Generation of rat forebrain tissues in mice.

Interspecies blastocyst complementation (IBC) provides a unique platform to study development and holds the potential to overcome worldwide organ shortages. Despite recent successes, brain tissue has not been achieved through IBC. Here, we developed an optimized IBC strategy based on C-CRISPR, which facilitated rapid screening of candidate genes and identified that Hesx1 deficiency supported the generation of rat forebrain tissue in mice via IBC. Xenogeneic rat forebrain tissues in adult mice were structurally and functionally intact. Cross-species comparative analyses revealed that rat forebrain tissues developed at the same pace as the mouse host but maintained rat-like transcriptome profiles. The chimeric rate of rat cells gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late pre-natal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRISPR-based IBC strategy holds great potential to broaden the study and application of interspecies organogenesis.

Neurulation of the cynomolgus monkey embryo achieved from 3D blastocyst culture.

Neural tube (NT) defects arise from abnormal neurulation and result in the most common birth defects worldwide. Yet, mechanisms of primate neurulation remain largely unknown due to prohibitions on human embryo research and limitations of available model systems. Here, we establish a three-dimensional (3D) prolonged in vitro culture (pIVC) system supporting cynomolgus monkey embryo development from 7 to 25 days post-fertilization. Through single-cell multi-omics analyses, we demonstrate that pIVC embryos form three germ layers, including primordial germ cells, and establish proper DNA methylation and chromatin accessibility through advanced gastrulation stages. In addition, pIVC embryo immunofluorescence confirms neural crest formation, NT closure, and neural progenitor regionalization. Finally, we demonstrate that the transcriptional profiles and morphogenetics of pIVC embryos resemble key features of similarly staged in vivo cynomolgus and human embryos. This work therefore describes a system to study non-human primate embryogenesis through advanced gastrulation and early neurulation.

The Transcriptome and DNA Methylome Landscapes of Human Primordial Germ Cells.

Germ cells are vital for transmitting genetic information from one generation to the next and for maintaining the continuation of species. Here, we analyze the transcriptome of human primordial germ cells (PGCs) from the migrating stage to the gonadal stage at single-cell and single-base resolutions. Human PGCs show unique transcription patterns involving the simultaneous expression of both pluripotency genes and germline-specific genes, with a subset of them displaying developmental-stage-specific features. Furthermore, we analyze the DNA methylome of human PGCs and find global demethylation of their genomes. Approximately 10 to 11 weeks after gestation, the PGCs are nearly devoid of any DNA methylation, with only 7.8% and 6.0% of the median methylation levels in male and female PGCs, respectively. Our work paves the way toward deciphering the complex epigenetic reprogramming of the germline with the aim of restoring totipotency in fertilized oocytes.

Primate gastrulation and early organogenesis at single-cell resolution.

Our understanding of human early development is severely hampered by limited access to embryonic tissues. Due to their close evolutionary relationship with humans, nonhuman primates are often used as surrogates to understand human development but currently suffer from a lack of in vivo datasets, especially from gastrulation to early organogenesis during which the major embryonic cell types are dynamically specified. To fill this gap, we collected six Carnegie stage 8-11 cynomolgus monkey (Macaca fascicularis) embryos and performed in-depth transcriptomic analyses of 56,636 single cells. Our analyses show transcriptomic features of major perigastrulation cell types, which help shed light on morphogenetic events including primitive streak development, somitogenesis, gut tube formation, neural tube patterning and neural crest differentiation in primates. In addition, comparative analyses with mouse embryos and human embryoids uncovered conserved and divergent features of perigastrulation development across species-for example, species-specific dependency on Hippo signalling during presomitic mesoderm differentiation-and provide an initial assessment of relevant stem cell models of human early organogenesis. This comprehensive single-cell transcriptome atlas not only fills the knowledge gap in the nonhuman primate research field but also serves as an invaluable resource for understanding human embryogenesis and developmental disorders.

Off-target RNA mutation induced by DNA base editing and its elimination by mutagenesis.

Recently developed DNA base editing methods enable the direct generation of desired point mutations in genomic DNA without generating any double-strand breaks1-3, but the issue of off-target edits has limited the application of these methods. Although several previous studies have evaluated off-target mutations in genomic DNA4-8, it is now clear that the deaminases that are integral to commonly used DNA base editors often bind to RNA9-13. For example, the cytosine deaminase APOBEC1-which is used in cytosine base editors (CBEs)-targets both DNA and RNA12, and the adenine deaminase TadA-which is used in adenine base editors (ABEs)-induces site-specific inosine formation on RNA9,11. However, any potential RNA mutations caused by DNA base editors have not been evaluated. Adeno-associated viruses are the most common delivery system for gene therapies that involve DNA editing; these viruses can sustain long-term gene expression in vivo, so the extent of potential RNA mutations induced by DNA base editors is of great concern14-16. Here we quantitatively evaluated RNA single nucleotide variations (SNVs) that were induced by CBEs or ABEs. Both the cytosine base editor BE3 and the adenine base editor ABE7.10 generated tens of thousands of off-target RNA SNVs. Subsequently, by engineering deaminases, we found that three CBE variants and one ABE variant showed a reduction in off-target RNA SNVs to the baseline while maintaining efficient DNA on-target activity. This study reveals a previously overlooked aspect of off-target effects in DNA editing and also demonstrates that such effects can be eliminated by engineering deaminases.

Optimized nitrogen application ameliorates the photosynthetic performance and yield potential in peanuts as revealed by OJIP chlorophyll fluorescence kinetics.

BACKGROUND: Nitrogen (N) is a crucial element for increasing photosynthesis and crop yields. The study aims to evaluate the photosynthetic regulation and yield formation mechanisms of different nodulating peanut varieties with N fertilizer application. METHOD: The present work explored the effect of N fertilizer application rates (N0, N45, N105, and N165) on the photosynthetic characteristics, chlorophyll fluorescence characteristics, dry matter, N accumulation, and yield of four peanut varieties. RESULTS: The results showed that N application increased the photosynthetic capacity, dry matter, N accumulation, and yield of peanuts. The measurement of chlorophyll a fluorescence revealed that the K-phase, J-phase, and I-phase from the OJIP curve decreased under N105 treatment compared with N0, and WOI, ET0/CSM, RE0/CSM, ET0/RC, RE0/RC, φPo, φEo, φRo, and Ψ0 increased, whereas VJ, VI, WK, ABS/RC, TR0/RC, DI0/RC, and φDo decreased. Meanwhile, the photosystem activity and electron transfer efficiency of nodulating peanut varieties decreased with an increase in N (N165). However, the photosynthetic capacity and yield of the non-nodulating peanut variety, which highly depended on N fertilizer, increased with an increase in N. CONCLUSION: Optimized N application (N105) increased the activity of the photosystem II (PSII) reaction center, improved the electron and energy transfer performance in the photosynthetic electron transport chain, and reduced the energy dissipation of leaves in nodulating peanut varieties, which is conducive to improving the yield. Nevertheless, high N (N165) had a positive effect on the photosystem and yield of non-nodulating peanut. The results provide highly valuable guidance for optimizing peanut N management and cultivation measures.

Expected Eight-Week Prenatal Versus Twelve-Week Perinatal Tenofovir Alafenamide Prophylaxis to Prevent Mother-To-Child Transmission of Hepatitis B Virus: A Multicenter, Prospective, Open-label, Randomized Controlled Trial.

INTRODUCTION: The course of maternal antiviral prophylaxis to prevent mother-to-child transmission of hepatitis B virus (HBV-MTCT) varies greatly, and it has not been demonstrated in a randomized controlled study. METHODS: In this multicenter, open-label, randomized controlled trial, eligible pregnant women with HBV DNA of 5.3-9.0 log10 IU/mL who received tenofovir alafenamide fumarate (TAF) from the first day of 33 gestational weeks to delivery (expected eight-week) or to four-week postpartum (expected twelve-week) were randomly enrolled at a 1:1 ratio and followed until six-month postpartum. All infants received standard immunoprophylaxis (hepatitis B immunoglobulin and vaccine). The primary endpoint was the safety of mothers and infants. The secondary endpoint was infants' HBV-MTCT rate at seven months of age. RESULTS: Among 119 and 120 intention-to-treat pregnant women, 115 and 116 women were followed until delivery, and 110 and 112 per-protocol mother-infant dyads in two groups completed the study. Overall, TAF was well tolerated, no one discontinued therapy due to adverse events (0/239, 0%, 95% confidence interval [CI] 0%-1.6%), and no infant had congenital defects or malformations at delivery (0/231, 0%, 95% CI 0%-1.6%). The infants' physical development at birth (n=231) and at seven months (n=222) were normal. Furthermore, 97.0% (224/231, 95% CI 93.9%-98.5%) of women achieved HBV DNA <5.3 log10 IU/mL at delivery. The intention-to-treat and per-protocol infants' HBV-MTCT rates were 7.1% (17/239, 95% CI 4.5%-11.1%) and 0% (0/222, 95% CI 0%-1.7%) at seven months of age. Comparatively, 15.1% (18/119, 95% CI 9.8%-22.7%) versus 18.3% (22/120, 95% CI 12.4%-26.2%) of women in the two groups had mildly elevated alanine aminotransferase levels at three-month and six-month postpartum, respectively (P=0.507); notably, no one experienced alanine aminotransferase flare (0% [0/119, 95% CI 0%-3.1%] versus 0% [0/120, 0%-3.1%]). DISCUSSION: Maternal TAF prophylaxis to prevent HBV-MTCT is generally safe and effective, and expected eight-week prenatal duration is feasible. ClinicalTrials.gov, NCT04850950.

Impact of neoadjuvant chemotherapy on breast cancer-related lymphedema after axillary lymph node dissection: a retrospective cohort study.

PURPOSE: We aimed to evaluate whether neoadjuvant chemotherapy (NAC) could be a risk factor for breast cancer-related lymphedema (BCRL) associated with axillary lymph node dissection (ALND). PATIENTS AND METHODS: A total of 596 patients with cT0-4N0-3M0 breast cancer who underwent ALND and chemotherapy were retrospectively analyzed between March 2012 and March 2022. NAC was administered in 188 patients (31.5%), while up-front surgery in 408 (68.5%). Univariate and multivariable Cox regression analyses were performed to determine whether NAC was an independent risk factor for BCRL. With propensity score matching (PSM), the NAC group and up-front surgery group were matched 1:1 by age, body mass index (BMI), molecular subtypes, type of breast surgery, and the number of positive lymph nodes. Kaplan-Meier survival analyses were performed for BCRL between groups before and after PSM. Subgroup analyses were conducted to explore whether NAC differed for BCRL occurrence in people with different characteristics. RESULTS: At a median follow-up of 36.3 months, 130 patients (21.8%) experienced BCRL [NAC, 50/188 (26.60%) vs. up-front surgery, 80/408 (19.61%); P = 0.030]. Multivariable analysis identified that NAC [hazard ratio, 1.503; 95% CI (1.03, 2.19); P = 0.033] was an independent risk factor for BCRL. In addition, the hormone receptor-negative/human epidermal growth factor receptor 2-negative (HR-/HER2-) subtype, breast-conserving surgery (BCS), and increased positive lymph nodes significantly increased BCRL risk. After PSM, NAC remained a risk factor for BCRL [hazard ratio, 1.896; 95% CI (1.18, 3.04); P = 0.007]. Subgroup analyses showed that NAC had a consistent BCRL risk in most clinical subgroups. CONCLUSION: NAC receipt has a statistically significant increase in BCRL risk in patients with ALND. These patients should be closely monitored and may benefit from early BCRL intervention.

Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

DNA mismatch repair system regulates the expression of PD-L1 through DNMTs in cervical cancer.

BACKGROUND: Cervical cancer (CC) is a potential clinical application of PD-1/PD-L1 inhibitor. We aimed to study the mechanism of DNA mismatch repair (MMR) system regulating the expression of PD-L1 in CC through DNA methyltransferase (DNMTs). METHODS: We collected pathological specimens from 118 cases of CC to analyze the relationship between PD-L1 expression and DNMTs in different MMR states. RNA interference (RNAi) technique was used to simulate the formation of CC cell line with MMR deficiency (dMMR) state, and subcutaneous tumor formation experiment was carried out in nude mice to verify the relationship between PD-L1 expression and DNMTs in MMR state. RESULTS: The PD-L1 positive rate in 118 cases of CC was 58.47%, while the microsatellite instability (MSI) status accounted for 5.93%. There was a significant difference in the expression of PD-L1 between patients within the dMMR and MMR proficient (pMMR) groups (χ2 = 21.405, P < 0.001). Subcutaneous inoculation after infection of Siha cells led to successful tumorigenesis in nude mice, accompanied by a significant increase in the level of PD-L1 expression in the mouse tumors, while the expression level of MLH1 and MSH2 protein decreased significantly. We also found that PD-L1 expression was closely related to the expression of DNMTs. CONCLUSION: PD-L1 is universal expressed on the surface of CC cells, dMMR status enhances the expression of PD-L1 on the surface of CC cells, dMMR states of CC are related to the demethylation status of the PD-L1 gene promoter region.

Multispecies Ion Acceleration in 3D Magnetic Reconnection with Hybrid-Kinetic Simulations.

Magnetic reconnection drives multispecies particle acceleration broadly in space and astrophysics. We perform the first 3D hybrid simulations (fluid electrons, kinetic ions) that contain sufficient scale separation to produce nonthermal heavy-ion acceleration, with fragmented flux ropes critical for accelerating all species. We demonstrate the acceleration of all ion species (up to Fe) into power-law spectra with similar indices, by a common Fermi acceleration mechanism. The upstream ion velocities influence the first Fermi reflection for injection. The subsequent onsets of Fermi acceleration are delayed for ions with lower charge-mass ratios (Q/M), until growing flux ropes magnetize them. This leads to a species-dependent maximum energy/nucleon ∝(Q/M)^{α}. These findings are consistent with in situ observations in reconnection regions, suggesting Fermi acceleration as the dominant multispecies ion acceleration mechanism.

Recent Progress of Small Interfering RNA Delivery on the Market and Clinical Stage.

Small interfering RNAs (siRNAs) are promising therapeutic strategies, and five siRNA drugs have been approved by the Food and Drug Administration (FDA) and the European Commission (EC). This marks a significant milestone in the development of siRNA for clinical applications. The approved siRNA agents can effectively deliver siRNAs to the liver and treat liver-related diseases. Currently, researchers have developed diverse delivery platforms for transporting siRNAs to different tissues such as the brain, lung, muscle, and others, and a large number of siRNA drugs are undergoing clinical trials. Here, these delivery technologies and the latest advancements in clinical applications are summarized, and this Review provides a concise overview of the strategies employed for siRNA delivery to both hepatic and extrahepatic tissues.

Fisetin ameliorates fibrotic kidney disease in mice via inhibiting ACSL4-mediated tubular ferroptosis.

Kidney fibrosis is the hallmark of chronic kidney disease (CKD) progression, whereas no effective anti-fibrotic therapies exist. Recent evidence has shown that tubular ferroptosis contributes to the pathogenesis of CKD with persistent proinflammatory and profibrotic responses. We previously reported that natural flavonol fisetin alleviated septic acute kidney injury and protected against hyperuricemic nephropathy in mice. In this study, we investigated the therapeutic effects of fisetin against fibrotic kidney disease and the underlying mechanisms. We established adenine diet-induced and unilateral ureteral obstruction (UUO)-induced CKD models in adult male mice. The two types of mice were administered fisetin (50 or 100 mg·kg-1·d-1, i.g.) for 3 weeks or 7 days, respectively. At the end of the experiments, the mice were euthanized, and blood and kidneys were gathered for analyzes. We showed that fisetin administration significantly ameliorated tubular injury, inflammation, and tubulointerstitial fibrosis in the two types of CKD mice. In mouse renal tubular epithelial (TCMK-1) cells, treatment with fisetin (20 µM) significantly suppressed adenine- or TGF-ß1-induced inflammatory responses and fibrogenesis, and improved cell viability. By quantitative real-time PCR analysis of ferroptosis-related genes, we demonstrated that fisetin treatment inhibited ferroptosis in the kidneys of CKD mice as well as in injured TCMK-1 cells, as evidenced by decreased ACSL4, COX2, and HMGB1, and increased GPX4. Fisetin treatment effectively restored ultrastructural abnormalities of mitochondrial morphology and restored the elevated iron, the reduced GSH and GSH/GSSG as well as the increased lipid peroxide MDA in the kidneys of CKD mice. Notably, abnormally high expression of the ferroptosis key marker ACSL4 was verified in the renal tubules of CKD patients (IgAN, MN, FSGS, LN, and DN) as well as adenine- or UUO-induced CKD mice, and in injured TCMK-1 cells. In adenine- and TGF-ß1-treated TCMK-1 cells, ACSL4 knockdown inhibited tubular ferroptosis, while ACSL4 overexpression blocked the anti-ferroptotic effect of fisetin and reversed the cytoprotective, anti-inflammatory, and anti-fibrotic effects of fisetin. In summary, we reveal a novel aspect of the nephroprotective effect of fisetin, i.e. inhibiting ACSL4-mediated tubular ferroptosis against fibrotic kidney diseases.

Chromodomain Y-like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis.

Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y-like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD = 0.5 µM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5 mg·kg-1·d-1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.

[Ginsenoside Re regulates mitochondrial biogenesis through Nrf2/HO-1/PGC-1α pathway to reduce hypoxia/reoxygenation injury in H9c2 cells].

This article explored the mechanism by which ginsenoside Re reduces hypoxia/reoxygenation(H/R) injury in H9c2 cells by regulating mitochondrial biogenesis through nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)/peroxisome prolife-rator-activated receptor gamma coactivator-1α(PGC-1α) pathway. In this study, H9c2 cells were cultured in hypoxia for 4 hours and then reoxygenated for 2 hours to construct a cardiomyocyte H/R injury model. After ginsenoside Re pre-administration intervention, cell activity, superoxide dismutase(SOD) activity, malondialdehyde(MDA) content, intracellular reactive oxygen species(Cyto-ROS), and intramitochondrial reactive oxygen species(Mito-ROS) levels were detected to evaluate the protective effect of ginsenoside Re on H/R injury of H9c2 cells by resisting oxidative stress. Secondly, fluorescent probes were used to detect changes in mitochondrial membrane potential(ΔΨ_m) and mitochondrial membrane permeability open pore(mPTP), and immunofluorescence was used to detect the expression level of TOM20 to study the protective effect of ginsenoside Re on mitochondria. Western blot was further used to detect the protein expression levels of caspase-3, cleaved caspase-3, Cyto C, Nrf2, HO-1, and PGC-1α to explore the specific mechanism by which ginsenoside Re protected mitochondria against oxidative stress and reduced H/R injury. Compared with the model group, ginse-noside Re effectively reduced the H/R injury oxidative stress response of H9c2 cells, increased SOD activity, reduced MDA content, and decreased Cyto-ROS and Mito-ROS levels in cells. Ginsenoside Re showed a good protective effect on mitochondria by increasing ΔΨ_m, reducing mPTP, and increasing TOM20 expression. Further studies showed that ginsenoside Re promoted the expression of Nrf2, HO-1, and PGC-1α proteins, and reduced the activation of the apoptosis-related regulatory factor caspase-3 to cleaved caspase-3 and the expression of Cyto C protein. In summary, ginsenoside Re can significantly reduce I/R injury in H9c2 cells. The specific mechanism is related to the promotion of mitochondrial biogenesis through the Nrf2/HO-1/PGC-1α pathway, thereby increasing the number of mitochondria, improving mitochondrial function, enhancing the ability of cells to resist oxidative stress, and alleviating cell apoptosis.

[Tetrahydropalmatine inhibiting mitophagy through ULK1/FUNDC1 pathway to alleviate hypoxia/reoxygenation injury in H9c2 cells].

This study explored the specific mechanism by which tetrahydropalmatine(THP) inhibited mitophagy through the UNC-51-like kinase 1(ULK1)/FUN14 domain containing 1(FUNDC1) pathway to reduce hypoxia/reoxygenation(H/R) injury in H9c2 cells. This study used H9c2 cells as the research object to construct a cardiomyocyte H/R injury model. First, a cell viability detection kit was used to detect cell viability, and a micro-method was used to detect lactate dehydrogenase(LDH) leakage to evaluate the protective effect of THP on H/R injury of H9c2 cells. In order to evaluate the protective effect of THP on mitochondria, the chemical fluorescence method was used to detect intracellular reactive oxygen species, intramitochondrial reactive oxygen species, mitochondrial membrane potential, and autophagosomes, and the luciferin method was used to detect intracellular adenosine 5'-triphosphate(ATP) content. Western blot was further used to detect the ratio of microtubule-associated protein 1 light chain 3(LC3) membrane type(LC3-Ⅱ) and slurry type(LC3-Ⅰ) and activated cleaved caspase-3 expression level. In addition, ULK1 expression level and its phosphorylation degree at Ser555 site, as well as the FUNDC1 expression level and its phosphorylation degree of Ser17 site were detected to explore its specific mechanism. The results showed that THP effectively reduced mitochondrial damage in H9c2 cells after H/R. THP protected mitochondria by reducing the level of reactive oxygen species in cells and mitochondria, increasing mitochondrial membrane potential, thereby increasing cellular ATP production, enhancing cellular activity, reducing cellular LDH leakage, and finally alleviating H/R damage in H9c2 cells. Further studies have found that THP could reduce the production of autophagosomes, reduce the LC3-Ⅱ/LC3-Ⅰ ratio, and lower the expression of the apoptosis-related protein, namely cleaved caspase-3, indicating that THP could reduce apoptosis by inhibiting autophagy. In-depth studies have found that THP could inhibit the activation of the ULK1/FUNDC1 pathway of mitophagy and the occurrence of mitophagy by reducing the phosphorylation degree of ULK1 at Ser555 and FUNDC1 at Ser17. The application of ULK1 agonist BL-918 reversely verified the effect of THP on reducing the phosphorylation of ULK1 and FUNDC1. In summary, THP inhibited mitophagy through the ULK1/FUNDC1 pathway to reduce H/R injury in H9c2 cells.

Cognitive impairment after sleep deprivation: The role of precuneus related connectivity on the intra-individual variability changes.

OBJECTIVE: Intra-individual variability (IIV) in cognitive performance is thought to reflect the efficiency with which attentional resources are allocated in different circumstances requiring cognitive control. IIV in cognitive performance is associated with the strength of the negative correlation between task-positive network and default mode network (DMN) activity. In this study, we investigated the impact of sleep deprivation (SD) on functional connectivity (FC) between the DMN and psychomotor vigilance task-related network (PVT-RN), and its relationship with IIV in cognitive performance. METHODS: Two analyses, network-level independent component analysis (NL-ICA) and region-level (RL)-ICA, were employed to compare the coefficient of variation (CV) of the PVT between normal sleep and SD conditions across 67 healthy participants. RESULTS: After SD, in NL-ICA, the FC between the PVT-RN and DMN was positively correlated with the CV of the PVT, as well as the changes therein, compared with normal sleep. Using a mask derived from the DMN and PVT-RN, the RL-ICA revealed that 12 edges/connections between DMN and PVT independent components were associated with the CV of the PVT, with nine of these connections involving the precuneus. CONCLUSIONS: These findings suggest that the precuneus may play a crucial role in the interactions of various brain functions during the PVT, with the connections between the precuneus and frontoparietal and somatosensory networks being significantly altered after SD. Moreover, following SD, weakened negative FC between the precuneus and bilateral inferior parietal lobule may disrupt the balance between cognitive and executive control functions, leading to a decline in cognitive performance.

Prognostic Value of Preoperative Assessment of Left Ventricular Function in Patients Undergoing Percutaneous Coronary Intervention.

Background: Patients may experience a decline in cardiac function even after successful percutaneous coronary intervention (PCI). It is apparent that the assessment of left ventricular (LV) function before PCI is often overlooked. The purpose of this review is to explore the significance of LV function assessment before PCI by comparing the differences in short- and long-term PCI outcomes between patients with different LV ejection fraction (LVEF) stratified preoperatively. Methods: PubMed and Scopus were searched to identify potential studies from January 1, 2001 through January 1, 2022. Results: A total of 969,868 participants in 33 studies at different stratifications of baseline LVEF were included in this review and their PCI outcomes were stratified for analysis. The hazard ratio of all-cause mortality within 30 days, one year and greater than 1 year after PCI between patients with abnormal and normal LVEF were 2.96 [95% CI, 2.2, 3.98], 3.14 [95% CI, 1.64, 6.01] and 3.08 [95% CI, 2.6, 3.64]; moderately impaired LV function versus normal were 2.32 [95% CI, 1.85, 2.91], 2.04 [95% CI, 1.37, 3.03], 1.93 [95% CI, 1.54, 2.44]; poor LV function versus normal were 4.84 [95% CI, 3.83, 6.1], 4.48 [95% CI, 1.37, 14.68], 6.59 [95% CI, 4.23, 10.27]. Conclusions: A moderate or severe reduction in patients' LVEF may have a serious impact on PCI prognosis. We strongly advocate for adequate assessment of LVEF before PCI as this will assist in choosing the optimal revascularization and postoperative treatment, thereby reducing short- and long-term mortality.

Association between whole blood essential trace elements and cognitive function in older adults.

BACKGROUND: Essential trace elements (ETEs) are essential nutrients for keeping the nervous system functioning. Associations between ETEs and cognitive function are still inconclusive and limited. OBJECTIVES: We aimed to investigate the individual and joint associations between ETEs and cognitive function among older adults. METHODS: A population (N = 2181) at an average age≥ 65 from Yiwu cohort in China was available for this study. Whole blood chromium (Cr), selenium (Se), manganese (Mn), and copper (Cu) concentrations were measured by inductively coupled plasma mass spectrometry (ICP-MS). Cognitive function was assessed using the Mini-Mental State Examination (MMSE), consisting of five specific cognitive domains: orientation, registry, attention and calculation, recall, and language and praxis. Linear regression, restricted cubic spline (RCS) analysis, and Bayesian kernel machine regression (BKMR) were used to analyze the individual and joint associations between ETEs and cognitive function. RESULTS: The association between Cr and MMSE score presented an inverted-U shape (Q3 versus Q1: ß = 0.774, 95 % CI: 0.297, 1.250; Q4 versus Q1: ß = 0.481, 95 % CI: 0.006, 0.956); and Cr was especially associated with the registry, recall, and language and praxis. Per IQR (36.32 µg/L) increase of Se was positively associated with the MMSE score (ß = 0.497, 95 % CI: 0.277, 0.717) and all five cognitive domains. The BKMR showed that the dose-response association between Se and cognitive function increased initially and then decreased with increasing Se concentration when fixed the other ETEs in median. ETEs mixture was positively associated with cognitive function, and Se (posterior inclusion probabilities, PIPs = 0.915) was the most important contributor within the ETEs mixture. CONCLUSIONS: The nonlinear association between Cr and cognitive function suggested further exploration of an appropriate concentration range for ETEs. A positive association between mixed ETEs and cognitive function is a reminder that their joint association should be considered. Further prospective studies or intervention studies are warranted to validate our findings in the future.

Smartphone-Enabled Fluorescence and Colorimetric Platform for the On-Site Detection of Hg2+ and Cl- Based on the Au/Cu/Ti3C2 Nanosheets.

Smartphone-assisted fluorescence and colorimetric methods for the on-site detection of Hg2+ and Cl- were established based on the oxidase-like activity of the Au-Hg alloy on the surface of Au/Cu/Ti3C2 NSs. The Au nanoparticles (NPs) were constructed via in-situ growth on the surface of Cu/Ti3C2 NSs and characterized by different characterization techniques. After the addition of Hg2+, the formation of Hg-Au alloys could promote the oxidization of o-phenylenediamine (OPD) to generate a new fluorescence emission peak of 2,3-diaminopenazine (ADP) at 570 nm. Therefore, a turn-on fluorescence method for the detection of Hg2+ was established. As the addition of Cl- can influence the fluorescence of ADP, the fluorescence intensity was constantly quenched to achieve the continuous quantitative detection of Cl-. Therefore, a turn-off fluorescence method for the detection of Cl- was established. This method had good linear ranges for the detection of Hg2+ and Cl- in 8.0-200.0 nM and 5.0-350.0 µM, with a detection limit of 0.8 nM and 27 nM, respectively. Depending on the color change with the detection of Hg2+ and Cl-, a convenient on-site colorimetric method for an analysis of Hg2+ and Cl- was achieved by using digital images combined with smartphones (color recognizers). The digital picture sensor could analyze RGB values in concentrations of Hg2+ or Cl- via a smartphone app. In summary, the proposed Au/Cu/Ti3C2 NSs-based method provided a novel and more comprehensive application for environmental monitoring.