Immunotherapy for Type 1 Diabetes Mellitus by Adjuvant-Free Schistosoma Japonicum-Egg Tip-Loaded Asymmetric Microneedle Patch (STAMP)

BACKGROUND: Type 1 diabetes mellitus (T1DM) is an autoimmune disease mediated by autoreactive T cells and dominated by Th1 response polarization. Insulin replacement therapy faces great challenges to this autoimmune disease, requiring highly frequent daily administration. Intriguingly, the progression of T1DM has proven to be prevented or attenuated by helminth infection or worm antigens for a relatively long term. However, the inevitable problems of low safety and poor compliance arise from infection with live worms or direct injection of antigens. Microneedles would be a promising candidate for local delivery of intact antigens, thus providing an opportunity for the clinical immunotherapy of parasitic products. METHODS: We developed a Schistosoma japonicum-egg tip-loaded asymmetric microneedle patch (STAMP) system, which serves as a new strategy to combat TIDM. In order to improve retention time and reduce contamination risk, a specific imperfection was introduced on the STAMP (asymmetric structure), which allows the tip to quickly separate from the base layer, improving reaction time and patient\u27s comfort. After loading Schistosoma japonicum-egg as the immune regulator, the effects of STAMP on blood glucose control and pancreatic pathological progression improvement were evaluated in vivo. Meanwhile, the immunoregulatory mechanism and biosafety of STAMP were confirmed by histopathology, qRT-PCR, ELISA and Flow cytometric analysis. RESULTS: Here, the newly developed STAMP was able to significantly reduce blood glucose and attenuate the pancreatic injury in T1DM mice independent of the adjuvants. The isolated Schistosoma japonicum-eggs micron slowly degraded in the skin and continuously released egg antigen for at least 2 weeks, ensuring localization and safety of antigen stimulation. This phenomenon should be attributed to the shift of Th2 immune response to reduce Th1 polarization. CONCLUSION: Our results exhibited that STAMP could significantly regulate the blood glucose level and attenuate pancreatic pathological injury in T1DM mice by balancing the Th1/Th2 immune responses, which is independent of adjuvants. This technology opens a new window for the application of parasite products in clinical immunotherapy

Novel protocol to identify true hybrids in normal oleate x high oleate crosses in peanut

A novel hybrid identification protocol was developed for F0:1 peanut seeds resulting from crosses between normal oleate cultivars with wild type FAD2B gene and high oleate genotypes with an A insertion in FAD2B gene. Presence of a series of overlapped peaks in trace file of the PCR product amplified with bF19/R1 primers was an indication of hybridity. This protocol may facilitate high oleate breeding and genetic studies in peanut

Long-term exposure to PM2.5 and fasting plasma glucose in non-diabetic adolescents in Yogyakarta, Indonesia

Background: Indonesia is facing serious air pollution. However, very few studies have been conducted to examine the health risks of air pollution in Indonesia, particularly for adolescents. Objective: To assess the association between long-term exposure to ambient particles with a diameter of <2.5 mm (PM2.5) and fasting plasma glucose (FPG) in adolescents. Methods: A cross-sectional study was conducted in 482 adolescents aged 14e18 years in Yogyakarta, Indonesia in 2016. We finally included 469 (97.30%) participants who had no missing data for data analysis. We collected individual data on socio-demographics, behavioral habits, and health information through standardized questionnaires. Satellite-based PM2.5 concentrations from 2013 to 2016 were assigned based on participants’ residential addresses. The association between PM2.5 and FPG was examined using a generalized linear regression model while FPG was modeled as a continuous variable. An ordered logistic regression model was used to assess the relationship between PM2.5 and FPG categories. Results: Every 1 mg/m3 increase in PM2.5 was associated with a 0.34 mg/dL [95 confidence interval (95% CI): 0.08 mg/dL, 0.59 mg/dL] increase in FPG levels. Comparing with the low FPG level (under 86 mg/dL), every 1 mg/m3 increase in PM2.5 was associated with a 10.20% (95% CI: 1.60%, 19.80%) increase in the odds of impaired fasting glucose (IFG) (100e125 mg/dL). Stratified analyses indicated greater effects on participants with hypertension [odds ratio (OR) ¼ 1.30, 95% CI: 1.09, 1.57] and those had higher physical activities (OR ¼ 1.36, 95% CI: 1.09, 1.57). Adolescents’ sex, obesity status and different cutoff points of FPG did not modify the association between the exposure to PM2.5 and FPG levels. Conclusion: Long-term exposure to PM2.5 was associated with increased FPG levels in Indonesian nondiabetic adolescents.Wenhua Yu, Dian Caturini Sulistyoningrum, Danijela Gasevic, Rongbin Xu, Madarina Julia, Indah Kartika Murni, Zhuying Chen, Peng Lu, Yuming Guo, Shanshan L

Machine Learning of Pair-Contact Process with Diffusion

The pair-contact process with diffusion (PCPD), a generalized model of the ordinary pair-contact process (PCP) without diffusion, exhibits a continuous absorbing phase transition. Unlike the PCP, whose nature of phase transition is clearly classified into the directed percolation (DP) universality class, the model of PCPD has been controversially discussed since its infancy. To our best knowledge, there is so far no consensus on whether the phase transition of the PCPD falls into the unknown university classes or else conveys a new kind of non-equilibrium phase transition. In this paper, both unsupervised and supervised learning are employed to study the PCPD with scrutiny. Firstly, two unsupervised learning methods, principal component analysis (PCA) and autoencoder, are taken. Our results show that both methods can cluster the original configurations of the model and provide reasonable estimates of thresholds. Therefore, no matter whether the non-equilibrium lattice model is a random process of unitary (for instance the DP) or binary (for instance the PCP), or whether it contains the diffusion motion of particles, unsupervised leaning can capture the essential, hidden information. Beyond that, supervised learning is also applied to learning the PCPD at different diffusion rates. We proposed a more accurate numerical method to determine the spatial correlation exponent $\nu_{\perp}$, which, to a large degree, avoids the uncertainty of data collapses through naked eyes. Our extensive calculations reveal that $\nu_{\perp}$ of PCPD depends continuously on the diffusion rate $D$, which supports the viewpoint that the PCPD may lead to a new type of absorbing phase transition.Comment: 15 pages, 11 figure

Mutations associated with no durable clinical benefit to immune checkpoint blockade in Non-S-Cell lung cancer

(1) Background: The immune checkpoint blockade (ICB) has shown promising efficacy in non-small-cell lung cancer (NSCLC) patients with significant clinical benefits and durable responses, but the overall response rate to ICBs is only 20%. The lack of responsiveness to ICBs is currently a central problem in cancer immunotherapy. (2) Methods: Four public cohorts comprising 2986 patients with NSCLC were included in the study. We screened 158 patients with NSCLC with no durable clinical benefit (NDB) to ICBs in the Rizvi cohort and identified NDB-related gene mutations in these patients using univariate and multivariate Cox regression analyses. Programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), neoantigen load, tumor-infiltrating lymphocytes, and immune-related gene expression were analyzed for identifying gene mutations. A comprehensive predictive classifier model was also built to evaluate the efficacy of ICB therapy. (3) Results: Mutations in FAT1 and KEAP1 were found to correlate with NDB in patients with NSCLC to ICBs; however, the analysis suggested that only mutation in FAT1 was valuable in predicting the efficacy of ICB therapy, and that mutation in KEAP1 acted as a prognostic but not a predictive biomarker for NSCLC. Mutations in FAT1 were associated with a higher TMB and lower multiple lymphocyte infiltration, including CD8 (T-Cell Surface Glycoprotein CD8)+ T cells. We established a prognostic model according to PD-L1 expression, TMB, smoking status, treatment regimen, treatment type, and FAT1 mutation, which indicated good accuracy by receiver operating characteristic (ROC) analysis (area under the curve (AUC) for 6-months survival: 0.763; AUC for 12-months survival: 0.871). (4) Conclusions: Mutation in FAT1 may be a predictive biomarker in patients with NSCLC who exhibit NDB to ICBs. We proposed an FAT1 mutation-based model for screening more suitable NSCLC patients to receive ICBs that may contribute to individualized immunotherapy.info:eu-repo/semantics/publishedVersio

Transgenic Rat Model of Neurodegeneration Caused by Mutation in the \u3ci\u3eTDP\u3c/i\u3e Gene

TDP-43 proteinopathies have been observed in a wide range of neurodegenerative diseases. Mutations in the gene encoding TDP-43 (i.e., TDP) have been identified in amyotrophic lateral sclerosis (ALS) and in frontotemporal lobe degeneration associated with motor neuron disease. To study the consequences of TDP mutation in an intact system, we created transgenic rats expressing normal human TDP or a mutant form of human TDP with a M337V substitution. Overexpression of mutant, but not normal, TDP caused widespread neurodegeneration that predominantly affected the motor system. TDP mutation reproduced ALS phenotypes in transgenic rats, as seen by progressive degeneration of motor neurons and denervation atrophy of skeletal muscles. This robust rat model also recapitulated features of TDP-43 proteinopathies including the formation of TDP-43 inclusions, cytoplasmic localization of phosphorylated TDP-43, and fragmentation of TDP-43 protein. TDP transgenic rats will be useful for deciphering the mechanisms underlying TDP-43– related neurodegenerative diseases

5,11,17,23-Tetra­bromo-25,26,27,28-tetra­kis(4-tolyl­sulfon­yloxy)-2,8,14,20-tetra­thia­calix[4]arene dichloro­methane solvate

In the crystal structure of the title compound, C52H36Br4O12S8·CH2Cl2, the thia­calix[4]arene unit adopts a 1,3-alternate conformation with an intra­molecular C—H⋯O hydrogen bond and four C—H⋯π inter­actions, with the four 4-MeC6H4SO3 groups located alternately above and below the virtual plane (R) defined by the four bridging S atoms. The benzene ring of each 4-MeC6H4SO3 unit is nearly perpendicular to one of the two neighboring phenol rings with inter­planar angles varying from 72.97 (13) to 78.70 (13)°, while the dihedral angles between the plane (R) and the phenol rings range from 83.04 (7) to 84.30 (9)°. In the supra­molecular structure, a solvent-bridged dimer composed of two main mol­ecules is formed by four inter­molecular C—H⋯O hydrogen bonds and locally creates an R 4 4(26) motif. Such dimers associate further into chains by inter­dimer C—Cl⋯O short contacts [Cl⋯O 3.182 (5) Å]. Finally, these chains are linked into a two-dimensional network by a combination of inter­chain C—Br⋯O inter­actions [Br⋯O = 3.183 (3) and 2.966 (4) Å] as well as C—H⋯O hydrogen bonds

Transcription Factor BACH1 in Cancer: Roles, Mechanisms, and Prospects for Targeted Therapy

Transcription factor BTB domain and CNC homology 1 (BACH1) belongs to the Cap \u27n\u27 Collar and basic region Leucine Zipper (CNC-bZIP) family. BACH1 is widely expressed in mammalian tissues, where it regulates epigenetic modifications, heme homeostasis, and oxidative stress. Additionally, it is involved in immune system development. More importantly, BACH1 is highly expressed in and plays a key role in numerous malignant tumors, affecting cellular metabolism, tumor invasion and metastasis, proliferation, different cell death pathways, drug resistance, and the tumor microenvironment. However, few articles systematically summarized the roles of BACH1 in cancer. This review aims to highlight the research status of BACH1 in malignant tumor behaviors, and summarize its role in immune regulation in cancer. Moreover, this review focuses on the potential of BACH1 as a novel therapeutic target and prognostic biomarker. Notably, the mechanisms underlying the roles of BACH1 in ferroptosis, oxidative stress and tumor microenvironment remain to be explored. BACH1 has a dual impact on cancer, which affects the accuracy and efficiency of targeted drug delivery. Finally, the promising directions of future BACH1 research are prospected. A systematical and clear understanding of BACH1 would undoubtedly take us one step closer to facilitating its translation from basic research into the clinic

SOX on Tumors, a Comfort or a Constraint?

The sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) family, composed of 20 transcription factors, is a conserved family with a highly homologous HMG domain. Due to their crucial role in determining cell fate, the dysregulation of SOX family members is closely associated with tumorigenesis, including tumor invasion, metastasis, proliferation, apoptosis, epithelial-mesenchymal transition, stemness and drug resistance. Despite considerable research to investigate the mechanisms and functions of the SOX family, confusion remains regarding aspects such as the role of the SOX family in tumor immune microenvironment (TIME) and contradictory impacts the SOX family exerts on tumors. This review summarizes the physiological function of the SOX family and their multiple roles in tumors, with a focus on the relationship between the SOX family and TIME, aiming to propose their potential role in cancer and promising methods for treatment