Airway hillocks are injury-resistant reservoirs of unique plastic stem cells.

Airway hillocks are stratified epithelial structures of unknown function1. Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia2,3. Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of 'squamous metaplasia', which is long thought to be a precursor of lung cancer.

Mild Therapeutic Hypothermia Alleviated Myocardial Ischemia/Reperfusion Injury via Targeting SLC25A10 to Suppress Mitochondrial Apoptosis.

Myocardial ischemia/reperfusion injury (MI/RI) is identified as a severe vascular emergency, and the treatment strategy of MI/RI still needs further improvement. The present study aimed to investigate the potential effects of mild therapeutic hypothermia (MTH) on MI/RI and underlying mechanisms. In ischemia/reperfusion (I/R) rats, MTH treatment significantly improved myocardial injury, attenuated myocardial infarction, and inhibited the mitochondrial apoptosis pathway. The results of proteomics identified SLC25A10 as the main target of MTH treatment. Consistently, SLC25A10 expressions in I/R rat myocardium and hypoxia and reoxygenation (H/R) cardiomyocytes were significantly suppressed, which was effectively reversed by MTH treatment. In H/R cardiomyocytes, MTH treatment significantly improved cell injury, mitochondrial dysfunction, and inhibited the mitochondrial apoptosis pathway, which were partially reversed by SLC25A10 deletion. These findings suggested that MTH treatment could protect against MI/RI by modulating SLC25A10 expression to suppress mitochondrial apoptosis pathway, providing new theoretical basis for clinical application of MTH treatment for MI/RI.

Dynamic Failure Experimental Study of a Gravity Dam Model on a Shaking Table and Analysis of Its Structural Dynamic Characteristics.

Investigating the dynamic response patterns and failure modes of concrete gravity dams subjected to strong earthquakes is a pivotal area of research for addressing seismic safety concerns associated with gravity dam structures. Dynamic shaking table testing has proven to be a robust methodology for exploring the dynamic characteristics and failure modes of gravity dams. This paper details the dynamic test conducted on a gravity dam model on a shaking table. The emulation concrete material, featuring high density, low dynamic elastic modulus, and appropriate strength, was meticulously designed and fabricated. Integrating the shaking table conditions with the model material, a comprehensive gravity dam shaking table model test was devised to capture the dynamic response of the model under various dynamic loads. Multiple operational conditions were carefully selected for in-depth analysis. Leveraging the dynamic strain responses, the progression of damage in the gravity dam model under these diverse conditions was thoroughly examined. Subsequently, the recorded acceleration responses were utilized for identifying dynamic characteristic parameters, including the acceleration amplification factor in the time domain, acceleration response spectrum characteristics in the frequency domain, and modal parameters reflecting the inherent characteristics of the structure. To gain a comprehensive understanding, a comparative analysis was performed by aligning the observed damage development with the identified dynamic characteristic parameters, and the sensitivity of these identified parameters to different levels of damage was discussed. The findings of this study not only offer valuable insights for conducting and scrutinizing shaking table experiments on gravity dams but also serve as crucial supporting material for identifying structural dynamic characteristic parameters and validating damage diagnosis methods for gravity dam structures.

The significance of targeting lysosomes in cancer immunotherapy.

Lysosomes are intracellular digestive organelles that participate in various physiological and pathological processes, including the regulation of immune checkpoint molecules, immune cell function in the tumor microenvironment, antigen presentation, metabolism, and autophagy. Abnormalities or dysfunction of lysosomes are associated with the occurrence, development, and drug resistance of tumors. Lysosomes play a crucial role and have potential applications in tumor immunotherapy. Targeting lysosomes or harnessing their properties is an effective strategy for tumor immunotherapy. However, the mechanisms and approaches related to lysosomes in tumor immunotherapy are not fully understood at present, and further basic and clinical research is needed to provide better treatment options for cancer patients. This review focuses on the research progress related to lysosomes and tumor immunotherapy in these.

Association of refractive outcome with postoperative anterior chamber depth measured with 3 optical biometers.

PURPOSE: This study evaluated the relationship between refractive outcomes and postoperative anterior chamber depth (ACD, measured from corneal epithelium to lens) measured by swept-source optical coherence tomography (SS-OCT), optical low-coherence reflectometry (OLCR), and Scheimpflug devices under the undilated pupil. METHODS: Patients undergoing cataract phacoemulsification with intraocular lens (IOL) implantation in a hospital setting were enrolled. Postoperative ACD (postACD) was performed with an SS-OCT device, an OLCR device, and a Scheimpflug device at least 1 month after cataract surgery. After adjusting the mean predicted error to 0, differences in refractive outcomes were calculated with the Olsen formula using actual postACD measured from 3 devices and predicted value. RESULTS: Overall, this comparative case study included 69 eyes of 69 patients, and postACD measurements were successfully taken using all 3 devices. The postACD measured with the SS-OCT, OLCR, and Scheimpflug devices was 4.59 ± 0.30, 4.50 ± 0.30, and 4.54 ± 0.32 mm, respectively. Statistically significant differences in postACD were found among 3 devices (P < 0.001), with intraclass correlation coefficients (ICCs) and Bland-Altman showing good agreement. No significant difference in median absolute error was found with the Olsen formula using actual postACD obtained with 3 devices. Percentage prediction errors were within ± 0.50 D in 65% (OLCR), 70% (Scheimpflug), and 67% (SS-OCT) calculated by actual postACD versus 64% by predicted value. CONCLUSION: Substantial agreement was found in postACD measurements obtained from the SS-OCT, OLCR, and Scheimpflug devices, with a trend toward comparable refractive outcomes in the Olsen formula. Meanwhile, postACD measurements may be potentially superior for the additional enhancement of refractive outcomes.

Single-cell analysis of immune and stroma cell remodeling in clear cell renal cell carcinoma primary tumors and bone metastatic lesions.

BACKGROUND: Despite therapeutic advances, once a cancer has metastasized to the bone, it represents a highly morbid and lethal disease. One third of patients with advanced clear cell renal cell carcinoma (ccRCC) present with bone metastasis at the time of diagnosis. However, the bone metastatic niche in humans, including the immune and stromal microenvironments, has not been well-defined, hindering progress towards identification of therapeutic targets. METHODS: We collected fresh patient samples and performed single-cell transcriptomic profiling of solid metastatic tissue (Bone Met), liquid bone marrow at the vertebral level of spinal cord compression (Involved), and liquid bone marrow from a different vertebral body distant from the tumor site but within the surgical field (Distal), as well as bone marrow from patients undergoing hip replacement surgery (Benign). In addition, we incorporated single-cell data from primary ccRCC tumors (ccRCC Primary) for comparative analysis. RESULTS: The bone marrow of metastatic patients is immune-suppressive, featuring increased, exhausted CD8 + cytotoxic T cells, T regulatory cells, and tumor-associated macrophages (TAM) with distinct transcriptional states in metastatic lesions. Bone marrow stroma from tumor samples demonstrated a tumor-associated mesenchymal stromal cell population (TA-MSC) that appears to be supportive of epithelial-to mesenchymal transition (EMT), bone remodeling, and a cancer-associated fibroblast (CAFs) phenotype. This stromal subset is associated with poor progression-free and overall survival and also markedly upregulates bone remodeling through the dysregulation of RANK/RANKL/OPG signaling activity in bone cells, ultimately leading to bone resorption. CONCLUSIONS: These results provide a comprehensive analysis of the bone marrow niche in the setting of human metastatic cancer and highlight potential therapeutic targets for both cell populations and communication channels.

Tumor-derived GABA promotes lung cancer progression by influencing TAMs polarization and neovascularization.

BACKGROUND: Gamma-aminobutyric acid (GABA), a common neurotransmitter, has been found in various cancers but its origin and its role in the tumor immune microenvironment remains unclear. METHODS: Here, we reported the expression of glutamate decarboxylase 1 (GAD1, converting glutamate into GABA) in lung cancer tissues based on the publicly available database, and explored the effects and underlying mechanism of GABA on lung cancer progression. RESULTS: Compared with normal tissues, GAD1 was aberrantly overexpressed in lung adenocarcinoma (LUAD) based on TCGA database. Furthermore, the LUAD patients' overall survival was negatively correlated with the GAD1 expression levels. Our work found that a GABAa receptor inhibitor had a therapeutic effect on mouse tumors and significantly reduced tumor size and weight. Further experiments showed that GABA derived from tumor cells promoted tumor progression not by directly affecting cancer cells but by affecting macrophages polarization in the tumor microenvironment. We found that GABA inhibited the NF-κB pathway and STAT3 pathway to prevent macrophages from polarizing towards M1 type, while promoting macrophage M2 polarization by activating the STAT6 pathway. GABA was also found to promote tumor neovascularization by increasing the expression of FGF2 in macrophages. CONCLUSIONS: These results suggest that GABA affects tumor progression by regulating macrophage polarization, and targeting GABA and its signaling pathway may represent a potential therapy for lung cancer.

Cooperative regulation of Zhx1 and hnRNPA1 drives the cardiac progenitor-specific transcriptional activation during cardiomyocyte differentiation.

The zinc finger proteins (ZNFs) mediated transcriptional regulation is critical for cell fate transition. However, it is still unclear how the ZNFs realize their specific regulatory roles in the stage-specific determination of cardiomyocyte differentiation. Here, we reported that the zinc fingers and homeoboxes 1 (Zhx1) protein, transiently expressed during the cell fate transition from mesoderm to cardiac progenitors, was indispensable for the proper cardiomyocyte differentiation of mouse and human embryonic stem cells. Moreover, Zhx1 majorly promoted the specification of cardiac progenitors via interacting with hnRNPA1 and co-activated the transcription of a wide range of genes. In-depth mechanistic studies showed that Zhx1 was bound with hnRNPA1 by the amino acid residues (Thr111-His120) of the second Znf domain, thus participating in the formation of cardiac progenitors. Together, our study highlights the unrevealed interaction of Zhx1/hnRNPA1 for activating gene transcription during cardiac progenitor specification and also provides new evidence for the specificity of cell fate determination in cardiomyocyte differentiation.

Serine hydroxymethyltransferase 2 knockdown induces apoptosis in ccRCC by causing lysosomal membrane permeabilization via metabolic reprogramming.

Serine hydroxymethyltransferase 2 (SHMT2) plays an important role in converting serine to glycine and supplying carbon to one-carbon metabolism to sustain cancer cell proliferation. However, the expression, function, and underlying mechanisms of SHMT2 in clear cell renal cell carcinoma (ccRCC) remain largely unknown. In this study, we demonstrated that SHMT2 was upregulated in ccRCC tissues compared with controls and associated with patient survival. SHMT2 knockdown inhibited proliferation, migration, and invasion in ccRCC cells. Overexpression of SHMT2 promoted tumor progression. Mechanistically, SHMT2 depletion disrupted one-carbon metabolism, increased reactive oxygen species (ROS) levels, and decreased ATP levels via metabolic reprogramming, which destroyed cell homeostasis. The SHMT2 knockdown-induced stress activated autophagy. A mass of autophagosomes fused with lysosomes, resulting in lysosomal membrane permeabilization (LMP) and leakage of lysosomal contents into the cytoplasm, which eventually led to apoptosis. Our work reveals that SHMT2 functions as an oncogenic gene to promote ccRCC progression. SHMT2 depletion induces apoptosis by causing LMP through excessive activation of the autophagy-lysosome pathway via metabolic reprogramming.

Exosomal circTUBGCP4 promotes vascular endothelial cell tipping and colorectal cancer metastasis by activating Akt signaling pathway.

BACKGROUND: Exosome is crucial mediator and play an important role in tumor angiogenesis. Tip cell formation is a prerequisite for persistent tumor angiogenesis which causes tumor metastasis. However, the functions and underlying mechanisms of tumor cell-derived exosomes in angiogenesis and tip cell formation remain less understood. METHODS: Exosomes derived from serum of colorectal cancer (CRC) patients with metastasis/non-metastasis and CRC cells were isolated by ultracentrifugation. CircRNAs in these exosomes were analyzed by circRNA microarray. Then, exosomal circTUBGCP4 was identified and verified by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). Loss- and gain-of-function assays were performed to explore the effect of exosomal circTUBGCP4 on vascular endothelial cell tipping and colorectal cancer metastasis in vitro and in vivo. Mechanically, bioinformatics analysis, biotin-labeled circTUBGCP4/ miR-146b-3p RNA pulldown, RNA immunoprecipitation (RIP), and luciferase reporter assay were used to confirm the interaction among circTUBGCP4, miR-146b-3p, and PDK2. RESULTS: Here, we showed that exosomes derived from CRC cells enhanced vascular endothelial cell migration and tube formation via inducing filopodia formation and endothelial cell tipping. We further screened the upregulated circTUBGCP4 in serum of CRC patients with metastasis compared to non-metastasis. Silencing circTUBGCP4 expression in CRC cell-derived exosomes (CRC-CDEs) inhibited endothelial cell migration, tube formation, tip cell formation, and CRC metastasis. Overexpression of circTUBGCP4 had opposite results in vitro and in vivo. Mechanically, circTUBGCP4 upregulated PDK2 to activate Akt signaling pathway by sponging miR-146b-3p. Moreover, we found that miR-146b-3p could be a key regulator for vascular endothelial cell dysfunction. Exosomal circTUBGCP4 promoted tip cell formation and activated the Akt signaling pathway by inhibiting miR-146b-3p. CONCLUSIONS: Our results suggest that colorectal cancer cells generate exosomal circTUBGCP4, which causes vascular endothelial cell tipping to promote angiogenesis and tumor metastasis by activating Akt signaling pathway.

Spatiotemporal dynamic of subtropical forest carbon storage and its resistance and resilience to drought in China.

Subtropical forests are rich in vegetation and have high photosynthetic capacity. China is an important area for the distribution of subtropical forests, evergreen broadleaf forests (EBFs) and evergreen needleleaf forests (ENFs) are two typical vegetation types in subtropical China. Forest carbon storage is an important indicator for measuring the basic characteristics of forest ecosystems and is of great significance for maintaining the global carbon balance. Drought can affect forest activity and may even lead to forest death and the stability characteristics of different forest ecosystems varied after drought events. Therefore, this study used meteorological data to simulate the standardized precipitation evapotranspiration index (SPEI) and the Biome-BGC model to simulate two types of forest carbon storage to quantify the resistance and resilience of EBF and ENF to drought in the subtropical region of China. The results show that: 1) from 1952 to 2019, the interannual drought in subtropical China showed an increasing trend, with five extreme droughts recorded, of which 2011 was the most severe one; 2) the simulated average carbon storage of the EBF and ENF during 1985-2019 were 130.58 t·hm-2 and 78.49 t·hm-2, respectively. The regions with higher carbon storage of EBF were mainly concentrated in central and southeastern subtropics, where those of ENF mainly distributed in the western subtropic; 3) The median of resistance of EBF was three times higher than that of ENF, indicating the EBF have stronger resistance to extreme drought than ENF. Moreover, the resilience of two typical forest to 2011 extreme drought and the continuous drought events during 2009 - 2011 were similar. The results provided a scientific basis for the response of subtropical forests to drought, and indicating that improve stand quality or expand the plantation of EBF may enhance the resistance to drought in subtropical China, which provided certain reference for forest protection and management under the increasing frequency of drought events in the future.

LncCMRR Plays an Important Role in Cardiac Differentiation by Regulating the Purb/Flk1 Axis.

As crucial epigenetic regulators, long noncoding RNAs (lncRNAs) play critical functions in development processes and various diseases. However, the regulatory mechanism of lncRNAs in early heart development is still limited. In this study, we identified cardiac mesoderm-related lncRNA (LncCMRR). Knockout (KO) of LncCMRR decreased the formation potential of cardiac mesoderm and cardiomyocytes during embryoid body differentiation of mouse embryonic stem (ES) cells. Mechanistic analyses showed that LncCMRR functionally interacted with the transcription suppressor PURB and inhibited its binding potential at the promoter region of Flk1, which safeguarded the transcription of Flk1 during cardiac mesoderm formation. We also carried out gene ontology term and signaling pathway enrichment analyses for the differentially expressed genes after KO of LncCMRR, and found significant correlation of LncCMRR with cardiac muscle contraction, dilated cardiomyopathy, and hypertrophic cardiomyopathy. Consistently, the expression level of Flk1 at E7.75 and the thickness of myocardium at E17.5 were significantly decreased after KO of LncCMRR, and the survival rate and heart function index of LncCMRR-KO mice were also significantly decreased as compared with the wild-type group. These findings indicated that the defects in early heart development led to functional abnormalities in adulthood heart of LncCMRR-KO mice. Conclusively, our findings elucidate the main function and regulatory mechanism of LncCMRR in cardiac mesoderm formation, and provide new insights into lncRNA-mediated regulatory network of mouse ES cell differentiation.

Cmarr/miR-540-3p axis promotes cardiomyocyte maturation transition by orchestrating Dtna expression.

The immature phenotype of embryonic stem cell-derived cardiomyocytes (ESC-CMs) limits their application. However, the molecular mechanisms of cardiomyocyte maturation remain largely unexplored. This study found that overexpression of long noncoding RNA (lncRNA)-Cmarr, which was highly expressed in cardiomyocytes, promoted the maturation change and physiological maturation of mouse ESC-CMs (mESC-CMs). Moreover, transplantation of cardiac patch overexpressing Cmarr exhibited better retention of mESC-CMs, reduced infarct area by enhancing vascular density in the host heart, and improved cardiac function in mice after myocardial infarction. Mechanism studies identified that Cmarr acted as a competitive endogenous RNA to impede the repression of miR-540-3p on Dtna expression and promoted the binding of the dystrophin-glycoprotein complex (DGC) and yes-associated protein (YAP), which in turn reduced the proportion of nuclear YAP and the expression of YAP target genes. Therefore, this study revealed the function and mechanism of Cmarr in promoting cardiomyocyte maturation and provided a lncRNA that can be used as a functional factor in the construction of cardiac patches for the treatment of myocardial infarction.

[Relationship between blood electrolytes and prognosis of patients with severe coronavirus disease 2019].

OBJECTIVE: To analyze the relationship between blood electrolytes and the prognosis of patients with severe coronavirus disease 2019 (COVID-19) and to provide assistance for clinical decision-making. METHODS: The clinical data of patients with severe COVID-19 admitted to intensive care unit (ICU) of the Wuhan Third Hospital by the Shanghai aid-Hubei medical team from January 21 to March 4, 2020 were collected. Excluding ineligible patients, 110 patients were finally enrolled. The patients' gender, age, temperature, heart rate, systolic and diastolic blood pressure, clinical symptoms at admission, time of symptom onset, duration of fever, and relevant indicators at admission to ICU (including blood potassium, chloride, sodium, calcium, phosphorus, and magnesium, etc.) and prognosis were analyzed. The patients were grouped by blood potassium or calcium levels or blood potassium/calcium ratio. The Kaplan-Meier survival curves were used to analyze the survival of patients in each group. The relationship between the potassium/calcium ratio and the prognosis was analyzed using restricted cubic spline plots. The relationship between each index in the different models and the prognosis was analyzed using Cox regression models. RESULTS: Among 110 severe COVID-19 patients, 78 cases survived, and 32 cases died. Compared with the surviving group, patients in the death group had higher blood potassium levels [mmol/L: 4.25 (3.80, 4.65) vs. 3.90 (3.60, 4.20), P < 0.05] and lower blood calcium levels (mmol/L: 2.00±0.14 vs. 2.19±0.18, P < 0.05). The Kaplan-Meier survival curves showed that patients in the potassium > 4.2 mmol/L group had a worse prognosis than the potassium < 3.8 mmol/L group and the potassium 3.8-4.2 mmol/L group (P = 0.011), patients in the calcium > 2.23 mmol/L group had a better prognosis than the calcium < 2.03 mmol/L group and the calcium 2.03-2.23 mmol/L group, and the lower calcium group had a worse prognosis (P = 0.000 15). Cox regression analysis showed that the hazard ratio (HR) of blood potassium and calcium were 2.08 and 0.01, respectively, in model 1 (single blood potassium or calcium) and in model 2 (model 1 plus age and gender), the HR of blood potassium and calcium were 1.98 and 0.01 respectively, which were significantly associated with patient prognosis (all P < 0.05). Patients in the group with the potassium/calcium ratio > 1.9 had higher blood potassium levels and a higher proportion of mechanical ventilation, lower calcium levels and lower proportion of survival, and longer time of ICU admission compared with the groups with the potassium/calcium ratio < 1.7 and 1.7-1.9. The Kaplan-Meier survival curves showed that the survival rate of the potassium/calcium ratio > 1.9 group was the lowest (P < 0.000 1), and there was no statistically significant difference in survival between the potassium/calcium ratio < 1.7 group and the potassium/calcium ratio 1.7-1.9 group. A restricted cubic spline plot corrected for age and gender showed that patients in the potassium/calcium ratio > 1.8 group had HR values > 1. Cox regression analysis corrected for other indicators showed that the potassium/calcium ratio was still associated with patient prognosis (HR = 4.85, P = 0.033). CONCLUSION: Blood potassium, calcium, and the potassium/calcium ratio at ICU admission are related to the prognosis of patients with severe COVID-19, and the potassium/calcium ratio is an independent risk factor for the death of patients. The higher the potassium/calcium ratio, the worse the prognosis of patients.

Simulated net ecosystem productivity of subtropical forests and its response to climate change in Zhejiang Province, China.

Net ecosystem productivity (NEP) is an important index that indicates the carbon sequestration capacity of forest ecosystems. However, the effect of climate change on the spatiotemporal variability in NEP is still unclear. Using the Integrated Terrestrial Ecosystem Carbon-budget (InTEC) model, this study takes the typical subtropical forests in the Zhejiang Province, China as an example, simulated the spatiotemporal patterns of forest NEP from 1979 to 2079 based on historically observed climate data (1979-2015) and data from three representative concentration pathway (RCP) scenarios (RCP2.6, RCP4.5, and RCP8.5) provided by the Coupled Model Intercomparison Project 5 (CMIP5). We analyzed the responses of NEP at different forest age classes to the variation in meteorological factors. The NEP of Zhejiang's forests decreased from 1979 to 1985 and then increased from 1985 to 2015, with an annual increase rate of 9.66 g C·m-2·yr-1 and a cumulative NEP of 364.99 Tg·C. Forest NEP decreased from 2016 to 2079; however, the cumulative NEP continued to increase. The simulated cumulative NEP under the RCP2.6, RCP4.5, and RCP8.5 scenarios was 750 Tg·C, 866 Tg·C, and 958 Tg·C, respectively, at the end of 2079. Partial correlation analysis between forest NEP at different age stages and meteorological factors showed that temperature is the key climatic factor that affects the carbon sequestration capacity of juvenile forests (1979-1999), while precipitation is the key climatic factor that affects middle-aged forests (2000-2015) and mature forests (2016-2079). Adopting appropriate management strategies for forests, such as selective cutting of different ages, is critical for the subtropical forests to adapt to climate change and maintain their high carbon sink capacity.

Effect of CRISPR/Cas9-Edited PD-1/PD-L1 on Tumor Immunity and Immunotherapy.

Clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease9 (CRISPR/Cas9) gene editing technology implements precise programming of the human genome through RNA guidance. At present, it has been widely used in the construction of animal tumor models, the study of drug resistance regulation mechanisms, epigenetic control and innovation in cancer treatment. Tumor immunotherapy restores the normal antitumor immune response by restarting and maintaining the tumor-immune cycle. CRISPR/Cas9 technology has occupied a central position in further optimizing anti-programmed cell death 1(PD-1) tumor immunotherapy. In this review, we summarize the recent progress in exploring the regulatory mechanism of tumor immune PD-1 and programmed death ligand 1(PD-L1) based on CRISPR/Cas9 technology and its clinical application in different cancer types. In addition, CRISPR genome-wide screening identifies new drug targets and biomarkers to identify potentially sensitive populations for anti-PD-1/PD-L1 therapy and maximize antitumor effects. Finally, the strong potential and challenges of CRISPR/Cas9 for future clinical applications are discussed.

LncRNA SOX1-OT V1 acts as a decoy of HDAC10 to promote SOX1-dependent hESC neuronal differentiation.

Long noncoding RNAs (lncRNAs) are abundantly expressed in the nervous system, but their regulatory roles in neuronal differentiation are poorly understood. Using a human embryonic stem cell (hESC)-based 2D neural differentiation approach and a 3D cerebral organoid system, we show that SOX1-OT variant 1 (SOX1-OT V1), a SOX1 overlapping noncoding RNA, plays essential roles in both dorsal cortical neuron differentiation and ventral GABAergic neuron differentiation by facilitating SOX1 expression. SOX1-OT V1 physically interacts with HDAC10 through its 5' region, acts as a decoy to block HDAC10 binding to the SOX1 promoter, and thus maintains histone acetylation levels at the SOX1 promoter. SOX1 in turn activates ASCL1 expression and promotes neuronal differentiation. Taken together, we identify a SOX1-OT V1/HDAC10-SOX1-ASCL1 axis, which promotes neurogenesis, highlighting a role for lncRNAs in hESC neuronal differentiation.

m6A Modification in Non-Coding RNA: The Role in Cancer Drug Resistance.

Cancer drug resistance has always been a major difficulty in cancer therapy. In the face of drug pressure, resistant cancer cells show complex molecular mechanisms including epigenetic changes to maintain survival. Studies prove that cancer cells exhibit abnormal m6A modification after acquiring drug resistance. m6A modification in the target RNA including non-coding RNA can be a controller to determine the fate and metabolism of RNA by regulating their stability, subcellular localization, or translation. In particular, m6A-modified non-coding RNA plays multiple roles in multiple drug-resistant cancer cells, which can be a target for cancer drug resistance. Here, we provide an overview of the complex regulatory mechanisms of m6A-modified non-coding RNA in cancer drug resistance, and we discuss its potential value and challenges in clinical applications.

Refractive outcomes of second-eye adjustment methods on intraocular lens power calculation in second eye.

BACKGROUND: To investigate the refractive outcomes of second-eye adjustment (SEA) methods in different intraocular lens (IOL) power calculation formulas for second eye following bilateral sequential cataract surgery. METHODS: This retrospective consecutive case-series study included 234 eyes from 234 patients who underwent bilateral sequential phacoemulsification and implantation of enVista MX60 in a hospital setting. Postoperative refraction outcomes calculated by standard formulas (SRK/T and Barrett Universal II, BUII) with SEA method were compared with those calculated by an artificial intelligence-based IOL power calculation formula (PEARL DGS) under second eye enhancement (SEE) method. The median absolute error (MedAE), mean absolute error (MAE) and percentage prediction errors (PE) of eyes within ±0.25 diopters (D), ±0.50 D, ±0.75 D and ± 1.00 D were determined. RESULTS: Overall, the improvement in MedAE after SEA was significant for PEARL DGS (p < 0.01), SRK/T (p < 0.001) and BUII (p = 0.031), which increased from 74.36, 71.37, and 77.78% to 83.33, 80.34, and 79.49% of eyes within a PE of ±0.50 D, respectively. For first eyes with a medium axial length (22-26 mm), PEARL DGS with SEE had the lowest MedAE (0.21 D). For a first-eye MAE over 0.50 D, SEA method led to significant improvement in the second eye (p < 0.01). Interocular axis length differences exceeding 0.3 mm were associated with weaker effects using SEA in the studied formulas (p > 0.05). CONCLUSIONS: Either SEA method with SRK/T and BUII formulas or second-eye enhancement method based on the PEARL DGS formula can improve postoperative refractive outcomes in second eye.