Costimulation molecules differentially regulate the ERK-Zfp831 axis to shape T follicular helper cell differentiation.

T follicular helper (Tfh) cells play essential roles in regulating humoral immunity, especially germinal center reactions. However, how CD4+ T cells integrate the antigenic and costimulatory signals in Tfh cell development is still poorly understood. Here, we found that phorbol 12-myristate 13-acetate (PMA) + ionomycin (P+I) stimulation, together with interleukin-6 (IL-6), potently induce Tfh cell-like transcriptomic programs in vitro. The ERK kinase pathway was attenuated under P+I stimulation; ERK2 inhibition enhanced Tfh cell development in vitro and in vivo. We observed that inducible T cell costimulator (ICOS), but not CD28, lacked the ability to activate ERK, which was important in sustaining Tfh cell development. The transcription factor Zfp831, whose expression was repressed by ERK, promoted Tfh cell differentiation by directly upregulating the expression of the transcription factors Bcl6 and Tcf7. We have hence identified an ERK-Zfp831 axis, regulated by costimulation signaling, in critical regulation of Tfh cell development.

Febrile Temperature Critically Controls the Differentiation and Pathogenicity of T Helper 17 Cells.

Fever, an evolutionarily conserved physiological response to infection, is also commonly associated with many autoimmune diseases, but its role in T cell differentiation and autoimmunity remains largely unclear. T helper 17 (Th17) cells are critical in host defense and autoinflammatory diseases, with distinct phenotypes and pathogenicity. Here, we show that febrile temperature selectively regulated Th17 cell differentiation in vitro in enhancing interleukin-17 (IL-17), IL-17F, and IL-22 expression. Th17 cells generated under febrile temperature (38.5°C-39.5°C), compared with those under 37°C, showed enhanced pathogenic gene expression with increased pro-inflammatory activities in vivo. Mechanistically, febrile temperature promoted SUMOylation of SMAD4 transcription factor to facilitate its nuclear localization; SMAD4 deficiency selectively abrogated the effects of febrile temperature on Th17 cell differentiation both in vitro and ameliorated an autoimmune disease model. Our results thus demonstrate a critical role of fever in shaping adaptive immune responses with implications in autoimmune diseases.

Imaging the Magnetic Anisotropy in Ultrathin Fe4GeTe2 with a Nitrogen-Vacancy Magnetometer.

Two-dimensional (2D) FenGeTe2, with n = 3, 4, and 5, has been realized in experiments, showing strong magnetic anisotropy with enhanced critical temperature (Tc). The understanding of its magnetic anisotropy is crucial for the exploration of more stable 2D magnets and its spintronic applications. Here, we report a quantitative reconstruction of the magnetization magnitude and its direction in ultrathin Fe4GeTe2 using nitrogen vacancy centers. Through imaging stray magnetic fields, we identified the spin-flop transition at approximately 80 K, resulting in a change of the easy axis from the out-of-plane direction to the in-plane direction. Moreover, by analyzing the thermally activated escape behavior of the magnetization near Tc in terms of the Ginzburg-Landau model, we observed the in-plane magnetic anisotropy effect and the formation capability of magnetic domains at ∼0.4 µm2 µT-1. Our findings contribute to the quantitative understanding of the magnetic anisotropy effect in a vast range of 2D van der Waals magnets.

Direct visualization of a static incommensurate antiferromagnetic order in Fe-doped Bi2Sr2CaCu2O8+δ.

In cuprate superconductors, due to strong electronic correlations, there are multiple intertwined orders which either coexist or compete with superconductivity. Among them, the antiferromagnetic (AF) order is the most prominent one. In the region where superconductivity sets in, the long-range AF order is destroyed. Yet the residual short-range AF spin fluctuations are present up to a much higher doping, and their role in the emergence of the superconducting phase is still highly debated. Here, by using a spin-polarized scanning tunneling microscope, we directly visualize an emergent incommensurate AF order in the nearby region of Fe impurities embedded in the optimally doped Bi2Sr2CaCu2O8+δ (Bi2212). Remarkably, the Fe impurities suppress the superconducting coherence peaks with the gapped feature intact, but pin down the ubiquitous short-range incommensurate AF order. Our work shows an intimate relation between antiferromagnetism and superconductivity.

Alteration of Lipid Profile Between Subclinical Hypothyroidism and Well-Matched Controls: A Meta-Analysis.

In previous studies, subclinical hypothyroidism (SCH) has been associated with altered lipid profiles. However, since the discrepancy between these study results may reside in the great heterogeneity of the populations studied, this relationship is controversial. This study aimed to explore the changes in total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) between subclinical hypothyroidism (SCH) and well-matched euthyroid (EU) groups. Multiple databases were searched for publications before December 1, 2021, including cross-sectional studies on the association between SCH and lipid profile matched by age, gender, and BMI. Twenty-five articles with 3347 participants were included for meta-analysis. The results showed that the TC, TG, and LDL-c levels of the SCH groups were higher than the EU groups (TC, SMD=0.49, 95% CI 0.27, 0.71, p<0.001) (TG, SMD=0.43, 95% CI 0.21, 0.64, p<0.05 ) (LDL-c, SMD=0.75, 95% CI 0.46, 1.03, p<0.001 ). The HDL-c levels of the SCH group were lower than the control group (SMD=-0.53, 95% CI -0.81, -0.25, p<0.05). SCH has a larger impact on LDL-c than the other three indicators. After subgroup analyses, there was a larger impact on lipid alteration in the subgroup of TSH>10 µIU/ml, especially on LDL-c. This study found that SCH was associated with altered lipid profiles. Appropriate clinical treatment may be needed to prevent dyslipidemia and related diseases.

Effects of different iodine levels on the DNA methylation of intrinsic apoptosis-associated genes and analysis of gene-environment interactions in patients with autoimmune thyroiditis.

Iodine is an essential nutrient that may change the occurrence of autoimmune thyroiditis (AIT). Apoptosis and DNA methylation participate in the pathogenesis and destructive mechanism of AIT. We detected the methylation and the expression of mRNA of intrinsic apoptosis-associated genes (YWHAG, ING4, BRSK2 and GJA1) to identify the potential interactions between the levels of methylation in these genes and different levels of iodine. 176 adult patients with AIT in Shandong Province, China, were included. The MethylTargetTM assay was used to verify the levels of methylation. We used PCR to detect the mRNA levels of the candidate genes. Interactions between methylation levels of the candidate genes and iodine levels were evaluated with multiplicative and addictive interaction models and GMDR. In the AIT group, YWHAG_1 and six CpG sites and BRSK2_1 and eight CpG sites were hypermethylated, whereas ING4_1 and one CpG site were hypomethylated. A negative correlation was found between methylation levels of YWHAG and mRNA expression. The combination of iodine fortification, YWHAG_1 hypermethylation and BRSK2_1 hypermethylation was significantly associated with elevated AIT risk. A four-locus model (YWHAG_1 × ING4_1 × BRSK2_1 × iodine level) was found to be the best model of the gene-environment interactions. We identified abnormal changes in the methylation status of YWHAG, ING4 and BRSK2 in patients with AIT in different iodine levels. Iodine fortification not only affected the methylation levels of YWHAG and BRSK2 but also interacted with the methylation levels of these genes and may ultimately increase the risk of AIT.

A descriptive analysis of the coverage of newborn care services among women who delivered in health facilities in 17 sub-Saharan African countries.

BACKGROUND: Sub-Saharan Africa (SSA) has seen an increase in facility-based births over the years. However, the region has the world's highest newborn mortality rate (42% in 2019). Quality care around the time of birth can avert these deaths. This study examined the newborn care interventions given to women who gave birth in health facilities in 17 countries in SSA. METHODS: A cross-sectional population-based study was conducted. We used data from the most recent Demographic and Health Surveys (DHS) conducted in 17 sub-Saharan African countries. We analysed a weighted sample of 226,706 women aged 15-49 years who gave birth in the five years preceding the surveys. We described the coverage of nine newborn care services, namely weighing at birth, breastfeeding initiation within 1 h after birth, skin-to-skin contact, temperature measurement, cord examination, counselling on newborn danger signs, counselling on breastfeeding, breastfeeding observation, and child health assessment before discharge. RESULTS: Overall, 72.0% (95% CI: 71.1, 72.8) of births occurred in health facilities, ranging from 40.0% (95% CI: 38.0, 42.1) in Nigeria to 96.3% (95% CI: 95.4, 97.1) in South Africa. Weighing at birth was the most common intervention (91.4%), followed by health checks before discharge (81%). The other interventions, including those given immediately at birth (breastfeeding and skin-to-skin contact), had suboptimal coverage. For instance, 66% of newborns were breastfed within 1 h after birth, and 56% had immediate skin-to-skin contact. Service coverage varied considerably by country and healthcare provider type. CONCLUSIONS: The majority of the examined services, namely early breastfeeding, skin-to-skin contact, cord examination, temperature measurement, counselling on newborn danger signs, breastfeeding observation, and counselling on breastfeeding, were found to have suboptimal coverage. Even though many pregnant women in SSA give birth in healthcare facilities, some newborns do not always get the care they need to be healthy and live. This is a missed chance to improve newborn health and survival around the time of birth.

The Whole Blood DNA Methylation Patterns of Extrinsic Apoptotic Signaling Pathway Related Genes in Autoimmune Thyroiditis among Areas with Different Iodine Levels.

Autoimmune thyroiditis (AIT) has a complex etiology and the susceptibility to it is determined by a combination of genetic and environmental factors, although these are not yet fully understood. The present research aimed to explore the DNA methylation patterns in whole blood of extrinsic apoptotic signaling pathway related genes in AIT among areas with different iodine levels. We selected the iodine-fortification areas (IFA), iodine-adequate areas (IAA) and water-based iodine-excess areas (IEA) from Shandong Province of China as survey sites. Totally 176 AIT cases and 176 controls were included. MethylTargetTM and QT-PCR technology were used to detect candidate genes' DNA methylation levels and mRNA expression levels, respectively. We found that DAPK1 DNA methylation levels in AIT cases (especially in female) were significantly higher than controls (t=2.7715, P=0.0059; t=2.4638, P=0.0143 in female). There were differences in DAPK1(t=2.5384, P=0.0121), TNFSF8(t=2.1667, P=0.0334) and TNFAIP8(t=2.5672, P=0.0121) genes methylation between cases and controls with different water iodine levels. The mRNA expression of DAPK1(t=4.329, P<0.001) and TNFAIP8(t=3.775, P<0.001) in the cases were increased. We identified the differences in the DNA methylation status of the extrinsic apoptotic signaling pathway related genes between AIT and controls and in different iodine levels areas. The results were verified at the mRNA level. The environmental iodine may affect DNA methylation to some extent.

The Relationship between PTPN22 R620W Polymorphisms and the Susceptibility to Autoimmune Thyroid Diseases: An Updated Meta-analysis.

The protein tyrosine phosphatase non-receptor 22 (PTPN22) R620W polymorphism has been related to susceptibility to autoimmune thyroid disease (AITD) with inconsistent results. Therefore, this meta-analysis was designed to assess a more accurate association between the PTPN22 R620W polymorphism and AITD susceptibility. A systematic search of the EMBASE, PubMed, Web of Science, CBM, CNKI, and WanFang databases was performed to determine relevant publications. Statistical analyses of the odds ratios (ORs), 95% confidence intervals (CIs), and p values were performed using STATA software. Our meta-analysis included 18 separate studies comprised of 4,726 cases and 4,220 controls. In the allele and all genetic models, PTPN22 R620W polymorphism and Graves' disease (GD) (allele model TvsC: OR = 1.573; 95% CI = 1.378-1.795; P < .001) and Hashimoto's thyroiditis (HT) (allele model TvsC: OR = 1.737; 95% CI = 1.230-2.454; P = .002) susceptibility was positively associated. A racial subgroup analysis showed that the T allele significantly increased AITD susceptibility in all genetic models involving Caucasians, but not in Asians. This meta-analysis showed that the PTPN22 R620W polymorphism is associated with the risk of GD and HT in the overall study population. In addition, the PTPN22 R620W polymorphism is associated with elevated AITD risk in Caucasians, but not in Asians.

T Follicular Helper Cells Regulate Humoral Response for Host Protection against Intestinal Citrobacter rodentium Infection.

Citrobacter rodentium colonizes at the colon and causes mucosal inflammation in mice. Previous studies have revealed the importance of the innate and adaptive immune response for controlling C. rodentium infection. In the present study, we examined the role of T follicular helper (Tfh) cells in intestinal C. rodentium infection using mice with Bcl6 deficiency in T cells. Tfh cells were absolutely required at the late, but not the early, phase to control infection. Compared with control mice, we observed systemic pathogen dissemination and more severe colitis in Tfh-deficient mice. Furthermore, the susceptibility of Tfh-deficient mice correlated with an impaired serum IgG1 response to infection, and serum Abs from infected wild-type mice protected Tfh-deficient mice from infection. The transfer of wild-type Tfh cells also restored the levels of IgG1 and led to effective clearance of the pathogens in Tfh-deficient mice. Moreover, during C. rodentium infection, IL-21- and IL-4-producing Tfh cells were increased obviously in wild-type mice, correlating with IgG1 as the major isotype in germinal center B cells. Taken together, our work highlights the requirement and the function of Tfh cells in regulating humoral response for the host protection against C. rodentium infection.

Effect of different iodine levels on the DNA methylation of PRKAA2, ITGA6, THEM4 and PRL genes in PI3K-AKT signaling pathway and population-based validation from autoimmune thyroiditis patients.

PURPOSE: Autoimmune thyroiditis (AIT) is one of the most common autoimmune endocrine diseases. The currently recognized causes are genetic susceptibility, environmental factors and immune disorders. It is important to clarify the pathogenesis for the prevention, diagnosis, treatment of AIT and scientific iodine supplementation. This study analyzed the DNA methylation levels of PRKAA2, ITGA6, PRL and THEM4 genes related to PI3K-AKT signaling pathway, compared the DNA methylation levels between cases and controls from different water iodine levels in Shandong Province of China, and evaluated the contribution of PI3K-AKT signaling pathway-related genes in AIT. METHODS: A total of 176 adult AIT patients were included from three different water iodine areas, and 176 healthy controls were included according to gender, age and BMI. According to the results of the Illumina Methylation 850 K BeadChip in our previous research, the significant methylation differences of genes on the PI3K-AKT signaling pathway related to AIT were determined. The MethylTarget™ assay was used to detect the methylation levels of the target genes, and real-time PCR experiments were used to verify the mRNA expression levels. RESULTS: Compared with the control group, PRKAA2_3 and 15 CpG sites were hyper-methylated. ITGA6 gene and 2 CpG sites were hypo-methylated in AIT cases. The mRNA expression of ITGA6 gene was negatively correlated with the DNA methylation levels of ITGA6 gene and 2 CpG sites. Compared with cases and controls in areas with different water iodine levels, methylation differences were mainly in PRKAA2 and ITGA6 genes. The methylation levels of PRKAA2_1 and PRKAA2_3 were positively correlated with age. The methylation levels of PRL and THEM4 genes were negatively correlated with age. The methylation level of PRKAA2_3 was positively correlated with FT4. CONCLUSION: In summary, we identified aberrant DNA methylation levels of PRKAA2 and ITGA6 genes related to PI3K-AKT signaling pathway in the blood of AIT patients. Both iodine supplementation after long-term iodine deficiency and iodine excess can affect the DNA methylation levels of PRKAA2 and ITGA6 genes, and the former affects more obviously. In ITGA6 gene, this aberrant epigenetic modification is associated with the increased mRNA expression.

Iodine nutrition status of women after 10 years of Lipiodol supplementation: a cross-sectional study in Xinjiang, China.

This study examined the contribution of long-term use of Lipiodol capsules, as a supplement to iodised salt to the control of iodine deficiency disorders among women in Xinjiang of China. A total of 1220 women across Kashgar, Aksu, Turpan and Yili Prefectures were surveyed in 2017. Lipiodol capsules were administered twice yearly in Kashgar and once yearly in Aksu and Turpan, but not in Yili. Urinary iodine concentration (UIC), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroglobulin antibody, thyroid peroxidase antibody and thyroid volume values were assessed. All the women in the four areas were in a state of non-iodine deficiency by UIC. The UIC were higher than adequate in Kashgar and Aksu (619·4 v. 278·6 µg/l). Thyroid hormone levels differed significantly in Turpan and Yili (FT3: 4·4 v. 4·6 pmol/l, FT4: 13·8 v. 14·2 pmol/l, TSH: 2·0 v. 2·7 mIU/l), but did not differ significantly in Kashgar, Aksu and Yili. The four areas did not differ significantly with regard to thyroid nodules, autoimmune thyroiditis or goitre. However, the detection rates of subclinical hypothyroidism (16·6 %) and total thyroid dysfunction (25·4 %) were higher among women in Yili. The supplementation with Lipiodol capsules had improved the iodine nutrition status of women in iodine-deficient areas of Xinjiang since 2006. To avoid negative effects of excess iodine, we suggest a gradual discontinuation of Lipiodol capsules in women with special needs based on the existing iodine nutrition level of local women.

Influenza A Virus Infection Induces Viral and Cellular Defective Ribosomal Products Encoded by Alternative Reading Frames.

The importance of antiviral CD8+ T cell recognition of alternative reading frame (ARF)-derived peptides is uncertain. In this study, we describe an epitope (NS1-ARF21-8) present in a predicted 14-residue peptide encoded by the +1 register of NS1 mRNA in the influenza A virus (IAV). NS1-ARF21-8 elicits a robust, highly functional CD8+ T cell response in IAV-infected BALB/c mice. NS1-ARF21-8 is presented from unspliced NS mRNA, likely from downstream initiation on a Met residue that comprises the P1 position of NS1-ARF21-8 Derived from a 14-residue peptide with no apparent biological function and negligible impacts on IAV infection, infectivity, and pathogenicity, NS1-ARF21-8 provides a clear demonstration of how immunosurveillance exploits natural errors in protein translation to provide antiviral immunity. We further show that IAV infection enhances a model cellular ARF translation, which potentially has important implications for virus-induced autoimmunity.

Associations between water iodine concentration and the prevalence of dyslipidemia in Chinese adults: A cross-sectional study.

Iodine is important in both thyroid function and lipid metabolism. Some studies have explored the effect of thyroid hormones (THs) and urinary iodine concentration (UIC) on serum lipid levels. However, the association between iodine intake and dyslipidemia has not been well established. This study aimed to investigate the relationship between water iodine concentration (WIC) and dyslipidemia, including hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C). A cross-sectional survey was conducted involving 409, 390 and 436 adults (≥18 years) from the iodine-deficient (median water iodine, MWI < 10 µg/L), iodine-adequate (MWI between 40 and 100 µg/L) and iodine-excess (MWI > 100 µg/L) areas, respectively. WIC, total cholesterol (TC), triglyceride (TRIG), HDL-C and LDL-C were measured. The prevalence of dyslipidemia were calculated based on the level of WIC using the chi-square method. To further explore whether prevalence was associated with WIC, simple linear regressions and multiple logistic regression models were used. Compared to those with WIC of 40-100 µg/L, a WIC of >100 µg/L was found to be protective associated with against the occurrence of hypertriglyceridemia [adjusted odds ratio (AOR) = 0.649, 95% confidence interval (CI): 0.455-0.924] and low HDL-C (AOR = 0.429, 95% CI: 0.264-0.697). The prevalence of hypertriglyceridemia, low HDL-C and high LDL-C as a function of WIC was found to be an inverted U-shaped association with a zenith at a WIC of 40-100 µg/L. Collectively, our research showed that serum lipid levels are related to WIC. The benefit effect association between WIC and dyslipidemia appears in cases of iodine excess (>100 µg/L).

Relationship between excess iodine, thyroid function, blood pressure, and blood glucose level in adults, pregnant women, and lactating women: A cross-sectional study.

High water iodine concentration in drinking water can lead to excessive iodine, which will affect normal thyroid function, blood glucose, and blood pressure, especially among pregnant and lactating women. The aim of the present study was to determine the relationship between iodine, thyroid function, blood pressure, and blood glucose level among adults, and pregnant and lactating women in areas that are iodine-adequate (IA) and iodine-excess (IE) with respect to iodine concentrations in drinking water. A cross-sectional survey was conducted involving 144 pregnant and 237 lactating women in Shanxi Province, and 828 adults in Shandong Province. Water iodine, urinary iodine, thyroid function, blood pressure, and blood glucose were measured. Compared with the IA area, the water iodine concentration (WIC) in the IE area was higher (adults, 325.00 µg/L vs. 71.40 µg/L; pregnant and lactating women, 464.80 µg/L vs. 57.50 µg/L). For adults, and pregnant and lactating women, in the IE area, the urinary iodine concentration (UIC), free thyroxine (FT4 [except for lactating women]), and systolic blood pressure (only adults 18-40 years of age) were significantly higher, while the blood glucose level and the prevalence of hyperglycemia (except for adults) was lower, and the free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb), and hypertension-positive rates of the three populations were not significantly different. For adults, systolic and diastolic pressure were positively correlated with FT3 and FT4, respectively, while the blood glucose level were inversely associated with the WIC. For pregnant women, systolic pressure and the WIC, diastolic pressure and FT4, blood glucose level and FT3 were all positively correlated, while the blood glucose level was inversely associated with TSH, WIC and UIC. For lactating women, systolic pressure was positively correlated with WIC and UIC, while blood glucose level were inversely associated with WIC and UIC. Pregnant and lactating women in the IE area were at lower risk for an association with hyperglycemia. Collectively, our research showed that long-term exposure to high water iodine is a high-risk factor for abnormal blood pressure and a low-risk factor for abnormal blood glucose level, especially for special populations such as pregnant and lactating women. Moreover, enhanced monitoring of blood pressure and blood glucose level in people with abnormal thyroid function in areas with high water iodine is important.

Autoimmune thyroid diseases after 25 years of universal salt iodisation: an epidemiological study of Chinese adults in areas with different water iodine levels.

The present study aimed to evaluate the status of iodine nutrition and thyroid function in adults, to understand the distribution of thyroid disease in people with autoimmune thyroid disease (AITD) in different water iodine areas and to explore the relationship between serum iodine, urine iodine and thyroid function in people with AITD. A cross-sectional survey was conducted in areas of Shandong Province with different water iodine levels, and subsequently 1225 adults were enrolled from iodine-deficient (ID), iodine-adequate (IA) and iodine-excess (IE) areas. Urinary iodine, water iodine, salt iodine, serum iodine and thyroid function were measured. According to the urine iodine concentration, the ID and IA areas were defined as iodine sufficient and the IE area as iodine excessive. Urine iodine, serum iodine, free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels were comparatively higher in the IE area. The positive rate of thyroglobulin antibody (19·1 %) and the prevalence of AITD (21·8 %) were higher in the ID areas; the prevalence of subclinical hypothyroidism was lowest in the ID areas (7·3 %) and highest in the IE area (16·3 %). Among the AITD population, urinary iodine concentration, free triiodothyronine, FT4 and TSH had a non-linear correlation with serum iodine; abnormal TSH level, serum iodine concentration > 110 µg/l and goitre were risk factors for AITD in adults, especially females. Our data collectively suggest that universal salt iodisation has improved the iodine nutritional status of the population in ID areas in China. Non-step-by-step iodine fortification may induce the transformation of thyroid autoimmune diseases from recessive-to-dominant in susceptible people. Moreover, enhanced monitoring of thyroid function in people with AITD is important.

Improving tumor sensitivity by the introduction of an ester chain to triaryl derivatives targeting PD-1/PD-L1.

PD-1/PD-L1 pathway blockade is a promising immunotherapy for the treatment of cancer. In this manuscript, a series of triaryl compounds containing ester chains were designed and synthesized based on the pharmacophore studies of the lead BMS-1. After several SAR iterations, 22 showed the best biochemical activity binding to hPD-L1 with an IC50 of 1.21 nM in HTRF assay, and a KD value of 5.068 nM in SPR analysis. Cell-based experiments showed that 22 effectively promoted A549 cell death by restoring T-cell immune function. 22 showed significant in vivo antitumor activity in a 4T1 mouse model without obvious toxicity, with a TGI rate of 67.8 % (20 mg/kg, ip). Immunohistochemistry data indicated that 22 activates the immune activity in tumors. These results suggest that 22 is a promising compound for further development of PD-1/PD-L1 inhibitor for cancer therapy.

Purification and immobilization of ß-glucosidase using surface modified mesoporous silica Santa Barbara Amorphous 15 for eco-friendly preparation of sagittatoside A.

Functionalized mesoporous materials have become a promising carrier for enzyme immobilization. In this study, Santa Barbara Amorphous 15 (SBA-15) was modified by N-aminoethyl-γ-aminopropyl trimethoxy (R). R-SBA-15 was employed to purify and immobilize recombinant ß-glucosidase from Terrabacter ginsenosidimutans (BgpA) in one step for the first time. Optimum pH of the constructed R-SBA-15@BgpA were 7.0, and it has 20 â„ƒ higher optimal temperature than free enzyme. Relative activity of R-SBA-15@BgpA still retained > 70% at 42 â„ƒ after 8-h incubation. The investigation on organic reagent resistance revealed that the immobilized enzyme can maintain strong stability in 15% DMSO. In leaching test and evaluation of storage stability, only trace amount of protein was detected in buffer of the immobilized enzyme after storage at 4 â„ƒ for 33 days, and the immobilized BgpA still maintained > 50% relative activity. It also demonstrated good reusability, with 76.1% relative activity remaining after fourteen successive enzymatic hydrolyses of epimedin A to sagittatoside A. The newly proposed strategy is an effective approach for the purification and immobilization of BgpA concurrently. In addition, R-SBA-15@BgpA was demonstrated to have high efficiency and stability in this application, suggesting its great feasibility and potential to produce bioactive compounds such as secondary glycosides or aglycones from natural products.

Discovery of Covalent MLKL PROTAC Degraders via Optimization of a Theophylline Derivative Ligand for Treating Necroptosis.

Mixed lineage kinase domain-like pseudokinase (MLKL) initiates necroptosis and could serve as a therapeutic target related to a series of human diseases. Proteolysis-targeting chimeras (PROTACs) are useful tools for degrading pathological proteins and blocking disease processes. Using computer-aided modeling and molecular dynamics simulations, we developed a series of covalent MLKL PROTACs by linking and optimizing a theophylline derivative that covalently targets MLKL. Via structure-activity relationship studies, MP-11 was identified as a potent MLKL PROTAC degrader. Furthermore, MP-11 showed lower toxicity than the original MLKL ligand, exhibiting nanomolar-scale antinecroptotic activity on human cell lines. Xenograft model studies showed that MP-11 effectively degraded MLKL in vivo. Importantly, our study demonstrates that the covalent binding strategy is an effective approach for designing MLKL-targeting PROTACs, serving as a model for developing PROTACs to treat future necroptosis-related human diseases.

Tunable Emissive CsPbBr3/Cs4PbBr6 Quantum Dots Engineered by Discrete Phase Transformation for Enhanced Photogating in Field-Effect Phototransistors.

Precise control of quantum structures in hybrid nanocrystals requires advancements in scientific methodologies. Here, on the design of tunable CsPbBr3/Cs4PbBr6 quantum dots are reported by developing a unique discrete phase transformation approach in Cs4PbBr6 nanocrystals. Unlike conventional hybrid systems that emit solely in the green region, this current strategy produces adjustable luminescence in the blue (450 nm), cyan (480 nm), and green (510 nm) regions with high photoluminescence quantum yields up to 45%, 60%, and 85%, respectively. Concentration-dependent studies reveal that phase transformation mechanisms and the factors that drive CsBr removal occur at lower dilutions while the dissolution-recrystallization process dominates at higher dilutions. When the polymer-CsPbBr3/Cs4PbBr6 integrated into a field-effected transistor the resulting phototransistors featured enhanced photosensitivity exceeding 105, being the highest reported for an n-type phototransistor, while maintaining good transistor performances as compared to devices consisting of polymer-CsPbBr3 NCs.