Immune checkpoint inhibitors-associated diabetes and ketoacidosis were found in FAERS: A Real-World Evidence Database Study.

OBJECTIVE: To investigate the risk of developing diabetes and ketoacidosis in clinical patients with Immune checkpoint inhibitors (ICIs). METHODS: We looked in the FDA Adverse Event Reporting System (FAERS) for reports of ICIs-associated DM and ketoacidosis between January 2004 and March 2022. We explored the signals using fourfold table-based proportional imbalance algorithms. Patient characteristics, country distribution, and outcomes of adverse reactions were described. Kruskal-Wallis test was used to compare the time of onset and prognosis of adverse reactions. RESULTS: A total of 2,110 reports of ICIs-related DM were included in the study. The largest number of reports was from Japan (752, 35.64%), followed by the United States and France (624, 29.57%; 183, 8.67%). Seven drugs detected signals of DM and ketoacidosis according to four proportional imbalance algorithms: Nivolumab, Pembrolizumab, Cemiplimab, Dostarlimab, Atezolizumab, Avelumab, and Durvalumab. Diabetes and ketoacidosis generally occured early in the course of ICIs treatment, the median time to event onset was 144.5 (interquartile range 27-199) days. ICIs-related diabetes and ketoacidosis events resulted in 934 major medical events (44.3%), 524 hospitalizations (24.8%), 60 life-threatening events (2.8%), 42 deaths (2.0%), and 39 disability events (1.8%). CONCLUSION: The study reveals the risk and characteristics of diabetes and ketoacidosis associated with ICIs, which may provide evidence for post-marketing evaluation. Careful consideration should be given to the possibility of an increased risk of diabetes and ketoacidosis after using ICIs, and careful monitoring for diabetes and ketoacidosis is recommended.

Tunable linear-to-circular terahertz polarization convertor enabled by a plasmonic nanocomposite metasurface.

We proposed and demonstrated a metasurface based terahertz polarizer consisting of an optically responsive nanocomposite and a flexible base body, which fulfilled the function of linear-to-circular polarization conversion in transmission mode. Meanwhile, as the dynamic and stretchable materials enable the active manipulation of conversion points, evident frequency shifts for circular polarization transformation were discovered by applying laser irradiation and tension. Hence the modulation of conversion points covered a broadband with combination of those two external excitations. This THz polarization convertor may find its applications in polarization controls and beam steering, which also provides a low-cost and large-scale manufacturable method to achieve versatile active THz devices.

Laparoscopic placement of left renal vein extravascular stenting in treatment of nutcracker syndrome: Techniques and long-term outcomes.

OBJECTIVES: We aimed to assess the feasibility and efficacy of laparoscopic extravascular stent in treatment of nutcracker syndrome by transperitoneal or retroperitoneal approach. METHODS: Seventy-six patients with nutcracker syndrome were retrospectively enrolled from a tertiary referral center, and underwent transperitoneal (63 patients) or retroperitoneal (13 patients) laparoscopic extravascular stent from March 2011 to December 2020. Surgical parameters, complications, imaging and clinical outcomes were collected and analyzed. RESULTS: All procedures were successfully carried out without open conversion. The median operation time, estimated blood loss, and postoperative hospital day were 120 (interquartile range [IQR]: 90-144) min, 20 (IQR: 10-30) ml, and 7 (IQR: 6-9) days. At a median follow-up of 52 (range: 9-127) months, 60 (79%) patients had complete symptom resolution, 14 (18%) patients had significant symptom improvement, and 2 (3%) patients reported no symptom improvement. Ninety-four percent (50/53) of hematuria, 91% (30/33) of proteinuria, and 89% (25/28) of flank/abdominal pain resolved after extravascular LRV stenting. No significant differences were detected in surgery parameters and recovery rates of clinical symptoms between two approaches (each p > 0.05). However, patients with transperitoneal approach need longer to achieve complete recovery compared with retroperitoneal approach (8.7 vs. 1.5 months, p = 0.016). CONCLUSIONS: Laparoscopic extravascular stent performed either transperitoneally or retroperitoneally is a feasible and effective option in treatment of nutcracker syndrome. Retroperitoneal laparoscopic extravascular stent required shorter time to achieve complete recovery, which should be considered whenever possible in surgical decision-making.

Evaluating Incidence, Location, and Predictors of Positive Surgical Margin Among Chinese Men Undergoing Robot-Assisted Radical Prostatectomy.

PURPOSE: To evaluate the incidence and locations of positive surgical margin (PSM) among Chinese men undergoing RARP and identify the preoperative predictors for PSM. METHODS: We retrospectively identified 393 patients who underwent RARP according to inclusion criteria by single surgeon in our hospital. PSM was defined as the presence of cancer adjacent to inked surface of the specimen and categorized into four groups based on locations: apex, posterolateral, base, and multifocal. Logistic regression analysis was performed to identify the predictors of overall and location-specific PSM. RESULTS: The overall PSM rate was 133/393 (34%). The PSM rates for pT2, pT3, and pT4 stage were 63/278 (23%), 50/89 (56%), and 20/26 (77%), respectively. The estimated rates for apical, posterolateral, basal, and multifocal PSM were 8%, 4%, 7%, and 14%, respectively. In univariate analysis, overall PSM related to tPSA, f/tPSA, percentage of positive needles, and Gleason score. Multifocal PSM correlated with smoking history, drinking history, tPSA, f/tPSA, percentage of positive needles, and Gleason score. In multivariate analysis, percentage of positive needles reminded the only independent predictor for overall (OR = 10.5, 95% CI: 2.58-44.4) and basal PSM (OR = 24.0, 95% CI: 3.22-179.4). The f/tPSA (OR = 2.59, 95% CI: 2.18-5.71) and percentage of positive needles (OR = 31.0, 95% CI: 3.17-303) were independent risk factors for multifocal PSM. CONCLUSION: The multifocal sites were the most common location of positive surgical margin, followed by apical and basal sites among Chinese patients undergoing RARP. The percentage of positive needles was an independent predictor for overall, basal, and multifocal PSM.

MALAT1 rs619586 polymorphism functions as a prognostic biomarker in the management of differentiated thyroid carcinoma.

This study aimed to explore the roles of miR-214 and MALAT1 rs619586 polymorphism in the control and survival of differentiated thyroid carcinoma (DTC) via Cox regression analyses. The levels of MALAT1, miR-214, and CTNNB1 in different experimental groups were compared to study the interaction among MALAT1, miR-214, and CTNNB1. MTT and colony assays were used to investigate the role of rs619586 polymorphism in cell growth. The G allele of rs619586 polymorphism obviously decreased the 5-year survival of patients with DTC. Additionally, compared with AA-genotyped patients, patients carrying the AG/GG genotypes of MALAT1 rs619586 polymorphism showed much higher levels of DTC grade and CTNNB1 expression, along with lower levels of MALAT1 and miR-214 expression. Furthermore, the transcription activity of MALAT1 was significantly lowered by the rs619586G allele or miR-214 mimic, while the miR-214 inhibitor upregulated the luciferase activity of MALAT1. Additionally, miR-214 inhibited CTNNB1 expression by targeting CTNNB1 3'-untranslated region. Finally, the G allele of MALAT1 rs619586 polymorphism apparently promoted cell proliferation. Our study indicated that miR-214 inhibited MALAT1 expression by directly binding to the G allele of MALAT1 rs619586 polymorphism, thus inhibiting CTNNB1 expression and promoting cell proliferation in the pathogenesis of DTC. Therefore, MALAT1 rs619586 polymorphism could be used to predict the prognosis of DTC.

Recent advances in functionalized ferrite nanoparticles: From fundamentals to magnetic hyperthermia cancer therapy.

Cancers are fatal diseases that lead to most death of human beings, which urgently require effective treatments methods. Hyperthermia therapy employs magnetic nanoparticles (MNPs) as heating medium under external alternating magnetic field. Among various MNPs, ferrite nanoparticles (FNPs) have gained significant attention for hyperthermia therapy due to their exceptional magnetic properties, high stability, favorable biological compatibility, and low toxicity. The utilization of FNPs holds immense potential for enhancing the effectiveness of hyperthermia therapy. The main hurdle for hyperthermia treatment includes optimizing the heat generation capacity of FNPs and controlling the local temperature of tumor region. This review aims to comprehensively evaluate the magnetic hyperthermia treatment (MHT) of FNPs, which is accomplished by elucidating the underlying mechanism of heat generation and identifying influential factors. Based upon fundamental understanding of hyperthermia of FNPs, valuable insights will be provided for developing efficient nanoplatforms with enhanced accuracy and magnetothermal properties. Additionally, we will also survey current research focuses on modulating FNPs' properties, external conditions for MHT, novel technical methods, and recent clinical findings. Finally, current challenges in MHT with FNPs will be discussed while prospecting future directions.

Transrectal versus transperineal prostate biopsy for cancer detection in patients with gray-zone prostate-specific antigen: a multicenter, real-world study.

Knowledge about the effect of different prostate biopsy approaches on the prostate cancer detection rate (CDR) in patients with gray-zone prostate-specific antigen (PSA) is limited. We performed this study to compare the CDR among patients who underwent different biopsy approaches and had rising PSA levels in the gray zone. Two hundred and twenty-two patients who underwent transrectal prostate biopsy (TRB) and 216 patients who underwent transperineal prostate biopsy (TPB) between June 2016 and September 2022 were reviewed in this study. In addition, 110 patients who received additional targeted biopsies following the systematic TPB were identified. Clinical parameters, including age, PSA derivative, prostate volume (PV), and needle core count, were recorded. The data were fitted via propensity score matching (PSM), adjusting for potential confounders. TPB outperformed TRB in terms of the CDR (49.6% vs 28.3%, P = 0.001). The clinically significant prostate cancer (csPCa) detection rate was not significantly different between TPB and TRB (78.6% vs 68.8%, P = 0.306). In stratified analysis, TPB outperformed TRB in CDR when the age of patients was 65-75 years (59.0% vs 22.0%, P < 0.001), when PV was 25.00-50.00 ml (63.2% vs 28.3%, P < 0.001), and when needle core count was no more than 12 (58.5% vs 31.5%, P = 0.005). The CDR ( P = 0.712) and detection rate of csPCa ( P = 0.993) did not significantly differ among the systematic, targeted, and combined biopsies. TPB outperformed TRB in CDR for patients with gray-zone PSA. Moreover, performing target biopsy after systematic TPB provided no additional benefits in CDR.

Gold nanoclusters with enhanced near-infrared emission and its application as sensors for biological molecules.

Ultrasmall gold nanoclusters (NCs) have been engineered as a new kind of functional material due to their excellent photoluminescence properties. However, the synthesis of highly luminescent water-soluble nanoclusters with near-infrared (NIR) emission remains limited. Herein, we developed a pH-regulated strategy to facilitate the construction of self-assemblies with enhanced luminescence based on aggregation-induced emission (AIE) strategy. Using 2-mercaptobenzoic acid (MBA) as reductant and stabilizer, the original weakly luminescent AuNCs exhibited intense emission by adjusting pH controllably. The formation of compact organized nanostructures could effectively restrict the rotation and vibration of capping ligands by non-covalent interactions, which reduced the nonradiative relaxation from excited states and finally improved the emission properties of AuNCs. Moreover, the assemblies possess many intriguing features including bright NIR luminescence and excellent biocompatibility, which could be used as luminous probes in biological molecules sensing (tyrosinase (TYR) and dopamine (DA)) and promising candidates for cell imaging. This study provides a simple and feasible strategy for developing metal NCs-based smart optical materials in the field of bioscience.

HDAC3 Inhibition Promotes Antitumor Immunity by Enhancing CXCL10-Mediated Chemotaxis and Recruiting of Immune Cells.

It is generally believed that histone deacetylase (HDAC) inhibitors, which represent a new class of anticancer agents, exert their antitumor activity by directly causing cell-cycle arrest and apoptosis of tumor cells. However, in this study, we demonstrated that class I HDAC inhibitors, such as Entinostat and Panobinostat, effectively suppressed tumor growth in immunocompetent but not immunodeficient mice. Further studies with Hdac1, 2, or 3 knockout tumor cells indicated that tumor-specific inactivation of HDAC3 suppressed tumor growth by activating antitumor immunity. Specifically, we found that HDAC3 could directly bind to promotor regions and inhibit the expression of CXCL9, 10, and 11 chemokines. Hdac3-deficient tumor cells expressed high levels of these chemokines, which suppressed tumor growth in immunocompetent mice by recruiting CXCR3+ T cells into the tumor microenvironment (TME). Furthermore, the inverse correlation between HDAC3 and CXCL10 expression in hepatocellular carcinoma tumor tissues also suggested HDAC3 might be involved in antitumor immune regulation and patient survival. Thus, our studies have illustrated that HDAC3 inhibition suppresses tumor growth by enhancing immune cell infiltration into the TME. This antitumor mechanism may be helpful in guiding HDAC3 inhibitor-based treatment.

Tapped area detection and new tapping line location for natural rubber trees based on improved mask region convolutional neural network.

Aiming at the problem that the rubber tapping robot finds it difficult to accurately detect the tapped area and locate the new tapping line for natural rubber trees due to the influence of the rubber plantation environment during the rubber tapping operation, this study proposes a method for detecting the tapped area and locating the new tapping line for natural rubber trees based on the improved mask region convolutional neural network (Mask RCNN). First, Mask RCNN was improved by fusing the attention mechanism into the ResNeXt, modifying the anchor box parameters, and adding a tiny fully connected layer branch into the mask branch to realize the detection and rough segmentation of the tapped area. Then, the fine segmentation of the existing tapping line was realized by combining edge detection and logic operation. Finally, the existing tapping line was moved down a certain distance along the center line direction of the left and right edge lines of the tapped area to obtain the new tapping line. The tapped area detection results of 560 test images showed that the detection accuracy, segmentation accuracy, detection average precision, segmentation average precision, and intersection over union values of the improved Mask RCNN were 98.23%, 99.52%, 99.6%, 99.78%, and 93.71%, respectively. Compared with other state-of-the-art approaches, the improved Mask RCNN had better detection and segmentation performance, which could better detect and segment the tapped area of natural rubber trees under different shooting conditions. The location results of 560 new tapping lines under different shooting conditions showed that the average location success rate of new tapping lines was 90% and the average location time was 0.189 s. The average values of the location errors in the x and y directions were 3 and 2.8 pixels, respectively, and the average value of the total location error was 4.5 pixels. This research not only provides a location method for the new tapping line for the rubber tapping robot but also provides theoretical support for the realization of rubber tapping mechanization and automation.

Manipulating the Assembly of Au Nanoclusters for Luminescence Enhancement and Circularly Polarized Luminescence.

Au nanocluster (AuNCs)-based luminescent functional materials have attracted the interest of researchers owing to their small size, tractable surface modification, phosphorescence lifetime and biocompatibility. However, the poor luminescence quantum yield (QY) of AuNCs limits their practical applications. Herein, we synthesized a type of AuNCs modified by 4,6-diamino-2-mercaptopyrimidine hydrate (DPT-AuNCs). Furthermore, organic acids, i.e., citric acid (CA) and tartaric acid (TA), were chosen for co-assembly with DPT-AuNCs to produce AuNCs-based luminescent materials with enhanced emission. Firstly, it was found that CA could significantly enhance the emission of DPT-AuNCs with the formation of red emission nanofibers (QY = 17.31%), which showed a potential for usage in I- detection. The n···π/π···π interaction between the CA and the DPT ligand was proposed as crucial for the emission. Moreover, chiral TA could not only improve the emission of DPT-AuNCs, but could also transfer its chirality to DPT-AuNCs and induce the formation of circularly polarized luminescence (CPL)-active nanofibers. It was demonstrated that the CPL signal could increase 4.6-fold in a ternary CA/TA/DPT-AuNCs co-assembly system. This work provides a convenient way to build AuNCs-based luminescent materials as probes, and opens a new avenue for building CPL-active materials by achiral NCs through a co-assembly strategy.

Deeper insights into the effects of substrate to inoculum ratio selection on the relationship of kinetic parameters, microbial communities, and key metabolic pathways during the anaerobic digestion of food waste.

The substrate to inoculum ratio (S/I) is a crucial factor that affects not only the stability of the anaerobic digestion (AD) of food waste (FW) but also the methanogenic capacity of the substrate. This is of great significance for the start-up of small-scale batch reactors and the directional regulation of methanogenesi and organic acid production. Most studies have merely clarified the optimal S/I ratio for methane production and revealed the basic composition of microbial communities. However, the mechanism of microbial interactions and the metabolic pathways behind the optimal S/I ratio still remain unclear. Herein, the effects of different S/I ratios (VS basis) on the relationship of kinetic parameters, microbial communities, and metabolic pathways during the AD process of FW were holistically explored. The results revealed that high S/I ratios (4:1, 3:1, 2:1, and 1:1) were prone to irreversible acidification, while low S/I ratios (1:2, 1:3, and 1:4) were favorable for methanogenesis. Moreover, a kinetic analysis demonstrated that the methane yield of S/I = 1:3 were the highest. A bioinformatics analysis found that the diversity of bacteria and archaea of S/I = 1:3 were the most abundant, and the enrichment of Bacteroides and Synergistetes could help to establish a syntrophic relationship with hydrogenotrophic methanogens, which could aid in the fulfillment of a unique niche in the system. In contrast to the findings with the other S/I ratios, the cooperation among microbes in S/I = 1:3 was more apparent. Notably, the abundances of genes encoding key enzymes involved in the methanogenesis pathway under S/I = 1:3 were all the highest. This knowledge will be helpful for revealing the influence mechanism of the ratio relationship between microorganisms and substrates on the biochemical metabolic process of anaerobic digestion, thereby providing effective guidance for the directional regulation of FW batch anaerobic reactors.

LncRNA B4GALT1-AS1 promotes non-small cell lung cancer cell growth via increasing ZEB1 level by sponging miR-144-3p.

Background: Long noncoding RNAs (lncRNAs) are emerging as key players in the development and progression of cancer. Several malignancies involve dysregulated long noncoding ribonucleic acids (lncRNAs) in non-small cell lung cancer cell growth and their aggressive phenotypes. LncRNA B4GALT1-AS1 is important in the advancement of various malignancies, although its contribution to non-small cell lung cancer (NSCLC) remains unexplored. Methods: LncRNA B4GALT1-AS1 in NSCLC tissues was detected and further validated in a cohort of non-small cell lung cancer tissues. The effects of lncRNA B4GALT1-AS1 on proliferation were determined by in vitro experiments. The B4GALT1-AS1-miR-144-3p-ZEB1 axis was assessed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Furthermore, the mechanism of B4GALT1-AS1 was investigated using loss-of-function assays in vitro. Results: We showed significant upregulation of B4GALT1-AS1 in cell lines and tissues of NSCLC. B4GALT1-AS1 knockdown impeded the in vitro proliferation-related characteristics of the NSCLC cells. The demonstration of the binding capacity of B4GALT1-AS1 and miR-144-3p was predicted by bioinformatics and luciferase reporter activity assay. The B4GALT1-AS1 and miR-144-3p interaction was shown by using rescue experiments. NSCLC has a positive association with its target, zinc finger e-box binding homeobox 1 (ZEB1). Conclusions: In summary, the progression of NSCLC was facilitated by lncRNA B4GALT1-AS1 via interaction with miR-144-3p and positive regulation of ZEB1 expression.

CDK2 Inhibition Enhances Antitumor Immunity by Increasing IFN Response to Endogenous Retroviruses.

Inhibitors of cyclin-dependent kinase-2 (CDK2) are commonly used against several solid tumors, and their primary mechanisms of action were thought to include cell proliferation arrest, induction of cancer cell apoptosis and induction of differentiation. Here, we found that CDK2 inhibition by either small molecular inhibitors or genetic Cdk2 deficiency promoted antitumor immunity in murine models of fibrosarcoma and lung carcinoma. Mechanistically, CDK2 inhibition reduced phosphorylation of RB protein and transcription of E2F-mediated DNA methyltransferase 1 (DNMT1), which resulted in increased expression of endogenous retroviral RNA and type I IFN (IFN-I) response. The increased IFN-I response subsequently promoted antitumor immunity by enhancing tumor antigen presentation and CD8+ T-cell infiltration. Our studies provide evidence that inhibition of CDK2 in cancer cells suppresses tumor growth by enhancing antitumor immune responses in the tumor microenvironment, suggesting a new mechanism to enhance antitumor immunity by CDK2 inhibitors.

Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1.

BACKGROUND: In 2015, herpes simplex virus 1 (HSV-1)-derived talimogene laherparepvec (T-VEC) was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer treatment. However, its antitumor application is limited to local treatment of melanoma, and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor immunity. We hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this virus. METHODS: We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against HSV-1. Then, we tested the effect of BACH1 deficiency on immunogenic cell death induced by HSV-1. Furthermore, we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor models. RESULTS: We identified eight IFN-stimulated genes (ISGs) controlling HSV-1 replication, among which BTB and CNC homology 1 (BACH1) suppressed HSV-1 replication by inhibiting the transcription of ICP4, ICP27, and UL39. Loss of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis, HMGB1 secretion, and calreticulin exposure in tumor cells. More importantly, hemin, an FDA-approved drug known to downregulate BACH1, significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor site. CONCLUSIONS: Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.

In utero exposure to polychlorinated biphenyls and reduced neonatal physiological development from Guiyu, China.

Primitive electronic-waste recycling resulted in serious pollution of polychlorinated biphenyls (PCBs) in the environment of Guiyu, China. We aimed to assess body burdens of PCBs and potential health risks for neonates. Umbilical cord blood (UCB) samples were collected from Guiyu, and the control area of Chaonan, China. PCBs in UCB were determined by gas chromatography coupled with mass spectrometry. The median ∑PCBs concentration was 338.56 ng g⁻¹ lipid in UCB samples from Guiyu, vs. 140.16 ng g⁻¹ lipid in samples from Chaonan. Mothers' involvement in electronic-waste recycling activities and house used as family workshop were the significant factors that contributed to ∑PCBs level. Some individual PCB congeners were found to correlate with reduced neonatal height, weight, Apgar scores, gestational age, and body mass index (BMI). Difference of ∑PCBs level was found between normal birth and adverse birth outcomes. Neonates from Guiyu are exposed to high levels of PCBs; prenatal exposure to PCBs appears to influence neonatal health, but still needs further confirmation.

Assessment of cadmium exposure for neonates in Guiyu, an electronic waste pollution site of China.

This study aimed to determine the levels of placental cadmium (PCd) and cord blood cadmium (CBCd) and the resulting expression of placental metallothionein (MT) in neonates and to investigate cadmium (Cd) exposure levels in neonates and mothers who live in Guiyu, China, an electronic waste (e-waste) pollution site. Among the 423 mothers included in the study from 2004/2005 to 2007, 289 lived in Guiyu (exposed group) and 134 lived in Chaonan, located 10 km away from Guiyu (controls) and had never been exposed to e-waste pollution. CBCd and PCd levels were measured by atomic absorption spectrometry. Placental MT was examined by immunohistochemistry. Information on maternal and neonatal characteristics and exposure conditions was obtained from hospital records and by personal interviews. For the 3 years, the median CBCd was higher for Guiyu neonates than for controls (3.61 vs. 1.25 µg/L), with 25.61% of Guiyu subjects exhibiting a median CBCd that exceeded the safety limit defined by the World Health Organization (5 µg/L), as compared with 14.18% of control neonates (p < 0.01). In Guiyu, the mean PCd was higher than that for controls (0.17 ± 0.48 vs. 0.10 ± 0.11 µg/g, p ≤ 0.01). The high levels of CBCd and PCd were significantly associated with parents' occupational and environmental exposure to e-waste recycling pollutants. Staining for MT was positive and dense for 67.00% (67/100) of Guiyu neonates as compared with 32.69% (17/52) of controls (p < 0.01). Exposure to e-waste recycling pollutants increased Cd exposure in neonates, which was accompanied by increased placental MT expression.

Fabrication of a chiral luminescent hydrogel from gold nanoclusters via molecular recognition.

A novel supramolecular chiral hydrogel with enhanced emission was obtained by the co-assembly of achiral thiobarbituric acid-modified gold nanoclusters (TBA-AuNCs) with chiral histidine molecules. Chirality transfer from histidine to the supramolecular hydrogels was achieved through the π-π stacking and intermolecular H-bonding based on molecular recognition. This work gives a creative strategy for the building of chiral nanocluster-based materials.

Lateral Habenula Glutamatergic Neurons Modulate Isoflurane Anesthesia in Mice.

Since their introduction in the 1840s, one of the largest mysteries of modern anesthesia are how general anesthetics create the state of reversible loss of consciousness. Increasing researchers have shown that neural pathways that regulate endogenous sleep-wake systems are also involved in general anesthesia. Recently, the Lateral Habenula (LHb) was considered as a hot spot for both natural sleep-wake and propofol-induced sedation; however, the role of the LHb and related pathways in the isoflurane-induced unconsciousness has yet to be identified. Here, using real-time calcium fiber photometry recordings in vivo, we found that isoflurane reversibly increased the activity of LHb glutamatergic neurons. Then, we selectively ablated LHb glutamatergic neurons in Vglut2-cre mice, which caused a longer induction time and less recovery time along with a decrease in delta-band power in mice under isoflurane anesthesia. Furthermore, using a chemogenetic approach to specifically activate LHb glutamatergic neurons shortened the induction time and prolonged the recovery time in mice under isoflurane anesthesia with an increase in delta-band power. In contrast, chemogenetic inhibition of LHb glutamatergic neurons was very similar to the effects of selective lesions of LHb glutamatergic neurons. Finally, optogenetic activation of LHb glutamatergic neurons or the synaptic terminals of LHb glutamatergic neurons in the rostromedial tegmental nucleus (RMTg) produced a hypnosis-promoting effect in isoflurane anesthesia with an increase in slow wave activity. Our results suggest that LHb glutamatergic neurons and pathway are vital in modulating isoflurane anesthesia.

Neurons in the Locus Coeruleus Modulate the Hedonic Effects of Sub-Anesthetic Dose of Propofol.

Propofol is a worldwide-used intravenous general anesthetic with ideal effects, but hedonic effects of propofol have been reported and cause addictive issue. There is little known about the neurobiological mechanism of hedonic effects of propofol. Increasing researches have shown that the dopaminergic nervous system of the ventral tegmental area (VTA) and the noradrenergic system of locus coeruleus (LC) play a crucial role in hedonic experiences, which are putative sites for mediating the hedonic effects of propofol. In the present study, rat hedonic response scale and place conditioning paradigm were employed to examine the euphoric effects of propofol. In vivo GCaMP-based (AVV-hSyn-GCaMP6s) fiber photometry calcium imaging was used to monitor the real-time neuronal activity in VTA and LC area in rats exhibiting propofol-induced euphoric behaviors. Then DREADDs (designer receptors exclusively activated by designer drugs) modulation using rAAV-hSyn-hM4D(Gi)-EGFP was performed to confirm the neuronal substrate that mediates the euphoric effects of propofol. The score of hedonic facial responses was significantly increased in the 4 mg/kg group compared with that of the 0 mg/kg group. The locomotor activity in the propofol-paired compartment was significantly increased at the 4 mg/kg dose compared with that of the saline-paired group. When compared with the 0 mg/kg group, the place preference increased in the 4 mg/kg group. Administration of 4 mg/kg of propofol triggers reliable increases in GcaMP fluorescence. However, in the VTA GcaMP-expressing rats, administration of 4 mg/kg of propofol did not induce any change of GcaMP signals. The facial score and the place preference, which increased by 4 mg/kg propofol were abolished by chemogenetic inhibition of the neuronal activity in the LC area. Our results suggest that LC noradrenergic neurons, not VTA dopaminergic neurons, are directly involved in the hedonic effects of sub-anesthetic dose of propofol.