Sub-Band Assisted Z-Scheme for Effective Non-Sacrificial H2O2 Photosynthesis.

Photosynthesis of H2O2 from earth-abundant O2 and H2O molecules offers an eco-friendly route for solar-to-chemical conversion. The persistent challenge is to tune the photo-/thermo- dynamics of a photocatalyst toward efficient electron-hole separation while maintaining an effective driving force for charge transfer. Such a case is achieved here by way of a synergetic strategy of sub-band-assisted Z-Scheme for effective H2O2 photosynthesis via direct O2 reduction and H2O oxidation without a sacrificial agent. The optimized SnS2/g-C3N4 heterojunction shows a high reactivity of 623.0 µmol g-1 h-1 for H2O2 production under visible-light irradiation (λ > 400 nm) in pure water, ≈6 times higher than pristine g-C3N4 (100.5 µmol g-1 h-1). Photodynamic characterizations and theoretical calculations reveal that the enhanced photoactivity is due to a markedly promoted lifetime of trapped active electrons (204.9 ps in the sub-band and >2.0 ns in a shallow band) and highly improved O2 activation, as a result of the formation of a suitable sub-band and catalytic sites along with a low Gibbs-free energy for charge transfer. Moreover, the Z-Scheme heterojunction creates and sustains a large driving force for O2 and H2O conversion to high value-added H2O2.

Biological impact and therapeutic potential of a novel camptothecin derivative (FLQY2) in pancreatic cancer through inactivation of the PDK1/AKT/mTOR pathway.

BACKGROUND: Camptothecin (CPT), a pentacyclic alkaloid with antitumor properties, is derived from the Camptotheca acuminata. Topotecan and irinotecan (CPT derivatives) were first approved by the Food and Drug Administration for cancer treatment over 25 years ago and remain key anticancer drugs today. However, their use is often limited by clinical toxicity. Despite extensive development efforts, many of these derivatives have not succeeded clinically, particularly in their effectiveness against pancreatic cancer which remains modest. AIM OF THE STUDY: This study aimed to evaluate the therapeutic activity of FLQY2, a CPT derivative synthesized in our laboratory, against pancreatic cancer, comparing its efficacy and mechanism of action with those of established clinical drugs. METHODS: The cytotoxic effects of FLQY2 on cancer cells were assessed using an MTT assay. Patient-derived organoid (PDO) models were employed to compare the sensitivity of FLQY2 to existing clinical drugs across various cancers. The impact of FLQY2 on apoptosis and cell cycle arrest in Mia Paca-2 pancreatic cancer cells was examined through flow cytometry. Transcriptomic and proteomic analyses were conducted to explore the underlying mechanisms of FLQY2's antitumor activity. Western blotting was used to determine the levels of proteins regulated by FLQY2. Additionally, the antitumor efficacy of FLQY2 in vivo was evaluated in a pancreatic cancer xenograft model. RESULTS: FLQY2 demonstrated (1) potent cytotoxicity; (2) superior tumor-suppressive activity in PDO models compared to current clinical drugs such as gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infinitinib, and lenvatinib; (3) significantly greater tumor inhibition than paclitaxel liposomes in a pancreatic cancer xenograft model; (4) robust antitumor effects, closely associated with the inhibition of the TOP I and PDK1/AKT/mTOR signaling pathways. In vitro studies revealed that FLQY2 inhibited cell proliferation, colony formation, induced apoptosis, and caused cell cycle arrest at nanomolar concentrations. Furthermore, the combination of FLQY2 and gemcitabine exhibited significant inhibitory and synergistic effects. CONCLUSION: The study confirmed the involvement of topoisomerase I and the PDK1/AKT/mTOR pathways in mediating the antitumor activity of FLQY2 in treating Mia Paca-2 pancreatic cancer. Therefore, FLQY2 has potential as a novel therapeutic option for patients with pancreatic cancer.

Effects of esketamine on postoperative fatigue syndrome in patients after laparoscopic resection of gastric carcinoma: a randomized controlled trial.

BACKGROUND: Despite the implementation of various postoperative management strategies, the prevalence of postoperative fatigue syndrome (POFS) remains considerable among individuals undergoing laparoscopic radical gastrectomy. While the N-methyl-D-aspartic acid receptor antagonist esketamine has demonstrated efficacy in enhancing sleep quality and alleviating postoperative pain, its impact on POFS remains uncertain. Consequently, the objective of this study is to ascertain whether perioperative administration of esketamine can effectively mitigate the occurrence of POFS in patients undergoing laparoscopic radical gastrectomy. METHODS: A total of 133 patients diagnosed with gastric cancer were randomly assigned to two groups, namely the control group (Group C) (n = 66) and the esketamine group (Group E) (n = 67), using a double-blind method. The Group C received standardized anesthesia, while the Group E received esketamine in addition to the standardized anesthesia. The primary outcome measure assessed was the Christensen fatigue score at 3 days after the surgical procedure, while the secondary outcomes included the disparities in postoperative fatigue, postoperative pain, sleep quality, and adverse reactions between the two groups. RESULTS: In the group receiving esketamine, the fatigue scores of Christensen on the third day after surgery were significantly lower compared to the Group C (estimated difference, -0.70; 95% CI, -1.37 to -0.03; P = 0.040). Additionally, there was a significant decrease in the occurrence of fatigue in the Group E compared to the Group C on the first and third days following surgery (P < 0.05). Also, compared to individuals who had distal gastrectomy, those who had entire gastrectomy demonstrated a higher degree of postoperative tiredness reduction with esketamine. Furthermore, the Group E exhibited reduced postoperative pain and improved sleep in comparison to the Group C. Both groups experienced similar rates of adverse events. CONCLUSIONS: The use of esketamine during the perioperative period can improve POFS after laparoscopic radical gastrectomy, without adverse reactions. TRIAL REGISTRATION: Registered in the Chinese Clinical Trial Registry (ChiCTR2300072167) on 05/06 /2023.

Molybdenum inhibited the growth of Phytophthora nicotiana and improved the resistance of Nicotiana tabacum L. against tobacco black shank.

Tobacco black shank (TBS) is a soil-borne fungal disease caused by Phytophthora nicotiana (P. nicotianae), significantly impeding the production of high-quality tobacco. Molybdenum (Mo), a crucial trace element for both plants and animals, plays a vital role in promoting plant growth, enhancing photosynthesis, bolstering antioxidant capacity, and maintaining ultrastructural integrity. However, the positive effect of Mo on plant biotic stress is little understood. This study delves into the inhibitory effects of Mo on P. nicotianae and seeks to unravel the underlying mechanisms. The results showed that 16.32 mg/L of Mo significantly inhibited mycelial growth, altered mycelial morphological structure, damaged mycelial cell membrane, and ultimately led to the leakage of cell inclusions. In addition, 0.6 mg/kg Mo applied in soil significantly reduced the severity of TBS. Mo increased photosynthetic parameters and photosynthetic pigment contents of tobacco leaves, upregulated expression of NtPAL and NtPPO resistance genes, as well as improved activities of SOD, POD, CAT, PPO, and PAL in tobacco plants. Furthermore, Mo could regulate nitrogen metabolism and amino acids metabolism to protect tobacco plants against P. nicotianae infection. These findings not only present an ecologically sound approach to control TBS but also contribute valuable insights to the broader exploration of the role of microelements in plant disease management.

Multi-omics network analysis on samples from sequential biopsies reveals vital role of proliferation arrest for Macrosteatosis related graft failure in rats after liver transplantation.

To investigate the molecular impact of graft MaS on post-transplant prognosis, based on multi-omics integrative analysis. Rats were fed by methionine-choline deficient diet (MCD) for MaS grafts. Samples were collected from grafts by sequential biopsies. Transcriptomic and metabolomic profilings were assayed. Post-transplant MaS status showed a close association with graft failure. Differentially expressed genes (DEGs) for in-vivo MaS were mainly enriched on pathways of cell cycle and DNA replication. Post-transplant MaS caused arrests of graft regeneration via inhibiting the E2F1 centered network, which was confirmed by an in vitro experiment. Data from metabolomics assays found insufficient serine/creatine which is located on one­carbon metabolism was responsible for MaS-related GF. Pre-transplant MaS caused severe fibrosis in long-term survivors. DEGs for grafts from long-term survivors with pre-transplant MaS were mainly enriched in pathways of ECM-receptor interaction and focal adhesion. Transcriptional regulatory network analysis confirmed SOX9 as a key transcription factor (TF) for MaS-related fibrosis. Metabolomic assays found elevation of aromatic amino acid (AAA) was a major feature of fibrosis in long-term survivors. Graft MaS in vivo increased post-transplant GF via negative regulations on graft regeneration. Pre-transplant MaS induced severe fibrosis in long-term survivors via activations on ECM-receptor interaction and AAA metabolism.

Hydrogen-Bond-Enhanced Photoreforming of Biomass Furans over a Urea-Incorporated Cu(II) Porphyrin Framework.

Solar-driven upgrading of biomass-derived 5-hydroxylmethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA) holds great promise for sustainable production of bio-plastics and resins. However, the process is limited by poor selectivity and sluggish kinetics due to the vertical coordination of HMF at relatively strong metal sites. Here, we purposely developed a Cu(II) porphyrin framework featuring side-chain incorporated urea linkages, denoted as TBUPP-Cu MOF, to render HMF a weak hydrogen bond at the urea site and flat adsorption via π-π stacking with the benzene moiety. The unique configuration promotes the approaching of -CHO of HMF to the photoexcited porphyrin ring towards kinetically and thermodynamically favourable intermediate formation and subsequent desorption. The charge localisation and orbital energy alignment enable the selective activation of O2 over the porphyrin to generate ⋅O2 - and 1O2 instead of highly oxidative H2O2 and ⋅OH via spin-flip electron transfer, which drive the ambient oxidation of proximal -CHO. The effective utilisation of redox species and circumvented over-oxidation facilitate a FDCA selectivity of >90 % with a high turnover number of 193 molHMF molCu -1. The facile purification of high-purity FDCA and zero-waste recycling of intermediates and durable catalyst feature TBUPP-Cu MOF a promising photo-oxidation platform towards net-zero biorefining and organic transformations.

Investigation of stable pulse mode-locking regimes in a NALM figure-9 Er-doped fiber laser.

We demonstrate three typical mode-locking processes of a nonlinear amplifying loop mirror (NALM) fiber laser via a general nonlinear Schrödinger equation-based (GNLSE) simulation model. First, the pulse evolutions in the NALM cavity were separately simulated under asymmetric and weakly asymmetric conditions. We found that the splitting ratio and positions of the gain fiber can result in a suitable phase bias between clockwise and counter-clockwise beams, enabling the realization of a self-starting low-threshold operating condition. To assess the roles of the splitting ratio and gain in the mode-locking process, we simulated three pulse formation processes: in the soliton, stretched-pulse, and dissipative soliton mode-locking regimes. The simulation results show that the splitting ratio, gain, and dispersion directly influence the mode-locking condition and pulse characteristics, thereby providing effective quantified guidance for high-quality pulse generation. Finally, an experimental NALM oscillation operating under stretched pulse conditions was established to investigate the impact of the splitting ratio and pump power on the pulse characteristics. The experimental results prove that the splitting ratio, gain, and dispersion can be used to manipulate the mode-locking threshold, self-starting threshold, nonlinear effects, and pulse characteristics.

Real-time revealing of Cherenkov radiation evolution in optical fibers.

The generation of Cherenkov radiation (CR) is determined by the phase-matching condition, but the experimental observation on the phase change of its transient process is still incomplete. In this paper, we use the dispersive temporal interferometer (DTI) technique to real-time reveal the buildup and evolution of CR. Experiments show that when the pump power varies, the phase-matching conditions also change, which is mainly affected by the nonlinear phase shift caused by the Kerr effect. Further simulation results propose that both pulse power and pre-chirp management have a significant impact on phase-matching. The CR wavelength can be shortened and the generation position can be moved forward by adding a suitable positive chirp or increasing the incident peak power. Our work directly reveals the evolution of CR in optical fibers and provides a method for optimizing it.

Human antimicrobial peptide LL-37 contributes to Alzheimer's disease progression.

As a prime mover in Alzheimer's disease (AD), microglial activation requires membrane translocation, integration, and activation of the metamorphic protein chloride intracellular channel 1 (CLIC1), which is primarily cytoplasmic under physiological conditions. However, the formation and activation mechanisms of functional CLIC1 are unknown. Here, we found that the human antimicrobial peptide (AMP) LL-37 promoted CLIC1 membrane translocation and integration. It also activates CLIC1 to cause microglial hyperactivation, neuroinflammation, and excitotoxicity. In mouse and monkey models, LL-37 caused significant pathological phenotypes linked to AD, including elevated amyloid-ß, increased neurofibrillary tangles, enhanced neuronal death and brain atrophy, enlargement of lateral ventricles, and impairment of synaptic plasticity and cognition, while Clic1 knockout and blockade of LL-37-CLIC1 interactions inhibited these phenotypes. Given AD's association with infection and that overloading AMP may exacerbate AD, this study suggests that LL-37, which is up-regulated upon infection, may be a driving force behind AD by acting as an endogenous agonist of CLIC1.

Thymosin ß4, a potential marker of malignancy and prognosis in hepatocellular carcinoma.

BACKGROUND: The lack of effective early diagnostic markers is an obstacle in clinical diagnosis and treatment of hepatocellular carcinoma (HCC). Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is an increasing popular approach for identification of clinically relevant parameters including biomarkers. PATIENTS AND METHODS: 540 subjects, including 274 HCC, 119 liver cirrhosis, 89 hepatitis, and 58 healthy volunteers were enrolled. MALDI-TOF MS was used to select potential novel biomarkers from serum of HCC patients. Its clinical application was evaluated by experiments and clinical data analysis. RESULTS: We identified Thymosin ß4 (Tß4) in serum by MALDI-TOF MS. The expression of Tß4 was detected up-regulating in HCC cells and tissues which enhanced motility of HCC cells. More important, the level of serum Tß4 was significantly elevated in HCC patients. The AUROC showed the optimum diagnostic cut-off was 1063.6 ng/mL, ROC and 95% CI of Tß4 (0.908; 0.880-0.935) were larger than that of serum AFP (0.712; 0.662-0.762; p < 0.001). The sensitivity (91.3% vs 83.1%) and specificity (81.2% vs 20.3%) of serum Tß4 were higher than alpha-fetoprotein (AFP). In AFP-negative HCC, the sensitivity could reach to 80.5%. ROC analysis showed serum Tß4 had a better performance compared with AFP in distinguishing early-stage and small HCC. Tß4 is correlated with TNM stage (p = 0.016) and vascular invasion (p = 0.005). Survival analysis indicated the survival time of Tß4 positive patients was shorter (p < 0.001). Cox analysis suggested Tß4 could be an independent factor for HCC prognosis. CONCLUSION: Tß4 may serve as a novel biomarker for HCC diagnosis and prognosis.

Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1.

Necroptosis is a form of regulated necrosis involved in various pathological diseases. The process of necroptosis is controlled by receptor-interacting kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase domain-like protein (MLKL), and pharmacological inhibition of these kinases has been shown to have therapeutic potentials in a variety of diseases. In this study, using drug repurposing strategy combined with high-throughput screening (HTS), we discovered that AZD4547, a previously reported FGFR inhibitor, is able to interfere with necroptosis through direct targeting of RIPK1 kinase. In both human and mouse cell models, AZD4547 blocked RIPK1-dependent necroptosis. In addition, AZD4547 rescued animals from TNF-induced lethal shock and inflammatory responses. Together, our study demonstrates that AZD4547 is a potent and selective inhibitor of RIPK1 with therapeutic potential for the treatment of inflammatory disorders that involve necroptosis.

Specific foraminal changes originate from degenerative spondylolisthesis on computed tomographic images.

PURPOSE: Operative treatment for degenerative spondylolisthesis (DS) is accompanied by the high incidence of nerve injury. Foraminal structures, especially the hypertrophied facet joints, have significant impacts on the adjacent nerve. This study aims to identify the specific foraminal changes relating to DS and nerve injury. METHODS: The CT images of 70 patients with DS and 50 patients without lumbar disease were collected. The length and height of the foraminal structure were measured horizontally and vertically on sagittally reconstructed images. Horizontal stenosis, meaning to pending compression to nerve root after complete reduction, was evaluated on the image located to the middle of the foramen. Chi-square test or T-test were carried out using SPSS 26.0. RESULTS: The hyperplasia of the superior articular process (SAP) and articular capsule (Ac) incidence rates in DS group was significantly more common than that of the control group (9.2 vs 0.0%, 42.9 vs 2.0%). The height and width of the SAP and Ac in vertical and horizontal directions were significantly greater than those in the control group (4.95 mm vs - 0.47 mm, P < 0.0001; 3.28 vs 0.02 mm, P < 0.0001; 5.27 vs3.44 mm, P < 0.0001; 2.60 vs 0.37 mm, P < 0.0001). In the DS group, hyperplasia of the SAP and Ac accounted for 9 and 43% respectively, 85 and 45% of which were accompanied by horizontal stenosis of the intervertebral foramen. CONCLUSION: DS is usually characterized of excessive hyperplasia of the SAP and Ac, both of which are possible elements of nerve root injury after complete reduction in operation and should be focused on during surgery.

The reciprocal relations among self-compassion, and depression among adolescents after the Jiuzhaigou earthquake: A three-wave cross-lagged study.

BACKGROUND: Previous cross-sectional studies have examined the relationship between self-compassion and depression. Although it is often implicitly assumed that self-compassion may increase the vulnerability of an individual to depression, only a few studies have assessed whether self-compassion is a cause or a consequence of depression or both. METHOD: To examine such reciprocal effects, we assessed self-compassion and depression via self-report measures. At the baseline assessment (Time 1, T1), 450 students (M = 13.72, SD = 0.83, 54.2% females) participated 10 months after the Jiuzhaigou earthquake. We reassessed the T1 sample after 6- and 12-month intervals. At Time 2 (T2) assessment, 398 (56.0% female participants) of the Wave 1 participants were retained, and at Time 3 (T3) assessment, 235 (52.5% female participants) of the T1 and T2 participants were retained. RESULTS: Cross-lagged analyses indicated that positive self-compassion could significantly reduce subsequent depression. However, depression did not significantly predict later positive self-compassion. Negative self-compassion at T1 increased depression at T2, but negative self-compassion at T2 did not significantly predict depression at T3. In addition, positive self-compassion significantly reduced subsequent negative self-compassion. CONCLUSIONS: Positive self-compassion appears to protect adolescents against depression and maintain this protection over time, whereas negative self-compassion may worsen depression in adolescents during the initial stages of traumatic events. Additionally, positive self-compassion may decrease the level of negative self-compassion.

A General Protocol for Synthesizing Thiolated Folate Derivatives.

Folic acid (FA) has shown great potential in the fields of targeted drug delivery and disease diagnosis due to its highly tumor-targeting nature, biocompatibility, and low cost. However, FA is generally introduced in targeted drug delivery systems through macromolecular linkage via complex synthetic processes, resulting in lower yields and high costs. In this work, we report a general protocol for synthesizing thiolated folate derivatives. The small molecule thiolated folate (TFa) was first synthesized with a purity higher than 98.20%. First, S-S-containing diol was synthesized with a purity higher than 99.44 through a newly developed green oxidation protocol, which was carried out in water with no catalyst. Then, folic acid was modified using the diol through esterification, and TFa was finally synthesized by breaking the disulfide bond. Further, the synthesized TFa was utilized to modify silver nanoparticles. The results showed that TFa could be easily bonded to metal particles. The protocol could be extended to the synthesis of a series of thiolated derivatives of folate, such as mercaptohexyl folate, mercaptoundecyl folate, etc., which would greatly benefit the biological applications of FA.

The reciprocal relations among self-compassion, posttraumatic stress disorder, and posttraumatic growth among adolescents after the Jiuzhaigou earthquake: a three-wave cross-lagged study.

BACKGROUND: Previous cross-sectional studies have examined the relationship between self-compassion, post-traumatic stress disorder (PTSD), and post-traumatic growth (PTG). But no study has tested whether self-compassion is a cause or a consequence of PTSD, PTG, or both. AIMS: The cross-lag analysis was used to examine the reciprocal effects among self-compassion, PTSD, and PTG. METHOD: We used data from 244 adolescents who had experienced earthquakes. We assessed self-compassion, PTSD, and PTG via self-report measures after the earthquake in Jiuzhaigou, as well as 6 and 12 months later. RESULTS: Cross-lagged analyses indicated that positive self-compassion could significantly predict subsequent PTSD and PTG. Meanwhile, PTSD and PTG also predicted later positive self-compassion. Negative self-compassion at T1 increased PTSD at T2, and neither PTSD nor PTG significantly predicted subsequent negative self-compassion. In addition, negative self-compassion at T1 significantly predicted positive self-compassion at T2, while positive self-compassion at T2 significantly predicted negative self-compassion at T3. CONCLUSIONS: Positive self-compassion is a protective factor of post-traumatic psychological response, and it is maintained for a long time, while negative self-compassion may aggravate the negative psychological outcomes of adolescents in the early stage of experiencing traumatic events. In addition, positive and negative self-compassion can influence each other over time.

Real-time observation of phase transition of bifurcation evolution in mode-locked lasers.

By using the dispersive temporal holography technology, we observe the real-time dynamics of period-doubling bifurcation evolution in an ultrafast fiber laser. The pulse properties including the phase, polarization state, chirp, pulse width, and pulse energy are fully bifurcated, which embody the bifurcation induced "phase transition." There are two types of bifurcation in the laser buildup: one to many bifurcation towards the chaos and the multiple bifurcated pulses back to the stationary state along the reversed trajectory. Both of them can be explained by the rule of the same phase transition. We conclude and illustrate the differences and connections to another common pulsation, the Hopf bifurcation. The findings can promote an understanding of the bifurcations in ultrafast lasers, and are beneficial for an improvement of laser stability.

CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers.

Oncogene HER2 is amplified in 20%-25% of human breast cancers and 6.1%-23.0% of gastric cancers, and HER2-directed therapy significantly improves the outcome for patients with HER2-positive cancers. However, drug resistance is still a clinical challenge due to primary or acquired mutations and drug-induced negative regulatory feedback. In this study, we discovered a potent irreversible HER2 kinase inhibitor, CHMFL-26, which covalently targeted cysteine 805 of HER2 and effectively overcame the drug resistance caused by HER2 V777L, HER2 L755S, HER2 exon 20 insertions, and p95-HER2 truncation mutations. CHMFL-26 displayed potent antiproliferation efficacy against HER2-amplified and mutant cells through constant HER2-mediated signaling pathway inhibition and apoptosis induction. In addition, CHMFL-26 suppressed tumor growth in a dose-dependent manner in xenograft mouse models. Together, these results suggest that CHMFL-26 may be a potential novel anti-HER2 agent for overcoming drug resistance in HER2-positive cancer therapy.

Preparation of a camptothecin analog FLQY2 self-micelle solid dispersion with improved solubility and bioavailability.

BACKGROUND: 7-p-trifluoromethylphenyl-FL118 (FLQY2) is a camptothecin analog with excellent antitumor efficacy against various solid tumors. However, its poor solubility and low bioavailability limited the development of the drug. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), an emerging carrier for preparing solid dispersion (SD), encapsulated FLQY2 to circumvent the above limitations. RESULTS: In this project, FLQY2-SD was prepared by solvent evaporation method and self-assembled into micelles in aqueous solutions owing to the amphiphilic nature of Soluplus®. The physicochemical characterizations demonstrated that FLQY2 existed in a homogeneous amorphous form in SD and was rapidly dissolved. The micelles did not affect cytotoxicity or cellular uptake of FLQY2 in vitro, and the oral bioavailability was increased by 12.3-fold compared to the FLQY2 cyclodextrin suspension. The pharmacokinetics of FLQY2-SD showed rapid absorption, accumulation in the intestine, and slow elimination via fecal. Metabolite identification studies showed 14 novel metabolites were identified, including 12 phase I metabolites (M1-M12) and 2 phase II metabolites (M13-M14), of which M2 (oxidation after decarboxylation) and M7 (dioxolane ring cleavage) were the primary metabolites in the positive mode and negative mode, respectively. The tumor growth inhibition rate (TGI, 81.1%) of FLQY2-SD (1.5 mpk, p.o./QW) in tumor-bearing mice after oral administration was higher than that of albumin-bound Paclitaxel (15 mpk, i.v./Q4D) and Irinotecan hydrochloride (100 mpk, i.p./QW). CONCLUSIONS: The successful preparation, pharmacokinetics, and pharmacodynamics studies of FLQY2-SD showed that the solubility and bioavailability of FLQY2 were improved, which facilitated the further druggability development of FLQY2.

Microcystin-leucine arginine induces skin barrier damage and reduces resistance to pathogenic bacteria in Lithobates catesbeianus tadpoles.

Despite the importance of the skin mucosal barrier and commensal microbiota for the health of amphibians, the potential of environmental contaminants to disrupt the skin mucosal barrier and microbiota have rarely been studied in toxicology. In this study, tadpoles (Lithobates catesbeianus) were exposed to 0, 0.5, and 2 µg/L of microcystin-leucine arginine (MC-LR) for 30 days to explore the impacts of environmentally realistic MC-LR concentrations on the physical skin barrier, immune barrier, commensal microbiota, and skin resistance to pathogenic bacterial invasion. MC-LR exposure significantly reduced the collagen fibrils in the dermis of skin tissues and down-regulated tight junction and stratum corneum-related gene transcriptions, suggesting the damage caused by MC-LR to the physical barrier of the skin. Increased skin eosinophils and upregulated transcriptions of inflammation-related genes in the exposed tadpoles underline the development of skin inflammation resulting from MC-LR exposure even at environmentally realistic concentrations. Comparative transcriptome and immunobiochemical analyses found that antimicrobial peptides (Brevinin-1PLc, Brevinin-2GHc, and Ranatuerin-2PLa) and lysozyme were down-regulated in the exposed groups, while complement, pattern recognition receptor, and specific immune processes were up-regulated. However, the content of endotoxin lipopolysaccharide produced by bacteria increased in a dose-dependent pattern. The disc diffusion test showed a reduced ability of skin supernatant to inhibit pathogenic bacteria in the exposed groups. Analysis of microbial 16 S rRNA gene by high-throughput sequencing revealed that MC-LR interfered with the abundance, composition, and diversity of the skin commensal microbiota, which favored the growth of pathogen-containing genera Rhodococcus, Acinetobacter, and Gordonibacter. In summary, the current study provides the first clues about the impact of MC-LR on the integrity and function of skin barrier of amphibians. These new toxicological evidences can facilitate a more comprehensive evaluation of the ecological risk of MC-LR to amphibians.

SLR-superscaffolder: a de novo scaffolding tool for synthetic long reads using a top-to-bottom scheme.

BACKGROUND: Synthetic long reads (SLR) with long-range co-barcoding information are now widely applied in genomics research. Although several tools have been developed for each specific SLR technique, a robust standalone scaffolder with high efficiency is warranted for hybrid genome assembly. RESULTS: In this work, we developed a standalone scaffolding tool, SLR-superscaffolder, to link together contigs in draft assemblies using co-barcoding and paired-end read information. Our top-to-bottom scheme first builds a global scaffold graph based on Jaccard Similarity to determine the order and orientation of contigs, and then locally improves the scaffolds with the aid of paired-end information. We also exploited a screening algorithm to reduce the negative effect of misassembled contigs in the input assembly. We applied SLR-superscaffolder to a human single tube long fragment read sequencing dataset and increased the scaffold NG50 of its corresponding draft assembly 1349 fold. Moreover, benchmarking on different input contigs showed that this approach overall outperformed existing SLR scaffolders, providing longer contiguity and fewer misassemblies, especially for short contigs assembled by next-generation sequencing data. The open-source code of SLR-superscaffolder is available at https://github.com/BGI-Qingdao/SLR-superscaffolder . CONCLUSIONS: SLR-superscaffolder can dramatically improve the contiguity of a draft assembly by integrating a hybrid assembly strategy.