Association of hypertension and long-term blood pressure changes with new-onset diabetes in the elderly: A 10-year cohort study.

AIM: To explore the correlation between new-onset diabetes (NOD), hypertension and blood pressure management among elderly individuals in China. MATERIALS AND METHODS: A cohort analysis involved 1380 participants aged 60 years or older, initially free of diabetes in 2008, from the Chinese Longitudinal Healthy Longevity Survey. Follow-up assessments occurred every 2-3 years. The relationship between hypertension, blood pressure changes and NOD was analysed using multivariable-adjusted Cox regression. RESULTS: By 2018, 102 participants developed diabetes, while 1278 remained without diabetes. The cumulative diabetes prevalence increased from 3.1% at 3 years to 7.4% at 10 years. Hypertension prevalence increased from 20.9% at baseline to 41.0% at 10 years, with higher rates in those diagnosed with diabetes during follow-up. Multivariate analysis identified age, gender, baseline hypertension and systolic blood pressure (SBP) as independent predictors of NOD. Hypertension combined with overweight/obesity significantly increased the risk of NOD (hazard ratio [HR] 2.837; 95% confidence interval [CI], 1.680-4.792). We evaluated participants' blood pressure management levels in 2008 and 2011, then tracked the onset of diabetes from 2011 to 2018. Compared with participants with an average SBP below 120 mmHg in 2008 and 2011, those with SBP of 140 mmHg or higher had an 8-fold higher risk of developing NOD (adjusted HR8.492, 95% CI 2.048-35.217, P = .003), the highest risk group. Participants with SBP of 130-139.9 mmHg also had a significantly increased risk (adjusted HR 5.065, 95% CI 1.186-21.633, P = .029), while those with SBP of 120-129.9 mmHg showed no significant difference (HR 2.730, 95% CI 0.597-12.481, P = .195). Consistently high SBP (≥ 130 mmHg) further increased NOD risk (adjusted HR 3.464, 95% CI 1.464-8.196, P = .005). CONCLUSIONS: Significant predictors of NOD included age, gender, baseline hypertension and blood pressure management. Maintaining SBP consistently below 130 mmHg may be an effective strategy to reduce the incidence of NOD in the general elderly population.

MLSNet: a deep learning model for predicting transcription factor binding sites.

Accurate prediction of transcription factor binding sites (TFBSs) is essential for understanding gene regulation mechanisms and the etiology of diseases. Despite numerous advances in deep learning for predicting TFBSs, their performance can still be enhanced. In this study, we propose MLSNet, a novel deep learning architecture designed specifically to predict TFBSs. MLSNet innovatively integrates multisize convolutional fusion with long short-term memory (LSTM) networks to effectively capture DNA-sparse higher-order sequence features. Further, MLSNet incorporates super token attention and Bi-LSTM to systematically extract and integrate higher-order DNA shape features. Experimental results on 165 ChIP-seq (chromatin immunoprecipitation followed by sequencing) datasets indicate that MLSNet consistently outperforms several state-of-the-art algorithms in the prediction of TFBSs. Specifically, MLSNet reports average metrics: 0.8306 for ACC, 0.8992 for AUROC, and 0.9035 for AUPRC, surpassing the second-best methods by 1.82%, 1.68%, and 1.54%, respectively. This research delineates the effectiveness of combining multi-size convolutional layers with LSTM and DNA shape-based features in enhancing predictive accuracy. Moreover, this study comprehensively assesses the variability in model performance across different cell lines and transcription factors. The source code of MLSNet is available at https://github.com/minghaidea/MLSNet.

RBC-hitchhiking PLGA nanoparticles loading ß-glucan as a delivery system to enhance in vitro and in vivo immune responses in mice.

Red blood cells (RBCs) naturally trap some bacterial pathogens in the circulation and kill them by oxidative stress. Following neutralization, the bacteria are presented to antigen-presenting cells in the spleen by the RBCs. This ability of RBCs has been harnessed to develop a system where they play a crucial role in enhancing the immune response, offering a novel approach to enhance the body's immunity. In this work, a conjugate, G-OVA, was formed by connecting ß-glucan and OVA through a disulfide bond. Poly (lactic-co-glycolic acid) (PLGA) was then employed to encapsulate G-OVA, yielding G-OVA-PLGA. Finally, the nanoparticles were adsorbed onto RBCs to develop G-OVA-PLGA@RBC. The results demonstrated that the delivery of nanoparticles by RBCs enhanced the antibody response to antigens both in vitro and in vivo. The objective of this study was to investigate the increased immune activity of G-OVA-PLGA nanoparticles facilitated by RBCs transportation and to elucidate some of its underlying mechanisms. These findings are anticipated to contribute valuable insights for the development of efficient and safe immune enhancers.

Probiotic Bacillus subtilis QST713 improved growth performance and enhanced the intestinal health of yellow-feather broilers challenged with coccidia and Clostridium perfringens.

In this study, we investigated the effects of dietary supplementation with Bacillus subtilis (QST713) on the performance and intestinal health of yellow feather broilers under Coccidia and Clostridium perfringens (CP) challenge or CP alone. One-day-old yellow-feathered broiler roosters (n = 600) were randomly assigned to 5 groups (6 replicates with 20 roosters per replicate): the Con blank group, the CIC.p group (d24 Coccidia+d28-30 of CP challenge), the CIC.p + BS group (CIC.p +100 mg/kg B. subtilis), the C.p group (d 28-34 of CP challenge), and the C.p +BS group (C.p +100 mg/kg B. subtilis). The experiment lasted 80 d. The birds were evaluated for parameters such as average daily gain (ADG), average daily feed intake (ADFI), feed efficiency (F/G), intestinal lesion score, villus histomorphometry, intestinal tight junctions, inflammatory factors, and cecal microorganisms. The results revealed that 1) C.p. increased the F/G of broilers from 22 to 42 d (P < 0.05), whereas CIC.p. significantly decreased the 42 d and 80 d body weights (BW) and 22-42 d and 1-80 d ADG (P < 0.05) and significantly increased the 22 to 42 d and 1 to 80 d F/G (P < 0.05). The number of intestinal lesions significantly increased at 35 d and 42 d (P < 0.05). CIC.p significantly decreased the jejunum and ileum villus height (VH) and the ileum villus height/crypt depth (P < 0.05) at 35 d. The challenge significantly upregulated the expression of Claudin-1 and IL-4 mRNAs in the jejunum at 35 d and significantly downregulated the expression of IL-10 mRNA in the ileum at 35 d (P < 0.05); the number of unique OTUs in the challenge group decreased significantly after challenge treatment, and the relative abundances of Romboutsia at 35 d and Cladomyces and Lactobacillus at 42 d decreased significantly (P < 0.05). 2) Compared with the challenge groups, the addition of BS decreased the F/G of broilers from 22 to 42 d. Compared with the CIC group, the addition of BS significantly increased the F/G of broilers from 22 to 42 d. Compared with that in the CIC.p group, the addition of BS significantly increased the VH in the jejunum and ileum at 35 d (P < 0.05). Compared with the challenge groups, the BS groups presented significantly lower mRNA expression levels of Claudin-1 (P < 0.05) in the jejunum at 35 d. The Shannon and Chao indices suggested that BS increased the alpha diversity of cecum microorganisms in broilers. Dietary supplementation with B. subtilis can alleviate the damage to intestinal morphology and intestinal barrier function, as well as the altered cecal flora structure in broilers caused by Coccidia and C. perfringens infections.

Peripapillary retinal thickness and its risk factors in dry-type high myopia.

INTRODUCTION: To evaluate the alterations in the peripapillary retinal thickness and its risk factors in dry-type high myopia (HM). METHODS: One hundred and twenty eyes in 69 HM subjects were collected from March 2023 to July 2023 with the best-corrected visual acuity (BCVA), axial length, type of myopic maculopathy, and peripapillary retinal thickness. Divided into three groups according to the international photo-graphic classification system: Category 0 (C0) with no myopic retinal degenerative lesions, Category 1 (C1) with tessellated fundus, and Category 2 (C2) with diffuse chorioretinal atrophy. Peripapillary retinal thickness was assessed using swept-source optical coherence tomography (SS-OCT) B-scans. All data were analyzed with the SPSS software version 23.0 by one-way ANOVA test among three groups. Linear regression and pearson correlation analysis were used to determine the relationships among measurements. RESULTS: The retinal thickness of the peripapillary was measured from the superior, nasal, inferior, and temporal directions around the optic disc. The superior, nasal, and inferior peripapillary retinal thickness in the C2 group decreased significantly in all three groups. The retinal thicknesses of the peripapillary decreased significantly with the increase of AL and refractive diopter in the superior, nasal, and inferior. There was no significant difference between peripapillary retinal thickness and the wide macular staphyloma. CONCLUSIONS: Individuals in the C2 group had a thinner peripapillary retinal thickness than other groups, except for the temporal sector. The retinal thicknesses of the peripapillary decreased significantly with the increase of AL and increased significantly with the increase of refractive diopter, except for the temporal sector. The retinal thickness of the peripapillary decreased significantly with the increase of age in dry-type HM. The wide macular staphyloma had no significant effect on the thickness of the peripapillary in dry-type HM.

Brain targeted biomimetic siRNA nanoparticles for drug resistance glioblastoma treatment.

Glioblastoma multiforme (GBM), the most aggressive intracranial neoplasm, remains incurable at present, primarily due to drug resistance, which significantly contributes to elevated recurrence rates and dismal prognosis. Signal transducer and activator of transcription 3 (STAT3) is a critical gene closely associated with GBM drug resistance and the progression of GBM stem cells (GSCs), making it a promising therapeutic target. In this study, we developed cancer cell membrane-cloaked biomimetic nanoparticles to deliver STAT3 siRNA to reverse drug resistance in homologous GBM. These biomimetic nanoparticles leverage homotypic targeting, rapid endosome escape, and fast siRNA release, leading to efficient in vitro STAT3 knockdown in both temozolomide-resistant U251-TR cells and X01 GSCs. Moreover, benefited from the membrane functionalization, significant prolonged blood circulation, improved blood brain barrier (BBB) penetration and GBM tumor accumulation are achieved by these siRNA biomimetic nanoparticles. Importantly, these nanoparticles effectively inhibit tumor proliferation, significantly extending median survival time in orthotopic U251-TR (43.5 d versus 20 d for PBS control) and X01 GSC-bearing mouse xenografts (52 d versus 19.5 d for PBS control). Altogether, this biomimetic siRNA platform offers a promising strategy for gene therapy targeting drug-resistant GBM.

Efficacy and safety of vunakizumab in moderate-to-severe chronic plaque psoriasis: a randomized, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Vunakizumab, a novel anti-IL-17A antibody, has showed promising efficacy for moderate-to-severe plaque psoriasis in a phase 2 trial. OBJECTIVE: We conducted a double-blind, randomized phase 3 trial (NCT04839016) to further evaluate vunakizumab in this population. METHODS: 690 subjects were randomized (2:1) to receive vunakizumab 240 mg or placebo at weeks 0, 2, 4 and 8. At week 12, subjects on placebo were switched to vunakizumab 240 mg (weeks 12, 14, 16 and q4w thereafter). The co-primary endpoints were ≥90% improvement from baseline in the psoriasis area-and-severity index score (PASI 90) and a static Physicians Global Assessment score of 0/1 (sPGA 0/1) at week 12. RESULTS: At week 12, the vunakizumab group showed higher PASI 90 (76.8% vs 0.9%) and sPGA 0/1 (71.8% vs 0.4%) response rates, as well as higher PASI 75 (93.6% vs 4.0%), PASI 100 (36.6% vs 0.0%) and sPGA 0 (38.2% vs 0.0%) response rates (all two-sided P<0.0001 vs placebo). Efficacy was maintained through week 52 with continuous vunakizumab. Possible treatment-related serious adverse events occurred in 0.9% of vunakizumab-treated subjects. LIMITATIONS: Chinese subjects only; no active comparator. CONCLUSION: Vunakizumab demonstrated robust clinical response at week 12 and through week 52, with good tolerability in moderate-to-severe plaque psoriasis.

[Progress in fetal fraction prediction of placental diseases].

Placental diseases may affect the outcome of pregnancy and long-term health of the mother and fetus. Fetal fraction is a key indicator for the success of non-invasive prenatal testing, and has been associated with gestational age, body mass index and fetal chromosomal aneuploidies. Many studies have found that fetal fraction is also related to placenta-derived diseases and may become a new predictor for such diseases. This article has summarized the association between the two, with an aim to provide new ideas for the prediction of placental diseases.

Efficacy of Sacubitril Valsartan sodium tablets in patients with heart failure combined with pulmonary infection and long-term recurrence rate.

OBJECTIVE: To observe the therapeutic effect of Sacubitril Valsartan sodium tablets (SVST) on heart failure (HF) complicated by pulmonary infection (PI), and to provide a reference for future medication. METHODS: A total of 89 patients with HF complicated by PI who were treated at Dongying People's Hospital from January 2019 to May 2020 were selected as study subjects in this retrospective study. The control group consisted of 41 patients who received conventional treatment, while the study group included 48 patients who received SVST in addition to conventional treatment. The time to disappearance/improvement of chest tightness, shortness of breath, cough, and moist rales in both groups were recorded. The levels of brain natriuretic peptide (BNP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and procalcitonin (PCT) were measured before and after treatment. Changes in cardiac function were observed, and the Clinical Pulmonary Infection Score (CPIS) and Sequential Organ Failure Assessment (SOFA) were used to assess PI. The clinical efficacy and adverse reactions were evaluated after treatment. Follow-up lasted 2 years, during which the readmission rate due to HF and mortality rate were calculated. RESULTS: Patients in the study group experienced a shorter time to disappearance/improvement of chest tightness, shortness of breath, cough, and moist rales compared to the control group (all P<0.05). The study group also showed reduced levels of BNP, IL-6, TNF-α, and PCT, as well as lower CPIS and SOFA scores after treatment (all P<0.05), with significantly improved cardiac function (P<0.05). Additionally, the total effective rate was higher in the study group than in the control group (P<0.05), and there was no significant difference in adverse reactions between the two groups (P>0.05). Follow-up revealed no difference in mortality between the two groups (P>0.05), but the study group had a lower readmission rate (P<0.05). CONCLUSION: SVST is effective in treating HF complicated by PI, ensures a good prognosis for patients, and is recommended for clinical use.

Prognostic model for hepatocellular carcinoma based on necroptosis-related genes and analysis of drug treatment responses.

Objective: Recent studies reveal that necroptosis is pivotal in tumorigenesis, cancer metastasis, cancer immunity, and cancer subtypes. Apoptosis or necroptosis of hepatocytes in the liver microenvironment can determine the subtype of liver cancer. However, necroptosis-related genomes have rarely been analyzed in hepatocellular carcinoma (HCC). Therefore, this study aims to construct an HCC risk scoring model based on necroptosis-related genes and to validate its predictive performance in overall survival prediction and immunotherapy efficacy evaluation in HCC, as well as to analyze drug treatment responses. Methods: This study analyzed clinical information and RNA-seq expression data of liver cancer patients from TCGA public data, identified necroptosis-related genes, and conducted GO and KEGG enrichment analyses. Using Cox regression analysis and LASSO analysis to identify independent prognostic factors, a predictive model was established and validated in clinical subgroups, and correlation analysis with immune cells and ssGSEA differential analysis were conducted. Finally, potential drugs for HCC were screened to explore the drug sensitivity of different subtypes. Results: We identified 19 differentially expressed necroptosis-related genes and constructed a predictive model with 3 independent prognostic factors through stepwise Cox regression. Validation results from clinical subgroups showed that the constructed model performed well in risk prediction, and ssGSEA differential analysis results were significant. We analyzed 55 immunotherapy drugs, and clustered them by distinct IC50 values to guide drug selection for HCC patients. Notable, Bleomycin, Obatoclax. Mesylate, PF.562271, PF.02341066, QS11, X17. AAG, and Bl. D1870 exhibited significantly different sensitivities in different subtypes, providing references for clinical practice in HCC patients.

Correlation between circulating lipoprotein(a) levels and cardiovascular events risk in patients with type 2 diabetes.

Background: High circulatory lipoprotein(a) [Lp(a)] concentration promotes atherosclerosis; however, its efficacy in predicting the extent of atherosclerotic coronary heart disease (CHD) with coronary artery obstruction and major adverse cardiovascular events (MACEs) in diabetic patients remains questionable. This study aimed to examine whether elevated circulating Lp(a) levels exacerbate CHD and to assess their utility in predicting MACEs in individuals diagnosed with type 2 diabetes mellitus (T2DM). Methods: In total, 4332 patients diagnosed with T2DM who underwent coronary angiography (CAG) were included and categorized into two groups (CHD and non-CHD) based on the CAG results. We used a correlation analysis to explore the potential links between the levels of circulating Lp(a) and CHD severity. Cox regression analysis was performed to evaluate MACEs. Results: The concentrations of circulating Lp(a) were markedly elevated in the CHD group and positively correlated with disease severity. Our results indicate that elevated circulating Lp(a) is a crucial risk factor that significantly contributes to both the progression and severity of CHD. The differences between the two groups are evident in the risk of CHD occurrence [odds ratio (OR) = 1.597, 95 % confidence interval (CI): 1.354-1.893, p < 0.001], the different levels of vessel involvement (OR = 1.908 for triple-vessel vs. single-vessel disease, 95 % CI: 1.401-2.711, p < 0.001), and their relation to the Gensini Score (OR = 2.002 for high vs. low GS, 95 % CI: 1.514-2.881, p < 0.001). Over the course of the 7-year follow-up period, the multivariate Cox regression analysis indicated that increased levels Lp(a) levels are independently associated with the occurrence of MACEs [hazard ratio (HR) = 1.915, 95 % CI: 1.571-2.493, p < 0.001]. Conclusion: We confirmed a positive correlation among circulating Lp(a) levels, CHD lesions count, and Gensini scores. Moreover, Lp(a) levels have predictive significance for the occurrence of MACEs in T2DM patients.

Deep learning approaches for non-coding genetic variant effect prediction: current progress and future prospects.

Recent advancements in high-throughput sequencing technologies have significantly enhanced our ability to unravel the intricacies of gene regulatory processes. A critical challenge in this endeavor is the identification of variant effects, a key factor in comprehending the mechanisms underlying gene regulation. Non-coding variants, constituting over 90% of all variants, have garnered increasing attention in recent years. The exploration of gene variant impacts and regulatory mechanisms has spurred the development of various deep learning approaches, providing new insights into the global regulatory landscape through the analysis of extensive genetic data. Here, we provide a comprehensive overview of the development of the non-coding variants models based on bulk and single-cell sequencing data and their model-based interpretation and downstream tasks. This review delineates the popular sequencing technologies for epigenetic profiling and deep learning approaches for discerning the effects of non-coding variants. Additionally, we summarize the limitations of current approaches in variant effect prediction research and outline opportunities for improvement. We anticipate that our study will offer a practical and useful guide for the bioinformatic community to further advance the unraveling of genetic variant effects.

Wildfire-related PM2.5 and cause-specific cancer mortality.

Wildfires have devastating effects on society and public health. However, little evidence from population-based cohort has been performed to analyze the relationship of wildfire-related PM2.5, an important component of wildfire smoke, with cancer-specific mortality. We aimed to explore this relationship and identify vulnerable populations in UK with lower levels of wildfire-related PM2.5 exposure. The study consisted of 492394 participants (age: 38-73 years) recruited by UK Biobank during 2004-2010. The cumulative wildfire-related PM2.5 within 10 kilometers of residence over three years was used as exposure, which was assessed by chemical transport and machine learning models. A time-varying Cox regression was utilized to explore the relationship of exposure with diverse cancer-specific mortality outcomes. Subgroup analyses of a range of potential modifiers were performed. Each 10 µg/m3 increment of 3-year cumulative exposure was related to a 0.4 % greater risk of total cancer (95 %CI: 1.001-1.007), a 1.1 % greater risk of lung cancer (95 %CI: 1.004-1.018), and a 2.7 % greater risk of lip, oral cavity and pharynx (LOP) cancer (95 %CI: 1.005-1.049). Higher vulnerability in the wildfire-related PM2.5-lung cancer relationship was found among participants being retired than those with other employment status. Even lower levels of exposure to PM2.5 from wildfires were related to elevated mortality risks for cancer from total, lung, LOP, highlighting the importance of wildfire prevention and control. Further investigations are warranted to enrich and extend existing knowledge in this field.

Targeting Senescent Cells in Atherosclerosis: Pathways to Novel Therapies.

Targeting senescent cells has recently emerged as a promising strategy for treating age-related diseases, such as atherosclerosis, which significantly contributes to global cardiovascular morbidity and mortality. This review elucidates the role of senescent cells in the development of atherosclerosis, including persistently damaging DNA, inducing oxidative stress and secreting pro-inflammatory factors known as the senescence-associated secretory phenotype. Therapeutic approaches targeting senescent cells to mitigate atherosclerosis are summarized in this review, which include the development of senotherapeutics and immunotherapies. These therapies are designed to either remove these cells or suppress their deleterious effects. These emerging therapies hold potential to decelerate or even alleviate the progression of AS, paving the way for new avenues in cardiovascular research and treatment.

Therapeutic efficacy and in vivo distribution of human umbilical cord-derived mesenchymal stem cell spheroids transplanted via B-Ultrasound-guided percutaneous portal vein puncture in rhesus monkey models of liver fibrosis.

BACKGROUND: Liver fibrosis can progress to end-stage cirrhosis and liver cancer. Mesenchymal stem cells (MSCs) were considered the most promising therapeutic strategy, but most of the MSCs injected intravenously traditionally are trapped in the lungs, rapidly reducing their survival ability. MSC spheroids cultured in 3D have shown higher tolerance to fluid shear stress and better survival than dissociated MSCs. Simulating the route of orthotopic liver transplantation, transplanting MSC spheroids into the liver via hepatic portal vein may impact superior therapeutic effects. METHODS: In the present study, human umbilical cord-derived MSC spheroids (hUC-MSCsp) were transplanted into rhesus monkey models of liver fibrosis via B-ultrasound-guided percutaneous portal vein puncture with minimized body invasion. The therapeutic effect is evaluated through hematology, ultrasound, and pathology. To study the effect of hUC-MSCsp on gene expression in rhesus monkeys with liver injury, transcriptome sequencing analysis was performed on the livers of rhesus monkeys. The distribution of transplanted hUC-MSCsp was traced with RNA scope technology. RESULTS: We found that hUC-MSCsp significantly restored liver function, including ALT, AST, ALB, GLOB and bilirubin. hUC-MSCsp also significantly reduced liver collagen deposition and inflammatory infiltration, and promote dismission of liver ascites. Subsequently, the therapeutic effects were further validated in TGF-ß1/Smad pathway by global transcription profile. The distribution of transplanted hUC-MSCsp were also tracked, and we found that hUC-MSCsp distributed in the liver in a sphere status at 1 h after transplantation. After 16 days, the hUC-MSCsp were dispersed into dissociated cells that were predominantly distributed in the spleen, and a significant number of dissociated cells were still present in the liver. CONCLUSIONS: This study reveals the distributions of transplanted hUC-MSCsp after liver portal vein transplantation, and provides a novel approach and new insights into the molecular events of potential molecular events underlying the treatment of liver fibrosis with hUC-MSCsp.

Investigation of co-flow step emulsification (CFSE) microfluidic device and its applications in digital polymerase chain reaction (ddPCR).

HYPOTHESIS: The co-flow step emulsification (CFSE) is very sensitive to the two-phase fluid interfaces, we conjecture that the CFSE hydrodynamic model depends on several key factors and the droplet generation process can be precisely controlled, thus to obtain droplet emulsions with the "ultra-high volume fraction of inner-phase" and "flexible droplet size" characteristics. The resulting droplets are expected to be applied to droplet digital PCR (ddPCR) with "high information density" and "wide dynamic range" advances. EXPERIMENTS: By combining numerical simulation and fluid dynamics experiments, we have investigated the crucial parameters affecting the CFSE two-phase interface and finally achieved the prediction and guidance for CFSE droplet production. FINDINGS: With the help of the CFSE device, multivolume droplet populations were produced on demand. Then, ddPCR tests were performed with DNA concentrations from 10 copies/µL to 20,000 copies/µL. The CFSE device owns an ultra-wide dynamic range (up to 5 orders of magnitude), showing excellent quantification ability of nucleic acid targets.

Cryo-EM: A window into the dynamic world of RNA molecules.

RNAs are critical for complex cellular functions, characterized by their structural versatility and ability to undergo conformational transitions in response to cellular cues. The elusive structures of RNAs are being unraveled with unprecedented clarity, thanks to the technological advancements in structural biology, including nuclear magnetic resonance (NMR), X-ray crystallography, cryo-electron microscopy (cryo-EM) etc. This review focuses on examining the revolutionary impact of cryo-EM on our comprehension of RNA structural dynamics, underscoring the technique's contributions to structural biology and envisioning the future trajectory of this rapidly evolving field.

c-Myc alone is enough to reprogram fibroblasts into functional macrophages.

BACKGROUND: Macrophage-based cell therapy is promising in solid tumors, but the efficient acquisition of macrophages remains a challenge. Induced pluripotent stem cell (iPSC)-induced macrophages are a valuable source, but time-consuming and costly. The application of reprogramming technologies allows for the generation of macrophages from somatic cells, thereby facilitating the advancement of cell-based therapies for numerous malignant diseases. METHODS: The composition of CD45+ myeloid-like cell complex (MCC) and induced macrophage (iMac) were analyzed by flow cytometry and single-cell RNA sequencing. The engraftment capacity of CD45+ MCC was evaluated by two transplantation assays. Regulation of c-Myc on MafB was evaluated by ChIP-qPCR and promoter reporter and dual luciferase assays. The phenotype and phagocytosis of iMac were explored by flow cytometry and immunofluorescence. Leukemia, breast cancer, and patient-derived tumor xenograft models were used to explore the anti-tumor function of iMac. RESULTS: Here we report on the establishment of a novel methodology allowing for reprogramming fibroblasts into functional macrophages with phagocytic activity by c-Myc overexpression. Fibroblasts with ectopic expression of c-Myc in iPSC medium rapidly generated CD45+ MCC intermediates with engraftment capacity as well as the repopulation of distinct hematopoietic compartments. MCC intermediates were stably maintained in iPSC medium and continuously generated functional and highly pure iMac just by M-CSF cytokine stimulation. Single-cell transcriptomic analysis of MCC intermediates revealed that c-Myc up-regulated the expression of MafB, a major regulator of macrophage differentiation, to promote macrophage differentiation. Characterization of the iMac activity showed NF-κB signaling activation and a pro-inflammatory phenotype. iMac cells displayed significantly increased in vivo persistence and inhibition of tumor progression in leukemia, breast cancer, and patient-derived tumor xenograft models. CONCLUSIONS: Our findings demonstrate that c-Myc alone is enough to reprogram fibroblasts into functional macrophages, supporting that c-Myc reprogramming strategy of fibroblasts can help circumvent long-standing obstacles to gaining "off-the-shelf" macrophages for anti-cancer immunotherapy.

Electrochemical Platform Based on the Bi2Te3 Family of Topological Insulators for the Detection of SARS-CoV-2 Pathogenic Factors.

Accurate and rapid detection of the causative agent of a disease is of great importance in controlling the spread of the disease. This work developed a biosensor with the Bi2Te3 family of topological insulators for detection of the SARS-CoV-2 virulence factor. The Bi2Te3 family is a three-dimensional topological insulator material with topologically protected surface states; the presence of these surface states facilitates charge transfer between the electrode and electrolyte interface. Compared with the detection performance of Bi2Se3, BiSbTeSe2, and a trivial insulator like Sb2Se3, Bi2Te3 exhibits superior characteristics. A Bi2Te3 electrochemical detection platform is utilized to fabricate a sensor that can detect SARS-CoV-2 DNA, RNA, and antigen for label-free target detection. The concentration range of DNA detection by the biosensor using Bi2Te3 is between 1.0 × 10-15 and 1.0 × 10-10 M, and the detection limit can reach 1.41 × 10-16 M. Furthermore, it exhibits excellent selectivity and maintains good stability even after being stored for 14 days. This study provides a new way to apply topological insulator materials in the field of biosensors and use their unique electronic structure to improve the accuracy and speed of disease detection and diagnosis.

Endogenous cell membrane interactome mapping for the GLP-1 receptor in different cell types.

The GLP-1 receptor, one of the most successful drug targets for the treatment of type 2 diabetes and obesity, is known to engage multiple intracellular signaling proteins. However, it remains less explored how the receptor interacts with proteins on the cell membrane. Here, we present a ligand-based proximity labeling approach to interrogate the native cell membrane interactome for the GLP-1 receptor after agonist simulation. Our study identified several unreported putative cell membrane interactors for the endogenous receptor in either a pancreatic ß cell line or a neuronal cell line. We further uncovered new regulators of GLP-1 receptor-mediated signaling and insulinotropic responses in ß cells. Additionally, we obtained a time-resolved cell membrane interactome map for the receptor in ß cells. Therefore, our study provides a new approach that is generalizable to map endogenous cell membrane interactomes for G-protein-coupled receptors to decipher the molecular basis of their cell-type-specific functional regulation.