of hepatic fibrosis. MicroRNAs regulate gene expression at the posttranscriptional level and are involved in regulation of inflammatory cytokine/chemokine synthesis. In this study, we showed that soluble egg antigen (SEA) stimulation and Schistosoma japonicum infection downregulate miR-27b expression and increase KH-type splicing regulatory protein (KSRP) mRNA and protein levels in vitro and in vivo. miR-27b regulates the stabilization of TGF-ß1 mRNA through targeting KSRP by interacting with their AU-rich elements in hepatocytes and non-parenchymal cells, which has an effect on the activation of HSCs. Importantly, our results have shown that either knockdown miR-27b or overexpression of KSRP attenuates S. japonicum-induced hepatic fibrosis in vivo. Therefore, our study highlights the crucial role of miR-27b and KSRP in the negative regulation of immune reactions in hepatocyte and non-parenchymal cells in response to SEA stimulation and S. japonicum infection. It reveals that manipulation of miR-27b or KSRP might be a useful strategy not only for treating Schistosome-induced hepatic fibrosis but also for curing hepatic fibrosis in general.

Morphology and activities of cell populations of haemocytes in Oncomelania hupensis following Schistosoma japonicum infection.

Oncomelania hupensis is the only obligatory intermediate host of Schistosoma japonicum, the pathogen of zoonosis schistosomiasis. Haemocytes play a critical role in the cellular immune defence of O. hupensis against S. japonicum challenge. Here, the morphology and classification of haemocytes of O. hupensis were investigated by Giemsa staining and light microscopy, combining with the scanning and transmission electron microscopy and flow cytometry. Granulocytes and hyalinocytes were confirmed as two main types of haemocytes, account for ~ 10% and ~ 90% of all haemocytes, with size varying in 4.3-10.9 µm and 0.4-30.8 µm, respectively. Subpopulations can be identified further by granule feature, shape, size, and surface and inner structure of cells. The heterogeneity in morphology implied varied developmental process and function of haemocyte subpopulations. After the S. japonicum challenge, haemocytes of O. hupensis respond to S. japonicum invasion immediately. The dynamic change of haemocyte subpopulations indicates that the small hyalinocyte could differentiate into a larger one or granulocyte after S. japonicum challenge, and the granulocytes and larger hyalinocytes play leading roles in early defence reaction, but in different ways. Phagocytosis and apoptosis of haemocytes in O. hupensis were proved to be related to immune defence against S. japonicum, with the combined effect of granulocytes and larger hyalinocytes. However, the main pathway of each subpopulation to take effect in different periods need further investigation.

Mechanism by which the combination of SjCL3 and SjGAPDH protects against Schistosoma japonicum infection.

A vaccine is an important method to control schistosomiasis. Molecules related to lung-stage schistosomulum are considered potential vaccine candidates. We previously showed that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and cathepsin L3 (CL3) displayed differential expression in the lung-stage schistosomula of Schistosoma japonicum cocultured with host cells. In the present study, we prepared the two proteins and detected the protective effects of SjGAPDH by immunizing mice with this protein alone and in combination with SjCL3 with or without Freund's adjuvant. Then, we investigated the possible mechanisms underlying S. japonicum infection. The results showed that vaccination of adjuvanted SjGAPDH decreased the worm burden (37.8%) and egg load (38.1%), and the combination of adjuvanted SjGAPDH and SjCL3 further decreased the worm burden (65.6%) and egg load (70.9%) during Schistosoma japonicum infection. However, the immunization of a combination of adjuvant-free SjGAPDH and SjCL3 displayed a lower protective effect (< 15%) than those of the adjuvanted SjCL3, the adjuvanted SjGAPDH, and a combination of adjuvanted SjGAPDH and SjCL3. Flow cytometric results showed that the frequency of regulatory T cells (Tregs) was lower (P < 0.05) in the group with adjuvanted SjGAPDH and SjCL3 (2.61%) than the remaining groups. The enzyme-linked immunosorbent assay (ELISA) results indicated that except for the uninfected and infected control groups, the remaining groups displayed a Th1-type shift in immune responses. These results showed the immunization of SjGAPDH resulted in partial protection (approximately 38%); inoculation with a combination of SjCL3 and SjGAPDH in Freund's adjuvant resulted in a high immunoprotective effect (> 65%) against Schistosoma japonicum infection in mice, which was possibly caused by the reduced percentage of Tregs and a Th1-type shift in immune responses; and SjCL3 has no adjuvant-like effect, dissimilar to SmCL3.

ACE2 and Innate Immunity in the Regulation of SARS-CoV-2-Induced Acute Lung Injury: A Review.

Despite the protracted battle against coronavirus acute respiratory infection (COVID-19) and the rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), no specific and effective drugs have to date been reported. Angiotensin-converting enzyme 2 (ACE2) is a zinc metalloproteinase and a critical modulator of the renin-angiotensin system (RAS). In addition, ACE2 has anti-inflammatory and antifibrosis functions. ACE has become widely known in the past decade as it has been identified as the primary receptor for SARS-CoV and SARS-CoV-2, being closely associated with their infection. SARS-CoV-2 primarily targets the lung, which induces a cytokine storm by infecting alveolar cells, resulting in tissue damage and eventually severe acute respiratory syndrome. In the lung, innate immunity acts as a critical line of defense against pathogens, including SARS-CoV-2. This review aims to summarize the regulation of ACE2, and lung host cells resist SARS-CoV-2 invasion by activating innate immunity response. Finally, we discuss ACE2 as a therapeutic target, providing reference and enlightenment for the clinical treatment of COVID-19.

Characteristics and function of cathepsin L3 from Schistosoma japonicum.

Schistosomiasis is still prevalent and seriously endangering the health of people and livestock in many countries. There have been great efforts to develop vaccines against schistosomiasis for prolonged protection in epidemic areas. Molecules from lung-stage schistosomula have been regarded as potential vaccine candidates against schistosomiasis. Our previous work has shown that cathepsin L3 from Schistosoma japonicum (SjCL3) is expressed in lung-stage schistosomula, but its role is not well known. In the present study, we characterized SjCL3 and detected its effect as a possible vaccine in vivo and in vitro. From the results of quantitative PCR (qPCR) and western blot, SjCL3 was present throughout the lifecycle of the worm, and its relative expressed level was higher in the liver eggs and adult worms than other stages. Additionally, immunofluorescence assay showed that SjCL3 was mainly concentrated in the eggshell, alimentary canal, and musculature of worms. Compared with the adjuvant group, the immunization of SjCL3 in mice resulted in a 28.9% decrease in worm burden and a 29.2% reduction in egg number in the host liver. In antibody-dependent cell-mediated cytotoxicity (ADCC) insecticidal experiments in vitro, the existence of SjCL3 could in part suppress adherence between macrophages and worm. The above results indicated that the immunization of SjCL3 could induce limited immune protection against S. japonicum infection in mice, and this protease played a role in breaking the process of ADCC, which was beneficial to the survival of worms.

Protein extract from head-foot tissue of Oncomelania hupensis promotes the growth and development of mother sporocysts of Schistosoma japonicum via upregulation of parasite aldolase gene.

Previous studies showed that protein extract from head-foot tissue of Oncomelania hupensis (O. hupensis) (PhfO), when cocultured with mother sporocysts of Schistosoma japonicum (S. japonicum), was beneficial for parasite's growth and development but the underlying mechanisms remain unclear. One possible strategy for PhfO to promote the growth and development of mother sporocysts of S. japonicum is to upregulate parasite's survival genes. Fructose-1,6-bisphosphate aldolase (ALD), an essential enzyme of glycometabolism in the energy metabolism process, plays an important role in the survival and the growth and development of schistosomes. Using an in vitro coculture system, in this study, we analyzed the potential involvement of the ald gene in the growth and development of mother sporocysts of S. japonicum following coculture with PhfO. We found that coculture with PhfO promoted the growth and development and the survival of mother sporocysts, and increased parasites' ATP consumption level. Mother sporocysts cocultured with PhfO showed a significantly increased expression of the ald gene at both RNA and protein levels. The ALD protein mainly expressed in the cytoplasm of mother sporocysts. Knockdown of ald gene in parasites decreased the ALD protein expression and the ATP consumption level, suppressed the growth and development, and attenuated the survival of mother sporocysts. In ald knockdown mother sporocysts, the effects of PhfO on the ALD expression, the ATP consumption level, the growth and development, and the survival of larvae were significantly abolished. Therefore, the data suggest that PhfO could promote the growth and development, and the survival of mother sporocysts of S. japonicum via upregulating the expression of the ald gene.

Sorafenib and praziquantel synergistically attenuate Schistosoma japonicum-induced liver fibrosis in mice.

Liver fibrosis is an important process that occurs in most types of chronic liver diseases and often results in the end stage of liver diseases, such as cirrhosis, portal hypertension, and hepatocellular carcinoma. Sorafenib, a multiple tyrosine kinase inhibitor, has been shown to inhibit liver fibrosis in multiple experimental fibrosis mouse and rat models. The aim of this study was to test the therapeutic effect of sorafenib on liver fibrosis induced by infection with a parasite, Schistosoma japonicum, in mice. Mice were percutaneously infected through the abdomen with Schistosoma cercariae to develop a schistosomula liver fibrosis model. Eight weeks after infection, infected mice were treated with the anti-parasitic agent praziquantel for 2 days and sorafenib for 2 weeks. Hepatic histopathological changes were assessed using hematoxylin and eosin (HE) and Masson's trichome staining. The hepatic expression levels of collagen I, collagen III, alpha-smooth muscle actin (α-SMA), platelet-derived growth factor (PDGF), and PDGF receptor-beta (PDGFR-ß) were analyzed by immunohistochemistry and western blot. Praziquantel administration alone but not sorafenib reduced liver fibrosis, and the combination of praziquantel and sorafenib significantly attenuated liver fibrosis in S. japonicum-infected mice. Moreover, sorafenib plus praziquantel markedly decreased the hepatic deposition of collagen and expression of fibrogenic genes in these mice. In conclusion, the use of sorafenib following praziquantel treatment may represent a potential therapeutic strategy for liver fibrosis induced by S. japonicum in patients.

Impact of microorganisms, humidity, and temperature on the enantioselective degradation of imazethapyr in two soils.

Imazethapyr (IM) is a chiral herbicide composed of an (-)-R-enantiomer and an (+)-S-enantiomer with differential herbicidal activity. In this study, the effects of microbial organisms, humidity, and temperature on the selective degradation of the (-)-R- and (+)-S-enantiomers of IM were determined in silty loam (SL) and clay loam (CL) soil with different pH values. The (-)-R-enantiomer of IM was preferentially degraded in two soils under different microorganism, humidity, and temperature conditions. The average half-lives of R-IM ranged from 43 to 66.1 days and were significantly shorter (P < 0.05) than those of S-IM, which ranged from 51.4 to 79.8 days. The enantiomer fraction (EF = (+)-S-enantiomer/((-)-R-enantiomer + (+)-S-enantiomer)) values were used to describe the enantioselectivity of degradation of IM were >0.5 (P < 0.05) in two unsterilized soils under different humidity and temperature conditions. The highest EF values were observed at unsterilized CL soil samples under 50% maximum water-holding capacity (MWHC) and 25 °C environmental conditions. The EF values of the IM enantiomers were significantly higher (P < 0.05) in CL soils (higher pH = 5.81) and were 0.581 (unsterilized) and 0.575 (50% MWHC; 25 °C) compared with those recorded in SL soil (lower pH = 4.85). In addition, this study revealed that microbial organisms preferentially utilized the more herbicidal active IM enantiomer.

Immunization with recombinant schistosome adenylate kinase 1 partially protects mice against Schistosoma japonicum infection.

Highly effective and safe prophylactic vaccines are urgently needed to sustainably control schistosomiasis, one of the most serious endemic zoonoses in China. In this study, we characterized adenylate kinase 1 from Schistosoma japonicum (SjAK1), a phosphotransferase that regulates cellular energy and metabolism, and evaluated its potential as a recombinant vaccine. Based on real-time quantitative PCR, western blot, and immunolocalization, SjAK1 is active throughout the life of the worm, although its expression is higher in 21-day-old schistosomula, adult worms, and eggs deposited in the host liver. Further, the enzyme accumulates in the eggshell, intestinal epithelium, integument of adult worms and in the vitellaria tissue in female worms. A 594-bp full-length complementary DNA (cDNA) encoding SjAK1 was synthesized from total RNA of 3-day-old schistosomes, and immunization with recombinant SjAK1 reduced worm burden by 50%, decreased the density of eggs deposited in the host liver by 40%, and reduced the area of granulomas in the host liver by 56%. ELISA results showed that recombinant SjAK1 also stimulated Th1 cytokines such as IL-2 and IFN-γ, but not IL-5 and IL-4. Collectively, a recombinant form of the enzyme SjAK1 elicits partial protective immunity against Schistosoma japonicum infection and the induction of Th1 cytokines. Thus, the enzyme has potential as a component of a multivalent vaccine against schistosomiasis.

[The Effect of Lipopolysaccharide-Induced Mouse B Cell Activation on Schistosoma japonicum Development].

OBJECTIVE: To investigate the effect of lipopolysaccharide (LPS)-induced B cell activation on the development of Schistosoma japonicum. METHODS: Eighteen BALB/c nude mice deficient in T cells and 23 BALB/c SCID mice deficient in T and B cells were used in this study. Each was infected with 30 ± 1 S. japonicum cercariae. The nude (n=9, NL group) and SCID (n=12, SL group) mice then received 2-3 (every two weeks) intraperitoneal injections with LPS (100 µg/mL, 0.2 mL for each mouse). The remaining nude(n=9, N group) and SCID (n=11, S group) mice received PBS injection as control. The mice were sacrificed on days 28 and 36 after infection (n=4/5, 4/5, 5/6, 6/6 for N, NL, S and SL groups, respectively), and adult worms were collected by hepatic portal vein perfusion. The collecting rate of the adult worms was calculated, the body-length measured, and pairs of worms recorded. The liver tissue was collected and digested with 5% KOH, and the number of eggs per gram of liver tissue was calculated. The levels of TGF-ß, IFN-γ and IL-10 in peripheral blood were evaluated. Spleen cell suspension was prepared for detecting the proportion of regulatory B cells (Bregs) in splenic lymphocytes. RESULTS: On day 28 after infection, the body-lengths of male worms in NL and N groups were (7.65±2.85) mm and (5.28±1.64) mm (P<0.01), and those of female worms were (9.64±1.99) mm and (7.49±1.63) mm (P<0.01), respectively. On day 36 after infection, the number of eggs per gram of liver tissue was significantly higher in the NL group than in the N group (1 088±297 vs 715±404, P<0.05), and significantly lower in the SL group than in the S group (217±33 vs 573±160, P<0.01). The proportions of CD(hi)CD5(+)CD19(+) Bregs in N group on days 28 and 36 after infection were (12.73±0.96)% and (37.15±3.04)% (P<0.05), respectively, with no significant difference with that of NL group. The serum levels of TGF-ß and IFN-y on day 28 after infection were significantly different between N and NL groups (TGF-ß, 101.75±46.72 vs 260.90±45.34 pg/mL; IFN-y, 7.91±1.62 vs 14.11±3.72 pg/mL, both P<0.01). Similarly, significant difference was found for the plasma level of IL-10 on day 36 after infection between the S and N groups (41.85±3.14 vs 66.25±4.16 pg/mL, P<0.01), and between the SL and NL groups (44.48±3.87 vs 72.22±17.76 pg/mL, P<0.01), but not between the LPS groups and the control groups. CONCLUSION: LPS can induce the release of cytokines (e.g. TGF-ß) from B cells of mice infected with S. japonium, to facilitate the early development of adult female and male worms.

Effect of cytotoxic T-lymphocyte-associated protein 4 on CD4(+)CD25(+) regulatory T cells in murine schistosomiasis japonica.

In a previous study we demonstrated that CD4(+)CD25(+) regulatory T cells (Tregs) contributed to the escape of Schistosoma japonicum (S. japonicum) from the host's immune responses. In this paper, we studied the effect of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on CD4(+)CD25(+) Tregs in murine Schistosomiasis japonica and its corresponding role in the immune evasion of S. japonicum in mice. The results showed substantial reductions of worm burden and egg production in worm groups treated with anti-CD25 or anti-CTLA-4 monoclonal antibodies (mAb) compared to an infected but untreated control. The reduction effect was even enhanced in an experimental group co-treated with both mAbs. Compared to the control group, the percentage of CD4(+)CD25(+) Tregs was very much lower in the anti-CD25 mAb group as determined by FACS analyses and higher in the anti-CTLA-4 mAb group. ELISA analyses showed that both the anti-CTLA-4 mAb and the co-treated groups had higher levels of cytokines compared to the control group as well as larger egg granuloma sizes as determined by microscopical analyses of liver sections of infected mice. These results suggest that treatment with an anti-CTLA-4 mAb allows the host to clear S. japonicum, but at the cost of elevated pathological damage. The latter indicated a role of CTLA-4 in granuloma formation. Moreover, CD4(+)CD25(+) Tregs and CTLA-4 may exert synergistic effects during immune evasion processes by enhancing Th1-type immune response.

Infection with Clonorchis sinensis (Cobbold, 1875) Metacercariae in Fish from the East Lake of Wuhan: Freshwater Fish in Urban Lakes May Act as Infection Sources of Liver Fluke.

The liver fluke disease caused by Clonorchis sinensis is one of the most serious food-borne parasitic diseases in China. Many freshwater fish and shrimps can be infected with C. sinensis metacercariae as the second intermediate hosts in endemic regions. Owing to the lack of infected humans and the good administration of pet dogs and cats in cities of non-endemic regions, few fish are expected to be infected with C. sinensis metacercariae in urban lakes. To determine the infection of C. sinensis metacercariae in freshwater fish and shrimps in urban lakes, a total of 18 fish species and one shrimp species were investigated in the East Lake of Wuhan City. Metacercariae were isolated by artificial digestive juice and identified using morphology and rDNA-ITS2 sequences. Five species of fish, Pseudorasbora parva, Ctenogobius giurinus, Squalidus argentatus, Hemiculter leuciclus, and Rhodeus spp., were infected with C. sinensis metacercariae. The overall prevalence of C. sinensis was 32.5%. The highest prevalence was found in P. parva with 57.9%, while S. argentatus exhibited the highest mean abundance (13.9). Apart from the C. sinensis metacercariae, four species of other trematode metacercariae were also identified across twelve fish species in total. Owing to the consumption of undercooked fish and feeding cats with small fish caught by anglers, there is a potential risk that the small fish infected with C. sinensis metacercariae may act as an infection source to spread liver fluke. Given the complete life cycle of C. sinensis, stray cats and rats were inferred to act as the important final hosts of C. sinensis in urban lakes in non-endemic areas.

KHSRP ameliorates acute liver failure by regulating pre-mRNA splicing through its interaction with SF3B1.

Acute liver failure (ALF) is characterized by the rapidly progressive deterioration of hepatic function, which, without effective medical intervention, results in high mortality and morbidity. Here, using proteomic and transcriptomic analyses in murine ALF models, we found that the expression of multiple splicing factors was downregulated in ALF. Notably, we found that KH-type splicing regulatory protein (KHSRP) has a protective effect in ALF. Knockdown of KHSRP resulted in dramatic splicing defects, such as intron retention, and led to the exacerbation of liver injury in ALF. Moreover, we demonstrated that KHSRP directly interacts with splicing factor 3b subunit 1 (SF3B1) and enhances the binding of SF3B1 to the intronic branch sites, thereby promoting pre-mRNA splicing. Using splicing inhibitors, we found that Khsrp protects against ALF by regulating pre-mRNA splicing in vivo. Overall, our findings demonstrate that KHSRP is an important splicing activator and promotes the expression of genes associated with ALF progression by interacting with SF3B1; thus, KHSRP could be a possible target for therapeutic intervention in ALF.

Effect of elevated CO2 on phosphorus nutrition of phosphate-deficient Arabidopsis thaliana (L.) Heynh under different nitrogen forms.

Phosphorus (P) nutrition is always a key issue regarding plants responses to elevated CO(2). Yet it is unclear of how elevated CO(2) affects P uptake under different nitrogen (N) forms. This study investigated the influence of elevated CO(2) (800 µl l(-1)) on P uptake and utilization by Arabidopsis grown in pH-buffered phosphate (P)-deficient (0.5 µM) hydroponic culture supplying with 2mM nitrate (NO(3)(-)) or ammonium (NH(4)(+)). After 7 d treatment, elevated CO(2) enhanced the biomass production of both NO(3)(-)- and NH(4) (+)-fed plants but decreased the P amount absorbed per weight of roots and the P concentration in the shoots of plants supplied with NH(4)(+). In comparison, elevated CO(2) increased the amount of P absorbed per weight of roots, as well as the P concentration in plants and alleviated P deficiency-induced symptoms of plants supplied with NO(3)(-). Elevated CO(2) also increased the root/shoot ratio, total root surface area, and acid phosphatase activity, and enhanced the expression of genes or transcriptional factors involving in P uptake, allocation and remobilization in P deficient plants. Furthermore, elevated CO(2) increased the nitric oxide (NO) level in roots of NO(3)(-)-fed plants but decreased it in NH(4)(+)-fed plants. NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) inhibited plant P acquisition by roots under elevated CO(2). Considering all of these findings, this study concluded that a combination of elevated CO(2) and NO(3)(-) nutrition can induce a set of plant adaptive strategies to improve P status from P-deficient soluble sources and that NO may be a signalling molecule that controls these processes.

Cloning and characterization of a bone morphogenetic protein homologue of Schistosoma japonicum.

Bone morphogenetic proteins (BMPs) are known to play an important role in the regulation of cell proliferation, survival, differentiation and apoptosis in many vertebrates and invertebrates through the TGF-ß signaling pathway. Although the TGF-ß signaling pathway exists in schistosomes, BMP homologue, a ligand of TGF-ß in Schistosoma japonicum, has not yet been identified. In this study, a BMP homologue of S. japonicum was cloned and characterized. The full length SjBMP cDNA is 3,020 bp and encodes 928 amino acids, which include a TGF-ß superfamily conserved domain at the C-terminus. BLAST analysis showed that, SjBMP has 68%, 51% and 43% homology with BMP from Schistosoma mansoni, Schmidtea mediterranea and Dugesia japonica at the amino acid level, respectively. According to data from real-time PCR, SjBMP was expressed in lung-stage schistosomula, 21-day liver-stage schistosomula, 50-day adult worms (the male and female), and eggs. The PCR data also indicated that, there was a ≈ 27- and ≈ 37-fold increase of SjBMP transcripts in the lung-stage schistosomula and eggs, respectively, and that there was relatively more SjBMP transcript in the adult male worm than in the adult female, in which the hepatic schistosomula was set as the calibrator for calculation. In situ hybridization based on FITC-labeled specific antisense oligonucleotide probes showed that SjBMP mRNA localized to the ovary of female worms and the integument and epithelium of female and male worms. After treatment with double-stranded RNA (dsRNA) at a concentration of 8 × 10(-2) µg/ml, which was added to the culture medium every other day for a week, the level of SjBMP mRNA in the cultured adult mixed-sex S. japonicum decreased at a range of ≈ 25-98% within 7 days compared with the level of SjBMP mRNA in the blank control group. On the 2nd day, the number of eggs produced per pair of worms decreased 28.7%, and the percent of normal eggs also decreased (12.7% vs. 4.3%) in the SjBMP dsRNA-treated group when compared with the eggs laid by the blank control group. No difference was detected between the two groups on the 7th day of treatment, because the eggs of the untreated worms were also mostly abnormal, similar to the eggs laid by the treated group. In addition, no significant difference in the morphological structure of the adult worms was observed. Thus, the preliminary in vitro experiment indicated that SjBMP may be involved in the oviposition behavior of S. japonicum, and further studies based on the recombinant virus vector-induced steady knockdown of SjBMP or in vivo experiments are required for more in-depth investigation.

The new national integrated strategy emphasizing infection sources control for schistosomiasis control in China has made remarkable achievements.

Schistosomiasis japonica remains one important public health concern that cause great loss of humans' health and social-economic development in the Peoples' Republic of China. At the end of 1990s and the beginning of 2000s, there were still about 0.8 million patients and nearly 85 million people living in the epidemic areas around China. We undertook full analysis of the epidemiological data of schistosomiasis taken from the report of schistosomiasis status in People's Republic of China from 1999 to 2010 for effectiveness assessment of China's new strategy for schistosomiasis control nationwide after its implementation since the beginning the 21st century. The schistosomiasis-endemic uncontrolled counties or towns decreased in number from 1,149 in 2002 to 643 in 2010 at a rate of 44%. The number of schistosomiasis patients decreased from nearly 800,000 to less than 326,000 in 2010 at a decrease rate of more than 50%. The number of acute schistosomiasis patients also decreased significantly, and only 43 cases were reported in 2010. The infection rates of cattle in the endemic uncontrolled provinces decreased greatly though the number of cattle and the actual snail habitat areas remained large with no obvious decline. The schistosome infection rates of human and cattle both decreased significantly by more than 64% and 75%. However, most of the uncontrolled schistosomiasis-endemic areas, schistosomiasis patients, and acute cases are generally located in the four provinces (Hunan, Hubei, Jiangxi, and Anhui) of the lake regions in the middle and lower reach of the Yangtze River, and the egg-positive rates in diagnosed human in endemic Hunan and Hubei remained higher than 10%. Therefore, the new strategy of schistosomiasis control via integrated measures emphasizing infection source control is scientific and successful around China, though it is essential to explore an effective and sustainable strategy for schistosomiasis control in the tough lake and marshland regions of China. The four provinces (Hunan, Hubei, Jiangxi, and Anhui) of the lake regions in China are the main battlefield of China's schistosomiasis control in the present and future.

Investigation of the Degradation Mechanism of SiC MOSFET Subjected to Multiple Stresses.

The performance requirements for power devices in airborne equipment are increasingly demanding, while environmental and working stresses are becoming more diverse. The degradation mechanisms of devices subjected to multiple stresses become more complex. Most proposed degradation mechanisms and models in current research only consider a single stress, making it difficult to describe the correlation between multiple stresses and the correlation of failures. Then, a multi-physical field coupling model based on COMSOL is proposed. The influence relationship between temperature, moisture, electrical load, and vibration during device operation is considered, and a three-dimensional finite element model is built to investigate the multi-stress degradation mechanism under multi-physical field coupling. The simulation results show that, compared with single-stress models, the proposed multi-stress coupled model can more accurately simulate the degradation process of SiC MOSFET. This provides references for improving the reliability design of power device packaging.