A hot-emitter transistor based on stimulated emission of heated carriers.

Hot-carrier transistors are a class of devices that leverage the excess kinetic energy of carriers. Unlike regular transistors, which rely on steady-state carrier transport, hot-carrier transistors modulate carriers to high-energy states, resulting in enhanced device speed and functionality. These characteristics are essential for applications that demand rapid switching and high-frequency operations, such as advanced telecommunications and cutting-edge computing technologies1-5. However, the traditional mechanisms of hot-carrier generation are either carrier injection6-11 or acceleration12,13, which limit device performance in terms of power consumption and negative differential resistance14-17. Mixed-dimensional devices, which combine bulk and low-dimensional materials, can offer different mechanisms for hot-carrier generation by leveraging the diverse potential barriers formed by energy-band combinations18-21. Here we report a hot-emitter transistor based on double mixed-dimensional graphene/germanium Schottky junctions that uses stimulated emission of heated carriers to achieve a subthreshold swing lower than 1 millivolt per decade beyond the Boltzmann limit and a negative differential resistance with a peak-to-valley current ratio greater than 100 at room temperature. Multi-valued logic with a high inverter gain and reconfigurable logic states are further demonstrated. This work reports a multifunctional hot-emitter transistor with significant potential for low-power and negative-differential-resistance applications, marking a promising advancement for the post-Moore era.

Bloodmeals fuel dengue virus replication in the female mosquito Aedes aegypti.

Vector competence defines the ability of a vector to acquire, host, and transmit a pathogen. Understanding the molecular determinants of the mosquitos' competence to host dengue virus (DENV) holds promise to prevent its transmission. To this end, we employed RNA-seq to profile mRNA transcripts of the female Aedes aegypti mosquitos feeding on naïve vs viremic mouse. While most transcripts (12,634) did not change their abundances, 360 transcripts showed decreases. Biological pathway analysis revealed representatives of the decreased transcripts involved in the wnt signaling pathway and hippo signaling pathway. One thousand three hundred fourteen transcripts showed increases in abundance and participate in 21 biological pathways including amino acid metabolism, carbon metabolism, fatty acid metabolism, and oxidative phosphorylation. Inhibition of oxidative phosphorylation with antimycin A reduced oxidative phosphorylation activity and ATP concentration associated with reduced DENV replication in the Aedes aegypti cells. Antimycin A did not affect the amounts of the non-structural proteins 3 and 5, two major components of the replication complex. Ribavirin, an agent that reduces GTP concentration, recapitulated the effects of reduced ATP concentration on DENV replication. Knocking down one of the oxidative phosphorylation components, ATP synthase subunit ß, reduced DENV replication in the mosquitos. In summary, our results suggest that DENV enhances metabolic pathways in the female Aedes aegypti mosquitos to supply nutrients and energy for virus replication. ATP synthase subunit ß knockdown might be exploited to reduce the mosquitos' competence to host and transmit DENV. IMPORTANCE: Through evolution, the mosquito-borne viruses have adapted to the blood-feeding behaviors of their opportunist hosts to fulfill a complete lifecycle in humans and mosquitos. Disruption in the mosquitos' ability to host these viruses offers strategies to prevent diseases caused by them. With the advent of genomic tools, we discovered that dengue virus (DENV) benefited from the female mosquitos' bloodmeals for metabolic and energetic supplies for replication. Chemical or genetic disruption in these supplies reduced DENV replication in the female mosquitos. Our discovery can be exploited to produce genetically modified mosquitos, in which DENV infection leads to disruption in the supplies and thereby reduces replication and transmission. Our discovery might be extrapolated to prevent mosquito-borne virus transmission and the diseases they cause.

A Histopathologic Image Analysis for the Classification of Endocervical Adenocarcinoma Silva Patterns Depend on Weakly Supervised Deep Learning.

Twenty-five percent of cervical cancers are classified as endocervical adenocarcinomas (EACs), which comprise a highly heterogeneous group of tumors. A histopathologic risk stratification system known as the Silva pattern system was developed based on morphology. However, accurately classifying such patterns can be challenging. The study objective was to develop a deep learning pipeline (Silva3-AI) that automatically analyzes whole slide image-based histopathologic images and identifies Silva patterns with high accuracy. Initially, a total of 202 patients with EACs and histopathologic slides were obtained from Qilu Hospital of Shandong University for developing and internally testing the Silva3-AI model. Subsequently, an additional 161 patients and slides were collected from seven other medical centers for independent testing. The Silva3-AI model was developed using a vision transformer and recurrent neural network architecture, utilizing multi-magnification patches, and its performance was evaluated based on a class-specific area under the receiver-operating characteristic curve. Silva3-AI achieved a class-specific area under the receiver-operating characteristic curve of 0.947 for Silva A, 0.908 for Silva B, and 0.947 for Silva C on the independent test set. Notably, the performance of Silva3-AI was consistent with that of professional pathologists with 10 years' diagnostic experience. Furthermore, the visualization of prediction heatmaps facilitated the identification of tumor microenvironment heterogeneity, which is known to contribute to variations in Silva patterns.

Improving anti-cancer drug response prediction using multi-task learning on graph convolutional networks.

Predicting the therapeutic effect of anti-cancer drugs on tumors based on the characteristics of tumors and patients is one of the important contents of precision oncology. Existing computational methods regard the drug response prediction problem as a classification or regression task. However, few of them consider leveraging the relationship between the two tasks. In this work, we propose a Multi-task Interaction Graph Convolutional Network (MTIGCN) for anti-cancer drug response prediction. MTIGCN first utilizes an graph convolutional network-based model to produce embeddings for both cell lines and drugs. After that, the model employs multi-task learning to predict anti-cancer drug response, which involves training the model on three different tasks simultaneously: the main task of the drug sensitive or resistant classification task and the two auxiliary tasks of regression prediction and similarity network reconstruction. By sharing parameters and optimizing the losses of different tasks simultaneously, MTIGCN enhances the feature representation and reduces overfitting. The results of the experiments on two in vitro datasets demonstrated that MTIGCN outperformed seven state-of-the-art baseline methods. Moreover, the well-trained model on the in vitro dataset GDSC exhibited good performance when applied to predict drug responses in in vivo datasets PDX and TCGA. The case study confirmed the model's ability to discover unknown drug responses in cell lines.

SiX2 (X = S, Se) Nanowire Gate-All-Around MOSFETs for Sub-5 nm Applications.

The gate-all-around (GAA) field-effect transistor (FET) holds great potential to support next-generation integrated circuits. Nanowires such as carbon nanotubes (CNTs) are one important category of channel materials in GAA FETs. Based on first-principles investigations, we propose that SiX2 (X = S, Se) nanowires are promising channel materials that can significantly elevate the performance of GAA FETs. The sub-5 nm SiX2 (X = S, Se) nanowire GAA FETs exhibit excellent ballistic transport properties that meet the requirements of the 2013 International Technology Roadmap for Semiconductors (ITRS). Compared to CNTs, they are also advantageous or at least comparable in terms of gate controllability, device dimensions, etc. Importantly, SiSe2 GAA FETs show superb gate controllability due to the ultralow minimum subthreshold swing (SSmin) that breaks "Boltzmann's tyranny". Moreover, the energy-delay product (EDP) of SiX2 GAA FETs is significantly lower than that of the CNT FETs. These features make SiX2 nanowires ideal channel material in the sub-5 nm GAA FET devices.

Union With Recursive Feature Elimination: A Feature Selection Framework to Improve the Classification Performance of Multicategory Causes of Death in Colorectal Cancer.

Despite the use of machine learning tools, it is challenging to properly model cause-specific deaths in colorectal cancer (CRC) patients and choose appropriate treatments. Here, we propose an interesting feature selection framework, namely union with recursive feature elimination (U-RFE), to select the union feature sets that are crucial in CRC progression-specific mortality using The Cancer Genome Atlas (TCGA) dataset. Based on the union feature sets, we compared the performance of 5 classification algorithms, including logistic regression (LR), support vector machines (SVM), random forest (RF), eXtreme gradient boosting (XGBoost), and Stacking, to identify the best model for classifying 4-category deaths. In the first stage of U-RFE, LR, SVM, and RF were used as base estimators to obtain subsets containing the same number of features but not exactly the same specific features. Union analysis of the subsets was then performed to determine the final union feature set, effectively combining the advantages of different algorithms. We found that the U-RFE framework could improve various models' performance. Stacking outperformed LR, SVM, RF, and XGBoost in most scenarios. When the target feature number of the RFE was set to 50 and the union feature set contained 298 deterministic features, the Stacking model achieved F1_weighted, Recall_weighted, Precision_weighted, Accuracy, and Matthews correlation coefficient of 0.851, 0.864, 0.854, 0.864, and 0.717, respectively. The performance of the minority categories was also significantly improved. Therefore, this recursive feature elimination-based approach of feature selection improves performances of classifying CRC deaths using clinical and omics data or those using other data with high feature redundancy and imbalance.

IL-6 from cerebrospinal fluid causes widespread pain via STAT3-mediated astrocytosis in chronic constriction injury of the infraorbital nerve.

BACKGROUND: The spinal inflammatory signal often spreads to distant segments, accompanied by widespread pain symptom under neuropathological conditions. Multiple cytokines are released into the cerebrospinal fluid (CSF), potentially inducing the activation of an inflammatory cascade at remote segments through CSF flow. However, the detailed alteration of CSF in neuropathic pain and its specific role in widespread pain remain obscure. METHODS: A chronic constriction injury of the infraorbital nerve (CCI-ION) model was constructed, and pain-related behavior was observed on the 7th, 14th, 21st, and 28th days post surgery, in both vibrissa pads and hind paws. CSF from CCI-ION rats was transplanted to naïve rats through intracisternal injection, and thermal and mechanical allodynia were measured in hind paws. The alteration of inflammatory cytokines in CCI-ION's CSF was detected using an antibody array and bioinformatic analysis. Pharmacological intervention targeting the changed cytokine in the CSF and downstream signaling was performed to evaluate its role in widespread pain. RESULTS: CCI-ION induced local pain in vibrissa pads together with widespread pain in hind paws. CCI-ION's CSF transplantation, compared with sham CSF, contributed to vibrissa pad pain and hind paw pain in recipient rats. Among the measured cytokines, interleukin-6 (IL-6) and leptin were increased in CCI-ION's CSF, while interleukin-13 (IL-13) was significantly reduced. Furthermore, the concentration of CSF IL-6 was correlated with nerve injury extent, which gated the occurrence of widespread pain. Both astrocytes and microglia were increased in remote segments of the CCI-ION model, while the inhibition of astrocytes in remote segments, but not microglia, significantly alleviated widespread pain. Mechanically, astroglial signal transducer and activator of transcription 3 (STAT3) in remote segments were activated by CSF IL-6, the inhibition of which significantly mitigated widespread pain in CCI-ION. CONCLUSION: IL-6 was induced in the CSF of the CCI-ION model, triggering widespread pain via activating astrocyte STAT3 signal in remote segments. Therapies targeting IL-6/STAT3 signaling might serve as a promising strategy for the widespread pain symptom under neuropathological conditions.

High-Strength and High-Toughness Supramolecular Materials for Self-Healing Triboelectric Nanogenerator.

The development of self-healing materials provides a new opportunity and challenge for advancing triboelectric nanogenerators (TENGs). However, the low strength and low toughness of self-healing triboelectric materials often result in the deformation or breakage of TENG under high mechanical loads, thereby limiting their potential applications. Herein, a new strategy for fabricating self-healing triboelectric materials is reported, which introduces cross-linking networks with hydrogen bonds and metal coordination bonds. The desired high performance can be achieved by simply adjusting the molar ratio of the metal to the ligand. When the molar ratio is 1:2, the tensile strength, toughness, and elongation at break of the material reached 13.7 MPa, 76.9 MJ m-3, and 1321%, respectively. Furthermore, its self-healing efficiency can reach 74% at 70 °C in 6 h. Working in contact-separation mode, the electrical output can reach 164 V, 18.2 µA, 57.5 nC, with a maximum power density of 2.54 W m-2. Notably, even if it is sheared, the electrical output performances of TENG can be completely recovered to the original state. In addition, the developed TENG exhibits excellent output stability over 10 000 contact separation cycles. This study presents a promising approach for the development of stretchable smart generators.

Computer-Aided Synthesis Planning (CASP) and Machine Learning: Optimizing Chemical Reaction Conditions.

Computer-aided synthesis planning (CASP) has garnered increasing attention in light of recent advancements in machine learning models. While the focus is on reverse synthesis or forward outcome prediction, optimizing reaction conditions remains a significant challenge. For datasets with multiple variables, the choice of descriptors and models is pivotal. This selection dictates the effective extraction of conditional features and the achievement of higher prediction accuracy. This review delineates the origins of data in conditional optimization, the criteria for descriptor selection, the response models, and the metrics for outcome evaluation, aiming to acquaint readers with the latest research trends and facilitate more informed research in this domain.

Machine-learning model comprising five clinical indices and liver stiffness measurement can accurately identify MASLD-related liver fibrosis.

BACKGROUND & AIMS: aMAP score, as a hepatocellular carcinoma risk score, is proven to be associated with the degree of chronic hepatitis B-related liver fibrosis. We aimed to evaluate the ability of aMAP score for metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD)-related fibrosis diagnosis and establish a machine-learning (ML) model to improve the diagnostic performance. METHODS: A total of 946 biopsy-proved MASLD patients from China and the United States were included in the analysis. The aMAP score, demographic/clinical indices and liver stiffness measurement (LSM) were included in seven ML algorithms to build fibrosis diagnostic models in the training set (N = 703). The performance of ML models was evaluated in the external validation set (N = 125). RESULTS: The AUROCs of aMAP versus fibrosis-4 index (FIB-4) and aspartate aminotransferase-platelet ratio (APRI) in cirrhosis and advanced fibrosis were (0.850 vs. 0.857 [P = 0.734], 0.735 [P = 0.001]) and (0.759 vs. 0.795 [P = 0.027], 0.709 [P = 0.049]). When using dual cut-off values, aMAP had a smaller uncertainty area and higher accuracy (26.9%, 86.6%) than FIB-4 (37.3%, 85.0%) and APRI (59.0%, 77.3%) in cirrhosis diagnosis. The seven ML models performed satisfactorily in most cases. In the validation set, the ML model comprising LSM and 5 indices (including age, sex, platelets, albumin and total bilirubin used in aMAP calculator), built by logistic regression algorithm (called LSM-plus model), exhibited excellent performance. In cirrhosis and advanced fibrosis detection, the LSM-plus model had higher accuracy (96.8%, 91.2%) than LSM alone (86.4%, 67.2%) and Agile score (76.0%, 83.2%), respectively. Additionally, the LSM-plus model also displayed high specificity (cirrhosis: 98.3%; advanced fibrosis: 92.6%) with satisfactory AUROC (0.932, 0.875, respectively) and sensitivity (88.9%, 82.4%, respectively). CONCLUSIONS: The aMAP score is capable of diagnosing MASLD-related fibrosis. The LSM-plus model could accurately identify MASLD-related cirrhosis and advanced fibrosis.

Trimethylamine from Subtropical Forests Rival Total Farmland Emissions in China.

Many types of living plants release gaseous trimethylamine (TMA), making it a potentially important contributor to new particle formation (NPF) in remote areas. However, a panoramic view of the importance of forest biogenic TMA at the regional scale is lacking. Here, we pioneered nationwide mobile measurements of TMA across a transect of contiguous farmland in eastern China and a transect of subtropical forests in southern China. In contrast to the farmland route, TMA concentrations measured during the subtropical forest route correlated significantly with isoprene, suggesting potential TMA emissions from leaves. Our high time-resolved concentrations obtained from a weak photo-oxidizing atmosphere reflected freshly emitted TMA, indicating the highest emission intensity from irrigated dryland (set as the baseline of 10), followed by paddy field (7.1), subtropical evergreen forests (5.9), and subtropical broadleaf and mixed forests (4.3). Extrapolating their proportions roughly to China, subtropical forests alone, which constitute half of the total forest area, account for nearly 70% of the TMA emissions from the nation's total farmland. Our estimates, despite the uncertainties, take the first step toward large-scale assessment of forest biogenic amines, highlighting the need for observational and modeling studies to consider this hitherto overlooked source of TMA.

Characterization of oral biomarkers during early healing at augmented dental implant sites.

AIM: The aim of this study is to assess early wound healing expression of local angiogenic biomarkers following connective tissue graft (CTG) at dental implant sites. METHODS: Twenty-eight subjects with single dental implants exhibiting a soft tissue dehiscence were included and randomly treated with CTG, either with coronally advanced flap (CAF) or with tunnel technique (TUN). Peri-implant crevicular fluid (PICF) was collected at the midfacial and midlingual aspect of the implant sites at baseline and at 3, 7, 14, 30, and 90 days after the surgical intervention. The expression of angiogenin (ANG), fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF), tissue inhibitor of metalloproteinases-2 (TIMP-2), and vascular endothelial growth factor (VEGF) was investigated over a period of 3 months. Patient-reported outcomes, clinical measurements, and ultrasonography scans at multiple time points were also evaluated. RESULTS: The longitudinal regression revealed a significant difference in the expression of VEGF and TIMP-2 between CAF- and TUN-treated sites over 3 months (p = .033 and p = .004, respectively), whereas no significant differences were observed for ANG, FGF-2 and PDGF between the two groups. At 7 days, a direct correlation was observed between ANG levels and ultrasonographic color velocity in the CAF group (p < .001) and between ANG levels and ultrasonographic color power in the TUN group (p = .028). VEGF levels and ultrasonographic mean perfused area of the CTG were significantly correlated at the 7-day time point (p < .001 for both CAF and TUN). The expression of VEGF at 7 days was directly associated with mucosal thickness gain at 1 year (p < .001 for both groups). Early TIMP-2 expression showed an inverse correlation with time to recovery (p = .002). TIMP-2 levels at 3 months exhibited inverse correlations with mean dehiscence coverage (p = .004) and the rate of complete dehiscence coverage (p = .012). CONCLUSION: PICF biomarkers can be used to monitor early wound healing events following soft tissue grafting at implant sites. VEGF and TIMP-2 showed correlations with the 1-year clinical and volumetric outcomes, as well as with post-operative patient-reported outcomes and Doppler Ultrasonographic tissue perfusion-related parameters.

Synthesis and Application of Specific N2H4 Fluorescent Probes with AIE Effect Based on Pyrazole Structure.

Two fluorescent probes, Y1-2 were synthesized from 2-acetonaphthone, 4-acetylbiphenyl, and phenyl hydrazine by Vilsmeier-Haack reaction and Knoevenagel condensation. Their recognition efficacies for N2H4 were tested by UV-visible absorption spectroscopy and fluorescence emission spectroscopy. The recognition mechanism were studies by density-functional theory calculations, and the effect of pH on N2H4 recognition was also studied. The results showed that the probe Y1-2 has high selectivity and a low detection limit for N2H4, and the recognition of N2H4 can be accomplished at physiological pH. The probes have had obvious aggregation-induced luminescence effect, large Stokes shift, high sensitivity, and can be successfully applied to live cell imaging.

Long-term mental health cost of the Great Chinese Famine.

The Great Chinese Famine (1959-1961) claimed tens of millions of lives. This study aims to causally examine the long-term mental health cost it imposed on those who survived. To estimate the nationwide total mental health cost, we use a novel dataset to measure the famine intensity of every prefecture-level region, match it to a nationally representative survey, and then identify the long-term effects of the famine on the depression of rural residents then in the early years of their lives. Difference-in-differences estimates reveal that a one-standard-deviation rise in the experienced famine intensity increased a standard measure of depression by about 0.039 and 0.064 if the individual experienced the famine at ages 0-2 and 3-5, respectively. This translates into roughly 7.99 million cases of severe depressive symptoms caused by the famine, which is likely an undercount. Examining the mechanisms behind the large effects, we find that important roles were played by starvation experience and childhood maltreatment, as well as the primary mediators including other health outcomes, economic status, and social relationship. Our findings shed light on how large-scale food security failures impact the mental well-being of the survivors.

Prophylactic anti-reflux procedure for children undergoing laparoscopic gastrostomy: Rethinking of the routine practice.

AIM: Laparoscopic gastrostomy is a frequently performed procedure in children requiring long-term enteral nutrition. The role of prophylactic anti-reflux surgery during gastrostomy placements is controversial. The current study aims to evaluate the role of prophylactic anti-reflux procedures during gastrostomy placement. METHODS: A retrospective single-center analysis of all children without reflux receiving laparoscopic gastrostomy from January 2005 through December 2021 was performed. Demographics and clinical outcomes were compared between patients receiving gastrostomy placement alone and patients receiving gastrostomy with prophylactic anti-reflux surgery. RESULTS: A total of 79 patients had a confirmed absence of reflux by a 24-h pH/impedance study before operation. Thirty-six of these patients underwent prophylactic anti-reflux surgery (PAR) while 43 received gastrostomy (PG) alone. The operative time and conversion rate were significantly higher in the PAR group (140.5 ± 67.5 vs. 80.2 ± 66.8 min, p = 0.0001 and 8.3% vs. 0%, p = 0.04). There were no major complications in either group. De novo reflux was detected in five patients (11.6%) in the PG group. None of these patients progressed to require anti-reflux surgery. CONCLUSION: The occurrence of de novo reflux after laparoscopic gastrostomy was low and could be managed without anti-reflux surgery. A routine pre-operative pH study is helpful for appropriate patient selection to avoid unnecessary anti-reflux surgery, which lengthens operative time and increases the conversion rate.

The Clinical Value of Apparent Diffusion Coefficient of Readout Segmentation of Long Variable Echo Trains and Correlation With Ki-67 Expression in Distal Rectal Cancer.

OBJECTIVE: The aim of the study is to explore the clinical value of the apparent diffusion coefficient (ADC) derived from the readout segmentation of long variable echo trains (RESOLVE) technique for identifying clinicopathologic features of distal rectal cancer and correlations between ADC and Ki-67 expression. METHODS: The data of 112 patients with a proven pathology of distal rectal cancer who underwent preoperative magnetic resonance imaging were retrospectively analyzed. The mean ADC value was measured using the "full-layer and center" method. Differences in ADC values and Ki-67 expression in different clinical stages, pathological types, and tumor differentiation were compared using analysis of variance. Correlations between ADC value and clinicopathologic features were assessed using Spearman correlation analysis. RESULTS: Interobserver agreement of confidence levels from 2 radiologists was excellent for ADC measurement ( k =  0.85). Patients with a lower clinical stage, well-differentiated adenocarcinomas, and a higher possibility of mucinous adenocarcinoma exhibited a positive correlation with higher ADC values, but these factors were negatively correlated with Ki-67 expression (all P < 0.05). We found that ADC value was negatively correlated with Ki-67 expression ( r = -0.62, P < 0.001). CONCLUSIONS: The ADC value generated by RESOLVE sequences was significantly associated with clinicopathologic features and Ki-67 expression in patients with distal rectal cancer in this study. Thus, the ADC value could be considered a new noninvasive imaging biomarker that could be helpful in predicting the biological properties of distal rectal cancer.

A xonotlite nanofiber bioactive 3D-printed hydrogel scaffold based on osteo-/angiogenesis and osteoimmune microenvironment remodeling accelerates vascularized bone regeneration.

BACKGROUND: Coordination between osteo-/angiogenesis and the osteoimmune microenvironment is essential for effective bone repair with biomaterials. As a highly personalized and precise biomaterial suitable for repairing complex bone defects in clinical practice, it is essential to endow 3D-printed scaffold the above key capabilities. RESULTS: Herein, by introducing xonotlite nanofiber (Ca6(Si6O17) (OH)2, CS) into the 3D-printed silk fibroin/gelatin basal scaffold, a novel bone repair system named SGC was fabricated. It was noted that the incorporation of CS could greatly enhance the chemical and mechanical properties of the scaffold to match the needs of bone regeneration. Besides, benefiting from the addition of CS, SGC scaffolds could accelerate osteo-/angiogenic differentiation of bone mesenchymal stem cells (BMSCs) and meanwhile reprogram macrophages to establish a favorable osteoimmune microenvironment. In vivo experiments further demonstrated that SGC scaffolds could efficiently stimulate bone repair and create a regeneration-friendly osteoimmune microenvironment. Mechanistically, we discovered that SGC scaffolds may achieve immune reprogramming in macrophages through a decrease in the expression of Smad6 and Smad7, both of which participate in the transforming growth factor-ß (TGF-ß) signaling pathway. CONCLUSION: Overall, this study demonstrated the clinical potential of the SGC scaffold due to its favorable pro-osteo-/angiogenic and osteoimmunomodulatory properties. In addition, it is a promising strategy to develop novel bone repair biomaterials by taking osteoinduction and osteoimmune microenvironment remodeling functions into account.

Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway.

BACKGROUND: Impaired osteo-/angiogenesis, excessive inflammation, and imbalance of the osteoimmune homeostasis are involved in the pathogenesis of the alveolar bone defect caused by periodontitis. Unfortunately, there is still a lack of ideal therapeutic strategies for periodontitis that can regenerate the alveolar bone while remodeling the osteoimmune microenvironment. Quercetin, as a monomeric flavonoid, has multiple pharmacological activities, such as pro-regenerative, anti-inflammatory, and immunomodulatory effects. Despite its vast spectrum of pharmacological activities, quercetin's clinical application is limited due to its poor water solubility and low bioavailability. RESULTS: In this study, we fabricated a quercetin-loaded mesoporous bioactive glass (Quercetin/MBG) nano-delivery system with the function of continuously releasing quercetin, which could better promote the bone regeneration and regulate the immune microenvironment in the alveolar bone defect with periodontitis compared to pure MBG treatment. In particular, this nano-delivery system effectively decreased injection frequency of quercetin while yielding favorable therapeutic results. In view of the above excellent therapeutic effects achieved by the sustained release of quercetin, we further investigated its therapeutic mechanisms. Our findings indicated that under the periodontitis microenvironment, the intervention of quercetin could restore the osteo-/angiogenic capacity of periodontal ligament stem cells (PDLSCs), induce immune regulation of macrophages and exert an osteoimmunomodulatory effect. Furthermore, we also found that the above osteoimmunomodulatory effects of quercetin via macrophages could be partially blocked by the overexpression of a key microRNA--miR-21a-5p, which worked through inhibiting the expression of PDCD4 and activating the NF-κB signaling pathway. CONCLUSION: In summary, our study shows that quercetin-loaded mesoporous nano-delivery system has the potential to be a therapeutic approach for reconstructing alveolar bone defects in periodontitis. Furthermore, it also offers a new perspective for treating alveolar bone defects in periodontitis by inhibiting the expression of miR-21a-5p in macrophages and thereby creating a favorable osteoimmune microenvironment.

Outcomes of antiretroviral treatment for 0-14-year-old children living with HIV in Ganzhou, China, 2006-2023.

BACKGROUND: Studies on antiretroviral therapy (ART) in children living with HIV (CLHIV) are limited due to the small population and low accession rate of ART. METHODS: All 0-14-year-old CLHIV admitted to the Ganzhou Center for Disease Control and Prevention from January 2006 to June 2023 were included retrospectively. The information of treatment regimens, disease progression, and laboratory tests of the patients under ART were used to explore the outcomes and impacts of long-term ART. The normality of all the data was tested by the Shapiro-Wilk test. RESULTS: From 2006 to 2023, 18 CLHIV were reported in Ganzhou. Among them, 11 received ART and were followed up for 60.0 ± 48.4 months. After receiving ART, the median viral load of them decreased from 89,600 copies/ml to 22 copies/ml (P = 0.007), the median CD4+ T cell count increased from 380.7 cells/µL to 661.9 cells/µL (P = 0.028), and the median CD8+ T cell count decreased from 1065.8 cells/µL to 983.3 cells/µL (P = 0.584). The laboratory test results regarding liver function, renal function, blood cell count, and glucolipid metabolism tended to be within normal reference ranges, and the mean height-for-age z-score and weight-for-age z-score increased. However, all the three CLHIV who received cotrimoxazole developed pneumocystis carinii pneumonia, upper respiratory infection, skin lesions, bacterial pneumonia and/or thrush; the mean body-mass-index-for-age z-score decreased from 0.52 to -0.63. CONCLUSION: For CLHIV, ART could effectively inhibit the replication of HIV and improve the immune function of patients. More studies that focus on ART in CLHIV are urgently needed.

Potential causal associations between leisure sedentary behaviors, physical activity, sleep traits, and myopia: a Mendelian randomization study.

BACKGROUND: Myopia is the most prevalent refractive error and a growing global health concern that significantly affects visual function. Researchers have recently emphasized considerably on the influence of lifestyle on myopia incidence and development. This study investigates the relationship between leisure sedentary behaviors (LSB)/physical activity (PA)/sleep traits and myopia. METHODS: LSB, PA, and sleep trait-associated genetic variants were used as instrument variables in a Mendelian randomization (MR) study to examine their causal effects on myopia. Summary genome-wide association studies (GWASs) statistical data for LSB and PA were obtained from UK Biobank, and the data of sleep traits was obtained from UK Biobank, UK Biobank and 23andMe, and FinnGen. We used summary statistics data for myopia from MRC IEU. The MR analyses was performed using the inverse variance-weighted (IVW), MR-Egger, weighted median, and MR Pleiotropy RESidual Sum and Outlier methods. RESULTS: Computer use was genetically predicted to increase the myopia risk [IVW odds ratio (OR) = 1.057; 95% confidence interval (CI), 1.038-1.078; P = 7.04 × 10- 9]. The self-reported moderate-to-vigorous physical activity (MVPA) (IVW OR = 0.962; 95% CI, 0.932-0.993; P = 1.57 × 10- 2) and television watching (IVW OR = 0.973; 95% CI, 0.961-0.985, P = 1.93 × 10- 5) were significantly associated with a lower myopia risk. However, genetically predicted sleep traits or accelerometer-measured physical activity had no significant associations with myopia. CONCLUSION: Our results indicated that computer use is a risk factor for myopia, whereas television watching and MVPA may protect against myopia. These findings shed new light on possible strategies for reducing the prevalence of myopia.