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Bisphenol A (BPA) has been reported to injure the developing and adult brain. However, the underlying mechanism still remains elusive. This study used neuro-2a cells as a cellular model to investigate the neurotoxic effects of BPA. Microtubule-associated protein 2 (MAP2) and tau protein maintain microtubule normal function and promote the normal development of the nervous system. Synaptophysin (SYP) and drebrin (Dbn) proteins are involved in regulating synaptic plasticity. Cells were exposed to the minimum essential medium (MEM), 0.01% (v/v) DMSO, and 150 μM BPA for 12, 24, or 36 h. Morphological analysis revealed that the cells in the BPA-treated groups shrank and collapsed compared with those in the control groups. CCK-8 and lactate dehydrogenase assay (LDH) assays showed that the mortality of neuro-2a cells increased as the BPA treatment time was prolonged. Ultrastructural analysis further revealed that cells demonstrated nucleolar swelling, dissolution of nuclear and mitochondrial membranes, and partial mitochondrial condensation following exposure to BPA. BPA also decreased the relative protein expression levels of MAP2, tau, and Dbn. Interestingly, the relative protein expression levels of SYP increased. These results indicated that BPA inhibited the proliferation and disrupted cytoskeleton and synaptic integrity of neuro-2a cells.

Background: Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. First-line treatment of aGVHD is corticosteroid. Second-line therapy mainly comprises immunosuppressants. However, ∼ 25% of the patients have a steroid-resistant and therapy-refractory disease, which is associated with a very poor prognosis. An alternative therapy option for steroid-refractory and therapy-refractory aGVHD is the use of mesenchymal stromal cells (MSCs). Here, we report the results of 88 patients with grade III-IV aGVHD treated with human umbilical cord derived mesenchymal stromal cells (UC-MSC). Methods: There were 18 children and 70 adults with grade III/ IV aGVHD (82% grade IV). These patients were either resistant to steroids or refractory to 1–5 additional immunosuppressants. UC-MSCs were transfused at a median dose of 1 × 106 cells/kg with a median of 4 times (range, 1 to 16). Results: Median time between the onset of aGVHD and the first infusion of UC-MSC was 7 days (range, 3–88). The day 28 overall response rate was 51.14%, of these, 24 patients (27.27%) showed complete remission (CR), 21 (23.86%) showed partial remission (PR). The estimated survival probability at 100 days was 43.3%. And after a median follow-up of 66 months (26–122 months), the survival rate was approximately 33% (29/88). Patients developed acute gastrointestinal (GI) tract and liver GVHD showed worse overall response in day 28 than patients only with acute GI GVHD (21% vs. 58%; p= 0.037). No patient had severe side effects. Conclusions: These results suggest that UC-MSC treatment was safe and effective in children and adults, and should be considered for treating steroid-refractory aGVHD. Trial registration: ClinicalTrials: NCT01754454. Registered 21 December 2012 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01754454?cond=msc+gvhd&draw=2&rank=8

BACKGROUND: Dietary polyphenols including anthocyanins target multiple organs. OBJECTIVE: We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G). METHODS: Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2). RESULTS: In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P 3-fold, P

Florfenicol (FLO) is one of the most popular antibacterial drugs used in veterinary clinics and aquaculture. The drug was found to decrease the hatchability of eggs laid by treated hens in veterinary clinics and research work. However, the pathological changes in developing embryos and their cardiovascular system and the mechanism underlying FLO-induced embryonic death remain unclear. In the present study, fertilized eggs laid by hens treated with a therapeutic dose of FLO were collected and incubated. Results showed that FLO exposure repressed embryonic development and induced early embryonic death. As a result, FLO decreased the hatchability and increased the proportion of weak chicks. Moreover, FLO exposure led to embryonic lethality and inhibited the development of chick embryos as characterized by decreased weights, lagging distribution of Hamburger–Hamilton stages, and dysplastic eyes. Pathological examination indicated that FLO exposure affected the normal development of the heart in 4.5-day-old chick embryos, as characterized by shorter transverse cardiac diameter, disordered arrangement of trabecular muscles in ventricles, and reduced thickness of ventricular walls. Furthermore, FLO decreased blood vascular densities and downregulated the expression levels of key angiogenesis-related genes, including the vascular endothelial growth factor and fibroblast growth factor, in the yolk sac membrane. These findings indicated that FLO exposure restricted vascular development during early embryonic development. In summary, our data suggest that the restricted growth and abnormal cardiovascular development may be responsible for FLO-induced early embryonic death. Thus, these findings can be useful for guiding the proper use of FLO and in laying a foundation for further studies on the mechanism of FLO-induced embryonic toxicity.

Lead (Pb) is a widespread environmental heavy metal that can damage the cerebral cortex and hippocampus, and reduce the learning and memory ability in humans and animals. In vivo and in vitro models of acute lead acetate exposure were established to further study the mechanism of neurons injury. In this study, 4-week-old female Kunming mice were randomly divided into four groups. Each group was treated with distilled water with different Pb concentrations (0, 2.4, 4.8 and 9.6 mM). Mice were killed, and brain tissues were collected to detect the changes in synaptic plasticity-related protein expression. Furthermore, Neuro-2A cells were treated with 0, 5, 25 and 50 μM lead acetate for 24 h to observe the changes in cell morphology and function. In in vivo experiment, results showed that the expression levels of cytoskeleton-associated and neural function-related proteins decreased in a dose-dependent manner in the mouse brain tissue. In in vitro experiment, compared with the control group, Pb treatment groups were observed with smaller and round cells, decreased cell density and number of synapses. In the Pb exposure group, the survival rate of nerve cells decreased evidently, and the permeability of the cell membrane was increased. Western blot results showed that the expression of cytoskeleton-associated and function-related proteins decreased gradually with increased Pb exposure dose. Confocal laser scanning microscopy results revealed the morphological and volumetric changes in Neuro-2A cells, and a dose-dependent reduction in the number of axon and dendrites. These results suggested that abnormal neural structures and inhibiting expression of synaptic plasticity-related proteins might be the possible mechanisms of Pb-induced mental retardation in human and animals, thereby laying a foundation for the molecular mechanism of Pb neurotoxicity.

Bisphenol A (BPA) is one of the typical environmental endocrine disruptors. BPA was leached from polycarbonate containers into food and water, and it has been detected in collective samples from humans. Microtubule-associated protein 2 (MAP2) and Tau maintain microtubule normal function and promote the normal development of the nervous system. Synaptophysin (SYP) and drebrin (Dbn) proteins are involved in regulating synaptic plasticity. This study aimed to determine the adverse effects of BPA on Neuro-2a cells by investigating the synaptic and cytoskeletal damage. Cells were exposed to 0 (Minimum Essential Medium, MEM), 0.01% (v/v) DMSO and 150 µM BPA for 12, 24, or 36 h. Morphological analysis revealed that the cells in the BPA-treated groups shrank, collapsed, and had a reduced number of synapses compared with those in the control groups. CCK-8 and LDH assays showed that the mortality of Neuro-2a cells increased as the BPA treatment time was prolonged. Transmission electron microscopic analysis further revealed that cells demonstrated nucleolar swelling and nuclear membrane and partial mitochondrial dissolution or condensation following BPA exposure. BPA also significantly decreased the relative protein expression levels of MAP2, Tau, and Dbn (P < 0.01). Interestingly, the relative protein expression levels of SYP increased (P < 0.01). These results indicated that BPA damaged the development and proliferation of Neuro-2a cells by disrupting cytoskeleton and synaptic integrity.

The precise regulation of the T-cell activation process is critical for overall immune homeostasis. Although protein phosphatase 2A (PP2A) is required for T-cell development and function, the role of PPP2CB, which is the catalytic subunit β isoform of PP2A, remains unknown. In the present study, using a T cell-specific knockout mouse of PPP2CB (PPP2CB

Bisphenol A (2,2-bis(4'-hydroxyphenyl) propane, BPA) is a well-known endocrine-disrupting compound that is widely used in various daily products and exhibits embryonic development toxicity and genotoxicity. However, the affected signaling pathways involved in embryonic development especially the interactions of involved proteins remain unclear. In our previous study (Ge et al., 2021), BPA induces DNA damage and apoptosis in Xenopus embryos, resulting in multiple malformations of larvae. However, the signaling pathways induced for apoptosis response to DNA damage are still not well elucidated. Here, we systematically elucidated the enriched pathways affected by BPA and illustrated the interactions of involved proteins. Results indicated that BPA affected multiple embryonic development pathways including Hippo, TGF-β, Wnt, and Notch pathways. Furthermore, the protein-protein interaction network suggested that the c-Abl/YAP

ObjectivesAt present, reinfusions of chimeric antigen receptor (CAR)-T cell have exhibited limited efficacy, while their efficacy on extramedullary relapse remains to be further elucidated in B-cell acute lymphoblastic leukemia (B-ALL). Although combination with IL-15 demonstrated the potential to enhance antitumor activity of CAR-T, the efficacy of this approach remains to be validated clinically.MethodsWe reported a patient with B-ALL with extramedullary relapse after allogeneic stem cell transplantation and who was resistant to chemotherapy and radiotherapy. In total, he received four treatments with CAR-T cells repeatedly under the status of disease progression.ResultsFirst, the patient received autologous murine CAR19-CD28-CD3ζ-T cells and achieved full resolution of extramedullary leukemia lasting 8 months. After systemic disease relapse, he received autologous humanized CAR22-41BB-CD3ζ-tEGFR-T cells and achieved complete remission (CR) with incomplete blood count recovery (CRi) with minimal residual disease (MRD) negativity in the bone marrow and shrinkage of extramedullary leukemia. Over 2 months later, he experienced a relapse of the systemic disease and he received autologous murine CAR19-41BB-CD3ζ-mIL15-T cells and achieved CRiMRD- lasting 5 months with the strongest expansion and persistence of CAR. Finally, on relapse of CD19− medullary disease, he received allogeneic humanized CAR22-41BB-CD3ζ-tEGFR-T cells but only achieved a transient decrease in the number of blasts. No CAR-T-cell-related encephalopathy syndrome was observed, and all side effects were manageable.ConclusionOur report hints the feasibility and safety of CD19 CAR-T cell expressing membrane-bound IL-15 for patient with B-ALL even if relapsed after multiple CAR-T-cell therapies.

Angiotensin II (AngII) regulates pigment synthesis by tyrosinase in melanocytes. To evaluate the association between AngII and coat color formation, we detected the expression distribution of AngII in white and black sheep skins by LC-ESI-MS/MS, western blot, quantitative real-time-PCR (qPCR) and distribution of AngII by immunohistochemistry.Liquid chromatography-electrospray ionization tandem MS (LC-ESI-MS/MS) results showed that AngII was found in white and black skin tissues of sheep. Western blot results verified the LC-ESI-MS/MS results and suggested that AngII was expressed at significantly higher levels in black sheep skins compared with the white sheep skins. Quantitative real time PCR (qRT-PCR) results also revealed that the expression level of AngII mRNA was higher in black sheep skins than that in white sheep skins. Immunohistochemical analysis further demonstrated that AngII protein was localized in the hair bulb and outer root sheath of hair follicle in sheep. In summary, protein and transcripts exhibited the same expression pattern in white and black sheep skins. Furthermore, the expressions of AngII in the hair bulb and outer root sheath of black sheep were stronger than those in white sheep. These results suggested that AngII functions in sheep coat color regulation and offer a novel insight for further investigation on the role of AngII in the coat color formation in sheep.

Fluoride, a geochemical element, can damage the brain and result in dysfunction of the central nervous system. In recent years, fluoride-induced neurotoxicity has become one of research focuses of environmental toxicology. Our previous study showed that fluoride could induce the structural damages of the cerebral cortex and reduce the learning and memory abilities of mice offspring. However, the underlying mechanisms of these effects remain unclear. In this study, primary neurons were isolated from the cerebral cortices of postnatal 1-day SD rats. The primary cultured cerebral cortical neurons were adherent and the cellular network was obvious. Neurons were identified by Nissl's staining and were used for experiments. Different concentrations of sodium fluoride (0.5, 1.0, 1.5, 2.0 and 2.5 mM) were chosen to explore its toxic effects on neuron of SD rats in vitro. Results showed that neuronal morphology was obviously damaged in 2.0 and 2.5 mM, but was not adversely affected in 0.5 and 1 mM. Further studies revealed that the neurites of neuron were shrunken and even became fractured with the increase in NaF dose, which have been detected by scanning electron microscopy (SEM). Meanwhile, TEM showed marginated chromatin, widened nuclear gaps, damaged nuclei and swollen or even absent mitochondria in 1.5, 2 and 2.5 mM group. The cytoskeletal staining was consistent with the above results. The number of neurites of cerebral cortical neuron significantly decreased after fluoride exposure by immunofluorescent assay. In summary, high fluoride (1.5, 2 and 2.5 mM) concentrations exerted a significant toxic effect on the cellular morphologies and neural formation of primary cultured cortical neurons. These findings provide new insights into the roles of NaF in neuronal damage and can contribute to an improved understanding of fluoride-induced neurotoxicity.

This study characterized the multidose pharmacokinetic (PK) characteristics of posaconazole tablets used as prophylactic antifungal therapy in Chinese patients with acute myelogenous leukemia (AML) at risk for invasive fungal infection (IFI). Participants in this open-label, single-arm, phase 1b study received posaconazole 300 mg twice daily on day 1 and then once daily for up to 28 days. In the intensive PK sampling subgroup, posaconazole was administered under fasting conditions on days 1 and 8, and blood samples were regularly collected over 24 h. Trough PK sampling was conducted in all participants on days 1, 2, 3, 8, 14, 21, and 28 without regard for food intake. Population PK characteristics were predicted using PK modeling. Primary endpoints were steady-state average concentration (Cavg) and percentage of participants with steady-state Cavg (predicted and observed) > 500 ng/ml. Treatment safety and efficacy were secondary endpoints. Sixty-five adult Chinese participants were enrolled. On day 8, steady-state arithmetic mean Cavg was 1610 ng/ml (% coefficient of variation [%CV] 42.8%) in the intensive PK subgroup (n = 20). All participants achieved a steady-state Cavg > 500 ng/ml. Predicted Cavg (pCavg) was 1770 ng/ml (%CV 33.7%) in the total population (n = 64); 92.2% of participants had pCavg values ≥ 500 ng/ml (n = 59). The posaconazole tablet safety profile was consistent with that of the oral formulation, and the IFI rate was 3%. In Chinese AML patients, the posaconazole 300-mg tablet provided PK data comparable with those of previous studies and was generally well tolerated and efficacious. ClinicalTrials.gov, NCT02387983.

Fluoride (F) exposure causes cognitive dysfunction in humans and animals. However, the precise molecular mechanisms by which fluoride exerts its neurotoxic effects are poorly understood. In this study, an animal model of fluoride exposure was created by providing ICR mice were treated with vehicle F at a dose of 0 (control group), 50 (low-fluoride group) or 100 mg/L (high-fluoride group) in water for one month. After the mice mated, parents and offspring were treated and maintained under these conditions. The cognitive abilities of the mice were examined using a Morris water maze test. Results indicated that fluoride exposure significantly prolonged the escape latency period and decreased the number of crossings in a particular zone. Histopathologic analysis revealed the shrinkage and fragmentation of glial cells in the fluoride-treated groups. Pyramidal cells in the cerebral cortices of fluoride-treated groups were fewer than those of the control group. The expression of microtubule-associated protein 2 (MAP2) and synaptic proteins of the cerebral cortex in mouse offspring was assayed using RT-PCR and Western blot. Fluoride exposure possibly induced a significantly decreased expression of MAP2, synaptophysin (SYP) and developmentally regulated brain protein (Dbn) at protein and mRNA levels. Glutamate receptor (N-methyl-d-aspartate receptor, NMDAR) was also expressed, and this finding was consistent with the reduced MAP2, SYP and Dbn expression. Therefore, fluoride-mediated reduction in cognitive dysfunction is likely caused by the disruption of the expression of these synapse-associated proteins, resulting in attenuated neuronal functioning.

It has been reported that fluoride exposure may cause serious public health problems, particularly neurotoxicity. However, the underlying mechanisms remain unclear. This study used Neuro-2A cells to investigate the effects of fluoride on the cytoskeleton. The Neuro-2A cells were exposed to 0, 1, 2, 4 and 6 mM sodium fluoride (NaF) for 24 h. Cell viability and lactate dehydrogenase (LDH) release were examined. It was observed that exposure to NaF reduced cell viability, disrupted cellular membrane integrity, and high levels of LDH were released. The observed changes occurred in a dose response manner. Morphologic observations showed that cell became rounded and were loosely adherent following exposure to NaF. Axon spines and normal features disappeared with high dose NaF treatment. The expression of MAP2 and synaptophysin decreased, particularly at 4 mM and 6 mM (P < 0.05) for MAP2. These results corroborate the morphologic observations. The content of glutamate and NMDAR (glutamate receptor) protein were assessed to help understand the relationship between synapses and neurotransmitter release using ELISA and Western-blot. Compared with the control, glutamate and NMDAR expression declined significantly at 4 mM and 6 mM (P < 0.05) group. Finally, the ultrastructural changes observed with increasing doses of NaF were: disappearance of synapses, mitochondrial agglutination, vacuole formation, and cellular edema. Taken together, NaF exposure disrupted cellular integrity and suppressed the release of neurotransmitters, thus effecting neuronal function. These findings provide deeper insights into roles of NaF in neuron damage, which could contribute to a better understanding of fluoride-induced neurotoxicity.

Bisphenol A (BPA) is an environmental chemical that induces neurotoxic effects for human. Synaptophysin (SYP) and drebrin (Dbn) proteins are involved in regulating synaptic morphology. The stability of the cytoskeleton in nerve cells in the brain is regulated by Tau and MAP2. This study aimed to determine the toxicity of BPA to Neuro-2a cells by investigating the synaptic and cytoskeletal damage induced in these cells by 24 h of exposure to 0 (MEM), 50, 100, 150, or 200 μM BPA or DMSO. MTT and LDH assays showed that the death rates of Neuro-2a cells increased, as the BPA concentration increased. Ultrastructural assays revealed that cells underwent nucleolar swelling as well as nuclear membrane and partial mitochondrial dissolution or condensation, following BPA exposure. Morphological analysis further revealed that compared with the cells in the control group, the cells in the BPA-treated groups shrank, became rounded, and exhibited a reduced number of synapses. BPA also significantly decreased the relative protein and mRNA expression levels of Dbn, MAP2 and Tau (P .01), but increased the relative protein and mRNA expression levels of SYP (P .01). These results indicated that BPA suppressed the development and proliferation of Neuro-2a cells by disrupting cellular and synaptic integrity and inflicting cytoskeleton injury.

Summary The safety of CRISPR (clustered regularly interspaced short palindromic repeats)–based genome editing in the context of human gene therapy is largely unknown. CCR5 is a reasonable but not a...

Sudden death syndrome (SDS), which is a cardiac-related condition commonly observed in chickens selected for rapid growth, causes significant economic losses to the global poultry industry. Its pathogenesis in broilers is poorly understood, and little is known about the proteome of the heart tissue of SDS broilers. A quantitative proteomic approach using isobaric tags for relative and absolute quantification labeling of peptides was used to characterize the protein expression profiles in the left ventricle of SDS broilers. These proteins were further analyzed by bioinformatics, and two proteins were validated by western blot analysis. We identified 186 differentially expressed proteins (DEPs), of which 72 were upregulated, and 114 were downregulated in the SDS group. Functional annotation suggested that 7 DEPs were related to cardiac muscle contraction, and another 7 DEPs were related to cardiac energy metabolism. Protein interaction network predictions indicated that differences in cardiac muscle contraction between SDS and healthy groups were regulated by troponin T, tropomyosin alpha-1 chain, fast myosin heavy chain HCIII, myosin-1B, coronin, and myoglobin, whereas differences in cardiac energy metabolism and biosynthesis of amino acids were regulated by gamma-enolase, phosphoglycerate mutase, NADH-ubiquinone oxidoreductase chain 2, serine/threonine-protein kinase, myoglobin, and alpha-amylase. Our expression profiles provide useful information and new insights into key proteins to elucidate SDS for further studies.

Bisphenol A (BPA), an endocrine-disrupting chemical that is largely produced and used in the plastics industry, causes environmental pollution and is absorbed by humans through consumption of food and liquids in polycarbonate containers. BPA exerts developmental and genetic toxicities to embryos and offsprings, but the embryotoxicity mechanism of this chemical is unclear. This study aimed to explore the toxic effect of BPA on embryonic development and elucidate its toxicity mechanism. Embryos of Xenopus laevis as a model were treated with different concentrations (0.1, 1, 10, and 20 μM) of BPA at the two-cell stage to investigate the developmental toxicity of BPA. Embryonic development and behaviors were monitored 24 h-96 h of BPA exposure. BPA concentrations greater than 1 μM exerted significant teratogenic effects on the Xenopus embryos, which showed short tail axis, miscoiled guts, and bent notochord as the main malformations. The 20 μM BPA-treated embryos were seriously damaged in all aspects and exhibited deformity, impaired behavioral ability, and tissue damage. The DNA integrity and apoptosis of the Xenopus embryos were also investigated. Exposure to BPA concentrations higher than 0.1 μM significantly induced DNA damage (p 0.05). The 10 and 20 μM BPA-treated embryos exhibited higher levels of cleaved caspase-3 protein than the control. The ratios of bax/bcl-2 mRNA were significantly higher in the 10 μM and 20 μM-treated embryos than the ratio in the control group. Overall, data indicated that BPA can delay the early development, induce DNA damage and apoptosis, and eventually cause multiple malformations in Xenopus embryos.

Cadmium (Cd) is considered a possible etiological factor in neurodegenerative diseases. However, the exact mechanism by which Cd induces neurotoxicity is not well elucidated. In this study, Neuro-2a cells were treated with 0, 10, 20, and 40 μM cadmium chloride for 24 hours to investigate the effects of Cd on the cytoskeleton of nerve cells. MTT assay and ELISA assay were used to examine cell viability and release of lactate dehydrogenase (LDH) from cells, respectively. Results showed that Cd reduced cell viability and increased the release of LDH in a dose-dependent manner (P < 0.05). The morphology of treated cell was damaged as indicated by cell collapse and dimensionality reduction. Moreover, the axonal spines and normal features of Cd-treated neurons disappeared. We checked the ultrastructure of Neuro-2a cells and found that Cd-induced swelling, membrane damage, overflow of cytoplasm contents, and cell fragmentation. Damaged mitochondria, expanded endoplasmic reticulum, and abnormal microfilaments were found in Cd-treated cells rather than in untreated cells. Compared with the control group, the relative release of glutamate in the supernatant after Cd treatment was reduced, indicating that Cd exposure could reduce the release of glutamate by inhibiting the function of nerve-2a cells. Cd decreased the mRNA and protein expression levels of cytoskeletal proteins including DBN, SYP, and TAU, which might promote cytoskeleton alterations in Cd-treated cells. In conclusion, Cd-induced actin cytoskeleton alterations and dysfunction of cultured neurons. The results of the present study provide new insights for the investigation of Cd-induced neurotoxicity.

Background: Steady-state bone marrow (SS-BM) and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell (G-BM/G-PBSC) are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation. Here, we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen (HLA)-identical sibling transplantation. Methods: A total of 226 patients (acute myelogenous leukemia-complete remission 1, chronic myelogenous leukemia-chronic phase 1) received SS-BM, G-BM, or G-PBSC from an HLA-identical sibling. Clinical outcomes (graft-versus-host disease [GVHD], overall survival, transplant-related mortality [TRM], and leukemia-free survival [LFS]) were analyzed. Results: When compared to SS-BM, G-BM gave faster recovery time to neutrophil or platelet (P < 0.05). Incidence of grade III-IV acute GVHD and extensive chronic GVHD (cGVHD) was lower than seen with SS-BM (P < 0.05) and similar to G-PBSC. Although the incidence of cGVHD in the G-BM group was similar to SS-BM, both were lower than G-PBSC (P < 0.05). G-BM and G-PBSC exhibited similar survival, LFS, and TRM, but were significantly different from SS-BM (P < 0.05). There were no significant differences in leukemia relapse rates among the groups (P > 0.05). Conclusions: G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM. We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

Lead poisoning is a geochemical disease. On the other hand, lead is highly carcinogenic and exhibits liver and kidney toxicity. This element can also cross the blood-brain barrier, reduce learning and memory ability and damage the structure of the cerebral cortex and hippocampus. To further investigate the mechanism of lead neurotoxicity, 4-week-old Kunming mice were used to explore the effects of different concentrations of Pb2+ (0, 2.4, 4.8 and 9.6 mM) for 9 days. In this study, pathological and ultrastructural changes in brain cells of the treated group were related to damages to mitochondria, chromatin and the nucleus. Lead content in blood was tested by atomic absorption spectroscopy, which showed high lead concentrations in the blood with increasing doses of lead. Distribution of lead in nerve cells was analysed by transmission electron microscopy with energy dispersive spectroscopy. Data showed the presence of lead in nucleopores, chromatin and nuclear membrane of nerve cells in the treatment groups, whereas lead content increased with increasing doses of lead acetate. Finally, microtubule-associated protein 2 (MAP2) mRNA and protein expression levels were detected by real-time PCR and Western blotting, which showed a reduction in MAP2 expression with increasing lead doses in the mouse brain. These findings suggest that acute lead poisoning can cause significant dose-dependent toxic effects on mouse brain function and can contribute to better understanding of lead-induced toxicity.

Inefficient homing of systemically infused mesenchymal stem cells (MSCs) limits the efficacy of existing MSC-based clinical graft-versus-host disease (GvHD) therapies. Secondary lymphoid organs (SLOs) are the major niches for generating immune responses or tolerance. MSCs home to a wide range of organs, but rarely to SLOs after intravenous infusion. Thus, we hypothesized that targeted migration of MSCs into SLOs may significantly improve their immunomodulatory effect. Here, chemokine receptor 7 (CCR7) gene, encoding a receptor that specifically guides migration of immune cells into SLOs, was engineered into a murine MSC line C3H10T1/2 by retrovirus transfection system (MSCs/CCR7). We found that infusion of MSCs/CCR7 potently prolonged the survival of GvHD mouse model. The infused MSCs/CCR7 migrate to SLOs, relocate in proximity with T lymphocytes, therefore, potently inhibited their proliferation, activation, and cytotoxicity. Natural killer (NK) cells contribute to the early control of leukemia relapse. Although MSCs/CCR7 inhibited NK cell activity in vitro coculture, they did not impact on the proportion and cytotoxic capacities of NK cells in the peripheral blood of GvHD mice. In an EL4 leukemia cell loaded GvHD model, MSCs/CCR7 infusion preserved the graft-versus-leukemia (GvL) effect. In conclusion, this study demonstrates that CCR7 guides migration of MSCs to SLOs and thus highly intensify their in vivo immunomodulatory effect while preserving the GvL activity. This exciting therapeutic strategy may improve the clinical efficacy of MSC based therapy for immune diseases. Stem Cells 2014;32:1890–1903

A mild and efficient method for the conversion of fatty acid methyl esters from lard into ascorbyl esters via lipase-catalyzed transesterification in co-solvent mixture is described. A solvent engineering strategy was firstly applied to improve fatty acid ascorbyl esters production. The co-solvent mixture of 30% t-pentanol:70% isooctane (v/v) was optimal. Response surface methodology (RSM) and central composite design (CCD) were employed to estimate the effects of reaction parameters, such as reaction time (12–36 h), temperature (45–65 °C), enzyme amount (10–20%, w/w, of fat acid methyl esters), and substrate molar ratio of fatty acid methyl esters to ascorbic acid (8:1–12:1) for the synthesis of fatty acid ascorbyl esters in co-solvent mixture. Based on the RSM analysis, the optimal reaction conditions were determined as follows: reaction time 34.32 h, temperature 54.6 °C, enzyme amount 12.5%, substrate molar ratio 10.22:1 and the maximum conversion of fatty acid ascorbyl esters was 69.18%. The method proved to be applicable for the synthesis of ascorbyl esters using Novozym 435 in solvent.

The structures of the As–nucleobases (As–adenine, –guanine, –cytosine, –thymine, and –uracil) and their anions are studied at the density functional B3LYP with a double-ζ plus diffuse (DZP++) basis set. The lowest energy structures of these complexes are presented. For the case of neutral systems, a strong association between arsenic atom and nucleobases is found and the ground state structures are R–As–H (R = nucleobases radical) complexes. For anions, the most stable structures are also R–As–H forms, but their association sites are different from corresponding neutrals with the exception of As–adenine. The extra electron of the anions is mainly localized on the arsenic atom. The adiabatic electron affinity (AEA), the vertical electron affinity (VEA), and the vertical detachment energy (VDE) for these complexes are reported. The formation energies of these complexes are also estimated, respectively, in order to examine relative stabilities. The stability order is As–guanine > As–adenine > As–uracil > As–cytosine > As–thymine.

The molecular structures, electron affinities, and dissociation energies of the Si n Na/Si n Na − ( n ⩽ 10) species have been investigated by means of five hybrid and pure density functional theory (DFT) methods. The basis sets used in this work is of double- ζ plus polarization quality with additional diffuse functions, denoted DZP++. The geometries are fully optimized with each DFT method independently. Three different types of the neutral-anion energy separations presented in this work are the adiabatic electron affinity (EA ad ), the vertical electron affinity (EA vert ), and the vertical detachment energy (VDE). Compared with the limited experimental values of EA ad and VDE, the BPW91 and B3PW91 scheme provided the most reliable EA ad and VDE values. The dissociation energy D e (Si n Na → Si n +Na) for the neutral Si n Na and D e ( Si n Na - → Si n - + Na ) for the anionic Si n Na − species have also been reported and used to understand relative stability.

The geometries and energies of Si n H 2 ( n = 3, 5–10) have been systematically investigated by means of MP2/6-311++G ∗∗ //MP2/6-31G ∗∗ and B3LYP/6-311++G ∗∗ schemes. Several geometric arrangements have been considered for each cluster. All the geometries considered have been completely optimized within the given symmetry constrains. The results show that the ground state geometries of Si 4 H 2 , Si 6 H 2 , and Si 8 H 2 are attaching two H-atoms to one Si-atom and others are bonding two H-atoms to two Si-atoms. The results of the lowest energy structure of Si n H 2 at MP2 levels are the same as those of results at B3LYP levels with the exception of Si 5 H 2 . However, the MP4(SDQ) result is the same as the B3LYP for Si 5 H 2 . At B3LYP level of theory, dissociation energies of the lowest energy structures of Si n H 2 ( n = 3–10) have been computed and used to understand relative stability. Other properties, such as HOMO-LUMO gap, hardness, vertical electron affinities, and vertical ionization potential have been assessed.

To further find effective method to improve the long term survival of refractory or relapsed acute myeloid leukemia (AML) patients, we retrospectively analyzed the outcomes of myeloablative hematopoietic stem cell transplantation (HSCT) for 133 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) therapy related AML(t-AML) in not remission status. The overall 3-year OS and DFS were 40.9% and 35.6% respectively. The variables associated with improved long term DFS were a bone marrow blast cell count less than 20% and an intensified conditioning regimen. In addition, the t-AML group had higher rates of relapse and III-IV acute GVHD than the primary AML group. The unrelated donor group had similar OS and DFS with sibling groups. Our study suggested that decreasing bone marrow blast cell counts before HSCT and strengthening the conditioning regimen may improve long-term DFS for refractory/relapsed AML patients, and unrelated donor group can get similar effect when compared to the sibling group.

The silicon hydrides clusters structures and electron affinities of the Si 4 H n /Si 4 H n − ( n =2–10) species have been examined using three density functional theory (DFT) methods. The basis set used in this work is of double-ζ plus polarization quality with additional diffuse s- and p-type functions, denoted DZP++. The geometries are fully optimized with each DFT method independently. Three different types of energy separations presented in this work are the adiabatic electron affinity (EA ad ), the vertical electron affinity (EA vert ), and the vertical detachment energy (VDE). The most reliable EAad, obtained at the B3LYP and BPW91 levels of theory, are 1.53 or 1.54 eV (Si 4 H 2 ), 2.45 or 2.47 eV (Si 4 H 3 for C s ← C 1 ) and 2.50 eV for C 1 ← C 1 of Si 4 H 3 , 1.73 or 1.79 eV (Si 4 H 4 ), 2.43 or 2.38 eV (Si 4 H 5 ), 1.61 or 1.55 eV (Si 4 H 6 ), 2.20 or 2.23 eV (Si 4 H 7 ), and 2.34 or 2.37 eV (Si 4 H 9 ). For Si 4 H 8 and Si 4 H 10 , there are no reliable EA ad but there are reliable VDE. The values of VDE are from 1.29 eV (BPW91) to 1.63 eV (B3LYP) for Si 4 H 8 , and from 0.55 eV (B3LYP) to 0.69 eV (BPW91) for Si 4 H 10 .

The structures and energies of neutral and charged arsenic sulfides As n S2 (−1,0,+1) (n = 1–6) were investigated systematically by means of the Gaussian-3 (G3) scheme. The ground-state structures of these species are presented. The ground-state structures of As n S2 can be viewed as the lowest-energy structure of neutral As n+1S by replacing an As atom with a S atom. To be more precise, the ground-state structures of As n S2 can be viewed as the lowest-energy structure of neutral As n+2 by replacing two As atoms with two S atoms, in which the feature of sulfur bonding is edge-bridging. No rule could be found for the ground state structure of As n S2 − and As n S2 +. In As n S2 −, the feature of sulfur bonding is either edge-bridging or a terminal atom, and in AsnS2 + the feature of sulfur bonding is edge-bridging analogous to As n S2. The potential energy surfaces of As4S2 and its charged species are very flat. So co-existence for many isomers of As4S2 and its charged species are possible. The reliable adiabatic electron affinities (AEAs) and adiabatic ionization potentials (AIPs) of As n S2 were estimated. There are odd-even alternations in both AEAs and AIPs as a function of size of As n S2. The dissociation energies (DEs) of S [and/or its ion S(−/+)] from As n S2 clusters and their ions were calculated and used to reveal relative stability.

The geometries, electronic structures and energies of small ScSi n species (n = 1-6) and their anions have been systematically investigated by means of the higher level of the ccCA-TM, G4, and G4(MP2) schemes. The global minima of these clusters have been presented. The global minima of neutral ScSi n (n = 1-6) and their anions are "substitutional structure" which is derived from Si n+1 by replacing a Si atom with a Sc atom. The adiabatic electron affinities for ScSi n have been estimated. Compared with limited experimental data, the average absolute deviations from experiment for ccCA-TM, G4, and G4(MP2) are 0.21 eV, 0.22 eV, and 0.25 eV, respectively. The dissociation energies of Sc atom from the lowest-energy structure of ScSi n clusters have been evaluated to examine relative stabilities. The electron affinities and dissociation energies predicted by ccCA-TM, G4, and G4(MP2) methods, especially for ccCA-TM and G4, differ little from each other. The agreement may indicate they are reliable.

The structures and energies of neutral and charged monomethylated arsenic species CH(3)As(n)((-1,0,+1)) (n = 1-7) have been systematically investigated with the Gaussian-3 (G3) method. The ground-state structures of monomethylated arsenic species including the neutrals and the ions are vertex-methylated type. The lowest-energy structures of neutral methylated arsenic species and their ions can be viewed as being derived from corresponding to neutral and ionic arsenic clusters, respectively. The reliable electron affinities and ionization potentials of CH(3)As(n) have been evaluated. And there are odd-even alternations in both electron affinities and ionization potentials as a function of size of CH(3)As(n). The dissociation energies of CH(3) from neutral CH(3)As(n) and their ions have been calculated to examine relative stabilities. The results characterized the odd-numbered neutral CH(3)As(n) as more stable than the even-numbered systems, and the even-numbered cationic CH(3)As(n)(+) as more stable than the odd-numbered species with the exception of n = 1. The dissociation energy of CH(3)As(+) is the maximum among all of these values. There are no odd-even alternations for anionic CH(3)As(n)(-) with n ≤ 7.

The equilibrium geometries and energies of neutral BeSi(n) (n = 2-10) species and their anions have been studied at the highest level of Gaussian-3 (G3) theory. The results reveal that the ground-state structures of these clusters are Be-encapsulated in silicon cages with nor= 8. The reliable adiabatic electron affinities of BeSi(n) have been predicted to be 1.68 eV for BeSi(2), 1.87 eV for BeSi(3), 2.33 eV for BeSi(4), 2.29 eV for BeSi(5), 2.11 eV for BeSi(6), 2.37 eV for BeSi(7), 2.95 eV for BeSi(8), 2.74 eV for BeSi(9), and 1.92 eV for BeSi(10). The dissociation energies of Be atom from BeSi(n), Si atom from BeSi(n), and Si atom from Si(n) clusters have also been calculated, respectively, to examine relative stabilities. The trend of stability of BeSi(n) changed with n is converse to that of Si(n) when nor= 7. From nor= 8, the encapsulated Be atom in silicon cages not only results in an identical trend for stability of BeSi(n) and Si(n) but also improves the stability of Si(n) clusters.