Type 2 diabetes (T2D) is characterized by the malfunction of pancreatic β cells. Susceptibility and pathogenesis of T2D can be affected by multiple factors, including sex differences. However, the ...mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq), we demonstrate the presence of sexually dimorphic transcriptomes in mouse β cells. Using a high-fat diet-induced T2D mouse model, we identified sex-dependent T2D altered genes, suggesting sex-based differences in the pathological mechanisms of T2D. Furthermore, based on islet transplantation experiments, we found that compared to mice with sex-matched islet transplants, sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway of β cells. Moreover, the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance. These data suggest sexual dimorphism in T2D pathogenicity, indicating that sex should be considered when treating T2D. We hope that our findings could provide new insights for the development of precision medicine in T2D.
The therapeutic applications of antibodies are manifold and the emergence of SARS-CoV-2 provides a cogent example of the value of rapidly identifying biologically active antibodies. We describe an ...approach called SLISY (Sequencing-Linked ImmunoSorbent assaY) that in a single experiment can assess the binding specificity of millions of clones, be applied to any screen that links DNA sequence to a potential binding moiety, and requires only a single round of biopanning. We demonstrate this approach using an scFv library applied to cellular and protein targets to identify specific or broadly reacting antibodies. For a cellular target, we use paired HLA knockout cell lines to identify a panel of antibodies specific to HLA-A3. For a protein target, SLISY identifies 1279 clones that bound to the Receptor Binding Domain of the SARS-CoV-2 spike protein, with >40% of tested clones also neutralizing its interaction with ACE2 in in vitro assays. Using a multi-comparison SLISY against the Beta, Gamma, and Delta variants, we recovered clones that exhibited broad-spectrum neutralizing potential in vitro. By evaluating millions of scFvs simultaneously against multiple targets, SLISY allows the rapid identification of candidate scFvs with defined binding profiles facilitating the identification of antibodies with the desired biological activity.
Granulysin (GNLY), an antimicrobial protein present in the granules of human cytotoxic T lymphocytes and natural killer (NK) cells, is produced as an intact 15-kDa form that is cleaved to yield a ...9-kDa form. Alarmins are endogenous mediators that can induce recruitment and activation of antigen-presenting cells (APCs) and consequently promote the generation of immune response. We hypothesized that GNLY might function as an alarmin. Here, we report that both 9- and 15-kDa forms of recombinant GNLY-induced in vitro chemotaxis and activation of both human and mouse dendritic cells (DCs), recruited inflammatory leucocytes, including APCs in mice, and promoted antigen-specific immune responses upon coadministration with an antigen. GNLY-induced APC recruitment and activation required the presence of Toll-like receptor 4. The observed activity of recombinant GNLY was not due to endotoxin contamination. The capability of the supernatant of GNLY-expressing HuT78 cells to activate DC was blocked by anti-GNLY antibodies. Finally we present evidence that supernatants of degranulated human NK92 or primary NK cells also activated DCs in a GNLY- and Toll-like receptor 4–dependent manner, indicating the physiologic relevance of our findings. Thus, GNLY is the first identified lymphocyte-derived alarmin capable of promoting APC recruitment, activation, and antigen-specific immune response.
Uneven current density distribution in a proton exchange membrane fuel cell (PEMFC) can decrease the reactant and catalyst utilization, reduce the energy conversion efficiency of the whole fuel cell, ...and even lead to a shortened cell life. Therefore, studying current density distribution has a critical role in the research and development of PEMFC. To investigate the distribution of the proton exchange membrane fuel cells' local current density under different operating conditions, a single cell using the segmented cell technique consisting of 36 zones was designed. The results show that the maximum current density first appears at the outlet and then moves to the inlet. In addition, when the cell output is stable, the most negligible current density appears in the cell's middle area. The current density distribution was improved when the cell temperature was 50 °C. Compared with other operation temperatures (without cooling, 40 °C, 60 °C), the current density is decreased by 14.0 %, 9.8 %, and 40.6 %, respectively. At the same time, the cell voltage is increased by 10 %, 6.45 % and 22.22 %, respectively. Higher gas pressure is more favourable to improving cell performance and the uniformity of current density distribution. However, when the cathode gas pressure exceeds that of the anode, the reverse inverse current is pronounced in the middle of the cell at the starting process. The reverse duration of the 50 °C cell is reduced by 30 s (25.4 %) compared to the cell without cooling.
Group 2 innate lymphoid cells (ILC2s) are the most dominant ILCs in heart tissue, and sex-related differences exist in mouse lung ILC2 phenotypes and functions; however, it is still unclear whether ...there are sex differences in heart ILC2s. Compared with age-matched wild-type (WT) male mice, 8-week-old but not 3-week-old WT female mice harbored an obviously greater percentage and number of heart ILC2s in homeostasis. However, the percentage of killer-cell lectin-like receptor G1 (Klrg1).sup.- ILC2s was higher, but the Klrg1.sup.+ ILC2s were lower in female mice than in male mice in both heart tissues of 3- and 8-week-old mice. Eight-week-old Rag2.sup.-/- mice also showed sex differences similar to those of age-matched WT mice. Regarding surface marker expression, compared to age-matched male mice, WT female mice showed higher expression of CD90.2 and Ki67 and lower expression of Klrg1 and Sca-1 in heart total ILC2s. There was no sex difference in IL-4 and IL-5 secretion by male and female mouse heart ILC2s. Increased IL-33 mRNA levels within the heart tissues were also found in female mice compared with male mice. By reanalyzing published single-cell RNA sequencing data, we found 2 differentially expressed genes between female and male mouse heart ILC2s. Gene set variation analysis revealed that the glycine, serine and threonine metabolism pathway was upregulated in female heart ILC2s. Subcluster analysis revealed that one cluster of heart ILC2s with relatively lower expression of Semaphorin 4a and thioredoxin interacting protein but higher expression of hypoxia-inducible lipid droplet-associated. These results revealed greater numbers of ILC2s, higher expression of CD90.2, reduced Klrg1 and Sca-1 expression in the hearts of female mice than in male mice and no sex difference in IL-4 and IL-5 production in male and female mouse heart ILC2s. These sex differences in heart ILC2s might be due to the heterogeneity of IL-33 within the heart tissue.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MicroRNAs (miRNAs) as small non-coding RNA transcripts bind their complementary sequences in the 3'-untranslated region (3'-UTR) of target messenger RNAs (mRNAs) to regulate their expression. It is ...known that miR-372 belongs to the miR-371-373 gene cluster and has been found to be abnormally expressed in a variety of cancers, but its precise mechanism in cancer remains to be discovered. In this study, miR-372-3p expression was assessed in 153 frozen tissue samples, including primary diagnosed colon cancer and matched normal and adjacent tissues, using real time quantitative polymerase chain reaction (qPCR). An analysis of qPCR data revealed a significant reduction in miR-372-3p expression (by >2-fold) in colon cancer tissues in 51.5% (34/66) of patients. Consistent with this, mimicking the increased miR-372-3p levels in SW480 colon cancer cells significantly suppressed cell growth and proliferation. Although no direct correlation was found between the low level of miR-372-3p and certain tumor-related factors, such as p53, HRE-2, PMS2, MLH1, MSH2, MSH6, HDAC4, p21, and Wee1, in colon cancer tissues, an inverse relationship between miR-372-3p and Ki67 (a marker of proliferation) or miR-372-3p and MAP3K2(MEKK2), which plays a critical role in the MAPK signaling pathways, was confirmed using tissue samples. The target relationship between miR-372-3p and MAP3K2 was verified using luciferase assays in SW480 colon cancer cells. As expected, miR-372-3p mimics significantly suppressed the luciferase activity of pMIR-luc/MAP3K2 3'-UTR in cells, suggesting that miR-372-3p modulates the expression of MAP3K2 by directly targeting its 3'-UTR. Overall, the results obtained herein suggest that miR-372-3p may function as a tumor-suppressor miRNA in colon cancer by targeting MAP3K2.
This study reinspects the dominant modes of different types of El Niño from the perspectives of monthly mean and seasonality using a combined technique referred as RC-REOF. Several features have been ...revealed. (1) The explained variances of eastern Pacific (EP) El Niño and central Pacific (CP) El Niño are comparable, in the ranges of 33–43 and 23–28 %, respectively. (2) This feature is more in line with the frequent occurrence of CP El Niño compared to the result from orthogonal EOF analysis in which El Niño Modoki explains a smaller variance of 11–12 %. (3) Both special patterns of EP El Niño and CP El Niño are of
equatorial asymmetry
that is often overlooked previously by the traditional Niño indices. Based on the features captured by the two leading RC-REOF modes, the authors propose a new pair of Niño indices referred to as Niño3b and Niño4b that have the following advantages: (1) simple calculation, (2) robust and stable relationship with the EP/CP El Niño modes, (3) more representative for Pacific decadal signals, (4) easier to distinguish ENSO types, and (5) without restriction by orthogonality, and others. The Niño3b and Niño4b indices are potentially useful for both scientific research and real-time monitoring of the two types of El Niño. Besides, an index namely Niño3.4b is also introduced to describe the hybrid ENSO events, with relatively equal covariance to EP El Niño and CP El Niño and with larger covariance at decadal time scale than index Niño3.4.
Propolis is widely used in health preservation and disease healing; it contains many ingredients. The previous study had revealed that the ethanolic or water extracts of propolis have a wide range of ...efficacy, such as antiviral, immune enhancement, anti-inflammatory, and so on, but its antiviral components and underlying mechanism of action remain unknown. In this study, we investigated the chemical composition, anti-porcine parvovirus (PPV) effectiveness, and immunological enhancement of propolis flavone ethanolic extracts. The chemical composition of propolis flavone was distinguished by ultra-performance liquid chromatography-quadrupole/time-of-flight tandem mass spectrometry analysis. In this study, the presence and characterization of 26 major components were distinguished in negative ionization modes to evaluate the effects of propolis flavonoid used as an adjuvant on the immune response of Landrace-Yorkshire hybrid sows immunized with an inactivated vaccine of PPV. Thirty Landrace-Yorkshire hybrid sows were randomly assigned to one of three groups, and the sows in the adjuvant groups were intramuscularly injected with PPV vaccine with a 2.0-ml propolis flavonoid adjuvant (PA) and oil emulsion adjuvant. After that, serum hemagglutination inhibition antibody titers and specific immunoglobulin (Ig)M and IgG subclasses were measured to evaluate the adjuvant effects of propolis flavonoid on the humoral immune responses, as well as peripheral lymphocyte proliferation activity and serum concentrations of Th1 and Th2 cytokines for cellular immunity. Results indicated an enhancing effect of PA on IgM, interleukins 2 and 4, interferon-γ, and IgG subclass responses. Especially in the effect of improving cellular immune response, the PA was the best. These findings suggested that PA can significantly enhance the immune responses against the PPV vaccine and could be an alternative way to improve PPV vaccination in sows. Furthermore, we screened the PF chemical components to the effectiveness of anti-PPV. Ferulic acid has an excellent anti-PPV effect.
The El Niño–Southern Oscillation (ENSO) plays a critical role in predicting the winter surface temperature over East Asia. Numerous studies have attempted to improve the seasonal forecasting skill in ...view of the combined effects of ENSO and oceanic–tropospheric factors. However, high uncertainty and notable challenges still exist in using the ENSO to predict the surface temperature. Here, we showed that tropical stratospheric forcings (Quasi-Biennial Oscillation, QBO) could disrupt the response of the surface temperature to ENSO. The response of the East Asian surface temperature to El Niño/La Niña events evidently weakened in winter during the westerly/easterly phase of the QBO. This disruption has shown an increasing trend in recent decades, limiting the usefulness of ENSO alone as a seasonal predictor of the surface temperature. The modulation of the QBO on the East Asian surface temperature is achieved mainly by affecting subtropical zonal winds and North Pacific wave activity. Our analyses suggest that the QBO is a nonnegligible predictor in improving seasonal forecasts of the East Asian surface temperature, even comparable to the ENSO.
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