Research on the Construction of a Series of Transition Metal-Substituted Keggin-Type TMSPOMs@PCN-224 Composites through the Encapsulation Method and Their Electron Transfer Mechanism in CO2RR.

In order to take advantage of the distinct reversible multielectron transfer properties of polyoxometalates (POMs) and increase the electron density at the active sites during the electrochemical reduction of CO2 (CO2RR), a range of transition metal-doped polyoxometalates (TMSPOMs) was entrapped within the porphyrin-based framework of PCN-224 via an encapsulation method, known as TMSPOMs@PCN-224 (TMSPOMs = [XW11O39MII(H2O)]n-, [XW11O40VIV]n-, M = CoII, MnII; X = Si, n = 6; X = P, n = 5). The central elements (Si, P) and the incorporated transition metals (VIV, CoII, and MnII) both play a role in adjusting the electronic structure and electron transfer during the CO2RR process. Remarkably, the composite material with cobalt substitution displayed significantly improved performance. Through fine-tuning the POM loading, the electrocatalytic activity was optimized, leading to an impressive Faradaic efficiency for CO production (FECO) of 89.9% for SiW11Co@PCN-224, a significant improvement compared to the 12.1% FECO of PCN-224. Furthermore, the electrochemical stability of this catalyst was demonstrated over 20 h. Comparative analyses involving six composite materials indicated a relationship between the negative charge of the polyanions and their ability to facilitate effective electron transfer, ultimately enhancing the catalyst's performance. Meanwhile, these findings were supported by density functional theory (DFT) calculations.

Comparison and optimization of different CRISPR/Cas9 donor-adapting systems for gene editing.

Gene knock-in in mammalian cells usually uses homology-directed repair (HDR) mechanism to integrate exogenous DNA template into the target genome site. However, HDR efficiency is often low, and the co-localization of exogenous DNA template and target genome site is one of the key limiting factors. To improve the efficiency of HDR mediated by CRISPR/Cas9 system, our team and previous studies fused different adaptor proteins with SpCas9 protein and expressed them. By using their characteristics of binding to specific DNA sequences, many different CRISPR/SpCas9 donor adapter gene editing systems were constructed. In this study, we used them to knock-in eGFP gene at the 3'-end of the terminal exon of GAPDH and ACTB genes in HEK293T cells to facilitate a comparison and optimization of these systems. We utilized an optimized donor DNA template design method, validated the knock-in accuracy via PCR and Sanger sequencing, and assessed the efficiency using flow cytometry. The results showed that the fusion of yGal4BD, hGal4BD, hLacI, hTHAP11 as well as N57 and other adaptor proteins with the C-terminus of SpCas9 protein had no significant effect on its activity. At the GAPDH site, the donor adapter systems of SpCas9 fused with yGal4BD, hGal4BD, hLacI and hTHAP11 significantly improved the knock-in efficiency. At the ACTB site, SpCas9 fused with yGal4BD and hGal4BD significantly improved the knock-in efficiency. Furthermore, increasing the number of BS in the donor DNA template was beneficial to enhance the knock-in efficiency mediated by SpCas9-hTHAP11 system. In conclusion, this study compares and optimizes multiple CRISPR/Cas9 donor adapter gene editing systems, providing valuable insights for future gene editing applications.

Green preparation of CaO-based CO2 adsorbent by calcium-induced hydrogenation of shell wastes at room/moderate temperature.

Capturing CO2 using clamshell/eggshell-derived CaO adsorbent can not only reduce carbon emissions but also alleviate the impact of trash on the environment. However, organic acid was usually used, high-temperature calcination was often performed, and CO2 was inevitably released during preparing CaO adsorbents from shell wastes. In this work, CaO-based CO2 adsorbent was greenly prepared by calcium-induced hydrogenation of clamshell and eggshell wastes in one pot at room/moderate temperature. CO2 adsorption experiments were performed in a thermogravimetric analyzer (TGA). The adsorption performance of the adsorbents obtained from the mechanochemical reaction (BM-C/E-CaO) was superior to that of the adsorbents obtained from the thermochemical reaction (Cal-C/E-CaO). The CO2 adsorption capacity of BM-C-CaO at 650 °C is up to 36.82 wt%, but the adsorption decay rate of the sample after 20 carbonation/calcination cycles is only 30.17%. This study offers an alternative energy-saving method for greenly preparing CaO-based adsorbent from shell wastes.

Brainstem control of vocalization and its coordination with respiration.

Phonation critically depends on precise controls of laryngeal muscles in coordination with ongoing respiration. However, the neural mechanisms governing these processes remain unclear. We identified excitatory vocalization-specific laryngeal premotor neurons located in the retroambiguus nucleus (RAmVOC) in adult mice as being both necessary and sufficient for driving vocal cord closure and eliciting mouse ultrasonic vocalizations (USVs). The duration of RAmVOC activation can determine the lengths of both USV syllables and concurrent expiration periods, with the impact of RAmVOC activation depending on respiration phases. RAmVOC neurons receive inhibition from the preBötzinger complex, and inspiration needs override RAmVOC-mediated vocal cord closure. Ablating inhibitory synapses in RAmVOC neurons compromised this inspiration gating of laryngeal adduction, resulting in discoordination of vocalization with respiration. Our study reveals the circuits for vocal production and vocal-respiratory coordination.

Multifunctional fish-skin collagen-based hydrogel sealant with dual-dynamic-bond cross-linked for rapid hemostasis and accelerated wound healing.

Collagen (COL) is the most widespread functional protein. Designing and developing dual-dynamic-bond cross-linked COL adhesive hydrogel sealants with multifunctional is highly advantageous for achieving a superior wound closure effect and hemostasis. In this study, we developed hybrid hydrogels consisting of fish-skin COL, oxidized sodium alginate (OSA), borax and polyvinyl alcohol (PVA) to enhance full-thickness wound healing. The hydrogels were furnished with first-rate self-healing capabilities through the dual-dynamic-bond cross-linking of dynamic Schiff base bonds (COL-OSA) and diol boric acid bonds (OSA-borax) with reversible breakage and re-formation. Moreover, the incorporation of PVA stimulated the formation of hydrogen bonds in the system, bolstering the stability of the hydrogel framework. The prepared hydrogel manifests self-healing, injectability, multifunctional adhesiveness and biodegradability. In vivo assessment of the hemostatic capacity of COSP20 hydrogel was superior to gauze both in the mice liver injury model and mice tail amputation model. In addition, a full-thickness skin wound model in mice revealed that the COSP20 hydrogel facilitated faster wound closure by accelerating reepithelialization, COL deposition and angiogenesis. These findings illustrate the potential of hybrid fish-skin COL-based hydrogels to enhance wound healing and promote rapid tissue repair, and provide new possibilities for the effective utilization of marine fishery resources.

Network Pharmacology-Based Identification of Key Pharmacological Mechanism of Shen-qi-di-huang Decoction Acting on Uremia.

This study employs network pharmacology to uncover the pharmacological mechanisms underlying Shen-qi-di-huang decoction's efficacy in treating uremia. We identified a total of 927 differentially expressed genes (DEGs) through differential expression analysis and the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform, of which 607 were downregulated and 320 were upregulated. We also obtained the effective biological components and related target gene information of Chinese herbal medicines such as Renshen, Huangqi, shudihuang, Shanyao, Fuling, Mudanpi, and Shanzhuyu in Shen-qi-di-huang decoction and constructed a regulatory relationship network between molecular components and target genes in Shen-qi-di-huang decoction. We then constructed a protein-protein interaction (PPI) network of 15 targeted genes (RXRA, ND6, CYP1B1, SLPI, CDKN1A, RB1, HIF1A, MYC, HSPB1, IFNGR1, NQO1, IRF1, RASA1, PSMG1 and MAP2K4) using the STRING database and visualized the PPI network using the software Cytoscape. In addition, we revealed the key molecular functions of uremia through Gene Ontology (GO) enrichment analysis, mainly including neuron apoptotic process, cellular response to oxidative stress, regulation of neuron apoptotic process, neuron projection cytoplasm, RNA polymerase II transcription regulator complex, plasma membrane bounded cell projection cytoplasm, NADH and NADPH dehydrogenase (quinone) activity, protein kinase inhibitor and ubiquitin protein ligase binding, etc. Finally, we identified important biological pathways in uremia through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, which mainly concentrated in Kaposi sarcoma-associated, small cell lung cancer, Gastric cancer, Hepatitis B and C, Hepatocellular carcinoma, Thyroid cancer, Bladder cancer, MAPK signaling pathway, ErbB signaling pathway, Th17 cell differentiation, HIF-1 signaling pathway, Thyroid hormone signaling pathway and Cell cycle, etc. Using integrated bioinformatical analysis, we elucidated key pharmacological mechanisms based on targeted genes, which was enable early identification of patients with uremia and would contribute to early clinical diagnosis and treatment of patients.

Brainstem premotor mechanisms underlying vocal production and vocal-respiratory coordination.

Speech generation critically depends on precise controls of laryngeal muscles and coordination with ongoing respiratory activity. However, the neural mechanisms governing these processes remain unknown. Here, we mapped laryngeal premotor circuitry in adult mice and viral-genetically identified excitatory vocal premotor neurons located in the retroambiguus nucleus (RAm VOC ) as both necessary and sufficient for driving vocal-cord closure and eliciting mouse ultrasonic vocalizations (USVs). The duration of RAm VOC activation determines the lengths of USV syllables and post-inspiration phases. RAm VOC -neurons receive inhibitory inputs from the preBötzinger complex, and inspiration needs can override RAm VOC -mediated vocal-cord closure. Ablating inhibitory synapses in RAm VOC -neurons compromised this inspiration gating of laryngeal adduction, resulting in de-coupling of vocalization and respiration. Our study revealed the hitherto unknown circuits for vocal pattern generation and vocal-respiratory coupling. One-Sentence Summary: Identification of RAm VOC neurons as the critical node for vocal pattern generation and vocal-respiratory coupling.

Exploring the role of sandwich-type polyoxometalates in {K10(PW9O34)2M4(H2O)2}@PCN-222 (M = Mn, Ni, Zn) for electroreduction of CO2 to CO.

To overcome the drawbacks of high solubility and instability of polyoxometalates (POMs) in aqueous solution and to expand their application in the electrocatalytic reduction of CO2 (ECR), we assemble sandwich-type POMs, K10[(PW9O34)2M4(H2O)2] (M = Mn, Ni, Zn, shortened as P2W18M4), into the hexagonal channel of a porphyrin-based metal-organic framework (MOF) PCN-222 to form P2W18M4@PCN-222 composites. Their ECR behavior displays polyoxoanion-dependent activity. P2W18Mn4@PCN-222 demonstrates a faradaic efficiency of 72.6% for the CO product (FECO), more than four times that of PCN-222 (FECO = 18.1%), and exhibits exceptional electrochemical stability over 36 h. P2W18Ni4@PCN-222 and P2W18Zn4@PCN-222 slightly increase (26.9%) and decrease (3.2%) in FECO, respectively. We combine the results with density functional theory (DFT) calculations to help understand the intrinsic reasons which reveals that the rate-determining step (RDS) reaction energy of P2W18Mn4@PCN-222 and P2W18Ni4@PCN-222 is significantly reduced compared to that of PCN-222. It is different in P2W18Zn4@PCN-222. Frontier molecular orbitals electron distribution results hint at directional electron transfer from P2W18Mn4/P2W18Ni4 to the porphyrin ring active center in PCN-222, promoting the electro-reduction of CO2 activity. By contrast, P2W18Zn4 may accumulate electrons from PCN-222, thus facilitating the hydrogen evolution reaction (HER). This work reveals the critical role of sandwich-type POMs in manipulating the electron transfer pathway during the electrocatalytic process. Our findings would broaden the scope of POM applications in electrochemical carbon dioxide reduction.

Chemical constituents, pharmacological action, antitumor application, and toxicity of Strychnine Semen from Strychnons pierriana A.W.Hill.: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: The dried and mature seeds of Strychnons pierriana A.W.Hill. have been called Strychnine Semen(S. Semen). It have been used in traditional Chinese medicine for nearly 400 years. In recent decades, scholars at home and abroad have widely used S. Semen in the treatment of tumor diseases, showing good anti-tumor effects. In this paper, the modern research achievements of S. Semen are reviewed, including traditional uses, phytochemistry, pharmacology, and toxicology. AIM OF THE STUDY: In recent years, the research on S. Semen has increased gradually, especially the research on its anti-tumor. This paper not only reviewed the traditional uses, chemical constituents and pharmacological activities of S. Semen, but also comprehensively listed the mechanisms of Strychnos in the treatment of different tumors, providing a review for further research and development of Strychnos resources. MATERIALS AND METHODS: A systematic review of the literature on Fuzi was performed using several resources, namely classic books on Chinese herbal medicine and various scientific databases, such as PubMed, the Web of Science, and the China Knowledge Resource Integrated databases. RESULTS: The main constituents of S. Semen include alkaloids, terpenoids, steroids, and their glycosides. Modern studies have proved that S. Semen has a wide range of pharmacological effects, including anti-inflammatory and analgesic, anti-thrombotic, myocardial cell protection, immune regulation, nerve excitation, and anti-tumor effects. Among them, the anti-tumor effect has been the focus of research in recent years. S. Semen have a certain therapeutic effect on many kinds of tumors, such as liver cancer, colon cancer, and stomach cancer in the digestive system, breast, cervical, and ovarian cancer in the reproductive system, myeloma and leukemia in the blood system, and those in the nervous system and the immune system. CONCLUSION: Strychnine has an inhibitory effect on a variety of tumors. However, modern studies of strychnine are incomplete, and more in-depth studies are needed on its stronger bioactive constituents and potential pharmacological effects. The antitumor effect of Strychnine is worth further exploration.

Tumor necrosis factor-related lncRNAs predict prognosis and immunotherapy response for patients with lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) has become one of the most lethal cancers, for which the recurrence and survival rates remain unfavorable. The tumor necrosis factor (TNF) family is involved in tumorigenesis and tumor progression. Various long non-coding RNAs (lncRNAs) play important roles by mediating the TNF family in cancer. Therefore, this study aimed to construct a TNF-related lncRNA signature to predict prognosis and immunotherapy response in LUAD. Methods: The expression of TNF family members and their related lncRNAs in a total of 500 enrolled LUAD patients was collected from The Cancer Genome Atlas (TCGA). Univariate Cox and the least absolute shrinkage and selection operator (LASSO)-Cox analysis was used to construct a TNF family-related lncRNA prognostic signature. Kaplan-Meier (KM) survival analysis was used to evaluate survival status. The time-dependent area under the receiver operating characteristic (ROC) curve (AUC) values were used to assess the predictive value of the signature to 1-, 2-, and 3-year overall survival (OS). Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify the signature-related biological pathways. Furthermore, tumor immune dysfunction and exclusion (TIDE) analysis was employed to evaluate immunotherapy response. Results: A total of 8 TNF-related lncRNAs significantly associated with OS of LUAD patients were used to construct a TNF family-related lncRNA prognostic signature. According to risk score, these patients were divided into high- and low-risk subgroups. The KM survival analysis indicated that patients in the high-risk group showed significantly less favorable OS than that of low-risk group. The AUC values in predicting 1-, 2-, and 3-year OS were 0.740, 0.738, and 0.758, respectively. Moreover, the GO and KEGG pathway analyses demonstrated that these lncRNAs were closely involved in immune-related signaling pathways. The further TIDE analysis indicated that high-risk patients had a lower TIDE score than that of low-risk patients, indicating that high-risk patients may be appropriate candidates for immunotherapy. Conclusions: For the first time, this study constructed and validated a prognostic predictive signature of LUAD patients based on TNF-related lncRNAs, and the signature showed good performance to predict immunotherapy response. Therefore, this signature may provide new strategies for individualized treatment of LUAD patients.

Chemical constituents, pharmacological effects, toxicology, processing and compatibility of Fuzi (lateral root of Aconitum carmichaelii Debx): A review.

ETHNOPHARMACOLOGICAL RELEVANCE: The lateral root of Aconitum carmichaelii Debx is known as Fuzi in Chinese. It is traditionally valued and used for dispelling cold, relieving pain effects, restoring 'Yang,' and treating shock despite its high toxicity. This review aims to provide comprehensive information on the chemical composition, pharmacological research, preparation, and compatibility of Fuzi to help reduce its toxicity and increase its efficiency, based on the scientific literature. In addition, this review will establish a new foundation for further studies on Fuzi. MATERIALS AND METHODS: A systematic review of the literature on Fuzi was performed using several resources, namely classic books on Chinese herbal medicine and various scientific databases, such as PubMed, the Web of Science, and the China Knowledge Resource Integrated databases. RESULTS: Fuzi extracts contain diester-type alkaloids, monoester-type alkaloids, other types of alkaloids, and non-alkaloids types, and have various pharmacological activities, such as strong heart effect, effect on blood vessels, and antidepressant, anti-diabetes, anti-inflammatory, pain-relieving, antitumor, immunomodulatory, and other therapeutic effects. However, these extracts can also lead to various toxicities such as cardiotoxicity, neurotoxicity, reproductive toxicity, hepatotoxicity, and embryonic toxicity. In vivo and in vitro experiments have demonstrated that different processing methods and suitable compatibility with other herbs can effectively reduce the toxicities and increase the efficiency of Fuzi. CONCLUSION: The therapeutic potential of Fuzi has been demonstrated in conditions, such as heart failure, various pains, inflammation, and tumors, which is attributed to the diester-type alkaloids, monoester-type alkaloids, other types of alkaloids, and non-alkaloid types. In contrast, they are also toxic components. Proper processing and suitable compatibility can effectively reduce toxicity and increase the efficiency of Fuzi. Thus more pharmacological and toxicological mechanisms on main active compounds are necessary to be explored.

General Anesthesia Activates a Central Anxiolytic Center in the BNST.

Low doses of general anesthetics like ketamine and dexmedetomidine have anxiolytic properties independent of their sedative effects. How these different drugs exert these anxiolytic effects is not well understood. We discovered a population of GABAergic neurons in the oval division of the bed nucleus of the stria terminalis that is activated by multiple anesthetics and the anxiolytic drug diazepam (ovBNST GA ). A majority of ovBNST GA neurons express neurotensin receptor 1 (Ntsr1) and innervate brain regions known to regulate anxiety and stress responses. Optogenetic activation ovBNST GA or ovBNST Ntsr1 neurons significantly attenuated anxiety-like behaviors in both naïve animals and mice with inflammatory pain, while inhibition of these cells increased anxiety. Notably, activation of these neurons decreased heart rate and increased heart rate variability, suggesting that they reduce anxiety through modulation of the autonomic nervous system. Our study identifies ovBNST GA /ovBNST Ntsr1 neurons as one of the brain's endogenous anxiolytic centers and a potential therapeutic target for treating anxiety-related disorders. HIGHLIGHTS: General anesthetics and anxiolytics activate a population of neurons in the ovBNSTAnesthesia-activated ovBNST neurons bidirectionally modulate anxiety-like behaviorMost anesthesia-activated ovBNST neurons express neurotensin receptor 1 ovBNST Ntsr1 neuron activation shifts autonomic responses to an anxiolytic state.

Chaetoglobosin E inhibits tumor growth and promotes the anti-tumor efficacy of cytotoxic drugs in esophageal squamous cell carcinoma by targeting PLK1.

Background: Currently, there is no satisfactory treatment available for esophageal squamous cell carcinoma (ESCC), and thus, there is a pressing need to develop effective drugs. Chaetoglobosin E, a cytochalasan alkaloid derived from metabolites of Chaetomium madrasense 375, is a chaetoglobosin with intense anti-tumor activity. Therefore, revealing its anti-tumor mechanism for the application of cytochalasans is crucial. Methods: The cytotoxic effect of chaetoglobosin E and cisplatin on esophageal cancer KYSE-30, KYSE-150, and TE-1 cells was detected using cell viability or colony formation assays. The cell cycle, apoptosis, autophagy, invasion, and metastasis were assayed by flow cytometry or western blot. The potential target of chaetoglobosin E was assayed by RNA sequencing (RNA-seq) and large loop prediction software analysis and was assessed by western blot and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of its target on cell pyroptosis was assayed using overexpression and silence experiments. Results: Chaetoglobosin E significantly inhibited the proliferation of KYSE-30, KYSE-150, and TE-1 cells, especially KYSE-30 cells. Our results showed that chaetoglobosin E induced the G2/M phase arrest of KYSE-30 cells, followed by the down-regulation of cyclinB1, CDC2, and p-CDC2, and up-regulation of p21. Moreover, chaetoglobosin E also decreased the anti-apoptotic protein expression of Bcl-2, increased apoptotic expression of Bax, increased autophagy protein expressions of beclin1 and LC3, decreased invasion and metastasis protein expression of E-cadherin, and increased expression of vimentin. The RNA-seq and large loop prediction software analysis results indicated that its potential target might be polo-like kinase 1 (PLK1). Moreover, results also showed that chaetoglobosin E can reverse the PLK1 overexpression plasmid-induced up-regulation of the PLK1 protein. Furthermore, we found that chaetoglobosin E induced pyroptosis via the activation of the gasdermin E (GSDME) protein. Further studies showed that the high expression of PLK1 inactivated the GSDME protein, while the knockdown of PLK1 expression activated the GSDME protein, indicating that chaetoglobosin E induced cell pyroptosis by inhibiting PLK1. Conclusions: This study suggested that chaetoglobosin E may be a novel lead compound to the treatment of ESCC patients by targeting PLK1, and elucidated for the first time that PLK1 was involved in a new pyroptosis mechanism.

Somatosensory cortical signature of facial nociception and vibrotactile touch-induced analgesia.

Pain relief by vibrotactile touch is a common human experience. Previous neurophysiological investigations of its underlying mechanism in animals focused on spinal circuits, while human studies suggested the involvement of supraspinal pathways. Here, we examine the role of primary somatosensory cortex (S1) in touch-induced mechanical and heat analgesia. We found that, in mice, vibrotactile reafferent signals from self-generated whisking significantly reduce facial nociception, which is abolished by specifically blocking touch transmission from thalamus to the barrel cortex (S1B). Using a signal separation algorithm that can decompose calcium signals into sensory-evoked, whisking, or face-wiping responses, we found that the presence of whisking altered nociceptive signal processing in S1B neurons. Analysis of S1B population dynamics revealed that whisking pushes the transition of the neural state induced by noxious stimuli toward the outcome of non-nocifensive actions. Thus, S1B integrates facial tactile and noxious signals to enable touch-mediated analgesia.

A CRISPR/Cas9-Gal4BD donor adapting system for enhancing homology-directed repair.

The fast-rising CRISPR-derived gene editing technologies has been widely used in the fields of life science and biomedicine, as well as plant and animal breeding. However, the efficiency of homology-directed repair (HDR), an important strategy for gene knock-in and base editing, remains to be improved. In this study, we came up with the term Donor Adapting System (DAS) to summarize those CRISPR/Cas9 systems modified with adaptor for driving aptamer-fused donor DNA. A set of CRISPR/Cas9-Gal4BD DAS was designed in our study. In this system, Gal4 DNA binding domain (Gal4BD) is used as adaptor to fuse with Cas9 protein, and Gal4 binding sequence (Gal4BS) is used as aptamer to bind to the double-stranded DNA (dsDNA) donor, in order to improve the HDR efficiency. Preliminary results from the HEK293T-HDR.GFP reporter cell line show that the HDR editing efficiency could be improved up to 2-4 times when donor homologous arms under certain length (100-60 bp). Further optimization results showed that the choice of fusion port and fusion linker would affect the expression and activity of Cas9, while the Cas9-Gal4BD fusion with a GGS5 linker was the prior choice. In addition, the HDR efficiency was likely dependent on the aptamer-dsDNA donor design, and single Gal4BD binding sequence (BS) addition to the 5'-end of intent dsDNA template was suggested. Finally, we achieved enhanced HDR editing on the endogenous AAVS1 and EMX1 sites by using the CRISPR/Gal4BD-Cas9 DAS, which we believe can be applied to facilitate animal molecular design breeding in the future.

Novel recombinant human thyroid-stimulating hormone in aiding postoperative assessment of patients with differentiated thyroid cancer-phase I/II study.

PURPOSE: Thyroid hormone withdrawal (THW) inevitably induced hypothyroidism in patients with differentiated thyroid cancer (DTC), and we aimed to evaluate the safety and efficacy of a novel recombinant human thyroid-stimulating hormone (rhTSH, ZGrhTSH) as an alternative of THW in China. METHODS: Totally, 64 DTC patients were enrolled with 24 in the dose-escalation cohort equally grouped into 0.9 mg × 1 day, 0.9 mg × 2 day, 1.8 mg × 1 day, and 1.8 mg × 2 day dosage, and 40 further enrolled into 0.9 mg × 2 day dose-expansion cohort. All patients underwent both ZGrhTSH phase and levothyroxine (L-T4) withdrawal phase for self-comparison in terms of TSH levels, the radioactive iodine (RAI) uptake, stimulated thyroglobulin level, and the quality of life (QoL). RESULTS: In ZGrhTSH phase, no major serious adverse events were observed, and mild symptoms of headache were observed in 6.3%, lethargy in 4.7%, and asthenia in 3.1% of the patients, and mostly resolved spontaneously within 2 days. Concordant RAI uptake was noticed in 89.1% (57/64) of the patients between ZGrhTSH and L-T4 withdrawal phases. The concordant thyroglobulin level with a cut-off of 1 µg/L was noticed in 84.7% (50/59) of the patients without the interference of anti-thyroglobulin antibody. The QoL was far better during ZGrhTSH phase than L-T4 withdrawal phase, with lower Billewicz (- 51.30 ± 4.70 vs. - 39.10 ± 16.61, P < 0.001) and POMS (91.70 ± 16.70 vs. 100.40 ± 22.11, P = 0.011) scores which indicate the lower the better. Serum TSH level rose from basal 0.11 ± 0.12 mU/L to a peak of 122.11 ± 42.44 mU/L 24 h after the last dose of ZGrhTSH. In L-T4 withdrawal phase, a median of 23 days after L-T4 withdrawal was needed, with the mean TSH level of 82.20 ± 31.37 mU/L. The half-life for ZGrhTSH clearance was about 20 h. CONCLUSION: The ZGrhTSH held the promise to be a safe and effective modality in facilitating RAI uptake and serum thyroglobulin stimulation, with better QoL of patients with DTC compared with L-T4 withdrawal.

One-pot preparation of H2-mixed CH4 fuel and CaO-based CO2 sorbent by the hydrogenation of waste clamshell/eggshell at room temperature.

The preparation of clean fuel or CO2 adsorbents using industrial and domestic garbage is an alternative way of meeting global energy needs and alleviating environmental problems. Herein, H2-mixed CH4 fuel and CaO-based CO2 sorbent were first prepared in one pot by the mechanochemical reaction of pretreated clamshell or eggshell wastes (carbon and calcium source) with calcium hydride (hydrogen source) at room temperature. In the above reactions, CH4 was the sole hydrocarbon product, and its yield reached 78.23%. The H2/CH4 ratio of the produced H2-mixed CH4 fuel was tunable according to the need by changing the reaction conditions. It is inspiring that the simultaneously formed solid CaO/carbon products were efficient CaO-based sorbents, which possessed a higher CO2 adsorption capacity (49.81-58.74 wt.%) at 650 °C and could maintain good adsorption stability in 30 carbonation/calcination cycles (average activity loss per cycle of only 1.6%). The three achievements of the idea are that it can simultaneously eliminate clamshell or eggshell wastes, obtain valuable clean fuel, and acquire efficient CaO-based sorbents.

Thoracic Endovascular Aortic Repair of Highly Tapered Type B Aortic Dissection with Proximal Tapered Stent Grafts and Distal Restrictive Stent Grafts.

BACKGROUND: This study evaluated aortic remodeling in highly tapered type B aortic dissection (TBAD) patients who underwent thoracic endovascular aortic repair (TEVAR) with a proximal tapered stent graft plus a distal restrictive stent graft to maximize thoracic coverage while avoiding distal excessive oversizing. METHODS: Thirty-four patients presenting with highly tapered TABD were randomized to restricted TEVAR (r-TEVAR) and standard TEVAR groups. Highly tapered TBAD was defined as the maximal diameter of the true lumen at proximal and distal thoracic aorta landing zone tapers greater than 8 mm or taper ratio greater than 20%. Patients in the r-TEVAR group underwent proximal tapered stent grafts plus distal restrictive stent grafts, to match the taper ratio of the descending thoracic aorta (DTA) and extend the length of stent coverage. Patients in the standard TEVAR group underwent proximal tapered stent grafts implantation without distal restrictive stent grafts. Aortic remodeling was estimated by computed tomography angiography (CTA) during the follow-up. RESULTS: In total, 16 patients underwent r-TEVAR, and 18 patients underwent standard TEVAR. The taper ratio of the stent graft matched the DTA in the r-TEVAR group (24.7 ± 3.4% vs. 27.3 ± 4.2%, P = 0.068), but did not match that in the standard TEVAR group (13.5 ± 3.3% vs. 30.5 ± 9.6%, P < 0.001). The length of stent graft coverage in the r-TEVAR group was longer than that in the standard TEVAR group (220.4 ± 21.1 mm vs. 175.3 ± 17.8 mm, P < 0.001). Compared with the standard TEVAR group, the r-TEVAR group had better complete remodeling of the DTA at 6 months (40% vs. 5.6%, P = 0.03), 12 months (60% vs. 16.7%, P = 0.027), and 24 months (78.6% vs. 41.2%, P = 0.036) after the operation. There was no difference in the cumulative survival rate between the r-TEVAR and standard TEVAR groups (P = 0.166). CONCLUSIONS: The r-TEVAR with overlapping proximal tapered stent grafts and distal restrictive stent grafts can match the taper of highly tapered TABD, extend the length of stent graft coverage, and lead to better remodeling of the DTA than standard TEVAR.

The PARP1 Inhibitor Niraparib Represses DNA Damage Repair and Synergizes with Temozolomide for Antimyeloma Effects.

Purpose: Poly(ADP-ribose) polymerase 1 (PARP1) is necessary for single-strand break (SSB) repair by sensing DNA breaks and facilitating DNA repair through poly ADP-ribosylation of several DNA-binding and repair proteins. Inhibition of PARP1 results in collapsed DNA replication fork and double-strand breaks (DSBs). Accumulation of DSBs goes beyond the capacity of DNA repair response, ultimately resulting in cell death. This work is aimed at assessing the synergistic effects of the DNA-damaging agent temozolomide (TMZ) and the PARP inhibitor niraparib (Nira) in human multiple myeloma (MM) cells. Materials and Methods: MM RPMI8226 and NCI-H929 cells were administered TMZ and/or Nira for 48 hours. CCK-8 was utilized for cell viability assessment. Cell proliferation and apoptosis were detected flow-cytometrically. Immunofluorescence was performed for detecting γH2A.X expression. Soft-agar colony formation assay was applied to evaluate the antiproliferative effect. The amounts of related proteins were obtained by immunoblot. The combination index was calculated with the CompuSyn software. A human plasmacytoma xenograft model was established to assess the anti-MM effects in vivo. The anti-MM activities of TMZ and/or Nira were evaluated by H&E staining, IHC, and the TUNEL assay. Results: The results demonstrated that cotreatment with TMZ and Nira promoted DNA damage, cell cycle arrest, and apoptotic death in cultured cells but also reduced MM xenograft growth in nude mice, yielding highly synergistic effects. Immunoblot revealed that TMZ and Nira cotreatment markedly increased the expression of p-ATM, p-CHK2, RAD51, and γH2A.X, indicating the suppression of DNA damage response (DDR) and elevated DSB accumulation. Conclusion: Inhibition of PARP1 sensitizes genotoxic agents and represents an important therapeutic approach for MM. These findings provide preliminary evidence for combining PARP1 inhibitors with TMZ for MM treatment.