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Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has been regarded as the standard treatment regimen for classical Hodgkin lymphoma. In recent years, ABVD-like regimens, which emerged due to shortages and the lung toxicity of bleomycin or the emergence of immune checkpoint inhibitors and antibody-drug conjugates, may be favorable, but have not yet been tested.We compared the outcomes of ABVD with ABVD-like regimens, which include bleomycin was completely or partially omitted; meanwhile, etoposide or PD-1 inhibitors were added.5-Year progression-free survival (PFS) was higher for ABVD than ABVD-like regimens in young patients (82.1% vs. 67.0%, p = 0.029), patients with serum beta-2 microglobulin (β2-MG) ≥ 1.85 mg/L (75.8% vs. 57.6%, p = 0.046), and advanced-stage patients with IPS score 4-7(63.1%, 18.3%, p = 0.038). For elderly (60.5% vs.76.1%, p = 0.089), patients with β2-MG 1.85 mg/L (83.1% vs 76.1%, p = 0.282), and advanced-stage patients with IPS score 0-3(84.6% vs. 81.3%, p = 0.476), 5-year PFS for ABVD did not differ from ABVD-like regimens. Elderly patients treated with bleomycin-free regimens showed a better survival trend compared with ABVD (99.3% vs. 61.3%, p = 0.270).ABVD is superior to ABVD-like regimens in achieving PFS in young patients or patients with poor prognosis including high IPS score and β2-MG level. ABVD-like regimens are as effective as ABVD in elderly or low-risk patients including low IPS score and β2-MG level; elderly patients treated with bleomycin-free regimens exhibit a better survival trend compared with ABVD.

Extranodal natural killer/T‐cell lymphoma, nasal type (ENKL) is a rare peripheral T‐cell lymphoma that predominantly occurs in Asian and South American populations. The treatment of ENKL has been a challenge for a long time. This study was conducted to compare the clinical efficacy and safety of cisplatin, dexamethasone, gemcitabine, and pegaspargase (DDGP) and methotrexate, dexamethasone, ifosfamide, L‐asparaginase, and etoposide (SMILE) regimens for relapsed/refractory ENKL and explore the prognostic factors. From October 2014 to July 2019, 54 patients with relapsed/refractory ENKL who received DDGP or SMILE chemotherapy were retrospectively assessed in this study. Thirty‐one patients received DDGP chemotherapy and 23 patients received SMILE chemotherapy. A higher complete response rate was observed in patients treated with DDGP regimen (61.3% vs. 30.4%, P = 0.025). The DDGP group (95% confidence interval (CI) of 5‐year progression‐free survival (PFS): 24.6–66.2%; 95% CI of 5‐year overall survival (OS): 8.5–91.7%) was also significantly associated with longer 5‐year PFS and 5‐year OS (P = 0.008 for 5‐year PFS, P = 0.023 for 5‐year OS). More serious leucopenia (P = 0.021), neutropenia (P = 0.041), and allergy (P = 0.040) were observed in the SMILE group. Post‐treatment Epstein–Barr virus (EBV)‐DNA status (P = 0.001 for PFS, P = 0.018 for OS) was identified as a significant prognostic factor for PFS and OS in multivariate analysis. The present research suggested that compared with SMILE chemotherapy, DDGP chemotherapy can significantly improve the response and survival of relapsed/refractory ENKL with better tolerance. Post‐treatment EBV‐DNA status was identified as a significant prognostic factor for PFS and OS in relapsed/refractory ENKL.

IMPORTANCE: The L-asparaginase–based SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen has shown higher response rates and survival benefit over an anthracycline-containing regimen. However, the safety profile was not satisfied. A well-tolerated regimen with promising efficacy is lacking. OBJECTIVE: To compare the efficacy and safety of the DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) regimen with the SMILE regimen in newly diagnosed advanced-stage (III/IV) extranodal natural killer/T-cell lymphoma (ENKL). DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, multicenter, randomized clinical trial that took place across 12 participating hospitals in China from January 2011 to February 2019. Patients were eligible if they were 14 to 70 years old with newly diagnosed ENKL in stages III/IV and had an Eastern Cooperative Oncology Group performance status of 0 to 2. Eligible patients were evenly randomized to either the DDGP or SMILE group. INTERVENTIONS: Patients in each group were treated with the assigned regimen every 21 days for 6 cycles. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS), and secondary end points included overall response rate and overall survival (OS). The adverse events between the DDGP and SMILE groups were compared. RESULTS: Among the 87 randomized patients, 80 received treatment (40 in the DDGP group and 40 in the SMILE group); the median (IQR) age was 43 (12) years, and 51 (64%) were male. The baseline characteristics were similar between the groups. At a median follow-up of 41.5 months, the median PFS was not reached in the DDGP group vs 6.8 months in the SMILE group (HR, 0.42; 95% CI, 0.23-0.77; P = .004), and the median OS was not reached in the DDGP group vs 75.2 months in the SMILE group (HR, 0.41; 95% CI, 0.19-0.89, P = .02). The PFS rate at 3 years and OS rate at 5 years were higher in the DDGP group vs the SMILE group (3-year PFS, 56.6% vs 41.8%; 5-year OS, 74.3% vs 51.7%). The overall response rate was higher in the DDGP group than in the SMILE group (90.0% vs 60.0%; P = .002). Grade 3 and 4 hematologic toxic effects were more frequently reported in the SMILE group vs the DDGP group (leukopenia, 85.0% vs 62.5%; neutropenia, 85.0% vs 65.0%). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the DDGP regimen showed promising preliminary results for patients with newly diagnosed local advanced ENKL. A confirmation trial based on larger population is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01501149

The shear-stress cospectrum and the horizontal and vertical temperature-flux cospectra in the convective boundary layer (CBL) are predicted using the multi-point Monin–Obukhov similarity (MMO theory). MMO theory was recently proposed and then derived from first principles by Tong and Nguyen (Journal of the Atmospheric Sciences, 2015, Vol. 72, 4337 – 4348) and Tong and Ding (Journal of Fluid Mechanics, 2019, Vol. 864, 640 – 669) to address the issue of the incomplete similarity in the Monin–Obukhov similarity theory. According to MMO theory, the CBL has a two-layer structure: the convective layer ( $$z \gg -L$$ ) and the convective–dynamic layer ( $$z \ll -L$$ ). The former consists of the convective range ( $$k \ll -1/L$$ ) and the inertial range ( $$k \gg 1/z$$ ), while the latter consists of the convective range, the dynamic range ( $$-1/L \ll k\ll 1/z$$ ), and the inertial range, where z, k, and L are the height from the ground, the horizontal wavenumber, and the Obukhov length, respectively. We use MMO theory to predict the cospectra for the convective range and the dynamic range. They have the same scaling in the convective range for both $$z \ll -L$$ and $$z \gg -L$$ . The shear-stress cospectrum and the vertical temperature-flux cospectrum have $$k^0$$ scaling in both the convective and dynamic ranges. The horizontal temperature-flux cospectrum has $$k^{-1/3}$$ and $$k^{-1}$$ scaling in the convective and dynamic ranges respectively. The predicted scaling exponents are in general agreement with high-resolution large-eddy-simulation results. However, the horizontal temperature-flux cospectrum is found to change sign from the dynamic range (negative) to the convective range (positive), which is shown to be caused by the temperature–pressure-gradient interaction.

Objective: This study aimed to evaluate the safety, efficacy, and feasibility of the rituximab, fotemustine, pemetrexed, and dexamethasone (R-FPD) regimen followed by whole-brain radiotherapy (WBRT) for patients with primary central nervous system lymphoma (PCNSL). Methods: A prospective, single-center phase II clinical trial was conducted. Patients with PCNSL newly diagnosed at the First Affiliated Hospital of Zhengzhou University between July 2018 and July 2020 were studied. The R-FPD regimen consisted of rituximab (375 mg/m2 i.v. on D0), fotemustine (100 mg/m2 i.v. on D1), pemetrexed (600 mg/m2 i.v. on D1), and dexamethasone (40 mg i.v. on D1-5). Patients 60 years or younger who showed a complete response (CR) were treated with 23.4 Gy of WBRT after the end of chemotherapy; those older than 60 years with CR were treated with a wait-and-see approach; and those who did not show CR after the 4th cycle of chemotherapy were given salvage WBRT 30 Gy + local tumor field irradiation up to 45 Gy, regardless of age. Results: A total of 30 patients were included. After 2 cycles, the objective response rate (ORR) was 96.5% (28/29, 1 CR, 27 PR, 0 SD, and 1 PD). After 4 cycles, the ORR was 73.1% (19/26, 11 CR, 8 PR, 4 SD, and 3 PD). After WBRT, the ORR was 90.9% (10/11, 7 CR, 3 PR, and 1 SD). The grade III and IV toxicity responses were mainly leukopenia (20.0%), thrombocytopenia (23.3%), and anemia (10.0%). Conclusions: Fotemustine-based therapy in combination with rituximab chemotherapy followed by WBRT can improve outcomes, providing ORR benefits and favorable tolerability in patients newly diagnosed with PCNSL.

ObjectiveThe prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R-DLBCL) after second-line treatment failure is extremely poor. This study prospectively observed the efficacy and safety of decitabine with a modified cisplatin, cytarabine, and dexamethasone (DHAP) regimen in R/R-DLBCL patients who failed second-line treatment.MethodsTwenty-one R/R-DLBCL patients were enrolled and treated with decitabine and a modified DHAP regimen. The primary endpoints were overall response rate (ORR) and safety. The secondary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsORR reached 50% (complete response rate, 35%), five patients (25%) had stable disease (SD) with disease control rate (DCR) of 75%. Subgroup analysis revealed patients over fifty years old had a higher complete response rate compared to younger patients (P = 0.005), and relapsed patients had a better complete response rate than refractory patients (P = 0.031). Median PFS was 7 months (95% confidence interval, 5.1-8.9 months). Median OS was not achieved. One-year OS was 59.0% (95% CI, 35.5%-82.5%), and two-year OS was 51.6% (95% confidence interval, 26.9%-76.3%). The main adverse events (AEs) were grade 3/4 hematologic toxicities such as neutropenia (90%), anemia (50%), and thrombocytopenia (70%). Other main non-hematologic AEs were grade 1/2 nausea/vomiting (40%) and infection (50%). No renal toxicity or treatment-related death occurred.ConclusionDecitabine with a modified DHAP regimen can improve the treatment response and prognosis of R/R-DLBCL patients with good tolerance to AEs, suggesting this regimen has potential as a possible new treatment option for R/R-DLBCL patients after second-line treatment failure.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT03579082.

Glycoprotein non-metastatic melanoma protein B (GPNMB) has been confirmed to be related to the pathogenesis of tumors. However, the potential impact of GPNMB on the progression of diffuse large B-cell lymphoma (DLBCL) is unclear. In this study, the expression levels of GPNMB and Yes-associated protein (YAP) were analyzed using qRT-PCT and Western blot assay. Cell counting kit-8, EdU, and flow cytometry assays were used to detect the proliferation and apoptosis of DLBCL cells. A nude mice xenograft model was established for in vivo research. Results showed that GPNMB and YAP1 were upregulated in DLBCL cell lines. Knockdown of GPNMB inhibited cell proliferation and promoted apoptosis in DLBCL cells. Additionally, the expression levels of YAP1 and the downstream effector of Hippo pathway (c-myc) were markedly decreased when GPNMB was knocked down. Moreover, knockdown of GPNMB inhibited the nuclear translocation of β-catenin protein, which could be abolished by YAP1 overexpression. Simultaneously, the anti-proliferative and pro-apoptotic effects of GPNMB knockdown could be reversed by YAP1 overexpression or LiCl (the activator of Wnt/β-catenin pathway). Furthermore, the mice xenograft model confirmed that inhibition of GPNMB restrained the tumorigenesis of DLBCL in vivo. In conclusion, GPNMB could partly activate the Wnt/β-catenin signaling pathway by targeting YAP1, so as to participate in tumorigenesis of DLBCL.

The Monin–Obukhov similarity theory (MOST) is the foundation for understanding the atmospheric surface layer. It hypothesizes that nondimensional surface-layer statistics are functions of [Formula: see text] only, where z and L are the distance from the ground and the Obukhov length, respectively. In particular, it predicts that in the convective surface layer, local free convection (LFC) occurs at heights [Formula: see text] and [Formula: see text], where [Formula: see text] is the inversion height. However, as a hypothesis, MOST is based on phenomenology. In this work we derive MOST and the LFC scaling from the equations for the velocity and potential temperature variances using the method of matched asymptotic expansions. Our analysis shows that the dominance of the buoyancy and shear production in the outer ([Formula: see text]) and inner ([Formula: see text]) layers, respectively, results in a nonuniformly valid solution and a singular perturbation problem and that [Formula: see text] is the thickness of the inner layer. The inner solutions are found to be functions of [Formula: see text] only, providing a proof of MOST for the vertical velocity and potential temperature variances. Matching between the inner and outer solutions results in the LFC scaling. We then obtain the corrections to the LFC scaling near the edges of the LFC region ([Formula: see text] and [Formula: see text]). The nondimensional coefficients in the expansions are determined using measurements. The resulting composite expansions provide unified expressions for the variance profiles in the convective atmospheric surface layer and show very good agreement with the data. This work provides strong analytical support for MOST.

The pressure–strain-rate correlation and pressure fluctuations in convective and near neutral atmospheric surface layers are investigated. Their scaling properties, spectral characteristics, the contributions from the different source terms in the pressure Poisson equation and the effects of the wall are investigated using high-resolution (up to $2048^{3}$) large-eddy simulation fields and through spectral predictions. The pressure–strain-rate correlation was found to have the mixed-layer and surface-layer scaling in the strongly convective and near neutral atmospheric surface layers, respectively. Its apparent surface-layer scaling in the moderately convective surface layer is due to the slow variations of the mixed-layer contribution, and is an inherent problem for single-point statistics in a multi-scale surface layer. In the strongly convective surface layer the pressure spectrum has an approximate $k^{-5/3}$ scaling range for small wavenumbers ($kz\ll 1$) due to the turbulent–turbulent contribution, and does not follow the surface-layer scaling, where $k$ and $z$ are the horizontal wavenumber and the distance from the surface respectively. The pressure–strain-rate cospectrum components have a $k^{-1}$ scaling range, consistent with our prediction using the surface layer parameters. It is dominated by the buoyancy contribution. Thus the anisotropy in the surface layer is due to the energy redistribution caused by the density fluctuations of the large eddies, rather than the turbulent–turbulent (inertial) effects. In the near neutral surface layer, the turbulent–turbulent and rapid contributions are primarily responsible for redistribution of energy from the streamwise velocity component to the vertical and spanwise components, respectively. The pressure–strain-rate cospectra peak near $kz\sim 1$, and have some similarities to those in the strongly convective surface layer for $kz\ll 1$. For the moderately convective surface layer, the pressure–strain-rate cospectra change signs at scales of the order of the Obukhov length, thereby imposing it as a horizontal length scale in the surface layer. This result provides strong support to the multipoint Monin–Obukhov similarity recently proposed by Tong & Nguyen (J. Atmos. Sci., vol. 72, 2015, pp. 4337–4348). We further decompose the pressure into the free-space (infinite domain), the wall reflection and the harmonic contributions. In the strongly convective surface layer, the free-space contribution to the pressure–strain-rate correlation is dominated by the buoyancy part, and is the main cause of the surface-layer anisotropy. The wall reflection enhances the anisotropy for most of the surface layer, suggesting that the pressure source has a large coherence length. In the near neutral surface layer, the wall reflection is small, suggesting a much smaller source coherence length. The present study also clarifies the understanding of the role of the turbulent–turbulent pressure, and has implications for understanding the dynamics and structure as well as modelling the atmospheric surface layer.

The mean velocity profile in the convective atmospheric boundary layer (CBL) is derived analytically. The shear-stress budget equations and the mean momentum equations are employed in the derivation. The multi-point Monin–Obukhov similarity (MMO) recently proposed and analytically derived by Tong & Nguyen (J. Atmos. Sci., vol. 72, 2015, pp. 4337–4348) and Tong & Ding (J. Fluid Mech., vol. 864, 2019, pp. 640–669) provides the scaling properties of the statistics in the shear-stress budget equations. Our previous and present studies have shown that the CBL is mathematically a singular perturbation problem. Therefore, we obtain the mean velocity profile using the method of matched asymptotic expansions. Three scaling layers are identified: the outer layer, which includes the mixed layer, the inner-outer layer and the inner-inner layer, which includes the roughness layer. There are two overlapping layers, the local-free-convection layer and the log layer, respectively. Two new velocity-defect laws are discovered: the mixed-layer velocity-defect law and the surface-layer velocity-defect law. The local-free-convection mean profile is obtained by asymptotically matching the expansions in the first two layers. The log law is obtained by matching the expansions in the last two layers. The von Karman constant is obtained using velocity and length scales, and therefore has a physical interpretation. A new friction law, the convective logarithmic friction law, is obtained. The present work provides an analytical derivation of the mean velocity profile hypothesized in the Monin–Obukhov similarity theory, and is part of a comprehensive derivation of the MMO scaling from first principles.

Objective:To evaluate the safety, efficacy, and feasibility of rituximab, fotemustine, pemetrexed and dexamethasone (R-FPD) regimen for primary central nervous system lymphoma (PCNSL) patients. Methods:A prospective, single-center, single-arm, phase II clinical trial. Patients with newly diagnosed PCNSL diagnosed from the First Affiliated Hospital of Zhengzhou University from July 2018 to July 2020. R-FPD regimen consisted of rituximab (375 mg/m2 i.v. on D0), fotemustine (100mg/m2 i.v. on D1) ,pemetrexed (600mg/m2 i.v. on D1), and dexamethasone (40 mg i.v. on D1).(NCT04083066) Results: 30 patients were included. After two cycles, the objective response rate(ORR) was 96.4%(27/28,26 PR,1 CR,0 SD,0 PD,2 Censored),the disease control rate(DCR) was 96.4%(27/28); After four cycles, the ORR was 71.4% (15/21, 5PR,10 CR,1SD,5PD,7NR,2 Censored),DCR was 76.2%(16/21). The median progression-free survival (PFS) was 20.3 months (95%CI:5.2--35.4),The median overall survival (OS) was 22.0 months (95%CI:16.1-27.9).The grade III-IV toxicities were mainly leukopenia(17.9%), thrombocypenia(25%) and anemia(10.7%). Conclusion: Fotemustine-based in combination with Rituximab chemotherapy can improve outcomes with the progress free survival and the overall survival benefits, as well as with better tolerability for newly diagnosed PCNSL patients. Keywords: rituximab; primary central nervous system lymphoma; pemetrexed; fotemustine; efficacy Disclosures No relevant conflicts of interest to declare.

Nasal-type natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy with poor outcomes. The treatment of NKTCL requires intensive chemotherapy. Long noncoding RNAs (lncRNAs) have been implicated in many cancers, including NKTCL. The elucidation of the multidrug resistance (MDR) may greatly contribute to explore novel therapeutic strategies. Herein, we explored the roles and potential regulatory mechanism of lncRNAs small nucleolar RNA host gene 12 (SNHG12) in MDR of NKTCL. We found that SNHG12 was upregulated in NKTCL tissue sections, and its high expression was positively correlated with clinical grade of malignancy of NKTCL. c-Myc and SNHG12 expression was upregulated in NKTCL cell lines. c-Myc- and SNHG12 overexpression promoted proliferation and inhibited sensitivity to cisplatin (CDDP) in NK/T-cell lymphoma cell line YTS cells, and c-Myc and SNHG12-downregulation inhibited proliferation and enhanced sensitivity to CDDP in SNK-6 cells. Moreover, c-Myc- and SNHG12 overexpression increased Ki67 and P-gp expression in YTS cells, whereas c-Myc and SNHG12-downregulation reduced the Ki67 and P-gp expression in SNK-6 cells. Correlational analyses revealed that c-Myc expression was positively correlated with SNHG12 expression in NKTCL tissues. Mechanism research showed that SNHG12 was a direct transcriptional target of c-Myc and c-Myc promoted SNHG12 expression in NKTCL cell lines. Further research showed that SNHG12 overexpression reversed the effects of c-Myc downregulation on proliferation and sensitivity to CDDP in NKTCL cell lines. Taken together, our findings first report that c-Myc mediated upregulation of SNHG12 promotes proliferation and inhibits drug sensitivity in NKTCL, which provides new insights into the therapeutic target for NKTCL.

Background Esophageal carcinoma is the eighth prevalent malignancy and ranks the sixth in carcinoma-related death worldwide. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) has been identified as a tumor suppressor in multiple carcinomas. However, its roles and molecular mechanisms underlying esophageal carcinoma progression are still undefined till now. Methods RT-qPCR assay was employed to detect the expression of TIPE2 mRNA. TIPE2 protein expression was measured by using western blot assay. Ad-V and Ad-TIPE2 adenoviruses were constructed to overexpress TIPE2. The effects of TIPE2 overexpression on cell proliferation, invasion and apoptosis were assessed by MTT and Edu incorporation assays, transwell invasion assay and flow cytometry analysis, respectively. The effect of TIPE2 overexpression on xenograft tumor growth was determined by measuring tumor volume and weight, together with immunohistochemistry assay. The effect of TIPE2 overexpression on the Wnt/β-catenin signaling pathway was evaluated by detecting the protein levels of β-catenin, c-Myc and cyclinD1 in EC9076 cells and xenograft tumors of esophageal carcinoma. Results TIPE2 expression was downregulated in esophageal carcinoma tissues and cells. Adenovirus-mediated TIPE2 overexpression suppressed cell proliferation and invasion, and induced apoptosis in esophageal carcinoma cells. Enforced expression of TIPE2 inhibited tumor growth in vivo, as evidenced by the reduced tumor volume, tumor weight and proliferating cell nuclear antigen expression. Overexpression of TIPE2 inhibited the Wnt/β-catenin signaling pathway in esophageal carcinoma in vitro and in vivo. Conclusions These results suggest that TIPE2 suppressed progression and tumorigenesis of esophageal carcinoma via inhibition of the Wnt/β-catenin pathway.

Abundant isoforms and dynamic posttranslational modifications cause the separation and identification of histone variants to be experimentally challenging. To meet this need, we employ two-dimensional electrophoretic gel separation followed by mass spectrometric detection which takes advantage of the chelation of Cu2+ with amino acid residues exposed on the surfaces of the histone proteins. Acid-extracted rat liver histones were first mixed with CuSO4 solution and then separated in one dimension with triton–acid–urea (TAU) gel electrophoresis and in a second dimension using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The separations result from both the changes in charge and mass upon Cu2+ chelation. Identities of each separated gel bands were obtained by using matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS). It was found that the migration of H3 histone isoforms of rat liver is markedly affected by the use of Cu2+ ions.

Selective isolation of mono- and multi-phosphorylated peptides is important for understanding how a graded protein kinase or phosphatase signal can precisely modulate the on and off states of signal transduction pathways. Here we report that metal ions at exposed octahedral sites of nano-ferrites, including Fe3O4, NiFe₂O₄, ZnFe₂O₄ and NiZnFe₂O₄, have distinctly selective coordination abilities with mono- and multi- phosphopeptides. Due to their intrinsic magnetic properties and high surface area to volume ratios, these nanoparticles enable the rapid isolation of mono- and multi-phosphopeptides by an external magnetic field. Model phosphoprotein α-casein and two synthesized mono- and di-phosphopeptides have been chosen for proof-of-principle demonstrations, and these nanoparticles have also been applied to phosphoproteome profiling of zebrafish eggs. It is shown that NiZnFe₂O₄ is highly selective for multi-phosphopeptides. In contrast, Fe₃O₄, NiFe₂O₄ and ZnFe₂O₄ can bind with both mono- and multi-phosphopeptides with relatively stronger affinity towards mono-phosphopeptides.

Selective isolation of mono- and multi-phosphorylated peptides is important for understanding how a graded protein kinase or phosphatase signal can precisely modulate the on and off states of signal transduction pathways. Here we report that metal ions at exposed octahedral sites of nano-ferrites, including Fe3O4, NiFe₂O₄, ZnFe₂O₄ and NiZnFe₂O₄, have distinctly selective coordination abilities with mono- and multi- phosphopeptides. Due to their intrinsic magnetic properties and high surface area to volume ratios, these nanoparticles enable the rapid isolation of mono- and multi-phosphopeptides by an external magnetic field. Model phosphoprotein α-casein and two synthesized mono- and di-phosphopeptides have been chosen for proof-of-principle demonstrations, and these nanoparticles have also been applied to phosphoproteome profiling of zebrafish eggs. It is shown that NiZnFe₂O₄ is highly selective for multi-phosphopeptides. In contrast, Fe₃O₄, NiFe₂O₄ and ZnFe₂O₄ can bind with both mono- and multi-phosphopeptides with relatively stronger affinity towards mono-phosphopeptides.

Nanosized carbon based sorbents have been widely used for separation, enrichment and desalting of biological samples because of their distinguished characteristics. In this work, magnetic nanoparticles of nitrogen enriched carbon (mnNEC) have been developed for enrichment of organochlorine pesticide DDT and metabolite DDE that have been accumulated in zebrafish during the course of environmental exposure. Polymerization of pyrrole was performed in the aqueous suspension of Fe(3)O(4) nanoparticles. Resultant core-shell nanoparticules coated with polypyrrole were then subjected to a process of carbonization under high temperature and nitrogen atmospheric condition. The presence of nitrogen atoms in carbon nanoparticles increases the hydrophilicity and dispersability in aqueous samples. It has been experimentally demonstrated that mnNEC can be effectively dispersed in aqueous samples and rapidly isolated by the application of an external magnetic field. Recoveries of DDT and DDE from water range from 90% to 102% and 85-97% respectively. In combination with Selected Ion Monitoring (SIM) experiments of gas chromatography-mass spectrometry, the detection limit can be down to low ng/mL level. By using mnNEC approach, two interesting results have been found for zebrafish with 60 days exposure to DDT (1 μg/l). (1) There is higher concentration of DDT (37-143 ng/g) and DDE (173-1108 ng/g) in male zebrafish body tissues than that of female (7-52 ng/g and 146-362 ng/g for DDT and DDE respectively). (2) There is high ratio of DDE/DDT for both female and male zebrafish, implying high environmental persistence and ongoing bioaccumulation.