The LIDPAD Mouse Model Captures the Multisystem Interactions and Extrahepatic Complications in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents an impending global health challenge. Current management strategies often face setbacks, emphasizing the need for preclinical models that faithfully mimic the human disease and its comorbidities. The liver disease progression aggravation diet (LIDPAD), a diet-induced murine model, extensively characterized under thermoneutral conditions and refined diets is introduced to ensure reproducibility and minimize species differences. LIDPAD recapitulates key phenotypic, genetic, and metabolic hallmarks of human MASLD, including multiorgan communications, and disease progression within 4 to 16 weeks. These findings reveal gut-liver dysregulation as an early event and compensatory pancreatic islet hyperplasia, underscoring the gut-pancreas axis in MASLD pathogenesis. A robust computational pipeline is also detailed for transcriptomic-guided disease staging, validated against multiple harmonized human hepatic transcriptomic datasets, thereby enabling comparative studies between human and mouse models. This approach underscores the remarkable similarity of the LIDPAD model to human MASLD. The LIDPAD model fidelity to human MASLD is further confirmed by its responsiveness to dietary interventions, with improvements in metabolic profiles, liver histopathology, hepatic transcriptomes, and gut microbial diversity. These results, alongside the closely aligned changing disease-associated molecular signatures between the human MASLD and LIDPAD model, affirm the model's relevance and potential for driving therapeutic development.

Effect of Secondary Foaming on the Structural Properties of Polyurethane Polishing Pad.

Polyurethane polishing pads are important in chemical mechanical polishing (CMP). Thus, understanding how to decrease the density but increase the porosity is a crucial aspect of improving the efficiency of a polyurethane polishing pad. According to the principle of gas generation by thermal decomposition of sodium bicarbonate and ammonium bicarbonate, polyurethane polishing pad was prepared by a secondary foaming method. The influence of adding such an inorganic foaming agent as an auxiliary foaming agent on the structure, physical properties, and mechanical properties of polyurethane polishing pads was discussed. The results showed that compared with the polyurethane polishing pad without an inorganic foaming agent, the open-pore structure increased, the density decreased, and the porosity and water absorption increased significantly. The highest porosity and material removal rate (MRR) with sodium bicarbonate added was 3.3% higher than those without sodium bicarbonate and 33.8% higher than those without sodium bicarbonate. In addition, the highest porosity and MRR with ammonium bicarbonate were 7.2% higher and 47.8% higher than those without ammonium bicarbonate. Therefore, it was finally concluded that the optimum amount of sodium bicarbonate to be added was 3 wt%, and the optimum amount of ammonium bicarbonate to be added was 1 wt%.

Effect of Oxidant Concentration on the Oxide Layer Thickness of 304 Stainless Steel.

Ultra-thin 304 stainless steel can be used to flexibly display substrates after they have been subjected to chemical mechanical polishing (CMP). The thickness of the chemical oxide layer directly affects the polishing efficiency and surface quality of 304 stainless steel. In the study presented in the following paper, the thickness variation of the chemical oxide layer of 304 stainless steel was analyzed following electrochemical corrosion under different oxidant concentration conditions. Furthermore, the impact of the oxidant concentration on the grooves, chips, and scratch depth-displacement-load curves was investigated during a nano-scratching experiment. Through this process, we were able to reveal the chemical reaction mechanism between 304 stainless steel materials and oxidizers. The corrosion rate was found to be faster at 8% oxidant content. The maximum values of the scratch depth and elastic-plastic critical load were determined to be 2153 nm and 58.47 mN, respectively.

Flexible Nanofiber Pressure Sensors with Hydrophobic Properties for Wearable Electronics.

In recent years, flexible pressure sensors have received considerable attention for their potential applications in health monitoring and human-machine interfaces. However, the development of flexible pressure sensors with excellent sensitivity performance and a variety of advantageous characteristics remains a significant challenge. In this paper, a high-performance flexible piezoresistive pressure sensor, BC/ZnO, is developed with a sensitive element consisting of bacterial cellulose (BC) nanofibrous aerogel modified by ZnO nanorods. The BC/ZnO pressure sensor exhibits excellent mechanical and hydrophobic properties, as well as a high sensitivity of -15.93 kPa-1 and a wide range of detection pressure (0.3-20 kPa), fast response (300 ms), and good cyclic durability (>1000). Furthermore, the sensor exhibits excellent sensing performance in real-time monitoring of a wide range of human behaviors, including mass movements and subtle physiological signals.

Focused ultrasound-mediated cerium-based nanoreactor against Parkinson's disease via ROS regulation and microglia polarization.

Neuronal damage caused by oxidative stress and inflammatory microenvironment dominated by microglia are the main obstacles in the treatment of Parkinson's disease (PD). In this study, we developed an integrated nanoreactor Q@CeBG by encapsulating CeO2 nanozyme and quercetin (Que) into glutathione-modified bovine serum albumin, and then selected focused ultrasound (FUS) to temporarily open the blood-brain barrier (BBB) to enhance the accumulation level of Q@CeBG in the brain. Q@CeBG exhibited superior multi-ROS scavenging activity. Under the assistance of FUS, Q@CeBG nanoreactor can penetrate the BBB and act on neurons as well as microglia, reducing the neuron's oxidative stress level and polarizing microglia's phenotype from proinflammatory M1 to anti-inflammatory M2. In vitro and In vivo experiments demonstrated that Q@CeBG nanoreactor with good biocompatibility exhibit outstanding neuroprotection and immunomodulatory effects. In short, this dual synergetic nanoreactor will become a reliable platform against PD.

Trends and disparities in non-communicable diseases in the Western Pacific region.

The WHO Western Pacific region bears disproportionate deaths from non-communicable diseases (NCDs), with increased overall NCD proportional mortality over the past two decades. The disease burden of mental health increased, resulting from rapid ageing, enhanced stress, and the COVID-19 pandemic, but it was largely neglected. The highly diverse cultures, religions, political systems, socioeconomic contexts, lifestyles, and environmental factors probably have led to massive disparities across countries in NCD mortality, risk factors, and NCD management. Geographically, East Asia had the lowest NCD mortality whilst Pacific islands had the highest. Economic booms, ageing, nutrition transition, social stress, prevalent tobacco use, and fast-increasing obesity and hyperglycaemia are important drivers of NCDs. Men tended to have more adverse behavioural and metabolic risk factors. Rural residents are catching up with their urban counterparts in metabolic risk factors and conditions. Sustainable strategies tailored to NCD patterns are needed to fight the NCD epidemic and related disparities.

Three-dimensional array of microbubbles sonoporation of cells in microfluidics.

Sonoporation is a popular membrane disruption technique widely applicable in various fields, including cell therapy, drug delivery, and biomanufacturing. In recent years, there has been significant progress in achieving controlled, high-viability, and high-efficiency cell sonoporation in microfluidics. If the microchannels are too small, especially when scaled down to the cellular level, it still remains a challenge to overcome microchannel clogging, and low throughput. Here, we presented a microfluidic device capable of modulating membrane permeability through oscillating three-dimensional array of microbubbles. Simulations were performed to analyze the effective range of action of the oscillating microbubbles to obtain the optimal microchannel size. Utilizing a high-precision light curing 3D printer to fabricate uniformly sized microstructures in a one-step on both the side walls and the top surface for the generation of microbubbles. These microbubbles oscillated with nearly identical amplitudes and frequencies, ensuring efficient and stable sonoporation within the system. Cells were captured and trapped on the bubble surface by the acoustic streaming and secondary acoustic radiation forces induced by the oscillating microbubbles. At a driving voltage of 30 Vpp, the sonoporation efficiency of cells reached 93.9% ± 2.4%.

Postoperative acute kidney injury increases short- and long-term death risks in elderly patients (≥ 75 years old) undergoing coronary artery bypass graft surgery.

PURPOSE: To explore the incidence of postoperative acute kidney injury (AKI) after coronary artery bypass grafting (CABG) in elderly Chinese patients (≥ 75 years old) and its impacts on the short- and long-term prognosis. METHODS: A total of 493 patients aged 75-88 years old who underwent CABG from two medical centers between January 2006 and October 2021 were involved. Perioperative (preoperative and 7 days after operation) serum creatinine (Scr) levels were measured in all the enrolled patients. Univariate and multivariate logistic regression analyses were conducted to explore the independent risk factors of postoperative in-hospital mortality. Kaplan-Meier curves and COX model were used to test the risk factors of all-cause death during follow-up. Propensity score matching was used to balance differences between AKI and control groups. The primary outcome event was in-hospital death, and the secondary outcome was all-cause death during follow-up. RESULTS: The 198 patients were diagnosed with postoperative AKI. Intra-aortic balloon pump (IABP), cardiopulmonary bypass, and postoperative AKI were independent risk factors of in-hospital death. Gender, New York Heart Association Classification, preoperative eGFR, last eGFR within 7 days after operation, postoperative AKI, and postoperative renal function all impacted long-term prognosis. After 1:1 matching, 190 patients were included in the AKI and control groups. Use of IABP, use of cardiopulmonary bypass, and occurrence of postoperative AKI were still independent risk factors of in-hospital death. Preoperative eGFR, last eGFR within 7 days after operation, postoperative AKI and postoperative renal function all impacted long-term prognosis. CONCLUSION: The incidence of postoperative AKI in elderly patients undergoing CABG is high, and postoperative AKI is an independent risk factor of both short- and long-term postoperative prognosis.

Preparation of injectable porcine skin-derived collagen and its application in delaying skin aging by promoting the adhesion and chemotaxis of skin fibroblasts.

Collagen, as the main component of human skin, plays a vital role in maintaining dermal integrity. Its loss will lead to dermis destruction and collapse, resulting in skin aging. At present, injection of exogenous collagen is an important means to delay skin aging. In this study, high-purity collagen was extracted from porcine skin. Our research revealed that it can effectively promote the adhesion and chemotaxis of HSF cells. It can also reduce the expression of ß-galactosidase, decrease ROS levels, and increase the expression of the collagen precursors, p53 and p16 in HSF cells during senescence. After local injection into the aging skin of rats, it was found that the number of cells and type I collagen fibers in the dermis increased significantly, and the arrangement of these fibers became more uniform and orderly. Moreover, the important thing is that it is biocompatible. To sum up, the porcine skin collagen we extracted is an anti-aging biomaterial with application potential.

Advances of Liquid Biopsy for Diagnosis of Atrial Fibrillation and Its Recurrence After Ablation in Clinical Application.

Atrial fibrillation (AF) is a common arrhythmia disease with high morbidity in clinical practice and leads to stroke, heart failure, peripheral embolism, and other severe complications. With aging of the society, AF has become one of the biggest public health challenges. Effective treatments including antiarrhythmic drugs, electrical cardioversion, and ablation (with or without catheters) can alleviate the symptoms of AF. Ablation is the most effective method for the treatment of persistent AF, but cannot cure all patients. Recurrence of AF is a realistic and unavoidable problem. For early predicting and warning of AF and its recurrence, liquid biopsy for accurate molecular analysis of biofluids is a new strategy with potential value and easy sampling and can detect genetic and epigenetic polymorphisms, especially microRNAs. In this review, liquid biopsy is constructed as a new powerful way for diagnosing AF and predicting its recurrence, contributing to the treatment of AF.

Natural Occurrence of Regulated and Emerging Mycotoxins in Wheat Grains and Assessment of the Risks from Dietary Mycotoxins Exposure in China.

Wheat grains are susceptible to contamination with various natural mycotoxins including regulated and emerging mycotoxins. This study surveyed the natural presence of regulated mycotoxins, such as deoxynivalenol (DON) and zearalenone (ZEN), and emerging mycotoxins such as beauvericin (BEA), enniatins (ENNs such as ENA, ENA1, ENB, ENB1) and Alternaria mycotoxins (i.e., alternariol monomethyl ether (AME), alternariol (AOH), tenuazonic acid (TeA), tentoxin (TEN), and altenuene (ALT)) in wheat grains randomly collected from eight provinces across China in 2021. The results revealed that each wheat grain sample was detected with at least one type of mycotoxin. The detection rates of these mycotoxins ranged from 7.1% to 100%, with the average occurrence level ranging from 1.11 to 921.8 µg/kg. DON and TeA were the predominant mycotoxins with respect to both prevalence and concentration. Approximately 99.7% of samples were found to contain more than one toxin, and the co-occurrence of ten toxins (DON + ZEN + ENA + ENA1 + ENB + ENB1 + AME + AOH + TeA + TEN) was the most frequently detected combination. The dietary exposure to different mycotoxins among Chinese consumers aged 4-70 years was as follows: 0.592-0.992 µg/kg b.w./day for DON, 0.007-0.012 µg/kg b.w./day for ZEN, 0.0003-0.007 µg/kg b.w./day for BEA and ENNs, 0.223-0.373 µg/kg b.w./day for TeA, and 0.025-0.041 µg/kg b.w./day for TEN, which were lower than the health-based guidance values for each mycotoxin, with the corresponding hazard quotient (HQ) being far lower than 1, implying a tolerable health risk for Chinese consumers. However, the estimated dietary exposure to AME and AOH was in the range of 0.003-0.007 µg/kg b.w./day, exceeding the Threshold of Toxicological Concern (TTC) value of 0.0025 µg/kg b.w./day, demonstrating potential dietary risks for Chinese consumers. Therefore, developing practical control and management strategies is essential for controlling mycotoxins contamination in the agricultural systems, thereby ensuring public health.

Topological properties of Xene tuned by perpendicular electric field and exchange field in the presence of Rashba spin-orbit coupling.

Xene (X=Si, Ge, Sn) is a typical and promising two-dimensional topological insulator with many novel topological properties. Here, we investigate the topological properties of Xene tuned by a perpendicularly applied electric field, exchange field, and Rashba spin-orbit coupling (RSOC) using the tight-binding (TB) method. We show that in the presence of RSOC, the system can be converted from a quantum spin Hall (QSH) insulator into a conventional band insulator (BI) by a weak perpendicular electric field or into a quantum anomalous Hall (QAH) insulator by a weak exchange field. Additionally, a suitable combination of electric and exchange fields can give rise to a valley-polarized metallic (VPM) state. Furthermore, we explore the competition between the electric field and exchange field in tuning the topological states owing to the Rashba coupling effect. When the electric field is stronger than the exchange field, the system tends to be in a topologically trivial BI state; otherwise, it will be a QAH insulator. More intriguingly, for a fixed exchange field and RSOC, as the perpendicular electric field increase continuously from zero, the system undergoes multiphase (e.g. QSH-VPM-BI) transitions. This paves the way for designing multiphase transition devices through external single-field regulation.

Bioinformatics analysis of gene expression profile and functional analysis in periodontitis and Parkinson's disease.

Periodontitis is a chronic inflammatory disease inextricably linked to both the innate and acquired immune systems of the body. Parkinson's disease (PD) is a neurodegenerative disease caused by immune system dysfunction. Although recent studies suggest that a clinical relationship exists between PD and periodontitis, the pathogenesis of this relationship is unclear. Therefore, in the present study, we obtained datasets of periodontitis and PD from the Gene Expression Omnibus (GEO) database and extracted 785 differentially expressed genes (DEGs), including 15 common upregulated genes and four common downregulated genes. We performed enrichment analyses of these DEGs using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses. We found that the genes were mainly enriched in keratinocyte differentiation, neuronal cell bodies, and structural constituents of epidermis terms, and pathways such as immune response and synaptic pathways. In addition, we screened matching hub genes by constructing a protein-protein interaction (PPI) network map and a Molecular Complex Detection (MCODE) map using the Cytoscape software. The hub genes were then subjected to GO enrichment analysis, which revealed that the dopamine biosynthetic process, dopaminergic synapse and dopamine-binding terms, and dopaminergic synapse and serotonergic synapse pathways were primarily where they were expressed. Finally, we selected four of these genes for validation in the periodontitis and PD datasets, and we confirmed that these hub genes were highly sensitive and specific for diagnosing and monitoring PD and periodontitis. In conclusion, the above experimental results indicate that periodontitis is a high-risk factor for PD, and the association between these two conditions is mainly manifested in immune and dopamine-related pathways. Hub genes, such as the CDSN, TH, DDC, and SLC6A3 genes, may serve as potential biomarkers for diagnosing or detecting PD.

Construction of a double-responsive modified guar gum nanoparticles and its application in oral insulin administration.

The use of intelligent insulin delivery systems has become more important for treating diabetes. In this study, a dual-responsive oral insulin delivery nanocarrier that responds to glucose and pH has been developed. First, the oleic acid hydrophobic modified guar gum (GG) was synthesized by the esterification reaction, and the γ-polyglutamic acid (γ-PGA) was coupled with GG by the amidation reaction. The obtained pH-responsive copolymer (γ-PGA-GG) was cross-linked by concanavalin A to obtain pH/glucose dual-responsive nanocarriers, and insulin was effectively loaded into the dual-responsive nanocarriers. The insulin-loaded nanoparticles can achieve effective pH and glucose responses, releasing insulin on demand. In vitro and in vivo studies demonstrated the dual-responsive nanoparticles can protect insulin against the pH changes in the digestive tract and deliver insulin into the body to exert a hypoglycemic effect. Moreover, the dual-responsive nanoparticles have significant potential to be employed for oral insulin delivery.

NIR-Assisted MgO-Based Polydopamine Nanoparticles for Targeted Treatment of Parkinson's Disease through the Blood-Brain Barrier.

The blood-brain barrier (BBB) is a major limiting factor that prevents the treatment of Parkinson's disease (PD). In the present study, MgOp@PPLP nanoparticles are explored by using MgO nanoparticles as a substrate, polydopamine as a shell, wrapping anti-SNCA plasmid inside, and modifying polyethylene glycol, lactoferrin, and puerarin on the surface to improve the hydrophilicity, brain targeting and antioxidant properties of the particles, respectively. MgOp@PPLP exhibits superior near-infrared radiation (NIR) response. Under the guidance of photothermal effect, these MgOp@PPLP particles are capable of penetrating the BBB and be taken up by neuronal cells to exert gene therapy and antioxidant therapy. In both in vivo and in vitro models of PD, MgOp@PPLP exhibits good neuroprotective effects. Therefore, combined with noninvasive NIR radiation, MgOp@PPLP nanoplatform with good biocompatibility becomes an ideal material to combat neurodegenerative diseases.

Label-free and highly sensitive detection of CRP based on the combination of nicking endonuclease-assisted signal amplification and capillary electrophoresis-UV assay.

Elevated C-reactive protein (CRP) levels are linked with bacterial infection, local inflammation in osteoarthritis and the increased risk of developing cardiovascular disease. Here, a sensitive and label-free CRP assay is developed by combining cyclic enzymatic signal amplification and capillary electrophoresis (CE) with UV detection. This assay is constructed of base pairing and target recognition. Thereinto, nicking endonuclease (NEase) can recognize the specific nucleotide sequences in double-stranded DNA (dsDNA), which is formed by a CRP aptamer and its complementary DNA (cDNA). Sequentially, NEase cleaves only cDNA to produce signal DNAs. Therefore, a large number of signal DNAs are generated through continuous enzyme cleavage. In the presence of CRP, the aptamer recognizes and binds to CRP with high affinity and selectivity, which results in a decrease in signal DNAs, and thus the UV absorption value of CE significantly decreases, too. A wide linear range was obtained between 0.0125 and 15 µg mL-1 (0.11-130.5 nM) in 1% human serum with a detection limit of 4 ng mL-1 (35 pM). Additionally, the proposed method is universal and can be applied to analyze other similar substances by altering the matched aptamer.

Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

Pathogen detection and characterization from throat swabs using unbiased metatranscriptomic analyses.

OBJECTIVES: Infectious diseases are common but are not easily or readily diagnosed with current methodologies. This problem is further exacerbated by the constant presence of mutated, emerging, and novel pathogens. One of the most common sites of infection by many pathogens is the human throat. However, there is no universal diagnostic test that can distinguish these pathogens. Metatranscriptomic (MT) analysis of the throat represents an important and novel development in infectious disease detection and characterization, because it is able to identify all pathogens using a fully unbiased approach. METHODS: To test the utility of an MT approach to pathogen detection, throat samples were collected from participants before, during, and after an acute sickness. RESULTS: Clear sickness-associated shifts in pathogenic microorganisms were detected in the patients. Important insights into microbial functions and antimicrobial resistance genes were obtained. CONCLUSION: MT analysis of the throat represents an effective method for the unbiased identification and characterization of pathogens. Because MT data include all microorganisms in the sample, this approach should not only allow the identification of pathogens, but provide an understanding of the effects of the resident throat microbiome in the context of human health and disease.

Colorectal Cancer Develops Inherent Radiosensitivity That Can Be Predicted Using Patient-Derived Organoids.

Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here, we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDO) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically expanded Lgr5+ intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination-mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses. SIGNIFICANCE: Analysis of inherent tissue radiosensitivity of patient-derived organoids may provide a readout predictive of neoadjuvant therapy response to radiation in rectal cancer, potentially allowing pretreatment stratification of patients likely to benefit from this approach.

Stimulating the Hematopoietic Effect of Simulated Digestive Product of Fucoidan from Sargassum fusiforme on Cyclophosphamide-Induced Hematopoietic Damage in Mice and Its Protective Mechanisms Based on Serum Lipidomics.

Hematopoietic damage is a serious side effect of cytotoxic drugs, and agents promoting hematopoiesis are quite important for decreasing the death rate in cancer patients. In our previous work, we prepared the simulated digestive product of fucoidan from Sargassum fusiforme, DSFF, and found that DSFF could activate macrophages. However, more investigations are needed to further evaluate whether DSFF could promote hematopoiesis in the chemotherapy process. In this study, the protective effect of DSFF (1.8-7.2 mg/kg, i.p.) on cyclophosphamide-induced hematopoietic damage in mice and the underlying mechanisms were investigated. Our results show that DSFF could restore the numbers of white blood cells, neutrophils, and platelets in the peripheral blood, and could also retard bone marrow cell decrease in mice with cyclophosphamide-induced hematopoietic damage. UPLC/Q-Extraction Orbitrap/MS/MS-based lipidomics results reveal 16 potential lipid biomarkers in a serum that responded to hematopoietic damage in mice. Among them, PC (20:1/14:0) and SM (18:0/22:0) were the key lipid molecules through which DSFF exerted protective actions. In a validation experiment, DSFF (6.25-100 µg/mL) could also promote K562 cell proliferation and differentiation in vitro. The current findings indicated that DSFF could affect the blood cells and bone marrow cells in vivo and thus showed good potential and application value in alleviating the hematopoietic damage caused by cyclophosphamide.