Imidacloprid removal by modified graphitic biochar with Fe/Zn bimetallic oxides.

Coping with the critical challenge of imidacloprid (IMI) contamination in sewage treatment and farmland drainage purification, this study presents a pioneering development of an advanced modified graphitic white melon seed shells biochar (Fe/Zn@WBC). The Fe/Zn@WBC demonstrates a substantial enhancement in adsorption efficiency for IMI, achieving a remarkable removal rate of 87.69% within 30 min and a significantly higher initial adsorption rate parameter h = 4.176 mg g-1·min-1. This significant improvement outperforms WBC (12.22%, h = 0.115 mg g-1·min-1) and highlights the influence of optimized adsorption conditions at 900 °C and the graphitization degree resulting from Fe/Zn bimetallic oxide modification. Characterization analysis and batch sorption experiments including kinetics, isotherms, thermodynamics and pH factors illustrate that chemical adsorption is the main type of adsorption mechanism responsible for this superior ability to remove IMI through pore filling, hydrogen bonding, hydrophobic interaction, electrostatics interaction, π-π interactions as well as complexation processes. Furthermore, we demonstrate exceptional stability of Fe/Zn@WBC across a broad pH range (pH = 3-11), co-existing ions presence along with humic acid under various real water conditions while maintaining high removal efficiency. This study presents an advanced biochar adsorbent, Fe/Zn@WBC, with efficient adsorption capacity and easy preparation. Through three regeneration cycles via pyrolysis method, it demonstrates excellent pyrolysis regeneration capabilities with an average removal efficiency of 92.02%. The magnetic properties enable rapid separation facilitated by magnetic analysis. By elucidating the efficacy and mechanistic foundations of Fe/Zn@WBC, this research significantly contributes to the field of environmental remediation by providing a scalable solution for IMI removal and enhancing scientific understanding of bimetallic oxides-hydrophilic organic pollutant interactions.

Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma.

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.

Dual-path transformer-based network with equalization-generation components prediction for flexible vibrational sensor speech enhancement in the time domain.

The flexible vibrational sensor (FVS) has the potential to become a popular wearable communication device because of its natural noise shielding characteristics and soft materials. However, FVS speech faces a severe loss of frequency components. To improve speech quality, a time-domain neural network model based on the dual-path transformer combined with equalization-generation components prediction (DPT-EGNet) is proposed. More specifically, the DPT-EGNet consists of five modules, namely the pre-processing module, dual-path transformer module, equalization module, generation module, and post-processing module. The dual-path transformer module is leveraged to extract the local and global contextual relationship of long-term speech sequences, which is extremely beneficial for inferring the missing components. The equalization and generation modules are designed according to the characteristics of FVS speech, which further improve the speech quality by simulating the inversion process of the speech distortion. The experimental results demonstrate that the proposed model effectively improves the quality of FVS speech; the average perceptual evaluation of speech quality (PESQ), short-time objective intelligibility (STOI), and composite measure for overall speech quality (COVL) scores of three males and three females are relatively increased by 64.19%, 29.63%, and 101.37%, which is superior to other baseline models developed in different domains. The proposed model also has significantly lower complexity than the others.

Matrix metalloproteinase-2 in oncostatin M-induced sarcomere degeneration in cardiomyocytes.

Cardiomyocyte dedifferentiation may be an important source of proliferating cardiomyocytes facilitating cardiac repair. Cardiomyocyte dedifferentiation and proliferation induced by oncostatin-M (OSM) is characterized by sarcomere degeneration. However, the mechanism underlying sarcomere degeneration remains unclear. We hypothesized that this process may involve matrix metalloproteinase-2 (MMP-2), a key protease localized at the sarcomere in cardiomyocytes. We tested the hypothesis that MMP-2 is involved in the sarcomere degeneration that characterizes cardiomyocyte dedifferentiation. Confocal immunofluorescence and biochemical methods were used to explore the role of MMP-2 in OSM-induced dedifferentiation of neonatal rat ventricular myocytes (NRVM). OSM caused a concentration- and time-dependent loss of sarcomeric α-actinin and troponin-I in NRVM. Upon OSM-treatment, the mature sarcomere transformed to a phenotype resembling a less-developed sarcomere, i.e., loss of sarcomeric proteins and Z-disk transformed into disconnected Z bodies, characteristic of immature myofibrils. OSM dose dependently increased MMP-2 activity. Both the pan-MMP inhibitor GM6001 and the selective MMP-2 inhibitor ARP 100 prevented sarcomere degeneration induced by OSM treatment. OSM also induced NRVM cell cycling and increased methyl-thiazolyl-tetrazolium (MTT) staining, preventable by MMP inhibition. These results suggest that MMP-2 mediates sarcomere degeneration in OSM-induced cardiomyocyte dedifferentiation and thus potentially contributes to cardiomyocyte regeneration.

Sensing Home: A Cost-Effective Design for Smart Home via Heterogeneous Wireless Networks.

The aging population has inspired the marketing of advanced real time devices for home health care, more and more wearable devices and mobile applications, which have emerged in this field. However, to properly collect behavior information, accurately recognize human activities, and deploy the whole system in a real living environment is a challenging task. In this paper, we propose a feasible wireless-based solution to deploy a data collection scheme, activity recognition model, feedback control and mobile integration via heterogeneous networks. We compared and found a suitable algorithm that can be run on cost-efficient embedded devices. Specifically, we use the Super Set Transformation method to map the raw data into a sparse binary matrix. Furthermore, designed front-end devices of low power consumption gather the living data of the habitant via ZigBee to reduce the burden of wiring work. Finally, we evaluated our approach and show it can achieve a theoretical time-slice accuracy of 98%. The mapping solution we propose is compatible with more wearable devices and mobile apps.

MMP-2 is localized to the mitochondria-associated membrane of the heart.

Matrix metalloproteinase-2 (MMP-2) has been extensively studied in the context of extracellular matrix remodeling but is also localized within cells and can be activated by prooxidants to proteolyze specific intercellular targets. Although there are reports of MMP-2 in mitochondria, a critical source of cellular oxidative stress, these studies did not take into account the presence within their preparations of the mitochondria-associated membrane (MAM), a subdomain of the endoplasmic reticulum (ER). We hypothesized that MMP-2 is situated in the MAM and therefore investigated its subcellular distribution between mitochondria and the MAM. Immunogold electron microscopy revealed MMP-2 localized in mitochondria of heart sections from mice. In contrast, immunofluorescence analysis of an MMP-2:HaloTag fusion protein expressed in HL-1 cardiomyocytes showed an ER-like distribution, with greater colocalization with an ER marker (protein disulfide isomerase) relative to the mitochondrial marker, MitoTracker red. Although MMP-2 protein and enzymatic activity were present in crude mitochondrial fractions, once these were separated into purified mitochondria and MAM, MMP-2 was principally associated with the latter. Thus, although mitochondria may contain minimal levels of MMP-2, the majority of MMP-2 previously identified as "mitochondrial" is in fact associated with the MAM. We also found that calreticulin, an ER- and MAM-resident Ca(2+) handling protein and chaperone, could be proteolyzed by MMP-2 in vitro. MAM-localized MMP-2 could therefore potentially impact mitochondrial function by affecting ER-mitochondrial Ca(2+) signaling via its proteolysis of calreticulin.

Uterine vasculature remodeling in human pregnancy involves functional macrochimerism by endothelial colony forming cells of fetal origin.

The potency of adult-derived circulating progenitor endothelial colony forming cells (ECFCs) is drastically surpassed by their fetal counterparts. Human pregnancy is associated with robust intensification of blood flow and vascular expansion in the uterus, crucial for placental perfusion and fetal supply. Here, we investigate whether fetal ECFCs transmigrate to maternal bloodstream and home to locations of maternal vasculogenesis, primarily the pregnant uterus. In the first instance, endothelial-like cells, originating from mouse fetuses expressing paternal eGFP, were identified within uterine endothelia. Subsequently, LacZ or enhanced green fluorescent protein (eGFP)-labeled human fetal ECFCs, transplanted into immunodeficient (NOD/SCID) fetuses on D15.5 pregnancy, showed similar integration into the mouse uterus by term. Mature endothelial controls (human umbilical vein endothelial cells), similarly introduced, were unequivocally absent. In humans, SRY was detected in 6 of 12 myometrial microvessels obtained from women delivering male babies. The copy number was calculated at 175 [IQR 149-471] fetal cells per millimeter square endothelium, constituting 12.5% of maternal vessel lumina. Cross-sections of similar human vessels, hybridized for Y-chromosome, positively identified endothelial-associated fetal cells. It appears that through ECFC donation, fetuses assist maternal uterine vascular expansion in pregnancy, potentiating placental perfusion and consequently their own fetal supply. In addition to fetal growth, this cellular mechanism holds implications for materno-fetal immune interactions and long-term maternal vascular health.

Production and secretion of Lactobacillus crispatus ß-galactosidase in Pichia pastoris.

Lactobacillus ß-galactosidases are mostly heterodimeric proteins, which are encoded by the two overlapping genes, lacL and lacM, and produced in recombinant prokaryotic systems for higher yield. This is the first report on the expression of a heterodimeric ß-galactosidase from Lactobacillus crispatus B470 in Pichia pastoris. The overlapping consecutive genes, lacL and lacM, that shared 17 nucleotides were cloned from the genomic DNA of L. crispatus. A recombinant plasmid harboring both expression cassettes of lacL and lacM was constructed and transformed into P. pastoris GS115 competent cells. Two recombinant P. pastoris strains (GSLac01 and GSLac02) showed the highest ß-galactosidase activities of 24.5 and 31.0 U/ml in the culture supernatants, respectively. The recombinant ß-galactosidase (LcLacLM) from GSLac02 was purified to electrphoretic homogeneity by ion-exchange chromatography and molecular sieve chromatography. Similar to most Lactobacillus ß-galactosidases that operate at moderately thermophilic and weak acid to neutral conditions, LcLacLM showed optimal activity at 50°C and pH 5.5-6.5. It's the first report on functional and secretory expression of LacLM-type ß-galactosidase in eukaryotic system. This strategy might be applied to the expression of other overlapping genes.

Bisthiourea immobilized UiO-66-NH2 supported Fe2O3 nanoparticles to accelerate dual centers Fenton-like reaction.

In this paper, an efficient catalyst UiO-66-BTU/Fe2O3 was synthesized by using bisthiourea modified zirconium-based metal organic framework (Zr-MOF). The UiO-66-BTU/Fe2O3 system features outstanding Fenton-like activity that is 22.84 times and 12.91 times larger than Fe2O3 and conventional UiO-66-NH2/Fe2O3 system. It also exhibits good stability, broad pH range and recycle ability. Through comprehensive mechanistic investigations, we have ascribed the excellent catalytic performance of the UiO-66-BTU/Fe2O3 system to 1O2 and HO as the reactive intermediates, cause Zr centers can make complexation with Fe to form dual centers. Meanwhile, the CS on the bisthiourea can form Fe-S-C bonds with Fe2O3, reducing the redox potential of Fe(III)/Fe(II) and influencing the decomposing of H2O2, which indirectly regulate the interaction between Fe and Zr to accelerate electron transfer during the reaction. This work exhibits the design and understanding of the iron oxides incorporated in modified MOFs with excellent Fenton-like catalytic performance to remove phenoxy acid herbicides.

Serum soluble BCMA can be used to monitor relapse of multiple myeloma patients after chimeric antigen receptor T-cell immunotherapy.

PURPOSE: Chimeric antigen receptor T-cell (CAR-T) therapy has been proven very effective in treating hematologic malignancies. Ciltacabtagene autoleucel (cilta-cel), a second-generation CAR-T cell with double B cell maturation antigen (BCMA) targeting binding domains, showed an 88% overall response rate (ORR) in patients with relapsed/refractory multiple myeloma (MM), which were carried out in our institute. This study aimed to assess the prognostic potential of soluble BCMA (sBCMA) in serum as a biomarker in MM after CAR-T therapy. PATIENTS AND METHODS: Serum samples (n = 44) from MM patients were collected before and after CAR-T therapy. The level of sBCMA was analyzed by enzyme-linked immunosorbent assay (ELISA). Additionally, three patients' long-term longitudinal analysis were performed. RESULTS: Serum sBCMA level was correlated with the percentage of malignant plasma cells in bone marrow (r = 0.613). After CAR-T infusion, the sBCMA level in serum of MM patients decreased markedly (median: 508,513 pg/mL before CAR-T infusion, 89,198 pg/mL in the first month, 8448 pg/mL in the second months, and 6010 pg/mL in the third month after CAR-T infusion). In patients who obtained objective response (≥ PR), re-elevated sBCMA indicated the possibility of disease recurrence. At a cutoff 69,326.27 pg/mL, sBCMA shows high sensitivity (87.5%) and specificity (88.5%) for identifying relapse of MM after CAR-T therapy. CONCLUSION: Our results suggested that serum sBCMA level changes in response to the clinical status of MM patients after anti-BCMA CAR-T therapy. Furthermore, sBCMA may be a auxiliary biomarker for disease monitoring in MM patients after CAR-T therapy.

Phase II, Open-Label Study of Ciltacabtagene Autoleucel, an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor-T-Cell Therapy, in Chinese Patients With Relapsed/Refractory Multiple Myeloma (CARTIFAN-1).

PURPOSE: CARTIFAN-1 aimed to evaluate the efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeting chimeric antigen receptor T-cell therapy, in Chinese patients with relapsed/refractory multiple myeloma (RRMM). METHODS: This pivotal phase II, open-label study (ClinicalTrials.gov identifier: NCT03758417), conducted across eight sites in China, enrolled adult patients with RRMM who had received ≥ 3 lines of prior therapy, including a proteasome inhibitor and immunomodulatory drug. Patients received a single infusion of cilta-cel (target dose 0.75 × 106 chimeric antigen receptor-positive viable T cells/kg). The primary end point was overall response rate. Secondary end points included progression-free survival (PFS), overall survival (OS), and incidence and severity of adverse events (AEs). RESULTS: As of the clinical cutoff of July 19, 2021, 48 patients received a cilta-cel infusion. At an 18-month median follow-up, the overall response rate was 89.6% (95% CI, 77.3 to 96.5), with a median time to first response of approximately 1 month; 77.1% of patients (95% CI, 62.7 to 88.0) achieved complete response or better. Medians for duration of response, PFS, and OS were not reached. The 18-month PFS and OS rates were 66.8% (95% CI, 49.4 to 79.4) and 78.7% (95% CI, 64.0 to 88.0), respectively. Hematologic AEs were common, including anemia (100%), neutropenia (97.9%), lymphopenia (95.8%), and thrombocytopenia (87.5%). Cytokine release syndrome occurred in 97.9% of patients (35.4% grade 3/4); the median time to onset was 7 days, and the median duration was 5 days. Infections occurred in 85.4% of patients (37.5% grade 3/4). Ten deaths occurred after cilta-cel infusion, eight of which were due to treatment-related AEs. CONCLUSION: These data demonstrate a favorable risk-benefit profile for a single infusion of cilta-cel, resulting in early, deep, and durable responses in heavily pretreated patients with RRMM in China.

Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity.

Ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity, safeguarding receptor activation, and facilitating amplification of signal transduction across the cellular membrane. However, cell-surface antigen-induced multimerization (dubbed AIM herein) has not yet been consciously leveraged in chimeric antigen receptor (CAR) engineering for enriching T cell-based therapies. We co-developed ciltacabtagene autoleucel (cilta-cel), whose CAR incorporates two B-cell maturation antigen (BCMA)-targeted nanobodies in tandem, for treating multiple myeloma. Here we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated cytotoxicity. Crystallographic analysis of BCMA-nanobody complexes revealed atomic details of antigen-antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in solution. BCMA-induced nanobody CAR multimerization enhanced cytotoxicity, alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release, towards myeloma-derived cells. Our results provide a framework for contemplating the AIM approach in designing next-generation CARs.

Mechanisms of cytosolic targeting of matrix metalloproteinase-2.

Matrix metalloproteinase-2 (MMP-2) is best understood for its biological actions outside the cell. However, MMP-2 also localizes to intracellular compartments and the cytosol where it has several substrates, including troponin I (TnI). Despite a growing list of cytosolic substrates, we currently do not know the mechanism(s) that give rise to the equilibrium between intracellular and secreted MMP-2 moieties. Therefore, we explored how cells achieve the unique distribution of this protease. Our data show that endogenous MMP-2 targets inefficiently to the endoplasmic reticulum (ER) and shows significant amounts in the cytosol. Transfection of canonical MMP-2 essentially reproduces this targeting pattern, suggesting it is the quality of the MMP-2 signal sequence that predominantly determines MMP-2 targeting. However, we also found that human cardiomyocytes express an MMP-2 splice variant which entirely lacks the signal sequence. Like the fraction of ER-excluded, full-length MMP-2, this variant MMP-2 is restricted to the cytosol and specifically enhances TnI cleavage upon hypoxia-reoxygenation injury in cardiomyocytes. Together, our findings describe for the first time a set of mechanisms that cells utilize to equilibrate MMP-2 both in the extracellular milieu and intracellular, cytosolic locations. Our results also suggest approaches to specifically investigate the overlooked intracellular biology of MMP-2.

Calpain inhibitors exhibit matrix metalloproteinase-2 inhibitory activity.

Matrix metalloproteinase (MMP)-2 is a zinc-dependent endopeptidase which, alongside its known extracellular actions, plays fundamental roles in oxidative stress-induced injury to the heart. Intracellular cleavage targets of MMP-2 selectively mediating this injury include the sarcomeric proteins troponin I, myosin light chain-1 and titin; some of these are also targeted by calpains. In myocardial ischemia and reperfusion injury, inhibitors of MMP-2 and some calpain inhibitors were shown to improve the recovery of contractile function. We hypothesized that the protective effects of calpain inhibitors may be due in part to their ability to inhibit MMP-2. Four calpain inhibitors (calpain inhibitor III, ALLM, ALLN, and PD-150606) were tested for their ability to inhibit MMP-2 in comparison to the selective MMP inhibitor ONO-4817. At 100 µM, all calpain inhibitors, except ALLM, showed significant inhibition of MMP-2 gelatinolytic activity. When assessed by the troponin I proteolysis assay, both ALLN and PD-150606, but neither ALLM nor calpain inhibitor III (at 20 µM), significantly inhibited MMP-2 activity. Using a fluorogenic MMP substrate peptide OmniMMP in a kinetic assay the rank order of IC(50) values against MMP-2 were: PD-150606

Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2).

BACKGROUND: LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. METHODS: LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. RESULTS: As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. CONCLUSIONS: The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.

Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation.

Although over 50 years have passed since its first laboratory description, intentional induction of immune tolerance to foreign antigens has remained an elusive clinical goal. We previously reported that the requirement for ABO compatibility in heart transplantation is not applicable to infants. Here, we show that ABO-incompatible heart transplantation during infancy results in development of B-cell tolerance to donor blood group A and B antigens. This mimics animal models of neonatal tolerance and indicates that the human infant is susceptible to intentional tolerance induction. Tolerance in this setting occurs by elimination of donor-reactive B lymphocytes and may be dependent upon persistence of some degree of antigen expression. These findings suggest that intentional exposure to nonself A and B antigens may prolong the window of opportunity for ABO-incompatible transplantation, and have profound implications for clinical research on tolerance induction to T-independent antigens relevant to xenotransplantation.

Combination therapy with diltiazem plus CsA/MMF/Pred or CsA/Aza/Pred triple immunosuppressive regimens for use in clinical kidney transplantation in Northwestern China.

OBJECTIVE: The effects of diltiazem on 1692 kidney transplant recipients under the immunosuppressive regimen of cyclosporine A (CsA) in combination with either mycophenolate mofetil or azothioprine were assessed. The two treatment groups were compared for blood concentrations of CsA, the extent of acceptable dosage reduction for the maintenance of immunotherapy, potential effects of kidney protection, and promotion of graft function. METHOD: We monitored changes of blood concentrations of CsA in the two different patient treatment groups for post-transplant graft function, episodes of acute rejection, and hepatic and renal toxicity in 1640 renal transplant recipients after treatment with diltiazem. RESULTS: In patients treated with the triple immunosuppressive regimen consisting of CsA, azothioprine, and prednisolone (Pred), the sub-group of patients receiving the diltiazem treatment saw a significantly reduced CsA dosage in comparison to the non-diltiazem group (control group 1) (P < 0.05), but the blood concentrations of CsA of the diltiazem group were higher than those of control group 1 (P < 0.01). Of the patients treated with CsA, mycophenolate mofetil, and Pred, the sub-group of patients also treated with diltiazem showed similar effects: CsA dosage was reduced (P < 0.01) and the blood concentrations of CsA significantly increased (P < 0.01) in comparison with those of control group 2. In addition, recovery time of graft function decreased to 4.7 ± 1.8 days and 3.9 ± 1.4 days in the two diltiazem treatment groups, respectively (P < 0.05), and the rate of acute rejection decreased to 21 (p < 0.05) and 7.9% (P < 0.01), respectively. CONCLUSION: In our cohort of renal transplantation patients, co-administration of CsA and diltiazem increased CsA blood concentration, thereby resulting in a reduction in its required dosage treatment, which lightened the patients' economic burden while improving primary and long-term kidney function by promoting the recovery of graft function and decreasing hepatic and renal toxicity. The co-administration of diltiazem may also reduce the rate of acute rejection, especially in patients who also receive the triple immunosuppressive regimen consisting of CsA, mycophenolate mofetil, and Pred.

Mechanism of selective gold adsorption on ion-imprinted chitosan resin modified by thiourea.

Thiourea-modified chitosan-imprinted resin (IM-TUCS) and a corresponding nonimprinted resin (NIM-TUCS) were synthesized and characterized using adsorption experiments. The adsorption results showed that adsorption reached equilibrium within 4 h. The adsorption data were better fitted using the Langmuir model (R2>0.99), and the gold adsorption capacities of IM-TUCS and NIM-TUCS were 933.2 and 373.7 mg·g-1, respectively. The IM-TUCS adsorbent was more suitable for gold than other coexisting anions and cations. The possible mechanism underlying Au(Ⅲ) adsorption on IM-TUCS was further investigated using X-ray photoelectron spectroscopy (XPS), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction analyses. The protonation of the amino group on the resin under low pH conditions promoted Au(Ⅲ) adsorption; O, N and S in the C‒OH, CË­S and C-NH2 groups contained in the IM-TUCS coordinated with Au(III) ions. The cross-linking of the imprinted resin provided holes that could hold Au(III), thus the imprinted resin supported more Au(III). The adsorption capacity of the IM-TUCS for Au(III) was significantly higher than that of the NIM-TUCS, which is attributed to the cross-linking of the imprinted resin. Moreover, the IM-TUCS showed specific recognition capabilities for Au(III). After elution with the eluent, IM-TUCS was reused for four cycles with a gold recovery rate of approximately 93%, revealing its high potential economic value.

Production Optimization of an Active ß-Galactosidase of Bifidobacterium animalis in Heterologous Expression Systems.

ß-Galactosidase (E.C.3.2.1.23) catalyzes the hydrolysis of lactose into glucose and galactose and the synthesis of galacto-oligosaccharides as well. The ß-galactosidases from bacteria, especially lactobacilli, and yeast have neutral pH and are much more likely to be developed as food additives. However, the challenges of cumbersome purification, product toxicity, and low yield in protein production have limited the commercialization of many excellent candidates. In this study, we identified a ß-galactosidase gene (bg42-106) in Bifidobacterium animalis ACCC05790 and expressed the gene product in Escherichia coli BL21(DE3) and Pichia pastoris GS115, respectively. The recombinant bG42-106 purified from E. coli cells was found to be optimally active at pH 6.0 and 60°C and had excellent stability over a wide pH range (5.0-8.0) and at high temperature (60°C). The specific activity of bG42-106 reached up to 2351 U/mg under optimal conditions. The galacto-oligosaccharide yield was 24.45 g/L after incubation with bG42-106 at 60°C for 2 h. When recombinant bG42-106 was expressed in Pichia pastoris GS115, it was found in the culture medium but only at a concentration of 1.73 U/ml. To increase its production, three strategies were employed, including codon optimization, disulfide formation, and fusion with a Cherry tag, with Cherry-tag fusion being most effective. The culture medium of P. pastoris that expressed Cherry-tagged bG42-106 contained 24.4 U/mL of ß-galactosidase activity, which is 14-fold greater than that produced by culture of P. pastoris harboring wild-type bG42-106.

Management of cytokine release syndrome related to CAR-T cell therapy.

Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5-10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer.