Patient-specific analysis of co-expression to measure biological network rewiring in individuals.

To effectively understand the underlying mechanisms of disease and inform the development of personalized therapies, it is critical to harness the power of differential co-expression (DCE) network analysis. Despite the promise of DCE network analysis in precision medicine, current approaches have a major limitation: they measure an average differential network across multiple samples, which means the specific etiology of individual patients is often overlooked. To address this, we present Cosinet, a DCE-based single-sample network rewiring degree quantification tool. By analyzing two breast cancer datasets, we demonstrate that Cosinet can identify important differences in gene co-expression patterns between individual patients and generate scores for each individual that are significantly associated with overall survival, recurrence-free interval, and other clinical outcomes, even after adjusting for risk factors such as age, tumor size, HER2 status, and PAM50 subtypes. Cosinet represents a remarkable development toward unlocking the potential of DCE analysis in the context of precision medicine.

Using graph-based model to identify cell specific synthetic lethal effects.

Synthetic lethal (SL) pairs are pairs of genes whose simultaneous loss-of-function results in cell death, while a damaging mutation of either gene alone does not affect the cell's survival. This makes SL pairs attractive targets for precision cancer therapies, as targeting the unimpaired gene of the SL pair can selectively kill cancer cells that already harbor the impaired gene. Limited by the difficulty of finding true SL pairs, especially on specific cell types, current computational approaches provide only limited insights because of overlooking the crucial aspects of cellular context dependency and mechanistic understanding of SL pairs. As a result, the identification of SL targets still relies on expensive, time-consuming experimental approaches. In this work, we applied cell-line specific multi-omics data to a specially designed deep learning model to predict cell-line specific SL pairs. Through incorporating multiple types of cell-specific omics data with a self-attention module, we represent gene relationships as graphs. Our approach achieves the prediction of SL pairs in a cell-specific manner and demonstrates the potential to facilitate the discovery of cell-specific SL targets for cancer therapeutics, providing a tool to unearth mechanisms underlying the origin of SL in cancer biology. The code and data of our approach can be found at https://github.com/promethiume/SLwise.

Germ line variant GFI1-36N affects DNA repair and sensitizes AML cells to DNA damage and repair therapy.

ABSTRACT: Growth factor independence 1 (GFI1) is a DNA-binding transcription factor and a key regulator of hematopoiesis. GFI1-36N is a germ line variant, causing a change of serine (S) to asparagine (N) at position 36. We previously reported that the GFI1-36N allele has a prevalence of 10% to 15% among patients with acute myeloid leukemia (AML) and 5% to 7% among healthy Caucasians and promotes the development of this disease. Using a multiomics approach, we show here that GFI1-36N expression is associated with increased frequencies of chromosomal aberrations, mutational burden, and mutational signatures in both murine and human AML and impedes homologous recombination (HR)-directed DNA repair in leukemic cells. GFI1-36N exhibits impaired binding to N-Myc downstream-regulated gene 1 (Ndrg1) regulatory elements, causing decreased NDRG1 levels, which leads to a reduction of O6-methylguanine-DNA-methyltransferase (MGMT) expression levels, as illustrated by both transcriptome and proteome analyses. Targeting MGMT via temozolomide, a DNA alkylating drug, and HR via olaparib, a poly-ADP ribose polymerase 1 inhibitor, caused synthetic lethality in human and murine AML samples expressing GFI1-36N, whereas the effects were insignificant in nonmalignant GFI1-36S or GFI1-36N cells. In addition, mice that received transplantation with GFI1-36N leukemic cells treated with a combination of temozolomide and olaparib had significantly longer AML-free survival than mice that received transplantation with GFI1-36S leukemic cells. This suggests that reduced MGMT expression leaves GFI1-36N leukemic cells particularly vulnerable to DNA damage initiating chemotherapeutics. Our data provide critical insights into novel options to treat patients with AML carrying the GFI1-36N variant.

Dose-dependent expression of GFI1 alters metabolism in the haematopoietic progenitors and MLL::AF9-induced leukaemic cells.

Growth factor independence 1 (GFI1) is a transcriptional repressor protein that plays an essential role in the differentiation of myeloid and lymphoid progenitors. We and other groups have shown that GFI1 has a dose-dependent role in the initiation, progression, and prognosis of acute myeloid leukaemia (AML) patients by inducing epigenetic changes. We now demonstrate a novel role for dose-dependent GFI1 expression in regulating metabolism in haematopoietic progenitor and leukaemic cells. Using in-vitro and ex-vivo murine models of MLL::AF9-induced human AML and extra-cellular flux assays, we now demonstrate that a lower GFI1 expression enhances oxidative phosphorylation rate via upregulation of the FOXO1- MYC axis. Our findings underscore the significance of therapeutic exploitation in GFI1-low-expressing leukaemia cells by targeting oxidative phosphorylation and glutamine metabolism.

Group-specific cellular metabolism in Medulloblastoma.

BACKGROUND: Cancer metabolism influences multiple aspects of tumorigenesis and causes diversity across malignancies. Although comprehensive research has extended our knowledge of molecular subgroups in medulloblastoma (MB), discrete analysis of metabolic heterogeneity is currently lacking. This study seeks to improve our understanding of metabolic phenotypes in MB and their impact on patients' outcomes. METHODS: Data from four independent MB cohorts encompassing 1,288 patients were analysed. We explored metabolic characteristics of 902 patients (ICGC and MAGIC cohorts) on bulk RNA level. Moreover, data from 491 patients (ICGC cohort) were searched for DNA alterations in genes regulating cell metabolism. To determine the role of intratumoral metabolic differences, we examined single-cell RNA-sequencing (scRNA-seq) data from 34 additional patients. Findings on metabolic heterogeneity were correlated to clinical data. RESULTS: Established MB groups exhibit substantial differences in metabolic gene expression. By employing unsupervised analyses, we identified three clusters of group 3 and 4 samples with distinct metabolic features in ICGC and MAGIC cohorts. Analysis of scRNA-seq data confirmed our results of intertumoral heterogeneity underlying the according differences in metabolic gene expression. On DNA level, we discovered clear associations between altered regulatory genes involved in MB development and lipid metabolism. Additionally, we determined the prognostic value of metabolic gene expression in MB and showed that expression of genes involved in metabolism of inositol phosphates and nucleotides correlates with patient survival. CONCLUSION: Our research underlines the biological and clinical relevance of metabolic alterations in MB. Thus, distinct metabolic signatures presented here might be the first step towards future metabolism-targeted therapeutic options.

Inhibiting PI3K-AKT-mTOR Signaling in Multiple Myeloma-Associated Mesenchymal Stem Cells Impedes the Proliferation of Multiple Myeloma Cells.

The microenvironment of cancer cells is receiving increasing attention as an important factor influencing the progression and prognosis of tumor diseases. In multiple myeloma (MM), a hematological cancer of plasma cells, mesenchymal stem cells (MSCs) represent an integral part of the bone marrow niche and tumor microenvironment. It has been described that MM cells alter MSCs in a way that MM-associated MSCs promote the proliferation and survival of MM cells. Yet, our understanding of the molecular mechanisms governing the interaction between MM cells and MSCs and whether this can be targeted for therapeutic interventions is limited. To identify potential molecular targets, we examined MSCs by RNA sequencing and Western blot analysis. We report that MSCs from MM patients with active disease (MM-Act-MSCs) show a distinct gene expression profile as compared with MSCs from patients with other (non-) malignant diseases (CTR-MSCs). Of note, we detected a significant enrichment of the PI3K-AKT-mTOR hallmark gene set in MM-Act-MSCs and further confirmed the increased levels of related proteins in these MSCs. Pictilisib, a pan-PI3K inhibitor, selectively reduced the proliferation of MM-Act-MSCs as compared with CTR-MSCs. Furthermore, pictilisib treatment impaired the MM-promoting function of MM-Act-MSCs. Our data thus provide a deeper insight into the molecular signature and function of MSCs associated with MM and show that targeting PI3K-AKT-mTOR signaling in MSCs may represent an additional therapeutic pathway in the treatment of MM patients.

SimFFPE and FilterFFPE: improving structural variant calling in FFPE samples.

BACKGROUND: Artifact chimeric reads are enriched in next-generation sequencing data generated from formalin-fixed paraffin-embedded (FFPE) samples. Previous work indicated that these reads are characterized by erroneous split-read support that is interpreted as evidence of structural variants. Thus, a large number of false-positive structural variants are detected. To our knowledge, no tool is currently available to specifically call or filter structural variants in FFPE samples. To overcome this gap, we developed 2 R packages: SimFFPE and FilterFFPE. RESULTS: SimFFPE is a read simulator, specifically designed for next-generation sequencing data from FFPE samples. A mixture of characteristic artifact chimeric reads, as well as normal reads, is generated. FilterFFPE is a filtration algorithm, removing artifact chimeric reads from sequencing data while keeping real chimeric reads. To evaluate the performance of FilterFFPE, we performed structural variant calling with 3 common tools (Delly, Lumpy, and Manta) with and without prior filtration with FilterFFPE. After applying FilterFFPE, the mean positive predictive value improved from 0.27 to 0.48 in simulated samples and from 0.11 to 0.27 in real samples, while sensitivity remained basically unchanged or even slightly increased. CONCLUSIONS: FilterFFPE improves the performance of SV calling in FFPE samples. It was validated by analysis of simulated and real data.

Curcumin as an Epigenetic Therapeutic Agent in Myelodysplastic Syndromes (MDS).

Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of GFI1 or presence of the GFI1-36N (serine replaced with asparagine) variant leads to epigenetic changes in human and murine AML blasts and accelerated the development of leukaemia in a murine model of human MDS and AML. We and other groups previously showed that the GFI1-36N allele or reduced expression of GFI1 in human AML blasts is associated with an inferior prognosis. Using GFI1-36S, -36N -KD, NUP98-HOXD13-tg mice and curcumin (a natural histone acetyltransferase inhibitor (HATi)), we now demonstrate that expansion of GFI1-36N or -KD, NUP98-HODXD13 leukaemic cells can be delayed. Curcumin treatment significantly reduced AML progression in GFI1-36N or -KD mice and prolonged AML-free survival. Of note, curcumin treatment had no effect in GFI1-36S, NUP98-HODXD13 expressing mice. On a molecular level, curcumin treatment negatively affected open chromatin structure in the GFI1-36N or -KD haematopoietic cells but not GFI1-36S cells. Taken together, our study thus identified a therapeutic role for curcumin treatment in the treatment of AML patients (homo or heterozygous for GFI1-36N or reduced GFI1 expression) and possibly improved therapy outcome.

Integrative genomic analysis of pediatric T-cell lymphoblastic lymphoma reveals candidates of clinical significance.

T-cell lymphoblastic lymphoma (T-LBL) is a heterogeneous malignancy of lymphoblasts committed to T-cell lineage. The dismal outcomes (15%-30%) after T-LBL relapse warrant establishing risk-based treatment. To our knowledge, this study presents the first comprehensive, systematic, integrated, genome-wide analysis including relapsed cases that identifies molecular markers of prognostic relevance for T-LBL. NOTCH1 was identified as the putative driver for T-LBL. An activated NOTCH/PI3K-AKT signaling axis and alterations in cell cycle regulators constitute the core oncogenic program for T-LBL. Mutated KMT2D was identified as a prognostic marker. The cumulative incidence of relapse was 47% ± 17% in patients with KMT2D mutations, compared with 14% ± 3% in wild-type KMT2D. Structural analysis of the mutated domains of KMT2D revealed a plausible impact on structure and functional consequences. These findings provide new insights into the pathogenesis of T-LBL, including high translational potential. The ongoing LBL 2018 trial (www.clinicaltrials.gov #NCT04043494) allows for prospective validation and subsequent fine tuning of the stratification criteria for T-LBL risk groups to improve survival of pediatric patients.

HOE-642 improves the protection of hypothermia on neuronal mitochondria after cardiac arrest in rats.

HOE-642 has been shown to provide significant protection in a variety of models of cerebral and myocardial ischemia/reperfusion injury. In this study, we examined the impact of HOE-642, a selective Na+/H+ exchanger 1 inhibitor, with or without hypothermia on neuronal and neuronal mitochondrial function during resuscitation. Cardiac arrest was induced by 8 min of asphyxia in rats. Five groups were included in this study: sham; normothermia (N); HOE-642 (HOE, 1 mg/kg); hypothermia (Hypo, 33±0.5°C); and HOE-642 plus hypothermia (HOE+Hypo). Survival and neurological deficit scores (NDS) were evaluated after 24 h of resuscitation. ΔΨm, mitochondrial swelling, ROS production, mitochondrial complex I-IV activity, and ultrastructural changes of the hippocampal mitochondria were evaluated. Survival in the HOE+Hypo group (85.7%) was higher than in the N group (42.9%) and HOE group (31.8%), P<0.05. NDS in the Hypo and HOE+Hypo groups were lower than in the N and HOE groups, P<0.05. ΔΨm in the HOE group (2.7±0.9) were higher than in the N (1.3±0.3) and Hypo (1.4±0.4) groups, P<0.05. Mitochondrial swelling in the N group was severe than in the HOE and Hypo groups, P<0.05. The production of ROS in the HOE and HOE+Hypo groups were lower than in the N group, P<0.05. Complex I-IV activity in the HOE+Hypo group was higher than in the other groups. The ultrastructure of mitochondria in the N group was severely damaged. The mitochondria maintained structural integrity in the HOE, Hypo and HOE+Hypo groups. HOE-642 plus hypothermia during resuscitation was beneficial than HOE-642 or hypothermia alone.

Effect of flurbiprofen axetil on postoperative delirium for elderly patients.

OBJECTIVES: Proinflammatory cytokines triggered by surgery and postoperative pain are major causes of postoperative delirium (POD). This study investigated the effects of flurbiprofen axetil on POD when used for postoperative analgesia after major noncardiac surgery in elderly patients. METHODS: Patients over 65 years old were randomly divided into two groups: the sufentanil group (S group), in which 150 µg of sufentanil was used in the patient-controlled analgesia (PCA) pump for 3 days; the sufentanil combined with flurbiprofen axetil group (SF group), in which 150 µg of sufentanil was combined with 300 mg of flurbiprofen axetil in the PCA pump for 3 days. The Confusion Assessment Method scale was used for POD evaluation. The pain intensity, side effects, and risk factors (age, gender, surgical position, and category of surgery) for POD were evaluated. RESULTS: Ultimately, 140 patients were included. The overall incidence of POD was not significantly different between the S and SF groups. The incidence of POD was significantly lower in the SF group than in the S group among patients over 70 years (5.1% vs. 20.7%, p = 0.045, odds ratio = 0.146, 95% confidence interval = 0.020-1.041). The incidence of POD was no difference in patients classified by the category of surgery, surgical position, or gender between groups. Sufentanil and flurbiprofen axetil in the PCA pump was completely used within 72 hr. The pain intensity, consumed sufentanil dosage of the PCA, and the side effects was not different between groups. CONCLUSIONS: Flurbiprofen axetil might reduce POD in patients over 70 years undergoing major noncardiac surgery.

Exploration of the optimal dose of HOE-642 for the protection of neuronal mitochondrial function after cardiac arrest in rats.

INTRODUCTION: It has been demonstrated HOE-642 ameliorates ischemic contracture, prevents post-resuscitation diastolic dysfunction, and favors the earlier return of contractile function. This study is the first report to explore the optimal dose of HOE-642 in protecting the neuronal mitochondrial function after cardiac arrest. METHODS: Cardiac arrest was induced by 8 min asphyxia in rats. There were Sham (S), Normothermic (NORM), and Hypothermic (HYPO) groups. The NORM or HYPO groups consist of four subgroups: NORM/HYPO + HOE-642 0, 1, 3, and 5 mg/kg. Survival and NDS were evaluated after 24 h of resuscitation. ΔΨm, mitochondrial swelling, ROS production, and mitochondrial complex IIV activity of the hippocampus were detected. RESULTS: Survival in the HYPO + 1 mg group was the best and significantly higher than in the NORM + 0 mg and NORM + 1 mg groups. NDS in the HYPO + 0 mg, HYPO + 1 mg, and HYPO + 3 mg groups was significantly lower than in the NORM + 0 mg group. ΔΨm in the NORM + 1 mg (n = 5) group was significantly higher than in the NORM + 0 mg (n = 8), NORM + 3 mg (n = 5), and NORM + 5 mg (n = 5) groups. The ROS production in the NORM + 1 mg and NORM + 3 mg groups were significantly lower than in the NORM + 0 mg and NORM + 5 mg groups. Complex I and III activities in the HYPO + 1 mg (n = 5) group were significantly higher than in the HYPO + 3 mg (n = 5), and HYPO + 5 mg (n = 5) groups. Complex II and IV activities in the NORM + 3 mg and HYPO + 3 mg groups were significantly higher than in the NORM + 0 mg, NORM + 1 mg, and HYPO + 0 mg (n = 4)groups. CONCLUSIONS: HOE-642 1 or 3 mg/kg showed benefits compared to HOE-642 5 mg/kg used when initiating resuscitation. When combined with hypothermia after cardiac arrest, HOE-642 1 or 3 mg/kg improved survival and neurological function compared with hypothermia or HOE-642 alone, however, HOE-642 5 mg/kg plus hypothermia did not.

Water printing of ferroelectric polarization.

Ferroelectrics, which generate a switchable electric field across the solid-liquid interface, may provide a platform to control chemical reactions (physical properties) using physical fields (chemical stimuli). However, it is challenging to in-situ control such polarization-induced interfacial chemical structure and electric field. Here, we report that construction of chemical bonds at the surface of ferroelectric BiFeO3 in aqueous solution leads to a reversible bulk polarization switching. Combining piezoresponse (electrostatic) force microscopy, X-ray photoelectron spectroscopy, scanning transmission electron microscopy, first-principles calculations and phase-field simulations, we discover that the reversible polarization switching is ascribed to the sufficient formation of polarization-selective chemical bonds at its surface, which decreases the interfacial chemical energy. Therefore, the bulk electrostatic energy can be effectively tuned by H+/OH- concentration. This water-induced ferroelectric switching allows us to construct large-scale type-printing of polarization using green energy and opens up new opportunities for sensing, high-efficient catalysis, and data storage.

A prospective, randomized, double-blind, placebo-controlled trial of acute postoperative pain treatment using opioid analgesics with intravenous ibuprofen after radical cervical cancer surgery.

This study assessed the efficacy and tolerability of intravenous ibuprofen in the improvement of post-operative pain control and the reduction of opioid usage. Patients were randomly divided into placebo, ibuprofen 400 mg and ibuprofen 800 mg groups. All patients received patient-controlled intravenous morphine analgesia after surgery. The first dose of study drugs was administered intravenously 30 min before the end of surgery and then every 6 hours, for a total of 8 doses after surgery. The primary endpoint of this study was the mean amount of morphine used during the first 24 hours after surgery. Morphine use was reduced significantly in the ibuprofen 800 mg group compared with the placebo group (P = 0.04). Tramadol use was reduced significantly in the ibuprofen 400 mg and ibuprofen 800 mg groups compared with the placebo group (P < 0.01). The area under the curve of visual analog scale pain ratings was not different between groups. Safety assessments and side effects were not different between the three groups. Intravenous ibuprofen 800 mg was associated with a significant reduction in morphine requirements, and it was generally well tolerated for postoperative pain management in patients undergoing radical cervical cancer surgery.

Doping-induced perturbation and percolation in the two-dimensional Anderson lattice.

We examine the doping effects in the two-dimensional periodic Anderson model using the determinant Quantum Monte Carlo (DQMC) method. We observe bound states around the Kondo hole site and find that the heavy electron states are destroyed at the nearest-neighbor sites. Our results show no clear sign of hybridization oscillation predicted in previous mean-field calculations. We further study the electron transport with increasing doping and as a function of temperature and obtain a critical doping xc ≈ 0.6 that marks a transition from the Kondo insulator regime to the single-ion Kondo regime. The value of xc is in good agreement with the predicted threshold for the site percolation. Our results confirm the percolative nature of the insulator-metal transition widely observed in doped Kondo insulators.

[Detecting effect comparison between MPAIA, DDIA and IHA for screening advanced schistosomiasis].

OBJECTIVE: To evaluate the effects of the magnetic particle antibody immunoassay (MPAIA), dipstick dye immunoassay (DDIA) and indirect hemagglutination assay (IHA), on detecting advanced schistosomiasis. METHODS: The sera of 224 cases of advanced schistosomiasis were detected by MPAIA, DDIA, and IHA, and the positive rates were compared. RESULTS: The positive rates of MPAIA, DDIA and IHA, were 67.14%, 14.29% and 16.52%, respectively,the positive coincidence rate of MPAIA is higher than the one of IHA and DDIA. CONCLUSION: The value of MPAIA is higher than that of DDIA or IHA in screening advanced schistosomiasis.

[Detection of urine antibodies to Schistosoma japonicum by magnetic particle affinity immunoassay].

OBJECTIVE: To explore a non-invasive method for detection of urine antibodies to Schistosoma japonicum. METHODS: The urine antibodies to S. japonicum were detected by magnetic particle affinity immunoassay (MPAIA) in 158 cases of schistosomiasis japonica and 100 health persons, and their serum antibodies to S. japonicum were also detected at the same time. RESULTS: The sample of urine by MPAIA was 10 microl original urine without any special treatment. The positive rate of urine and serum were 48.10% (76/158)and 88.61% (140/158), respectively. There was difference between the performance of two methods (chi2 = 60.24, P < 0.05). However, both of their specificity were 100% (100/100). CONCLUSION: MPAIA is viable for detection of urine antibodies to S. japonicum, but its sensitivity should be improved.

[Application of magnetic particle antibody immunoassay in detection of anti-Schistosoma japonicum egg antibody].

OBJECTIVE: To establish a magnetic particle antibody immunoassay (MPAIA) for the detection of specific antibody in sera of schistosomiasis patients. METHODS: Fluorescein isothiocyanate (FITC) was used to label Schistosoma japonicum soluble egg antigen (Sj-SEA). Anti-human IgG coated with alkaline phosphatase (ALP) as enzyme-labeled second antibody, and magnetic beads were coupled with sheep anti-FITC antibody as solid phase. Phenolphthale in monophosphate was used as substrate to set up MPAIA for the detection. Serum samples from cases with schistosomiasis or other helminth infections were tested. RESULTS: The positive rate of MPAIA was 96.7% (116/120) with the sera of S. japonicum-infected cases. No cross reaction was observed with sera of trichinellosis, paragonimiasis or cysticercosis cases. The positive titer with reference sample was 1: 1,600. The precision was lower than 10%. The MPAIA tips can be stored at 4 degrees C for 12 months. CONCLUSION: MPAIA shows a high sensitivity, proper specificity and long-term validity for schistosomiasis detection.

[Screening of mimic epitopes of Trichinella spiralis antigen from phage 12-mer peptide library].

OBJECTIVE: To screen special mimic epitopes of Trichinella spiralis antigen from peptide library for exploring new diagnostic antigens. METHODS: Ts-IgG purified from serum of trichinosis patients was used to screen the phage 12-mer peptide library for 5 rounds. 24 clones were picked out randomly to detect the immunoactivity. The sensitivity and specificity of the 6 clones (T1 - T6) whose A values were higher than others were tested by ELISA. RESULTS: The sensitivity of the clones T1 - T6 was the same with larval antigen of Trichinella spiralis (TsA) (positive rate: 100%, P > 0.05), and there was no difference in specificity between T1 - T6 and TsA (negative rate: 0 - 40%, P > 0.05); T3 and T6 did not react with sera from patients of paragonimiasis, showing higher specificity than TsA (P < 0.05); T6 did not react with sera from patients of schistosomiasis, also showing higher specificity than TsA (P < 0.05). CONCLUSION: The mimic antigenic epitopes of Trichinella spiralis have been successfully obtained by screening phage 12-mer peptide library.

[Screening of schistosomiasis japonica diagnostic antigen with phage 12-mer peptide library].

OBJECTIVE: To obtain the mimic epitope of specific and sensitive diagnostic antigen in schistosomiasis japonica from phage 12-mer peptide library. METHODS: Specific Ig was purified from sera of patients with acute schistosomiasis and used to immunoscreen the phage peptide library (PH. D.-12). After 3 rounds of panning, 10 positive plaques were selected and amplified. The immunoactivity of each clone was examined by ELISA. The sensitivity and specificity of immunoactive clones were confirmed by detecting the sera of patients with different parasitosis. RESULTS: Six clones could bind to the specific Ig purified from sera of patients with acute schistosomiasis. One clone with the highest A492 value showed a high sensitivity and specificity. CONCLUSION: The clone (SjA1) identified by the specific Ig from the library played a better part in the immunodiagnosis of schistosomiasis.