Immunogenic cell stress and death in the treatment of cancer.

The successful treatment of oncological malignancies which results in long-term disease control or the complete eradication of cancerous cells necessitates the onset of adaptive immune responses targeting tumor-specific antigens. Such desirable anticancer immunity can be triggered via the induction of immunogenic cell death (ICD) of cancer cells, thus converting malignant cells into an in situ vaccine that elicits T cell mediated adaptive immune responses and establishes durable immunological memory. The exploration of ICD for cancer treatment has been subject to extensive research. However, functional heterogeneity among ICD activating therapies in many cases requires specific co-medications to achieve full-blown efficacy. Here, we described the hallmarks of ICD and classify ICD activators into three distinct functional categories namely, according to their mode of action: (i) ICD inducers, which increase the immunogenicity of malignant cells, (ii) ICD sensitizers, which prime cellular circuitries for ICD induction by conventional cytotoxic agents, and (iii) ICD enhancers, which improve the perception of ICD signals by antigen presenting dendritic cells. Altogether, ICD induction, sensitization and enhancement offer the possibility to convert well-established conventional anticancer therapies into immunotherapeutic approaches that activate T cell-mediated anticancer immunity.

DNA demethylation in the hypothalamus promotes transcription of Agtr1a and Slc12a2 and hypertension development.

Increased expression of angiotensin II AT1A receptor (encoded by Agtr1a) and Na+-K+-Cl- cotransporter-1 (NKCC1, encoded by Slc12a2) in the hypothalamic paraventricular nucleus (PVN) contributes to hypertension development. However, little is known about their transcriptional control in the PVN in hypertension. DNA methylation is a critical epigenetic mechanism that regulates gene expression. Here, we determined whether transcriptional activation of Agtr1a and Slc12a2 results from altered DNA methylation in spontaneously hypertensive rats (SHR). Methylated DNA immunoprecipitation and bisulfite sequencing-PCR showed that CpG methylation at Agtr1a and Slc12a2 promoters in the PVN was progressively diminished in SHR compared with normotensive Wistar-Kyoto rats (WKY). Chromatin immunoprecipitation-quantitative PCR revealed that enrichment of DNA methyltransferases (DNMT1 and DNMT3A) and methyl-CpG binding protein 2, a DNA methylation reader protein, at Agtr1a and Slc12a2 promoters in the PVN was profoundly reduced in SHR compared with WKY. By contrast, the abundance of ten-eleven translocation enzymes (TET1-3) at Agtr1a and Slc12a2 promoters in the PVN was much greater in SHR than in WKY. Furthermore, microinjecting of RG108, a selective DNMT inhibitor, into the PVN of WKY increased arterial blood pressure and correspondingly potentiated Agtr1a and Slc12a2 mRNA levels in the PVN. Conversely, microinjection of C35, a specific TET inhibitor, into the PVN of SHR markedly reduced arterial blood pressure, accompanied by a decrease in Agtr1a and Slc12a2 mRNA levels in the PVN. Collectively, our findings suggest that DNA hypomethylation resulting from the DNMT/TET switch at gene promoters in the PVN promotes transcription of Agtr1a and Slc12a2 and hypertension development.

Brain α2δ-1-Bound NMDA Receptors Drive Calcineurin Inhibitor-Induced Hypertension.

BACKGROUND: Calcineurin is highly enriched in immune T cells and the nervous system. Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), are the cornerstone of immunosuppressive regimens for preserving transplanted organs and tissues. However, these drugs often cause persistent hypertension owing to excess sympathetic outflow, which is maintained by N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory input to the hypothalamic paraventricular nucleus (PVN). It is unclear how calcineurin inhibitors increase NMDAR activity in the PVN to augment sympathetic vasomotor activity. α2δ-1 (encoded by the Cacna2d1 gene), known colloquially as a calcium channel subunit, is a newly discovered NMDAR-interacting protein. In this study, we determined whether α2δ-1 plays a role in calcineurin inhibitor-induced synaptic NMDAR hyperactivity in the PVN and hypertension development. METHODS: Immunoblotting and coimmunoprecipitation assays were used to quantify synaptic protein levels and the physical interaction between GluN1 (the obligatory NMDAR subunit) and α2δ-1. Whole-cell patch-clamp recordings of retrogradely labeled, spinally projecting PVN were conducted in perfused brain slices to measure presynaptic and postsynaptic NMDAR activity. Radio-telemetry was implanted in rodents to continuously record arterial blood pressure in conscious states. RESULTS: Prolonged treatment with FK506 in rats significantly increased protein levels of α2δ-1, GluN1, and the α2δ-1-GluN1 complex in PVN synaptosomes. These effects were blocked by inhibiting α2δ-1 with gabapentin or interrupting the α2δ-1-NMDAR interaction with an α2δ-1 C-terminus peptide. Treatment with FK506 potentiated the activity of presynaptic and postsynaptic NMDARs in spinally projecting PVN neurons; such effects were abolished by gabapentin, Cacna2d1 knockout, or α2δ-1 C-terminus peptide. Furthermore, microinjection of α2δ-1 C-terminus peptide into the PVN diminished renal sympathetic nerve discharges and arterial blood pressure that had been increased by FK506 treatment. Remarkably, concurrent administration of gabapentin prevented the development of FK506-induced hypertension in rats. Additionally, FK506 treatment induced sustained hypertension in wild-type mice but not in Cacna2d1 knockout mice. CONCLUSIONS: α2δ-1 is essential for calcineurin inhibitor-induced increases in synaptic NMDAR activity in PVN presympathetic neurons and sympathetic outflow. Thus, α2δ-1 and α2δ-1-bound NMDARs represent new targets for treating calcineurin inhibitor-induced hypertension. Gabapentinoids (gabapentin and pregabalin) could be repurposed for treating calcineurin inhibitor-induced neurogenic hypertension.

mGluR5 from Primary Sensory Neurons Promotes Opioid-Induced Hyperalgesia and Tolerance by Interacting with and Potentiating Synaptic NMDA Receptors.

Aberrant activation of presynaptic NMDARs in the spinal dorsal horn is integral to opioid-induced hyperalgesia and analgesic tolerance. However, the signaling mechanisms responsible for opioid-induced NMDAR hyperactivity remain poorly identified. Here, we show that repeated treatment with morphine or fentanyl reduced monomeric mGluR5 protein levels in the dorsal root ganglion (DRG) but increased levels of mGluR5 monomers and homodimers in the spinal cord in mice and rats of both sexes. Coimmunoprecipitation analysis revealed that monomeric and dimeric mGluR5 in the spinal cord, but not monomeric mGluR5 in the DRG, directly interacted with GluN1. By contrast, mGluR5 did not interact with µ-opioid receptors in the DRG or spinal cord. Repeated morphine treatment markedly increased the mGluR5-GluN1 interaction and protein levels of mGluR5 and GluN1 in spinal synaptosomes. The mGluR5 antagonist MPEP reversed morphine treatment-augmented mGluR5-GluN1 interactions, GluN1 synaptic expression, and dorsal root-evoked monosynaptic EPSCs of dorsal horn neurons. Furthermore, CRISPR-Cas9-induced conditional mGluR5 knockdown in DRG neurons normalized mGluR5 levels in spinal synaptosomes and NMDAR-mediated EPSCs of dorsal horn neurons increased by morphine treatment. Correspondingly, intrathecal injection of MPEP or conditional mGluR5 knockdown in DRG neurons not only potentiated the acute analgesic effect of morphine but also attenuated morphine treatment-induced hyperalgesia and tolerance. Together, our findings suggest that opioid treatment promotes mGluR5 trafficking from primary sensory neurons to the spinal dorsal horn. Through dimerization and direct interaction with NMDARs, presynaptic mGluR5 potentiates and/or stabilizes NMDAR synaptic expression and activity at primary afferent central terminals, thereby maintaining opioid-induced hyperalgesia and tolerance.SIGNIFICANCE STATEMENT Opioids are essential analgesics for managing severe pain caused by cancer, surgery, and tissue injury. However, these drugs paradoxically induce pain hypersensitivity and tolerance, which can cause rapid dose escalation and even overdose mortality. This study demonstrates, for the first time, that opioids promote trafficking of mGluR5, a G protein-coupled glutamate receptor, from peripheral sensory neurons to the spinal cord; there, mGluR5 proteins dimerize and physically interact with NMDARs to augment their synaptic expression and activity. Through dynamic interactions, the two distinct glutamate receptors mutually amplify and sustain nociceptive input from peripheral sensory neurons to the spinal cord. Thus, inhibiting mGluR5 activity or disrupting mGluR5-NMDAR interactions could reduce opioid-induced hyperalgesia and tolerance and potentiate opioid analgesic efficacy.

NMDA Receptors at Primary Afferent-Excitatory Neuron Synapses Differentially Sustain Chemotherapy- and Nerve Trauma-Induced Chronic Pain.

The spinal dorsal horn contains vesicular glutamate transporter-2 (VGluT2)-expressing excitatory neurons and vesicular GABA transporter (VGAT)-expressing inhibitory neurons, which normally have different roles in nociceptive transmission. Spinal glutamate NMDAR hyperactivity is a crucial mechanism of chronic neuropathic pain. However, it is unclear how NMDARs regulate primary afferent input to spinal excitatory and inhibitory neurons in neuropathic pain. Also, the functional significance of presynaptic NMDARs in neuropathic pain has not been defined explicitly. Here we showed that paclitaxel treatment or spared nerve injury (SNI) similarly increased the NMDAR-mediated mEPSC frequency and dorsal root-evoked EPSCs in VGluT2 dorsal horn neurons in male and female mice. By contrast, neither paclitaxel nor SNI had any effect on mEPSCs or evoked EPSCs in VGAT neurons. In mice with conditional Grin1 (gene encoding GluN1) KO in primary sensory neurons (Grin1-cKO), paclitaxel treatment failed to induce pain hypersensitivity. Unexpectedly, SNI still caused long-lasting pain hypersensitivity in Grin1-cKO mice. SNI increased the amplitude of puff NMDA currents in VGluT2 neurons and caused similar depolarizing shifts in GABA reversal potentials in WT and Grin1-cKO mice. Concordantly, spinal Grin1 knockdown diminished SNI-induced pain hypersensitivity. Thus, presynaptic NMDARs preferentially amplify primary afferent input to spinal excitatory neurons in neuropathic pain. Although presynaptic NMDARs are required for chemotherapy-induced pain hypersensitivity, postsynaptic NMDARs in spinal excitatory neurons play a dominant role in traumatic nerve injury-induced chronic pain. Our findings reveal the divergent synaptic connectivity and functional significance of spinal presynaptic and postsynaptic NMDARs in regulating cell type-specific nociceptive input in neuropathic pain with different etiologies.SIGNIFICANCE STATEMENT Spinal excitatory neurons relay input from nociceptors, whereas inhibitory neurons repress spinal nociceptive transmission. Chronic nerve pain is associated with aberrant NMDAR activity in the spinal dorsal horn. This study demonstrates, for the first time, that chemotherapy and traumatic nerve injury preferentially enhance the NMDAR activity at primary afferent-excitatory neuron synapses but have no effect on primary afferent input to spinal inhibitory neurons. NMDARs in primary sensory neurons are essential for chemotherapy-induced chronic pain, whereas nerve trauma causes pain hypersensitivity predominantly via postsynaptic NMDARs in spinal excitatory neurons. Thus, presynaptic and postsynaptic NMDARs at primary afferent-excitatory neuron synapses are differentially engaged in chemotherapy- and nerve injury-induced chronic pain and could be targeted respectively for treating these painful conditions.

Calcineurin regulates synaptic Ca2+-permeable AMPA receptors in hypothalamic presympathetic neurons via α2δ-1-mediated GluA1/GluA2 assembly.

Hypertension is a major adverse effect of calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, used clinically as immunosuppressants. Calcineurin inhibitor-induced hypertension (CIH) is linked to augmented sympathetic output from the hypothalamic paraventricular nucleus (PVN). GluA2-lacking, Ca2+-permeable AMPA receptors (CP-AMPARs) are a key feature of glutamatergic synaptic plasticity, yet their role in CIH remains elusive. Here, we found that systemic administration of FK506 in rats significantly increased serine phosphorylation of GluA1 and GluA2 in PVN synaptosomes. Strikingly, FK506 treatment reduced GluA1/GluA2 heteromers in both synaptosomes and endoplasmic reticulum-enriched fractions from the PVN. Blocking CP-AMPARs with IEM-1460 induced a larger reduction of AMPAR-mediated excitatory postsynaptic current (AMPAR-EPSC) amplitudes in retrogradely labelled, spinally projecting PVN neurons in FK506-treated rats than in vehicle-treated rats. Furthermore, FK506 treatment shifted the current-voltage relationship of AMPAR-EPSCs from linear to inward rectification in labelled PVN neurons. FK506 treatment profoundly enhanced physical interactions of α2δ-1 with GluA1 and GluA2 in the PVN. Inhibiting α2δ-1 with gabapentin, α2δ-1 genetic knockout, or disrupting α2δ-1-AMPAR interactions with an α2δ-1 C terminus peptide restored GluA1/GluA2 heteromers in the PVN and diminished inward rectification of AMPAR-EPSCs in labelled PVN neurons induced by FK506 treatment. Additionally, microinjection of IEM-1460 or α2δ-1 C terminus peptide into the PVN reduced renal sympathetic nerve discharges and arterial blood pressure elevated in FK506-treated rats but not in vehicle-treated rats. Thus, calcineurin in the hypothalamus constitutively regulates AMPAR subunit composition and phenotypes by controlling GluA1/GluA2 interactions with α2δ-1. Synaptic CP-AMPARs in PVN presympathetic neurons contribute to augmented sympathetic outflow in CIH. KEY POINTS: Systemic treatment with the calcineurin inhibitor increases serine phosphorylation of synaptic GluA1 and GluA2 in the PVN. Calcineurin inhibition enhances the prevalence of postsynaptic Ca2+-permeable AMPARs in PVN presympathetic neurons. Calcineurin inhibition potentiates α2δ-1 interactions with GluA1 and GluA2, disrupting intracellular assembly of GluA1/GluA2 heterotetramers in the PVN. Blocking Ca2+-permeable AMPARs or α2δ-1-AMPAR interactions in the PVN attenuates sympathetic outflow augmented by the calcineurin inhibitor.

Identification and Quantification of Locus-Specific 8-Oxo-7,8-dihydroguanine in DNA at Ultrahigh Resolution Based on G-Triplex-Assisted Rolling Circle Amplification.

Damage of reactive oxygen species to various molecules such as DNA has been related to many chronic and degenerative human diseases, aging, and even cancer. 8-Oxo-7,8-dihydroguanine (OG), the most significant oxidation product of guanine (G), has become a biomarker of oxidative stress as well as gene regulation. The positive effect of OG in activating transcription and the negative effect in inducing mutation are a double-edged sword; thus, site-specific quantification is helpful to quickly reveal the functional mechanism of OG at hotspots. Due to the possible biological effects of OG at extremely low abundance in the genome, the monitoring of OG is vulnerable to signal interference from a large amount of G. Herein, based on rolling circle amplification-induced G-triplex formation and Thioflavin T fluorescence enhancement, an ultrasensitive strategy for locus-specific OG quantification was constructed. Owing to the difference in the hydrogen-bonding pattern between OG and G, the nonspecific background signal of G sites was completely suppressed through enzymatic ligation of DNA probes and the triggered specificity of rolling circle amplification. After the signal amplification strategy was optimized, the high detection sensitivity of OG sites with an ultralow detection limit of 0.18 amol was achieved. Under the interference of G sites, as little as 0.05% of OG-containing DNA was first distinguished. This method was further used for qualitative and quantitative monitoring of locus-specific OG in genomic DNA under oxidative stress and identification of key OG sites with biological function.

New G-Triplex DNA Dramatically Activates the Fluorescence of Thioflavin T and Acts as a Turn-On Fluorescent Sensor for Uracil-DNA Glycosylase Activity Detection.

G-triplexes are G-rich oligonucleotides composed of three G-tracts and have absorbed much attention due to their potential biological functions and attractive performance in biosensing. Through the optimization of loop compositions, DNA lengths, and 5'-flanking bases of G-rich sequences, a new stable G-triplex sequence with 14 bases (G3-F15) was discovered to dramatically activate the fluorescence of Thioflavin T (ThT), a water-soluble fluorogenic dye. The fluorescence enhancement of ThT after binding with G3-F15 reached 3200 times, which was the strongest one by far among all of the G-rich sequences. The conformations of G3-F15 and G3-F15/ThT were studied by circular dichroism. The thermal stability measurements indicated that G3-F15 was a highly stable G-triplex structure. The conformations of G3-F15 and G3-F15/ThT in the presence of different metal cations were studied thoroughly by fluorescent spectroscopy, circular dichroism, and nuclear magnetic resonance. Furthermore, using the G3-F15/ThT complex as a fluorescent probe, a robust and simple turn-on fluorescent sensor for uracil-DNA glycosylase activity was developed. This study proposes a new systematic strategy to explore new functional G-rich sequences and their ligands, which will promote their applications in diagnosis, therapy, and biosensing.

Distinguishable Magnetic Reporter Coordination with Buoyancy-Magnetism Separation for Immobilization-Free Dual-Target Electrochemical Immunosensing.

Simultaneous sensitive and precise determination of multibiomarkers is of great significance for improving detection efficiency, reducing diagnosis and treatment expenses, and elevating survival rates. However, the development of simple and portable biosensors for simultaneous determination of multiplexed targets in biological fluids still faces challenges. Herein, a unique and versatile immobilization-free dual-target electrochemical biosensing platform, which combines distinguishable magnetic signal reporters with buoyancy-magnetism separation, was designed and constructed for simultaneous detection of carcinoembryonic (CEA) and α-fetoprotein (AFP) in intricate biological fluids. To construct such distinguishable magnetic signal reporters with signal transduction, amplification, and output, secondary antibodies of CEA and AFP were respectively functionalized on methylene blue (MB) and 6-(ferrocenyl)hexanethiol (FeC) modified Fe3O4@Au magnetic nanocomposites. Meanwhile, a multifunctional flotation probe with dual target recognition, capture, and isolation capability was prepared by conjugating primary antibodies (Ab1-CEA, Ab1-AFP) to hollow buoyant microspheres. The target antigens of CEA and AFP can trigger a flotation-mediated sandwich-type immunoreaction and capture a certain amount of the distinguishable magnetic signal reporter, which enables the conversion of the target CEA and AFP quantities to the signal of the potential-resolved MB and FeC. Thus, the MB and FeC currents of magnetically adsorbed distinguishable magnetic reporters can be used to determine the CEA and AFP targets simultaneously and precisely. Accordingly, the proposed strategy exhibited a delightful linear response for CEA and AFP in the range of 100 fg·mL-1-100 ng·mL-1 with detection limits of 33.34 and 17.02 fg·mL-1 (S/N = 3), respectively. Meanwhile, no significant nonspecific adsorption and cross-talk were observed. The biosensing platform has shown satisfactory performance in the determination of real clinical samples. More importantly, the proposed approach can be conveniently extended to universal detection just by simply substituting biorecognition events. Thus, this work opens up a new promising perspective for dual and even multiple targets and offers promising potential applications in clinical diagnosis.

Transrectal Drainage Tube Use for Preventing Post-endoscopic Submucosal Dissection Coagulation Syndrome in Patients with Colorectal Lesions: A Multicenter Randomized Controlled Clinical Trial.

INTRODUCTION: Post-endoscopic submucosal dissection (ESD) coagulation syndrome (PECS) prevention is one of the common postoperative complications of colorectal ESD. Considering the increasing incidence of PECS, it is critical to investigate various prevention To evaluate the efficacy of transrectal drainage tubes (TDTs) in PECS prevention in patients following colorectal ESD. METHODS: From July 2022 to July 2023, a multicenter, randomized controlled clinical trial was conducted in 3 hospitals in China. Patients with superficial colorectal lesions ≥20 mm who had undergone ESD for a single lesion were enrolled. Initially, 229 patients were included in the study and 5 were excluded. 224 were randomly assigned to the TDT and non-TDT group in the end. This open-label study utilized a parallel design with a 1:1 allocation ratio, and endoscopists and patients were not blind to the randomization. And a 24Fr drainage tube was inserted approximately 10-15 cm above the anus after the ESD under the endoscopy and tightly attached to a drainage bag. The TDTs were removed in 1 to 3 days following the ESD. RESULTS: A total of 229 eligible patients were enrolled in this study and 5 patients were excluded. Ultimately, 224 patients were assigned to the TDT group(n=112) and non-TDT group(n=112). The median age for the patients was 63.45(IQR 57-71; 59 men [52.68%]) in the TDT group and 60.95(IQR 54-68; 60 men [53.57%]) in the non-TDT group. Intention-to-treat analysis showed patients in the TDT group had a lower incidence of PECS than patients in the non-TDT group (7 [6.25%] vs 20 [17.86%]; relative risk, 0.350; 95% CI,0.154-0.795; P =0.008). In the subgroup analysis, TDTs were found to prevent PECS in patients of the female gender(odd ratio, 0.097; 95% CI, 0.021-0.449; P =0.001), tumor size ＜4cm(odd ratio, 0.203; 95% CI, 0.056-0.728; P = 0.011), tumor located in the left-sided colorectum (odd ratio, 0. 339 95% CI, 0.120-0.957; P = 0.035) and shorter procedure time(＜45 mins) (odd ratio, 0.316; 95% CI, 0.113-0.879; P =0.023). The tube fell off in 1 case (0.89%) accidentally ahead of time. No TDT-related complication was observed. DISCUSSION: The results from this randomized clinical study indicate that the application of TDTs effectively reduced the incidence of PECS in patients after colorectal ESD (chictr.org.cn Identifier: ChiCTR2200062164).

n-Si/SiOx /CoOx -Mo Photoanode for Efficient Photoelectrochemical Water Oxidation.

Green hydrogen is considered to be the key for solving the emerging energy and environmental issues. The photoelectrochemical (PEC) process for the production of green hydrogen has been widely investigated because solar power is clean and renewable. However, mass production in this way is still far away from reality. Here, a Si photoanode is reported with CoOx as co-catalyst for efficient water oxidation. It is found that a high photovoltage of 350 mV can be achieved in 1.0 m K3 BO3 . Importantly, the photovoltage can be further increased to 650 mV and the fill factor of 0.62 is obtained in 1.0 m K3 BO3 by incorporating Mo into CoOx . The Mo-incorporated photoanode is also highly stable. It is shown that the incorporation of Mo can reduce the particle size of co-catalyst on the Si surface, improve the particle-distribution uniformity, and increase the density of particles, which can effectively enhance the light absorption and the electrochemical active surface area. Importantly, the Mo-incorporation results in high energy barrier in the heterojunction. All of these factors are attributed to improved the PEC performance. These findings may provide new strategies to maximize the solar-to-fuel efficiency by tuning the co-catalysts on the Si surface.

Platinum-Ruthenium Dual-Atomic Sites Dispersed in Nanoporous Ni0.85Se Enabling Ampere-Level Current Density Hydrogen Production.

Alkaline anion-exchange-membrane water electrolyzers (AEMWEs) using earth-abundant catalysts is a promising approach for the generation of green H2. However, the AEMWEs with alkaline electrolytes suffer from poor performance at high current density compared to proton exchange membrane electrolyzers. Here, atomically dispersed Pt-Ru dual sites co-embedded in nanoporous nickel selenides (np/Pt1Ru1-Ni0.85Se) are developed by a rapid melt-quenching approach to achieve highly-efficient alkaline hydrogen evolution reaction. The np/Pt1Ru1-Ni0.85Se catalyst shows ampere-level current density with a low overpotential (46 mV at 10 mA cm-2 and 225 mV at 1000 mA cm-2), low Tafel slope (32.4 mV dec-1), and excellent long-term durability, significantly outperforming the benchmark Pt/C catalyst and other advanced large-current catalysts. The remarkable HER performance of nanoporous Pt1Ru1-Ni0.85Se is attributed to the strong intracrystal electronic metal-support interaction (IEMSI) between Pt-Se-Ru sites and Ni0.85Se support which can greatly enlarge the charge redistribution density, reduce the energy barrier of water dissociation, and optimize the potential determining step. Furthermore, the assembled alkaline AEMWE with an ultralow Pt and Ru loading realizes an industrial-level current density of 1 A cm-2 at 1.84 volts with high durability.

Scalable Cathodic H2O2 Electrosynthesis using Cobalt-Coordinated Nanocellulose Electrocatalyst.

Converting hierarchical biomass structure into cutting-edge architecture of electrocatalysts can effectively relieve the extreme dependency of nonrenewable fossil-fuel-resources typically suffering from low cost-effectiveness, scarce supplies, and adverse environmental impacts. A cost-effective cobalt-coordinated nanocellulose (CNF) strategy is reported for realizing a high-performance 2e-ORR electrocatalysts through molecular engineering of hybrid ZIFs-CNF architecture. By a coordination and pyrolysis process, it generates substantial oxygen-capturing active sites within the typically oxygen-insulating cellulose, promoting O2 mass and electron transfer efficiency along the nanostructured Co3O4 anchored with CNF-based biochar. The Co-CNF electrocatalyst exhibits an exceptional H2O2 electrosynthesis efficiency of ≈510.58 mg L-1 cm-2 h-1 with an exceptional superiority over the existing biochar-, or fossil-fuel-derived electrocatalysts. The combination of the electrocatalysts with stainless steel mesh serving as a dual cathode can strongly decompose regular organic pollutants (up to 99.43% removal efficiency by 30 min), showing to be a desirable approach for clean environmental remediation with sustainability, ecological safety, and high-performance.

Brachytherapy in craniopharyngiomas: a systematic review and meta-analysis of long-term follow-up.

OBJECTIVE: Brachytherapy has been indicated as an alternative option for treating cystic craniopharyngiomas (CPs). The potential benefits of brachytherapy for CPs have not yet been clarified. The purpose of this work was to conduct a meta-analysis to analyze the long-term efficacy and adverse reactions profile of brachytherapy for CPs. MATERIALS AND METHODS: The relevant databases were searched to collect the clinical trials on brachytherapy in patients with CPs. Included studies were limited to publications in full manuscript form with at least 5-year median follow-up, and adequate reporting of treatment outcomes and adverse reactions data. Stata 12.0 was used for data analysis. RESULTS: According to the inclusion and exclusion criteria, a total of 6 clinical trials involving 266 patients with CPs were included in this meta-analysis. The minimum average follow-up was 5 years. The results of the meta-analysis showed that 1-year, 2-3 years and 5 years progression free survival rates (PFS) are 75% (95%CI: 66-84%), 62% (95%CI: 52-72%) and 57% (95%CI: 22-92%), respectively. At the last follow-up, less than 16% of patients with visual outcomes worser than baseline in all included studies. While, for endocrine outcomes, less than 32% of patients worser than baseline level. CONCLUSION: In general, based on the above results, brachytherapy should be considered as a good choice for the treatment of CP.

Construction and Validation of a Prognostic Model Based on Mitochondrial Genes in Prostate Cancer.

This study attempted to build a prostate cancer (PC) prognostic risk model with mitochondrial feature genes. PC-related MTGs were screened for Cox regression analyses, followed by establishing a prognostic model. Model validity was analyzed via survival analysis and receiver operating characteristic (ROC) curves, and model accuracy was validated in the GEO dataset. Combining risk score with clinical factors, the independence of the risk score was verified by using Cox analysis, followed by generating a nomogram. The Gleason score, microsatellite instability (MSI), immune microenvironment, and tumor mutation burden were analyzed in two risk groups. Finally, the prognostic feature genes were verified through a q-PCR test. Ten PC-associated MTGs were screened, and a prognostic model was built. Survival analysis and ROC curves illustrated that the model was a good predictor for the risk of PC. Cox regression analysis revealed that risk score acted as an independent prognostic factor. The Gleason score and MSI in the high-risk group were substantially higher than in the low-risk group. Levels of ESTIMATE Score, Immune Score, Stromal Score, immune cells, immune function, immune checkpoint, and immunopheno score of partial immune checkpoints in the high-risk group were significantly lower than in the low-risk group. Genes with the highest mutation frequencies in the two groups were SPOP, TTN, and TP53. The q-PCR results of the feature genes were consistent with the gene expression results in the database. The 10-gene model based on MTGs could accurately predict the prognosis of PC patients and their responses to immunotherapy.

Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow.

RATIONALE: Hypertension is a common and serious adverse effect of calcineurin inhibitors, including cyclosporine and tacrolimus (FK506). Although increased sympathetic nerve discharges are associated with calcineurin inhibitor-induced hypertension, the sources of excess sympathetic outflow and underlying mechanisms remain elusive. Calcineurin (protein phosphatase-2B) is broadly expressed in the brain, including the paraventricular nuclear (PVN) of the hypothalamus, which is critically involved in regulating sympathetic vasomotor tone. OBJECTIVE: We determined whether prolonged treatment with the calcineurin inhibitor causes elevated sympathetic output and persistent hypertension by potentiating synaptic N-methyl-D-aspartate (NMDA) receptor activity in the PVN. METHODS AND RESULTS: Telemetry recordings showed that systemic administration of FK506 (3 mg/kg per day) for 14 days caused a gradual and profound increase in arterial blood pressure in rats, which lasted at least 7 days after discontinuing FK506 treatment. Correspondingly, systemic treatment with FK506 markedly reduced calcineurin activity in the PVN and circumventricular organs, but not rostral ventrolateral medulla, and increased the phosphorylation level and synaptic trafficking of NMDA receptors in the PVN. Immunocytochemistry labeling showed that calcineurin was expressed in presympathetic neurons in the PVN. Whole-cell patch-clamp recordings in brain slices revealed that treatment with FK506 increased baseline firing activity of PVN presympathetic neurons; this increase was blocked by the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. Also, treatment with FK506 markedly increased presynaptic and postsynaptic NMDA receptor activity of PVN presympathetic neurons. Furthermore, microinjection of the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist into the PVN of anesthetized rats preferentially attenuated renal sympathetic nerve discharges and blood pressure elevated by FK506 treatment. In addition, systemic administration of memantine, a clinically used NMDA receptor antagonist, effectively attenuated FK506 treatment-induced hypertension in conscious rats. CONCLUSIONS: Our findings reveal that normal calcineurin activity in the PVN constitutively restricts sympathetic vasomotor tone via suppressing NMDA receptor activity, which may be targeted for treating calcineurin inhibitor-induced hypertension.

Progress on enhancing the charge separation efficiency of carbon nitride for robust photocatalytic H2 production.

Solar-driven H2 production from water splitting with efficient photocatalysts is a sustainable strategy to meet the clean energy demand and alleviate the approaching environmental issues caused by fossil fuel consumption. Among various semiconductor-based photocatalysts, graphitic carbon nitride (g-C3N4) has attracted much attention due to its advantages of long term-stability, visible light response, low cost, and easy preparation. However, the intrinsic Coulombic attraction between charge carriers and the interlayer electrostatic barrier of bulk g-C3N4 result in severe charge recombination and low charge separation efficiency. This perspective summarizes the recent progress in the development of g-C3N4 photocatalytic systems, and focuses on three main modification strategies for promoting charge transfer and minimizing charge recombination, including structural modulation, heterojunction construction, and cocatalyst loading. Based on this progress, we provide conclusions regarding the current challenges of further improving photocatalytic efficiency to fulfill commercial requirements, and propose some recommendations for the design of novel and satisfactory g-C3N4 photocatalysts, which is expected to progress the solar-to-hydrogen conversion.

Antiferromagnetic Chromium-Doped Tin Clusters.

The trend toward further miniaturization of micronano antiferromagnetic (AFM) spintronic devices has led to a strong demand for low-dimensional materials. The assembly of AFM clusters to produce such materials is a potential pathway that promotes studies on such clusters. In this work, we report on the discovery of the AFM Cr2Snx (x = 3-20) clusters with a stepwise growth at the density functional theory (DFT) level. In comparison, the two Cr atoms tend to stay together and be buried by Sn atoms, forming endohedral structures with one Cr atom encapsulated at size 9 and finally forming a full-encapsulated structure at size 17. Each successive cluster size is composed of its predecessor with an extra Sn atom adsorbed onto the face, giving evidence of stepwise growth. All these Cr2Snx (x = 3-20) clusters are antiferromagnets, except for the triplet-state ferrimagnetic Cr2Sn11, and all their singly negatively and positively charged ions are ferromagnets. The found stable Cr2Sn17 cluster can dimerize, yielding dimers and trimers without noticeably distorting the geometrical structure and magnetic properties of each of its constituent cluster monomers, making it possible as a building block for AFM materials.

The correlation between the main and minor lesions of synchronous multiple gastric neoplasms assessed gastroscopically and microscopically.

BACKGROUND: Patients with early gastric cancer (EGC) are at high risk of developing synchronous multiple gastric neoplasms (SMGNs) after undergoing endoscopic submucosal dissection (ESD). However, most previous studies have had small sample sizes, and few have focused on association studies. AIMS: This study aimed to analyze the associations between SMGN lesion data from patients with EGC treated with ESD and their correlation coefficients. METHODS: The clinical ESD data from two hospitals from January 2008 to January 2021 were retrospectively analyzed. The main lesions were defined as those with a significant depth of infiltration. The larger tumor diameter was considered the main lesion if the lesions had the same infiltration depth. RESULTS: Of the 1013 post-ESD cases examined, 95 cases (223 lesions) had SMGN, and 25 patients had more than three lesions. For the correlation analysis, 190 lesions were included. The study revealed a similarity in pathological type between main and minor lesions (rs = 0.37) and a positive correlation in infiltration depth (rs = 0.58). The mean diameter sizes of the main and minor lesions were 20.7 ± 8.3 mm and 13.1 ± 6.4 mm, respectively, with statistically significant differences (P < 0.001). A linear correlation was observed between the diameter size and a linear regression model was constructed, producing r = 0.38 [95% confidence interval (CI) 0.19-0.54], b = 0.29 (95% CI 0.14-0.44), t = 3.94, P < 0.001]. A correlation was identified between the vertical distribution of the main and minor lesions, the horizontal distribution, and the gross endoscopic morphology (ϕc = 0.25, P = 0.02; ϕc = 0.32, P < 0.001; ϕc = 0.60, P < 0.001). CONCLUSIONS: The correlation coefficients for microscopic characteristics were higher than those for gastroscopy. There is a significant positive correlation between the main and minor lesions regarding pathological stage and depth of infiltration, respectively. The spatial distribution of the lesions and the gastroscopic morphology were similar.

Comparison of vestibular aqueduct visualization on computed tomography and magnetic resonance imaging in patients with Ménière's disease.

BACKGROUND: The vestibular aqueduct (VA) serves an essential role in homeostasis of the inner ear and pathogenesis of Ménière's disease (MD). The bony VA can be clearly depicted by high-resolution computed tomography (HRCT), whereas the optimal sequences and parameters for magnetic resonance imaging (MRI) are not yet established. We investigated VA characteristics and potential factors influencing MRI-VA visibility in unilateral MD patients. METHODS: One hundred patients with unilateral MD underwent MRI with three-dimensional sampling perfection with application optimized contrasts using different flip angle evolutions (3D-SPACE) sequence and HRCT evaluation. The imaging variables included MRI-VA and CT-VA visibility, CT-VA morphology and CT-peri-VA pneumatization. RESULTS: The most frequent type of MRI-VA and CT-VA visualization was invisible VA and continuous VA, respectively. The MRI-VA visibility was significantly lower than CT-VA visibility. MRI-VA visibility had a weak positive correlation with ipsilateral CT-VA visualization. For the affected side, the MRI-VA visualization was negatively correlated with the incidence of obliterated-shaped CT-VA and positively with that of tubular-shaped CT-VA. MRI-VA visualization was not affected by CT-peri-VA pneumatization. CONCLUSION: In patients with MD, the VA visualization on 3D-SPACE MRI is poorer than that observed on CT and may be affected by its osseous configuration. These findings may provide a basis for further characterization of VA demonstrated by MRI and its clinical significance.