Long-range transcription factor binding sites clustered regions may mediate transcriptional regulation through phase-separation interactions in early human embryo.

In mammals, during the post-fertilization pre-implantation phase, the expression of cell type-specific genes is crucial for normal embryonic development, which is regulated by cis-regulatory elements (CREs). TFs control gene expression by interacting with CREs. Research shows that transcription factor binding sites (TFBSs) reflect the general characteristics of the regulatory genome. Here, we identified TFBSs from chromatin accessibility data in five stages of early human embryonic development, and quantified transcription factor binding sites-clustered regions (TFCRs) and their complexity (TC). Assigning TC values to TFCRs has made it possible to assess the functionality of these regulatory elements in a more quantitative way. Our findings reveal a robust correlation between TFCR complexity and gene expression starting from the 8Cell stage, which is when the zygotic genome is activated in humans. Furthermore, we have defined long-range TFCRs (LR-TFCRs) and conjecture that LR-TFCRs may regulate gene expression through phase-separation mechanisms during the early stages of human embryonic development.

PASTICCINO2 interacting with Golgi Anti-Apoptotic Proteins resists endoplasmic reticulum stress dependent on very long-chain fatty acids.

The endoplasmic reticulum (ER) is crucial for maintaining cell homeostasis because it is the primary site for synthesizing secreted and transmembrane proteins and lipids. The unfolded protein response (UPR) is activated to restore ER homeostasis under ER stress. However, the relationship between lipids and the ER stress response in plants is not well understood. Arabidopsis Golgi anti-apoptotic proteins (GAAPs) are involved in resisting ER stress. To elucidate the function of GAAPs, PASTICCINO2 (PAS2), involved in very long-chain fatty acid (VLCFA) synthesis, was found to interact with GAAPs and IRE1. Single pas2 and gaap1/gaap2pas2 double mutants exhibited increased seedling damage and impaired UPR response under chronic ER stress. Site mutation combined with genetic analysis revealed that the role of PAS2 in resisting ER stress depended on its VLCFA synthesis domain. VLCFA contents were upregulated under ER stress, which required GAAPs. Exogenous VLCFAs partially restored the defect in UPR upregulation caused by PAS2 or GAAP mutations under chronic ER stress. These findings demonstrate that the association of PAS2 with GAAPs confers plant resistance to ER stress by regulating VLCFA synthesis and the UPR. This provides a basis for further studies on the connection between lipids and cell fate decisions under stress.

Naringin Inhibits Macrophage Foam Cell Formation by Regulating Lipid Homeostasis and Metabolic Phenotype.

Imbalances in lipid uptake and efflux and inflammation are major contributors to foam cell formation, which is considered a therapeutic target to protect against atherosclerosis. Naringin, a citrus flavonoid abundant in citrus fruits, has been reported to exert an antiatherogenic function, but its pharmacological mechanism is unclear. Naringin treatment effectively inhibits foam cell formation in THP-1 and RAW264.7 macrophages. In this study, mechanically, naringin maintained lipid homeostasis within macrophages through downregulation of the key genes for lipid uptake (MSR1 and CD36) and the upregulation of ABCA1, ABCG1 and SR-B1, which are responsible for cholesterol efflux. Meanwhile, naringin significantly decreased the cholesterol synthesis-related genes and increased the genes involved in cholesterol metabolism. Subsequently, the results showed that ox-LDL-induced macrophage inflammatory responses were inhibited by naringin by reducing the proinflammatory cytokines IL-1ß, IL-6 and TNF-α, and increasing the anti- inflammatory cytokine IL-10, which was further verified by the downregulation of pro-inflammatory and chemokine-related genes. Additionally, we found that naringin reprogrammed the metabolic phenotypes of macrophages by suppressing glycolysis and promoting lipid oxidation metabolism to restore macrophage phenotypes and functions. These results suggest that naringin is a potential drug for the treatment of AS as it inhibits macrophage foam cell formation by regulating metabolic phenotypes and inflammation.

The transcription factor BMI1 increases hypoxic signaling in oral cavity epithelia.

The tongue epithelium is maintained by a proliferative basal layer. This layer contains long-lived stem cells (SCs), which produce progeny cells that move up to the surface as they differentiate. B-lymphoma Mo-MLV insertion region 1 (BMI1), a protein in mammalian Polycomb Repressive Complex 1 (PRC1) and a biomarker of oral squamous cell carcinoma, is expressed in almost all basal epithelial SCs of the tongue, and single, Bmi1-labelled SCs give rise to cells in all epithelial layers. We previously developed a transgenic mouse model (KrTB) containing a doxycycline- (dox) controlled, Tet-responsive element system to selectively overexpress Bmi1 in the tongue basal epithelial SCs. Here, we used this model to assess BMI1 actions in tongue epithelia. Genome-wide transcriptomics revealed increased levels of transcripts involved in the cellular response to hypoxia in Bmi1-overexpressing (KrTB+DOX) oral epithelia even though these mice were not subjected to hypoxia conditions. Ectopic Bmi1 expression in tongue epithelia increased the levels of hypoxia inducible factor-1 alpha (HIF1α) and HIF1α targets linked to metabolic reprogramming during hypoxia. We used chromatin immunoprecipitation (ChIP) to demonstrate that Bmi1 associates with the promoters of HIF1A and HIF1A-activator RELA (p65) in tongue epithelia. We also detected increased SC proliferation and oxidative stress in Bmi1-overexpressing tongue epithelia. Finally, using a human oral keratinocyte line (OKF6-TERT1R), we showed that ectopic BMI1 overexpression decreases the oxygen consumption rate while increasing the extracellular acidification rate, indicative of elevated glycolysis. Thus, our data demonstrate that high BMI1 expression drives hypoxic signaling, including metabolic reprogramming, in normal oral cavity epithelia.

Multiply restimulated human cord blood-derived Tregs maintain stabilized phenotype and suppressive function and predict their therapeutic effects on autoimmune diabetes.

BACKGROUND: Regulatory T cells (Tregs) are involved in the maintenance of immune homeostasis and immune regulation. Clinical trials on the adoptive transfer of Tregs have been ongoing for > 10 years. However, many unresolved issues remain in the production of readymade Treg products and selection of patients. Hence, this study aimed to develop a method to expand off-the-shelf Tregs derived from umbilical cord blood (UCB-Tregs) in vitro without changing their phenotype and inhibitory function. In addition, the study intended to design an approach to precisely select patients who are more likely to benefit from the adoptive Treg transfer therapy. METHODS: UCB-Tregs were isolated and cultured in a medium containing human recombinant IL-2 and rapamycin and then multiply restimulated with human T-activator CD3/CD28 dynabeads. The phenotype and suppressive capacity of Tregs were assessed on days 18 and 42. The relationship between the suppressive function of UCB-Tregs in vitro and clinical indicators was analyzed, and the ability of the in vitro suppressive capacity to predict the in vivo therapeutic effects was evaluated. RESULTS: UCB-Tregs expanded 123-fold and 5,981-fold at 18 and 42 days, respectively. The suppressive function of UCB-Tregs on the proliferation of immune cells at 42 days was not significantly different compared with that of UCB-Tregs obtained at 18 days. The suppression rate of UCB-Tregs to PBMCs was negatively correlated with the course of diabetes. Moreover, the high-suppression group exhibited a better treatment response than the low-suppression group during the 12-month follow-up period. CONCLUSIONS: Multiply restimulated UCB-Tregs expanded at a large scale without any alterations in their classical phenotypic features and inhibitory functions. The suppressive function of Tregs in vitro was negatively correlated with the disease duration. The present study revealed the possibility of predicting the in vivo therapeutic effects via the in vitro inhibition assay. Thus, these findings provided a method to obtain off-the-shelf Treg products and facilitated the selection of patients who are likely to respond to the treatment, thereby moving toward the goal of precision treatment.

Care, control and complications of hospitalised patients with type 1 diabetes in China: A nationwide-based registry study.

AIMS: To evaluate the status quo of type 1 diabetes (T1D) management and characteristics of hospitalised patients with T1D in China through a nationwide multicentre registry study, the China Diabetes Type 1 Study (CD1S). MATERIALS AND METHODS: Clinical data from the electronic hospital records of all people with T1D were retrospectively collected in 13 tertiary hospitals across 7 regions of China from January 2016 to December 2021. Patients were defined as newly diagnosed who received a diagnosis of diabetes for less than 3 months. RESULTS: Among the 4993 people with T1D, the median age (range) at diagnosis was 23.0 (1.0-87.0) years and the median disease duration was 2.0 years. The median haemoglobin A1c (HbA1c) level was 10.7%. The prevalence of obesity, overweight, dyslipidemia, and hypertension were 2.5%, 10.8%, 62.5% and 25.9%, respectively. The incidence rate of diabetic ketoacidosis at disease onset was 41.1%, with the highest in children <10 years of age (50.6%). In patients not newly diagnosed, 60.7% were diagnosed with at least one chronic diabetic complication, with the highest proportion (45.3%) of diabetic peripheral neuropathy. Chronic complications were detected in 79.2% of people with T1D duration ≥10 years. CONCLUSIONS: In the most recent years, there were still unsatisfactory metabolic control and high incidence of diabetic ketoacidosis as well as chronic diabetic complications among inpatients with T1D in China. The ongoing CD1S prospective study aims to improve the quality of T1D management nationally.

Retinoic acid receptor α activity in proximal tubules prevents kidney injury and fibrosis.

Chronic kidney disease (CKD) is characterized by a gradual loss of kidney function and affects ~13.4% of the global population. Progressive tubulointerstitial fibrosis, driven in part by proximal tubule (PT) damage, is a hallmark of late stages of CKD and contributes to the development of kidney failure, for which there are limited treatment options. Normal kidney development requires signaling by vitamin A (retinol), which is metabolized to retinoic acid (RA), an endogenous agonist for the RA receptors (RARα, ß, γ). RARα levels are decreased in a mouse model of diabetic nephropathy and restored with RA administration; additionally, RA treatment reduced fibrosis. We developed a mouse model in which a spatiotemporal (tamoxifen-inducible) deletion of RARα in kidney PT cells of adult mice causes mitochondrial dysfunction, massive PT injury, and apoptosis without the use of additional nephrotoxic substances. Long-term effects (3 to 4.5 mo) of RARα deletion include increased PT secretion of transforming growth factor ß1, inflammation, interstitial fibrosis, and decreased kidney function, all of which are major features of human CKD. Therefore, RARα's actions in PTs are crucial for PT homeostasis, and loss of RARα causes injury and a key CKD phenotype.

Association of human leukocyte antigen (HLA) footprints with the comorbidity of latent autoimmune diabetes in adults (LADA) and hepatitis C virus (HCV) infection: A multicenter cross-sectional study.

AIMS: This study aims to investigate the interplay between hepatitis C virus (HCV) infection and major forms of diabetes: type 1 diabetes (T1D), type 2 diabetes (T2D), and latent autoimmune diabetes in adults (LADA). METHODS: This multicenter study analyzed a cohort of 2699 diabetic and 7344 non-diabetic subjects who visited medical centers in China from 2014 to 2021. T1D, T2D, LADA, and HCV were diagnosed using standard procedures. High-throughput sequencing was conducted to identify genetic footprints of human leukocyte antigen (HLA) alleles and haplotypes at the DRB1, DQA1, and DQB1 loci. RESULTS: HCV infection was detected in 3 % (23/766) of LADA patients, followed by 1.5 % (15/977) of T2D patients, 1.4 % (13/926) of T1D patients, and 0.5 % (38/7344) of non-diabetic individuals. HCV prevalence was significantly higher in people with diabetes than in non-diabetic individuals (p < 0.01). HLA alleles (DQB1*060101, DQB1*040101) and haplotypes (DRB1*080302-DQA1*010301-DQB1*060101) in LADA patients with HCV revealed higher frequencies than in LADA patients without HCV (adjusted p < 0.03). Furthermore, a higher risk of diabetes complications was found among LADA patients with HCV infection (p < 0.001). CONCLUSIONS: LADA patients are susceptible to HCV infection, potentially associated with certain HLA alleles/haplotypes. Early diagnosis and treatment of HCV infection among people with diabetes are important for the management of severe complications.

EGR1 and EGR2 positively regulate plant ABA signaling by modulating the phosphorylation of SnRK2.2.

During abscisic acid (ABA) signaling, reversible phosphorylation controls the activity and accumulation of class III SNF1-RELATED PROTEIN KINASE 2s (SnRK2s). While protein phosphatases that negatively regulate SnRK2s have been identified, those that positively regulate ABA signaling through SnRK2s are less understood. In this study, Arabidopsis thaliana mutants of Clade E Growth-Regulating 1 and 2 (EGR1/2), which belong to the protein phosphatase 2C family, exhibited reduced ABA sensitivity in terms of seed germination, cotyledon greening, and ABI5 accumulation. Conversely, overexpression increased these ABA-induced responses. Transcriptomic data revealed that most ABA-regulated genes in egr1 egr2 plants were expressed at reduced levels compared with those in Col-0 after ABA treatment. Abscisic acid up-regulated EGR1/2, which interact directly with SnRK2.2 through its C-terminal domain I. Genetic analysis demonstrated that EGR1/2 function through SnRK2.2 during ABA response. Furthermore, SnRK2.2 de-phosphorylation by EGR1/2 was identified at serine 31 within the ATP-binding pocket. A phospho-mimic mutation confirmed that phosphorylation at serine 31 inhibited SnRK2.2 activity and reduced ABA responsiveness in plants. Our findings highlight the positive role of EGR1/2 in regulating ABA signaling, they reveal a new mechanism for modulating SnRK2.2 activity, and provide novel insight into how plants fine-tune their responses to ABA.

Blocking salt-inducible kinases with YKL-06-061 prevents PTZ-induced seizures in mice.

INTRODUCTION: Epilepsy is one of the most common neurological diseases, while over one third of adults with epilepsy still have inadequate seizure control. Although mutations in salt-inducible kinases (SIKs) have been identified in epileptic encephalopathy, it is not known whether blocking SIKs can prevent pentylenetetrazole (PTZ)-induced seizures. METHODS: We first determined the time course of SIKs (including SIK 1, 2, and 3) in the hippocampus of PTZ treated mice. And then, we evaluated the effects of anti-epilepsy drug valproate acid (VPA) on the expression of SIK 1, 2, and 3 in the hippocampus of PTZ treated mice. Next, we investigated the effect of different dose of SIKs inhibitor YKL-06-061 on the epileptic seizures and neuronal activation by determining the expression of immediate early genes (IEGs) in the PTZ treated mice. RESULTS: We found that PTZ selectively induced enhanced expression of SIK1 in the hippocampus, which was blocked by VPA treatment. Notably, YKL-06-061 decreased seizure activity and prevented neuronal overactivity, as indicated by the reduced expression of IEGs in the hippocampus and prefrontal cortex. CONCLUSION: Our findings provide the first evidence that SIK1 affects gene regulation in neuronal hyperactivity, which is involved in seizure behavior. Targeting SIK1 through the development of selective inhibitors may lead to disease-modifying therapies that reduce epilepsy progression.

Quassinoids from Twigs of Harrisonia perforata (Blanco) Merr and Their Anti-Parkinson's Disease Effect.

Six new C-20 and one new C-19 quassinoids, named perforalactones F-L (1-7), were isolated from twigs of Harrisonia perforata. Spectroscopic and X-ray crystallographic experiments were conducted to identify their structures. Through oxidative degradation of perforalactone B to perforaqussin A, the biogenetic process from C-25 quassinoid to C-20 via Baeyer-Villiger oxidation was proposed. Furthermore, the study evaluated the anti-Parkinson's disease potential of these C-20 quassinoids for the first time on 6-OHDA-induced PC12 cells and a Drosophila Parkinson's disease model of PINK1B9. Perforalactones G and I (2 and 4) showed a 10-15% increase in cell viability of the model cells at 50 µM, while compounds 2 and 4 (100 µM) significantly improved the climbing ability of PINK1B9 flies and increased the dopamine level in the brains and ATP content in the thoraces of the flies.

Tourism during health disasters: Exploring the role of health system quality, transport infrastructure, and environmental expenditures in the revival of the global tourism industry.

Tourism is one of the most important promoters of sustainable development in many nations and regions around the globe. Tourism expansion has been a significant contributor to social and economic growth, particularly in developing economies. It is, however, vulnerable to all kinds of health crises and natural disasters, no matter how small they are. The primary purpose of this study is to acquire an empirical understanding of the effects of health crises and disasters on international tourism. The SYS-GMM was used to examine the impact of health calamities and crises, carbon footprints from transportation, and green finance on the tourism of 51 countries between 2007 and 2020. The results showed that health crises and natural disasters have a big effect on international tourism. Alternatively, the presence of eco-friendly and secure transportation at tourist destinations has a positive effect on the tourism industry. The results also showed that environmental expenditures have positive short- and long-term effects on international tourism. Furthermore, the sensitivity of travelers to health crises and natural disasters varies over the short and long term. The study also showed that compared to normal times, international tourism dropped by more than 67% during COVID-19. Consequently, this research assists us in comprehending, predicting, and preventing the potential adverse effects of COVID-19 and other similar economic, health disasters and crises that could occur in the future and harm the tourism industry.

Fungal co-expression network analyses identify pathogen gene modules associated with host insect invasion.

The broad host range fungal insect pathogen, Beauveria bassiana, has been commercialized as an alternative to chemical insecticides for pest control worldwide. B. bassiana represents a unique model system with which to examine host-pathogen interactions, and a wide range of genes and processes have been studied. However, significant aspects of virulence, particularly on the genomic scale, remain poorly studied. Here, we have combined available transcriptomes with three newly generated data sets for a combined total analysis of 76 deep-sequenced samples covering growth, development, stress responses, and infection during the life cycle of B. bassiana. Co-expression network analyses resulted in the identification of gene modules enriched during two critical stages of the infection process, namely (i) cuticle penetration and (ii) in vivo hyphal body (dimorphic transition) growth capable of avoiding innate and humoral immune defenses. These analyses identify unique signatures of metabolism, signaling, secondary metabolite production, host defense suppression, membrane reorganization, effector production, and secretion for each stage, including genetic regulators and epigenetic patterns. These data provide a comprehensive framework for understanding and probing fungal adaptations to its pathogenic life cycle and expand the candidate repertoire for continued dissection of the host-pathogen interaction. IMPORTANCE Insect fungal pathogens have evolved unique strategies for overcoming host structural and immunological defenses that span from the sclerotized cuticle to innate and humoral cellular responses. Two critical stages of the infection process involve (i) cuticle penetration and (ii) immune evasion within the insect hemocoel. A set of 76 global transcriptomic data for B. bassiana that include the cuticle penetration and hemocoel growth stages were analyzed for patterns (gene modules) of expression, yielding unique insights into these different life stages. These analyses integrate gene networks involved in fungal development, stress response and pathogenesis to further the systematic understanding of the global processes integral to the unique adaptation employed by fungal pathogens of insects.

Retinoic Acid Receptor ß Loss in Hepatocytes Increases Steatosis and Elevates the Integrated Stress Response in Alcohol-Associated Liver Disease.

In alcohol-associated liver disease (ALD), hepatic reductions in vitamin A and perturbations in vitamin A metabolism are common. However, the roles that the vitamin A receptors, termed retinoic acid receptors (RARs), may have in preventing the pathophysiology of ALD remains unclear. Our prior data indicate that a RARß agonist limits the pathology of alcohol-related liver disease. Thus, we generated liver-specific AlbCre-RARß knockout (BKO) mice and compared them to wild type (WT) mice in an early ALD model. Both strains showed similar blood ethanol concentrations and ETOH-metabolizing enzymes. However, the livers of pair-fed-BKO and ETOH-BKO mice developed higher levels of steatosis and triglycerides than pair-fed-WT and ETOH-WT mice. The increased hepatic steatosis observed in the pair-fed-BKO and ETOH-BKO mice was associated with higher lipid synthesis/trafficking transcripts and lower beta-oxidation transcripts. ETOH-BKO mice also exhibited a higher integrated stress response (ISR) signature, including higher transcript and protein levels of ATF4 and its target, 4-EBP1. In human hepatocytes (HepG2) that lack RARß (RARß-KO), ETOH treatments resulted in greater reactive oxygen species compared to their parental cells. Notably, even without ETOH, ATF4 and 4-EBP1 protein levels were higher in the RARß-KO cells than in their parental cells. These 4-EBP1 increases were greatly attenuated in cultured ATF4-deficient and RARß/ATF4-deficient HepG2, suggesting that RARß is a crucial negative regulator of 4-EBP1 through ATF4 in cultured hepatocytes. Here, we identify RARß as a negative regulator of lipid metabolism and cellular stress in ALD.

Gap junction-transported cAMP from the niche controls stem cell progeny differentiation.

The niche has been shown to control stem cell self-renewal in different tissue types and organisms. Recently, a separate niche has been proposed to control stem cell progeny differentiation, called the differentiation niche. However, it remains poorly understood whether and how the differentiation niche directly signals to stem cell progeny to control their differentiation. In the Drosophila ovary, inner germarial sheath (IGS) cells contribute to two separate niche compartments for controlling both germline stem cell (GSC) self-renewal and progeny differentiation. In this study, we show that IGS cells express Inx2 protein, which forms gap junctions (GJs) with germline-specific Zpg protein to control stepwise GSC lineage development, including GSC self-renewal, germline cyst formation, meiotic double-strand DNA break formation, and oocyte specification. Germline-specific Zpg and IGS-specific Inx2 knockdowns cause similar defects in stepwise GSC development. Additionally, secondary messenger cAMP is transported from IGS cells to GSCs and their progeny via GJs to activate PKA signaling for controlling stepwise GSC development. Therefore, this study demonstrates that the niche directly controls GSC progeny differentiation via the GJ-cAMP-PKA signaling axis, which provides important insights into niche control of stem cell differentiation and highlights the importance of GJ-transported cAMP in tissue regeneration. This may represent a general strategy for the niche to control adult stem cell development in various tissue types and organisms since GJs and cAMP are widely distributed.

[Separation, characterization and anti-psoriasis effect of self-assembled nanoparticles from Shaoyao Gancao Decoction].

This study aims to separate and characterize self-assembled nanoparticles(SAN) from Shaoyao Gancao Decoction(SGD) and determine the content of active compounds. Further, we aimed to observe the therapeutic effect of SGD-SAN on imiquimod-induced psoriasis in mice. The separation of SGD was performed by dialysis, and the separation process was optimized by single factor experiment. The SGD-SAN isolated under the optimal process was characterized, and the content of gallic acid, albiflorin, paeoniflorin, liquiritin, isoliquiritin apioside, isoliquiritin, and glycyrrhizic acid in each part of SGD was determined by HPLC. In the animal experiment, mice were assigned into a normal group, a model group, a methotrexate group(0.001 g·kg~(-1)), and SGD, SGD sediment, SGD dialysate, and SGD-SAN groups of different doses(1, 2, and 4 g·kg~(-1)) respectively. The psoriasis grade of mice was evaluated based on the pathological changes of skin lesions, the content of inflammatory cytokines, organ index and other indicators. The results showed that SAN obtained by centrifugation at 13 000 r·min~(-1) for 30 min was stable after dialysis for 4 times, which were uniform spherical nanoparticles with the particle size of(164.43±1.34) nm, the polydispersity index of(0.28±0.05), and the Zeta potential of(-12.35±0.80) mV. The active compound content accounted for more than 70% of SGD. Compared with the model group, SAN and SGD decreased the skin lesion score, spleen index, and inflammatory cytokine levels(P<0.05 or P<0.01) and alleviated the skin thickening and infiltration of inflammatory cells. However, the sediment group and the dialysate group had no obvious effect. SGD showed a good therapeutic effect on imiquimod-induced psoriasis in mice, and SAN demonstrated the effect equivalent to SGD in a dose-dependent manner. Therefore, we conclude that the SAN formed during decocting is the main active form of SGD, which can lower the levels of inflammatory cytokines, promote the normal differentiation of keratinocytes, and reduce the infiltration of inflammatory cells in the treatment of psoriasis lesions in mice.

Combination therapy with saxagliptin and vitamin D for the preservation of ß-cell function in adult-onset type 1 diabetes: a multi-center, randomized, controlled trial.

Disease modifying therapies aiming to preserve ß-cell function in patients with adult-onset autoimmune type 1 diabetes are lacking. Here, we conducted a multi-centre, randomized, controlled trial to assess the ß-cell preservation effects of saxagliptin alone and saxagliptin combined with vitamin D as adjunctive therapies in adult-onset autoimmune type 1 diabetes. In this 3-arm trial, 301 participants were randomly assigned to a 24-month course of the conventional therapy (metformin with or without insulin) or adjunctive saxagliptin or adjunctive saxagliptin plus vitamin D to the conventional therapy. The primary endpoint was the change from baseline to 24 months in the fasting C-peptide. The secondary endpoints included the area under the concentration-time curve (AUC) for C-peptide level in a 2-h mixed-meal tolerance test, glycemic control, total daily insulin use and safety, respectively. The primary endpoint was not achieved in saxagliptin plus vitamin D group (P = 0.18) and saxagliptin group (P = 0.26). However, compared with the conventional therapy, 2-h C-peptide AUC from 24 months to baseline decreased less with saxagliptin plus vitamin D (-276 pmol/L vs. -419 pmol/L; P = 0.01), and not to the same degree with saxagliptin alone (-314 pmol/L; P = 0.14). Notably, for participants with higher glutamic acid decarboxylase antibody (GADA) levels, the decline of ß-cell function was much lower in saxagliptin plus vitamin D group than in the conventional therapy group (P = 0.001). Insulin dose was significantly reduced in both active treatment groups than in the conventional therapy group despite all groups having similar glycemic control. In conclusion, the combination of saxagliptin and vitamin D preserves pancreatic ß-cell function in adult-onset autoimmune type 1 diabetes, an effect especially efficacious in individuals with higher GADA levels. Our results provide evidence for a novel adjunct to insulin and metformin as potential initial treatment for adult-onset type 1 diabetes. (ClinicalTrials.gov identifier: NCT02407899).

Fus3/Kss1-MAP kinase and Ste12-like control distinct biocontrol-traits besides regulation of insect cuticle penetration via phosphorylation cascade in a filamentous fungal pathogen.

BACKGROUND: Homolog of the yeast Fus3/Kss1 mitogen-activated protein kinase (MAPK) pathway and its target transcription factor, Ste12-like, are involved in penetration of host cuticle/pathogenicity in many ascomycete pathogens. However, details of their interaction during fungal infection, as well as their controlled other virulence-associated traits, are unclear. RESULTS: Ste12-like (BbSte12) and Fus3/Kss1 MAPK homolog (Bbmpk1) interacted in nucleus, and phosphorylation of BbSte12 by Bbmpk1 was essential for penetration of insect cuticle in an insect fungal pathogen, Beauveria bassiana. However, some distinct biocontrol-traits were found to be mediated by Ste12 and Bbmpk1. In contrast to ΔBbmpk1 colony that grew more rapid than wild-type strain, inactivation of BbSte12 resulted in the opposite phenotype, which was consistent with their different proliferation rates in insect hemocoel after direct injection of conidia bypass the cuticle. Reduced conidial yield with decreased hydrophobicity was examined in both mutants, however they displayed distinct conidiogenesis, accompanying with differently altered cell cycle, distinct hyphal branching and septum formation. Moreover, ΔBbmpk1 showed increased tolerance to oxidative agent, whereas the opposite phenotype was seen for ΔBbSte12 strain. RNA sequencing analysis revealed that Bbmpk1 controlled 356 genes depending on BbSte12 during cuticle penetration, but 1077 and 584 genes were independently controlled by Bbmpk1 and BbSte12. CONCLUSION: BbSte12 and Bbmpk1 separately participate in additional pathways for control of conidiation, growth and hyphal differentiation, as well as oxidative stress response besides regulating cuticle penetration via phosphorylation cascade. © 2023 Society of Chemical Industry.

Transcriptomic analysis predicts the risk of progression of premalignant lesions in human tongue.

The 5-year survival rate for patients with oral squamous cell carcinomas (SCC), including tongue SCC, has not significantly improved over the last several decades. Oral potentially malignant disorders (OPMD), including oral dysplasias, are oral epithelial disorders that can develop into oral SCCs. To identify molecular characteristics that might predict conversion of OPMDs to SCCs and guide treatment plans, we performed global transcriptomic analysis of human tongue OPMD (n = 9) and tongue SCC (n = 11) samples with paired normal margin tissue from patients treated at Weill Cornell Medicine. Compared to margin tissue, SCCs showed more transcript changes than OPMDs. OPMDs and SCCs shared some altered transcripts, but these changes were generally greater in SCCs than OPMDs. Both OPMDs and SCCs showed altered signaling pathways related to cell migration, basement membrane disruption, and metastasis. We suggest that OPMDs are on the path toward malignant transformation. Based on patterns of gene expression, both OPMD and tongue SCC samples can be categorized into subclasses (mesenchymal, classical, basal, and atypical) similar to those seen in human head and neck SCC (HNSCC). These subclasses of OPMDs have the potential to be used to stratify patient prognoses and therapeutic options for tongue OPMDs. Lastly, we identified a gene set (ELF5; RPTN; IGSF10; CRMP1; HTR3A) whose transcript changes have the power to classify OPMDs and SCCs and developed a Firth logistic regression model using the changes in these transcripts relative to paired normal tissue to validate pathological diagnosis and potentially predict the likelihood of an OPMD developing into SCC, as data sets become available.