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Abstract Background The aim of this study was to investigate the effects and significance of rituximab (RTX) on the levels of T lymphocyte subsets in patients diagnosed with primary membranous nephropathy (PMN). Methods A total of 58 PMN patients and 25 healthy donors were chosen as the subjects. Among the PMN patients, 40 individuals received RTX treatment and completed at least 6 months of follow-up. All subjects underwent flow cytometry analysis to determine the peripheral blood lymphocyte subsets. The changes in anti-PLA2R antibody titers and 24-hour urinary protein levels were evaluated by ELISA and Biuret method before and after treatment. Results (1) The PMN group exhibited a significantly greater percentage of peripheral blood CD3−CD19+ B cells than the healthy group, which is consistent with the findings of previous reports. Additionally, compared with those in the peripheral blood of healthy individuals, the numbers of CD4+ central memory T cells, CD4+ effector memory T cells, CD4+/CD8+, and CD4+CD25+ T cells in the PMN peripheral blood were markedly greater. However, the number of peripheral blood Treg cells was reduced in the PMN group. (2) After 6 months of RTX treatment, PMN patients exhibited significant decreases in anti-PLA2R antibody titers, 24-hour urinary protein levels, and peripheral blood CD3−CD19+ B cells. Importantly, RTX administration decreased CD4+CD25+ T cells and CD4+/CD8+ in the peripheral blood of PMN patients and improved Treg cell levels. (3) RTX treatment induced alterations in the CD4+ T lymphocyte subsets in PMN patients, which did not correlate with B lymphocyte counts or anti-PLA2R antibody titers. Conclusions RTX treatment might have a beneficial impact on cellular immunity by effectively restoring the balance of CD4+ T lymphocyte subsets in PMN patients, which is beyond its effects on B cells and antibody production. Trial registration The research was registered at the First Affiliated Hospital of Soochow University. Registration Number: MR-32-23-016211. Registration Date: May 31, 2023.

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Fragrant rice has a high market value, and it is a popular rice type among consumers owing to its pleasant flavor. Plantation methods, nitrogen (N) fertilizers, and silicon (Si) fertilizers can affect the grain yield and fragrance of fragrant rice. However, the core commercial rice production attributes, namely the head rice yield (HRY) and 2-acetyl-1-pyrroline (2-AP) content of fragrant rice, under various nitrogen and silicon (N-Si) fertilization levels and different plantation methods remain unknown. The field experiment in this study was performed in the early seasons of 2018 and 2019 with two popular indica fragrant rice cultivars (Yuxiangyouzhan and Xiangyaxiangzhan). They were grown under six N-Si fertilization treatments (combinations of two levels of Si fertilizer, 0 kg Si ha−1 (Si0) and 150 kg Si ha−1 (Si1), and three levels of N fertilizer, 0 kg N ha−1 (N0), 150 kg N ha−1 (N1), and 220 kg N ha−1 (N2)) and three plantation methods (artificial transplanting (AT), mechanical transplanting (MT), and mechanical direct-seeding (MD)). The results showed that the N-Si fertilization treatments and all the plantation methods significantly affected the HRY and 2-AP content and related parameters of the two different fragrant rice cultivars. Compared with the Si0N0 treatment, the N-Si fertilization treatments resulted in higher HRY and 2-AP contents. The rates of brown rice, milled rice, head rice, and chalky rice of the fragrant rice also improved with the N-Si fertilization treatments. The N-Si fertilization treatments increased the activities of N metabolism enzymes and the accumulation of N and Si in various parts of the fragrant rice, and affected their antioxidant response parameters. The key parameters for the HRY and 2-AP content were assessed by redundancy analysis. Furthermore, the structural equation model revealed that the Si and N accumulation levels indirectly affected the HRY by affecting the N metabolism enzyme activity, N use efficiency, and grain quality of fragrant rice. Moreover, high N and Si accumulation directly promoted the 2-AP content or affected the antioxidant response parameters and indirectly regulated 2-AP synthesis. The interactions of the MT method with the N-Si fertilization treatments varied in the fragrant rice cultivars in terms of the HRY and 2-AP content, whereas the MD method was beneficial to the 2-AP content in both fragrant rice cultivars under the N-Si fertilization treatments.

Key Clinical Message There are no reports of application of inotuzumab ozogamicin (InO) for the treatment of MRD in r/r B‐ALL. We firstly report the efficacy of InO for a patient experienced morphological relapse after HSCT and molecular relapse after CART therapy.

Abstract Unlike many solid tumors, epithelial ovarian cancer (EOC) has a clear metastatic predilection to the adipocyte-rich niche, especially the omentum. However, the underlying mechanism driving this process remains incomplete. Here we show that SphK1 is over-expressed in omental metastases compared with ovarian primary tumors in EOC patients. In vitro, inhibition of SphK1 suppressed the metastatic ability of EOC induced by adipocytes. In vivo, blockage of SphK1 could attenuate the omental metastasis of EOC. Importantly, SphK1 modulates adipocyte-induced E/N-cadherin switch through Twist1, a key process in EOC metastasis. Our study reveals a previously unrecognized role of SphK1 in modulating the metastatic tropism of EOC to the adipocyte-rich niche, suggesting a new target for EOC therapy.

Abstract Heatwaves detrimentally affect human health and ecosystems. While previous studies focused on either temporal changes or spatial extents of heatwaves, their spatiotemporal contiguity and propagation patterns are unclear. Here, we investigate the climatology, long-term trends, and interannual variations of spatiotemporally contiguous heatwaves across China during 1961 to 2018. Two distinct propagation patterns are identified by introducing a spatiotemporally contiguous events tracking (SCET) method and the k-means clustering. Type 1 contiguous heatwaves mostly generate over eastern China and move southwestward at shorter distances, while Type 2 heatwaves generally initiate over western China and move southeastward at longer distances, with stronger intensity, longer lifetime, and larger coverage. Since the 1960s, both types exhibit significant increases in frequency, intensity, coverage, lifetime, and traveling distances, with relatively larger magnitudes for Type 2, but significant decreases in moving speed only appear for Type 1. On interannual timescale, preceding winter El Niño prolongs the duration and slows down the moving speed of Type 1 through the western North Pacific subtropical high. Type 2 contiguous heatwaves are intensified by the negative spring North Atlantic Oscillation via the upper-atmospheric Rossby wave train.

BackgroundStudies have shown that deaf individuals distribute more attention to the peripheral visual field and exhibit enhanced visual processing for peripheral stimuli relative to hearing individuals. This leads to better detection of peripheral target motion and simple static stimuli in hearing individuals. However, when threatening faces that represent dangerous signals appear as non-targets in the periphery, it remains unclear whether deaf individuals would retain an advantage over hearing individuals in detecting them.MethodsIn this study, 23 deaf and 28 hearing college students were included. A modified perceptual load paradigm and event-related potentials (ERPs) were adopted. In the task, participants were instructed to search for a target letter in a central letter array, while task-irrelevant face distractors (happy, neutral, and angry faces) were simultaneously presented in the periphery while the central perceptual load was manipulated.ResultsBehavioral data showed that angry faces slowed deaf participants' responses to the target while facilitating the responses of hearing participants. At the electrophysiological level, we found modulation of P1 amplitude by central load only in hearing individuals. Interestingly, larger interference from angry face distractors was associated with higher P1 differential amplitude only in deaf individuals. Additionally, the amplitude of N170 for happy face distractors was smaller than that for angry and neutral face distractors in deaf participants.ConclusionThe present data demonstrates that, despite being under central perceptual load, deaf individuals exhibit less attentional inhibition to peripheral, goal-irrelevant angry faces than hearing individuals. The result may reflect a compensatory mechanism in which, in the absence of auditory alertness to danger, the detection of visually threatening information outside of the current attentional focus has a high priority.

Abstract Background Adipocytes, active facilitators of epithelial ovarian cancer (EOC) growth, have been implicated in the link between obesity and EOC. However, the current understanding of the mechanisms underlying adipocyte-induced EOC cell proliferation remains incomplete. Results We provide the first evidence showing that sphingosine kinase (SphK) 1 is critical for adipocyte-induced EOC cell proliferation. Adipocytes are capable of activating SphK1, which then leads to extracellular signal-regulated kinase (ERK) phosphorylation. Moreover, adipocyte-induced SphK1 activation is ERK dependent. Furthermore, sphingosine 1-phosphate receptor (S1PR) 1 and S1PR3, key components of the SphK1 signalling pathway, participate in adipocyte-mediated growth-promoting action in EOC cells. Conclusions Our study reveals a previously unrecognized role of SphK1 in adipocyte-induced growth-promoting action in EOC, suggesting a new target for EOC therapy.

Abstract There is growing evidence that adipocytes play important roles in the progression of multiple cancers. Moreover, in obesity, adipocytes alter their original functions and contribute to the metabolic and inflammatory changes of adipose tissue microenvironment, which can further enhance tumor development. At present, the roles of adipocytes in the pathogenesis of epithelial ovarian cancer (EOC) are far from being fully elucidated. Herein, we summarized the recent advances in understanding the roles of adipocytes in EOC progression. Adipocytes, close neighbors of EOC tissue, promote EOC growth, invasion, metastasis and angiogenesis through adipokine secretion, metabolic remodeling and immune microenvironment modulation. Moreover, adipocytes are important therapeutic targets and may work as useful anticancer drug delivery depot for EOC treatment. Furthermore, adipocytes also act as a therapeutic obstacle for their involvement in EOC treatment resistance. Hence, better characterization of the adipocytes in EOC microenvironment and the crosstalk between adipocytes and EOC cells may provide insights into EOC progression and suggest novel therapeutic opportunities.

Abstract Follicle-stimulating hormone (FSH) is closely related to the pathogenesis and progression of epithelial ovarian cancer (EOC). However, until now, knowledge relating to FSH-driven signalling pathways that lead to the growth of EOC remained incomplete. We sought to explore whether sphingosine kinase (SphK) could mediate FSH-induced ovarian cancer cell proliferation and which pathway might be involved in this process. The expression of phospho-SphK1 and phospho-SphK2 was detected in sections of EOC tissues by Immunohistochemical staining, and clinical significances were analyzed by statistical analysis. EOC cells were treated with FSH or/and SKI-II. CCK8 assays and colony formation assays were used to investigate cell proliferation. Western blot was carried out to detect protein expression in EOC cell line after treated with FSH. Here, for the first time, we provide evidence that high expression levels of phospho-SphK1 and phospho-SphK2 were both prognostic indicators of overall survival (OS) in EOC. Additionally, the expression levels of both phospho-SphK1 and phospho-SphK2 were closely correlated with the expression level of follicle-stimulating hormone receptor (FSHR) in ovarian cancer tissues. FSH stimulated the phosphorylation of both SphK1 and SphK2 and was able to regulate the survival and growth of ovarian cancer cells by activating SphK1 and SphK2 through ERK1/2. Both isoenzymes of SphK were equally responsible for FSH-induced cell proliferation of EOC. Both Erk1/2 and Akt activation play important roles in mediating FSH-induced cell proliferation after phosphorylation of SphK. Moreover, our data demonstrated that S1P receptor 1 (S1PR1) and S1PR3, key components of the SphK signalling system, were involved in FSH-mediated proliferation of EOC. Taken together, the results of the current study revealed that SphK is an essential mediator in FSH-induced proliferation of ovarian cancer cells in EOC, which indicates a new signalling pathway that controls FSH-mediated growth in EOC and suggests a new strategy that pharmaceutically targets both isoenzymes of SphK for the management of ovarian cancer.

Carbamazepine is extensively used worldwide to treat a wide range of disorders such as epilepsy, peripheral neuralgia and bipolar disorder. Thrombocytopenia and hemorrhage have been identified in multiple carbamazepine-treated patients. However, the underlying mechanism remains poorly understood. Here, we show that platelets undergo apoptosis after carbamazepine treatment. The apoptotic platelets induced by carbamazepine are rapidly removed in vivo, which accounts for thrombocytopenia. We found that carbamazepine treatment attenuates the phosphorylation level of bcl-xl/bcl-2-associated death promoter (BAD), vasodilator-associated stimulated phosphoprotein (VASP) and GPIbβ in platelets, indicating an inhibition effect on protein kinase A (PKA). We further demonstrated that carbamazepine reduced PKA activity through PI3K/Akt/PDE3A signaling pathway. Pharmacological activation of PKA or inhibition of PI3K/Akt/PDE3A protects platelets from apoptosis induced by carbamazepine. Importantly, PDE3A inhibitors or PKA activator ameliorates carbamazepine-mediated thrombocytopenia in vivo. These findings shed light on a possible mechanism of carbamazepine-induced thrombocytopenia, designating PDE3A/PKA as a potential therapeutic target in the treatment of carbamazepine-induced thrombocytopenia.

Participation of nondispatchable renewable energy resources (RER) such as wind turbines (WT) and photovoltaic (PV) systems is one of the main challenges of these clean energy resources. Due to the uncertain nature of these resources, predictions of their amount of power in the day-ahead market is very difficult and associated with error. This paper introduces a novel model for the participation of the mentioned resource in the day-ahead power market based on error and economic loss minimization. An intra-market (IM) model was considered to update the predicted power of these resources before the planned time horizon. Furthermore, a new probabilistic forecasting model was proposed for uncertain parameters in both the day-ahead and intramarket. The mentioned model included an integrated system of renewable energy with another distributed generation, storage device, and demand response to compensate for all resource and load economic losses. By this approach, it can be claimed that, all microgrid participants i.e., load, producer and storage, have more profits in comparison with the power supply individually. To demonstrate the efficiency of the proposed model, we considered a test case that consisted of a wind turbine, PV, fuel cell, storage unit, and demand response, by taking into account the day-ahead, intra and unbalanced market. In this case study, daily, weekly, and monthly analyses were performed. The simulation results revealed the effectiveness and performance of the proposed modelling in comparison with other participation model.

Gestational diabetes mellitus (GDM) refers to pregnant women with impaired glucose tolerance, which could bring high risk to the mother and fetus. However, the early diagnosis and treatment of GDM remained unclear. In this study, 60 patients with GDM were selected as the research group and 50 healthy pregnant women as the control group. Tumor necrosis factor receptor 1 (TNFR1), tumor necrosis factor-α (TNF-α), and adiponectin (ADP) in the serum were measured by enzyme-linked immunosorbent assays (ELISAs). The levels of fasting blood glucose (FBG), fasting insulin (FINS), and glycosylated hemoglobin (HbA1c) were also detected to calculate homeostasis model assessment insulin resistance index (HOMA-IR) and pancreatic β-cell function index (HOMA-HBCl). Compared with the control group, the serum levels of TNFR1, TNF-α, and HbA1c in research group were significantly increased ( P

Although much progress has been made in identifying the large-scale drivers of recent summer precipitation variability in North China, the evolution of these drivers over longer time scales remains unclear. We investigate multidecadal and interannual variability in North China summer precipitation in the 110-year Coupled ECMWF Reanalysis of the Twentieth Century (CERA-20C), considering changes in regional moisture and surface energy budgets along with nine circulation indices linked to anomalous precipitation in this region. The CERA-20C record is separated into three distinct periods according to the running climatology of summer precipitation: 1901–1944 (neutral), 1945–1979 (wet), and 1980–2010 (dry). CERA-20C reproduces expected relationships between large-scale drivers and regional summer precipitation anomalies well during 1980–2010, but these relationships generally do not extend to earlier periods. For example, a strong relationship with the Eurasian teleconnection pattern only emerges in the late 1970s, while correlations with the El Niño-Southern Oscillation and the Pacific–Japan pattern change sign in the mid-twentieth century. We evaluate two possible reasons for this nonstationarity: (1) the underlying atmospheric model may require strong data assimilation constraints to capture large-scale circulation influences on North China, or (2) large-scale drivers inferred from recent records may be less general than expected. Our analysis indicates that both factors contribute to the identified nonstationarity in CERA-20C, with implications for the reliability of seasonal forecasts and climate projections based on current models.

Epidermal growth factor receptor (EGFR) overexpression and activation result in increased proliferation and migration of solid tumors including ovarian cancer. In recent years, mounting evidence indicates that EGFR is a direct and functional target of miR-7. In this study, we found that miR-7 expression was significantly downregulated in highly metastatic epithelial ovarian cancer (EOC) cell lines and metastatic tissues, whereas the expression of, EGFR correlated positively with metastasis in both EOC patients and cell lines. Overexpression of miR-7 markedly suppressed the capacities of cell invasion and migration and resulted in morphological changes from a mesenchymal phenotype to an epithelial-like phenotype in EOC. In addition, overexpression of miR-7 upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, accompanied with EGFR inhibition and AKT/ERK1/2 inactivation. Similar to miR-7 transfection, silencing of EGFR with this siRNA in EOC cells also upregulated CK-18 and β-catenin expression and downregulated Vimentin expression, and decreased phosphorylation of both Akt and ERK1/2, confirming that EGFR is a target of miR-7 in reversing EMT. The pharmacological inhibition of PI3K-AKT and ERK1/2 both significantly enhanced CK-18 and β-catenin expression and suppressed vimentin expression, indicating that AKT and ERK1/2 pathways are required for miR-7 mediating EMT. Finally, the expression of miR-7 and EGFR in primary EOC with matched metastasis tissues was explored. It was showed that miR-7 is inversely correlated with EGFR. Taken together, our results suggested that miR-7 inhibited tumor metastasis and reversed EMT through AKT and ERK1/2 pathway inactivation by reducing EGFR expression in EOC cell lines. Thus, miR-7 might be a potential prognostic marker and therapeutic target for ovarian cancer metastasis intervention.

We conducted this randomized trial to investigate the efficacy and safety of rapamycin treatment in adults with chronic immune thrombocytopenia (ITP). Eighty-eight patients were separated into the control (cyclosporine A plus prednisone) and experimental (rapamycin plus prednisone) groups. The CD4+CD25+CD127low regulatory T (Treg) cells level, Foxp3 mRNA expression, and the relevant cytokines levels were measured before and after treatment. The overall response (OR) was similar in both groups (experimental group versus control group: 58% versus 62%, P=0.70). However, sustained response (SR) was more pronounced in the experimental group than in the control group (68% versus 39%, P

The aim of this current study was to investigate the expression of the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) in human malignant ovarian tumors, and test TWEAK's potential role on tumor progression in cell models in-vitro. Using immunohistochemistry (IHC), we found that TWEAK and its receptor Fn14 were expressed in human malignant ovarian tumors, but not in normal ovarian tissues or in borderline/benign epithelial ovarian tumors. High levels of TWEAK expression was detected in the majority of malignant tumors (36 out of 41, 87.80%). Similarly, 35 out of 41 (85.37%) malignant ovarian tumors were Fn14 positive. In these malignant ovarian tumors, however, TWEAK/Fn14 expression was not corrected with patients' clinical subtype/stages or pathological features. In vitro, we demonstrated that TWEAK only inhibited ovarian cancer HO-8910PM cell proliferation in combination with tumor necrosis factor-α (TNF-α), whereas either TWEAK or TNF-α alone didn't affect HO-8910PM cell growth. TWEAK promoted TNF-α production in cultured THP-1 macrophages. Meanwhile, conditioned media from TWEAK-activated macrophages inhibited cultured HO-8910PM cell proliferation and invasion. Further, TWEAK increased monocyte chemoattractant protein-1 (MCP-1) production in cultured HO-8910PM cells to possibly recruit macrophages. Our results suggest that TWEAK/Fn14, by activating macrophages, could be ovarian tumor suppressors. The unique expression of TWEAK/Fn14 in malignant tumors indicates that it might be detected as a malignant ovarian tumor marker.

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Xanthomonas oryzae pv. oryzae (Xoo) causes severe bacterial leaf blight (BLB) disease to many Vietnamese major rice cultivars, including the TBR225. OsSWEET13 belongs to group III of the OsSWEET gene family encoding sugar transport proteins, which is considered one of the "susceptibility" genes (S genes) necessary for BLB disease. In this study, the rice cultivar TBR225 was determined to be susceptible to 19/20 Vietnamese Xoo isolates collected from the Northern provinces. Two of the three tested isolates (VXO_60 and VXO_96 isolates) were shown to up-regulate OsSWEET13 upon the Xoo infection of the TBR225 cultivar. The TBR225 OsSWEET13 promoter was isolated for sequencing analysis. The isolated DNA fragment was 615 bp in size, contained an effector binding element (EBE) PthXo2 that was recognized by the type III-secretory transcription activator-like (TAL) proteins of the Xoo. This promoter showed a similarity of more than 99% to the published OsSWEET13 promoter sequences (AP014967.1 and CP018167.1). Our findings are basic for the generation of highyielding rice varieties with resistance to BLB disease by genetic engineering in Vietnam. [ABSTRACT FROM AUTHOR]