Construction of a human cell landscape at single-cell level.

Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems1. However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a 'single-cell HCL analysis' pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology.

Ancient Mitogenomes Reveal the Maternal Genetic History of East Asian Dogs.

Recent studies have suggested that dogs were domesticated during the Last Glacial Maximum (LGM) in Siberia, which contrasts with previous proposed domestication centers (e.g. Europe, the Middle East, and East Asia). Ancient DNA provides a powerful resource for the study of mammalian evolution and has been widely used to understand the genetic history of domestic animals. To understand the maternal genetic history of East Asian dogs, we have made a complete mitogenome dataset of 120 East Asian canids from 38 archaeological sites, including 102 newly sequenced from 12.9 to 1 ka BP (1,000 years before present). The majority (112/119, 94.12%) belonged to haplogroup A, and half of these (55/112, 49.11%) belonged to sub-haplogroup A1b. Most existing mitochondrial haplogroups were present in ancient East Asian dogs. However, mitochondrial lineages in ancient northern dogs (northeastern Eurasia and northern East Asia) were deeper and older than those in southern East Asian dogs. Results suggests that East Asian dogs originated from northeastern Eurasian populations after the LGM, dispersing in two possible directions after domestication. Western Eurasian (Europe and the Middle East) dog maternal ancestries genetically influenced East Asian dogs from approximately 4 ka BP, dramatically increasing after 3 ka BP, and afterwards largely replaced most primary maternal lineages in northern East Asia. Additionally, at least three major mitogenome sub-haplogroups of haplogroup A (A1a, A1b, and A3) reveal at least two major dispersal waves onto the Qinghai-Tibet Plateau in ancient times, indicating eastern (A1b and A3) and western (A1a) Eurasian origins.

Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells.

Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.

Endothelial YAP/TEAD1-CXCL17 signaling recruits myeloid-derived suppressor cells against liver ischemia-reperfusion injury.

BACKGROUND AND AIMS: Liver ischemia-reperfusion injury (IRI) is a common complication of liver transplantation and hepatectomy and causes acute liver dysfunction and even organ failure. Myeloid-derived suppressor cells (MDSCs) accumulate and play immunosuppressive function in cancers and inflammation. However, the role of MDSCs in liver IRI has not been defined. APPROACH AND RESULTS: We enrolled recipients receiving OLT and obtained the pre-OLT/post-OLT blood and liver samples. The proportions of MDSCs were significantly elevated after OLT and negatively associated with liver damage. In single-cell RNA-sequencing analysis of liver samples during OLT, 2 cell clusters with MDSC-like phenotypes were identified and showed maturation and infiltration in post-OLT livers. In the mouse model, liver IRI mobilized MDSCs and promoted their infiltration in the damaged liver, and intrahepatic MDSCs were possessed with enhanced immunosuppressive function by upregulation of STAT3 signaling. Under treatment with αGr-1 antibody or adoptive transfer MDSCs to change the proportion of MDSCs in vivo, we found that intrahepatic MDSCs alleviated liver IRI-induced inflammation and damage by inhibiting M1 macrophage polarization. Mechanistically, bulk RNA-sequencing analysis and in vivo experiments verified that C-X-C motif chemokine ligand 17 (CXCL17) was upregulated by YAP/TEAD1 signaling and subsequently recruited MDSCs through binding with GPR35 during liver IRI. Moreover, hepatic endothelial cells were the major cells responsible for CXCL17 expression in injured livers, among which hypoxia-reoxygenation stimulation activated the YAP/TEAD1 complex to promote CXCL17 transcription. CONCLUSIONS: Endothelial YAP/TEAD1-CXCL17 signaling recruited MDSCs to attenuate liver IRI, providing evidence of therapeutic potential for managing IRI in liver surgery.

CgDM9CP-5-Integrin-MAPK Pathway Regulates the Production of CgIL-17s and Cgdefensins in the Pacific Oyster, Crassostrea gigas.

DM9 domain containing protein (DM9CP) is a family of newly identified recognition receptors exiting in most organisms except plants and mammals. In the current study, to our knowledge, a novel DM9CP-5 (CgDM9CP-5) with two tandem DM9 repeats and high expression level in gill was identified from the Pacific oyster, Crassostrea gigas. The deduced amino acid sequence of CgDM9CP-5 shared 62.1% identity with CgDM9CP-1 from C. gigas, and 47.8% identity with OeFAMeT from Ostrea edulis. The recombinant CgDM9CP-5 (rCgDM9CP-5) was able to bind d-mannose, LPS, peptidoglycan, and polyinosinic-polycytidylic acid, as well as fungi Pichia pastoris, Gram-negative bacteria Escherichia coli and Vibrio splendidus, and Gram-positive bacteria Staphylococcus aureus. The mRNA transcript of CgDM9CP-5 was highly expressed in gill, and its protein was mainly distributed in gill mucus. After the stimulations with V. splendidus and mannose, mRNA expression of CgDM9CP-5 in oyster gill was significantly upregulated and reached the peak level at 6 and 24 h, which was 13.58-fold (p < 0.05) and 14.01-fold (p < 0.05) of that in the control group, respectively. CgDM9CP-5 was able to bind CgIntegrin both in vivo and in vitro. After CgDM9CP-5 or CgIntegrin was knocked down by RNA interference, the phosphorylation levels of JNK and P38 in the MAPK pathway decreased, and the expression levels of CgIL-17s (CgIL-17-3, -4, -5, and -6), Cg-Defh1, Cg-Defh2, and CgMolluscidin were significantly downregulated. These results suggested that there was a pathway of DM9CP-5-Integrin-MAPK mediated by CgDM9CP-5 to regulate the release of proinflammatory factors and defensins in C. gigas.

Delivery of Synthetic Interleukin-22 mRNA to Hepatocytes via Lipid Nanoparticles Alleviates Liver Injury.

Hepatocellular injury, a pivotal contributor to liver diseases, particularly hepatitis, lacks effective pharmacological treatments. Interleukin-22 (IL-22), crucial for liver cell survival, shows potential in treating liver diseases by regulating repair and regeneration through signal transducer and activator of transcription 3 (STAT3) activation. However, the short half-life and off-target effects limit its clinical applications. To address these issues, lipid nanoparticles are employed to deliver synthetic IL-22 mRNA (IL-22/NP) for in situ IL-22 expression in hepatocytes. The study reveals that IL-22/NP exhibits liver-targeted IL-22 expression, with increased IL-22 levels detected in the liver as early as 3 h postintravenous injection, lasting up to 96 h. Furthermore, IL-22/NP activates STAT3 signaling in an autocrine or paracrine manner to upregulate downstream factors Bcl-xL and CyclinD1, inhibiting hepatocyte apoptosis and promoting cell proliferation. The therapeutic efficacy of IL-22/NP is demonstrated in both chronic and acute liver injury models, suggesting IL-22 mRNA delivery as a promising treatment strategy for hepatitis and liver diseases involving hepatocellular injury.

Secondary hemophagocytic lymphohistiocytosis in pediatric patients with visceral leishmaniasis and Epstein-Barr virus infection.

Visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (VL-HLH) is indistinguishable from those of HLH of other etiologies due to the overlap symptoms, posing a serious threat to life. In this study, we aimed to provide insights for early diagnosis and improve outcomes in pediatric patients with VL-HLH. We retrospectively analyzed the clinical and laboratory data of 10 pediatric patients with VL-HLH and 58 pediatric patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The median time from symptom onset to cytopenia in patients with VL-HLH and EBV-HLH was 11 days (interquartile range, 7-15 days) and five days (interquartile range, 3.75-9.25 days) (P = 0.005). Both groups showed liver injury and increased lactate dehydrogenase levels; however the levels of aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and lactate dehydrogenase in patients with VL-HLH were significantly lower than those in patients with EBV-HLH (P < 0.05). The fibrinogen and triglyceride levels were almost normal in VL-HLH patients but were significantly altered in EBV-HLH cases ( P < 0.05). The positive rate of first bone marrow microscopy examination, anti-rK39 IgG detection, and blood metagenomic next-generation sequencing was 50%, 100%, and 100%, respectively. After VL diagnosis, eight patients were treated with sodium stibogluconate and two were treated with liposomal amphotericin B. All the patients with VL-HLH recovered. Our study demonstrates that regular triglyceride and fibrinogen levels in pediatric patients with VL-HLH may help in differential diagnosis from EBV-HLH. VL-HLH is milder than EBV-HLH, with less severe liver injury and inflammatory responses, and timely treatment with antileishmanial agents is essential to improve the outcomes of pediatric patients with VL-HLH.

A novel genotype-phenotype between persistent-cloaca-related VACTERL and mutations of 8p23 and 12q23.1.

The mechanism underlying anorectal malformations (ARMs)-related VACTERL (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, and renal and limb abnormalities) remains unclear. Copy number variation (CNV) contributed to VACTERL pathogenicity. Here, we report a novel CNV in 8p23 and 12q23.1 identified in a case of ARMs-related VACTERL association. This 12-year-old girl presented a cloaca (urethra, vagina, and rectum opening together and sharing a single tube length), an isolated kidney, and a perpetuation of the left superior vena cava at birth. Her intelligence, growth, and development were slightly lower than those of normal children of the same age. Array comparative genomic hybridization revealed a 9.6-Mb deletion in 8p23.1-23.3 and a 0.52-Mb duplication in 12q23.1 in her genome. Furthermore, we reviewed the cases involving CNVs in patients with VACTERL, 8p23 deletion, and 12q23.1 duplication, and our case was the first displaying ARMs-related VACTERL association with CNV in 8p23 and 12q23.1. These findings enriched our understanding between VACTERL association and the mutations of 8p23 deletion and 12q23.1 duplication. IMPACT: This is a novel case of a Chinese girl with anorectal malformations (ARMs)-related VACTERL with an 8p23.1-23.3 deletion and 12q23.1 duplication. Cloaca malformation is presented with novel copy number variation in 8p23.1-23.3 deletion and 12q23.1 duplication.

Discovery of L15 as a novel Vif PROTAC degrader with antiviral activity against HIV-1.

Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin-proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15, Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).

A novel surface marker CD49d promotes TNF expression in oyster agranulocytes by mediating the MAPK pathway.

CD49d, encoded by the gene Integrin α4, is a significant member of cell adhesion receptors, which is widely expressed in various immune cells to trigger immune responses against invading pathogens. In the present study, the expression of CgCD49d and its regulatory role in TNF expression were investigated in the Pacific oyster Crassostrea gigas. There were five Int-alpha domains, an Integrin_alpha2 region and a unique FG-GAP repeat region inserted identified in CgCD49d. CgCD49d transcript was specifically expressed in haemocytes, and its mRNA expression level in haemocytes increased after LPS and Vibrio splendidus stimulation. After CgCD49d was blocked by using its antibody, the phosphorylation level of CgJNK in the MAPK signaling pathway and CgTNF transcripts decreased significantly post V. splendidus stimulation. After phosphorylation level of CgJNK was inhibited by using its inhibitor, the nuclear translocation of CgRel was restrained and CgTNF transcripts also decreased significantly post V. splendidus stimulation. Furthermore, CgCD49d was found to be mainly expressed in the agranulocyte subpopulation, and Alexa Fluor 488-conjugated CgCD49d antibody labeled agranulocytes with a circle of green fluorescence signals on CgCD49d+ agranulocyte surface under Confocal microscopy, which accounted for 24.9 ± 4.53% of total haemocytes. Collectively, these results suggested that CgCD49d promoted TNF expression in oyster haemocytes against bacterial invasion by mediating MAPK pathway, and it could be used as a surface marker to type and sort a subset of agranulocyte subpopulation among haemocytes.

The impact of first-trimester subchorionic hematomas on pregnancy outcomes after euploid embryo transfer: a retrospective cohort study.

BACKGROUND: The aim of the retrospective cohort study was to investigate the prognostic effect of subchorionic hematomas (SCH) in the first trimester on pregnancy outcomes after euploid embryo transfer. METHODS: We retrospectively analyzed women achieving singleton pregnancy by PGT-A or PGT-SR from January 2017 to January 2022. Patients were enrolled in the study if they had a viable intrauterine pregnancy at ultrasound between 6 0/7 and 8 0/7 weeks of gestation. Pregnancy outcomes as well as the incidence of maternal complications were compared between patients with and without SCH. Logistic regression was used for adjusting for potential confounding factors. RESULTS: A total of 1539 women were included, of which 298 with SCH and 1241 with non-SCH. The early miscarriage rate in SCH group was significantly higher than that in the non-SCH group (10.1% vs. 5.6%, adjusted odds ratio [aOR] 1.99, 95% confidence interval [CI] 1.25-3.16, P = 0.003). The live birth rate in SCH group was significantly lower than that in the non-SCH group. (85.6% vs. 91.2%, aOR 0.57, 95% CI 0.39-0.84, P = 0.005). In addition, SCH group had an increased risk of hypertensive disorder of pregnancy (HDP) (8.9% vs. 5.2%, P = 0.022), especially in hematoma with bleeding (19.3% vs. 6.0%, P = 0.002). The incidence of gestational diabetes mellitus (GDM), major congenital abnormalities rate, normal birth weight rate and low birth weight rate were similar between the two groups. CONCLUSIONS: The presence of SCH in the first trimester was associated with worse pregnancy outcomes after euploid embryo transfer, including an increased risk of early miscarriage and hypertensive disorder of pregnancy, along with a reduced live birth rate.

The Modification of H3K4me3 Enhanced the Expression of CgTLR3 in Hemocytes to Increase CgIL17-1 Production in the Immune Priming of Crassostrea gigas.

Increasing evidence confirms that histone modification plays a critical role in preserving long-term immunological memory. Immune priming is a novel form of immunological memory recently verified in invertebrates. Toll-like receptor (TLR) signaling and cytokines have been reported to be involved in the immune priming of the Pacific oyster Crassostrea gigas. In the present study, the expression of Toll-like receptor 3 (CgTLR3), myeloid differentiation factor 88-2 (CgMyd88-2) and interleukin 17-1 (CgIL17-1) was found to be elevated in the hemocytes of C. gigas at 6 h after the secondary stimulation with Vibrio splendidus, which was significantly higher than that at 6 h after the primary stimulation (p < 0.05). A significant increase in histone H3 lysine 4 trimethylation (H3K4me3) enrichment was detected in the promoter region of the CgTLR3 gene at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05). After the treatment with a histone methyltransferase inhibitor (5'-methylthioadenosine, MTA), the level of H3K4me3 at the promoter of the CgTLR3 gene decreased significantly at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was significantly repressed at 6 h after the secondary stimulation with V. splendidus (p < 0.05). Conversely, the treatment with monomethyl fumarate (MEF, an inhibitor of histone demethylases) resulted in a significant increase in H3K4me3 enrichment levels at the CgTLR3 promoter at 7 d after the primary stimulation (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was observed to increase significantly at 6 h after the secondary stimulation (p < 0.05). These results suggested that H3K4me3 regulated MyD88-dependent TLR signaling in the hemocytes of C. gigas, which defined the role of histone modifications in invertebrate immune priming.

Risk Factors Related to Postoperative Dizziness Among Patients Who Underwent General Anesthesia and Intraoperative Analgesics: A Prospective Cohort Study.

PURPOSE: To describe postoperative dizziness for patients who received analgesics during general anesthesia and to investigate the factors related to the trend of dizziness within 3 days after surgery. DESIGN: A prospective cohort study. METHODS: This is a longitudinal study. The severity of dizziness was assessed from the day of the surgery until the third day post surgery. Generalized estimation equation models were created to determine the predictive effect of each independent variable separately. FINDINGS: After surgery, the incidence of dizziness was 42.1%. Approximately 10% of participants experienced severe dizziness. Participants with postoperative nausea and vomiting were more likely to experience postoperative dizziness. In addition, age, education level, history of motion sickness, surgical specialties, laparoscopic surgery, and long-acting analgesic use had an impact on the trend of postoperative dizziness. More than 25% of participants who used long-acting analgesics experienced dizziness on the third postoperative day. CONCLUSIONS: Postoperative dizziness was common among participants who received analgesics during general anesthesia. Monitoring for postoperative dizziness may need to be prolonged, especially in patients taking long-acting analgesics. For patients at high risk for postoperative dizziness, preventive measures such as adjusting analgesic and anesthetic medications may be necessary.

Glycol Monomethyl Ether-Substituted Carbazolyl Hole-Transporting Material for Stable Inverted Perovskite Solar Cells with Efficiency of 25.52 .

Organic self-assembled molecules (OSAMs) based hole-transporting materials play a pivotal role in achieving highly efficient and stable inverted perovskite solar cells (IPSCs). However, the reported carbazol-based OSAMs have serious drawbacks, such as poor wettability for perovskite solution spreading due to the nonpolar surface, worse matched energy arrangement with perovskite, and limited molecular species, which greatly limit the device performance. To address above problems, a novel OSAM [4-(3,6-glycol monomethyl ether-9H-carbazol-9-yl) butyl]phosphonic acid (GM-4PACz) was synthesized as hole-transporting material by introducing glycol monomethyl ether (GM) side chains at carbazolyl unit. GM groups enhance the surface energy of Indium Tin Oxide (ITO)/SAM substrate to facilitate the nucleation and growth of up perovskite film, suppress cation defects, release the residual stress at SAM/perovskite interface, and evaluate energy level for matching with perovskite. Consequently, the GM-4PACz based IPSC achieves a champion PCE of 25.52 %, a respectable open-circuit voltage (VOC) of 1.21 V, a high stability, possessing 93.29 % and 91.75 % of their initial efficiency after aging in air for 2000 h or tracking at maximum power point for 1000 h, respectively.

A negative feedback loop between KLF9 and the EMT program dictates metastasis of hepatocellular carcinoma.

Metastasis is the primary cause of death of hepatocellular carcinoma (HCC), while the mechanism underlying this severe disease remains largely unclear. The Kruppel-like factor (KLF) family is one of the largest transcription factor families that control multiple physiologic and pathologic processes by governing the cellular transcriptome. To identify metastatic regulators of HCC, we conducted gene expression profiling on the MHCC97 cell series, a set of subclones of the original MHCC97 that was established by in vivo metastasis selection therefore harbouring differential metastatic capacities. We found that the expression of KLF9, a member of the KLF family, was dramatically repressed in the metastatic progeny clone of the MHCC97 cells. Functional studies revealed overexpression of KLF9 suppressed HCC migration in vitro and metastasis in vivo, while knockdown of KLF9 was sufficient to promote cell migration and metastasis accordingly. Mechanistically, we found the expression of KLF9 can reverse the pro-metastatic epithelial-mesenchymal transition (EMT) program via direct binding to the promoter regions of essential mesenchymal genes, thus repressing their expression. Interestingly, we further revealed that KLF9 was, in turn, directly suppressed by a mesenchymal transcription factor Slug, suggesting an intriguing negative feedback loop between KLF9 and the EMT program. Using clinical samples, we found that KLF9 was not only downregulated in HCC tissue compared to its normal counterparts but also further reduced in the HCC samples of whom had developed metastatic lesions. Together, we established a critical transcription factor that represses HCC metastasis, which is clinically and mechanically significant in HCC therapies.

Nyctinastic movement in legumes: Developmental mechanisms, factors and biological significance.

In legumes, a common phenomenon known as nyctinastic movement is observed. This movement involves the horizontal expansion of leaves during the day and relative vertical closure at night. Nyctinastic movement is driven by the pulvinus, which consists of flexor and extensor motor cells. The turgor pressure difference between these two cell types generates a driving force for the bending and deformation of the pulvinus. This review focuses on the developmental mechanisms of the pulvinus, the factors affecting nyctinastic movement, and the biological significance of this phenomenon in legumes, thus providing a reference for further research on nyctinastic movement.

Synthesis of Tetrahydro-ß-carbolines by a Manganese-Catalysed Oxidative Pictet-Spengler Reaction.

Herein, an efficient and green procedure for the synthesis of tetrahydro-ß-carbolines via dehydrogenative coupling of alcohols with tryptamines is reported. The reaction was carried out under mild conditions in the presence of a catalytic amount of the iPr PNP-Mn catalyst and a weak base (Na2 CO3 ). This method tolerated a variety of benzylic and aliphatic alcohol substrates with different functional groups and afforded diverse products in good to excellent isolated yields using tryptamines. Using this strategy, we successfully synthesised pharmaceutical molecules harman, harmaline, and harmine in a concise manner.

TET1-mediated microRNA-188-5p promoter hydroxymethylation regulates PTEN/PI3K/AKT signaling pathway in acute myeloid leukemia cells.

OBJECTIVE: Acute myeloid leukemia (AML) remains a common hematopoietic malignancy, and drug resistance greatly blunts the efficacy of chemotherapy in AML treatment. Adriamycin (ADM, also called doxorubicin), is one of the most widely used chemotherapeutics for treating cancers. Herein, we studied the molecular mechanisms underlying microRNA-188-5p (miR-188-5p)-mediated ADM resistance in AML. METHODS: Differentially expressed miRNAs were screened in normal and malignant hematopoietic cells by bioinformatics tools. MiR-188-5p expression in primary bone marrow CD34+ cells and AML cells was evaluated. AML/ADM cells were established using THP-1 and Kasumi-1 cells. The effect of miR-188-5p on the drug resistance in AML/ADM cells was examined by delivery of miR-188-5p-inhibitor. The binding relationship between TET1 and miR-188-5p was analyzed by ChIP, and the downstream target of miR-188-5p was predicted by bioinformatics analysis and validated by dual-luciferase assay. Finally, rescue experiments were carried out in vitro and in vivo. RESULTS: miR-188-5p was highly expressed in AML cells, and miR-188-5p-inhibitor sensitized the AML/ADM cells to ADM. Inhibition of TET1 reduced miR-188-5p promoter hydroxymethylation and downregulated miR-188-5p. miR-188-5p bound to the 3'UTR of PTEN to inhibit PTEN expression, and the PI3K/AKT signaling was activated upon inhibition of PTEN. Suppression of PTEN conferred resistance again to AML/ADM cells in the presence of miR-188-5p inhibitor. CONCLUSION: TET1 elevates miR-188-5p expression by promoting miR-188-5p promoter hydroxymethylation, and miR-188-5p inhibits PTEN expression to induce PI3K/AKT signaling pathway activation, leading to ADM resistance in AML.

Facets of impulsivity and reward in relation to binge-eating disorder course of illness among children: findings from the Adolescent Brain Cognitive Development study.

BACKGROUND: The present study examined facets of impulsivity and reward sensitivity [as measured by the UPPS-P Impulsive Behavior Scale and Behavioral Activation and Behavioral Inhibition Scales (BIS/BAS)] as multivariable predictors of subsequent binge-eating disorder (BED) course of illness in middle childhood. METHODS: The current sample included children aged 9-10 years (N = 9,438) who took part in the baseline and 1-year follow-up assessments of the Adolescent Brain Cognitive Development (ABCD) study. BED course was operationalized as those who never developed BED or subthreshold BED (SBED) ('control'), were diagnosed with BED/SBED at year 1 but not baseline ('developers'), were diagnosed with BED/SBED at baseline but not year 1 ('remitters'), or were diagnosed with BED/SBED at both times ('maintainers'). RESULTS: Higher baseline BIS/BAS reward responsivity scores were related to the greater likelihood of belonging to the maintainer group relative to the control and remitter groups (ORs1.12-1.19). Regarding covariates, higher baseline body mass index percentile and internalizing symptoms were related to the greater likelihood of BED development, remittance, and maintenance compared to the control group (ORs = 1.04-1.14); no variables were uniquely related to BED development. Exploratory analyses showed that the likelihood of belonging to the maintainer group compared to the control group was greatest at higher levels of negative urgency in combination with high reward responsivity. CONCLUSIONS: Heightened reward responsivity may convey risk for poorer BED course in children, while emotional disorder symptomatology may act as a more general risk and maintenance factor for BED.

Comparative Analysis of Laparoscopic Pancreatoduodenectomy in Elderly Patients: Safety, Efficacy, and Cost Evaluation.

BACKGROUND The use of laparoscopic pancreatoduodenectomy in elderly patients has sparked debate due to concerns about its safety. This study evaluates its safety and efficacy for elderly patients. MATERIAL AND METHODS We retrospectively analyzed data from 250 patients who underwent pancreatoduodenectomy between January 2015 and April 2022. Group A consisted of 100 non-elderly patients (under 70) who had laparoscopic procedures; Group B had 60 elderly patients (70 and above) with laparoscopic surgeries; and Group C included 90 elderly patients with open surgeries. Clinical outcomes were then compared across the groups. RESULTS Elderly patients undergoing laparoscopic pancreatoduodenectomy experienced a higher conversion rate (35% vs 19%), increased ICU admissions post-operation (45% vs 23%), a prolonged ICU stay, greater hospital expenses (¥118,782.48 vs ¥106,698.38), and a lower post-operative adjuvant therapy rate (31.91% vs 69.23%). However, they had fewer B-C pancreatic fistulas (5% vs 24%). Compared to open surgery in elderly patients, laparoscopic procedure showed benefits such as reduced blood loss (median of 200 ml) and fewer wound infections (3.33% vs 17.78%). On the downside, laparoscopy had a longer operation time (462.5 minutes vs 315 minutes), took longer before patients could resume oral intake (median of 5.5 days vs 5 days), and incurred higher hospitalization costs (¥118,782.48 vs ¥111,541.60). CONCLUSIONS While laparoscopic pancreatoduodenectomy in elderly patients may not match the outcomes seen in younger patients, it doesn't possess marked drawbacks when compared to open surgery. It is a safe and viable option for the elderly.