Structural and functional analyses of a germline KRAS T50I mutation provide insights into Raf activation.

A T50I substitution in the K-Ras interswitch domain causes Noonan syndrome and emerged as a third-site mutation that restored the in vivo transforming activity and constitutive MAPK pathway activation by an attenuated KrasG12D,E37G oncogene in a mouse leukemia model. Biochemical and crystallographic data suggested that K-RasT50I increases MAPK signal output through a non-GTPase mechanism, potentially by promoting asymmetric Ras:Ras interactions between T50 and E162. We generated a "switchable" system in which K-Ras mutant proteins expressed at physiologic levels supplant the fms like tyrosine kinase 3 (FLT3) dependency of MOLM-13 leukemia cells lacking endogenous KRAS and used this system to interrogate single or compound G12D, T50I, D154Q, and E162L mutations. These studies support a key role for the asymmetric lateral assembly of K-Ras in a plasma membrane-distal orientation that promotes the formation of active Ras:Raf complexes in a membrane-proximal conformation. Disease-causing mutations such as T50I are a valuable starting point for illuminating normal Ras function, elucidating mechanisms of disease, and identifying potential therapeutic opportunities for Rasopathy disorders and cancer.

Protocol for rheumatoid arthritis complicated with cardiovascular damage treated with Guanxining tablet with a randomized controlled trial.

Background: Cardiovascular disease (CVD) is the main cause of death in patients with rheumatoid arthritis (RA). Apart from traditional cardiovascular risk factors, immune dysfunction and chronic inflammation of RA are also risk factors for complex cardiovascular damage. Although methotrexate (MTX) is beneficial to CVD in RA patients by inhibiting inflammation, its adverse effects limit its clinical application. Therefore, it is essential to seek safer and more effective drugs. Objective: We aimed to assess the efficacy of Guanxining Tablet (GXNT) for rheumatoid arthritis complicated with cardiovascular damage. Methods: We will conduct a prospective single-center randomized trial. We will randomly divide 56 eligible patients into two groups. The treatment group will take GXNT and MTX treatment, and the control group will receive MTX and the placebo. The primary outcome measure will be aortic distensibility (AD). Secondary outcome measures will be Cardiac function which will contain right ventricular outflow tract diameter (RVOTD), aortic diameter (AOD), left atrium diameter (LAD), right ventricular end diastolic diameter (RVDD), left ventricular end diastolic diameter (LVDD), ejection fraction (EF%), fractional shortening (FS%), stroke volume (SV). Adverse events will be closely monitored during the entire trial period. Discussion: This trial is intended to determine whether the addition of GXNT will improve the prognosis of patients with rheumatoid arthritis and cardiovascular damage without severe adverse reactions. Completing this clinical trial might provide these patients with a novel and effective drug while avoiding adverse reactions similar to methotrexate. Trial registration: ChiCTR2000030247.

Enhancing Prognostic Assessment for Influenza-Associated Pneumonia: An Examination of Contributing Risk Factors.

Objective: This study aims to analyze the prognostic risk factors influencing patient outcomes in cases of influenza-associated pneumonia. Methods: We comprehensively analysed clinical data from patients admitted to the First Affiliated Hospital of Wenzhou Medical University between December 2017 and April 2019. Patients with confirmed influenza-associated pneumonia, determined through nucleic acid detection in throat swabs or sputum samples, were included in the study. The collected data were meticulously analyzed to identify significant prognostic risk factors. Results: A total of 151 patients diagnosed with influenza-associated pneumonia were included in the final analysis, yielding a fatality rate of 19.87% (30/151). The application of multivariate regression analysis revealed that several independent risk factors significantly affected the prognosis of patients afflicted with influenza-associated pneumonia. These included lymphocyte count (L), oxygenation index (O), albumin (A), and urinary (U) levels. Receiver operating characteristic (ROC) curve analysis further elucidated the prognostic value of these factors. Specifically, the Composite Index LOAU (Lymphocyte, Oxygenation index, Albumin, Urinary) demonstrated a robust area under the curve (AUC) of 0.909 (95% CI: 0.851-0.950), surpassing the performance of established scoring systems, such as the pneumonia severity index (PSI) (AUC = 0.746), Apache II (AUC = 0.732), and CURB-65 (AUC = 0.662). These differences were statistically significant (P < .05). Conclusions: The prognosis of influenza-associated pneumonia can be effectively predicted by assessing peripheral blood parameters, including lymphocyte count, albumin level, urinary markers, and the oxygenation index upon admission. Notably, the Composite Index LOAU, as a comprehensive amalgamation of these factors, holds promising potential to enhance prognostic precision and management outcomes in cases of influenza-associated pneumonia.

Development of a Microfluidic Chip System with Giant Magnetoresistance Sensor for High-Sensitivity Detection of Magnetic Nanoparticles in Biomedical Applications.

Magnetic nanoparticles (MNPs) have been widely utilized in the biomedical field for numerous years, offering several advantages such as exceptional biocompatibility and diverse applications in biology. However, the existing methods for quantifying magnetic labeled sample assays are scarce. This research presents a novel approach by developing a microfluidic chip system embedded with a giant magnetoresistance (GMR) sensor. The system successfully detects low concentrations of MNPs with magnetic particle velocities of 20 mm/s. The stray field generated by the magnetic subject flowing through the microchannel above the GMR sensor causes variations in the signals. The sensor's output signals are appropriately amplified, filtered, and processed to provide valuable indications. The integration of the GMR microfluidic chip system demonstrates notable attributes, including affordability, speed, and user-friendly operation. Moreover, it exhibits a high detection sensitivity of 10 µg/µL for MNPs, achieved through optimizing the vertical magnetic field to 100 Oe and the horizontal magnetic field to 2 Oe. Additionally, the study examines magnetic labeled RAW264.7 cells. This quantitative detection of magnetic nanoparticles can have applications in DNA concentration detection, protein concentration detection, and other promising areas of research.

Exploring a high-urease activity Bacillus cereus for self-healing concrete via induced CaCO3 precipitation.

The structural integrity and esthetic appeal of concrete can be compromised by concrete cracks. Promise has been shown by microbe-induced calcium carbonate precipitation (MICP) as a solution for concrete cracking, with a focus on urease-producing microorganisms in research. Bacillus cereus was isolated from soil and employed for this purpose in this study due to its high urease activity. The strain exhibited strong tolerance for alkaline media and high salt levels, which grew at a pH of 13 and 4% salt concentration. The repair of concrete cracks with this strain was evaluated by assessing the effects of four different thickeners at varying concentrations. The most effective results were achieved with 10 g/L of sodium carboxymethyl cellulose (CMC-Na). The data showed that over 90% repair of cracks was achieved by this system with an initial water penetration time of 30 s. The study also assessed the quantity and sizes of crystals generated during the bacterial mineralization process over time to improve our understanding of the process. KEY POINTS: • MICP using Bacillus cereus shows potential for repairing concrete cracks. • Strain tolerates alkaline media and high salt levels, growing at pH 13 and 4% salt concentration. • Sodium carboxymethyl cellulose (CMC-Na) at 10 g/L achieved over 90% repair of cracks.

Function of the R2R3-MYB Transcription Factors in Dalbergia odorifera and Their Relationship with Heartwood Formation.

R2R3-MYB transcription factors (TFs) form one of the most important TF families involved in regulating various physiological functions in plants. The heartwood of Dalbergia odorifera is a kind of high-grade mahogany and valuable herbal medicine with wide application. However, the role of R2R3-MYB genes in the growth and development of D. odorifera, especially their relevance to heartwood formation, has not been revealed. A total of 126 R2R3-MYBs were screened from the D. odorifera genome and named DodMYB1-126 based on their location on 10 chromosomes. The collinearity results showed that purification selection was the main driving force for the evolution of the R2R3-MYB TFs family, and whole genome/fragment replication event was the main form for expanding the R2R3-MYB family, generating a divergence of gene structure and function. Comparative phylogenetic analysis classified the R2R3-MYB TFs into 33 subfamilies. S3-7,10,12-13,21 and N4-7 were extensively involved in the metabolic process; S9,13,16-19,24-25 and N1-3,8 were associated with the growth and development of D. odorifera. Based on the differential transcriptional expression levels of R2R3-MYBs in different tissues, DodMYB32, DodMYB55, and DodMYB89 were tentatively screened for involvement in the regulatory process of heartwood. Further studies have shown that the DodMYB89, localized in the nucleus, has transcriptional activation activity and is involved in regulating the biosynthesis of the secondary metabolites of heartwood by activating the promoters of the structural genes DodI2'H and DodCOMT. This study aimed to comprehensively analyze the functions of the R2R3-MYB TFs and screen for candidate genes that might be involved in heartwood formation of D. odorifera.

[Summary of the best evidence for the energy and protein intake targets and calculation in critically ill patients].

OBJECTIVE: To evaluate and summarize the best evidence of energy and protein intake targets and calculation in adult critically ill patients, and to provide evidence-based basis for critical nutrition management. METHODS: Evidence related to energy and protein intake targets and calculation of adult critically ill patients, including guideline, expert consensus, systematic review and evidence summary, were systematically searched in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Cochrane Library, UpToDate, BMJ Best Practice, Joanna Briggs Institute (JBI), Web of Science, SinoMed, Medive, China National Knowledge Infrastructure, Wanfang database, VIP database, Guidelines International Network (GIN), National Institute for Health and Care Excellence (NICE), National Guideline Clearinghouse (NGC), Registered Nurses Association of Ontario (RNAO), and Society of Critical Care Medicine (SCCM) from January 2012 to June 2022. Two researchers independently evaluated the quality of the included literatures using the JBI Evidence-based Health Care Center evaluation tool and the Appraisal of Clinical Practice Guidelines for Research and Evaluation II (AGREE II), extracted and summarized the best evidence for the nutritional intake goal and calculation of adult critically ill patients, and described the evidence. RESULTS: A total of 18 literatures were included, including 5 clinical guidelines, 8 expert consensus, 3 systematic reviews and 2 evidence summaries. After literature quality evaluation, 18 articles were all enrolled. The evidence was summarized from the four aspects, including energy target calculation method, dose body weight, energy and protein intake target, and calculation method, 24 pieces of the best evidence were finally formed. CONCLUSIONS: The best evidence of energy and protein intake targets and calculation for critically ill patients was summarized based on evidence-based. Clinical medical staff can choose indirect calorimetry to calculate energy goals when equipment is available. Patient's height, body weight should be recorded accurately, dose body weight can be determined by body mass index (BMI). Meanwhile, blood urea nitrogen (BUN) loss, fat-free body weight, simple formulas and other methods should be used to continuously evaluate and adjust protein intake targets, to achieve the purpose of optimizing intensive nutrition support.

A Multi-factor Analysis of Revision in Total Hip Replacement Using the Collarless-Polished-Tapered Stems with Different Cups.

OBJECTIVE: Collarless-polished-tapered (CPT) stems have been widely used in total hip replacement (THR). Given that various types of cups are combined with CPT in clinical practice, however, what cup type performs the best for use with CPT is still unclear. This study aimed to investigate the effects of three types of commonly used cups with CPT on revision and survival life using multi-factor analysis. METHODS: This study is a cohort study using the data between October 1998 to September 2021. The data of THR patients with ZCA All-poly Acetabular Cup, Continuum Acetabular System, and Trilogy Acetabular System with CPT were collected from several hospitals in the UK. The patients aged from 20 to 97 (n = 5981, 2345 male and 3636 female). Age, gender, body mass index, diagnosis, surgeon grade, cup material, cup size, surgical approach, survival life, complications, and Harris hip scores (HHS) were analyzed in relation to revision status. SPSS statistical software was used to analyze the relationship among various factors. The main statistical methods included chi-square with cross tables, analysis of variance (ANOVA) and survival analysis. RESULTS: The results in relation to HHS shows that the continuum cup has the best outcome in the postoperative period of 1 and 5 years (1 year = 90.7, 5 years = 91.3; P < 0.001); the Trilogy cup was the second (1 year = 88.4, 5 years = 87.3; P < 0.001); and the ZCA cup was the third (1 year = 84.6, 5 years = 82.4; P < 0.001). However, the Trilogy cup performed the best regarding survival life on revision while the Continuum cup was the worst. CONCLUSION: When the CPT stem is combined with different cups, the trilogy cup shows the best characteristics in terms of survival trends with revision ratios compared with the continuum and ZCA cups, and is therefore recommended by this study.

Few-shot short utterance speaker verification using meta-learning.

Short utterance speaker verification (SV) in the actual application is the task of accepting or rejecting the identity claim of a speaker based on a few enrollment utterances. Traditional methods have used deep neural networks to extract speaker representations for verification. Recently, several meta-learning approaches have learned a deep distance metric to distinguish speakers within meta-tasks. Among them, a prototypical network learns a metric space that may be used to compute the distance to the prototype center of speakers, in order to classify speaker identity. We use emphasized channel attention, propagation and aggregation in TDNN (ECAPA-TDNN) to implement the necessary function for the prototypical network, which is a nonlinear mapping from the input space to the metric space for either few-shot SV task. In addition, optimizing only for speakers in given meta-tasks cannot be sufficient to learn distinctive speaker features. Thus, we used an episodic training strategy, in which the classes of the support and query sets correspond to the classes of the entire training set, further improving the model performance. The proposed model outperforms comparison models on the VoxCeleb1 dataset and has a wide range of practical applications.

Enhancing the robustness of vision transformer defense against adversarial attacks based on squeeze-and-excitation module.

Vision Transformer (ViT) models have achieved good results in computer vision tasks, their performance has been shown to exceed that of convolutional neural networks (CNNs). However, the robustness of the ViT model has been less studied recently. To address this problem, we investigate the robustness of the ViT model in the face of adversarial attacks, and enhance the robustness of the model by introducing the ResNet- SE module, which acts on the Attention module of the ViT model. The Attention module not only learns edge and line information, but also can extract increasingly complex feature information; ResNet-SE module highlights the important information of each feature map and suppresses the minor information, which helps the model to perform the extraction of key features. The experimental results show that the accuracy of the proposed defense method is 19.812%, 17.083%, 18.802%, 21.490%, and 18.010% against Basic Iterative Method (BIM), C&W, DeepFool, DI2FGSM, and MDI2FGSM attacks, respectively. The defense method in this paper shows strong robustness compared with several other models.

HBV precore G1896A mutation promotes growth of hepatocellular carcinoma cells by activating ERK/MAPK pathway.

Chronic hepatitis B virus (HBV) infection is one of the leading causes of hepatocellular carcinoma (HCC). The HBV genome is prone to mutate and several variants are closely related to the malignant transformation of liver disease. G1896A mutation (G to A mutation at nucleotide 1896) is one of the most frequently observed mutations in the precore region of HBV, which prevents HBeAg expression and is strongly associated with HCC. However, the mechanisms by which this mutation causes HCC are unclear. Here, we explored the function and molecular mechanisms of the G1896A mutation during HBV-associated HCC. G1896A mutation remarkably enhanced the HBV replication in vitro. Moreover, it increased tumor formation and inhibited apoptosis of hepatoma cells, and decreased the sensitivity of HCC to sorafenib. Mechanistically, the G1896A mutation could activate ERK/MAPK pathway to enhanced sorafenib resistance in HCC cells and augmented cell survival and growth. Collectively, our study demonstrates for the first time that the G1896A mutation has a dual regulatory role in exacerbating HCC severity and sheds some light on the treatment of G1896A mutation-associated HCC patients.

Bioinspired hot-spot engineering strategy towards ultrasensitive SERS sandwich biosensor for bacterial detection.

Surface-enhanced Raman spectroscopy (SERS) sandwich biosensors have received tremendous attention in early diagnosis of bacterial infections. However, efficiently engineering nanoscale plasmonic hots pots (HS) towards ultrasensitive SERS detection still remains challenging. Herein, we propose a bioinspired synergistic HS engineering strategy to construct ultrasensitive SERS sandwich bacterial sensor (named USSB), by coupling bioinspired signal module and plasmonic enrichment module to synergistically boost the number and intensity of HS. The bioinspired signal module is based on dendritic mesoporous silica nanocarrier (DMSN) loaded with plasmonic nanoparticles and SERS tag, while magnetic Fe3O4 nanoparticles coated with Au shell are employed in plasmonic enrichment module. We demonstrate that DMSN effectively shrank nanogaps between plasmonic nanoparticles to improve HS intensity. Meanwhile, plasmonic enrichment module contributed to plenty of additional HS inside and outside individual "sandwich". Ascribing to the boosted number and intensity of HS, the constructed USSB sensor exhibits ultrahigh detection sensitivity (7 CFU/mL) and selectivity towards model pathogenic bacteria of Staphylococcus aureus. Remarkably, the USSB sensor enables fast and accurate bacterial detection in real blood samples of septic mice, achieving early diagnosis of bacterial sepsis. The proposed bioinspired synergistic HS engineering strategy opens up a new direction for constructing ultrasensitive SERS sandwich biosensors, and may promote their advancing applications in the early diagnosis and prognosis of devastating diseases.

Traditional Chinese medicine use is associated with lower risk of pneumonia in patients with systemic lupus erythematosus: a population-based retrospective cohort study.

Objectives: To investigate the association between traditional Chinese medicine (TCM) therapy and the risk of pneumonia in patients with systemic lupus erythematosus (SLE). Methods: This population-based control study analyzed the data retrieved from the National Health Insurance Research database in Taiwan. From a cohort of 2 million records of the 2000-2018 period, 9,714 newly diagnosed patients with SLE were initially included. 532 patients with pneumonia and 532 patients without pneumonia were matched 1:1 based on age, sex, and year of SLE diagnosis using propensity score matching. The use of TCM therapy was considered from the SLE diagnosis date to the index date and the cumulative days of TCM therapy were used to calculate the dose effect. Conditional logistic regression was used to investigate the risk of pneumonia infection. Furthermore, to explore the severity of pneumonia in SLE, sensitivity analyses were performed after stratification using the parameters of emergency room visit, admission time, and antibiotic use. Results: TCM therapy for >60 days could significantly reduce the risk of pneumonia in patients with SLE (95% CI = 0.46-0.91; p = 0.012). Stratified analysis showed that TCM use also reduced the risk of pneumonia in younger and female patients with SLE by 34% and 35%, respectively. TCM for >60 days significantly reduced the risk of pneumonia in the follow-up periods of >2, >3, >7, and >8 years. In addition, the exposure of TCM for >60 days reduced the risk of pneumonia in patients with SLE who were treated with antibiotics for moderate or severe pneumonia. Finally, the study found that using formulae to tonify the kidney for more than 90 days and formulae to activate blood circulation for less than 30 days could significantly reduce the risk of pneumonia infection in patients with SLE. Conclusion: TCM use is associated with a lower risk of pneumonia among patients with SLE.

Chinese Clinical Named Entity Recognition From Electronic Medical Records Based on Multisemantic Features by Using Robustly Optimized Bidirectional Encoder Representation From Transformers Pretraining Approach Whole Word Masking and Convolutional Neural Networks: Model Development and Validation.

BACKGROUND: Clinical electronic medical records (EMRs) contain important information on patients' anatomy, symptoms, examinations, diagnoses, and medications. Large-scale mining of rich medical information from EMRs will provide notable reference value for medical research. With the complexity of Chinese grammar and blurred boundaries of Chinese words, Chinese clinical named entity recognition (CNER) remains a notable challenge. Follow-up tasks such as medical entity structuring, medical entity standardization, medical entity relationship extraction, and medical knowledge graph construction largely depend on medical named entity recognition effects. A promising CNER result would provide reliable support for building domain knowledge graphs, knowledge bases, and knowledge retrieval systems. Furthermore, it would provide research ideas for scientists and medical decision-making references for doctors and even guide patients on disease and health management. Therefore, obtaining excellent CNER results is essential. OBJECTIVE: We aimed to propose a Chinese CNER method to learn semantics-enriched representations for comprehensively enhancing machines to understand deep semantic information of EMRs by using multisemantic features, which makes medical information more readable and understandable. METHODS: First, we used Robustly Optimized Bidirectional Encoder Representation from Transformers Pretraining Approach Whole Word Masking (RoBERTa-wwm) with dynamic fusion and Chinese character features, including 5-stroke code, Zheng code, phonological code, and stroke code, extracted by 1-dimensional convolutional neural networks (CNNs) to obtain fine-grained semantic features of Chinese characters. Subsequently, we converted Chinese characters into square images to obtain Chinese character image features from another modality by using a 2-dimensional CNN. Finally, we input multisemantic features into Bidirectional Long Short-Term Memory with Conditional Random Fields to achieve Chinese CNER. The effectiveness of our model was compared with that of the baseline and existing research models, and the features involved in the model were ablated and analyzed to verify the model's effectiveness. RESULTS: We collected 1379 Yidu-S4K EMRs containing 23,655 entities in 6 categories and 2007 self-annotated EMRs containing 118,643 entities in 7 categories. The experiments showed that our model outperformed the comparison experiments, with F1-scores of 89.28% and 84.61% on the Yidu-S4K and self-annotated data sets, respectively. The results of the ablation analysis demonstrated that each feature and method we used could improve the entity recognition ability. CONCLUSIONS: Our proposed CNER method would mine the richer deep semantic information in EMRs by multisemantic embedding using RoBERTa-wwm and CNNs, enhancing the semantic recognition of characters at different granularity levels and improving the generalization capability of the method by achieving information complementarity among different semantic features, thus making the machine semantically understand EMRs and improving the CNER task accuracy.

PATL2 regulates mRNA homeostasis in oocytes by interacting with EIF4E and CPEB1.

The accumulation and storage of maternal mRNA is crucial for oocyte maturation and embryonic development. PATL2 is an oocyte-specific RNA-binding protein, and previous studies have confirmed that PATL2 mutation in humans and knockout mice cause oocyte maturation arrest or embryonic development arrest, respectively. However, the physiological function of PATL2 in the process of oocyte maturation and embryonic development is largely unknown. Here, we report that PATL2 is highly expressed in growing oocytes and couples with EIF4E and CPEB1 to regulate maternal mRNA expression in immature oocytes. The germinal vesicle oocytes from Patl2-/- mice exhibit decreasing maternal mRNA expression and reduced levels of protein synthesis. We further confirmed that PATL2 phosphorylation occurs in the oocyte maturation process and identified the S279 phosphorylation site using phosphoproteomics. We found that the S279D mutation decreased the protein level of PATL2 and led to subfertility in Palt2S279D knock-in mice. Our work reveals the previously unrecognized role of PATL2 in regulating the maternal transcriptome and shows that phosphorylation of PATL2 leads to the regulation of PATL2 protein levels via ubiquitin-mediated proteasomal degradation in oocytes.

Ambient Environment Adaptive Elastomer Constructed by Microphase Separation and Segment Complexation of Triblock Copolymers.

Elastomers with environmental adaption have attracted considerable attention for advanced applications in various areas. Here, we fabricate an ambient environment adaptive elastomer by assembling triblock copolymers polystyrene-b-poly(acrylic acid)-b-polystyrene (SAS) and polystyrene-b-poly(ethylene oxide)-b-polystyrene (SES). Owing to the microphase separation of triblock polymers and hydrogen-bonding complexation of their middle segments, the SAS/SES complex presents dichotomy of vitrified hard PS domains and soft PAA/PEO domains, which presents major relaxation transition in the temperature zone 10-30 °C and relative humidity (RH) 40-60%. The SAS/SES elastomer presents quick adaption to the ambient environment change with temperature and humidity coupling. Moreover, after a loading-unloading cycle training, the SAS/SES elastomer exhibits domain orientation, low energy dissipation, high recovery ratio, and distinct strain stiffening compared with the pristine complex. The SAS/SES elastomer has potential to be used as a sensing and adaption component for complicated intelligent systems.

MS2-MBP-Based Affinity Purification of Nucleus- or Cytoplasm-Localized lncRNA-Protein Complexes Formed In Vivo.

With recent emergence of huge number of long noncoding RNAs (lncRNAs), purification of lncRNA-protein (lncRNP) complexes is fundamental to understand the role of lncRNA and its biological function. However, lncRNP purification is still a daunting challenge. Here we describe a protocol to purify lncRNP formed in vivo with MS2-MBP-based affinity purification. Inducible lncRNA tagged with MS2 RNA hairpins is introduced into cells of interest, and RNP on tagged lncRNA is formed in vivo. MS2-MBP fusion protein is expressed in Escherichia coli and purified with amylose resin and HiTrap heparin column. The MS2 part of MS2-MBP fusion protein binds to the hairpins, and MBP part binds to amylose resin. We also describe a protocol to separate the nucleus and the cytoplasm so that lncRNP localized in the nucleus or cytoplasm can be individually purified. The amount of lncRNP purified is well sufficient for mass spectrometry analysis.

Characterization and quantification of microplastics in indoor environments.

Microplastics (MPs) have gradually attracted attention; however, people have paid limited attention to the existence of airborne microplastics, especially in indoor environments. In this study, we tracked microplastic deposition in offices, laboratories, dining halls, and dormitories. Results showed that the average microplastic abundance in the dormitory was the highest (14088.05 pcs/m3), followed by in the office (13097.13 pcs/m3), laboratory (7512.55 pcs/m3) and dining hall (4308.26 pcs/m3). The microplastics deposited at indoor environment were mostly dark, elongated and solid. The average particle size of the microplastics sampled at the four sampling points was 66.15 µm, but the size of the microplastics in the laboratory environment was smaller and more harmful. Airflow tests using air conditioners showed that turbulence increases the resuspension of microplastics. Our results also show that the frequency of human activities is one of the main factors leading to changes in the content of microplastics in indoor air, and turbulence caused by airflow will lead to the migration of microplastics in the indoor environment. In conclusion, indoor environments are prone to high microplastic concentration, which may pose certain potential risks to human health.

Detrimental role of SIX1 in hepatic lipogenesis and fibrosis of non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Aberrant lipid metabolism and accumulation of extracellular matrix proteins are hallmarks of the disease, but the underlying mechanisms are largely unknown. This study aims to elucidate the key role of sine oculis homeobox homologue 1 (SIX1) in the development of NAFLD. METHODS: Alb-Cre mice were administered the AAV9 vector for SIX1 liver-specific overexpression or knockdown. Metabolic disorders, hepatic steatosis, and inflammation were monitored in mice fed with HFHC or MCD diet. High throughput CUT&Tag analysis was employed to investigate the mechanism of SIX1 in diet-induced steatohepatitis. RESULTS: Here, we found increased SIX1 expression in the livers of NAFLD patients and animal models. Liver-specific overexpression of SIX1 using adeno-associated virus serotype 9 (AAV9) provoked more severe inflammation, metabolic disorders, and hepatic steatosis in the HFHC or MCD-induced mice model. Mechanistically, we demonstrated that SIX1 directly activated the expression of liver X receptor α (LXRα) and liver X receptor ß (LXRß), thus inducing de novo lipogenesis (DNL). In addition, our results also illustrated a critical role of SIX1 in regulating the TGF-ß pathway by increasing the levels of type I and II TGF-ß receptor (TGFßRI/TGFßRII) in hepatic stellate cells (HSCs). Finally, we found that liver-specific SIX1 deficiency could ameliorate diet-induced NAFLD pathogenesis. CONCLUSION: Our findings suggest a detrimental function of SIX1 in the progression of NAFLD. The direct regulation of LXRα/ß and TGF-ß signalling by SIX1 provides a new regulatory mechanism in hepatic steatosis and fibrosis.

Bi-allelic pathogenic variants in PABPC1L cause oocyte maturation arrest and female infertility.

Oocyte maturation arrest is one of the important causes of female infertility, but the genetic factors remain largely unknown. PABPC1L, a predominant poly(A)-binding protein in Xenopus, mouse, and human oocytes and early embryos prior to zygotic genome activation, plays a key role in translational activation of maternal mRNAs. Here, we identified compound heterozygous and homozygous variants in PABPC1L that are responsible for female infertility mainly characterized by oocyte maturation arrest in five individuals. In vitro studies demonstrated that these variants resulted in truncated proteins, reduced protein abundance, altered cytoplasmic localization, and reduced mRNA translational activation by affecting the binding of PABPC1L to mRNA. In vivo, three strains of Pabpc1l knock-in (KI) female mice were infertile. RNA-sequencing analysis showed abnormal activation of the Mos-MAPK pathway in the zygotes of KI mice. Finally, we activated this pathway in mouse zygotes by injecting human MOS mRNA, and this mimicked the phenotype of KI mice. Our findings reveal the important roles of PABPC1L in human oocyte maturation and add a genetic potential candidate gene to be screened for causes of infertility.