Unambiguous discrimination of all 20 proteinogenic amino acids and their modifications by nanopore.

Natural proteins are composed of 20 proteinogenic amino acids and their post-translational modifications (PTMs). However, due to the lack of a suitable nanopore sensor that can simultaneously discriminate between all 20 amino acids and their PTMs, direct sequencing of protein with nanopores has not yet been realized. Here, we present an engineered hetero-octameric Mycobacterium smegmatis porin A (MspA) nanopore containing a sole Ni2+ modification. It enables full discrimination of all 20 proteinogenic amino acids and 4 representative modified amino acids, Nω,N'ω-dimethyl-arginine (Me-R), O-acetyl-threonine (Ac-T), N4-(ß-N-acetyl-D-glucosaminyl)-asparagine (GlcNAc-N) and O-phosphoserine (P-S). Assisted by machine learning, an accuracy of 98.6% was achieved. Amino acid supplement tablets and peptidase-digested amino acids from peptides were also analyzed using this strategy. This capacity for simultaneous discrimination of all 20 proteinogenic amino acids and their PTMs suggests the potential to achieve protein sequencing using this nanopore-based strategy.

Simultaneous Identification of Vitamins B1, B3, B5, and B6 by an Engineered Nanopore.

Vitamin Bs, a group of water-soluble compounds, are essential nutrients for almost all living organisms. However, due to their structural heterogeneity, rapid and simultaneous analysis of multiple vitamin Bs is still challenging. In this paper, it is discovered that a hetero-octameric Mycobacterium smegmatis porin A (MspA) nanopore containing a sole nickel ion-bound nitrilotriacetic acid (NTA-Ni) adapter at its pore constriction is suitable for the simultaneous sensing of different vitamin Bs, including vitamin B1 (thiamine), vitamin B3 (nicotinic acid and nicotinamide), vitamin B5 (pantothenic acid), and vitamin B6 (pyridoxine, pyridoxal, and pyridoxamine). Assisted by a custom machine learning algorithm, all seven vitamin Bs can be fully distinguished, reporting a general accuracy of 99.9%. This method was further validated in the rapid analysis of commercial cosmetics and natural food, suggesting its potential uses in food and drug administration.

Simultaneous Identification of Major Thyroid Hormones by a Nickel Immobilized Biological Nanopore.

Thyroid hormones (THs) are a variety of iodine-containing hormones that demonstrate critical physiological impacts on cellular activities. The assessment of thyroid function and the diagnosis of thyroid disorders require accurate measurement of TH levels. However, largely due to their structural similarities, the simultaneous discrimination of different THs is challenging. Nanopores, single-molecule sensors with a high resolution, are suitable for this task. In this paper, a hetero-octameric Mycobacterium smegmatis porin A (MspA) nanopore containing a single nickel ion immobilized to the pore constriction has enabled simultaneous identification of five representative THs including l-thyroxine (T4), 3,3',5-triiodo-l-thyronine (T3), 3,3',5'-triiodo-l-thyronine (rT3), 3,5-diiodo-l-thyronine (3,5-T2) and 3,3'-diiodo-l-thyronine (3,3'-T2). To automate event classification and avoid human bias, a machine learning algorithm was also developed, reporting an accuracy of 99.0%. This sensing strategy is also applied in the analysis of TH in a real human serum environment, suggesting its potential use in a clinical diagnosis.

Single-Cell Profiling of Tumor Immune Microenvironment Reveals Immune Irresponsiveness in Gastric Signet-Ring Cell Carcinoma.

BACKGROUND & AIMS: Gastric cancer (GC) is a major cancer type characterized by high heterogeneity in both tumor cells and the tumor immune microenvironment (TIME). One intractable GC subtype is gastric signet-ring cell carcinoma (GSRCC), which is associated with poor prognosis. However, it remains unclear what the GSRCC TIME characteristics are and how these characteristics may contribute to clinical outcomes. METHODS: We enrolled 32 patients with advanced GC of diverse subtypes and profiled their TIME using an immune-targeted single-cell profiling strategy, including (1) immune-targeted single-cell RNA sequencing (n = 20 patients) and (2) protein expression profiling by a targeted antibody panel for mass cytometry (n = 12 patients). We also generated matched V(D)J (variable, diversity, and joining gene segments) sequencing of T and B cells along CD45+ immunocytes. RESULTS: We found that compared to non-GSRCC, the GSRCC TIME appears to be quiescent, where both CD4+ and CD8+ T cells are difficult to be mobilized, which further impairs the proper functions of B cells. CXCL13, mainly produced by follicular helper T cells, T helper type 17, and exhausted CD8+ T cells, is a central coordinator of this transformation. We show that CXCL13 expression can predict the response to immune checkpoint blockade in GC patients, which may be related to its effects on tertiary lymphoid structures. CONCLUSIONS: Our study provides a comprehensive molecular portrait of immune cell compositions and cell states in advanced GC patients, highlighting adaptive immune irresponsiveness in GSRCC and a mediator role of CXCL13 in TIME. Our targeted single-cell transcriptomic and proteomic profiling represents a powerful approach for TIME-oriented translational research.

Hybrid deep learning based prediction for water quality of plain watershed.

Establishing a highly reliable and accurate water quality prediction model is critical for effective water environment management. However, enhancing the performance of these predictive models continues to pose challenges, especially in the plain watershed with complex hydraulic conditions. This study aims to evaluate the efficacy of three traditional machine learning models versus three deep learning models in predicting the water quality of plain river networks and to develop a novel hybrid deep learning model to further improve prediction accuracy. The performance of the proposed model was assessed under various input feature sets and data temporal frequencies. The findings indicated that deep learning models outperformed traditional machine learning models in handling complex time series data. Long Short-Term Memory (LSTM) models improved the R2 by approximately 29% and lowered the Root Mean Square Error (RMSE) by about 48.6% on average. The hybrid Bayes-LSTM-GRU (Gated Recurrent Unit) model significantly enhanced prediction accuracy, reducing the average RMSE by 18.1% compared to the single LSTM model. Models trained on feature-selected datasets exhibited superior performance compared to those trained on original datasets. Higher temporal frequencies of input data generally provide more useful information. However, in datasets with numerous abrupt changes, increasing the temporal interval proves beneficial. Overall, the proposed hybrid deep learning model demonstrates an efficient and cost-effective method for improving water quality prediction performance, showing significant potential for application in managing water quality in plain watershed.

Nanopore Discrimination of Nucleotide Sugars.

Nucleotide sugars, the glycosyl donors in the biosynthesis of carbohydrates, are critical ingredients in the growth and development of all living organisms. A variety of nucleotide sugars simultaneously exist in biological samples. They, however, have only minor structural differences, which make them extremely difficult to discriminate. In this work, a phenylboronic acid (PBA)-modified Mycobacterium smegmatis porin A (MspA) hetero-octamer was applied to sense nucleotide sugars. Five representative nucleotide sugars, including guanosine diphosphate mannose (GDP-Man), adenosine diphosphate glucose (ADP-Glc), uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), uridine diphosphate glucose (UDP-Glc), and uridine diphosphate glucoronic acid (UDP-GlcA), were successfully distinguished. A custom machine learning algorithm was also employed to automatically identify events, reporting a general accuracy of 99.4%. This sensing strategy provides a rapid, direct, and accurate method for identifying different nucleotide sugars. However, single-molecule identification of nucleotide sugars has never been previously reported, to the best of our knowledge.

Altered topological properties and their relationship to cognitive functions in unilateral temporal lobe epilepsy.

OBJECTIVE: To investigate abnormalities in topological properties in unilateral temporal lobe epilepsy (TLE) with hippocampal sclerosis and their correlations with cognitive functions. METHODS: Thirty-eight patients with TLE and 19 age- and sex-matched healthy controls (HCs) were enrolled in this research and underwent resting-state functional magnetic resonance imaging (fMRI) examinations. Whole-brain functional networks of participants were constructed based on the fMRI data. Topological characteristics of the functional network were compared between patients with left and right TLE and HCs. Correlations between altered topological properties and cognitive measurements were explored. RESULTS: Compared with the HCs, patients with left TLE showed decreased clustering coefficient, global efficiency, and local efficiency (Eloc), and patients with right TLE showed decreased Eloc. We found altered nodal centralities in six regions related to the basal ganglia (BG) network or default mode network (DMN) in patients with left TLE and those in three regions related to reward/emotion network or ventral attention network in patients with right TLE. Patients with right TLE showed higher integration (reduced nodal shortest path length) in four regions related to the DMN and lower segregation (reduced nodal local efficiency and nodal clustering coefficient) in the right middle temporal gyrus. When comparing left TLE with right TLE, no significant differences were detected in global parameters, but the nodal centralities in the left parahippocampal gyrus and the left pallidum were decreased in left TLE. The Eloc and several nodal parameters were significantly correlated with memory functions, duration, national hospital seizure severity scale (NHS3), or antiseizure medications (ASMs) in patients with TLE. CONCLUSIONS: The topological properties of whole-brain functional networks were disrupted in TLE. Networks of left TLE were characterized by lower efficiency; right TLE was preserved in global efficiency but disrupted in fault tolerance. Several nodes with abnormal topological centrality in the basal ganglia network beyond the epileptogenic focus in the left TLE were not found in the right TLE. Right TLE had some nodes with reduced shortest path length in regions of the DMN as compensation. These findings provide new insights into the effect of lateralization on TLE and help us to understand the cognitive impairment of patients with TLE.

Efficacy of PD-1 Inhibitors in First-Line Treatment for Advanced Gastroesophageal Junction and Gastric Cancer by Subgroups: A Systematic Review and Meta-Analysis.

BACKGROUND: PD-1 inhibitors have been approved for the first-line treatment of patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced gastric/gastroesophageal junction cancer still needs to be precisely determined. OBJECTIVE: This objective of this study is to evaluate the efficacy of anti-PD-1/PD-L1 therapy in advanced gastric/gastroesophageal junction adenocarcinoma patients through a systematic review and meta-analysis of relevant clinical trials. METHOD: The PubMed, Embase, and Cochrane Library electronic databases were searched up to August 1, 2022, for clinical trials of anti-PD-1/PD-L1 immunotherapy for the first-line treatment of advanced gastroesophageal cancer. Hazard ratios and 95% confidence intervals for overall survival, progression-free survival, and objective response rates were extracted and pooled for meta-analysis. Prespecified subgroups included the following: agent type, PD-L1 expression, and high microsatellite instability. RESULTS: This study analyzed 5 RCTs involving 3,355 patients. Compared with the chemotherapy group, the combined immunotherapy group had a significantly higher objective response rate (OR = 0.63, 95% CI: 0.55-0.72, p < 0.00001) and prolonged overall survival (HR = 0.82, 95% CI: 0.76-0.88, p < 0.00001) and progression-free survival (HR = 0.75, 95% CI: 0.69-0.82, p < 0.00001). The combination of immunotherapy and chemotherapy prolonged OS in both MSI-H (HR = 0.38, p = 0.002) and MSS (HR = 0.78, p < 0.00001) populations, but there was a significant difference between groups (p = 0.02). However, in improving ORR, the benefit of ICI combined with chemotherapy in the MSS group and MSI-H group was not significantly different between groups (p = 0.52). Combination therapy with ICIs was more effective than chemotherapy alone in prolonging OS in the subgroup with a high CPS, regardless of the CPS cutoff for PD-L1. However, when the cutoff of CPS was 1, the difference between subgroups did not reach statistical significance (p = 0.12), while the benefit ratio of the MSI-H group was higher when the cutoff was 10 (p = 0.004) than when the cutoff value was 5 (p = 0.002). CONCLUSIONS: For first-line treatment of advanced gastroesophageal cancer, an ICI combination strategy is more effective than chemotherapy. The subgroup of patients with a CPS ≥10 has a more significant benefit, and CPS ≥10 has the potential to be used as an accurate marker of the dominant population of immuno-combined therapy.

Site-Specific Introduction of Bioorthogonal Handles to Nanopores by Genetic Code Expansion.

Site-specific functionalization of natural amino acid-containing biological nanopores is pivotal in single molecule sensing. However, pore engineering methodologies are restricted to a limited choice and introduction of unnatural chemical components is extremely difficult. Herein we report the genetic code expansion (GCE) strategy to introduce unnatural amino acid (UAA) to an octameric Mycobacterium smegmatis porin A (MspA) nanopore. GCE allows for rapid and efficient introduction of bioorthogonal reactive site (i.e., azide) to the pore rim, and conjugation of single stranded DNA or lysozyme was demonstrated. The lysozyme-conjugated pore was further used for the discrimination of different oligosaccharides, demonstrating a sensing capacity that a bare MspA nanopore does not possess. GCE with bioorthogonal handles, which has never been previously applied in the preparation of nanopores, is a versatile strategy for pore engineering and may further expand the application scenarios of nanopores.

Machine Learning Assisted Simultaneous Structural Profiling of Differently Charged Proteins in a Mycobacterium smegmatis Porin A (MspA) Electroosmotic Trap.

The nanopore is emerging as a means of single-molecule protein sensing. However, proteins demonstrate different charge properties, which complicates the design of a sensor that can achieve simultaneous sensing of differently charged proteins. In this work, we introduce an asymmetric electrolyte buffer combined with the Mycobacterium smegmatis porin A (MspA) nanopore to form an electroosmotic flow (EOF) trap. Apo- and holo-myoglobin, which differ in only a single heme, can be fully distinguished by this method. Direct discrimination of lysozyme, apo/holo-myoglobin, and the ACTR/NCBD protein complex, which are basic, neutral, and acidic proteins, respectively, was simultaneously achieved by the MspA EOF trap. To automate event classification, multiple event features were extracted to build a machine learning model, with which a 99.9% accuracy is achieved. The demonstrated method was also applied to identify single molecules of α-lactalbumin and ß-lactoglobulin directly from whey protein powder. This protein-sensing strategy is useful in direct recognition of a protein from a mixture, suggesting its prospective use in rapid and sensitive detection of biomarkers or real-time protein structural analysis.

A Nanopore-Based Saccharide Sensor.

Saccharides play critical roles in many forms of cellular activities. Saccharide structures are however complicated and similar, setting a technical hurdle for direct identification. Nanopores, which are emerging single molecule tools sensitive to minor structural differences between analytes, can be engineered to identity saccharides. A hetero-octameric Mycobacterium smegmatis porin A nanopore containing a phenylboronic acid was prepared, and was able to clearly identify nine monosaccharide types, including D-fructose, D-galactose, D-mannose, D-glucose, L-sorbose, D-ribose, D-xylose, L-rhamnose and N-acetyl-D-galactosamine. Minor structural differences between saccharide epimers can also be distinguished. To assist automatic event classification, a machine learning algorithm was developed, with which a general accuracy score of 0.96 was achieved. This sensing strategy is generally suitable for other saccharide types and may bring new insights to nanopore saccharide sequencing.

circPDE4B prevents articular cartilage degeneration and promotes repair by acting as a scaffold for RIC8A and MID1.

OBJECTIVES: Circular RNAs (circRNAs) have emerged as significant biological regulators. Herein, we aimed to elucidate the role of an unidentified circRNA (circPDE4B) that is reportedly downregulated in osteoarthritis (OA) tissues. METHODS: The effects of circPDE4B were explored in human and mouse chondrocytes in vitro. Specifically, RNA pull-down (RPD)-mass spectrometry analysis (MS), immunoprecipitation, glutathione-S-transferase (GST) pull-down, RNA immunoprecipitation and RPD assays were performed to verify the interactions between circPDE4B and the RIC8 guanine nucleotide exchange factor A (RIC8A)/midline 1 (MID1) complex. A mouse model of OA was also employed to confirm the role of circPDE4B in OA pathogenesis in vivo. RESULTS: circPDE4B regulates chondrocyte cell viability and extracellular matrix metabolism. Mechanistically, FUS RNA binding protein (FUS) was found to promote the splicing of circPDE4B, while downregulation of circPDE4B in OA is partially caused by upstream inhibition of FUS. Moreover, circPDE4B facilitates the association between RIC8A and MID1 by acting as a scaffold to promote RIC8A degradation through proteasomal degradation. Furthermore, ubiquitination of RIC8A at K415 abrogates RIC8A degradation. The circPDE4B-RIC8A axis was observed to play an important role in regulating downstream p38 mitogen-activated protein kinase (MAPK) signalling. Furthermore, delivery of a circPDE4B adeno-associated virus (AAV) abrogates the breakdown of cartilage matrix by medial meniscus destabilisation in mice, whereas a RIC8A AAV induces the opposite effect. CONCLUSION: This work highlights the function of the circPDE4B-RIC8A axis in OA joints, as well as its regulation of MAPK-p38, suggesting this axis as a potential therapeutic target for OA.

Allosteric Switching of Calmodulin in a Mycobacterium smegmatis porin†A (MspA) Nanopore-Trap.

Recent developments concerning large protein nanopores suggest a new approach to structure profiling of native folded proteins. In this work, the large vestibule of Mycobacterium smegmatis porin A (MspA) and calmodulin (CaM), a Ca2+ -binding protein, were used in the direct observation of the protein structure. Three conformers, including the Ca2+ -free, Ca2+ -bound, and target peptide-bound states of CaM, were unambiguously distinguished. A disease related mutant, CaM D129G was also discriminated by MspA, revealing how a single amino acid replacement can interfere with the Ca2+ -binding capacity of the whole protein. The binding capacity and aggregation effect of CaM induced by different ions (Mg2+ /Sr2+ /Ba2+ /Ca2+ /Pb2+ /Tb3+ ) were also investigated and the stability of MspA in extreme conditions was evaluated. This work demonstrates the most systematic single-molecule investigation of different allosteric conformers of CaM, acknowledging the high sensing resolution offered by the MspA nanopore trap.

Biochar-bacteria-plant combined potential for remediation of oil-contaminated soil.

Oil pollution is a common type of soil organic pollution that is harmful to the ecosystem. Bioremediation, particularly microbe-assisted phytoremediation of oil-contaminated soil, has become a research hotspot in recent years. In order to explore more appropriate bioremediation strategies for soil oil contamination and the mechanism of remediation, we compared the remediation effects of three plants when applied in combination with a microbial agent and biochar. The combined remediation approach of Tagetes erecta, microbial agent, and biochar exhibited the best plant growth and the highest total petroleum hydrocarbons degradation efficiency (76.60%). In addition, all of the remediation methods provided varying degrees of restoration of carbon and nitrogen contents of soils. High-throughput sequencing found that microbial community diversity and richness were enhanced in most restored soils. Some soil microorganisms associated with oil degradation and plant growth promotion such as Cavicella, C1_B045, Sphingomonas, MND1, Bacillus and Ramlibacter were identified in this study, among which Bacillus was the major component in the microbial agent. Bacillus was positively correlated with all soil remediation indicators tested and was substantially enriched in the rhizosphere of T. erecta. Functional gene prediction of the soil bacterial community based on the KEGG database revealed that pathways of carbohydrate metabolism and amino acid metabolism were up-regulated during remediation of oil-contaminated soils. This study provides a potential method for efficient remediation of oil-contaminated soils and thoroughly examines the biochar-bacteria-plant combined remediation mechanisms of oil-contaminated soil, as well as the combined effects from the perspective of soil bacterial communities.

Ultrafast removal of toxic Cr(VI) by the marine bacterium Vibrio natriegens.

The fastest-growing microbe Vibrio natriegens is an excellent platform for bioproduction processes. Until now, this marine bacterium has not been examined for bioremediation applications, where the production of substantial amounts of biomass would be beneficial. V. natriegens can perform extracellular electron transfer (EET) to Fe(III) via a single porin-cytochrome circuit conserved in Vibrionaceae. Electroactive microbes capable of EET to Fe(III) usually also reduce toxic metals such as carcinogenic Cr(VI), which is converted to Cr(III), thus decreasing its toxicity and mobility. Here, the performance of V. natriegens was explored for the bioremediation of Cr(VI). At a density of 100 mg/mL, V. natriegens removed 5-20 mg/L Cr(VI) within 30 s and 100 mg/L Cr(VI) within 10 min. In comparison, the model bacterium Escherichia coli grown to a comparable cell density removed Cr(VI) 36 times slower. To eliminate Cr(VI), V. natriegens had to be metabolically active, and functional outer-membrane c-type cytochromes were required. At the end of the Cr(VI) removal process, V. natriegens had reduced all of it into Cr(III) while adsorbing more than half of the metallic ions. These results demonstrate that V. natriegens, with its fast metabolism, is a viable option for the rapid treatment of aqueous pollution with Cr.

Topography- and depth-dependent rhizosphere microbial community characteristics drive ecosystem multifunctionality in Juglans mandshurica forest.

Rhizosphere microbial community characteristics and ecosystem multifunctionality (EMF), both affected by topographic factors, are closely correlated. However, more targeted exploration is yet required to fully understand the variations of rhizosphere microbial communities along topographic gradients in different soil layers, as well as whether and how they regulate EMF under specific site conditions. Here, we conducted relevant research on Juglans mandshurica forests at six elevation gradients and two slope positions ranging from 310 to 750 m in Tianjin Baxian Mountain. Results demonstrated that rhizosphere soil physicochemical properties and enzyme activities of both layers (0-20 cm and 20-40 cm) varied significantly with elevation, while only at top layer did slope position have significant impacts on most indicators. Bacterial richness and diversity were higher in the top layer at slope bottom and middle-high elevation, the difference in fungi was not as noticeable. Both topographic factors and soil depth significantly impacted microbial community structure, with Candidatus_Udaeobacter of bacteria, Mortierella, Sebacina, and Hygrocybe of fungi mainly contributing to the dissimilarity between communities. EMF rose with increasing elevation, bacteria were more critical drivers of this process than fungi, and topographic factors could affect EMF by altering bacterial diversity and dominant taxa abundance. For evaluating EMF, the aggregate structure of sub layer and the carbon cycle-related indicators of top layer were of higher importance. Our results revealed the depth-dependent characteristics of the rhizosphere microbial community along topographic gradients in studied stands, as well as the pivotal regulatory role of bacteria on EMF, while also highlighting depth as an important variable for analyzing soil properties and EMF. This work helps us better understand the response of individuals and communities of J. mandshurica to changing environmental conditions, further providing a scientific reference for the management and protection of secondary forests locally and in North China.

Core-Shell Composite Nanofibers with High Temperature Resistance, Hydrophobicity and Breathability for Efficient Daytime Passive Radiative Cooling.

Radiative cooling technology, which is renowned for its ability to dissipate heat without energy consumption, has garnered immense interest. However, achieving high performance, multifunctionality, and smart integration while addressing challenges such as film thickness and enhancing anisotropic light reflection remains challenging. In this study, a core-shell composite nanofiber, PVDF@PEI, is introduced and designed primarily from a symmetry-breaking perspective to develop highly efficient radiative cooling materials. Using a combination of solvent-induced phase separation (EIPS) inverse spinning and (aggregation) self-assembly methods (EISA or EIAA) and coaxial electrostatic spinning (ES), superconformal surface anisotropic porous nanofiber membranes are fabricated. These membranes exhibit exceptional thermal stability (up to 210 °C), high hydrophobicity (contact angle of 126°), robust UV protection (exceeding 99%), a fluorescence multiplication effect (with a 0.6% increase in fluorescence quantum efficiency), and good breathability. These properties enable the material to excel in a wide range of application scenarios. Moreover, this material achieved a remarkable daytime cooling temperature of 8 °C. The development of this fiber membrane offers significant advancements in the field of wearables and the multifunctionality of materials, paving new paths for future research and innovation.

Trichosanthin alleviates streptozotocin-induced type 1 diabetes mellitus in mice by regulating the balance between bone marrow-derived IL6+ and IL10+ MDSCs.

Myeloid-derived suppressor cells (MDSCs) occupy a pivotal role in the intricate pathogenesis of the autoimmune disorder, Type 1 diabetes mellitus (T1DM). Since our previous work demonstrated that trichosanthin (TCS), an active compound of Chinese herb medicine Tian Hua Fen, regulated immune response, we aimed to clarify the efficacy and molecular mechanism of TCS in the treatment of T1DM. To this end, T1DM mouse model was established by streptozotocin (STZ) induction. The mice were randomly divided into normal control group (Ctl), T1DM group (STZ), TCS treated diabetic group (STZ + TCS) and insulin-treated diabetic group (STZ + insulin). Our comprehensive evaluation encompassed variables such as blood glucose, glycosylated hemoglobin, body weight, pertinent biochemical markers, pancreatic histopathology, and the distribution of immune cell populations. Furthermore, we meticulously isolated MDSCs from the bone marrow of T1DM mice, probing into the expressions of genes pertaining to the advanced glycation end product receptor (RAGE)/NF-κB signaling pathway through RT-qPCR. Evidently, TCS exhibited a substantial capacity to effectively counteract the T1DM-induced elevation in random blood glucose, glycosylated hemoglobin, and IL-6 levels in plasma. Pathological scrutiny underscored the ability of TCS to mitigate the damage incurred by islets. Intriguingly, TCS interventions engendered a reduction in the proportion of MDSCs within the bone marrow, particularly within the IL-6+ MDSC subset. In contrast, IL-10+ MDSCs exhibited an elevation following TCS treatment. Moreover, we observed a significant down-regulation of relative mRNA of pro-inflammatory genes, including arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), RAGE and NF-κB, within MDSCs due to the influence of TCS. It decreases total MDSCs and regulates the balance between IL-6+ and IL-10+ MDSCs thus alleviating the symptoms of T1DM. TCS also down-regulates the RAGE/NF-κB signaling pathway, making it a promising alternative therapeutic treatment for T1DM. Collectively, our study offered novel insights into the underlying mechanism by which TCS serves as a promising therapeutic intervention for T1DM.

Decreased intrinsic neural timescale in treatment-naïve adolescent depression.

BACKGROUND: Major depressive disorder (MDD) is mainly characterized by its core dysfunction in higher-order brain cortices involved in emotional and cognitive processes, whose neurobiological basis remains unclear. In this study, we applied a relatively new developed resting-state functional magnetic resonance imaging (rs-fMRI) method of intrinsic neural timescale (INT), which reflects how long neural information is stored in a local brain area and reflects an ability of information integration, to investigate the local intrinsic neural dynamics using univariate and multivariate analyses in adolescent depression. METHOD: Based on the rs-fMRI data of sixty-six treatment-naïve adolescents with MDD and fifty-two well-matched healthy controls (HCs), we calculated an INT by assessing the magnitude of autocorrelation of the resting-state brain activity, and then compared the difference of INT between the two groups. Correlation between abnormal INT and clinical features was performed. We also utilized multivariate pattern analysis to determine whether INT could differentiate MDD patients from HCs at the individual level. RESULT: Compared with HCs, patients with MDD showed shorter INT widely distributed in cortical and partial subcortical regions. Interestingly, the decreased INT in the left hippocampus was related to disease severity of MDD. Furthermore, INT can distinguish MDD patients from HCs with the most discriminative regions located in the dorsolateral prefrontal cortex, angular, middle occipital gyrus, and cerebellar posterior lobe. CONCLUSION: Our research aids in advancing understanding the brain abnormalities of treatment-naïve adolescents with MDD from the perspective of the local neural dynamics, highlighting the significant role of INT in understanding neurophysiological mechanisms. This study shows that the altered intrinsic timescales of local neural signals widely distributed in higher-order brain cortices regions may be the neurodynamic basis of cognitive and emotional disturbances in MDD patients, and provides preliminary support for the suggestion that these could be used to aid the identification of MDD patients in clinical practice.

Transcriptome profiling of fast/glycolytic and slow/oxidative muscle fibers in aging and obesity.

Aging and obesity pose significant threats to public health and are major contributors to muscle atrophy. The trends in muscle fiber types under these conditions and the transcriptional differences between different muscle fiber types remain unclear. Here, we demonstrate distinct responses of fast/glycolytic fibers and slow/oxidative fibers to aging and obesity. We found that in muscles dominated by oxidative fibers, the proportion of oxidative fibers remains unchanged during aging and obesity. However, in muscles dominated by glycolytic fibers, despite the low content of oxidative fibers, a significant decrease in proportion of oxidative fibers was observed. Consistently, our study uncovered that during aging and obesity, fast/glycolytic fibers specifically increased the expression of genes associated with muscle atrophy and inflammation, including Dkk3, Ccl8, Cxcl10, Cxcl13, Fbxo32, Depp1, and Chac1, while slow/oxidative fibers exhibit elevated expression of antioxidant protein Nqo-1 and downregulation of Tfrc. Additionally, we noted substantial differences in the expression of calcium-related signaling pathways between fast/glycolytic fibers and slow/oxidative fibers in response to aging and obesity. Treatment with a calcium channel inhibitor thapsigargin significantly increased the abundance of oxidative fibers. Our study provides additional evidence to support the transcriptomic differences in muscle fiber types under pathophysiological conditions, thereby establishing a theoretical basis for modulating muscle fiber types in disease treatment.