A case of malonyl coenzyme A decarboxylase deficiency with novel mutations and literature review.

Introduction: Malonyl coenzyme A decarboxylase deficiency is caused by an abnormality in the MLYCD gene. The clinical manifestations of the disease involve multisystem and multiorgan. Methods: We collected and analyzed a patient's clinical characteristics, genetic chain of evidence and RNA-seq. We use the search term "Malonyl-CoA Decarboxylase Deficiency" on Pubmed to collect cases reported. Results: We report a 3-year-old girl who is presented with developmental retardation, myocardial damage and elevated C3DC. High-throughput sequencing identified heterozygous mutation (c.798G>A, p.Q266?) in the patient inherited from her father. The other heterozygous mutation (c.641+5G>C) was found in the patient inherited from her mother. RNA-seq showed that there were 254 differential genes in this child, among which 153 genes were up-regulated and 101 genes were down-regulated. Exon jumping events occurred in exons encoding PRMT2 on the positive chain of chromosome 21, which led to abnormal splicing of PRMT2. (P<0.05, FDR<0.05). The result of SNP showed that there were multiple mutation sites on chromosome 1, which may affect the downstream gene variation at the DNA level. The literature review identified 54 cases described since 1984. Discussion: It is the first report about the locus, adding a new item to the MLYCD mutation library. Developmental retardation and cardiomyopathy are the most common clinical manifestations, with commonly elevated malonate and malonyl carnitine levels in children.

Nanometer Resolution Mass Spectro-Microtomography for In-Depth Anatomical Profiling of Single Cells.

Visually identifying the molecular changes in single cells is of great importance for unraveling fundamental cellular functions as well as disease mechanisms. Herein, we demonstrated a mass spectro-microtomography with an optimal voxel resolution of ∼300 × 300 × 25 nm3, which enables three-dimensional tomography of chemical substances in single cells. This mass imaging method allows for the distinguishment of abundant endogenous and exogenous molecules in subcellular structures. Combined with statistical analysis, we demonstrated this method for spatial metabolomics analysis of drug distribution and subsequent molecular damages caused by intracellular drug action. More interestingly, thanks to the nanoprecision ablation depth (∼12 nm), we realized metabolomics profiling of cell membrane without the interference of cytoplasm and improved the distinction of cancer cells from normal cells. Our current method holds great potential to be a powerful tool for spatially resolved single-cell metabolomics analysis of chemical components during complex biological processes.

Metagenomic next-generation sequencing and proteomics analysis in pediatric viral encephalitis and meningitis.

Introduction: Early and accurate identification of pathogens is essential for improved outcomes in patients with viral encephalitis (VE) and/or viral meningitis (VM). Methods: In our research, Metagenomic next-generation sequencing (mNGS) which can identify viral pathogens unbiasedly was performed on RNA and DNA to identify potential pathogens in cerebrospinal fluid (CSF) samples from 50 pediatric patients with suspected VEs and/or VMs. Then we performed proteomics analysis on the 14 HEV-positive CSF samples and another 12 CSF samples from health controls (HCs). A supervised partial least squaresdiscriminant analysis (PLS-DA) and orthogonal PLS-DA (O-PLS-DA) model was performed using proteomics data. Results: Ten viruses in 48% patients were identified and the most common pathogen was human enterovirus (HEV) Echo18. 11 proteins overlapping between the top 20 DEPs in terms of P value and FC and the top 20 proteins in PLS-DA VIP lists were acquired. Discussion: Our result showed mNGS has certain advantages on pathogens identification in VE and VM and our research established a foundation to identify diagnosis biomarker candidates of HEV-positive meningitis based on MS-based proteomics analysis, which could also contribute toward investigating the HEV-specific host response patterns.

Changes in Thymic Size and Immunity Are Associated with Bronchopulmonary Dysplasia.

OBJECTIVE: Preterm infants with bronchopulmonary dysplasia (BPD) are at increased risk for dysfunctional immune responses in the postnatal period. This study aimed to verify the hypothesis that thymic function is altered in infants with BPD and changes in the expression of thymic function-related genes affect thymic development. STUDY DESIGN: Included in the study were infants who had a gestational age ≤32 weeks and survived to a postmenstrual age of ≥36 weeks. The clinical features and thymic size were comparatively studied between infants with and without BPD. Thymic function and the expression of thymic function-related genes were determined in BPD infants at birth, week 2, and 4 of life. The thymic size was ultrasonographically assessed in terms of the thymic index (TI) and thymic weight index (TWI). T-cell receptor excision circles (TRECs) and gene expression were quantitatively determined by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: Compared to non-BPD infants, their BPD counterparts had a shorter GA, lower birth weight, lower Apgar scores at birth, and were more likely to be of the male gender. BPD infants had an elevated incidence of respiratory distress syndrome and sepsis. TI was 1.73 ± 0.68 versus 2.87 ± 0.70 cm3 and TWI was 1.38 ± 0.45 versus 1.72 ± 0.28 cm3/kg in the BPD group versus the non-BPD group (p < 0.05). In BPD infants, no significant changes were observed in thymic size, lymphocyte counts, and TREC copy numbers at the first 2 weeks (p > 0.05), but they all exhibited a significant increase at week 4 (p < 0.05). BPD infants presented a trend toward increased expression of transforming growth factor-ß1 and decreased expression of forkhead box protein 3 (Foxp3) from birth to week 4 (p < 0.05). Nonetheless, no significant difference was found in IL-2 or IL-7 expression at all time points (p > 0.05). CONCLUSION: For preterm infants with BPD, reduced thymic size at birth might be associated with impaired thymic function. Thymic function was developmentally regulated in the BPD process. KEY POINTS: · For preterm infants with BPD, reduced thymic size at birth might be associated with impaired thymic.. · BPD infants had an elevated incidence of respiratory distress syndrome and sepsis.. · Thymic function was developmentally regulated in the BPD process..

Enhanced binding of ß-catenin and ß-TrCP mediates LMPt's anti-CSCs activity in colorectal cancer.

Cancer stem cells (CSCs), a subpopulation of tumor cells with the features of self-renewal, tumor initiation, and insensitivity to common physical and chemical agents, are the key to cancer relapses, metastasis, and resistance. Accessible CSCs inhibitory strategies are primarily based on small molecule drugs, yet toxicity limits their application. Here, we report a liposome loaded with low toxicity and high effectiveness of miriplatin, lipo-miriplatin (LMPt) with high miriplatin loading, and robust stability, exhibiting a superior inhibitory effect on CSCs and non-CSCs. LMPt predominantly inhibits the survival of oxaliplatin-resistant (OXA-resistant) cells composed of CSCs. Furthermore, LMPt directly blocks stemness features of self-renewal, tumor initiation, unlimited proliferation, metastasis, and insensitivity. In mechanistic exploration, RNA sequencing (RNA-seq) revealed that LMPt downregulates the levels of pro-stemness proteins and that the ß-catenin-mediated stemness pathway is enriched. Further research shows that either in adherent cells or 3D-spheres, the ß-catenin-OCT4/NANOG axis, the vital pathway to maintain stemness, is depressed by LMPt. The consecutive activation of the ß-catenin pathway induced by mutant ß-catenin (S33Y) and OCT4/NANOG overexpression restores LMPt's anti-CSCs effect, elucidating the key role of the ß-catenin-OCT4/NANOG axis. Further studies revealed that the strengthened binding of ß-catenin and ß-TrCP initiates ubiquitination and degradation of ß-catenin induced by LMPt. In addition, the ApcMin/+ transgenic mouse model, in which colon tumors are spontaneously formed, demonstrates LMPt's potent anti-non-CSCs activity in vivo.

Late-Onset Anti-GABAB Receptor Encephalitis: Clinical Characteristics and Outcomes Differing From Early-Onset Patients.

BACKGROUND AND OBJECTIVES: Existing evidence indicates anti-GABAB receptor encephalitis (GABABR-E) seems to occur more commonly later in life, yet the age-associated differences in clinical features and outcomes are not well determined. This study aims to explore the demographic, clinical characteristics, and prognostic differences between late-onset and early-onset GABABR-E and identify predictors of favorable long-term outcomes. METHODS: This is an observational retrospective study conducted in 19 centers from China. Data from 62 patients with GABABR-E were compared between late-onset (aged 50 years or older) and early-onset (younger than 50 years) groups and between groups with favorable outcomes (modified Rankin scale (mRS) ≤ 2) and poor outcomes (mRS >2). Logistic regression analyses were applied to identify factors affecting long-term outcomes. RESULTS: Forty-one (66.1%) patients experienced late-onset GABABR-E. A greater proportion of males, a higher mRS score at onset, higher frequencies of ICU admission and tumors, and a higher risk of death were demonstrated in the late-onset group than in the early-onset group. Compared with poor outcomes, patients with favorable outcomes had a younger onset age, a lower mRS score at onset, lower frequencies of ICU admission and tumors, and a greater proportion with immunotherapy maintenance for at least 6 months. On multivariate regression analysis, age at onset (OR, 0.849, 95% CI 0.739-0.974, p = 0.020) and the presence of underlying tumors (OR, 0.095, 95% CI 0.015-0.613, p = 0.013) were associated with poorer long-term outcomes, whereas immunotherapy maintenance for at least 6 months was associated with favorable outcomes (OR, 10.958, 95% CI 1.469-81.742, p = 0.020). DISCUSSION: These results demonstrate the importance of risk stratification of GABABR-E according to age at onset. More attention should be paid to older patients especially with underlying tumors, and immunotherapy maintenance for at least 6 months is recommended to achieve a favorable outcome.

Research on an Optimized Quarter-Wavelength Resonator-Based Triboelectric Nanogenerator for Efficient Low-Frequency Acoustic Energy Harvesting.

Sound wave is an extensively existing mechanical wave, especially in marine and industrial plants where low-frequency acoustic waves are ubiquitous. The effective collection and utilization of sound waves provide a fresh new approach to supply power for the distributed nodes of the rapidly developing Internet of Things technology. In this paper, a novel acoustic triboelectric nanogenerator (QWR-TENG) was proposed for efficient low-frequency acoustic energy harvesting. QWR-TENG consisted of a quarter-wavelength resonant tube, a uniformly perforated aluminum film, an FEP membrane, and a conductive carbon nanotube coating. Simulation and experimental studies showed that QWR-TENG has two resonance peaks in the low-frequency range, which effectively extends the response bandwidth of acoustic-electrical conversion. The structural optimized QWR-TENG has excellent electrical output performance, and the maximum output voltage, short-circuit current and transferred charge are 255 V, 67 µA, and 153 nC, respectively, under the acoustic frequency of 90 Hz and sound pressure level of 100 dB. On this basis, a conical energy concentrator was introduced to the entrance of the acoustic tube, and a composite quarter-wavelength resonator-based triboelectric nanogenerator (CQWR-TENG) was designed to further enhance the electrical output. Results showed that the maximum output power and the power density per unit pressure of CQWR-TENG reached 13.47 mW and 2.27 WPa-1m-2, respectively. Application demonstrations indicated that QWR/CQWR-TENG has good capacitor charging performance and is expected to realize power supply for distributed sensor nodes and other small electrical devices.

Fiber-integrated cantilever-based nanomechanical biosensors as a tool for rapid antibiotic susceptibility testing.

There is an urgent need for developing rapid and affordable antibiotic susceptibility testing (AST) technologies to inhibit the overuse of antibiotics. In this study, a novel microcantilever nanomechanical biosensor based on Fabry-Pérot interference demodulation was developed for AST. To construct the biosensor, a cantilever was integrated with the single mode fiber in order to form the Fabry-Pérot interferometer (FPI). After the attachment of bacteria on the cantilever, the fluctuations of cantilever caused by the bacterial movements were detected by monitoring the changes of resonance wavelength in the interference spectrum. We applied this methodology to Escherichia coli and Staphylococcus aureus, showing the amplitude of cantilever's fluctuations was positively related on the quantity of bacteria immobilized on the cantilever and associated with the bacterial metabolism. The response of bacteria to antibiotics was dependent on the types of bacteria, the types and concentrations of antibiotics. Moreover, the minimum inhibitory and bactericidal concentrations for Escherichia coli were obtained within 30 minutes, demonstrating the capacity of this method for rapid AST. Benefiting from the simplicity and portability of the optical fiber FPI-based nanomotion detection device, the developed nanomechanical biosensor in this study provides a promising technique for AST and a more rapid alternative for clinical laboratories.

IMF-PR: An Improved Morton-Filter-Based Pseudonym-Revocation Scheme in VANETs.

Vehicle ad hoc networks (VANETs) are special wireless networks which help vehicles to obtain continuous and stable communication. Pseudonym revocation, as a vital security mechanism, is able to protect legal vehicles in VANETs. However, existing pseudonym-revocation schemes suffer from the issues of low certificate revocation list (CRL) generation and update efficiency, along with high CRL storage and transmission costs. In order to solve the above issues, this paper proposes an improved Morton-filter-based pseudonym-revocation scheme for VANETs (IMF-PR). IMF-PR establishes a new distributed CRL management mechanism to maintain a low CRL distribution transmission delay. In addition, IMF-PR improves the Morton filter to optimize the CRL management mechanism so as to improve CRL generation and update efficiency and reduce the CRL storage overhead. Moreover, CRLs in IMF-PR store illegal vehicle information based on an improved Morton filter data structure to improve the compress ratio and the query efficiency. Performance analysis and simulation experiments showed that IMF-PR can effectively reduce storage by increasing the compression gain and reducing transmission delay. In addition, IMF-PR can also greatly improve the lookup and update throughput on CRLs.

Solid-Phase Polymerization Using Anion-Exchange Resin Can Almost Completely Crosslink Hemoglobin to Prepare Hemoglobin-Based Oxygen Carriers.

Introduction: A limitation of hemoglobin-based oxygen carriers (HBOCs) as oxygen therapeutics is unpolymerized hemoglobin, which induces vasoconstriction leading to hypertension. The removal of unpolymerized hemoglobin from polymerized hemoglobin (PolyHb) is complex, expensive, and time-consuming. Methods: Herein, we developed a method to completely polymerize hemoglobin almost without unpolymerized hemoglobin. Hemoglobin was adsorbed on the anion-exchange resin Q Sepharose Fast Flow or DEAE Sepharose Fast Flow, and acetal, a crosslinker prepared from glutaraldehyde and ethylene glycol, was employed to polymerize the hemoglobin. The polymerization conditions, including reaction time, pH, resin type, and molar ratios of glutaraldehyde to ethylene glycol and hemoglobin to acetal, were optimized. The blood pressure and blood gas of mice injected with PolyHb were monitored as well. Results: The optimal polymerization condition of PolyHb was when the molar ratio of glutaraldehyde to ethylene glycol was 1:20, and the molar ratio of 10 mg/mL hemoglobin adsorbed on anion-exchange resin to glutaraldehyde was 1:300 for 60 min. Under optimized reactive conditions, hemoglobin was almost completely polymerized, with <1% hemoglobin remaining unpolymerized, and the molecular weight of PolyHb was more centrally distributed. Furthermore, hypertension was not induced in mice by PolyHb, and there were also no pathological changes observed in arterial oxygen, blood gas, electrolytes, and some metabolic indicators. Conclusion: The findings of this study indicate that the use of solid-phase polymerization and acetal is a highly effective and innovative approach to HBOCs, resulting in the almost completely polymerized hemoglobin. These results offer promising implications for the development of new methods for preparing HBOCs.

CBL0137 activates ROS/BAX signaling to promote caspase-3/GSDME-dependent pyroptosis in ovarian cancer cells.

Curaxin CBL0137 was designed to regulate p53 and nuclear factor-κB simultaneously and exhibits antitumor activity by inhibiting tumor cell proliferation and inducing apoptosis in multiple cancers. However, whether CBL0137 can induce pyroptosis has not yet been reported. This study demonstrated that CBL0137 induces caspase-3/gasdermin E (GSDME)-dependent pyroptosis via the reactive oxygen species (ROS)/BAX pathway. In ovarian cancer cells, CBL0137 inactivated the chromatin remodeling complex which could facilitate chromatin transcription, leading to the decreased transcription of antioxidant genes and oxidation and causing increased ROS levels. BAX was recruited on the mitochondrial membrane by mitochondrial ROS and induced the release of cytochrome c to cleave caspase-3. This led to the cleavage of the N-terminal of GSDME to form pores on the cell membrane and induced pyroptosis. Results of in vivo experiments revealed that CBL0137 also had anti-tumor effects on ovarian cancer cells in vivo. Our study outcomes reveal the mechanisms and targets of CBL0137 inducing pyroptosis in ovarian cancer cells and indicate that CBL0137 is a promising therapeutic agent for ovarian cancer.

Simultaneous measurement of humidity and temperature based on fiber-tip microcantilever cascaded with fiber Bragg grating.

We demonstrated a hybrid sensor of fiber Bragg grating (FBG) and Fabry-Perot interferometer (FPI) based on fiber-tip microcantilever for simultaneous measurement of temperature and humidity. The FPI was developed using femtosecond (fs) laser-induced two-photon polymerization to print the polymer microcantilever at the end of a single-mode fiber, achieving a humidity sensitivity of 0.348 nm/%RH (40% to 90%, when temperature = 25 °C ± 0.1 °C), and a temperature sensitivity of -0.356 nm/°C (25 to 70 °C, when RH% = 40% ± 1%). The FBG was line-by-line inscribed in the fiber core by fs laser micromachining, with a temperature sensitivity of 0.012 nm/ °C (25 to 70 °C, when RH% = 40% ± 1%). As the shift of FBG-peak on the reflection spectra is only sensitive to temperature rather than humidity, the ambient temperature can be directly measured by the FBG. The output of FBG can also be utilized as temperature compensation for FPI-based humidity measurement. Thus, the measured result of relative humidity can be decoupled from the total shift of FPI-dip, achieving the simultaneous measurement of humidity and temperature. Gaining the advantages of high sensitivity, compact size, easy packaging, and dual parameter measurement, this all-fiber sensing probe is anticipated to be applied as the key component for various applications involving the simultaneous measurement of temperature and humidity.

Highly Stretchable and Robust Electrochemical Sensor Based on 3D Graphene Oxide-CNT Composite for Detecting Ammonium in Sweat.

Wearable electrochemical sensors have attracted tremendous attention and have been experiencing rapid growth in recent years. Sweat, one of the most suitable biological fluids for non-invasive monitoring, contains various chemical elements relating abundant information about human health conditions. In this work, a new type of non-invasive and highly stretchable potentiometric sweat sensor was developed based on all-solid-state ion-selective electrode (ISE) coupled with poly(dimethylsiloxane; PDMS) and polyurethane (PU). This highly stretchable composite of PDMS-PU allows the sensor to be robust, with the PDMS providing a flexible backbone and the PU enhancing the adhesion between the electrodes and the substrate. In addition, graphene-carbon nanotube (CNT) network 3D nanomaterials were introduced to modify the ion selective membrane (ISM) in order to increase the charge transfer activity of the ISEs, which also could minimize the formation of water layers on the electrode surface, as such nanomaterials are highly hydrophobic. As a result, the sensor demonstrated a wide detection range of NH4+ from 10-6 M to 10-1 M with high stability and sensitivity-showing a high sensitivity of 59.6 ± 1.5 mV/log [NH4+] and an LOD lower than 10-6 M. Under a strain of 40%, the sensor still showed a sensitivity of 42.7 ± 3.1 mV/log [NH4+]. The proposed highly stretchable and robust electrochemical sweat sensor provides a new choice for wearable-device-based personal daily healthcare management beyond hospital-centric healthcare monitoring.

Inhibitory effects of sesquiterpene lactones on the aggregation and cytotoxicity of prion neuropeptide.

The misfolding and conformational transformation of prion protein (PrP) are crucial to the progression of prion diseases. Screening for available natural inhibitors against prion proteins can contribute to the rational design and development of new anti-prion drugs and therapeutic strategies. The prion neuropeptide, PrP106-126 is commonly used as a model peptide of the abnormal PrPSc, and a number of potential inhibitors were explored against the amyloid fibril formation of PrP106-126. The well-known sesquiterpene lactone, artemisinin, shows diverse biological functions in anti-malarial, anti-cancer and lowering glucose. However, its inhibitory effect on PrP106-126 fibrillation is unclear. In this work, we selected two sesquiterpene lactones, artemisinin (1) and artesunate (2), to explore their roles in PrP106-126 aggregation by a series of physicochemical and biochemical methods. The results demonstrated that 1 and 2 could effectively impede the formation of amyloid fibrils and remodel the preformed fibrils. The binding of the small molecules to PrP106-126 was dominated by electrostatic, hydrophobic and hydrogen bonding interactions. In addition, both compounds exhibited neuroprotective effects by reducing peptide oligomerization. 2 showed better inhibition and regulation on peptide aggregation and cellular viability than 1 due to its specific succinate modification. Our study provides the information of sesquiterpene lactones to prevent PrP fibril formation and other related amyloidosis.

TCF1/LEF1 triggers Wnt-dependent chemokine/cytokine-induced inflammation and cadherin pathways to drive T-ALL cell migration.

T-cell acute lymphoblastic leukemia (T-ALL) is a type of aggressive hematologic malignancy. It progresses quickly and it is likely to be fatal within a few months without treatment. Despite the limitations of current clinical therapies, there is an urgent need for novel and targeted therapies. To explore potential targeted therapies, molecular genetic mechanisms of T-ALL metastasis must be uncovered. However, the genes and mechanisms that mediate T-ALL metastasis are largely unknown. Recent insights into T-ALL biology have identified several genes that can be grouped into several targetable signaling pathways. The Wnt/ß-catenin signaling pathway is one of the most important pathways. Our work investigated the functions of TCF1 and LEF1 in cell growth and migration mediated by the Wnt signaling pathway. We found that TCF1 and LEF1 knockdown weakly repressed T-ALL cell proliferation but distinctly impaired cell migration. T-ALL metastasis is dependent on cell migration and invasion. Our results displayed that TCF1 and LEF1 regulated T-ALL cell migration by the Wnt-dependent chemokine and cytokine-induced inflammation and cadherin signaling pathways. By transcriptionally regulating these pathways-associated genes, TCF1 and LEF1 inhibited cell adhesion and promoted cell migration and invasion.

Catheter ablation improved ejection fraction in persistent AF patients: a DECAAF-II sub analysis.

AIMS: The aim of our study was to assess differences in post-ablation atrial fibrillation (AF) recurrence and burden and to quantify the change in LVEF across different congestive heart failure (CHF) subcategories of the DECAAF-II population. METHODS AND RESULTS: Differences in the primary outcome of AF recurrence between CHF and non-CHF groups was calculated. The same analysis was performed for the three subgroups of CHF and the non-CHF group. Differences in AF burden after the 3-month blanking period between CHF and non-CHF groups was calculated. Improvement in LVEF was calculated and compared across the three CHF groups. Improvement was also calculated across different fibrosis stages. There was no significant differences in AF recurrence and AF burden after catheter ablation between CHF and non-CHF patients and between different CHF subcategories. Patients with heart failure with reduced ejection fraction (HFrEF) experienced the greatest improvement in EF following catheter ablation (CA, 16.66% ± 11.98, P < 0.001) compared to heart failure with moderately reduced LVEF, and heart failure with preserved EF (10.74% ± 8.34 and 2.00 ± 8.34 respectively, P-value < 0.001). Moreover, improvement in LVEF was independent of the four stages of atrial fibrosis (7.71 vs. 9.53 vs. 5.72 vs. 15.88, from Stage I to Stage IV respectively, P = 0.115). CONCLUSION: Atrial fibrillation burden and recurrence after CA is similar between non-CHF and CHF patients, independent of the type of CHF. Of all CHF groups, those with HFrEF had the largest improvement in LVEF after CA. Moreover, the improvement in ventricular function seems to be independent of atrial fibrosis in patients with persistent AF.

Acquired resistance to EGFR-TKIs in NSCLC mediates epigenetic downregulation of MUC17 by facilitating NF-κB activity via UHRF1/DNMT1 complex.

Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has brought significant benefits to non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, most patients eventually develop acquired resistance after treatment. This study investigated the epigenetic effects of mucin 17 (MUC17) in acquired drug-resistant cells of EGFR-TKIs. We found that GR/OR (gefitinib/osimertinib-resistance) cells enhance genome-wide DNA hypermethylation, mainly in 5-UTR associated with multiple oncogenic pathways, in which GR/OR cells exerted a pro-oncogenic effect by downregulating mucin 17 (MUC17) expression in a dose- and time-dependent manner. Gefitinib/osimertinib acquired resistance mediated down-regulation of MUC17 by promoting DNMT1/UHRF1 complex-dependent promoter methylation, thereby activating NF-κB activity. MUC17 increased the generation of IκB-α and inhibit NF-κB activity by promoting the expression of MZF1. In vivo results also showed that DNMT1 inhibitor (5-Aza) in combination with gefitinib/osimertinib restored sensitivity to OR/GR cells. Acquired drug resistance of gefitinib/osimertinib promoted UHRF1/DNMT1 complex to inhibit the expression of MUC17. MUC17 in GR/OR cells may act as an epigenetic sensor for biomonitoring the resistance to EGFR-TKIs.

ESRG is critical to maintain the cell survival and self-renewal/pluripotency of hPSCs by collaborating with MCM2 to suppress p53 pathway.

The mechanisms of self-renewal and pluripotency maintenance of human pluripotent stem cells (hPSCs) have not been fully elucidated, especially for the role of those poorly characterized long noncoding RNAs (lncRNAs). ESRG is a lncRNA highly expressed in hPSCs, and its functional roles are being extensively explored in the field. Here, we identified that the transcription of ESRG can be directly regulated by OCT4, a key self-renewal factor in hPSCs. Knockdown of ESRG induces hPSC differentiation, cell cycle arrest, and apoptosis. ESRG binds to MCM2, a replication-licensing factor, to sustain its steady-state level and nuclear location, safeguarding error-free DNA replication. Further study showed that ESRG knockdown leads to MCM2 abnormalities, resulting in DNA damage and activation of the p53 pathway, ultimately impairs hPSC self-renewal and pluripotency, and induces cell apoptosis. In summary, our study suggests that ESRG, as a novel target of OCT4, plays an essential role in maintaining the cell survival and self-renewal/pluripotency of hPSCs in collaboration with MCM2 to suppress p53 signaling. These findings provide critical insights into the mechanisms underlying the maintenance of self-renewal and pluripotency in hPSCs by lncRNAs.

High-Wettability Poly(dimethylsiloxane) Substrate for Ultrastable Conductive Three-Dimensional Woven Ag Nanowire Grids.

Three-dimensional (3D) woven Ag nanowire (AgNW) grids have great potential for enhancing the mechanical stabilities, conductivity, and transmittance of flexible transparent electrodes (FTEs). However, it is a great challenge to control the formation of 3D woven AgNW grids on various substrates, especially the poly(dimethylsiloxane) (PDMS) substrate. This work presents a microtransfer-printing method for preparing a high-wettability poly(dimethylsiloxane) (PDMS) substrate to control the formation of 3D woven AgNW grids. The as-prepared PDMS substrate shows a high wettability performance. The surface structures of the PDMS substrate can control the sharp shrinkage of the ink membrane to give rise to a uniform liquid membrane evaporation behavior, which is the key factor for preparing a uniform 3D woven nanowire network. A thin uniform 3D woven AgNW network with a low sheet resistance of 24.3 Ω/□ and high transmittance of 92% was coated on the PDMS substrate. The networks directly coated the surface of the replicated PDMS, which simplified the peeling process and protected the networks from peeling strain and mechanical deformations. Moreover, the increment of resistance retained a small value (∼5%) when bending cycles reached 9,000. An alternating current electroluminescent (ACEL) device was prepared, and the uniform electroluminescence implies that a defect-free electrode has been fabricated. These results indicate that the as-prepared FTEs have excellent mechanical performance and great potential for flexible optoelectronic applications.

Efficacy and safety of repeated low-dose rituximab therapy in relapsing-remitting multiple sclerosis: A retrospective case series study.

BACKGROUND: Rituximab (RTX) is an extensively used off-label drug for multiple sclerosis (MS), whereas the induction and maintenance regimens vary widely among studies. Few data are available on efficacy and safety of repeated low-dose RTX therapy in MS patients. OBJECTIVE: This study aimed to evaluate the efficacy and safety of repeated low-dose RTX therapy for relapsing-remitting MS (RRMS), the most common form of MS affecting approximately 85% of patients. METHODS: Nine RRMS patients were enrolled and the medical records were retrospectively reviewed. RTX at 100 mg per week for three consecutive weeks was used as induction therapy. Maintenance therapy was reinfusions of RTX at 100 mg every 6 months during the first year, followed by 100 mg every 6 to 12 months. Main outcome measures included annualized relapse rate (ARR), expanded disability status scale (EDSS) score, and T2 lesion burden on MRI for evaluating the efficacy of low-dose RTX regimen. Meanwhile, adverse events (AEs) were recorded to assess the safety of repeated RTX infusions. RESULTS: All patients were females with an average onset age of 25.4 ± 6.7 years. The median disease duration before the first RTX infusion was 56 (range, 3-108) months and the median follow-up period was 30 (range, 15-40) months. No relapses were recorded in all patients after RTX therapy. Repeated low-dose RTX therapy resulted in a dramatic reduction of median ARR (pre-RTX vs post-RTX, 1.1 vs 0, p = 0.012), median EDSS score (2.0 vs 0, p = 0.007), and the number of T2 lesions on MRI (35.6 ± 18.0 vs 29.4 ± 18.1, p = 0.001). A total of 35 episodes of AEs occurred during repeated low-dose RTX therapy, and all of them were mild and transient. CONCLUSION: Repeated low-dose RTX therapy is cost-effective for RRMS patients and shows a good safety profile. It may be a promising option for those having no access or poor response to first-line disease-modified drugs (DMDs), particularly in low- or middle-income countries.