Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient.

We report the 1-year results from one patient as the preliminary analysis of a first-in-human phase I clinical trial (ChiCTR2300072200) assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for type 1 diabetes treatment. The patient achieved sustained insulin independence starting 75 days post-transplantation. The patient's time-in-target glycemic range increased from a baseline value of 43.18% to 96.21% by month 4 post-transplantation, accompanied by a decrease in glycated hemoglobin, an indicator of long-term systemic glucose levels at a non-diabetic level. Thereafter, the patient presented a state of stable glycemic control, with time-in-target glycemic range at >98% and glycated hemoglobin at around 5%. At 1 year, the clinical data met all study endpoints with no indication of transplant-related abnormalities. Promising results from this patient suggest that further clinical studies assessing CiPSC-islet transplantation in type 1 diabetes are warranted.

Preferential formation of Z-RNA over intercalated motifs in long noncoding RNA.

Secondary structure is a principal determinant of lncRNA function, predominantly regarding scaffold formation and interfaces with target molecules. Noncanonical secondary structures that form in nucleic acids have known roles in regulating gene expression and include G-quadruplexes (G4s), intercalated motifs (iMs), and R-loops (RLs). In this paper, we used the computational tools G4-iM Grinder and QmRLFS-finder to predict the formation of each of these structures throughout the lncRNA transcriptome in comparison to protein-coding transcripts. The importance of the predicted structures in lncRNAs in biological contexts was assessed by combining our results with publicly available lncRNA tissue expression data followed by pathway analysis. The formation of predicted G4 (pG4) and iM (piM) structures in select lncRNA sequences was confirmed in vitro using biophysical experiments under near-physiological conditions. We find that the majority of the tested pG4s form highly stable G4 structures, and identify many previously unreported G4s in biologically important lncRNAs. In contrast, none of the piM sequences are able to form iM structures, consistent with the idea that RNA is unable to form stable iMs. Unexpectedly, these C-rich sequences instead form Z-RNA structures, which have not been previously observed in regions containing cytosine repeats and represent an interesting and underexplored target for protein-RNA interactions. Our results highlight the prevalence and potential structure-associated functions of noncanonical secondary structures in lncRNAs, and show G4 and Z-RNA structure formation in many lncRNA sequences for the first time, furthering the understanding of the structure-function relationship in lncRNAs.

The choroid plexus maintains adult brain ventricles and subventricular zone neuroblast pool, which facilitates poststroke neurogenesis.

The brain's neuroreparative capacity after injuries such as ischemic stroke is partly contained in the brain's neurogenic niches, primarily the subventricular zone (SVZ), which lies in close contact with the cerebrospinal fluid (CSF) produced by the choroid plexus (ChP). Despite the wide range of their proposed functions, the ChP/CSF remain among the most understudied compartments of the central nervous system (CNS). Here, we report a mouse genetic tool (the ROSA26iDTR mouse line) for noninvasive, specific, and temporally controllable ablation of CSF-producing ChP epithelial cells to assess the roles of the ChP and CSF in brain homeostasis and injury. Using this model, we demonstrate that ChP ablation causes rapid and permanent CSF volume loss in both aged and young adult brains, accompanied by disruption of ependymal cilia bundles. Surprisingly, ChP ablation did not result in overt neurological deficits at 1 mo postablation. However, we observed a pronounced decrease in the pool of SVZ neuroblasts (NBs) following ChP ablation, which occurs due to their enhanced migration into the olfactory bulb. In the middle cerebral artery occlusion model of ischemic stroke, NB migration into the lesion site was also reduced in the CSF-depleted mice. Thus, our study establishes an important role of ChP/CSF in regulating the regenerative capacity of the adult brain under normal conditions and after ischemic stroke.

A sodium/potassium switch for G4-prone G/C-rich sequences.

Metal ions are essential components for the survival of living organisms. For most species, intracellular and extracellular ionic conditions differ significantly. As G-quadruplexes (G4s) are ion-dependent structures, changes in the [Na+]/[K+] ratio may affect the folding of genomic G4s. More than 11000 putative G4 sequences in the human genome (hg19) contain at least two runs of three continuous cytosines, and these mixed G/C-rich sequences may form a quadruplex or a competing hairpin structure based on G-C base pairing. In this study, we examine how the [Na+]/[K+] ratio influences the structures of G/C-rich sequences. The natural G4 structure with a 9-nt long central loop, CEBwt, was chosen as a model sequence, and the loop bases were gradually replaced by cytosines. The series of CEB mutations revealed that the presence of cytosines in G4 loops does not prevent G4 folding or decrease G4 stability but increases the probability of forming a competing structure, either a hairpin or an intermolecular duplex. Slow conversion to the quadruplex in vitro (in a potassium-rich buffer) and cells was demonstrated by NMR. 'Shape-shifting' sequences may respond to [Na+]/[K+] changes with delayed kinetics.

Kirigami-based metastructures with programmable multistability.

SignificanceDifferent from most existing multistable structures whose multiple stable states are achieved through the combinational effect of bistable units, we invent a generic tristable kirigami cuboid. The three stable states have fundamentally distinct geometric configurations and chirality, and the transformation among them can be realized by tension/compression or clockwise/counterclockwise twist. Tessellating the units in series, a family of multistable metamaterials can be constructed, the mechanical behaviors of which are programmable by the unit geometry, the material of the elastic joints, the number of units, and the loading conditions. As a demonstration of the potential applications, a frequency reconfigurable antenna for 5G triple-band communication is developed based on a tristable unit, and the frequency tunability is verified by experiments.

Sono-blasting Triggered Cascading-Amplification of Oxidative Stress for Enhanced Interventional Therapy of Hepatocellular Carcinoma.

Interventional therapy is widely regarded as a highly promising treatment approach for nonsurgical liver cancer. However, the development of drug resistance and tolerance to hypoxic environments after embolization can lead to increased angiogenesis, enhanced tumor cell stemness, and greater invasiveness, resulting in metastasis and recurrence. To address these challenges, a novel approach involving the use of lecithin and DSPE-PEG comodified Ca2+ loaded (NH4)2S2O8 (LDCNSO) drug in combination with transcatheter arterial embolization (TAE) has been proposed. The sono-blasting effect of LDCNSO under ultrasound triggers a cascading amplification of oxidative stress, by releasing sulfate radical (·SO4-), hydroxyl radical (·OH), and superoxide (·O2-), inducing Ca2+ overload, and reducing glutathione (GSH) levels, which eventually leads to apoptosis. LDCNSO alongside TAE has demonstrated remarkable therapeutic efficacy in the rabbit orthotopic cancer model, resulting in significant inhibition of tumor growth. This research provides valuable insights for the effective treatment of orthotopic tumors.

Characteristics of Myocardial Structure and Central Carbon Metabolism during the Early and Compensatory Stages of Cardiac Hypertrophy.

Cardiac hypertrophy is a classical forerunner of heart failure and myocardial structural and metabolic remodeling are closely associated with cardiac hypertrophy. We aim to investigate the characteristics of myocardial structure and central carbon metabolism of cardiac hypertrophy at different stages. Using echocardiography and pathological staining, early and compensatory cardiac hypertrophy were respectively defined as within 7 days and from 7 to 14 days after transverse aortic constriction (TAC) in mice. Among mass-spectrometry-based metabolomics, we identified 45 central carbon metabolites. Differential metabolite analysis showed that six metabolites, including citrate, cis-aconitate and so on, decreased significantly on day 1 after TAC. Ten metabolites, including l-lactate, (S)-2-hydroxyglutarate and so on, were obviously changed on days 10 and 14. Pathway analysis showed that these metabolites were involved in seven metabolic pathways, including carbohydrates, amino acids and so on. Western blot showed the expression of ATP-citrate lyase, malate dehydrogenase 1 and lactate dehydrogenase A in myocardium changed markedly on day 3, while the phosphorylation level of AMP-activated protein kinase did not show significantly difference. We hope our research will promote deeper understanding and early diagnosis of cardiac hypertrophy in clinical practice. All raw data were deposited in MetaboLights (MTBLS10555).

A Molecular Coordination Strategy for Regulating the Interface of MoS2 Field Effect Transistors.

Chemically modifying monolayer two-dimensional transition metal dichalcogenides (TMDs) with organic molecules provides a wide range of possibilities to regulate the electronic and optoelectronic performance of both materials and devices. However, it remains challenging to chemically attach organic molecules to monolayer TMDs without damaging their crystal structures. Herein, we show that the Mo atoms of monolayer MoS2 (1L-MoS2) in defect states can coordinate with both catechol and 1,10-phenanthroline (Phen) groups, affording a facile route to chemically modifying 1L-MoS2. Through the design of two isomeric molecules (LA2 and LA5) comprising catechol and Phen groups, we show that attaching organic molecules to Mo atoms via coordinative bonds has no negative effect on the crystal structure of 1L-MoS2. Both theoretical calculation and experiment results indicate that the coordinative strategy is beneficial for (i) repairing sulfur vacancies and passivating defects; (ii) achieving a long-term and stable n-doping effect; and (iii) facilitating the electron transfer. Field effect transistors (FETs) based on the coordinatively modified 1L-MoS2 show high electron mobilities up to 120.3 cm2 V-1 s-1 with impressive current on/off ratios over 109. Our results indicate that coordinatively attaching catechol- or Phen-bearing molecules may be a general method for the nondestructive modification of TMDs.

A plant-specific SWR1 chromatin-remodeling complex couples histone H2A.Z deposition with nucleosome sliding.

Deposition of H2A.Z in chromatin is known to be mediated by a conserved SWR1 chromatin-remodeling complex in eukaryotes. However, little is known about whether and how the SWR1 complex cooperates with other chromatin regulators. Using immunoprecipitation followed by mass spectrometry, we found all known components of the Arabidopsis thaliana SWR1 complex and additionally identified the following three classes of previously uncharacterized plant-specific SWR1 components: MBD9, a methyl-CpG-binding domain-containing protein; CHR11 and CHR17 (CHR11/17), ISWI chromatin remodelers responsible for nucleosome sliding; and TRA1a and TRA1b, accessory subunits of the conserved NuA4 histone acetyltransferase complex. MBD9 directly interacts with CHR11/17 and the SWR1 catalytic subunit PIE1, and is responsible for the association of CHR11/17 with the SWR1 complex. MBD9, TRA1a, and TRA1b function as canonical components of the SWR1 complex to mediate H2A.Z deposition. CHR11/17 are not only responsible for nucleosome sliding but also involved in H2A.Z deposition. These results indicate that the association of the SWR1 complex with CHR11/17 may facilitate the coupling of H2A.Z deposition with nucleosome sliding, thereby co-regulating gene expression, development, and flowering time.

Integrated metabolome and transcriptome analyses reveal the molecular mechanism underlying dynamic metabolic processes during taproot development of Panax notoginseng.

BACKGROUND: Panax notoginseng (Burk) F. H. Chen is one of the most famous Chinese traditional medicinal plants. The taproot is the main organ producing triterpenoid saponins, and its development is directly linked to the quality and yield of the harvested P. notoginseng. However, the mechanisms underlying the dynamic metabolic changes occurring during taproot development of P. notoginseng are unknown. RESULTS: We carried out metabolomic and transcriptomic analyses to investigate metabolites and gene expression during the development of P. notoginseng taproots. The differentially accumulated metabolites included amino acids and derivatives, nucleotides and derivatives, and lipids in 1-year-old taproots, flavonoids and terpenoids in 2- and 3-year-old taproots, and phenolic acids in 3-year-old taproots. The differentially expressed genes (DEGs) are related to phenylpropanoid biosynthesis, metabolic pathway and biosynthesis of secondary metabolites at all three developmental stages. Integrative analysis revealed that the phenylpropanoid biosynthesis pathway was involved in not only the development of but also metabolic changes in P. notoginseng taproots. Moreover, significant accumulation of triterpenoid saponins in 2- and 3-year-old taproots was highly correlated with the up-regulated expression of cytochrome P450s and uridine diphosphate-dependent glycosyltransferases genes. Additionally, a gene encoding RNase-like major storage protein was identified to play a dual role in the development of P. notoginseng taproots and their triterpenoid saponins synthesis. CONCLUSIONS: These results elucidate the molecular mechanism underlying the accumulation of and change relationship between primary and secondary metabolites in P. notoginseng taproots, and provide a basis for the quality control and genetic improvement of P. notoginseng.

Cervical lymph node metastasis prediction from papillary thyroid carcinoma US videos: a prospective multicenter study.

BACKGROUND: Prediction of lymph node metastasis (LNM) is critical for individualized management of papillary thyroid carcinoma (PTC) patients to avoid unnecessary overtreatment as well as undesired under-treatment. Artificial intelligence (AI) trained by thyroid ultrasound (US) may improve prediction performance. METHODS: From September 2017 to December 2018, patients with suspicious PTC from the first medical center of the Chinese PLA general hospital were retrospectively enrolled to pre-train the multi-scale, multi-frame, and dual-direction deep learning (MMD-DL) model. From January 2019 to July 2021, PTC patients from four different centers were prospectively enrolled to fine-tune and independently validate MMD-DL. Its diagnostic performance and auxiliary effect on radiologists were analyzed in terms of receiver operating characteristic (ROC) curves, areas under the ROC curve (AUC), accuracy, sensitivity, and specificity. RESULTS: In total, 488 PTC patients were enrolled in the pre-training cohort, and 218 PTC patients were included for model fine-tuning (n = 109), internal test (n = 39), and external validation (n = 70). Diagnostic performances of MMD-DL achieved AUCs of 0.85 (95% CI: 0.73, 0.97) and 0.81 (95% CI: 0.73, 0.89) in the test and validation cohorts, respectively, and US radiologists significantly improved their average diagnostic accuracy (57% vs. 60%, P = 0.001) and sensitivity (62% vs. 65%, P < 0.001) by using the AI model for assistance. CONCLUSIONS: The AI model using US videos can provide accurate and reproducible prediction of cervical lymph node metastasis in papillary thyroid carcinoma patients preoperatively, and it can be used as an effective assisting tool to improve diagnostic performance of US radiologists. TRIAL REGISTRATION: We registered on the Chinese Clinical Trial Registry website with the number ChiCTR1900025592.

One-year outcomes of a novel venous stent for symptomatic iliofemoral venous obstruction: prospective cohort study.

BACKGROUND: A stent with characteristics of a hybrid design may have advantages in improving the patency of symptomatic iliofemoral vein obstruction. This study assessed the safety and effectiveness of the V-Mixtent Venous Stent in treating symptomatic iliofemoral outflow obstruction. METHODS: Eligible patients had a Clinical-Etiologic-Anatomic-Physiologic (CEAP) C classification of ≥ 3 or a Venous Clinical Severity Score (VCSS) pain score of ≥ 2. The primary safety endpoint was the rate of major adverse events within 30 days. The primary effectiveness endpoint was the 12-month primary patency rate. Secondary endpoints included changes in VCSS from baseline to 6 and 12 months, alterations in CEAP C classification, Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-14) scores at 12 months, and stent durability measures. RESULTS: Between December 2020 and November 2021, 171 patients were enrolled across 15 institutions. A total of 185 endovenous stents were placed, with 91.81% of subjects receiving one stent and 8.19% receiving 2 stents. Within 30 days, only two major adverse events occurred (1.17%; 95% confidence interval [CI], 0.14-4.16%), below the literature-defined performance goal of 11% (P < .001). The 12-month primary patency rate (91.36%; 95% CI, 85.93-95.19%; P < .001) exceeded the literature-defined performance goal. VCSS changes from baseline demonstrated clinical improvement at 6 months (- 4.30 ± 3.66) and 12 months (- 4.98 ± 3.67) (P < .001). Significant reduction in symptoms, as measured by CEAP C classification and CIVIQ-14, was observed from pre-procedure to 12 months (P < .001). CONCLUSIONS: The 12-month outcomes confirm the safety and effectiveness of the V-Mixtent Venous Stent in managing symptomatic iliofemoral venous outflow obstruction, including clinical symptom improvement compared to before treatment.

Carrier-Free Biomimetic Organic Nanoparticles with Super-High Drug Loading for Targeted NIR-II Excitable Triple-Modal Bioimaging and Phototheranostics.

Multimodal near-infrared II (NIR-II) theranostics combined with nanotechnology have emerged as promising treatments for cancer due to their noninvasive and high spatiotemporal nature. Traditional NIR-II theranostics typically comprise useless and massive inert carriers, resulting in low drug loading capacity, reduced therapeutic effects, and potential biotoxicity. To overcome these limitations, this work reports carrier-free NIR-II theranostics simultaneously with high drug loading capacity and multimodal NIR-II imaging capabilities for cancer phototheranostics in the NIR-II window. Carrier-free BTA nanoparticles (NPs) are prepared by self-assembling the NIR-II responsive conjugated oligomer BTA without adding coating agents; these NPs exhibited 100% drug loading and high-performance NIR-II theranostic capabilities. Cancer cell membranes are camouflaged on carrier-free BTA NPs to provide homologous targeting ability, enhanced stability, and 77.8% drug loading. Both in vitro and in vivo studies have indicated that biomimetic NPs provide efficient triple-modal guidance for NIR-II fluorescence, photoacoustic, and photothermal imaging and complete tumor elimination via photothermal therapy (PTT). Additionally, theranostics-based treatments with good biosecurity are demonstrated. This study contributes a new strategy for the design of high-drug-loading NIR-II theranostics and further promotes the clinical translation of theranostic agents.

Engineering Assembly of Plasmonic Virus-Like Gold SERS Nanoprobe Guided by Intelligent Dual-Machine Nanodevice for High-Performance Analysis of Tetracycline.

Accurate detection of trace tetracyclines (TCs) in complex matrices is of great significance for food and environmental safety monitoring. However, traditional recognition and amplification tools exhibit poor specificity and sensitivity. Herein, a novel dual-machine linkage nanodevice (DMLD) is proposed for the first time to achieve high-performance analysis of TC, with a padlock aptamer component as the initiation command center, nucleic acid-encoded multispike virus-like Au nanoparticles (nMVANs) as the signal indicator, and cascade walkers circuit as the processor. The existence of spike vertices and interspike nanogaps in MVANs enables intense electromagnetic near-field focusing, allowing distinct surface-enhanced Raman scattering (SERS) activity. Moreover, through the sequential activation between multistage walker catalytic circuits, the DLMD system converts the limited TC recognition into massive engineering assemblies of SERS probes guided by DNA amplicons, resulting in synergistic enhancement of bulk plasmonic hotspot entities. The continuously guaranteed target recognition and progressively promoted signal enhancement ensure highly specific amplification analysis of TC, with a detection limit as low as 7.94 × 10-16 g mL-1. Furthermore, the reliable recoveries in real samples confirm the practicability of the proposed sensing platform, highlighting the enormous potential of intelligent nanomachines for analyzing the trace hazards in the environment and food.

Changes in microbial composition and interaction patterns of female urogenital tract and rectum in response to HPV infection.

BACKGROUND: Previous studies have shown that changes in the microbial community of the female urogenital tract are associated with Human papillomavirus (HPV) infection. However, research on this association was mostly focused on a single site, and there are currently few joint studies on HPV infection and multiple sites in the female urogenital tract. METHODS: We selected 102 healthy women from Yunnan Province as the research object, collected cervical exfoliation fluid, vaginal, urethral, and rectal swabs for microbial community analysis, and measured bacterial load, and related cytokine content. The link between HPV, microbiota, and inflammation was comprehensively evaluated using bioinformatics methods. FINDINGS: The impact of HPV infection on the microbial composition of different parts varies. We have identified several signature bacterial genera that respond to HPV infection in several detection sites, such as Corynebacterium, Lactobacillus, Campylobacter, and Cutibacterium have been detected in multiple sites, reflecting their potential significance in cross body sites HPV infection responses. There was a solid microbial interaction network between the cervix, vagina, and urethra. The interrelationships between inflammatory factors and different bacterial genera might also affect the immune system's response to HPV infection. INTERPRETATION: It might be an effective strategy to prevent and treat HPV infection by simultaneously understanding the correlation between the microbial changes in multiple parts of the female urogenital tract and rectum and HPV infection, and controlling the microbial network related to HPV infection in different parts.

Significant accrual of soil organic carbon through long-term rice cultivation in paddy fields in China.

Paddy fields serve as significant reservoirs of soil organic carbon (SOC) and their potential for terrestrial carbon (C) sequestration is closely associated with changes in SOC pools. However, there has been a dearth of comprehensive studies quantifying changes in SOC pools following extended periods of rice cultivation across a broad geographical scale. Using 104 rice paddy sampling sites that have been in continuous cultivation since the 1980s across China, we studied the changes in topsoil (0-20 cm) labile organic C (LOC I), semi-labile organic C (LOC II), recalcitrant organic C (ROC), and total SOC. We found a substantial increase in both the content (48%) and density (39%) of total SOC within China's paddy fields between the 1980s to the 2010s. Intriguingly, the rate of increase in content and density of ROC exceeded that of LOC (I and II). Using a structural equation model, we revealed that changes in the content and density of total SOC were mainly driven by corresponding shifts in ROC, which are influenced both directly and indirectly by climatic and soil physicochemical factors; in particular temperature, precipitation, phosphorous (P) and clay content. We also showed that the δ13 CLOC were greater than δ13 CROC , independent of the rice cropping region, and that there was a significant positive correlation between δ13 CSOC and δ13 Cstraw . The δ13 CLOC and δ13 CSOC showed significantly negative correlation with soil total Si, suggesting that soil Si plays a part in the allocation of C into different SOC pools, and its turnover or stabilization. Our study underscores that the global C sequestration of the paddy fields mainly stems from the substantial increase in ROC pool.

DDX19A promotes gastric cancer cell proliferation and migration by activating the PI3K/AKT pathway.

BACKGROUND: DEAD-box RNA helicase 19 A (DDX19A) is overexpressed in cervical squamous cell carcinoma. However, its role in gastric cancer remains unclear. The present study aimed to explore the role and underlying mechanism of DDX19A in the development of gastric cancer. METHODS: The expression of DDX19A in gastric cancer and paracancerous tissues was evaluated through quantitative polymerase chain reaction, western blotting, and immunohistochemical staining. The biological functions of DDX19A in gastric cancer were determined using CCK8, plate colony-forming, and Transwell migration assays. The specific mechanism of DDX19A in gastric cancer cells was studied using western blotting, RNA-binding protein immunoprecipitation, mRNA half-life detection, and nuclear and cytoplasmic RNA isolation. RESULTS: DDX19A was highly expressed in gastric cancer and positively associated with malignant clinicopathological features and poor prognosis. Additionally, DDX19A promoted gastric cancer cell proliferation, migration, and epithelial-mesenchymal transition phenotypes. Mechanistically, DDX19A activated the PI3K/AKT pathway by upregulating phosphatidylinositol-3-kinase (PIK3CA) expression. Furthermore, DDX19A interacted with PIK3CA mRNA, stabilized it, and facilitated its export from the nucleus. CONCLUSIONS: Our study reveals a novel mechanism whereby DDX19A promotes the proliferation and migration of gastric cancer cells by enhancing the stability and nuclear export of PIK3CA mRNA, thereby activating the PI3K/AKT pathway.

Integrated multi-omics analyses revealed the association between rheumatoid arthritis and colorectal cancer: MYO9A as a shared gene signature and an immune-related therapeutic target.

BACKGROUND: Our study aims to explore the relationship, shared gene signature, and the underlying mechanisms that connect rheumatoid arthritis (RA) to colorectal cancer (CRC). METHODS: Mendelian randomization (MR) analysis was conducted to assess the causality between RA and CRC. Summary statistic data-based Mendelian randomization (SMR) leveraging eQTL data was employed to identify the CRC-related causal genes. Integrated analyses of single-cell RNA sequencing and bulk RNA sequencing were employed to comprehensively investigate the shared gene signature and potential mechanisms underlying the pathogenesis of both RA and CRC. Predictive analysis of the shared hub gene in CRC immunotherapy response was performed. Pan-cancer analyses were conducted to explore the potential role of MYO9A in 33 types of human tumors. RESULTS: MR analysis suggested that RA might be associated with a slight increased risk of CRC (Odds Ratio = 1.04, 95% Confidence Interval = 1.01-1.07, P = 0.005). SMR analysis combining transcriptome analyses identified MYO9A as a causal gene in CRC and a shared gene signature in both RA and CRC. MYO9A may contribute to tumor suppression, while downregulation of MYO9A may impact CRC tumorigenesis by disrupting epithelial polarity and architecture, resulting in a worse prognosis in CRC. Additionally, MYO9A shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. Pan-cancer analyses demonstrated MYO9A may have a protective role in the occurrence and progression of various human cancers. CONCLUSION: RA might be associated with a slight increased risk of CRC. MYO9A is a shared gene signature and a potential immune-related therapeutic target for both CRC and RA. Targeting the MYO9A-mediated loss of polarity and epithelial architecture could be a novel therapeutic approach for CRC.

Brain network integration underpins differential susceptibility of adolescent anxiety.

BACKGROUND: Parenting is a common and potent environmental factor influencing adolescent anxiety. Yet, the underlying neurobiological susceptibility signatures remain elusive. Here, we used a longitudinal twin neuroimaging study to investigate the brain network integration and its heritable relation to underpin the neural differential susceptibility of adolescent anxiety to parenting environments. METHODS: 216 twins from the Beijing Twin Study completed the parenting and anxiety assessments and fMRI scanning. We first identified the brain network integration involved in the influences of parenting at age 12 on anxiety symptoms at age 15. We then estimated to what extent heritable sensitive factors are responsible for the susceptibility of brain network integration. RESULTS: Consistent with the differential susceptibility theory, the results showed that hypo-connectivity within the central executive network amplified the impact of maternal hostility on anxiety symptoms. A high anti-correlation between the anterior salience and default mode networks played a similar modulatory role in the susceptibility of adolescent anxiety to paternal hostility. Genetic influences (21.18%) were observed for the connectivity pattern in the central executive network. CONCLUSIONS: Brain network integration served as a promising neurobiological signature of the differential susceptibility to adolescent anxiety. Our findings deepen the understanding of the neural sensitivity in the developing brain and can inform early identification and personalized interventions for adolescents at risk of anxiety disorders.

MicroRNA-139-5p mediates BMSCs impairment in diabetes by targeting HOXA9/c-Fos.

The properties and functions of BMSCs were altered by the diabetic microenvironment, and its mechanism was not very clear. In recent years, the regulation of the function of BMSCs by microRNA has become a research hotspot, meanwhile, HOX genes also have been focused on and involved in multiple functions of stem cells. In this study, we investigated the role of miR-139-5p in diabetes-induced BMSC impairment. Since HOXA9 may be a target gene of miR-139-5p, we speculated that miR-139-5p/HOXA9 might be involved in regulating the biological characteristics and the function of BMSCs in diabetes. We demonstrated that the miR-139-5p expression was increased in BMSCs derived from STZ-induced diabetic rats. MiR-139-5p mimics were able to inhibit cell proliferation, and migration and promoted senescence and apoptosis in vitro. MiR-139-5p induced the down-regulated expression of HOXA9 and c-Fos in BMSCs derived from normal rats. Moreover, miR-139-5p inhibitors reversed the tendency in diabetic-derived BMSCs. Further, gain-and-loss function experiments indicated that miR-139-5p regulated the functions of BMSCs by targeting HOXA9 and c-Fos. In vivo wound model experiments showed that the downregulation of miR-139-5p further promoted the epithelialization and angiogenesis of diabetic BMSC-mediated skin. In conclusion, induction of miR-139-5p upregulation mediated the impairment of BMSCs through the HOXA9/c-Fos pathway in diabetic rats. Therefore, miR-139-5p/HOXA9 might be an important therapeutic target in treating diabetic BMSCs and diabetic complications in the future.