Posttranscriptional regulation of de novo lipogenesis by glucose-induced O-GlcNAcylation.

O-linked ß-N-acetyl glucosamine (O-GlcNAc) is attached to proteins under glucose-replete conditions; this posttranslational modification results in molecular and physiological changes that affect cell fate. Here we show that posttranslational modification of serine/arginine-rich protein kinase 2 (SRPK2) by O-GlcNAc regulates de novo lipogenesis by regulating pre-mRNA splicing. We found that O-GlcNAc transferase O-GlcNAcylated SRPK2 at a nuclear localization signal (NLS), which triggers binding of SRPK2 to importin α. Consequently, O-GlcNAcylated SRPK2 was imported into the nucleus, where it phosphorylated serine/arginine-rich proteins and promoted splicing of lipogenic pre-mRNAs. We determined that protein nuclear import by O-GlcNAcylation-dependent binding of cargo protein to importin α might be a general mechanism in cells. This work reveals a role of O-GlcNAc in posttranscriptional regulation of de novo lipogenesis, and our findings indicate that importin α is a "reader" of an O-GlcNAcylated NLS.

CCR7 Chemokine Receptor-Inducible lnc-Dpf3 Restrains Dendritic Cell Migration by Inhibiting HIF-1α-Mediated Glycolysis.

CCR7 chemokine receptor stimulation induces rapid but transient dendritic cell (DC) migration toward draining lymph nodes, which is critical for the initiation of protective immunity and maintenance of immune homeostasis. The mechanisms for terminating CCR7-mediated DC migration remain incompletely understood. Here we have identified a long non-coding RNA lnc-Dpf3 whose feedback restrained CCR7-mediated DC migration. CCR7 stimulation upregulated lnc-Dpf3 via removing N6-methyladenosine (m6A) modification to prevent RNA degradation. DC-specific lnc-Dpf3 deficiency increased CCR7-mediated DC migration, leading to exaggerated adaptive immune responses and inflammatory injuries. Mechanistically, CCR7 stimulation activated the HIF-1α transcription factor pathway in DCs, leading to metabolic reprogramming toward glycolysis for DC migration. lnc-Dpf3 directly bound to HIF-1α and suppressed HIF-1α-dependent transcription of the glycolytic gene Ldha, thus inhibiting DC glycolytic metabolism and migratory capacity. We demonstrate a critical role for CCR7-inducible lnc-Dpf3 in coupling epigenetic and metabolic pathways to feedback-control DC migration and inflammatory responses.

Acetyl-CoA Derived from Hepatic Peroxisomal ß-Oxidation Inhibits Autophagy and Promotes Steatosis via mTORC1 Activation.

Autophagy is activated by prolonged fasting but cannot overcome the ensuing hepatic lipid overload, resulting in fatty liver. Here, we describe a peroxisome-lysosome metabolic link that restricts autophagic degradation of lipids. Acyl-CoA oxidase 1 (Acox1), the enzyme that catalyzes the first step in peroxisomal ß-oxidation, is enriched in liver and further increases with fasting or high-fat diet (HFD). Liver-specific Acox1 knockout (Acox1-LKO) protected mice against hepatic steatosis caused by starvation or HFD due to induction of autophagic degradation of lipid droplets. Hepatic Acox1 deficiency markedly lowered total cytosolic acetyl-CoA levels, which led to decreased Raptor acetylation and reduced lysosomal localization of mTOR, resulting in impaired activation of mTORC1, a central regulator of autophagy. Dichloroacetic acid treatment elevated acetyl-CoA levels, restored mTORC1 activation, inhibited autophagy, and increased hepatic triglycerides in Acox1-LKO mice. These results identify peroxisome-derived acetyl-CoA as a key metabolic regulator of autophagy that controls hepatic lipid homeostasis.

Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling.

Coordinated metabolic reprogramming and epigenetic remodeling are critical for modulating T cell function and differentiation. However, how the epigenetic modification controls Th17/Treg cell balance via metabolic reprogramming remains obscure. Here, we find that Setd2, a histone H3K36 trimethyltransferase, suppresses Th17 development but promotes iTreg cell polarization via phospholipid remodeling. Mechanistically, Setd2 up-regulates transcriptional expression of lysophosphatidylcholine acyltransferase 4 (Lpcat4) via directly catalyzing H3K36me3 of Lpcat4 gene promoter in T cells. Lpcat4-mediated phosphatidylcholine PC(16:0,18:2) generation in turn limits endoplasmic reticulum stress and oxidative stress. These changes decrease HIF-1α transcriptional activity and thus suppress Th17 but enhance Treg development. Consistent with this regulatory paradigm, T cell deficiency of Setd2 aggravates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis due to imbalanced Th17/Treg cell differentiation. Overall, our data reveal that Setd2 acts as an epigenetic brake for T cell-mediated autoimmunity through phospholipid remodeling, suggesting potential targets for treating neuroinflammatory diseases.

Astrocytes modulate a specific paraventricular thalamus-prefrontal cortex projection to enhance consciousness recovery from anesthesia.

Current anesthetic theory is mostly based on neurons and/or neuronal circuits. A role for astrocytes also has been shown in promoting recovery from volatile anesthesia, while the exact modulatory mechanism and/or the molecular target in astrocytes is still unknown. In this study, by animal models in male mice and electrophysiological recordings in vivo and in vitro, we found that activating astrocytes of paraventricular thalamus (PVT) and/or knocking down PVT astrocytic Kir4.1 promoted the consciousness recovery from sevoflurane anesthesia. Single-cell RNA sequencing of PVT reveals two distinct cellular subtypes of glutamatergic neurons: PVT GRM and PVT ChAT neurons. Patch-clamp recording results proved astrocytic Kir4.1-mediated modulation of sevoflurane on PVT mainly worked on PVT ChAT neurons, which projected mainly to the mPFC. In summary, our findings support the novel conception that there is a specific PVT-prefrontal cortex projection involved in consciousness recovery from sevoflurane anesthesia, which mediated by the inhibition of sevoflurane on PVT astrocytic Kir4.1 conductance.Significance Statement How volatile anesthetics work is not fully understood. Here, we demonstrate that the commonly used volatile anesthetic sevoflurane can inhibit astrocytic Kir4.1 conductance in PVT, which enhances neuronal firing of PVT neurons. Additionally, by single-cell sequencing, cholinergic neurons in the PVT (PVT ChAT ) are the neuronal substrates for astrocytic modulation in volatile anesthesia, which directly project to prefrontal cortex. Behaviorally, the modulation of astrocytes on PVT ChAT promotes electroencephalogram (EEG) transition of prefrontal cortex; and then accelerates emergence from sevoflurane anesthesia. In summary, this study is the first to identify that astrocytic Kir4.1 in wakeful nuclei is involved in consciousness recovery from volatile anesthetics, as well as the subcellular mechanism.

Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation.

The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis.

Modulating Nucleation and Crystal Growth of Tin Perovskite Films for Efficient Solar Cells.

The performance of tin halide perovskite solar cells (PSCs) has been severely limited by the rapid crystallization of tin perovskites, which usually leads to an undesirable film quality. In this work, we tackle this issue by regulating the nucleation and crystal growth of tin perovskite films using a small Lewis base additive, urea. The urea-SnI2 interaction facilitates the formation of larger and more uniform clusters, thus accelerating the nucleation process. Additionally, the crystal growth process is extended, resulting in a high-quality tin perovskite film with compact morphology, increased crystallinity, and reduced defects. Consequently, the efficiency of tin PSCs is significantly increased from 10.42% to 14.22%. This work highlights the importance of manipulating the nucleation and crystal growth of tin perovskites to realize efficient tin PSCs.

Fatty liver disease protective MTARC1 p.A165T variant reduces the protein stability of MTARC1.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease worldwide. MTARC1, encoded by the MTARC1 gene, is a mitochondrial outer membrane-anchored enzyme. Interestingly, the MTARC1 p.A165T (rs2642438) variant is associated with a decreased risk of NAFLD, indicating that MTARC1 might be an effective target. It has been reported that the rs2642438 variant does not have altered enzymatic activity so we reasoned that this variation may affect MTARC1 stability. In this study, MTARC1 mutants were generated and stability was assessed using a protein stability reporter system both in vitro and in vivo. We found that the MTARC1 p.A165T variant has dramatically reduced the stability of MTARC1, as assessed in several cell lines. In mice, the MTARC1 A168T mutant, the equivalent of human MTARC1 A165T, had diminished stability in mouse liver. Additionally, several MTARC1 A165 mutants, including A165S, A165 N, A165V, A165G, and A165D, had dramatically decreased stability as well, suggesting that the alanine residue of MTARC1 165 site is essential for MTARC1 protein stability. Collectively, our data indicates that the MTARC1 p.A165T variant (rs2642438) leads to reduced stability of MTARC1. Given that carriers of rs2642438 show a decreased risk of NAFLD, the findings herein support the notion that MTARC1 inhibition may be a therapeutic target to combat NAFLD.

Prognostic value of three-tiered scoring system for lymph-vascular space invasion in endometrial cancer: A systematic review and meta-analysis.

OBJECTIVE: To investigate the impact of lymph-vascular space invasion (LVSI) status on the prognosis of endometrial cancer (EC) according to a three-tiered scoring system for LVSI. METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and Clinical Trials.gov were searched from inception to September 1st, 2023. The analysis was conducted using STATA 16.0. RESULTS: A total of 9 studies with 4456 EC patients were included in the analysis. No LVSI was found in 72% of EC patients (95% CI 0.65-0.79), while focal and substantial LVSI were present in 16% (95% CI 0.11-0.21) and 13% (95% CI 0.08-018) of patients, respectively. Compared to the no LVSI group, the focal and substantial LVSI groups had poorer overall survival (for focal LVSI: HR 1.33, 95% CI 1.02-1.74; for substantial LVSI: HR 2.51, 95% CI 1.61-3.90), poorer disease-free survival (for substantial LVSI: HR 2.86, 95% CI 1.21-6.77), and an increased risk of recurrence, including pelvic recurrence (for focal LVSI: HR 2.05, 95% CI 1.03-4.07; for substantial LVSI: HR 6.06, 95% CI 3.31-11.08), distant recurrence (for focal LVSI: HR 2.04, 95% CI 1.42-2.92; for substantial LVSI: HR 3.36, 95% CI 2.35-4.793), and lymph node involvement (for focal LVSI: OR 3.52, 95% CI 1.339.34; for substantial LVSI: OR 5.42, 95% CI 2.78-10.58). Substantial LVSI was more prone to pelvic recurrence (HR 1.82, 95% CI 1.05-3.15) and distant recurrence (HR 2.21, 95% CI 1.48-3.28) than focal LVSI. CONCLUSIONS: EC patients with focal and substantial LVSI had poorer survival, recurrence, and a higher incidence of lymph node metastasis than patients without LVSI. The substantial LVSI group was associated with even worse prognosis than the focal LVSI group. The three-tiered LVSI scoring system might effectively predict the prognosis of EC and guide clinical decision-making. PROTOCOL REGISTRATION: CRD 42023451793.

Is pharmacologic venous Thromboprophylaxis necessary for patients undergoing minimally invasive surgery for endometrial Cancer? A systematic review and Meta-analysis.

OBJECTIVE: Given the low incidence of venous thromboembolism (VTE) in endometrial cancer patients undergoing minimally invasive surgery, coupled with the existing uncertainties within guidelines regarding pharmacologic thromboprophylaxis in this area, there is an urgent need for a comprehensive literature review. This review aims to evaluate the necessity of pharmacologic VTE prophylaxis in these patients. METHODS: PubMed, Embase, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, and ClinicalTrials.gov were systematically searched from inception to March 10, 2024. The analysis was performed using R version 4.2.3. RESULTS: Seven studies involving 3931 endometrial cancer patients were included in the analysis. Meta-analysis results revealed that within 30 days postoperatively, the incidence of VTE was 0.51% (5 out of 990) in the pharmacologic prophylaxis group and 0.70% (7 out of 995) in the mechanical prophylaxis group, with a relative risk (RR) of 1.14 (95% CI 0.19-6.95), indicating no significant difference between the groups. Additionally, within the same timeframe, the incidence of VTE was 0.37% (4 out of 1083) in the extended pharmacologic prophylaxis group and 1.14% (4 out of 352) in the non-extended pharmacologic prophylaxis group, yielding an RR of 0.41 (95% CI 0.11-1.54), again showing no significant difference between the groups. CONCLUSIONS: Our study indicates that routine pharmacological VTE prophylaxis may not be imperative for endometrial cancer patients undergoing minimally invasive surgery, as mechanical prophylaxis alone seems to be efficacious. However, it is crucial to acknowledge that a subset of high-risk patients may derive benefit from pharmacological prophylaxis or even extended regimens. Nonetheless, the absence of a validated risk prediction model for identifying such patients underscores the need for further research in this area. PROTOCOL REGISTRATION: CRD 42024516595.

Changes in information integration and brain networks during propofol-, dexmedetomidine-, and ketamine-induced unresponsiveness.

BACKGROUND: Information integration and network science are important theories for quantifying consciousness. However, whether these theories propose drug- or conscious state-related changes in EEG during anaesthesia-induced unresponsiveness remains unknown. METHODS: A total of 72 participants were randomised to receive i.v. infusion of propofol, dexmedetomidine, or ketamine at a constant infusion rate until loss of responsiveness. High-density EEG was recorded during the consciousness transition from the eye-closed baseline to the unresponsiveness state and then to the recovery of the responsiveness state. Permutation cross mutual information (PCMI) and PCMI-based brain networks in broadband (0.1-45 Hz) and sub-band frequencies were used to analyse drug- and state-related EEG signature changes. RESULTS: PCMI and brain networks exhibited state-related changes in certain brain regions and frequency bands. The within-area PCMI of the frontal, parietal, and occipital regions, and the between-area PCMI of the parietal-occipital region (median [inter-quartile ranges]), baseline vs unresponsive were as follows: 0.54 (0.46-0.58) vs 0.46 (0.40-0.50), 0.58 (0.52-0.60) vs 0.48 (0.44-0.53), 0.54 (0.49-0.59) vs 0.47 (0.42-0.52) decreased during anaesthesia for three drugs (P<0.05). Alpha PCMI in the frontal region, and gamma PCMI in the posterior area significantly decreased in the unresponsive state (P<0.05). The frontal, parietal, and occipital nodal clustering coefficients and parietal nodal efficiency decreased in the unresponsive state (P<0.05). The increased normalised path length in delta, theta, and gamma bands indicated impaired global integration (P<0.05). CONCLUSIONS: The three anaesthetics caused changes in information integration patterns and network functions. Thus, it is possible to build a quantifying framework for anaesthesia-induced conscious state changes on the EEG scale using PCMI and network science.

Olfactory bulb neurogenesis depending on signaling in the subventricular zone.

Olfaction is a crucial sense that is essential for the well-being and survival of individuals. Olfactory bulb (OB) is the first olfactory relay station, and its function depends on newly generated neurons from the subventricular zone (SVZ). These newly born neurons constantly migrate through the rostral migratory stream to integrate into existing neural networks within the OB, thereby contributing to olfactory information processing. However, the mechanisms underlying the contribution of SVZ adult neurogenesis to OB neurogenesis remain largely elusive. Adult neurogenesis is a finely regulated multistep process involving the proliferation of adult neural stem cells (aNSCs) and neural precursor cells, as well as the migration and differentiation of neuroblasts, and integration of newly generated neurons into preexisting neuronal circuitries. Recently, extensive studies have explored the mechanism of SVZ and OB neurogenesis. This review focused on elucidating various molecules and signaling pathways associated with OB neurogenesis dependent on the SVZ function. A better understanding of the mechanisms underlying the OB neurogenesis on the adult brain is an attractive prospect to induce aNSCs in SVZ to generate new neurons to ameliorate olfactory dysfunction that is involved in various diseases. It will also contribute to developing new strategies for the human aNSCs-based therapies.

Splenectomy as a part of cytoreductive surgery in ovarian cancer: systematic review and meta-analysis.

OBJECTIVE: The role of splenectomy on cytoreductive surgery in patients with ovarian cancer remains controversial. We conducted this meta-analysis to evaluate the safety and impact of survival outcome of splenectomy in patients with ovarian cancer. METHODS: In this meta-analysis we analyzed studies published in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and Clinical Trials. gov that appeared in our search from inception to November 10, 2023. RESULT: This meta-analysis included 10 studies, totaling 6297 patients, comprising one prospective and nine retrospective analyses. The results indicated no significant disparity in overall survival and mortality (OR 1.14, 95% CI 0.69 to 1.87, p=0.62) between the splenectomy cohort and the no splenectomy (required) cohort. Furthermore, relative to the no splenectomy (required) cohort, the splenectomy group showed a heightened incidence of overall post-operative complications (odds ratio (OR) 1.66, 95% CI 1.65 to 2.61, p=0.03), an extended duration of hospitalization (mean difference (MD) 2.88 days, 95% CI 2.09 to 3.67), an increased interval from surgery to the initiation of adjuvant chemotherapy (MD 4.44 days, 95% CI 2.41 to 6.07, p<0.0001), and a greater probability of undergoing reoperation (OR 4.7, 95% CI 1.91 to 11.55, p=0.0007). However, concerning the occurrence of specific post-operative complications such as anastomotic leakage (OR 0.97, 95% CI 0.33 to 2.84, p=0.95), pancreatic fistula (OR 3.25, 95% CI 0.63 to 16.7, p=0.16), abdominal abscess (OR 1.75, 95% CI 0.25 to 12.33, p=0.57), sepsis (OR 1.46, 95% CI 0.77 to 2.77, p=0.25), and thrombotic events (OR 1.82, 95% CI 0.93 to 3.57, p=0.08), no significant differences were observed between the two cohorts. CONCLUSION: Splenectomy does not impact the overall survival and mortality of patients with ovarian cancer. Thus, it can be considered an acceptably safe procedure to obtain optimal cytoreduction. However, caution should be taken when selecting patients for splenectomy because it is associated with an increased incidence of overall post-operative complications, prolonged hospital stays, delayed initiation of adjuvant chemotherapy, and an increased probability of requiring subsequent surgical interventions.

γ-Aminobutyric Acid-Ergic Development Contributes to the Enhancement of Electroencephalogram Slow-Delta Oscillations Under Volatile Anesthesia in Neonatal Rats.

BACKGROUND: General anesthetics (eg, propofol and volatile anesthetics) enhance the slow-delta oscillations of the cortical electroencephalogram (EEG), which partly results from the enhancement of (γ-aminobutyric acid [GABA]) γ-aminobutyric acid-ergic (GABAergic) transmission. There is a GABAergic excitatory-inhibitory shift during postnatal development. Whether general anesthetics can enhance slow-delta oscillations in the immature brain has not yet been unequivocally determined. METHODS: Perforated patch-clamp recording was used to confirm the reversal potential of GABAergic currents throughout GABAergic development in acute brain slices of neonatal rats. The power density of the electrocorticogram and the minimum alveolar concentrations (MAC) of isoflurane and/or sevoflurane were measured in P4-P21 rats. Then, the effects of bumetanide, an inhibitor of the Na + -K + -2Cl - cotransporter (NKCC1) and K + -Cl - cotransporter (KCC2) knockdown on the potency of volatile anesthetics and the power density of the EEG were determined in vivo. RESULTS: Reversal potential of GABAergic currents were gradually hyperpolarized from P4 to P21 in cortical pyramidal neurons. Bumetanide enhanced the hypnotic effects of volatile anesthetics at P5 (for MAC LORR , isoflurane: 0.63% ± 0.07% vs 0.81% ± 0.05%, 95% confidence interval [CI], -0.257 to -0.103, P < .001; sevoflurane: 1.46% ± 0.12% vs 1.66% ± 0.09%, 95% CI, -0.319 to -0.081, P < .001); while knockdown of KCC2 weakened their hypnotic effects at P21 in rats (for MAC LORR , isoflurane: 0.58% ± 0.05% to 0.77% ± 0.20%, 95% CI, 0.013-0.357, P = .003; sevoflurane: 1.17% ± 0.04% to 1.33% ± 0.04%, 95% CI, 0.078-0.244, P < .001). For cortical EEG, slow-delta oscillations were the predominant components of the EEG spectrum in neonatal rats. Isoflurane and/or sevoflurane suppressed the power density of slow-delta oscillations rather than enhancement of it until GABAergic maturity. Enhancement of slow-delta oscillations under volatile anesthetics was simulated by preinjection of bumetanide at P5 (isoflurane: slow-delta changed ratio from -0.31 ± 0.22 to 1.57 ± 1.15, 95% CI, 0.67-3.08, P = .007; sevoflurane: slow-delta changed ratio from -0.46 ± 0.25 to 0.95 ± 0.97, 95% CI, 0.38-2.45, P = .014); and suppressed by KCC2-siRNA at P21 (isoflurane: slow-delta changed ratio from 16.13 ± 5.69 to 3.98 ± 2.35, 95% CI, -18.50 to -5.80, P = .002; sevoflurane: slow-delta changed ratio from 0.13 ± 2.82 to 3.23 ± 2.49, 95% CI, 3.02-10.79, P = .003). CONCLUSIONS: Enhancement of cortical EEG slow-delta oscillations by volatile anesthetics may require mature GABAergic inhibitory transmission during neonatal development.

[Two new benzoyl-sesquiterpenes from Mesona chinensis].

Mesona chinensis is a common medicinal and edible plant in the Lingnan region of China, which has extensive pharmacological activity. However, the study of its chemical constituents is not sufficient. In this study, a variety of modern chromatographic separation techniques were used to isolate two compounds from 95% ethanol extract of the grass parts of M. chinensis. Their absolute configurations were determined by ultraviolet spectroscopy(UV), infrared spectroscopy(IR), high resolution mass spectrometry(HR-ESI-MS), 1D and 2D nuclear magnetic resonance(1D NMR and 2D NMR), and single-crystal X-ray diffraction(SC-XRD). Specifically, they were two new benzoyl-sesquiterpenes and named mesonanol A and mesonanol B, respectively. The results of the pharmacological activity evaluation showed that neither of the two new compounds showed obvious antiviral and anti-inflammatory activities.

Ambient Air Processed Inverted Inorganic Perovskite Solar Cells with over 21% Efficiency Enabled by Multifunctional Ethacridine Lactate.

All-inorganic cesium lead triiodide perovskites (CsPbI3) have attracted increasing attention due to their good thermal stability, remarkable optoelectronic properties, and adaptability in tandem solar cells. However, N2-filled glovebox is generally required to strictly control the humidity during film fabrication due to the moisture-induced black-to-yellow phase transition, which remains a great hinderance for further commercialization. Herein, we report an effective approach via incorporating multifunctional ethacridine lactate (EAL) to mitigate moisture invasion and enable the fabrication of efficient inverted (p-i-n) CsPbI3 perovskite solar cells (PSCs) under ambient condition. It is revealed that the lactate anions accelerate the crystallization of CsPbI3, shortening the exposure time to moisture during film fabrication. Meanwhile, the conjugated backbone and multiple functional groups in the ethacridine cations can interact with I- and Pb2+ to reduce the undesired defects, stabilize the perovskite structure and facilitate the charge transport in the film. Moreover, EAL incorporation also leads to better energy alignment, thus favoring charge extraction at both upper and bottom interfaces. Consequently, the device efficiency and stability are enormously enhanced, with the champion efficiency reaching 21.08%. This even surpasses the highest value reported for the devices fabricated in glovebox, representing a record efficiency of inverted all-inorganic PSCs.

Highly connected and highly variable: A Core brain network during resting state supports Propofol-induced unconsciousness.

Despite that leading theories of consciousness make diverging predictions for where and how neural activity gives rise to subjective experience, they all seem to partially agree that the neural correlates of consciousness (NCC) require globally integrated brain activity across a network of functionally specialized modules. However, it is not clear yet whether such functional configurations would be able to identify the NCC. We scanned resting-state fMRI data from 21 subjects during wakefulness, propofol-induced sedation, and anesthesia. Graph-theoretical analyses were conducted on awake fMRI data to search for the NCC candidates as brain regions that exhibit both high rich-clubness and high modular variability, which were found to locate in prefrontal and temporoparietal cortices. Another independent data set of 10 highly-sampled subjects was used to validate the NCC distribution at the individual level. Brain module-based dynamic analysis revealed two discrete reoccurring brain states, one of which was dominated by the NCC candidates (state 1), while the other state was predominately composed of primary sensory/motor regions (state 2). Moreover, state 1 appeared to be temporally more stable than state 2, suggesting that the identified NCC members could sustain conscious content as metastable network representations. Finally, we showed that the identified NCC was modulated in terms of functional connectedness and modular variability in response to the loss of consciousness induced by propofol anesthesia. This work offers a framework to search for neural correlates of consciousness by charting the brain network topology and provides new insights into understanding the roles of different regions in underpinning human consciousness.

Autophagy modulates the stability of Wee1 and cell cycle G2/M transition.

The mammalian cell cycle is divided into four sequential phases, namely G1 (Gap 1), S (synthesis), G2 (Gap 2), and M (mitosis). Wee1, whose turnover is tightly and finely regulated, is a well-known kinase serving as a gatekeeper for the G2/M transition. However, the mechanism underlying the turnover of Wee1 is not fully understood. Autophagy, a highly conserved cellular process, maintains cellular homeostasis by eliminating intracellular aggregations, damaged organelles, and individual proteins. In the present study, we found autophagy deficiency in mouse liver caused G2/M arrest in two mouse models, namely Fip200 and Atg7 liver-specific knockout mice. To uncover the link between autophagy deficiency and G2/M transition, we combined transcriptomic and proteomic analysis for liver samples from control and Atg7 liver-specific knockout mice. The data suggest that the inhibition of autophagy increases the protein level of Wee1 without any alteration of its mRNA abundance. Serum starvation, an autophagy stimulus, downregulates the protein level of Wee1 in vitro. In addition, the half-life of Wee1 is extended by the addition of chloroquine, an autophagy inhibitor. LC3, a central autophagic protein functioning in autophagy substrate selection and autophagosome biogenesis, interacts with Wee1 as assessed by co-immunoprecipitation assay. Furthermore, overexpression of Wee1 leads to G2/M arrest both in vitro and in vivo. Collectively, our data indicate that autophagy could degrade Wee1-a gatekeeper of the G2/M transition, whereas the inhibition of autophagy leads to the accumulation of Wee1 and causes G2/M arrest in mouse liver.

Metabolic enzyme Suclg2 maintains tolerogenicity of regulatory dendritic cells diffDCs by suppressing Lactb succinylation.

Metabolic reprogramming plays a pivotal role in the differentiation and function of immune cells including dendritic cells (DCs). Regulatory DCs can be generated in regional tissue niches like splenic stroma and act as an important part of stromal control of immune response for the maintenance of immune tolerance. However, the metabolic alterations during splenic stroma-driven regulatory DCs differentiation and the metabolic enzyme involved in regulatory DCs function remain poorly understood. By combining metabolomic, transcriptomic, and functional investigations of mature DCs (maDCs) and diffDCs (regulatory DCs differentiated from activated mature DCs through coculturing with splenic stroma), here we identified succinate-CoA ligase subunit beta Suclg2 as a key metabolic enzyme that reprograms the proinflammatory status of mature DCs into a tolerogenic phenotype via preventing NF-κB signaling activation. diffDCs downregulate succinic acid levels and increase the Suclg2 expression along with their differentiation from mature DCs. Suclg2-interference impaired the tolerogenic function of diffDCs in inducing T cell apoptosis and enhanced activation of NF-κB signaling and expression of inflammatory genes CD40, Ccl5, and Il12b in diffDCs. Furthermore, we identified Lactb as a new positive regulator of NF-κB signaling in diffDCs whose succinylation at the lysine 288 residue was inhibited by Suclg2. Our study reveals that the metabolic enzyme Suclg2 is required to maintain the immunoregulatory function of diffDCs, adding mechanistic insights into the metabolic regulation of DC-based immunity and tolerance.

Effect of preoperative cervical conization before hysterectomy on survival and recurrence of patients with cervical cancer: A systematic review and meta-analysis.

OBJECTIVE: Conization plays a therapeutic and diagnostic role in cervical cancer. We conducted a systematic review and meta-analysis to compare the clinical outcomes of patients with cervical cancer who underwent hysterectomy with versus without preoperative cervical conization. METHODS: In this meta-analysis, we analyzed studies published in PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), and Clinical Trials. gov that appeared in our search from inception to May 1, 2022. RESULTS: Eleven studies with 4184 participants were included in this review. There were 2122 patients in the preoperative conization group and 2062 patients in the non-conization group. The meta-analysis showed that disease free survival (DFS) (hazard ratio [HR]: 0.23; 95% CI: 0.12-0.44; 1616 participants; P = 0.030) and overall survival (OS) (HR: 0.54; 95% CI: 0.33-0.86; 1835 participants; P = 0.597) were improved in the preoperative conization group compared with those in the non-conization group. The risk for recurrence was lower in the preoperative conization group than in the non-conization group (odds ratio [OR]: 0.29; 95% CI: 0.17-0.48; 1099 participants; P = 0.434). There was no significant statistical difference regarding intraoperative adverse events (OR: 0.81; 95% CI: 0.18-3.70; 530 participants; P = 0.555) and postoperative adverse events (OR: 1.24; 95% CI: 0.54-2.85; 530 participants; P = 0.170) between the preoperative conization group and non-conization group. In subgroup analysis, patients who benefited more from preoperative conization, had underwent minimally invasive surgery, had smaller local tumor lesions, and had no lymph node involvement. CONCLUSIONS: Preoperative conization before radical hysterectomy may have a protective effect in the treatment of early cervical cancer, with better survival and less recurrence, especially when the patient is at an early stage and undergoes minimally invasive surgery.