Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds.

Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.

Organophosphate esters (OPEs) in corals of the South China Sea: Occurrence, distribution, and bioaccumulation.

Organophosphate esters (OPEs) have garnered significant attention in recent years. In view of the enormous ecosystem services value and severe degradation of coral reefs in the South China Sea, this study investigated the occurrence, distribution, and bioaccumulation of 11 OPEs in five coral regions: Daya Bay (DY), Weizhou Island (WZ), Sanya Luhuitou (LHT), Xisha (XS) Islands, and Nansha (NS) Islands. Although OPEs were detected at a high rate, their concentration in South China Sea seawater (1.56 ± 0.89 ng L-1) remained relatively low compared to global levels. All OPEs were identified in coral tissues, with Luhuitou (575 ± 242 ng g-1 dw) showing the highest pollution levels, attributed to intense human activities. Coral mucus, acting as a defense against environmental stresses, accumulated higher ∑11OPEs (414 ± 461 ng g-1 dw) than coral tissues (412 ± 197 ng g-1 dw) (nonparametric test, p < 0.05), and their compositional characteristics varied greatly. In the case of harsh aquatic environments, corals increase mucus secretion and then accumulate organic pollutants. Tissue-mucus partitioning varied among coral species. Most OPEs were found to be bioaccumulative (BAFs >5000 L kg-1) in a few coral tissue samples besides Triphenyl phosphate (TPHP). Mucus' role in the bioaccumulation of OPEs in coral shouldn't be ignored.

A machine learning algorithm based on circulating metabolic biomarkers offers improved predictions of neurological diseases.

BACKGROUND AND AIMS: A machine learning algorithm based on circulating metabolic biomarkers for the predictions of neurological diseases (NLDs) is lacking. To develop a machine learning algorithm to compare the performance of a metabolic biomarker-based model with that of a clinical model based on conventional risk factors for predicting three NLDs: dementia, Parkinson's disease (PD), and Alzheimer's disease (AD). MATERIALS AND METHODS: The eXtreme Gradient Boosting (XGBoost) algorithm was used to construct a metabolic biomarker-based model (metabolic model), a clinical risk factor-based model (clinical model), and a combined model for the prediction of the three NLDs. Risk discrimination (c-statistic), net reclassification improvement (NRI) index, and integrated discrimination improvement (IDI) index values were determined for each model. RESULTS: The results indicate that incorporation of metabolic biomarkers into the clinical model afforded a model with improved performance in the prediction of dementia, AD, and PD, as demonstrated by NRI values of 0.159 (0.039-0.279), 0.113 (0.005-0.176), and 0.201 (-0.021-0.423), respectively; and IDI values of 0.098 (0.073-0.122), 0.070 (0.049-0.090), and 0.085 (0.068-0.101), respectively. CONCLUSION: The performance of the model based on circulating NMR spectroscopy-detected metabolic biomarkers was better than that of the clinical model in the prediction of dementia, AD, and PD.

The molecular subtypes of autoimmune diseases.

Autoimmune diseases (ADs) are characterized by their complexity and a wide range of clinical differences. Despite patients presenting with similar symptoms and disease patterns, their reactions to treatments may vary. The current approach of personalized medicine, which relies on molecular data, is seen as an effective method to address the variability in these diseases. This review examined the pathologic classification of ADs, such as multiple sclerosis and lupus nephritis, over time. Acknowledging the limitations inherent in pathologic classification, the focus shifted to molecular classification to achieve a deeper insight into disease heterogeneity. The study outlined the established methods and findings from the molecular classification of ADs, categorizing systemic lupus erythematosus (SLE) into four subtypes, inflammatory bowel disease (IBD) into two, rheumatoid arthritis (RA) into three, and multiple sclerosis (MS) into a single subtype. It was observed that the high inflammation subtype of IBD, the RA inflammation subtype, and the MS "inflammation & EGF" subtype share similarities. These subtypes all display a consistent pattern of inflammation that is primarily driven by the activation of the JAK-STAT pathway, with the effective drugs being those that target this signaling pathway. Additionally, by identifying markers that are uniquely associated with the various subtypes within the same disease, the study was able to describe the differences between subtypes in detail. The findings are expected to contribute to the development of personalized treatment plans for patients and establish a strong basis for tailored approaches to treating autoimmune diseases.

Immune control in Kawasaki disease knowledge mapping: a bibliometric analysis.

BACKGROUND: Kawasaki disease is a systemic vascular disease with an unclear pathophysiology that primarily affects children under the age of five. Research on immune control in Kawasaki disease has been gaining attention. This study aims to apply a bibliometric analysis to examine the present and future directions of immune control in Kawasaki disease. METHODS: By utilizing the themes "Kawasaki disease," "Kawasaki syndrome," and "immune control," the Web of Science Core Collection database was searched for publications on immune control in Kawasaki disease. This bibliometric analysis was carried out using VOSviewers, CiteSpace, and the R package "bibliometrix." RESULTS: In total, 294 studies on immune control in Kawasaki disease were published in Web of Science Core Collection. The three most significant institutions were Chang Gung University, the University of California San Diego, and Kaohsiung Chang Gung Memorial Hospital. China, the United States, and Japan were the three most important countries. In this research field, Clinical and Experimental Immunology was the top-referred journal, while the New England Journal of Medicine was the most co-cited journal. The Web of Science Core Collection document by McCrindle BW et al. published in 2017 was the most cited reference. Additionally, the author keywords concentrated on "COVID-19," "SARS-CoV-2," and "multisystem inflammatory syndrome in children" in recent years. CONCLUSION: The research trends and advancements in immune control in Kawasaki disease are thoroughly summarised in this bibliometric analysis, which is the first to do so. The data indicate recent research frontiers and hot directions, making it easier for researchers to study the immune control of Kawasaki disease.

Effect of sunlight on vitamin D and hemoglobin levels among the residents of Ningbo, China.

PURPOSE: this study investigated the effect of sunlight on vitamin D and hemoglobin levels among the residents of Ningbo, China. The impact of gender, age, and season on vitamin D and hemoglobin levels was also explored. METHODS: a total of 8,481 research subjects, including 5,146 men and 3,335 women, who were permanent residents of Ningbo and received health checkups at Ningbo Second Hospital, were included in the study. Ningbo City climate bulletin data from 2019 to 2022 was also included. RESULTS: the study subjects received an average of 132.20 ± 40.05 h of sunlight exposure per month and had average vitamin D levels of 19.63 ± 6.61 ng/ml. Hemoglobin levels were adequate in 85.4 % of the participants and deficient in 14.6 %. Sunlight exposure correlated positively with vitamin D and negatively with hemoglobin levels. Regression analysis indicated that gender, age, and season affected vitamin D and hemoglobin levels to different degrees. CONCLUSION: in Ningbo, vitamin D deficiency was common in adults while hemoglobin levels were mostly normal. The amount of sunlight exposure had a significant effect on vitamin D and hemoglobin levels and this relationship was impacted by gender, age, and season.

Development of a 3-step sequential extraction method to investigate the fraction and affecting factors of 21 antibiotics in soils.

Antibiotic exist in various states after entering agricultural soil through the application of manure, including the aqueous state (I), which can be directly absorbed by plants, and the auxiliary organic extraction state (III), which is closely associated with the pseudo-permanence of antibiotics. However, effective analytical methods for extracting and affecting factors on fractions of different antibiotic states remain unclear. In this study, KCl, acetonitrile/Na2EDTA-McIlvaine buffer, and acetonitrile/water were successively used to extract states I, II, and III of 21 antibiotics in soil, and the recovery efficiency met the quantitative requirements. Random forest classification and variance partitioning analysis revealed that dissolved organic matter, pH, and organic matter were important factors affecting the recovery efficiency of antibiotic in states I, II, and III, respectively. Additionally, 65-day spiked soil experiments combined with Mantel test analysis suggested that pH, organic acids, heavy metals, and noncrystalline minerals differentially affected antibiotic type and state. Importantly, a structural equation model indicated that organic acids play a crucial role in the fraction of antibiotic states. Overall, this study reveals the factors influencing the fraction of different antibiotic states in soil, which is helpful for accurately assessing their ecological risk.

A review of disease risk prediction methods and applications in the omics era.

Risk prediction and disease prevention are the innovative care challenges of the 21st century. Apart from freeing the individual from the pain of disease, it will lead to low medical costs for society. Until very recently, risk assessments have ushered in a new era with the emergence of omics technologies, including genomics, transcriptomics, epigenomics, proteomics, and so on, which potentially advance the ability of biomarkers to aid prediction models. While risk prediction has achieved great success, there are still some challenges and limitations. We reviewed the general process of omics-based disease risk model construction and the applications in four typical diseases. Meanwhile, we highlighted the problems in current studies and explored the potential opportunities and challenges for future clinical practice.

Increase in Agricultural-Derived NHx and Decrease in Coal Combustion-Derived NOx Result in Atmospheric Particulate N-NH4+ Surpassing N-NO3- in the South China Sea.

The atmospheric deposition of anthropogenic active nitrogen significantly influences marine primary productivity and contributes to eutrophication. The form of nitrogen deposition has been evolving annually, alongside changes in human activities. A disparity arises between observation results and simulation conclusions due to the limited field observation and research in the ocean. To address this gap, our study undertook three field cruises in the South China Sea in 2021, the largest marginal sea of China. The objective was to investigate the latest atmospheric particulate inorganic nitrogen deposition pattern and changes in nitrogen sources, employing nitrogen-stable isotopes of nitrate (δ15N-NO3-) and ammonia (δ15N-NH4+) linked to a mixing model. The findings reveal that the N-NH4+ deposition generally surpasses N-NO3- deposition, attributed to a decline in the level of NOx emission from coal combustion and an upswing in the level of NHx emission from agricultural sources. The disparity in deposition between N-NH4+ and N-NO3- intensifies from the coast to the offshore, establishing N-NH4+ as the primary contributor to oceanic nitrogen deposition, particularly in ocean background regions. Fertilizer (33 ± 21%) and livestock (20 ± 6%) emerge as the primary sources of N-NH4+. While coal combustion continues to be a significant contributor to marine atmospheric N-NO3-, its proportion has diminished to 22 (Northern Coast)-35% (background area) due to effective NOx emission controls by the countries surrounding the South China Sea, especially the Chinese Government. As coal combustion's contribution dwindles, the significance of vessel and marine biogenic emissions grows. The daytime higher atmospheric N-NO3- concentration and lower δ15N-NO3- compared with nighttime further underscore the substantial role of marine biogenic emissions.

Serum Olink Proteomics-Based Identification of Protein Biomarkers Associated with the Immune Response in Ischemic Stroke.

The immune response is considered essential for pathology of ischemic stroke (IS), but it remains unclear which immune response-related proteins exhibit altered expression in IS patients. Here, we used Olink proteomics to examine the expression levels of 92 immune response-related proteins in the sera of IS patients (n = 88) and controls (n = 88), and we found that 59 of these proteins were differentially expressed. Feature variables were screened from the differentially expressed proteins by the least absolute shrinkage and selection operator (LASSO) and the random forest and by determining whether their proteins had an area under the curve (AUC) greater than 0.8. Ultimately, we identified six potential protein biomarkers of IS, namely, MASP1, STC1, HCLS1, CLEC4D, PTH1R, and PIK3AP1, and established a logistic regression model that used these proteins to diagnose IS. The AUCs of the models in the internal validation and the test set were 0.962 (95% confidence interval (CI): 0.895-1.000) and 0.954 (95% CI: 0.884-1.000), respectively, and the same protein detection method was performed in an external independent validation set (AUC: 0.857 (95% CI: 0.801-0.913)). These proteins may play a role in immune regulation via the C-type lectin receptor signaling pathway, the PI3K-AKT signaling pathway, and the B-cell receptor signaling pathway.

Bioinspired BSA@polydopamine@Fe Nanoprobe with Self-Purification Capacity for Targeted Magnetic Resonance Imaging of Acute Kidney Injury.

Contrast-enhanced magnetic resonance imaging (CE-MRI) of acute kidney injury (AKI) is severely hindered by the poor targeting capacity and potential toxicity of current contrast agents. Herein, we propose one-step fabrication of a bovine serum albumin@polydopamine@Fe (BSA@PDA@Fe, BPFe) nanoprobe with self-purification capacity for targeted CE-MRI of AKI. BSA endows the BPFe nanoprobe with renal tubule-targeting ability, and PDA is capable of completely inhibiting the intrinsic metal-induced reactive oxygen species (ROS), which are always involved in Fe/Mn-based agents. The as-prepared nanoprobe owns a tiny size of 2.7 nm, excellent solubility, good T1 MRI ability, superior biocompatibility, and powerful antioxidant capacity. In vivo CE-MRI shows that the BPFe nanoprobe can accumulate in the renal cortex due to the reabsorption effect toward the serum albumin. In the AKI model, impaired renal reabsorption function can be effortlessly detected via the diminishment of renal cortical signal enhancement. More importantly, the administration of the BPFe nanoprobe would not aggravate renal damage of AKI due to the outstanding self-purification capacity. Besides, the BPFe nanoprobe is employed for CE-MR angiography to visualize fine vessel structures. This work provides an MRI contrast agent with good biosafety and targeting ability for CE-MRI of kidney diseases.

Identifying functional subtypes of IgA nephropathy based on three machine learning algorithms and WGCNA.

BACKGROUND: IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis, which is a significant cause of renal failure. At present, the classification of IgAN is often limited to pathology, and its molecular mechanism has not been established. Therefore we aim to identify subtypes of IgAN at the molecular level and explore the heterogeneity of subtypes in terms of immune cell infiltration, functional level. METHODS: Two microarray datasets (GSE116626 and GSE115857) were downloaded from GEO. Differential expression genes (DEGs) for IgAN were screened with limma. Three unsupervised clustering algorithms (hclust, PAM, and ConsensusClusterPlus) were combined to develop a single-sample subtype random forest classifier (SSRC). Functional subtypes of IgAN were defined based on functional analysis and current IgAN findings. Then the correlation between IgAN subtypes and clinical features such as eGFR and proteinuria was evaluated by using Pearson method. Subsequently, subtype heterogeneity was verified by subtype-specific modules identification based on weighted gene co-expression network analysis(WGCNA) and immune cell infiltration analysis based on CIBERSORT algorithm. RESULTS: We identified 102 DEGs as marker genes for IgAN and three functional subtypes namely: viral-hormonal, bacterial-immune and mixed type. We screened seventeen genes specific to viral hormonal type (ATF3, JUN and FOS etc.), and seven genes specific to bacterial immune type (LIF, C19orf51 and SLPI etc.). The subtype-specific genes showed significantly high correlation with proteinuria and eGFR. The WGCNA modules were in keeping with functions of the IgAN subtypes where the MEcyan module was specific to the viral-hormonal type and the MElightgreen module was specific to the bacterial-immune type. The results of immune cell infiltration revealed subtype-specific cell heterogeneity which included significant differences in T follicular helper cells, resting NK cells between viral-hormone type and control group; significant differences in eosinophils, monocytes, macrophages, mast cells and other cells between bacterial-immune type and control. CONCLUSION: In this study, we identified three functional subtypes of IgAN for the first time and specific expressed genes for each subtype. Then we constructed a subtype classifier and classify IgAN patients into specific subtypes, which may be benefit for the precise treatment of IgAN patients in future.

Spatiotemporal distribution and potential risks of antibiotics in coastal water of Beibu Gulf, South China Sea: Livestock and poultry emissions play essential effect.

Antibiotics have been the subject of much attention in recent years due to their widespread use and the potential ecological risks and resistance risks. In this study, we conducted an extensive survey of 19 antibiotics in a wide range of waters of the Beibu Gulf during summer and winter (154 samples). The total concentrations of the 19 antibiotics (Σ19ABs, ng/L) were significantly higher in winter (n.d.-364) than in summer (n.d.-70.1) and were mainly concentrated in areas of seagoing rivers (1.50-364). The primary route for antibiotics entering Beibu Gulf was through riverine input. Precisely, florfenicol (FF) (n.d.-278 ng/L) discharged from livestock and poultry farms upstream of Nanliu River, predominantly in swine farming, constitutes the main pollutant in Beibu Gulf throughout the year. The Nanliu River (988 kg/a) accounts for 85% of the gulf's total annual antibiotic emission flux. Source analysis identified livestock and poultry farming, particularly swine farming, as the primary pollution source, contributing 58% in summer. Risk assessment reveals that algae (0.51 ± 0.56) exhibited relatively high sensitivity to antibiotics, presenting a medium-high risk at specific sites in Nanliu River during winter. Additionally, FF discharged from swine farming demonstrates a certain level of antibiotic resistance risk. Therefore, reinforcing control measures for antibiotic discharges from livestock and poultry farming, especially upstream of Nanliu River, can effectively mitigate antibiotic-related risks in the water bodies of Beibu Gulf.

Highly Efficient Aligned Ion-Conducting Network and Interface Chemistries for Depolarized All-Solid-State Lithium Metal Batteries.

Improving the long-term cycling stability and energy density of all-solid-state lithium (Li)-metal batteries (ASSLMBs) at room temperature is a severe challenge because of the notorious solid-solid interfacial contact loss and sluggish ion transport. Solid electrolytes are generally studied as two-dimensional (2D) structures with planar interfaces, showing limited interfacial contact and further resulting in unstable Li/electrolyte and cathode/electrolyte interfaces. Herein, three-dimensional (3D) architecturally designed composite solid electrolytes are developed with independently controlled structural factors using 3D printing processing and post-curing treatment. Multiple-type electrolyte films with vertical-aligned micro-pillar (p-3DSE) and spiral (s-3DSE) structures are rationally designed and developed, which can be employed for both Li metal anode and cathode in terms of accelerating the Li+ transport within electrodes and reinforcing the interfacial adhesion. The printed p-3DSE delivers robust long-term cycle life of up to 2600 cycles and a high critical current density of 1.92 mA cm-2. The optimized electrolyte structure could lead to ASSLMBs with a superior full-cell areal capacity of 2.75 mAh cm-2 (LFP) and 3.92 mAh cm-2 (NCM811). This unique design provides enhancements for both anode and cathode electrodes, thereby alleviating interfacial degradation induced by dendrite growth and contact loss. The approach in this study opens a new design strategy for advanced composite solid polymer electrolytes in ASSLMBs operating under high rates/capacities and room temperature.

Plasma lipidomic profiling reveals six candidate biomarkers for the prediction of incident stroke in patients with hypertension.

INTRODUCTION: The burden of stroke in patients with hypertension is very high, and its prediction is critical. OBJECTIVES: We aimed to use plasma lipidomics profiling to identify lipid biomarkers for predicting incident stroke in patients with hypertension. METHODS: This was a nested case-control study. Baseline plasma samples were collected from 30 hypertensive patients with newly developed stroke, 30 matched patients with hypertension, 30 matched patients at high risk of stroke, and 30 matched healthy controls. Lipidomics analysis was performed by ultrahigh-performance liquid chromatography-tandem mass spectrometry, and differential lipid metabolites were screened using multivariate and univariate statistical methods. Machine learning methods (least absolute shrinkage and selection operator, random forest) were used to identify candidate biomarkers for predicting stroke in patients with hypertension. RESULTS: Co-expression network analysis revealed that the key molecular alterations of the lipid network in stroke implicate glycerophospholipid metabolism and choline metabolism. Six lipid metabolites were identified as candidate biomarkers by multivariate statistical and machine learning methods, namely phosphatidyl choline(40:3p)(rep), cholesteryl ester(20:5), monoglyceride(29:5), triglyceride(18:0p/18:1/18:1), triglyceride(18:1/18:2/21:0) and coenzyme(q9). The combination of these six lipid biomarkers exhibited good diagnostic and predictive ability, as it could indicate a risk of stroke at an early stage in patients with hypertension (area under the curve = 0.870; 95% confidence interval: 0.783-0.957). CONCLUSIONS: We determined lipidomic signatures associated with future stroke development and identified new lipid biomarkers for predicting stroke in patients with hypertension. The biomarkers have translational potential and thus may serve as blood-based biomarkers for predicting hypertensive stroke.

Association between sleep pattern and incidence of hypertension: A prospective cohort study of older adult participants in the Chinese longitudinal healthy longevity survey.

BACKGROUND: The relationship between sleep duration or sleep quality and the risk of hypertension has been previously examined. However, little is known regarding the association between sleep duration and quality and the risk of developing hypertension in the older adult Chinese population. METHODS: The sleep patterns of 5683 participants without hypertension at baseline from the Chinese Longitudinal Healthy Longevity Survey were analyzed. Cox proportional hazard models were used to study the associations between sleep patterns and hypertension. RESULTS: It was found that 1712 (30.12%) of the 5683 participants had an unhealthy sleep pattern. After an average follow-up of 3.31 years, 1350 of the participants had hypertension. Compared with participants with an unhealthy sleep pattern, those with a healthy sleep pattern had a 20% (hazard ratio = 0.80, 95% confidence interval = 0.67-0.94, P = = 0.008) lower risk of incident hypertension in the fully adjusted models. In addition, an approximately linear dose-response association was observed between sleep duration and the incidence of hypertension (P for non-linear =0.43). Subgroup analyses demonstrated significant interactions between age and sleep pattern concerning hypertension (P for interaction <0.05). Several sensitivity analyses were conducted, and the obtained findings were similar to the main results. CONCLUSIONS: A healthy sleep pattern, comprising an adequate sleep duration and good sleep quality, can help reduce hypertension risk. Thus, a healthy sleep pattern is crucial to decreasing hypertension in older Chinese adults in a rapidly aging society.

Distribution and adsorption-desorption of organophosphate esters from land to sea in the sediments of the Beibu Gulf, South China Sea: Impact of seagoing river input.

Organophosphate esters (OPEs) have been a class of emerging environmental contaminants. However, studies on their environmental behavior, specifically their adsorption-desorption behavior between sediment and seawater in estuarine and coastal areas, remain limited. To address this gap, our study focused on investigating the levels and behavior of 11 OPEs in sediment samples collected from the Beibu Gulf, South China Sea, encompassing estuaries and coastal regions. The total concentrations of 11 OPEs (Σ11OPEs) in the sediments exhibit a significant decrease in summer, both in seagoing rivers (4.67 ± 2.74 ng/g dw) and the coastal zone (5.11 ± 3.71 ng/g dw), compared to winter levels in seagoing rivers (8.26 ± 4.70 ng/g dw) and the coastal zone (7.71 ± 3.83 ng/g dw). Chlorinated OPEs dominated the sediments, constituting 63 %-76 % of the total. Particularly, port and mariculture areas showed the highest levels of OPEs. Through load estimation analysis, it was revealed that the sedimentary OPEs in Qinzhou Bay (221 ± 128 kg) had the highest load, with input from the Qin River identified as a significant source. Chlorinated OPEs showed a trend of desorption from sediments to the water column with increasing salinity, emphasizing the crucial role of land-based OPEs input through suspended particulate matter in rivers as a pathway to the ocean. The impact of strong flow in estuarine environments was highlighted, as it can scour sediments, generate suspended sediments, and release OPEs into the water bodies. Additionally, the results of the ecological risk assessment indicated that most of the OPEs posed low-risk levels. However, attention is warranted for the contamination levels of some chlorinated OPEs, emphasizing the need for ongoing monitoring and assessment.

A retrospective study of alveolar bone remodelling after anterior retraction in orthodontic tooth extraction cases with clear aligners and fixed appliances.

OBJECTIVES: To evaluate alveolar bone dimensions and its relationship with tooth movement (retraction, intrusion and torque) during orthodontic treatment with fixed appliance and clear aligners. METHODS: Thirty-two patients were included in this retrospective clinical study. Cone beam computed tomography (CBCT) was collected before and after treatment to measure the volume of dehiscence and fenestrations in the maxillary anterior region, anterior alveolar bone thickness and height and degree of tooth movement. Rank-sum tests were used to compare the differences in alveolar bone defect volumes between clear aligners and fixed appliance, multiple linear regression analysis was used for study evaluation, and kappa statistics were used to assess internal consistency and test-retest reliability. RESULTS: Post-operatively, most alveolar bone defects occurred on the labial side. The incidence of bone fenestration was 23.96% in the clear aligner group and 26.18% in the fixed appliance group, which was higher than the incidence of bone dehiscence (5.21%). The labial bone height decreased by 0.272 mm, and the palatal bone height increased by 0.617 mm for every 1 mm downward intrusion of the anterior tooth apex in the fixed appliance group. In the clear aligner group, there was no significant change in the labial bone height, and the palatal bone height decreased by 0.447 mm for every 1 mm of anterior tooth retraction coronally. CONCLUSIONS: In the fixed appliance group, anterior tooth intrusion and retraction may have led to alveolar bone resorption by its compression at the cervical level. This study provides a three-dimensional tooth movement evaluation method by using CBCT.

Type I MADS-box transcription factor TaMADS-GS regulates grain size by stabilizing cytokinin signalling during endosperm cellularization in wheat.

Grain size is one of the important traits in wheat breeding programs aimed at improving yield, and cytokinins, mainly involved in cell division, have a positive impact on grain size. Here, we identified a novel wheat gene TaMADS-GS encoding type I MADS-box transcription factor, which regulates the cytokinins signalling pathway during early stages of grain development to modulate grain size and weight in wheat. TaMADS-GS is exclusively expressed in grains at early stage of seed development and its knockout leads to delayed endosperm cellularization, smaller grain size and lower grain weight. TaMADS-GS protein interacts with the Polycomb Repressive Complex 2 (PRC2) and leads to repression of genes encoding cytokinin oxidase/dehydrogenases (CKXs) stimulating cytokinins inactivation by mediating accumulation of the histone H3 trimethylation at lysine 27 (H3K27me3). Through the screening of a large wheat germplasm collection, an elite allele of the TaMADS-GS exhibits higher ability to repress expression of genes inactivating cytokinins and a positive correlation with grain size and weight, thus representing a novel marker for breeding programs in wheat. Overall, these findings support the relevance of TaMADS-GS as a key regulator of wheat grain size and weight.

Integrating multi-omics data to analyze the potential pathogenic mechanism of CTSH gene involved in type 1 diabetes in the exocrine pancreas.

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of insulin-producing pancreatic islet beta cells. Despite significant advancements, the precise pathogenesis of the disease remains unknown. This work integrated data from expression quantitative trait locus (eQTL) studies with Genome wide association study (GWAS) summary data of T1D and single-cell transcriptome data to investigate the potential pathogenic mechanisms of the CTSH gene involved in T1D in exocrine pancreas. Using the summary data-based Mendelian randomization (SMR) approach, we obtained four potential causative genes associated with T1D: BTN3A2, PGAP3, SMARCE1 and CTSH. To further investigate these genes'roles in T1D development, we validated them using a scRNA-seq dataset from pancreatic tissues of both T1D patients and healthy controls. The analysis showed a significantly high expression of the CTSH gene in T1D acinar cells, whereas the other three genes showed no significant changes in the scRNA-seq data. Moreover, single-cell WGCNA analysis revealed the strongest positive correlation between the module containing CTSH and T1D. In addition, we found cellular ligand-receptor interactions between the acinar cells and different cell types, especially ductal cells. Finally, based on functional enrichment analysis, we hypothesized that the CTSH gene in the exocrine pancreas enhances the antiviral response, leading to the overexpression of pro-inflammatory cytokines and the development of an inflammatory microenvironment. This process promotes ß cells injury and ultimately the development of T1D. Our findings offer insights into the underlying pathogenic mechanisms of T1D.