Dux activates metabolism-lactylation-MET network during early iPSC reprogramming with Brg1 as the histone lactylation reader.

The process of induced pluripotent stem cells (iPSCs) reprogramming involves several crucial events, including the mesenchymal-epithelial transition (MET), activation of pluripotent genes, metabolic reprogramming, and epigenetic rewiring. Although these events intricately interact and influence each other, the specific element that regulates the reprogramming network remains unclear. Dux, a factor known to promote totipotency during the transition from embryonic stem cells (ESC) to 2C-like ESC (2CLC), has not been extensively studied in the context of iPSC reprogramming. In this study, we demonstrate that the modification of H3K18la induced by Dux overexpression controls the metabolism-H3K18la-MET network, enhancing the efficiency of iPSC reprogramming through a metabolic switch and the recruitment of p300 via its C-terminal domain. Furthermore, our proteomic analysis of H3K18la immunoprecipitation experiment uncovers the specific recruitment of Brg1 during reprogramming, with both H3K18la and Brg1 being enriched on the promoters of genes associated with pluripotency and epithelial junction. In summary, our study has demonstrated the significant role of Dux-induced H3K18la in the early reprogramming process, highlighting its function as a potent trigger. Additionally, our research has revealed, for the first time, the binding of Brg1 to H3K18la, indicating its role as a reader of histone lactylation.

SEC: A core hub during cell fate alteration.

Pol II pause release is a rate-limiting step in gene transcription, influencing various cell fate alterations. Numerous proteins orchestrate Pol II pause release, thereby playing pivotal roles in the intricate process of cellular fate modulation. Super elongation complex (SEC), a large assembly comprising diverse protein components, has garnered attention due to its emerging significance in orchestrating physiological and pathological cellular identity changes by regulating the transcription of crucial genes. Consequently, SEC emerges as a noteworthy functional complex capable of modulating cell fate alterations. Therefore, a comprehensive review is warranted to systematically summarize the core roles of SEC in different types of cell fate alterations. This review focuses on elucidating the current understanding of the structural and functional basis of SEC. Additionally, we discuss the intricate regulatory mechanisms governing SEC in various models of cell fate alteration, encompassing both physiological and pathological contexts. Furthermore, leveraging the existing knowledge of SEC, we propose some insightful directions for future research, aiming to enhance our mechanistic and functional comprehension of SEC within the diverse landscape of cell fate alterations.

Visual pigment-deficient cones survive and mediate visual signaling despite the lack of outer segments.

Rhodopsin and cone opsins are essential for light detection in vertebrate rods and cones, respectively. It is well established that rhodopsin is required for rod phototransduction, outer segment disk morphogenesis, and rod viability. However, the roles of cone opsins are less well understood. In this study, we adopted a loss-of-function approach to investigate the physiological roles of cone opsins in mice. We showed that cones lacking cone opsins do not form normal outer segments due to the lack of disk morphogenesis. Surprisingly, cone opsin-deficient cones survive for at least 12 mo, which is in stark contrast to the rapid rod degeneration observed in rhodopsin-deficient mice, suggesting that cone opsins are dispensable for cone viability. Although the mutant cones do not respond to light directly, they maintain a normal dark current and continue to mediate visual signaling by relaying the rod signal through rod-cone gap junctions. Our work reveals a striking difference between the role of rhodopsin and cone opsins in photoreceptor viability.

lncRNA SYTL5-OT4 promotes vessel co-option by inhibiting the autophagic degradation of ASCT2.

AIMS: Vessel co-option is responsible for tumor resistance to antiangiogenic therapies (AATs) in patients with colorectal cancer liver metastasis (CRCLM). However, the mechanisms underlying vessel co-option remain largely unknown. Herein, we investigated the roles of a novel lncRNA SYTL5-OT4 and Alanine-Serine-Cysteine Transporter 2 (ASCT2) in vessel co-option-mediated AAT resistance. METHODS: SYTL5-OT4 was identified by RNA-sequencing and verified by RT-qPCR and RNA fluorescence in situ hybridization assays. The effects of SYTL5-OT4 and ASCT2 on tumor cells were investigated by gain- and loss-of-function experiments, and those of SYTL5-OT4 on ASCT2 expression were analyzed by RNA immunoprecipitation and co-immunoprecipitation assays. The roles of SYTL5-OT4 and ASCT2 in vessel co-option were detected by histological, immunohistochemical, and immunofluorescence analyses. RESULTS: The expression of SYTL5-OT4 and ASCT2 was higher in patients with AAT-resistant CRCLM. SYTL5-OT4 enhanced the expression of ASCT2 by inhibiting its autophagic degradation. SYTL5-OT4 and ASCT2 promoted vessel co-option by increasing the proliferation and epithelial-mesenchymal transition of tumor cells. Combination therapy of ASCT2 inhibitor and antiangiogenic agents overcame vessel co-option-mediated AAT resistance in CRCLM. CONCLUSION: This study highlights the crucial roles of lncRNA and glutamine metabolism in vessel co-option and provides a potential therapeutic strategy for patients with AAT-resistant CRCLM.

The knowledge, attitude and behavior of ICU nurses regarding ICU-acquired weakness: a cross-sectional survey.

BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is very common in ICU patients. It is important to understand the status quo of knowledge, attitude and behavior of ICU nurses about ICU-AW. This survey aimed to investigate the knowledge, attitude and behavior of ICU nurses about ICU-AW, to provide useful implications for clinical care. METHODS: ICU nurses from two tertiary hospitals in China from October 10 to November 15, 2023 were included. The ICU-AW knowledge, attitude and behavior questionnaire of ICU nurses with 31 items were used for survey. SPSS24.0 statistical software was used for data analysis. RESULTS: A total of 364 ICU nurses were included for survey. The ICU-AW knowledge of ICU nurses was 21.96 ± 5.72 (< 50% of the total knowledge score), the ICU-AW attitude of ICU nurses was 30.24 ± 5.05(< 75% of the total attitude score), the ICU-AW behavior of ICU nurses was 26.77 ± 5.81(< 75% of the total behavior score), the total score was 79.21 ± 12.69(< 75% of the total score). Nurses' ICU-AW knowledge, attitude and behavior were all correlated (all P < 0.05). Multiple linear regression analyses indicated that age, years of ICU work experience, professional ranks and titles, had received the training about the ICU-AW were the influencing factors of knowledge, attitude and behavior of ICU nurses about ICU-AW (all P < 0.05). CONCLUSIONS: The knowledge, attitude and behavior of ICU nurses' ICU-AW needs to be improved, and there are many influencing factors. Hospital nursing administrators should strengthen the training of nurses' ICU-AW knowledge and improve the cognitive and practical ability of ICU nurses on ICU-AW, so as to reduce the occurrence of ICU-AW.

Asymmetric Carbene-Alkyne Metathesis-Mediated Cascade: Synthesis of Benzoxazine Polychiral Polyheterocycles and Discovery of a Novel Pain Blocker.

This study introduces a novel approach for synthesizing Benzoxazine-centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene-alkyne metathesis-triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis-mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co-catalysis, ensuring precise stereo control as validated by X-ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo- and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8 g. In vivo studies demonstrate that intrathecal injection of 8 g effectively reverses mechanical hyperalgesia associated with chemotherapy-induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8 g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8 g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8 g as a promising, uniquely acting pain blocker, establishing a C5aR1-Nav1.7 connection in the context of CIPN.

Effect and safety of mesenchymal stem cells for patients with COVID-19: Systematic review and meta-analysis with trial sequential analysis.

The objective of this study was to assess whether mesenchymal stem cells (MSCs) therapy could offer survival advantages for patients with novel coronavirus disease 2019 (COVID-19). An electronic search of PubMed, Embase, Cochrane Library, Web of Science, WanFang, and CNKI was performed from December 1, 2019 to December 25, 2022. The primary outcome was all-cause mortality. Trial sequential analysis (TSA) was conducted in this meta analysis. Besides, subgroup analysis and meta-regression was performed using a random-effects model to find the potential sources of heterogeneity. Seventeen randomized controlled trials (RCTs) involving a total of 1073 patients with COVID-19 were included in this study. Compared with the control group, patients in the MSCs groups were associated with significantly reduced all-cause mortality (MSCs 18.4% vs. control 25.5%; risk ratio [RR] 0.73; 95% confidence interval [CI] 0.59-0.90; p = 0.004; I² = 0%). For all secondary outcomes, there wasn't significant improvement in the experimental group versus the control group regarding symptom remission rate (53.2%, 201/378 vs. 46.5%, 164/353; RR 1.15; 95% CI 1.00-1.32; p = 0.05; I² = 43%), but the pooled analysis revealed significant differences between the groups in length of hospital stay (MD: -3.82, 95% CI: -5.87 to -1.77; p = 0.0003, I2 = 0%), requirement of invasive mechanical ventilation (RR 0.52; 95% CI 0.33-0.82; p = 0.005; I2 = 0%) and post-CRP level (MD: -31.61; 95% CI -46.74 to -16.49; p < 0.0001). Moreover, regarding the incidence of adverse events (AEs) (RR 0.73; 95% CI 0.35-1.52; p = 0.39; I² = 44%) and serious adverse events (sAEs) (RR 0.87; 95% CI 0.40-1.92; p = 0.73; I² = 39%), no significant differences were observed between MSCs and control groups. The TSA analysis showed that the result of all-cause mortality might be false-positive result. Based on the pooled results in this study, compared with standard treatment, MSCs therapy may reduce all-cause mortality of patients with COVID-19 with no increase risk of AEs and sAEs, but may not improve symptom remission rate. Further more high-quality and large-sample RCTs should be performed to confirm these findings.

Cellular heterogeneity and transcriptomic profiles during intrahepatic cholangiocarcinoma initiation and progression.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is not fully investigated, and how stromal cells contribute to ICC formation is poorly understood. We aimed to uncover ICC origin, cellular heterogeneity, and critical modulators during ICC initiation/progression, and to decipher how fibroblast and endothelial cells in the stromal compartment favor ICC progression. APPROACH AND RESULTS: We performed single-cell RNA sequencing (scRNA-seq) using AKT/Notch intracellular domain-induced mouse ICC tissues at early, middle, and late stages. We analyzed the transcriptomic landscape, cellular classification and evolution, and intercellular communication during ICC initiation/progression. We confirmed the findings using quantitative real-time PCR, western blotting, immunohistochemistry or immunofluorescence, and gene knockout/knockdown analysis. We identified stress-responding and proliferating subpopulations in late-stage mouse ICC tissues and validated them using human scRNA-seq data sets. By integrating weighted correlation network analysis and protein-protein interaction through least absolute shrinkage and selection operator regression, we identified zinc finger, MIZ-type containing 1 (Zmiz1) and Y box protein 1 (Ybx1) as core transcription factors required by stress-responding and proliferating ICC cells, respectively. Knockout of either one led to the blockade of ICC initiation/progression. Using two other ICC mouse models (YAP/AKT, KRAS/p19) and human ICC scRNA-seq data sets, we confirmed the orchestrating roles of Zmiz1 and Ybx1 in ICC occurrence and development. In addition, hes family bHLH transcription factor 1, cofilin 1, and inhibitor of DNA binding 1 were identified as driver genes for ICC. Moreover, periportal liver sinusoidal endothelial cells could differentiate into tip endothelial cells to promote ICC development, and this was Dll4-Notch4-Efnb2 signaling-dependent. CONCLUSIONS: Stress-responding and ICC proliferating subtypes were identified, and Zmiz1 and Ybx1 were revealed as core transcription factors in these subtypes. Fibroblast-endothelial cell interaction promotes ICC development.

Chemotherapy-induced metastasis: molecular mechanisms and clinical therapies.

Chemotherapy, the most widely accepted treatment for malignant tumors, is dependent on cell death induced by various drugs including antimetabolites, alkylating agents, mitotic spindle inhibitors, antitumor antibiotics, and hormonal anticancer drugs. In addition to causing side effects due to non-selective cytotoxicity, chemotherapeutic drugs can initiate and promote metastasis, which greatly reduces their clinical efficacy. The knowledge of how they induce metastasis is essential for developing strategies that improve the outcomes of chemotherapy. Herein, we summarize the recent findings on chemotherapy-induced metastasis and discuss the underlying mechanisms including tumor-initiating cell expansion, the epithelial-mesenchymal transition, extracellular vesicle involvement, and tumor microenvironment alterations. In addition, the use of combination treatments to overcome chemotherapy-induced metastasis is also elaborated.

A diastereoselective three-component reaction for the assembly of succinimide and isatin hybrid molecules with potent anticancer activities.

A Rh2(OAc)4 catalyzed three-component reaction of vinyl diazosuccinimides with alcohols and isatins has been reported, which provides a practical assess to the direct assembly of succinimide and isatin hybrid molecules in good-to-high yields with excellent stereoselectivity. The antiproliferation activity of these synthesized succinimide and isatin hybrid products has been tested via the CCK8 assay in different cancer cell lines, and compounds 4g (SJSA-1, IC50 = 3.82 µM) and 4r (HCT-116, IC50 = 9.02 µM) exhibit higher anticancer potency than other tested compounds.

Gold-catalyzed carbocyclization and imidization of alkyne-tethered diazo compounds with nitrosoarenes for the synthesis of nitrones and naphthalene derivatives.

A gold-catalyzed carbocyclization/imidization cascade reaction has been developed,leading a facile access to the synthesis of functionalized nitrones in moderate to good yields under mild conditions. The reaction initiated by a catalytic 6-endo-dig diazo-yne carbocyclization to form the key endocyclic vinyl carbene from alkyne-tethered diazo compounds, followed by addition with nitrosoarenes that features an imidization process. Notably, these resulting nitrone products could be smoothly converted into different substituted naphthalenol analogues, such as 4-aminonaphthalen-1-ol, naphthalene-1,4-dione, and naphthalene-1,4-diol derivatives, in high yields. Moreover, the generated products exhibited potential tumor suppression activity in tested cancer celllines; compound 3c (HCT116 cells, IC50 = 7.41 µM; MCF-7 cells, IC50 = 14.28 µM) exhibits higher anticancer potency than other tested compounds.

Construction of Chiral Quaternary Carbon Centers via Asymmetric Metal Carbene gem-Dialkylation.

The catalytic asymmetric construction of all-carbon quaternary stereocenters has received tremendous interest over the past decades, and numerous efficient protocols have been disclosed based on the formation of one C-C bond between two assembling reactants. However, the use of asymmetric multi-component reactions that build two C-C bonds on the same carbonic center with concomitant assembly of quaternary stereocenters is rare and remains challenging. Herein, we disclose an enantioselective three-component reaction of α-diazo ketones with alkenes and 1,3,5-triazines under dirhodium/chiral phosphoric acid cooperative catalysis, which leads to a practical and atom-economic synthesis of poly-functionalized chiral ketones that bear a α-quaternary stereocenter in generally good to high yields with excellent enantioselectivities. In comparison to the previous method for the construction of tertiary and quaternary stereocenters via carbene gem-difunctionalization reactions, this reaction features an unprecedented gem-dialkylation process via sequential installation of two C-C bonds on the carbene center in one reaction, providing an essential complement to the asymmetric construction of all-carbon quaternary stereocenters using common and readily available starting materials.

[Analysis of Radio Frequency Identification Immunity Standard for Medical Equipment].

Aiming at the increasing application of RFID technology in the medical environment, this study introduces the foreign requirements for RFID immunity test of medical devices, compares them with the current immunity test requirements of medical devices in China, and puts forward the necessity of establishing relevant test specifications in China.

Diastereoselective aldol-type interception of phenolic oxonium ylides for the direct assembly of 2,2-disubstituted dihydrobenzofurans.

A Rh2(OAc)4 catalyzed intermolecular aldol-type interception of phenolic oxonium ylides with isatins has been developed, which provides an effective access to 2,2-disubstituted dihydrobenzofuran derivatives containing 3-hydroxyoxindole in high yields and with high diastereoselectivities under mild reaction conditions. The antiproliferation activity of these synthesized dihydrobenzofuran and 3-hydroxyoxindole hybrid products has been tested via the CCK8 assay in different cancer cell lines; compounds 3s and 3t exhibit good anticancer potency against human colon cancer cells (HCT116 cells, 3s: IC50 = 15.99 µM; 3t: IC50 = 14.48 µM) compared to other tested compounds.

A Rh(II)-catalyzed highly stereoselective [3 + 2] annulation of vinyl diazoacetates with indole-2-carbaldehyde for the synthesis of indolyl dihydrofurans.

A highly stereoselective Rh2(Oct)4-catalyzed [3 + 2] cycloaddition of vinyl diazoacetates with indolyl aldehyde has been developed. This protocol provides an efficient access to both cis and trans indolyl dihydrofurans with high yields and diastereoselectivities under mild conditions without or with Lewis acid as additive, respectively. Moreover, these generated functionalized dihydrofurans exhibit potent antiproliferation activity in three different cancer cell lines.

[Gait Measurement System Using Laser Range Sensor Based on Lower-limb Rehabilitation Robot].

Spatiotemporal gait parameters provide important information for the rehabilitation of patients with gait dysfunction. These parameters are often obtained by complex systems such as optical motioncapture system and pressure plates. However, these systems cannot be deployed at the lower-limb rehabilitation robot easily because of high costs, large area occupation and wearable requirements. We present a gait measurement system with a Light Detection And Ranging(LIDAR) laser sensor based on the lower-limb rehabilitation robot. Firstly, to calculate gait parameters, the data are aggregated into left and right legs by the clustering algorithm and the legs contour is fitted with two circles respectively according to the least square method. Then, the spatiotemporal gait parameters are defined based on the time and position of initial contact(IC) and toe off(TO). Finally, to verify the validity of the proposed system, we compared the results of the proposed system with a 3D motion capture system based on a lower-limb rehabilitation robot. Experimental results showed that the gait detection system can measure the parameters within a small range of error that testified the validation of the proposed system. This system proved to be a valid and reliable method for the measurement of gait parameters.

An Optimization Method of Precision Assembly Process Based on the Relative Entropy Evaluation of the Stress Distribution.

The entropy evaluation method of assembly stress has become a hot topic in recent years. However, the current research can only evaluate the maximum stress magnitude and stress magnitude uniformity, and it cannot evaluate the stress position distribution. In this paper, an evaluation method of stress distribution characterized by strain energy density distribution is proposed. In this method, the relative entropy is used as the evaluation index of the stress distribution difference between the error model and the ideal model. It can evaluate not only the stress magnitude, but also the stress position. On this basis, an optimization method of the precise assembly process which takes the relative entropy as the optimization objective is proposed. The stress distributions of the optical lens are evaluated, and the assembly angle of the spacer in the process of the optical lens system assembly is optimized. By comparing the stress distribution of the optimized model and the ideal model, the validity of this method is proved.

Optimization of Selective Assembly for Shafts and Holes Based on Relative Entropy and Dynamic Programming.

Selective assembly is the method of obtaining high precision assemblies from relatively low precision components. For precision instruments, the geometric error on mating surface is an important factor affecting assembly accuracy. Different from the traditional selective assembly method, this paper proposes an optimization method of selective assembly for shafts and holes based on relative entropy and dynamic programming. In this method, relative entropy is applied to evaluate the clearance uniformity between shafts and holes, and dynamic programming is used to optimize selective assembly of batches of shafts and holes. In this paper, the case studied has 8 shafts and 20 holes, which need to be assembled into 8 products. The results show that optimal combinations are selected, which provide new insights into selective assembly optimization and lay the foundation for selective assembly of multi-batch precision parts.

Entropy-Based Method to Evaluate Contact-Pressure Distribution for Assembly-Accuracy Stability Prediction.

Assembly accuracy and accuracy stability prediction are significant research directions for improving the reliability and efficiency of precision assembly. In this study, an improved method for assembly accuracy stability prediction, based on the contact-pressure distribution entropy, is presented. By using the contact-pressure distribution as the evaluation parameter instead of the strain-energy distribution, the improved method can not only predict the assembly accuracy of precision assembly more efficiently, but also predict the stability of the assembly accuracy with variations in the ambient temperature. The contact pressure has a clearer mechanical significance than strain energy density in the assembly process, which can be used to distinguish the actual contact area from the contact surface. Hence, the improved method is more efficient and accurate than the original. This study utilizes the same case used in the original method and an additional case from the actual production process to verify the improved method. The correctness and validity of the improved method are proved by these case studies.

A congenic line of the C57BL/6J mouse strain that is proficient in melatonin synthesis.

The C57BL/6J (B6) is the most common inbred mouse strain used in biomedical research in the United States. Yet, this strain is notoriously known for being deficient in the biosynthesis of melatonin, an important effector of circadian clocks in the brain and in the retina. Melatonin deficiency in this strain results from nonfunctional alleles of the genes coding 2 key enzymes of the melatonin synthesis pathway: arylalkylamine-N-acetyltransferase (Aanat) and N-acetylserotonin-O-methyltransferase (Asmt). By introducing functional alleles of the Aanat and Asmt genes from the melatonin-proficient CBA/CaJ (CBA) mouse strain to B6, we have generated a B6 congenic line that has acquired the capacity of rhythmic melatonin synthesis. In addition, the melatonin-dependent rhythm of dopamine release in the retina is restored in the B6 congenic line. Finally, we have partially characterized the Aanat and Asmt genes of the CBA strain and have identified multiple differences between CBA and B6 alleles, including single nucleotide polymorphism and deletion/insertion of DNA segments of various sizes. As an improved model organism with functional components of the melatonin synthesis pathway and melatonin-dependent circadian regulations, the new line will be useful to researchers studying melatonin physiological functions in a variety of fields including, but not limited to, circadian biology and neuroscience. In particular, the congenic line will be useful to speed up introduction of melatonin production capacity into genetically modified mouse lines of interest such as knockout lines, many of which are on B6 or mixed B6 backgrounds. The melatonin-proficient B6 congenic line will be widely distributed.