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During the 13 (1996-1997) and the 19 (2002-2003) Chinese National Antarctica Research Expeditions, we collected 60 discrete surface seawater samples along the cruise from the Chanjiang River (Yangtze) estuary (30°59′S, 122°26′E) through Taiwan Strait, the South China Sea, and the Eastern Indian Ocean to Prydz Bay, Antarctica (69°10′S, 74°30′E), and analyzed them for the Ra specific activity. The Ra specific activity of the Chanjiang River estuary surface water (3.15 Bq/m) was found to be the highest among all the surface samples because of the desorption of Ra from riverine particles. Between Chanjiang River estuary and 40°S, Ra specific activity was found to be relatively uniform with a mean value of 1.07 Bq/m ( n = 19, SD = 0.14), similar to that of the open ocean. From 40°S to 65°S, Ra specific activity increased intensively, then decreased moderately further southwards. Near the Antarctic shore, it increased again, to 2.31 Bq/m. This distribution was controlled by a combination of deep water upwelling, Southern Ocean fronts, water mixing and the continental Ra import. In Prydz Bay and the adjacent sea area, the mean Ra activity value was 2.26 Bq/m ( n = 31, SD = 0.28), with a relatively higher value outside of the bay and low Ra activity value in the center of the bay. This was consistent with the topography and hydrological setting of the bay. In addition, we extended the study area northward to the Arctic, by combining the published Ra dataset for surface water from the Bering Sea to the Japan Sea. We also discuss the Ra distribution of high latitude oceanic surface water and its mechanisms. [ABSTRACT FROM AUTHOR]

Multiple isotope systematics incorporating paired carbon isotopes (δ13C and ∆14C), strontium isotopes (87Sr/86Sr) and water isotopes (δ2H and δ18O) are used to investigate the coherent relationships among flow paths, chemical weathering regimes, and Sr export fluxes from the Lower Mississippi River. Monthly water samples were collected at a site near Baton Rouge, Louisiana, during 2006–2008 for measurements of water isotopic composition, the concentration and isotopic composition of dissolved inorganic carbon (DIC), and the concentration and isotopic ratio of Sr along with other selected major elements. Both δ2H and δ18O followed a similar seasonal pattern with a steady increase from a minimum in March to a maximum in July, indicating a shift of water sources from the snowmelt-dominant uppermost Upper Mississippi River during spring freshet to rainfall-induced midcontinent surface runoff and groundwater during other seasons. Values of δ13C-DIC ranged from −8.67‰ to −5.96‰ while Δ14C-DIC varied from −56.8‰ to 27.9‰, corresponding to a 14C age from contemporary to 415 yr BP. Generally, Δ14C-DIC increased with increasing δ13C-DIC, suggesting variations in bicarbonate sources in response to the shifts of flow paths and chemical weathering regimes. Depleted Δ14C-DIC and δ13C-DIC values during the wet seasons are likely contributed by carbonate mineral dissolution involving soil-derived CO 2 , while the higher Δ14C and relatively enriched δ13C-DIC values during the dry seasons mirror the atmospheric CO 2 signatures, implying the supply by silicate weathering and a seasonal CO 2 exchange between riverwater and the atmosphere which is enhanced by high primary production. Sr concentrations and 87Sr/86Sr ratios averaged 1.80 ± 0.26 μmol L−1 and 0.709866 ± 0.000248, respectively. Both Sr concentrations and 87Sr/86Sr ratios show a significant correlation with δ18O values, supporting a hydrologic control of the Sr provenance in the Mississippi River basin. Indeed, the radiogenic 87Sr from the Archean and early Proterozoic terrain in the uppermost Upper Mississippi River, the Sr released from carbonate-mineral dissolution, and the radiogenic 87Sr from silicate weathering are manifested in the Lower Mississippi River with modifications from the snowmelt flow, rainfall-induced surface runoffs, and subsurface/groundwater, respectively. Overall, our results suggest that different hydrological flow regimes play unique roles in regulating the chemical weathering processes and therefore the seasonal variations in isotope systematics and in the concentrations and export fluxes of both DIC and Sr from the Mississippi River. • The weathering regimes in the MRB were examined with multiple isotope systematics • Both Sr concentrations and 87Sr/86Sr are correlated with water isotopes • Variations in water sources regulate the Sr and bicarbonate provenance • Flow regimes control chemical weathering and isotope systematics [ABSTRACT FROM AUTHOR]

In the North Pacific Subtropical Gyre, which is one of the largest oligotrophic regions, there is a lack of information regarding the sources and transport of trace metals through water mass mixing. Rare earth elements (REEs) are essential for tracing lithogenic sources and water mass transport. In this study, we present dissolved REE concentrations and the factors controlling their distributions in the northwest Pacific during a GEOTRACES cruise (GP09). In the surface water along 11°N, we observed input signals from the Philippine and the Hawaiian Islands, characterized by positive Eu anomalies and slightly elevated REE concentrations. By incorporating our data and published REE data from the northwest Pacific to the southeast Pacific (40°N–40°S), we demonstrated that the REE concentrations and Yb/Nd ratios can distinguish North Pacific Intermediate Water (NPIW), Antarctic Intermediate Water (AAIW), and modified AAIW. By estimating the ratio of water mass mixing, we suggest that heavy REEs are predominantly contributed by water mass mixing (e.g., 93 % ± 4% for Yb) and can be used as semi-conservative tracers to quantify the mixing of NPIW and modified AAIW at the potential density of 27.2 kg/m3. At ∼800 m depth at stations K12, K13, and K14, weak negative Ce anomalies (>0.1) were observed, indicating the lateral transport of water masses imprinted with sediment signals from the Philippine Islands. In the deep waters (>1500 m) at the Luzon Strait (station K1), we propose that the weak Ce negative anomalies (>0.08) and low Yb/Nd ratios (<5), combined with the low beam transmission, are the result of particle resuspension and release. In deep water (>2000 m), combining high-resolution REE measurements with water mass analysis, our research reveals that dissolved REEs (except Ce) are dominantly controlled by water mass mixing (e.g., 80 %∼100 % for Yb and 70 %∼100 % for Nd). For the non-conservative behavior, which is not explained by water mass mixing, the residual fraction of heavy REEs (<20 % for Yb) originates from release of sinking particles (organic matter and siliceous particles), while the remaining concentrations of light REEs (<30 % for Nd) may be influenced by a combination of particle release and scavenging processes. These findings highlight valuable information about lithogenic sources and the proportions of REE distributions that are controlled by physical and biogeochemical processes. Moreover, it emphasizes the applicability of heavy REEs as effective tracers for understanding basin-scale water mass mixing in the northwest Pacific. [ABSTRACT FROM AUTHOR]

Innate γδ T cells play critical roles in mucosal immunity such as regulating intestinal epithelial homeostasis. In addition, γδ T cells are significantly increased in the inflamed mucosa of patients with ulcerative colitis. However, γδ T cells are a heterogeneous population. IL-17-producing versus IFNγ-producing γδ T cells play differential roles in different disease settings. Therefore, dissecting the exact role of different subsets of γδ T cells in colitis is essential for understanding colitis immunopathogenesis. In the current study, we found that TCR δ-deficient mice had a more severe dextran sodium sulfate (DSS)-induced colitis that was reduced upon reconstitution of γδT17 cells but not IFNγ-producing γδ T cells. Immunophenotyping of the cellular infiltrate upon DSS-induced colitis showed a reduced infiltration of Gr-1+CD11b+myeloid cells into the sites of inflammation in mice lacking γδT17 cells. Further experiments demonstrated that IL-17, IL-18, and chemokine CXCL5 were critical in Gr-1+CD11b+myeloid cell recruitment.In vitroT cell suppressive assay indicated that this Gr-1+CD11b+population was immunosuppressive. Depletion of Gr-1+CD11b+myeloid cells resulted in an increase severity of DSS-induced colitis. Our study elucidates a new immune pathway involving γδT17-dependent recruitment of Gr-1+CD11b+myeloid cells to the site of colitis inflammation important in the protection of colitis initiation and progression. [ABSTRACT FROM PUBLISHER]

Background: Clinical CAR T-cell therapy using integrating vector systems represents a promising approach for the treatment of hematological malignancies. Lentiviral and γ-retroviral vectors are the most commonly used vectors in the manufacturing process. However, the integration pattern of these viral vectors and subsequent effect on CAR T-cell products is still unclear.Methods: We used a modified viral integration sites analysis (VISA) pipeline to evaluate viral integration events around the whole genome in pre-infusion CAR T-cell products. We compared the differences of integration pattern between lentiviral and γ-retroviral products. We also explored whether the integration sites correlated with clinical outcomes.Results: We found that γ-retroviral vectors were more likely to insert than lentiviral vectors into promoter, untranslated, and exon regions, while lentiviral vector integration sites were more likely to occur in intron and intergenic regions. Some integration events affected gene expression at the transcriptional and post-transcriptional level. Moreover, γ-retroviral vectors showed a stronger impact on the host transcriptome. Analysis of individuals with different clinical outcomes revealed genes with differential enrichment of integration events. These genes may affect biological functions by interrupting amino acid sequences and generating abnormal proteins, instead of by affecting mRNA expression. These results suggest that vector integration is associated with CAR T-cell efficacy and clinical responses.Conclusion: We found differences in integration patterns, insertion hotspots and effects on gene expression vary between lentiviral and γ-retroviral vectors used in CAR T-cell products and established a foundation upon which we can conduct further analyses. [ABSTRACT FROM AUTHOR]

Background: Cytokine release syndrome (CRS) is a strong immune system response that can occur as a result of the reaction of a cellular immunotherapy with malignant cells. While the frequency and management of CRS in CAR T-cell therapy has been well documented, there is emerging interest in pre-emptive treatment to reduce CRS severity and improve overall outcomes. Accordingly, identification of genomic determinants that contribute to cytokine release may lead to the development of targeted therapies to prevent or abrogate the severity of CRS.Methods: Forty three clinical CD22 CAR T-cell products were collected for RNA extraction. 100 ng of mRNA was used for Nanostring assay analysis which is based on the nCounter platform. Several public datasets were used for validation purposes.Results: We found the expression of the PFKFB4 gene and glycolytic pathway activity were upregulated in CD22 CAR T-cells given to patients who developed CRS compared to those who did not experience CRS. Moreover, these results were further validated in cohorts with COVID-19, influenza infections and autoimmune diseases, and in tumor tissues. The findings were similar, except that glycolytic pathway activity was not increased in patients with influenza infections and systemic lupus erythematosus (SLE).Conclusion: Our data strongly suggests that PFKFB4 acts as a driving factor in mediating cytokine release in vivo by regulating glycolytic activity. Our results suggest that it would beneficial to develop drugs targeting PFKFB4 and the glycolytic pathway for the treatment of CRS. [ABSTRACT FROM AUTHOR]

Background: Gene transfer is an important tool for cellular therapies. Lentiviral vectors are most effectively transferred into lymphocytes or hematopoietic progenitor cells using spinoculation. To enable cGMP (current Good Manufacturing Practice)-compliant cell therapy production, we developed and compared a closed-system spinoculation method that uses cell culture bags, and an automated closed system spinoculation method to decrease technician hands on time and reduce the likelihood for microbial contamination. Methods: Sepax spinoculation, bag spinoculation, and static bag transduction without spinoculation were compared for lentiviral gene transfer in lymphocytes collected by apheresis. The lymphocytes were transduced once and cultured for 9 days. The lentiviral vectors tested encoded a CD19/CD22 Bispecific Chimeric Antigen Receptor (CAR), a FGFR4-CAR, or a CD22-CAR. Sepax spinoculation times were evaluated by testing against bag spinoculation and static transduction to optimize the Sepax spin time. The Sepax spinoculation was then used to test the transduction of different CAR vectors. The performance of the process using healthy donor and a patient sample was evaluated. Functional assessment was performed of the CD19/22 and CD22 CAR T-cells using killing assays against the NALM6 tumor cell line and cytokine secretion analysis. Finally, gene expression of the transduced T-cells was examined to determine if there were any major changes that may have occurred as a result of the spinoculation process. Results: The process of spinoculation lead to significant enhancement in gene transfer. Sepax spinoculation using a 1-h spin time showed comparable transduction efficiency to the bag spinoculation, and much greater than the static bag transduction method (83.4%, 72.8%, 35.7% n = 3). The performance of three different methods were consistent for all lentiviral vectors tested and no significant difference was observed when using starting cells from healthy donor versus a patient sample. Sepax spinoculation does not affect the function of the CAR T-cells against tumor cells, as these cells appeared to kill target cells equally well. Spinoculation also does not appear to affect gene expression patterns that are necessary for imparting function on the cell. Conclusions: Closed system-bag spinoculation resulted in more efficient lymphocyte gene transfer than standard bag transductions without spinoculation. This method is effective for both retroviral and lentiviral vector gene transfer in lymphocytes and may be a feasible approach for gene transfer into other cell types including hematopoietic and myeloid progenitors. Sepax spinoculation further improved upon the process by offering an automated, closed system approach that significantly decreased hands-on time while also decreasing the risk of culture bag tears and microbial contamination. [ABSTRACT FROM AUTHOR]

Vertical distributions of dissolved and particulate 210Po and 210Pb in the water column were examined along three transects occupied on July 2016 in the northern South China Sea (SCS) to investigate particle dynamics and export. In the mixed layer, 210Po was deficient with respect to 210Pb with a 210Po/210Pb activity ratio of 0.08–0.57 and an average of 0.31 ± 0.12. The 210Po/210Pb ratio increased to 0.39–0.96 with an average of 0.71 ± 0.16 at the base of the euphotic layer (100 m). 210Po was largely depleted relative to 210Pb again in the mesopelagic layer (100–1000 m). The activity ratio of 210Po/210Pb ranged from 0.12 to 1.04 with an average of 0.42 ± 0.20, suggesting an intensified particle scavenging. Meanwhile, the residence time of particulate 210Po (PPo) in the mesopelagic layer varied from 0.01 to 0.47 yr with an average of 0.11 ± 0.02 yr, also indicating the fast removal of particles. Both the disequilibrium between 210Po and 210Pb and the short residence time of PPo in the mesopelagic water indicated a stronger scavenging and subsequent removal of 210Po relative to 210Pb throughout the water column. Based on the observed 210Po deficit, the export flux of 210Po in the mesopelagic layer was estimated in the range of 96–625 dpm m−2 d−1 with an average of 382 ± 16 dpm m−2 d−1, which was an order of magnitude higher than that in the euphotic layer. Furthermore, the export flux of total particulate matter (TPM) in mesopelagic layer was estimated between 2.15 and 30.18 g m−2 d−1. Comparing to the TPM export flux in the euphotic layer (0.44–2.67 g m−2 d−1), the significantly elevated TPM export flux in the mesopelagic waters may require extra supply of particles in addition to sinking particles from the upper water column, which is likely sourced from the surrounding shelves in the northern SCS. • Large 210Po deficit relative to 210Pb was observed in the mesopelagic waters in the Northern SCS. • Particle export in the mesopelagic waters in the Northern SCS was estimated based on 210Po/210Pb disequilibrium. • The particle export in the mesopelagic waters was 8 times that in the euphotic zone. [ABSTRACT FROM AUTHOR]

The Taiwan Strait is a coastal sea with dynamic hydrologic condition and dissolved organic matter (DOM) cycling. To better understand its phosphorus (P) transformation, phosphate and bulk dissolved organic phosphorus (DOP) concentrations were determined in the surface water of the Taiwan Strait during 2010 and 2011 summers. The bulk DOP was further fractionated into the low molecular weight (LMW) DOP and colloidal organic phosphorus (COP) with the application of the cross-flow ultrafiltration technique at a size cut-off of 10 kDa. The surface water in the Taiwan Strait generally showed higher bulk DOP concentration than phosphate excluding estuarine stations. This is similar to the surface waters in the subtropical gyres, implying a P-deficient condition in the Taiwan Strait. The LMW-DOP followed a constant permeation behavior in the ultrafiltration experiments, allowing the quantification of LMW-DOP and COP concentrations with the ultrafiltration permeation model. The average COP concentration was 0.044 ± 0.022 μmol/L and 0.042 ± 0.027 μmol/L during 2010 and 2011 summers, respectively. Accordingly, COP accounted for 35 ± 13% and 34 ± 16% of bulk DOP during 2010 and 2011 summers, respectively, suggesting a substantial occurrence of organic phosphorus in the colloidal fraction. The C/P ratio decreased from LMW-DOM to bulk DOM and to colloidal organic matter (COM), supporting the degradation pathway of bulk DOM from colloidal to LMW fractions and the lability of COP in the Taiwan Strait. The fractionation of C/P ratio between bulk DOM and COM in the Taiwan Strait, denoted by the fractionation factor (F C/D), was comparable to the open oceans, but significantly stronger than rivers and estuaries. It might indicate an autochthonous input and rapid turnover of bulk DOP pool in the Taiwan Strait in the context of low phosphate concentration. The F C/D also showed a spatial variability in the Taiwan Strait, high in the South China Sea Warm Current and upwelling occupied stations and low in inshore areas influenced by terrestrial input. This further supports the F C/D as an indicator of bulk DOM sources besides its application to decipher the diagenetic status of bulk DOM and biogeochemical cycles of bulk DOP in the coastal oceans. • COP accounts for one third of DOP in the Taiwan Strait Surface Seawater. • COM shows a dynamic turnover and diagenetically young status based on C/P ratio. • Terrestrial input and internal waves affect the COP quantity. [ABSTRACT FROM AUTHOR]

• Acidified oceanic iron was directly measured using FIA and catalytic spectrometry. • Sodium sulfite was added into the DPD solution to improve the stability. • NTA-type resin was used for on-line Fe(III) chelation to distinguish Fe(II) and Fe(III) • A full vertical profile of dissolved Fe at SEATS station in South China Sea was present. A simple and sensitive flow injection analysis method using catalytic spectrometry was developed to measure sub-nanomolar levels of Fe(II) and Fe(II + III) in seawater using N,N -dimethyl- p -phenylenediamine dihydrochloride (DPD). Even without a preconcentration step, the minimum detection limit was 43 pmol/L, which was comparable to the limit of methods using a preconcentration step. DPD solutions were prepared using sodium sulfite as an antioxidant to increase the stability and extend the shelf-life of the reagent. The linear determination range was 6.0 nmol/L, and the relative standard deviation for sample measurements in 0.61 nmol/L Fe(II + III) was 4.4% (n = 14). The salinity and seawater matrix had a negligible impact on the results. The analytical results of the certified reference seawater NASS-5 (3.81 ± 0.21 nmol/L) agreed with the certified value (3.71 ± 0.63 nmol/L). The accuracy was further verified by measuring GEOTRACES Atlantic Ocean reference seawater samples. By adopting a nitrilotriacetic acid (NTA) Superflow chelating resin, the method was used for the on-line separation of the Fe(III)/Fe(II + III) redox pair. The method was used to assay dissolved Fe (<0.45 μm) in samples collected from the South East Asia Time-Series station in the South China Sea. [ABSTRACT FROM AUTHOR]

mRNA neoantigen cancer vaccine inducing neoantigen-specific T cell responses holds great promise for cancer immunotherapy; however, its clinical translation remains challenging because of suboptimal neoantigen prediction accuracy and low delivery efficiency, which compromise the in vivo therapeutic efficacy. We present a lipopolyplex (LPP)-formulated mRNA cancer vaccine encoding tandem neoantigens as a cancer therapeutic regimen. The LPP-formulated mRNA vaccines elicited robust neoantigen-specific CD8 + T cell responses in three syngeneic murine tumor models (CT26, MC38, and B16F10) to suppress tumor growth. Prophylactic cancer vaccine treatment completely prevented tumor development, and long-lasting memory T cells protected mice from tumor cell rechallenge. Combining the vaccine with immune checkpoint inhibitor further boosted the antitumor activity. Of note, LPP-based personalized cancer vaccine was administered in two cancer patients and induced meaningful neoantigen-specific T cell and clinical responses. In conclusion, we demonstrated that the LPP-based mRNA vaccine can elicit strong antitumor immune responses, and the results support further clinical evaluation of the therapeutic mRNA cancer vaccine.