Oxidative Tandem Cyclization of Aromatic Acids with (Benzo)thiophenes: One-Pot Access to Planar Sulfur-Containing Polycyclic Heteroarenes for Lipid-Droplet-Targeted Probes.

The efficient construction of π-conjugated polycyclic heteroarenes represents a significant task in the field of functional materials. A one-step oxidative tandem cyclization of aromatic acids with (benzo)thiophenes was developed to access planar sulfur-containing polycyclic heteroarenes. This protocol undergoes intermolecular cross-dehydrogenative coupling followed by intramolecular Friedel-Crafts acylation and provides a facile pathway to planar polycyclic compounds from inexpensive reactants. The synthesized heteroarenes serving as lipid-droplet-targeted probes exhibit outstanding performance with favorable biocompatibility and photostability.

Engineering Sclareol Production on the Leaf Surface of Nicotiana tabacum.

Sclareol, a diterpene alcohol, is the most common starting material for the synthesis of ambrox, which serves as a sustainable substitute for ambergris, a valuable fragrance secreted by sperm whales. Sclareol has also been proposed to possess antibacterial, antifungal, and anticancer activities. However, in nature, sclareol is only produced by a few plant species, including Cistus creticus, Cleome spinosa, Nicotiana glutinosa, and Salvia sclarea, which limits its commercial application. In this study, we cloned the two genes responsible for sclareol biosynthesis in S. sclarea, labda-13-en-8-ol diphosphate synthase (LPPS) and sclareol synthase (SS), and overexpressed them in tobacco (Nicotiana tabacum L.). The best transgenic tobacco lines accumulated 4.1 µg/cm2 of sclareol, which is comparable to the sclareol production of N. glutinosa, a natural sclareol producer. Thus, sclareol synthesis in tobacco represents a potential alternative means for the production of this high-value compound.

Self-Assembled Viscoelastic Surfactant Micelles with pH-Responsive Behavior: A New Fracturing-Displacement Integrated Working Fluid for Unconventional Reservoirs.

The integrated fracturing and oil recovery strategy is a new paradigm for achieving sustainable and cost-effective development of unconventional reservoirs. However, a single type of working fluid cannot simultaneously meet the different needs of fracturing and oil displacement processes. Here, we develop a pH-responsive fracturing-displacement integrated working fluid based on the self-assembled micelles of N,N-dimethyl oleoamine propylamine (DOAPA) and succinic acid (SA). By adjusting the pH of the working fluid, the DOAPA and SA molecules can be switched repeatedly between highly viscoelastic wormlike micelles and aqueous low-viscosity spherical micelles. The zero-shear viscosity of the working fluid enriched the wormlike micelles can reach more than 93,100 mPa·s, showing excellent viscoelasticity and sand-carrying properties. The working fluid is easy to gel-break when it encounters oil, generating a low-viscosity liquid without residue. In addition, the system has strong interfacial activity, which can greatly reduce the oil-water interfacial tension to form emulsions and can achieve reversible demulsification and re-emulsification by adjusting pH. Through the designed and fabricated microfluidic chip, it can be visualized that under the synergistic effect of viscoelasticity and interfacial activity DOAPA/SA can effectively expand the swept volume of tight fractured formations, promote pore wetting reversal and crude oil emulsification, and improve the displacement efficiency. The DOAPA/SA meets the design requirements of the fracturing-displacement integrated working fluids and provides a novel method and idea for constructing the integrated working fluids suitable for fracturing and displacement in unconventional reservoirs.

Comparative efficacy and safety of CDK4/6 inhibitors combined with endocrine therapies for HR+/HER2-breast cancer: Systematic review and network meta-analysis.

Background: In recent years, the combination of targeted drugs, such as Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, with endocrine therapy (ET), has emerged as a new research focus in the treatment of hormone receptor-positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer. This network meta-analysis aimed to systematically evaluate the efficacy and safety of CDK4/6 inhibitors combined with ET for HR+/HER2-breast cancer. Methods: A systematic search was conducted across PubMed, Web of Science, Cochrane Library, and GeenMedical databases to identify randomized controlled trials investigating the use of CDK4/6 inhibitors in combination with endocrine therapy for the treatment of HR+/HER2-breast cancer. The search period spanned from the inception of each database up to February 29, 2024. Data analysis was conducted using Stata 14.0 and R 4.1.0 software. Results: A total of 20 randomized controlled trials (RCTs) were included in this study, investigating the effectiveness of four CDK4/6 inhibitors-Abemaciclib, Dalpiciclib, Ribociclib, and Palbociclib-when combined with ET for the treatment of HR+/HER2-breast cancer. The results indicated that Abemaciclib + ET, Dalpiciclib + ET, Palbociclib + ET, and Ribociclib + ET exhibited similar therapeutic effects in terms of improving objective response rate (ORR), disease control rate (DCR) and reducing the occurrence of fatigue, all of which were superior to ET alone. However, in terms of prolonging progression-free survival (PFS) and overall survival (OS), Dalpiciclib + ET significantly improved PFS compared to Ribociclib + ET, Palbociclib + ET, Abemaciclib and Palbociclib. Ribociclib + ET significantly improved OS compared to Palbociclib + ET. Regarding overall adverse reaction events (AREs), Dalpiciclib + ET had a higher incidence compared to Ribociclib + ET. The incidence of neutropenia caused by Dalpiciclib + ET was significantly higher compared to Palbociclib + ET, Ribociclib + ET, Abemaciclib, and Palbociclib. Abemaciclib + ET demonstrated the worst safety profile concerning diarrhea. Conclusion: Abemaciclib + ET likely represents the most effective option in terms of therapeutic effects, but it is prone to causing diarrhea and fatigue. On the other hand, Dalpiciclib + ET likely demonstrates the best efficacy in terms of PFS but exhibits the poorest safety profile, particularly in relation to neutropenia. Therefore, clinicians should exercise increased vigilance in monitoring and managing adverse effects when prescribing Abemaciclib + ET and Dalpiciclib + ET.

LncRNA SNHG1 acts as a ceRNA for miR-216a-3p to regulate TMBIM6 expression in esophageal squamous cell carcinoma.

Background: The long noncoding RNA small nucleolar RNA host gene 1 (SNHG1) has been demonstrated to play a crucial role in the progression of esophageal squamous cell carcinoma (ESCC). The current study aims to explore the deeper molecular mechanisms of SNHG1 in ESCC. Methods: Fifty patients with ESCC were enrolled to assess overall survival. Quantitative real-time PCR was performed to measure the levels of SNHG1, miR-216a-3p, and TMBIM6 in ESCC cells. Functional assessments of SNHG1 on ESCC cells were conducted using CCK-8 assay, flow cytometry, and Transwell assays. Western blot was conducted to detect the protein levels of TMBIM6 and proapoptotic proteins (Calpain and Caspase-12). The interaction among SNHG1, miR-216a-3p, and TMBIM6 was assessed with luciferase reporter assays. Results: Our study revealed that SNHG1 was notably increased in both clinical ESCC samples and cellular lines. Upregulation of SNHG1 in ESCC tissues was indicative of poor overall survival. Functionally, SNHG1 knockdown significantly inhibited the proliferation, migration, and invasion while promoting apoptosis in ESCC cells. Mechanistically, SNHG1 functioned as a competing endogenous RNA by sequestering miR-216a-3p to modulate TMBIM6 levels in ESCC cells. Notably, inhibiting miR-216a-3p or restoring TMBIM6 reversed the inhibitory effect induced by SNHG1 knockdown in ESCC cells. Conclusions: We demonstrate for the first time that SNHG1 may act as a competing endogenous RNA and promote ESCC progression through the miR-216a-3p/TMBIM6 axis. This highlights the potential of SNHG1 as a target for ESCC treatment.

A ratiometric fluorescent probe with dual-targeting capability for heat shock imaging.

HSO3- is an important reactive sulfur species that maintains the normal physiological activities of living organisms and participates in a variety of redox homeostatic processes. It has been found that changes in HSO3- levels is closely related to the heat stroke phenomenon of the organism. Heat stroke causes damage to normal cells, which in turn causes damage to the body and even death. It is crucial to accurately monitor and track the physiological behavior of HSO3- during heat stroke. Herein, a ratiometric multifunctional fluorescent probe DRM-SO2 with dual-targeting ability to rapidly and precisely recognize HSO3- being constructed based on the FRET mechanism. DRM-SO2 has extra Large Stokes shift (216 nm), very high sensitivity (DL = 12.2 nM), fast response time and good specificity. When DRM-SO2 undergoes Michael addition with HSO3-, the fluorescence emission peak was blue-shifted from 616 nm to 472 nm, and a clear ratiometric signal appeared. The interaction between lysosomes and mitochondria in maintaining cellular homeostasis was investigated by the dual-targeting ability of the probe using HSO3- as a mediator. DRM-SO2 achieved successful targeting and real-time monitoring of exogenous and endogenous HSO3- in the cells. More importantly, imaging experiments in heat stroke mice revealed high HSO3- expression in intestinal tissues. This provides new ideas and research tools for early prevention of heat stroke-induced diseases such as intestinal injuries. In addition, the semi-quantitative monitoring experiments for paper-based visualization of HSO3- make the probe promising for the design of portable detectors.

Analysis of use of different rFSHs during IVF/ICSI-assisted conception in elderly population and effect of double trigger on clinical outcomes.

OBJECTIVE: To compare the number of oocytes retrieved and clinical outcomes of ovulation induction in an older population treated with in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) (IVF/ICSI) using different rFSH options and the effectiveness of antagonist treatment to induce ovulation using gonadotropin-releasing hormone agonists (GnRH-a) in combination with an human chorionic gonadotropin (HCG) trigger. METHODS: A total of 132 fresh cycles were selected for this study, which were treated with IVF/ICSI in our hospital from March 2022 to December 2022. Observations were made according to different subgroups and the effects of different triggering methods on the number of oocytes obtained, embryo quality, and clinical outcomes. RESULTS: The initial gonadotropin (Gn) dose, the number of oocytes, and the number of MII oocytes were higher in group A than in group B (p < .05), and the clinical pregnancy rate was 29.41% in group A. Group B had a clinical pregnancy rate of 27.5%. The double-trigger group was superior to the HCG-trigger group in terms of the number of 2PN, the number of viable embryos, and the number of high-quality embryos (p < .05). The use of a double-trigger regimen (OR = 0.667, 95%CI (0.375, 1.706), p = .024) was a protective factor for the clinical pregnancy rate, whereas AFC (OR = 0.925, 95%CI (0.867, 0.986), p = .017) was an independent factor for the clinical pregnancy rate. CONCLUSIONS: The use of a dual-trigger regimen of GnRH-a in combination with HCG using an appropriate antagonist improves pregnancy outcomes in fresh embryo transfer cycles in older patients.

Network Meta-Analysis: Effect of Cold Stress on the Gene Expression of Swine Adipocytes ATGL, CIDEA, UCP2, and UCP3.

Cold stress significantly affects gene expression in adipocytes; studying this phenomenon can help reveal the pathogeneses of conditions such as obesity and insulin resistance. Adipocyte triglyceride lipase (ATGL); cell death-inducing deoxyribonucleic acid (DNA) fragmentation factor subunit alpha (DFFA)-like effector (CIDEA); and uncoupling protein genes UCP1, UCP2, and UCP3 are the most studied genes in pig adipose tissues under cold stress. However, contradictory results have been observed in gene expression changes to UCP3 and UCP2 when adipose tissues under cold stress were examined. Therefore, we conducted a meta-analysis of 32 publications in total on the effect of cold stress on the expression of ATGL, CIDEA, UCP2, and UCP3. Our results showed that cold stress affected the expression of swine adipocyte genes; specifically, it was positively correlated with the expression of UCP3 in swine adipocytes. Conversely, expression of ATGL was negatively affected under cold stress conditions. In addition, the loss of functional UCP1 in pigs likely triggered a compensatory increase in UCP3 activity. We also simulated the docking results of UCP2 and UCP3. Our results showed that UCP2 could strongly bind to adenosine triphosphate (ATP), meaning that UCP3 played a more significant role in pig adipocytes.

Long-term antiviral therapy is associated with changes in the profile of transcriptionally active HBV integration in the livers of patients with CHB.

Hepatitis B virus (HBV) integration exists throughout the clinical course of chronic hepatitis B (CHB). This study investigated the effects of long-term antiviral therapy on the level and profiles of transcriptionally active HBV integration. Serial liver biopsies and paired blood samples were obtained from 16, 16, and 22 patients with CHB at baseline, 78, and 260 weeks of entecavir monotherapy or combined with pegylated interferon alfa, respectively. Serum HBV biomarkers were longitudinally assessed. RNA-seq and HIVID2 program was used to identify HBV-host chimeric RNAs transcribed from integrated DNA. The counts of HBV integration reads were positively related to both serum HBV DNA levels (r = 0.695, p = 0.004) and HBeAg titers (r = 0.724, p = 0.021) at baseline, but the positive correlation exited only to the serum HBsAg levels after 260 weeks of antiviral therapy (r = 0.662, p = 0.001). After 78 weeks of antiviral therapy, the levels of HBV integration expression decreased by 12.25 folds from baseline. The viral junction points were enriched at the S and HBx genes after the long-term antiviral therapy. HBs-FN1 became one of the main transcripts, with the mean proportion of HBs-FN1 in all integrated expression increased from 2.79% at baseline to 10.54% at Week 260 of antiviral treatment. Antiviral therapy may reduce but not eliminate the HBV integration events and integration expression. Certain integration events, such as HBs-FN1 can persist in long-term antiviral treatment.

Charge Transfer in Graphene-MoS2 Vertical Heterostructures Tuned by Stacking Order and Substrate-Introduced Electric Field.

Vertical van der Waals heterostructures composed of graphene (Gr) and transition metal dichalcogenides (TMDs) have created a fascinating platform for exploring optical and electronic properties in the two-dimensional limit. Numerous studies have focused on Gr/TMDs heterostructures to elucidate the underlying mechanisms of charge-energy transfer, quasiparticle formation, and relaxation following optical excitation. Nevertheless, a comprehensive understanding of interfacial charge separation and subsequent dynamics in graphene-based heterostructures remains elusive. Here, we have investigated the carrier dynamics of Gr-MoS2 heterostructures (including Gr/MoS2 and MoS2/Gr stacking sequences) grown on a fused silica substrate under varying photoexcitation energies by comprehensive ultrafast means, including time-resolved terahertz (THz) spectroscopy, THz emission spectroscopy, and transient absorption spectroscopy. Our findings highlight the impact of the substrate electric field on the efficiency of modulating the interfacial charge transfer (CT). Specifically, the optical excitation in Gr/MoS2 generates thermal electron injection from the graphene layer into the MoS2 layer with photon energy well below A-exciton of MoS2, whereas the interfacial CT in the MoS2/Gr is blocked by the electric field of the substrate. In turn, photoexcitation of the A exciton above leads to hole transfer from MoS2 to graphene, which occurs for both Gr-MoS2 heterostructures with opposite stacking orders, resulting in the opposite orientations of the interfacial photocurrent, as directly demonstrated by the out-of-phase THz emission. Moreover, we demonstrate that the recombination time of interfacial exciton is approximately ∼18 ps, whereas the defect-assisted interfacial recombination occurs on a time scale of ∼ns. This study provides valuable insights into the interplay between interfacial CT, substrate effects, and defect engineering in Gr-TMDs heterostructures, thereby facilitating the development of next-generation optoelectronic devices.

Preoperative Anxiolytic and Sedative Effects of Intranasal Remimazolam and Dexmedetomidine: A Randomized Controlled Clinical Study in Children Undergoing General Surgeries.

Purpose: Remimazolam, an ultra-short-acting and fast-metabolized sedative, has only been sporadically investigated in children. This study was performed to determine the beneficial effects of intranasal remimazolam or dexmedetomidine on preoperative anxiety in children undergoing general surgeries. Patients and Methods: Ninety children were randomly and equally assigned to Group R (intranasal remimazolam 1.5mg kg-1), Group D (intranasal dexmedetomidine 2 mcg kg-1), and Group C (intranasal distilled water). The primary outcomes were the preoperative anxiety scores using the modified Yale preoperative anxiety scale (m-Ypas). The secondary outcomes included the cooperation behaviour of intranasal drug application, preoperative sedation levels, parental separation anxiety scores (PSAS), and mask acceptance scores (MAS). Results: Group R showed a significant low anxiety at 10 min after intranasal premedication (vs group C, P=0.010; vs group D, P = 0.002) and at anaesthesia induction (vs group C, P = 0.004). Group D showed a significantly low anxiety score only prior to anaesthesia induction (vs group C, P = 0.005). Most children in group R achieved mild sedation at 10 min (vs group C, P < 0.001; vs group D, P < 0.001), with a few progressing to deep sedation afterwards, while group D tended toward deep sedation. Compared to Group C, patients in Group R performed significantly better on the MAS (P = 0.014) and PSAS (P = 0.008). However, remimazolam did cause poor cooperation behavior to the intranasal application due to its mucosal irritation (vs group C, P = 0.001; vs group D, P = 0.010). Conclusion: Both intranasal remimazolam and dexmedetomidine can effectively alleviate preoperative anxiety in children. While intranasal remimazolam has a rapid onset, it produces only mild sedation and causes substantial nasal irritation. Trial Registration: NCT04720963, January 22, 2021, ClinicalTrials.Gov.

Identification and functional characterization of laminin receptor in the mud crab, Scylla paramamosain, in response to MCDV-1 challenge.

Laminin receptor (LR), which mediating cell adhesion to the extracellular matrix, plays a crucial role in cell signaling and regulatory functions. In the present study, a laminin receptor gene (SpLR) was cloned and characterized from the mud crab (Scylla paramamosain). The full length of SpLR contained an open reading frame (ORF) of 960 bp encoding 319 amino acids, a 5' untranslated region (UTR) of 66 bp and a 3' UTR of 49 bp. The predicted protein comprised two Ribosomal-S2 domains and a 40S-SA-C domain. The mRNA of SpLR was highly expressed in the gill, followed by the hepatopancreas. The expression of SpLR was up-regulated after mud crab dicistrovirus-1(MCDV-1) infection. Knocking down SpLR in vivo by RNA interference significantly down-regulated the expression of the immune genes SpJAK, SpSTAT, SpToll1, SpALF1 and SpALF5. This study shown that the expression level of SpToll1 and SpCAM in SpLR-interfered group significantly increased after MCDV-1 infection. Moreover, silencing of SpLR in vivo decreased the MCDV-1 replication and increased the survival rate of mud crabs after MCDV-1 infection. These findings collectively suggest a pivotal role for SpLR in the mud crab's response to MCDV-1 infection. By influencing the expression of critical innate immune factors and impacting viral replication dynamics, SpLR emerges as a key player in the intricate host-pathogen interaction, providing valuable insights into the molecular mechanisms underlying MCDV-1 pathogenesis in mud crabs.

Essential roles of the nucleolus during early embryonic development: a regulatory hub for chromatin organization.

The nucleolus is the most prominent liquid droplet-like membrane-less organelle in mammalian cells. Unlike the nucleolus in terminally differentiated somatic cells, those in totipotent cells, such as murine zygotes or two-cell embryos, have a unique nucleolar structure known as nucleolus precursor bodies (NPBs). Previously, it was widely accepted that NPBs in zygotes are simply passive repositories of materials that will be gradually used to construct a fully functional nucleolus after zygotic genome activation (ZGA). However, recent research studies have challenged this simplistic view and demonstrated that functions of the NPBs go beyond ribosome biogenesis. In this review, we provide a snapshot of the functions of NPBs in zygotes and early two-cell embryos in mice. We propose that these membrane-less organelles function as a regulatory hub for chromatin organization. On the one hand, NPBs provide the structural platform for centric and pericentric chromatin remodelling. On the other hand, the dynamic changes in nucleolar structure control the release of the pioneer factors (i.e. double homeobox (Dux)). It appears that during transition from totipotency to pluripotency, decline of totipotency and initiation of fully functional nucleolus formation are not independent events but are interconnected. Consequently, it is reasonable to hypothesize that dissecting more unknown functions of NPBs may shed more light on the enigmas of early embryonic development and may ultimately provide novel approaches to improve reprogramming efficiency.

Exploring T-cell exhaustion features in Acute myocardial infarction for a Novel Diagnostic model and new therapeutic targets by bio-informatics and machine learning.

BACKGROUND: T-cell exhaustion (TEX), a condition characterized by impaired T-cell function, has been implicated in numerous pathological conditions, but its role in acute myocardial Infarction (AMI) remains largely unexplored. This research aims to identify and characterize all TEX-related genes for AMI diagnosis. METHODS: By integrating gene expression profiles, differential expression analysis, gene set enrichment analysis, protein-protein interaction networks, and machine learning algorithms, we were able to decipher the molecular mechanisms underlying TEX and its significant association with AMI. In addition, we investigated the diagnostic validity of the leading TEX-related genes and their interactions with immune cell profiles. Different types of candidate small molecule compounds were ultimately matched with TEX-featured genes in the "DrugBank" database to serve as potential therapeutic medications for future TEX-AMI basic research. RESULTS: We screened 1725 differentially expressed genes (DEGs) from 80 AMI samples and 71 control samples, identifying 39 differential TEX-related transcripts in total. Functional enrichment analysis identified potential biological functions and signaling pathways associated with the aforementioned genes. We constructed a TEX signature containing five hub genes with favorable prognostic performance using machine learning algorithms. In addition, the prognostic performance of the nomogram of these five hub genes was adequate (AUC between 0.815 and 0.995). Several dysregulated immune cells were also observed. Finally, six small molecule compounds which could be the future therapeutic for TEX in AMI were discovered. CONCLUSION: Five TEX diagnostic feature genes, CD48, CD247, FCER1G, TNFAIP3, and FCGRA, were screened in AMI. Combining these genes may aid in the early diagnosis and risk prediction of AMI, as well as the evaluation of immune cell infiltration and the discovery of new therapeutics.

Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis.

CONTEXT.­: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children. OBJECTIVE.­: To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH. DESIGN.­: We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients. RESULTS.­: A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor. CONCLUSIONS.­: Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.

Effect of Remimazolam on Emergence Delirium in Children Undergoing Laparoscopic Surgery: A Double-Blinded Randomized Trial.

BACKGROUND: Preventing emergence delirium is a clinical goal for pediatric anesthesia, yet there is no consensus on its prevention. This study investigated the hypothesis that a continuous infusion or a single bolus of remimazolam can reduce the incidence of emergence delirium in children. METHODS: A hundred and twenty children aged 1-6 years old were randomly and equally allocated into three groups: group RC, which received a continuous infusion of remimazolam at 1 mg kg -1 h -1; group RB, which received a single bolus of remimazolam at 0.2 mg kg -1 at the beginning of wound closure; and group C, which received a continuous infusion of saline at 1 mL kg -1 h -1 and single bolus of saline at 0.2 mL kg -1 at the beginning of sutures. The primary outcome was the incidence of emergence delirium assessed by pediatric anesthesia emergence delirium (PAED) scale. Secondary outcomes included the number of rescues propofol administrations in the post-anesthesia care unit (PACU), recovery time, end-tidal sevoflurane concentration when maintaining BIS within the range of 40-60, and adverse events. RESULTS: The incidence of emergence delirium in group RC (5%, vs. group C, risk ratio, 0.14; 95% CI, 0.04 to 0.59; P=0.001) and group RB (7.7%, vs. group C, risk ratio, 0.22; 95% CI, 0.07 to 0.71; P=0.003) was significantly lower compared with group C (32.5%). Propofol was given to 2 patients in each of groups RC and RB to treat delirium and to 10 patients in group C (group RC vs. group C, risk ratio, 0.20; 95% CI, 0.05 to 0.86; P=0.012; group RB vs. group C, risk ratio, 0.21; 95% CI, 0.05 to 0.88; P=0.014). No differences in the recovery time and adverse effects were detected. CONCLUSIONS: Both continuous infusion and single bolus administration of remimazolam can effectively reduce the occurrence of emergence delirium in children.

Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: primary and secondary gene responses with links to disease progression.

Constitutive Androstane Receptor (CAR, Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to later disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP, a halogenated xenochemical and selective CAR agonist ligand, induces pericentral steatosis marked by hepatic accumulation of cholesterol and neutral lipid, and elevated circulating alanine aminotransferase, indicating hepatocyte damage. TCPOBOP-induced steatosis was weaker in the pericentral region but stronger in the periportal region in females compared to males. Early (1-day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipogenesis and xenobiotic metabolism and oxidative stress protection pathways; late (2-wk) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for macrophage activation, immune response and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to pro-inflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle activated carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Overall, TCPOBOP exposure recapitulates histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary gene responses in liver non-parenchymal cells indicative of transition to a more advanced disease state. Upstream regulators of both the early and late TCPOBOP response genes include novel biomarkers for foreign chemical-induced metabolic dysfunction-associated steatotic liver disease.

Polycytosine RNA-binding protein 1 regulates osteoblast function via a ferroptosis pathway in type 2 diabetic osteoporosis.

BACKGROUND: Recently, type 2 diabetic osteoporosis (T2DOP) has become a research hotspot for the complications of diabetes, but the specific mechanism of its occurrence and development remains unknown. Ferroptosis caused by iron overload is con-sidered an important cause of T2DOP. Polycytosine RNA-binding protein 1 (PCBP1), an iron ion chaperone, is considered a protector of ferroptosis. AIM: To investigate the existence of ferroptosis and specific role of PCBP1 in the development of type 2 diabetes. METHODS: A cell counting kit-8 assay was used to detect changes in osteoblast viability under high glucose (HG) and/or ferroptosis inhibitors at different concentrations and times. Transmission electron microscopy was used to examine the morphological changes in the mitochondria of osteoblasts under HG, and western blotting was used to detect the expression levels of PCBP1, ferritin, and the ferroptosis-related protein glutathione peroxidase 4 (GPX4). A lentivirus silenced and overexpressed PCBP1. Western blotting was used to detect the expression levels of the osteoblast functional proteins osteoprotegerin (OPG) and osteocalcin (OCN), whereas flow cytometry was used to detect changes in reactive oxygen species (ROS) levels in each group. RESULTS: Under HG, the viability of osteoblasts was considerably decreased, the number of mitochondria undergoing atrophy was considerably increased, PCBP1 and ferritin expression levels were increased, and GPX4 expression was decreased. Western blotting results demonstrated that infection with lentivirus overexpressing PCBP1, increased the expression levels of ferritin, GPX4, OPG, and OCN, compared with the HG group. Flow cytometry results showed a reduction in ROS, and an opposite result was obtained after silencing PCBP1. CONCLUSION: PCBP1 may protect osteoblasts and reduce the harm caused by ferroptosis by promoting ferritin expression under a HG environment. Moreover, PCBP1 may be a potential therapeutic target for T2DOP.

A highly resolved nuclear phylogeny uncovers strong phylogenetic conservatism and correlated evolution of fruit color and size in Solanum L.

Mutualisms between plants and fruit-eating animals were key to the radiation of angiosperms. Still, phylogenetic uncertainties limit our understanding of fleshy-fruit evolution, as in the case of Solanum, a genus with remarkable fleshy-fruit diversity, but with unresolved phylogenetic relationships. We used 1786 nuclear genes from 247 species, including 122 newly generated transcriptomes/genomes, to reconstruct the Solanum phylogeny and examine the tempo and mode of the evolution of fruit color and size. Our analysis resolved the backbone phylogeny of Solanum, providing high support for its clades. Our results pushed back the origin of Solanum to 53.1 million years ago (Ma), with most major clades diverging between 35 and 27 Ma. Evolution of Solanum fruit color and size revealed high levels of trait conservatism, where medium-sized berries that remain green when ripe are the likely ancestral form. Our analyses revealed that fruit size and color are evolutionary correlated, where dull-colored fruits are two times larger than black/purple and red fruits. We conclude that the strong phylogenetic conservatism shown in the color and size of Solanum fruits could limit the influences of fruit-eating animals on fleshy-fruit evolution. Our findings highlight the importance of phylogenetic constraints on the diversification of fleshy-fruit functional traits.

Updating mRNA variants of the human RSK4 gene and their expression in different stressed situations.

We determined RNA spectrum of the human RSK4 (hRSK4) gene (also called RPS6KA6) and identified 29 novel mRNA variants derived from alternative splicing, which, plus the NCBI-documented ones and the five we reported previously, totaled 50 hRSK4 RNAs that, by our bioinformatics analyses, encode 35 hRSK4 protein isoforms of 35-762 amino acids. Many of the mRNAs are bicistronic or tricistronic for hRSK4. The NCBI-normalized NM_014496.5 and the protein it encodes are designated herein as the Wt-1 mRNA and protein, respectively, whereas the NM_001330512.1 and the long protein it encodes are designated as the Wt-2 mRNA and protein, respectively. Many of the mRNA variants responded differently to different situations of stress, including serum starvation, a febrile temperature, treatment with ethanol or ethanol-extracted clove buds (an herbal medicine), whereas the same stressed situation often caused quite different alterations among different mRNA variants in different cell lines. Mosifloxacin, an antibiotics and also a functional inhibitor of hRSK4, could inhibit the expression of certain hRSK4 mRNA variants. The hRSK4 gene likely uses alternative splicing as a handy tool to adapt to different stressed situations, and the mRNA and protein multiplicities may partly explain the incongruous literature on its expression and comports.