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The CRISPR-Cas system is a powerful gene editing technology, the clinical application of which is currently constrained due to safety concerns. A substantial body of safety research concerning Cas9 exists; however, scant attention has been directed toward investigating the safety profile of the emergent Cas13 system, which confers RNA editing capabilities. In particular, uncertainties persist regarding the potential cellular impacts of Cas13d in the absence of reliance on a cleavage effect. In this study, we conducted an initial exploration of the effects of Cas13d on HeLa cells. Total RNA and protein samples were extracted after transfection with a Cas13d-expressing plasmid construct, followed by transcriptomic and proteomic sequencing. Differential gene expression analysis identified 94 upregulated and 847 downregulated genes, while differential protein expression analysis identified 185 upregulated and 231 downregulated proteins. Subsequently, enrichment analysis was conducted on the transcriptome and proteome sequencing data, revealing that the PI3K-Akt signaling pathway is a common term. After intersecting the differentially expressed genes enriched in the PI3K-Akt signaling pathway with all the differentially expressed proteins, it was found that the expression of the related regulatory gene PFKFB4 was upregulated. Moreover, western blot analysis demonstrated that Cas13d can mediate PI3K-Akt signaling upregulation through overexpression of PFKFB4. CCK-8 assay, colony formation, and EdU experiments showed that Cas13d can promote cell proliferation. Our data demonstrate, for the first time, that Cas13d significantly impacts the transcriptomic and proteomic profiles, and proliferation phenotype, of HeLa cells, thus offering novel insights into safety considerations regarding gene editing systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

RNAs represent a class of programmable biomolecules capable of performing diverse biological functions. Recent studies have developed accurate RNA three-dimensional structure prediction methods, which may enable new RNAs to be designed in a structure-guided manner. Here, we develop a structure-to-sequence deep learning platform for the de novo generative design of RNA aptamers. We show that our approach can design RNA aptamers that are predicted to be structurally similar, yet sequence dissimilar, to known light-up aptamers that fluoresce in the presence of small molecules. We experimentally validate several generated RNA aptamers to have fluorescent activity, show that these aptamers can be optimized for activity in silico, and find that they exhibit a mechanism of fluorescence similar to that of known light-up aptamers. Our results demonstrate how structural predictions can guide the targeted and resource-efficient design of new RNA sequences., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Although coronavirus disease 2019 (COVID-19) has not been considered a public health emergency of international concern since last year, intermittent regional impacts still persist, and accurate testing remains crucial. Ribonuclease P protein subunit P30 ( RPP30 ) RNA, known for its broad and stable expression in tissue cells, was used to evaluate samples from 10 hospitals with over 3,000 negative nucleic acid tests. The results revealed that the overall pass rate for the collected samples was consistently low and exhibited significant heterogeneity. After reassessing the evaluative effectiveness of RPP30 RNA Ct values from the samples of 132 positive individuals under quarantine observation, it was used to identify factors affecting sampling quality. These factors included different stages ranging from sample collection to PCR processing, various characteristics of both samplers and individuals being sampled, as well as sampling season and location. The results indicated that post-sampling handling had minimal impact, winter and fever clinic samples showed higher quality, whereas children's samples had lower quality. The key finding was that the characteristics of samplers were closely related to sampling quality, emphasizing the role of subjectivity. Quality control warnings led to substantial improvements, confirming this finding. Consequently, although there are various factors during the testing process, the most critical aspect is to improve, supervise, and maintain standardized practices among sampling staff. IMPORTANCE This study further confirmed the reliability of internal references (IRs) in assessing sample quality, and utilized a large sample IR data to comprehensively and multidimensionally identify significant interference factors in nucleic acid test results. By further reminding and intervening in the subjective practices of specimen collectors, good results could be achieved., Competing Interests: The authors declare no conflict of interest.

Many studies have shown that myocardial infarction (MI) is significantly associated with atrial fibrillation (AF), but the causal relationship between MI and AF has not been established. Therefore, we performed this Mendelian randomization (MR) study to investigate the relationship between MI and AF. We used a publicly available summary statistical dataset for MI based on genome-wide analysis studies (GWAS; ebi-a-GCST011364; 14,825 cases and 2680 controls) and a summary statistical dataset for AF based on an European GWAS (finn-b-I9&#95;AF&#95;REIMB; 10,516 cases and 116,926 controls). The 2-sample bidirectional MR analysis was performed using the inverse-variance weighted (IVW), MR-Egger, and weighted median methods. The causal effect of MI on AF was analyzed using 30 MI-specific single nucleotide polymorphisms (SNPs) that were characterized as instrumental variables (IVs) based on the GWAS data. The causal effect of MI on AF was confirmed by the IVW (odds ratio [OR] 1.42; 95% confidence interval [CI] 1.27-1.58; P < .001), MR-Egger (OR: 1.49; 95% CI: 1.15-1.93; P = .005), and weighted median (OR: 1.42; 95% CI: 1.24-1.63; P < .001) analyses. Furthermore, in the reverse MR analyses, the causal effect of AF on MI was analyzed using 20 AF-specific SNPs that were screened as IVs. The causal effect of AF on MI was significant based on the results from the IVW method (OR: 1.05; 95% CI: 1.00-1.09; P = .033). In conclusion, the bidirectional MR analyses demonstrated a clear bidirectional causal association between MI and AF., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

This study aims to fabricate high internal phase emulsion gels (HIPEGs) using modified hemp protein isolates for microencapsulating cannabidiol (CBD) to enhance their chemical stability and bioaccessibility. Importantly, the combined effect of CBD concentrations (0.1 vs 0.5 wt%) and post gel storage conditions (before-refrigeration (BR) vs after-refrigeration (AR)) on the properties of HIPEGs were investigated. The results showed that the CBD concentration above 0.4 % is necessary to fabricate a stable HIPEG. The rheological properties of HIPEGs were influenced by CBD concentration and refrigeration. The AR gels with 0.5 % CBD showed the highest gel strength (up to 91.7 Pa) and solid-like structures. These properties allowed to HIPEGs maintain good physical stability during storage at 4, 25, and 37 °C for 14 days due to the interconnected polyhedral protein matrices and thick interfacial protein layers. These unique protein architectures offered superior protection against CBD degradation (<2 % of initial added amount) for 100 days during exposure to light and temperature (25 or 37 °C). The INFOGEST digestion results showed the BR gels effectively protected CBD during digestion and consequently improved their stability and bioaccessibility up to 95 % and 74 %, respectively. Overall, the fabricated HIPEGs could be valuable for nutraceutical delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The development of sequencing technology has promoted discovery of variants in the human genome. Identifying functions of these variants is important for us to link genotype to phenotype, and to diagnose diseases. However, it usually requires researchers to visit multiple databases. Here, we presented a one-stop webserver for variant function annotation tools (VCAT, https://biomed.nscc-gz.cn/zhaolab/VCAT/ ) that is the first one connecting variant to functions via the epigenome, protein, drug and RNA. VCAT is also the first one to make all annotations visualized in interactive charts or molecular structures. VCAT allows users to upload data in VCF format, and download results via a URL. Moreover, VCAT has annotated a huge number (1,262,041,068) of variants collected from dbSNP, 1000 Genomes projects, gnomAD, ICGC, TCGA, and HPRC Pangenome project. For these variants, users are able to searcher their functions, related diseases and drugs from VCAT. In summary, VCAT provides a one-stop webserver to explore the potential functions of human genomic variants including their relationship with diseases and drugs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study investigates the prognostic value of skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) measured by chest CT in relation to all-cause and cardiovascular disease (CVD) mortality among hemodialysis (HD) patients., Methods: A retrospective study was conducted from January 2015 to December 2021 involving HD patients at a dialysis center. Chest CT scans at the twelfth thoracic vertebra level (T12) were analyzed to assess SMI and SMD. Sex-specific cut-off values for two metrics were determined using maximally selected rank statistics. Hazard ratios (HRs) were calculated to evaluate the associations of SMI and SMD with mortality. The discrimination of prognostic models was also compared., Results: The study included 603 patients with a median age of 58 years. Of these, 187 (31.0%) patients with SMI < 30.00 cm 2 /m 2 (male) or < 25.04 cm 2 /m 2 (female) and 192 (31.8%) patients with SMD < 32.25 HU (male) or < 30.64 HU (female) were categorized as lower SMI and SMD, respectively. Over a median follow-up of 3.8 years, 144 deaths occurred. Multivariate Cox regression analysis showed that lower SMI and SMD were independently associated with all-cause mortality (SMI: HR = 1.47, 95% CI 1.03-2.10; SMD: HR = 1.75, 95% CI 1.20-2.54) and CVD mortality (SMI: HR = 1.74, 95% CI 1.03-2.94; SMD: HR = 1.72, 95% CI 1.02-2.95). Adding SMI and SMD to the established risk model improved the C-index from 0.82 to 0.87 (P < 0.001). Decision curve analysis showed that the prognostic model incorporating both SMI and SMD offered the highest net benefit for predicting all-cause mortality., Conclusions: Muscle metrics derived from CT scans at T12 level provide valuable prognostic information which could enhance the role of chest CT in muscle assessment among HD patients., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Serum uric acid (SUA), a product of purine metabolism, has been implicated in HF progression. However, the association between hyperuricaemia and the short-term readmission and mortality in patients with HF remains controversial., Methods: In this retrospective cohort study, we analysed data from a HF database specific to the Chinese population. The primary endpoint was short-term readmission or all-cause mortality within 90 days. Participants with HF were categorised into normouricaemia group (NUA) and hyperuricaemia group (HUA) based on a SUA threshold of 420 µmol/L. The association between SUA and primary endpoint was evaluated using Kaplan-Meier survival curves and Cox regression analysis., Results: Baseline characteristics revealed significant differences between NUA and HUA groups, with the latter exhibiting a higher prevalence of males, chronic kidney disease (CKD) and elevated levels of various biomarkers. During a 90-day follow-up, 493 (26.6%) participants reached the primary endpoint, with a higher incidence observed in the HUA group at 31.2%, compared with 20.1% in the NUA group. When a threshold effect was identified at 420 µmol/L, a non-linear association was observed between SUA and the primary endpoint. After adjusting for gender, age, New York Heart Association class, CKD, systolic blood pressure (SBP) and potassium, the HUA group exhibited a higher risk for the primary endpoint compared with the NUA group (HR: 1.40, 95% CI: 1.14 to 1.72, p=0.001). Additionally, the risk increased across quartiles of SUA (P for trend=0.002). Furthermore, stratified analyses indicated a stronger association in patients without CKD (P interaction=0.033)., Conclusion: Hyperuricaemia is independently associated with an increased risk of short-term readmission and mortality in patients with HF. Our findings suggest that monitoring and managing SUA could be crucial in improving patient with HF outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Grain boundary hardening and precipitation hardening are important mechanisms for enhancing the strength of metals. Here, we show that these two effects can be amplified simultaneously in nanocrystalline compositionally complex alloys (CCAs), leading to near-theoretical strength and large deformability. We develop a model nanograined (TiZrNbHf) 98 Ni 2 alloy via thermodynamic design. The Ni solutes, which has a large negative mixing enthalpy and different electronegativity to Ti, Zr, Nb and Hf, not only produce Ni-enriched local chemical inhomogeneities in the nanograins, but also segregate to grain boundaries. The resultant alloy achieves a 2.5 GPa yield strength, together with work hardening capability and large homogeneous deformability to 65% compressive strain. The local chemical inhomogeneities impede dislocation propagation and encourage dislocation multiplication to promote strain hardening. Meanwhile, Ni segregates to grain boundaries and enhances cohesion, suppressing the grain growth and grain boundary cracking found while deforming the reference TiZrNbHf alloy. Our alloy design strategy thus opens an avenue, via solute decoration at grain boundaries combined with local chemical inhomogeneities inside the grains, towards ultrahigh strength and large plasticity in nanostructured alloys., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Haematitum, a time-honored mineral-based Chinese medicine, has been used medicinally in China for over 2000 years. It is now included in the Chinese Pharmacopoeia and used clinically for treating digestive and respiratory diseases. The Chinese Materia Medica records that it is toxic and should not be taken for a long period, but there are few research reports on the toxicity of Haematitum and its potential toxicity mechanisms., Aim of the Study: This study aimed to evaluate the toxicity of Haematitum and calcined Haematitum, including organ toxicity, neurotoxicity, and reproductive toxicity. Further, it is also necessary to explore the mechanism of Haematitum toxicity and to provide a reference for the safe clinical use of the drug., Materials and Methods: The samples of Haematitum and calcined Haematitum decoctions were prepared. KM mice were treated with samples by gavage for 10 days, and lung damage and apoptosis were assessed by HE staining and TUNEL staining of lung tissues respectively. Metabolomics analysis was performed by HPLC-MS. Metallomics analysis was performed by ICP-MS. In addition, C. elegans was used as a model for 48 h exposure to examine the neurotoxicity and reproductive toxicity-related indices of Haematitum, including locomotor behaviors, growth and development, reproductive behaviors, AChE activities, sensory behaviors, apoptosis, and ROS levels., Results: The use of large doses of Haematitum decoction caused lung damage in mice. Neither calcined Haematitum decoction nor Haematitum decoction at clinically used doses showed organ damage. Metabolomics results showed that disorders in lipid metabolic pathways such as sphingolipid metabolism and glycerophospholipid metabolism may be important factors in Haematitum-induced pulmonary toxicity. High doses of Haematitum decoction caused neurological damage to C. elegans, while low doses of Haematitum decoction and calcined Haematitum decoction showed no significant neurotoxicity. Decoction of Haematitum and calcined Haematitum did not show reproductive toxicity to C. elegans. Toxicity was also not observed in the control group of iron (Ⅱ) and iron (Ⅲ) ions in equal amounts with high doses of Haematitum., Conclusions: Haematitum is relatively safe for routine doses and short-term use. Calcination can significantly reduce Haematitum toxicity, and this study provides a reference for safe clinical use., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Strategies to enhance the anti-tumor immune response of stereotactic ablative radiotherapy (SABR) at primary tumors and abscopal sites are under intensive investigation. Here we report a metabolizable binary supracluster (BSC gal ) that combines gold nanoclusters as radiosensitizing adjuvants with small interfering RNA (siRNA) targeting the immunosuppressive mediator galectin-1 (Gal-1). BSC gal comprises reversibly crosslinked cationic gold nanoclusters and siRNA complexes in a polymer matrix that biodegrades over weeks, facilitating clearance (90.3% in vivo clearance at 4 weeks) to reduce toxicity. The particle size well above the renal filtration threshold facilitates passive delivery to tumors. Using mouse models of head and neck cancer, we show that BSC gal augments the radiodynamic and immunotherapeutic effects of SABR at the primary and metastatic tumors by promoting tumor-inhibitory leukocytes, upregulating cytotoxic granzyme B and reducing immunosuppressive cell populations. It outperforms SABR plus Gal-1 antagonists, chemoradiation drug cisplatin or PD-1 inhibitor. This work presents a translatable strategy to converge focal radiosensitization with targeted immune checkpoint silencing for personalized radioimmunotherapy., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu+ homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu+ homeostasis in cancer cells are rarely explored because small molecule Cu+ chelators have poor binding affinity in comparison to the intracellular Cu+ chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu+ chaperone-inspired supramolecular approach to disrupt Cu+ homeostasis in cancer cells that induces programmed cell death. The Nap-FFMTCGGCR peptide self-assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu+ due to the presence of the unique MT/CGGC motif, which is conserved in intracellular Cu+ chaperones. Nap-FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells (MDA-MB-231), impairs the activity of Cu+ dependent co-chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap-FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self-assembly and Cu+ binding must work in synergy to successfully disrupt Cu+ homeostasis. We show that assembly-enhanced affinity for metal ions opens new therapeutic strategies to address disease-relevant metal ion homeostasis., (© 2024 Wiley‐VCH GmbH.)

In recent years, a new technique called computed tomography-derived fractional flow reserve (CT-FFR) has been developed. CT-FFR overcomes many limitations in the current gold-standard fractional flow reserve (FFR) techniques while maintaining a better concordance with FFR. This technique integrates static coronary CT angiography data with hydrodynamic models, employing algorithms rather than guidewire interventions to compute the FFR. In addition to diagnosing coronary heart disease, CT-FFR has been applied in the preoperative risk assessment of major adverse cardiovascular events (MACEs) in organ transplantation and transcatheter aortic valve replacement (TAVR). Continuous advancements in CT-FFR techniques and algorithms are expanding their applicability to other methodologies. Subsequently, with robust clinical trial validation, CT-FFR can potentially supersede FFR as the primary "gatekeeper" for interventions., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Understanding the interplay between people's daily sleep and physical activity and how geographic environment influences them are important for developing healthy cities. However, such research has been limited. This study aims to explore the bidirectional and nonlinear relationship between daily sleep and physical activity, and further investigate the comprehensive influences of multi-dimensional geographic environment on these health behaviors. Based on the objective data on sleep and physical activity over seven consecutive days using wrist-based accelerometers in Beijing, China, we developed a series of models to analyze the mutual influences between people's daily sleep and physical activity, and employed the generalized additive model (GAM) to examine their potential nonlinear relationships and how geographic environment - including meteorological conditions, built environment, and social environment - influences them. The results show that sleep and physical activity exhibit notable bidirectional relationship. Moderate-to-vigorous physical activity (MVPA) is observed to improve sleep quality, but it decreases sleep duration. In contrast, total sleep time (TST) exhibits an inverted U-shaped pattern with both MVPA and total step counts, with the optimal sleep duration at 5 h. Furthermore, meteorological factors, built environment characteristics, and social environment have significant linear or nonlinear effects on people's daily sleep and physical activity. The outcomes of this study offer valuable insights for enhancing residents' health and developing healthy cities., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In photoperiod-sensitive plants, the CO-like gene (CONSTANS-like, COL) has a crucial function in regulating the timing of flowering. The blooming period in foxtail millet is greatly influenced by the duration of daylight; however, there is a scarcity of data regarding the molecular properties of the COL genes in the foxtail millet. In this study, we conducted a comprehensive analysis of the COL gene family in foxtail millet at the genome-wide level. We identified 11 SiCOL genes and performed gene structure analysis, which showed pronounced variation in gene length and intron number among the genes. The examination of COL proteins in foxtail millet and other plant species using phylogenetic analysis revealed that they could be clustered into three distinct groups. Cis-element analysis identified elements related to light-responsiveness, hormones, and abiotic stress in the promoter region of the SiCOL gene. Furthermore, tissue-specific expression analysis showed widespread expression of all 11 SiCOL genes in various foxtail millet tissues and organs, particularly in leaves and panicles. Collinearity analysis identified 14 syntenic gene pairs in both foxtail millet and rice. The results also revealed diurnal oscillations in the transcription levels of SiCOL genes under different light conditions. Moreover, among the 11 genes, SiCO, SiCOL1, and SiCOL6 expression levels were negatively correlated with flowering time variation in two foxtail cultivars. Additionally, upon constructing a network of predicted molecular interactions, FLOWER LOCUS-like (FTL) and Phytochromea A (PHY A) were suggested to potentially interact with SiCO, SiCOL1, and SiCOL6. SiCO, SiCOL1, and SiCOL6 have the potential for flowering and heading in foxtail millet. This research enhances our comprehension of the role and control of the SiCOL gene family constituents in foxtail millet, establishing a basis for future investigations., (© 2024. The Author(s).)

The endophytic fungus Aspergillus iranicus , capable of producing bioactive substances, was isolated from the roots of Houttuynia cordata Thunb. Through chromatographic methods, five compounds were isolated in this study for the first time from the fermentation broth and mycelia of the endophytic fungus Aspergillus iranicus obtained from Houttuynia cordata Thunb. using ethyl acetate extracts. These compounds were identified as palmitic acid ( 1 ), protocatechuic acid ( 2 ), 4-hydroxybenzophenone ( 3 ), stigmasterol ( 4 ), and β-sitosterol ( 5 ). The IC 50 values for compound 2 was 1.32 mg/mL, which indicate strong DPPH radical scavenging activity. Compounds 2 , 3 , and 5 significantly inhibited the growth of Escherichia coli , demonstrating MIC values of 6.25, 3.13, and 3.13 mg/mL, respectively. Additionally, displaying a MIC value of 0.78 mg/mL, compound 3 demonstrated remarkable inhibition against Candida albicans growth. These findings suggest the presence of endophytic fungi in H. cordata , producing several valuable medicinal secondary metabolites.

The skid resistance of asphalt pavement is an important factor affecting road safety. However, few studies have characterized the contribution of the macro- and micro-texture to the skid resistance of asphalt pavement. In this paper, the generalized extreme studentized deviate (GESD) and neighboring-region interpolation algorithm (NRIA) were used to identify and replace outliers, and median filters were used to suppress noise in texture data to reconstruct textures. On this basis, the separation of the macro- and micro-texture and the Monte Carlo algorithm were used to characterize the skid resistance of asphalt pavement. The results show that the GESD method can accurately identify outliers in the texture, and the median filtering can eliminate burrs in texture data while retaining more original detail information. The contribution of the macro-texture on the skid resistance is mainly attributed to the frictional resistance caused by the adhesion and elastic hysteresis, and the main contribution of the micro-texture is a micro-bulge cutting part in the friction mechanism. This investigation can provide inspiration for the interior mechanism and the specific relationship between the pavement textures and the skid resistance of asphalt pavement.

Background: T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL., Methods: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse., Results: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo., Conclusions: Our study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Primary liver cancer (PLC) is a primary cause of cancer-related death worldwide, and novel treatments are needed due to the limited options available for treatment and tumor heterogeneity. 66 surgically removed PLC samples were cultured using the self-developed 2:2 method, and the final success rate for organoid culture was 40.9%. Organoid performance has been evaluated using comprehensive molecular measurements, such as whole-exome and RNA sequencing, as well as anticancer drug testing. Multiple organoids and their corresponding tumor tissues contained several of the same mutations, with all pairs sharing conventional TP53 mutations. Regarding copy number variations and gene expression, significant correlations were observed between the organoids and their corresponding parental tumor tissues. Comparisons at the molecular level provided us with an assessment of organoid-to-tumor concordance, which, in combination with drug sensitivity testing provided direct guidance for treatment selection. Finally, we were able to determine an appropriate pharmacological regimen for a patient with ICC, demonstrating the clinical practicality in tailoring patient-specific drug regimens. Our study provides an organoid culture technology that can cultivate models that retain most of the molecular characteristics of tumors and can be used for drug sensitivity testing, demonstrating the broad potential application of organoid technology in precision medicine for liver cancer treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: The growing body of research on kidney disease in children has identified a broad spectrum of genetic etiologies., Methods: We conducted a prospective study to evaluate the efficacy of an optimized genetic test and subclinical changes in a real-world context before kidney transplantation. All cases involved recipients under the age of 18 who underwent whole exome sequencing (ES) between 2013 and 2022., Results: The study population included 244 children, with a median age of 13.1 years at transplantation. ES provided a molecular genetic diagnosis in 114 (46.7%) probands with monogenic variants in 15 known disease-causing genes. ES confirmed the suspected clinical diagnosis in 74/244 (30.3%) cases and revised the pre-exome clinical diagnoses in 40/244 (16.4%) cases. ES also established a specific underlying cause for kidney failure for 19 patients who had previously had an unknown etiology. Genetic diagnosis influenced clinical management in 88 recipients (36.1%), facilitated genetic counseling for 18 families (7.4%), and enabled comprehensive assessment of living donor candidates in 35 cases (14.3%)., Conclusions: Genetic diagnosis provides critical insights into the pathogenesis of kidney disease, optimizes clinical strategies concerning risk assessment of living donors, and enhances disease surveillance of recipients., (© 2024. The Author(s).)

Hydrogels, due to their excellent microstructure and mechanical strength, have become a novel biomaterial in wound dressing. However, plant proteins have never been considered because of their poor original gelling performances and insufficient rheological properties. Here, we reported the fabrication of a plant protein-based thermal-reversible gel using a reverse micelle-extracted hemp protein isolate (HPI). A systematic study was conducted to fully reveal their microstructure, rheological properties, and anti-inflammatory effect to lay a foundation for this newly developed plant protein hydrogel as a potential natural wound dressing. By modulating protein concentration (4% HPI) and temperature (85 °C), a thermal-reversible HPI gel appeared as a filament structure with the major molecular driving force of hydrophobic interactions and hydrogen bonds. By characterizing the rheological properties, lower gel strength and wider linear viscoelastic regime were determined in the thermal-reversible HPI gel compared with a thermal-irreversible HPI gel. Besides, large amplitude oscillatory shear data identified the thermal-reversible gel as a soft gel which demonstrated intracycle strain stiffening and shear thinning behavior. Moreover, the thermal-reversible HPI gel is nontoxic and has benefits in neutrophil growth with injectability and perfect wound coverage. This study opens a novel means to form a natural thermal-reversible hydrogel that can be a new material source for wound dressing.

Background: This study aims to analyze the adverse event reports (AERs) to vericiguat using data from the Food and Drug Administration Adverse Event Reporting System (FAERS) and provide evidence for the clinical use., Methods: AERs due to vericiguat from 2021Q1 to 2024Q1 identified as the primary suspect were screened, with duplicate reports subsequently eliminated. Various quantitative signal detection methods, including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network, and multi-item gamma poisson shrinker, were then employed for data mining and analysis. Signal strength is represented by the 95% confidence interval, information component (IC), and empirical Bayesian geometric mean (EBGM)., Results: A total of 617 vericiguat-related AERs were identified. Strong signals were observed in 21 system organ classes. Furthermore, the most frequently reported preferred terms (PT) was hypotension ( n  = 86, ROR 25.92, PRR 24.11, IC 4.59, EBGM 24.07), followed by dizziness ( n  = 52, ROR 6.44, PRR 6.20, IC 2.63, EBGM 6.20), malaise ( n  = 25, ROR 3.59, PRR 3.54, IC 1.82, EBGM 3.54), blood pressure decreased ( n  = 23, ROR 20.00, PRR 19.64, IC 4.29, EBGM 19.61), and anemia ( n  = 21, ROR 6.67, PRR 6.57, IC 2.72, EBGM 6.57)., Conclusions: This study extended the adverse reactions documented in the FDA instruction and provided supplementary evidence regarding the clinical safety of vericiguat.

Given the substantial risks associated with ultraviolet B (UVB) radiation-induced solar dermatitis, enhancing current strategies to combat UVB regarding skin diseases is imperative. The cross-talk between ferroptosis and inflammation has been proven to be an essential factor in UVB-induced solar dermatitis, whereas detailed process of how their interaction contributes to this remains unclear. Therefore, further investigation of ferroptosis-mediated processes and identification of corresponding inhibitory approaches hold promise for repairing skin damage. Senkyunolide I (Sen I), a bioactive component mainly extracted from the traditional Chinese medicinal plants, Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels, has demonstrated efficacy in combating oxidative stress and inflammation. In this study, we utilized UVB-irradiated HaCaT cells as an in vitro model and C57BL/6J mice as an in vivo model of solar dermatitis. Our findings revealed the pivotal roles of autophagy and ferroptosis in inducing skin inflammation, particularly emphasizing the activation of ferroptosis through macroautophagy. Surprisingly, this mechanism operated independently of ferritinophagy, a classical autophagy-driven ferroptosis pathway. Instead, our results highlighted Transferrin Receptor 1 (TfR1), tightly controlled by autophagy, as a crucial mediator of ferroptosis execution and amplifier of subsequent lethal signals. Furthermore, extracellular High Mobility Group Box 1 protein (HMGB1), released following UVB-induced ferroptotic cells from activated autophagic flux, initiated a feedback loop with TfR1, propagating ferroptosis to neighboring cells and exacerbating damage. Remarkably, Sen I administration showed a significant protective effect against UVB damage in both in vitro and in vivo models by interrupting this cascade. Consequently, we have illuminated a novel therapeutic pathway post-UVB exposure and identified Sen I as a potent natural molecule that safeguarded against UVB-induced solar dermatitis by suppressing the autophagy-ferroptosis-HMGB1-TfR1 axis, highlighting a new frontier in photoprotection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

JOURNAL/nrgr/04.03/01300535-202410000-00027/figure1/v/2024-02-06T055622Z/r/image-tiff Spinal cord injury is a disabling condition with limited treatment options. Multiple studies have provided evidence suggesting that small extracellular vesicles (SEVs) secreted by bone marrow mesenchymal stem cells (MSCs) help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury. Strikingly, hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs (HSEVs) exhibit increased therapeutic potency. We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair. SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation. HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation. HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro. MicroRNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that miR-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1. Reducing miR-146a-5p expression in HSEVs partially attenuated macrophage polarization. Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting miR-146a-5p, which alters macrophage polarization. This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Background: There have been some studies on the occurrence of ESR1 and 2 polymorphisms and AIS, but some data extraction is wrong, and there are no studies on the progress of AIS., Methods: Computer searches were conducted on PubMed, EMBASE, ScienceDirect and Scopus from the establishment of the database to April 2024. Cross-sectional and case-control studies on estrogen receptor ESR1, two single nucleotide polymorphisms, and the occurrence and development of AIS were collected, and statistical analysis was performed using the Revman 5.3 software., Results: In the comparison of the association between single nucleotide polymorphisms of estrogen receptors ESR1 and 2 and the occurrence and development of AIS, eight studies were included, including 2706 cases and 1736 controls.The results showed that the AA genotype [OR = 0.50,95%Cl(0.34,0.72),P = 0.0003] at the XbaI locus of ESR1,CC genotype [OR = 1.67,95%Cl(1.16,2.42), P = 0.006], C allele [OR = 1.28,95%Cl(1.03,1.59),P = 0.03], and T allele [OR = 0.78,95%] Cl(0.63,0.97),P = 0.03] at the PvuII locus of ESR1 and TT genotype [OR = 0.50,95%Cl(0.26,0.93),P = 0.03] at the AlwNI locus of ESR2 showed statistically significant differences between the progressive and stable AIS patients., Conclusion: Single nucleotide polymorphisms of ESR1 and ESR2 were not related to the occurrence of AIS; however, some of them were related to the progression of AIS., (© 2024. The Author(s).)

Developing sustainable matrix and efficient bonding mode for preparing room temperature phosphorescence (RTP) materials with full-color afterglows is attractive but still challenging. Here, xylan, a hemicellulose by-product from the paper mill, is used to construct full-color RTP materials based on imine bonds. Xylan is oxidation by periodate to introduce aldehyde groups to increase reaction sites; aromatic amines with different π conjugations can be readily anchored to dialdehyde xylan (DAX) by imine chemistry. The dual rigid environments were constructed by hydrogen bonding and imine covalent bonding, which can facilitate the triplet population and suppress non-radiative transitions, thus the xylan derivatives display satisfactory RTP performances. As the degree of conjugation of the chromophore increases, the afterglow colors can be changed from blue to green, yellow, and then to red. Thus, such a universal, facile, and eco-friendly strategy can be used to fabricate full-color RTP materials, which show a bright future in information encryption and advanced anti-counterfeiting. These results unambiguously state that the biodegradable paper mill waste-based RTP materials are convincingly expected to replace and surpass petroleum polymer-based counterparts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Peripheral T-cell lymphoma (PTCL) is an extensive class of heterogeneous diseases with dismal outcomes. Brentuximab vedotin (BV) is an antibody‒drug conjugate (ADC) comprising CD30-directed antibody. This review aimed to evaluate the efficacy and safety of BV for treating PTCL. We searched the PubMed, Embase, Cochrane Library and Web of Science databases for studies evaluating the efficacy of BV alone or in combination with other drugs for treating PTCL. The primary outcome measures included objective response rate (ORR), complete remission (CR), progression-free survival (PFS) and overall survival (OS). The secondary outcomes included 5-year OS, 5-year PFS and adverse events. 22 studies involving 1137 patients were included. These studies reported the use patterns of BV, ORR, CR, PFS, OS, and adverse events. The pooled ORR and CR rate were 68% (95% CI: 59%-75%) and 43% (95% CI: 34%-53%). For survival outcomes, the longest median PFS was 8.3 months, and the longest median OS was 26.3 months. The most common adverse event was peripheral neuropathy and neutropenia. The analysis suggested that BV alone or in combination with other drugs improved the response and survival rates in PTCL patients and was associated with tolerable adverse effects.

Vascular calcification (VC) poses significant challenges in cardiovascular health. This study employs single-cell transcriptome sequencing to dissect cellular dynamics in this process. We identify distinct cell subgroups, notably in vascular smooth muscle cells (VSMCs), and observe differences between calcified atherosclerotic cores and adjacent regions. Further exploration reveals ID3 as a key gene regulating VSMC function. In vitro experiments demonstrate ID3's interaction with USP1 and E12, modulating cell proliferation and osteogenic differentiation. Animal models confirm the critical role of the USP1/ID3/E12/P21 axis in VC. This study sheds light on a novel regulatory mechanism, offering potential therapeutic targets., Competing Interests: Declaration of competing interest The author declares no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

The Parrot Borna virus 4 (PaBV-4) is the primary causative agent of parrot developmental disorder (PDD), leading to symptoms such as bloating, undigested feed in stool, decreased appetite, diarrhea, and weight loss. Its impact on the parrot industry has been significant, therefore, it is imperative to develop a rapid detection method for PaBV-4. The detection of PaBV-4 was achieved through the development of an RT-RAA assay, which involved the design of specific probes and primers targeting the N gene. This method allows for detection at 41°C within 30 min and has a minimum detection threshold of 8.56 × 10 1 copies/μL. The RT-RAA method demonstrated specific detection of PaBV-4 without any cross-reactivity observed with H5N6, H7N9, H9N2 avian influenza virus, newcastle disease virus (NDV), avian infectious bronchitis virus (IBV) and Parrot Borna virus 2 (PaBV-2). The coefficient of variation for the 3 repeatability experiments was below 10%. Tissue samples from 28 suspected cases of PaBV related deaths in parrots were analyzed using both RT-RAA and RT-qPCR methods. The sensitivity and specificity of both methods were 100%, demonstrating perfect agreement between them as indicated by a kappa value of 1. In conclusion, this study created a RT-RAA method for PaBV-4 detection successfully., Competing Interests: DISCLOSURES We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The American Cancer Society has recommended high-risk human papillomavirus (HPV) testing as the primary screening method for cervical cancer since 2020. Up to this point, the transition from Pap test cytology-based screening or co-testing with cytology and HPV testing has been slow and limited. However, more health systems in the United States are in the process of implementing this change. The transition to HPV-based screening requires a triage strategy for positive results. Genotyping to specifically detect HPV types 16 and 18 in conjunction with reflex cytology for the remaining high-risk HPV genotypes has been the recommended method. Testing options including Dual Stain for p16/Ki-67 and extended HPV genotyping are currently being incorporated into treatment algorithms as alternatives. Methylation testing is another promising method extensively investigated around the world. This review, performed by members of the Clinical Practice Committee of the American Society of Cytopathology, examines the rationale behind the switch away from reliance on Pap test cytology in the cervical cancer screening algorithm and the opportunities and problems associated with the most promising alternative approaches. Published studies that give insight into the performance characteristics of these newer tests are reviewed. At the present time, Pap test cytology remains a viable triage option for positive HPV screening results, but alternative tests have significant appeal and should be considered in tandem with the decision to offer primary HPV screening., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: This study aims to evaluate the integration of optical coherence tomography (OCT) and peripheral blood immune indicators for predicting oral cancer prognosis by artificial intelligence., Methods: In this study, we examined patients undergoing radical oral cancer resection and explored inherent relationships among clinical data, OCT images, and peripheral immune indicators for oral cancer prognosis. We firstly built a peripheral blood immune indicator-guided deep learning feature representation method for OCT images, and further integrated a multi-view prognostic radiomics model incorporating feature selection and logistic modeling. Thus, we can assess the prognostic impact of each indicator on oral cancer by quantifying OCT features., Results: We collected 289 oral mucosal samples from 68 patients, yielding 1,445 OCT images. Using our deep radiomics-based prognosis model, it achieved excellent discrimination for oral cancer prognosis with the area under the receiver operating characteristic curve (AUC) of 0.886, identifying systemic immune-inflammation index (SII) as the most informative feature for prognosis prediction. Additionally, the deep learning model also performed excellent results with 85.26% accuracy and 0.86 AUC in classifying the SII risk., Conclusions: Our study effectively merged OCT imaging with peripheral blood immune indicators to create a deep learning-based model for inflammatory risk prediction in oral cancer. Additionally, we constructed a comprehensive multi-view radiomics model that utilizes deep learning features for accurate prognosis prediction. The study highlighted the significance of the SII as a crucial indicator for evaluating patient outcomes, corroborating our clinical statistical analyses. This integration underscores the potential of combining imaging and blood indicators in clinical decision-making., Trial Registration: The clinical trial associated with this study was prospectively registered in the Chinese Clinical Trial Registry with the trial registration number (TRN) ChiCTR2200064861. The registration was completed on 2021., (© 2024. The Author(s).)

The live attenuated yellow fever vaccine (YF17D) has caused controversial safety issues in history with low-yield problems, which has led to a large population being unable to be vaccinated and vaccine shortage in facing recent outbreaks. Here, we report a safer live attenuated vaccine candidate, YF17D-Δ77, which contains 77 nucleotides deletion in the 3' untranslated region (3' UTR) of the YF17D genome. YF17D-Δ77 exhibited no neurotropism and decreased viscerotropism and caused significantly lower lethality in mice compared to YF17D. Mechanistically, the deletion enhanced the sensitivity of the virus to type I and type II interferon responses, which hindered viral replication. Encouragingly, YF17D-Δ77 provided comparable immune protection in mice as did YF17D. Even 10 PFU of YF17D-Δ77 completely protected mice against YFV-Asibi challenge. In addition, the Δ77 mutation showed excellent stability after successive passages in Vero cells. Collectively, the data suggest that further development of YF17D-Δ77 as vaccine candidate is warranted., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Introduction: Dental sleep medicine is an emerging field within dentistry. While limited education in sleep medicine has been reported among US predoctoral dental schools, no study has been conducted among postgraduate dental programs. This study compared the extent and exposure to sleep medicine education among US postgraduate programs in orthodontics, pediatric dentistry, orofacial pain (OFP), general practice residency (GPR), and advanced education in general dentistry (AEGD)., Methods: A REDCap survey was distributed among N = 391 US postgraduate programs investigating the nature, content, and modality of sleep education during the 2023-24 academic year., Results: Among 68 responding programs (43.1% GPR, 18.5% AEGD, 18.5% orthodontics, 12.3% pediatric dentistry, and 7.7% OFP), faculty with sleep training constituted 7.5%, with 2.6% being board certified in sleep medicine. Approximately 41.8% of programs offered sleep medicine courses, with differences among specialties (100% OFP, 42.9% GPR, 37.5% pediatric dentistry, 33.3% orthodontics, 16.7% AEGD; p = 0.032). Didactic teaching comprised 7.8 ± 14.6 h/year (range 0 h/year in 21.5% to 80 h/year in 1.5%), with differences across programs (OFP = 44.0 ± 17.7, orthodontics = 8.7 ± 11.0, GPR = 5.0 ± 8.0, pediatric dentistry = 2.1 ± 1.9, and AEGD = 2.9 ± 5.4; p < 0.001), and constituted the primary modality of instruction (mainly obstructive sleep apnea, bruxism, sleep physiology). Screening and treatment for sleep-related disorders were provided by 35.9% and 37.9% of programs, respectively, with variations among specialties (p = 0.004)., Conclusion: Our findings revealed an average of 7.8 h/year of didactic sleep medicine instruction, which differed across specialties. OFP offered the highest level of didactic and clinical training. These findings emphasize the need for increased dental sleep medicine education to address the increasing involvement of dental professionals in managing sleep-related disorders., (© 2024 American Dental Education Association.)

Lymphomas are a highly heterogeneous group of tumors that are classified into several subtypes. The gold standard method for the molecular profiling of lymphoma is based on invasive lymph node or tissue biopsy. However, this method cannot accurately capture spatial tumor heterogeneity in each patient as well as systemic tumor invasion and tumor burden. Circulating tumor DNA (ctDNA) is an emerging and highly versatile biomarker that overcomes the basic limitations of imaging scanning and tissue biopsy; has the characteristics of being simple, rapid, and non-invasive; and has good specificity and high sensitivity. ctDNA testing has been applied to a variety of subtypes of lymphoma and has been used for somatic mutation genotyping, efficacy monitoring during treatment, detection of minimal residual disease, and the prediction of survival, which may help clinicians make better clinical decisions in the diagnosis and treatment of lymphoma patients. Furthermore, this study also aims to review the different methods of ctDNA analysis and describe the specific applications of ctDNA in different lymphoma subtypes.

Transition metal oxides have been widely used in microwave-absorbing materials, but how to improve impedance matching is still an urgent problem. Therefore, we introduced urea as a polymer carbon source into a three-dimensional porous structure modified by Co 3 O 4 nanoparticles and explored the influence of different heat treatment temperatures on the wave absorption properties of the composite. The nanomaterials, when calcined at a temperature of 450 °C, exhibited excellent microwave absorption capabilities. Specifically, at an optimized thickness of 9 mm, they achieved a minimum reflection loss (RL min ) of -97.3 dB, accompanied by an effective absorption bandwidth (EAB) of 9.83 GHz that comprehensively covered both the S and Ku frequency bands. On the other hand, with a thickness of 3 mm, the RL min was recorded as -17.9 dB, with an EAB of 5.53 GHz. This excellent performance is attributed to the multi-facial polarization and multiple reflections induced by the magnetic loss capability of Co 3 O 4 nanoparticles, the electrical conductivity of C, and the unique three-dimensional structure of diatomite. For the future development of bio-based microwave absorption, this work provides a methodology and strategy.

Background & Aims: XBP1, most conserved transcription factor of endoplasmic reticulum stress, plays important roles in physiological and pathologic settings and has profound effects on disease progression and prognosis, so it is necessary to investigate XBP1 in macrophage-originated sterile inflammation during liver ischemia/reperfusion injury (IRI). Macrophage XBP1 expression and liver injury are analyzed in patients undergoing ischemia-related hepatectomy., Methods: A myeloid-specific male XBP1-knockout (XBP1 M-KO ) strain is created for function and mechanism of XBP1 on macrophage-derived sterile inflammation in murine liver IRI with in vitro parallel research. Macrophages cocultured with hypoxia-treated hepatocytes are applied to investigate impact of XBP1 in vitro, with analysis of RNA sequencing and databases., Results: Clinically, macrophage XBP1 expression significantly increases in ischemic liver tissues and positively correlates with liver injury after hepatectomy. Less hepatocellular damage is presented in XBP1 M-KO mice than in XBP1-proficient (XBP1 FL/FL ) control animals. In vitro, XBP1 deficiency inhibits sterile inflammation and migration in macrophages cocultured with hypoxia-treated hepatocytes. Analysis of RNA sequencing and databases determines Metallothionein 2 (MT2) as XBP1 target gene, negatively regulated by binding with its promoter. XBP1 deficiency increases MT2 and IKBα expression, but inhibits nuclear factor-κB-p65 phosphorylation, markedly neutralizing XBP1 M-KO -related benefits by promoting sterile inflammation during liver IRI., Conclusions: XBP1 promotes macrophage-originated sterile inflammation, increases liver IRI by binding to MT2 promoter, and regulates MT2/nuclear factor-κB pathway, potentially therapeutic for clinical liver IRI., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Lysine lactylation (Kla), an epigenetic mark triggered by lactate during glycolysis, including the Warburg effect, bridges metabolism and gene regulation. Enzymes such as p300 and HDAC1/3 have been pivotal in deciphering the regulatory dynamics of Kla, though questions about additional regulatory enzymes, their specific Kla substrates, and the underlying functional mechanisms persist. Here, we identify SIRT1 and SIRT3 as key "erasers" of Kla, shedding light on their selective regulation of both histone and non-histone proteins. Proteomic analysis in SIRT1/SIRT3 knockout HepG2 cells reveals distinct substrate specificities toward Kla, highlighting their unique roles in cellular signaling. Notably, we highlight the role of specific Kla modifications, such as those on the M2 splice isoform of pyruvate kinase (PKM2), in modulating metabolic pathways and cell proliferation, thereby expanding Kla's recognized functions beyond epigenetics. Therefore, this study deepens our understanding of Kla's functional mechanisms and broadens its biological significance., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Biodegradable zinc (Zn) alloys stand out as promising contenders for biomedical applications due to their favorable mechanical properties and appropriate degradation rates, offering the potential to mitigate the risks and expenses associated with secondary surgeries. While current research predominantly centers on the in vitro examination of Zn alloys, notable disparities often emerge between in vivo and in vitro findings. Consequently, conducting in vivo investigations on Zn alloys holds paramount significance in advancing their clinical application. Different element compositions and processing methods decide the mechanical properties and biological performance of Zn alloys, thus affecting their suitability for specific medical applications. This paper presents a comprehensive overview of recent strides in the development of biodegradable Zn alloys, with a focus on key aspects such as mechanical properties, toxicity, animal experiments, biological properties, and molecular mechanisms. By summarizing these advancements, the paper aims to broaden the scope of research directions and enhance the understanding of the clinical applications of biodegradable Zn alloys.

Paired immunoglobin-like type 2 receptor beta (PILRB) mainly plays a crucial role in regulating innate immunity, but whether PILRB is involved in cancer is poorly understood. Here, we report that PILRB potentiates the PI3K/AKT pathway to drive gastric tumorigenesis by binding and stabilizing IRS4, which could hyperactivate the PI3K/AKT pathway. Firstly, the levels of PILRB are upregulated in human gastric cancer (GC) specimens and associated with poor prognosis in patients with GC. In addition, our data show that PILRB promotes cell proliferation, colony formation, cell migration and invasion in GC cells in vitro and in vivo. Mechanistically, PILRB recruits the deubiquitination enzymes OTUB1 to IRS4 and relieves K48-linked ubiquitination of IRS4, protecting IRS4 protein from proteasomal-mediated degradation and subsequent activation of the PI3K/AKT pathway. Importantly, the levels of PILRB are positively correlated with IRS4 in GC specimens. Meanwhile, we also found that PILRB reprogrammed cholesterol metabolism by altering ABCA1 and SCARB1 expression levels, and PILRB-expression confers GC cell resistance to statin treatment. Taken together, our findings illustrate that the oncogenic role of PILRB in gastric tumorigenesis, providing new insights into the regulation of PI3K/AKT signaling in GC and establishing PILRB as a biomarker for simvastatin therapy resistance in GC., (© 2024. The Author(s).)

Pain management is an important aspect of dermatologic procedures, which are typically performed on awake patients in outpatient settings. The first-line modalities for procedural analgesia during most dermatologic procedures are topical and injectable local anesthetics, such as lidocaine. However, in some medical and cosmetic dermatologic procedures, pain cannot be effectively managed with local anesthetics due to procedure-specific lack of efficacy, large treatment surface areas, high dosage requirements, allergies, or other contraindications. In these circumstances, methoxyflurane inhalers may be highly beneficial. Methoxyflurane (Penthrox®) has demonstrated efficacy for providing pain relief in randomized controlled trials in patients who presented to emergency departments with acute trauma-related pain, as well as in patients undergoing painful procedures for other medical indications. The limited side effect profile, ease of patient self-administration, rapid onset and quick resolution of central nervous system effects following cessation makes methoxyflurane an ideal choice for analgesia during outpatient dermatologic procedures. This review provides an overview of the supporting evidence for methoxyflurane inhalers and clinical commentary on potential indications for methoxyflurane use in dermatology., Competing Interests: Leah Johnston does not have any conflicts of interest to disclose. Benjamin Barankin has been an advisor and speaker for Paladin Labs. Jaggi Rao has been an advisor and speaker for Paladin Labs. Andrei Metelitsa has been an advisor and speaker for Abbvie, Clarion, Galderma, Merz Pharma, Paladin Labs. Susan Poelman has been an advisor and speaker for Abbvie, Galderma, Merz Pharma and Paladin Labs. Geeta Yadav has been an advisor and speaker for Paladin Labs. Funding sources: None., (Copyright 2024 by SkinCareGuide.com Ltd. Skin Therapy Letter© is published 6 times annually by SkinCareGuide.com Ltd, 1003 - 1166 Alberni Street, Vancouver, British Columbia, Canada, V6E 3Z3. All rights reserved. Reproduction in whole or in part by any process is strictly forbidden without prior consent of the publisher in writing.)

Kabuki syndrome (KS) is a rare congenital disorder with distinctive characteristics. Herein, we describe a KS patient carrying a novel mutation in the KMT2D gene, c.11785C > T (p.Gln3929*). The patient presented with typical eyelid deformities, including eversion of the lateral lower eyelids, long palpebral fissures, hypertelorism, and medial epicanthus. Orbital computed tomography revealed orbital bone malformation with temporally and inferiorly displaced zygomatic bone. The bilateral orbits were shallow with an enlarged angle between the lateral walls. Zygomatic and maxillary bone dysplasia were also observed. Orbital bone anomalies are thought to be one of the characteristics of KS., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: A rectal impalement injury is a rare type of penetrating injury that involves a solid object being forcefully inserted through anal opening. The removal of such injuries should be planned carefully with preparedness to assess and manage associated injuries in the pelvis and peri-anal region., Case Description: An elderly female, around 65 years old, had a history of accidental penetration of an iron rod into her anal orifice. The patient was hemodynamically stable, and the distal end of the penetrated rod was visible in the anal verge on arrival. On evaluation, we found that the object had perforated the posterior wall of the middle 1/3rd of the rectum and had traversed retroperitoneally, bypassing all major vessels and viscera., Discussion: We performed exploratory laparotomy, and the iron rod was extracted from the anal canal under vision, and a diversion colostomy of the sigmoid colon was performed. The patient had an uneventful recovery, and the reversal of the sigmoid colostomy was done after 3 months., Conclusion: Rectal impalement injuries are rare and serious. It requires a multidisciplinary approach involving a general surgeon, a vascular surgeon, and a urologist since it is associated with a higher incidence of involving major pelvic organs and vessels. In our case, the penetrating object had bypassed all major vessels, which is a rare occurrence., Competing Interests: Conflict of interest statement None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The existing evidence on the association between interpregnancy interval (IPI) and pregnancy outcomes primarily focuses on singleton pregnancies, with limited research on twin pregnancies., Objective: This study aimed to investigate the association between IPI and adverse perinatal outcomes in twin pregnancies., Study Design: This population-based, retrospective cohort study analyzed data from the National Center for Health Statistics in the United States between 2016 and 2020. We included multiparous women aged 18 to 45 years with live-born twins without congenital anomalies, born between 26 and 42 weeks of gestation. Poisson regression models, adjusted for potential confounders, were used to evaluate the associations between IPI and adverse outcomes, including preterm birth (PTB) <36 weeks, small for gestational age (SGA), neonatal intensive care unit (NICU) admission, neonatal composite morbidity, and infant death. Missing data on covariates were managed using multiple imputations. Dose-response analyses were performed using the restricted cubic splines (RCS) approach. Subgroup analyses were stratified by maternal age, parity, and combination of neonatal sex. Sensitivity analyses were conducted using complete data and excluding pregnancies with intervening events during the IPI., Results: A total of 143,014 twin pregnancies were included in the analysis. Compared to the referent group (IPI of 18-23 months), an IPI of less than 6 months was associated with an increased risk of PTB<36 weeks (RR, 1.21; 95% confidence interval [95% CI]: 1.17-1.25), SGA (RR, 1.11; 95% CI: 1.03-1.18), neonatal composite morbidity (RR, 1.19; 95% CI: 1.12-1.27), NICU admission (RR, 1.18; 95% CI: 1.14-1.22), and infant death (RR, 1.29; 95% CI: 1.05-1.60). An IPI of 5 years or more was associated with an increased risk of PTB<36 weeks (RR, 1.18; 95% CI: 1.15-1.21), SGA (RR, 1.24; 95% CI: 1.18-1.30), neonatal composite morbidity (RR, 1.10; 95% CI: 1.05-1.15), and NICU admission (RR, 1.14; 95% CI: 1.11-1.17). The dose-response analyses showed that these outcomes had U-shaped or J-shaped associations with IPI. The associations between IPI and the outcomes slightly differed by advanced maternal age, parity, and combination of neonatal sex. The sensitivity analyses yielded similar results to the main findings., Conclusion: Extreme IPI, less than 6 months or more than 5 years, was associated with adverse outcomes in twin pregnancies. IPI could be used as a predictor for risk stratification in high-risk twin pregnancies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Optimal gestational weight change (GWC) is little known among pregnant women with gestational diabetes mellitus (GDM)., Objectives: This study aimed to explore the optimal GWC ranges for women with GDM and validate these ranges compared with the Institute of Medicine (IOM) guidelines., Methods: A population-based cohort study using natality data from the National Center for Health Statistics in the United States included 1,338,460 mother-infant pairs with GDM from 2014 to 2020. Poisson regression models were performed to identify GWC ranges (GDM targets) associated with acceptable risks (<10% increase) for a severity-weighted composite outcome including preterm birth (PTB) <37 wk, large for gestational age (LGA, birthweight >90th percentile) and small for gestational age (SGA, birthweight <10th percentile). These targets were validated in individual outcomes including PTB, LGA, SGA, hypertensive disorders of pregnancy, neonatal intensive care unit admission, and neonatal respiratory morbidity, and compared with the IOM guidelines using logistic regression models with population-attributable fractions (PAFs) calculated., Results: The severity-weighted composite outcome had a U-shaped or a J-shaped relationship with GWC across body mass index categories. The GDM targets were 14.1 to 20.3 kg, 9.0 to 17.0 kg, 4.8 to 13.8 kg, -0.8 to 10.8 kg, -2.4 to 8.2 kg, and -8.3 to 6.0 kg for underweight, normal weight, overweight, class 1 obesity, class 2 obesity, and class 3 obesity, respectively. GWC outside the GDM or the IOM targets was associated with increased adverse perinatal outcomes in validation analyses. PAFs indicated that the IOM guidelines reduced a similar or higher proportion of adverse perinatal outcomes compared with the GDM targets for women with GDM, except for those with class 2 and 3 obesity., Conclusions: The IOM guidelines are generally applicable for women with GDM, except for women with moderate and severe obesity. The optimal GWC ranges for women with GDM and moderate to severe obesity may be lower than the IOM guidelines., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Breast cancer is the most prevalent malignant tumor among women with high heterogeneity. Traditional techniques frequently struggle to comprehensively capture the intricacy and variety of cellular states and interactions within breast cancer. As global precision medicine rapidly advances, single-cell RNA sequencing (scRNA-seq) has become a highly effective technique, revolutionizing breast cancer research by offering unprecedented insights into the cellular heterogeneity and complexity of breast cancer. This cutting-edge technology facilitates the analysis of gene expression profiles at the single-cell level, uncovering diverse cell types and states within the tumor microenvironment. By dissecting the cellular composition and transcriptional signatures of breast cancer cells, scRNA-seq provides new perspectives for understanding the mechanisms behind tumor therapy, drug resistance and metastasis in breast cancer. In this review, we summarized the working principle and workflow of scRNA-seq and emphasized the major applications and discoveries of scRNA-seq in breast cancer research, highlighting its impact on our comprehension of breast cancer biology and its potential for guiding personalized treatment strategies.