Tailoring d-p Orbital Hybridization to Decipher the Essential Effects of Heteroatom Substitution on Redox Kinetics.

The heteroatom substitution is considered as a promising strategy for boosting the redox kinetics of transition metal compounds in hybrid supercapacitors (HSCs) although the dissimilar metal identification and essential mechanism that dominate the kinetics remain unclear. It is presented that d-p orbital hybridization between the metal and electrolyte ions can be utilized as a descriptor for understanding the redox kinetics. Herein, a series of Co, Fe and Cu heteroatoms are respectively introduced into Ni3Se4 cathodes, among them, only the moderate Co-substituted Ni3Se4 can hold the optimal d-p orbital hybridization resulted from the formed more unoccupied antibonding states π*. It inevitably enhances the interfacial charge transfer and ensures the balanced OH- adsorption-desorption to accelerate the redox kinetics validated by the lowest reaction barrier (0.59 eV, matching well with the theoretical calculations. Coupling with the lower OH- diffusion energy barrier, the prepared cathode delivers ultrahigh rate capability (~68.7% capacity retention even the current density increases by 200 times), and an assembled HSC also presents high energy/power density. This work establishes the principles for determining heteroatoms and deciphers the underlying effects of the heteroatom substitution on improving redox kinetics and the rate performance of battery-type electrodes from a novel perspective of orbital-scale manipulation.

4-Oxo-2-Nonenal- and Agitation-Induced Aggregates of α-Synuclein and Phosphorylated α-Synuclein with Distinct Biophysical Properties and Biomedical Applications.

α-Synuclein (α-syn) can form oligomers, protofibrils, and fibrils, which are associated with the pathogenesis of Parkinson's disease and other synucleinopathies. Both the lipid peroxidation product 4-oxo-2-nonenal (ONE) and agitation can induce aggregation of α-syn and phosphorylated α-syn. Thus, clarification of the characteristics of different α-syn species could help to select suitable aggregates for diagnosis and elucidate the pathogenesis of diseases. Here, we characterized ONE-induced wild-type (WT) α-syn aggregates (OW), ONE-induced phosphorylated α-syn (p-α-syn) aggregates (OP), agitation-induced α-syn preformed fibrils (PFF), and agitation-induced p-α-syn preformed fibrils (pPFF). Thioflavin T (ThT) dying demonstrated that OW and OP had fewer fibrils than the PFF and pPFF. Transmission electron microscopy revealed that the lengths of PFF and pPFF were similar, but the diameters differed. OW and OP had more compact structures than PFF and pPFF. Aggregation of p-α-syn was significantly faster than WT α-syn. Furthermore, OW and OP were more sodium dodecyl sulfate-stable and proteinase K-resistant, suggesting greater stability and compactness, while aggregates of PFF and pPFF were more sensitive to proteinase K treatment. Both ONE- and agitation-induced aggregates were cytotoxic when added exogenously to SH-SY5Y cells with increasing incubation times, but the agitation-induced aggregates caused cell toxicity in a shorter time and more p-α-syn inclusions. Similarly, p-proteins were more cytotoxic than non-p-proteins. Finally, all four aggregates were used as standard antigens to establish sandwich enzyme-linked immunosorbent assay (ELISA). The results showed that the recognition efficiency of OW and OP was more sensitive than that of PFF and pPFF. The OW- and OP-specific ELISA for detection of p-α-syn and α-syn in plasma samples of Thy1-α-syn transgenic mice showed that the content of aggregates could reflect the extent of disease. ONE and agitation induced the formation of α-syn aggregates with distinct biophysical properties and biomedical applications.

The Mechanism and Function of circlRP6 Targeting miR-145 in Occurrence of Intracranial Aneurysms.

Objective: To explore the differential expression of circLRP6 targeted miR-145 in intracranial aneurysms and its regulation of VSMC biological activity, providing a theoretical foundation for the study of intracranial aneurysm regulation by circLRP6. Methods: Expression levels of circLRP6 and miR-145 mRNA were measured in intracranial aneurysms and superficial temporal arteries. In vitro experiments were conducted using TNF-αstimulated HBVSMCs to evaluate the expression of circLRP6 and miR-145, as well as cell proliferation, apoptosis, migration, and related protein expression. Results: CircLRP6 was low expressed in intracranial aneurysms, and MiR-145 showed a trend of Overexpression; With the increase of circLRP6 expression in intracranial aneurysms, expression of miR-145 decreased. The correlation coefficient, r, was -0.5139; After TNF- α following stimulation, phenotype of VSMCs changed, expression of circLRP6 in cells decreased, and expression of miR-145 increased; CircLRP was successfully overexpressed or knocked out in VSMCs cells; Overexpression of circLRP6 can inhibit concentration expression of miR-145; VSMCs cells showed an increasing trend with time. Overexpression of circLRP6 can inhibit the proliferation process of VSMCs cells, The proliferation activity of cells was enhanced after circLRP6 knockout, and Overexpression of miR-145 could enhance the proliferation activity of VSMCs; Overexpression of circLRP6 could promote apoptosis process of VSMCs, while knockout of circLRP6 and Overexpression of miR-145 could inhibit apoptosis ability of VSMCs; Overexpression of circLRP6 can inhibit migration ability of VSMCs cells. Overexpression of circLRP6 after knockout and miR-145 can enhance the migration ability of cells; After circLRP6 overexpression in VSMCs, α-SMA, SM22α And expression concentration of Calponin protein increased, IL-1ß. The concentration and expression of MMP-2 and MMP-9 protein decreased After knockout of circLRP6 and Overexpression of miR-145, α-SMA, SM22α, And expression concentration of Calponin protein decreased, IL-1ß. The expression of MMP-2 and MMP-9 protein increased (P < .05). Conclusion: CircLRP6 is low expressed in intracranial aneurysms and negatively correlates with miR-145 expression. CircLRP6 may be involved in the development of intracranial aneurysms by influencing VSMC phenotype transformation. CircLRP6 acts as a natural sponge for miR-145, regulating VSMC proliferation, migration, and differentiation and promoting apoptosis, ultimately inhibiting the development of intracranial aneurysms. This study provides a theoretical basis for clinical research on the mechanism of intracranial aneurysms.

Recent Advances in Electrospinning Techniques for Precise Medicine.

In the realm of precise medicine, the advancement of manufacturing technologies is vital for enhancing the capabilities of medical devices such as nano/microrobots, wearable/implantable biosensors, and organ-on-chip systems, which serve to accurately acquire and analyze patients' physiopathological information and to perform patient-specific therapy. Electrospinning holds great promise in engineering materials and components for advanced medical devices, due to the demonstrated ability to advance the development of nanomaterial science. Nevertheless, challenges such as limited composition variety, uncontrollable fiber orientation, difficulties in incorporating fragile molecules and cells, and low production effectiveness hindered its further application. To overcome these challenges, advanced electrospinning techniques have been explored to manufacture functional composites, orchestrated structures, living constructs, and scale-up fabrication. This review delves into the recent advances of electrospinning techniques and underscores their potential in revolutionizing the field of precise medicine, upon introducing the fundamental information of conventional electrospinning techniques, as well as discussing the current challenges and future perspectives.

Development of Novel ß-Carboline/Furylmalononitrile Hybrids as Type I/II Photosensitizers with Chemo-Photodynamic Therapy and Minimal Toxicity.

Chemo-photodynamic therapy is a treatment method that combines chemotherapy and photodynamic therapy and has demonstrated significant potential in cancer treatment. However, the development of chemo-photodynamic therapeutic agents with fewer side effects still poses a challenge. Herein, we designed and synthesized a novel series of ß-carboline/furylmalononitrile hybrids 10a-i and evaluated their chemo-photodynamic therapeutic effects. Most of the compounds were photodynamically active and exhibited cytotoxic effects in four cancer cells. In particular, 10f possessed type-I/II photodynamic characteristics, and its 1O2 quantum yield increased by 3-fold from pH 7.4 to 4.5. Most interestingly, 10f exhibited robust antiproliferative effects by tumor-selective cytotoxicities and hypoxic-overcoming phototoxicities. In addition, 10f generated intracellular ROS and induced hepatocellular apoptosis, mitochondrial damage, and autophagy. Finally, 10f demonstrated extremely low acute toxicity (LD50 = 1415 mg/kg) and a high tumor-inhibitory rate of 80.5% through chemo-photodynamic dual therapy. Our findings may provide a promising framework for the design of new photosensitizers for chemo-photodynamic therapy.

Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.

Unveiling gene regulatory networks during cellular state transitions without linkage across time points.

Time-stamped cross-sectional data, which lack linkage across time points, are commonly generated in single-cell transcriptional profiling. Many previous methods for inferring gene regulatory networks (GRNs) driving cell-state transitions relied on constructing single-cell temporal ordering. Introducing COSLIR (COvariance restricted Sparse LInear Regression), we presented a direct approach to reconstructing GRNs that govern cell-state transitions, utilizing only the first and second moments of samples between two consecutive time points. Simulations validated COSLIR's perfect accuracy in the oracle case and demonstrated its robust performance in real-world scenarios. When applied to single-cell RT-PCR and RNAseq datasets in developmental biology, COSLIR competed favorably with existing methods. Notably, its running time remained nearly independent of the number of cells. Therefore, COSLIR emerges as a promising addition to GRN reconstruction methods under cell-state transitions, bypassing the single-cell temporal ordering to enhance accuracy and efficiency in single-cell transcriptional profiling.

SLC38A3 Promotes the Proliferation and Migration of Tumor Cells and Predicts Poor Prognosis in Colorectal Cancer.

Previous studies have revealed that abnormal expressions of membrane transporters were associated with colorectal cancer (CRC). We herein performed a comprehensive bioinformatics analysis to identify the key transporter protein-related genes involved in CRC and potential mechanisms. Differentially expressed transporter protein-related genes (DE-TPRGs) were identified from CRC and normal samples using The Cancer Genome Atlas database. SLC38A3 expression was validated by immunohistochemistry and RT-qPCR, and the potential mechanism was explored. A total of 63 DE-TPRGs (29 up-regulated and 34 down-regulated) were screened. Inside, ABCC2, ABCG2, SLC4A4, SLC9A3, SLC15A1, and SLC38A3 were identified as hub genes. SLC38A3 is indeed upregulated in colorectal cancer patients. Furthermore, we found that knockdown of SLC38A3 inhibited the proliferation and migration of HCT116 cells, and Hsp70 ATPase activator could rescue it. Overall, SLC38A3 is a novel potential biomarker involved in CRC progression and promotes the proliferation and migration of tumor cells by positively regulating the function of Hsp70.

Research progress of prodrugs for the treatment of cerebral ischemia.

It is well-known that pharmacotherapy plays a pivotal role in the treatment and prevention of cerebral ischemia. Nevertheless, existing drugs, including numerous natural products, encounter various challenges when applied in cerebral ischemia treatment. These challenges comprise poor brain absorption due to low blood-brain barrier (BBB) permeability, limited water solubility, inadequate bioavailability, poor stability, and rapid metabolism. To address these issues, researchers have turned to prodrug strategies, aiming to mitigate or eliminate the adverse properties of parent drug molecules. In vivo metabolism or enzymatic reactions convert prodrugs into active parent drugs, thereby augmenting BBB permeability, improving bioavailability and stability, and reducing toxicity to normal tissues, ultimately aiming to enhance treatment efficacy and safety. This comprehensive review delves into multiple effective prodrug strategies, providing a detailed description of representative prodrugs developed over the past two decades. It underscores the potential of prodrug approaches to improve the therapeutic outcomes of currently available drugs for cerebral ischemia. The publication of this review serves to enrich current research progress on prodrug strategies for the treatment and prevention of cerebral ischemia. Furthermore, it seeks to offer valuable insights for pharmaceutical chemists in this field, offer guidance for the development of drugs for cerebral ischemia, and provide patients with safer and more effective drug treatment options.

Rho kinase inhibitor Y-27632 downregulates IL-1ß expression in mice with experimental autoimmune myocarditis.

Autoimmune myocarditis is the limited or diffuse inflammation of the myocardium due to dysfunctional cellular and humoral immunity mechanisms. We constructed mouse models of experimental autoimmune myocarditis (EAM) using peptide MyHC-α614-629. On the day after secondary immunization, the mice were intraperitoneally injected with Rho kinase (ROCK) inhibitor Y-27632. On day 21, the cardiac tissues were harvested and weighed. The hearts of EAM mice were significantly enlarged and whitened. Furthermore, body weight (BW) slowly increased during the treatment period, the heart weight (HW) and the ratio of HW/eventual BW were increased, and inflammatory infiltration and fibrosis were aggravated in the myocardial tissue. Y-27632 treatment improved the aforementioned phenotypic and pathological features of EAM mice. Mechanistic analysis revealed a significant increase in Notch1, Hes1, Jag2, Dil1, Toll-like receptor (Tlr) 2, and interleukin (IL)-1ß expression in the myocardial tissue of EAM mice. Notably, IL-1ß expression was correlated with that of Notch1 and Tlr2. Following Y-27632 treatment, the expression of key target genes of the Notch signaling pathway (Notch1, Hes1, Dil1, and Jag2) and Tlr2 were obviously decreased. Y-27632 treatment also decreased the number of monocytes in the spleen of EAM mice. Thus, ROCK inhibitor Y-27632 exerted a protective effect in EAM mice by downregulating IL-1ß expression. This study aimed to provide a reference point for the future treatment of myocarditis in clinical settings.

Assessment of rare earth elements variations in five water systems in Beijing: Distribution, geochemical features, and fractionation patterns.

This study investigates the distribution of rare earth elements (REEs) within the Beijing water system, specifically examining the Yongding, Chaobai, Beiyun, Jiyun, and Daqing rivers. Results indicate that the Beiyun River exhibits the highest REE concentrations, ranging from 35.95 to 59.78 µg/mL, while the Daqing River shows the lowest concentrations, ranging from 15.79 to 17.48 µg/mL. LREEs (La to Nd) predominate with a total concentration of 23.501 µg/mL, leading to a notable LREE/HREE ratio of 7.901. Positive Ce anomalies (0.70-1.11) and strong positive Eu anomalies (1.38-2.49) were observed. The study suggests that the Beijing water system's REEs may originate from geological and anthropogenic sources, such as mining and industrial activities in neighboring regions, including Inner Mongolia. These findings underscore the importance of ongoing monitoring and effective water management strategies to address REE-related environmental concerns.

Catalytic Oxidation of Benzene over Atomic Active Site AgNi/BCN Catalysts at Room Temperature.

Benzene is the typical volatile organic compound (VOC) of indoor and outdoor air pollution, which harms human health and the environment. Due to the stability of their aromatic structure, the catalytic oxidation of benzene rings in an environment without an external energy input is difficult. In this study, the efficient degradation of benzene at room temperature was achieved by constructing Ag and Ni bimetallic active site catalysts (AgNi/BCN) supported on boron-carbon-nitrogen aerogel. The atomic-scale Ag and Ni are uniformly dispersed on the catalyst surface and form Ag/Ni-C/N bonds with C and N, which were conducive to the catalytic oxidation of benzene at room temperature. Further catalytic reaction mechanisms indicate that benzene reacted with ·OH to produce R·, which reacted with O2 to regenerate ·OH. Under the strong oxidation of ·OH, benzene was oxidized to form alcohols, carboxylic acids, and eventually CO2 and H2O. This study not only significantly reduces the energy consumption of VOC catalytic oxidation, but also improves the safety of VOC treatment, providing new ideas for the low energy consumption and green development of VOC treatment.

[Whole-cell catalytic production of pseudouridine by recombinant Escherichia coli].

Pseudouridine is the most abundant modified nucleoside found in non-coding RNA and is widely used in biological and pharmaceutical fields. However, current methods for pseudouridine production suffer from drawbacks such as complex procedures, low efficiency and high costs. This study presents a novel enzymatic cascade reaction route in Escherichia coli, enabling the whole-cell catalytic synthesis of pseudouridine from uridine. Initially, a metabolic pathway was established through plasmid-mediated overexpression of endogenous pseudouridine-5-phosphase glycosidase, ribokinase, and ribonucleoside hydrolase, resulting in the accumulation of pseudouridine. Subsequently, highly active endogenous ribonucleoside hydrolase was screened to enhance uridine hydrolysis and provide more precursors for pseudouridine synthesis. Furthermore, modifications were made to the substrates and products transport pathways to increase the pseudouridine yield while avoiding the accumulation of by-product uridine. The resulting recombinant strain Ψ-7 catalyzed the conversion of 30 g/L uridine into 27.24 g/L pseudouridine in 24 h, achieving a conversion rate of 90.8% and a production efficiency of 1.135 g/(L·h). These values represent the highest reported yield and production efficiency achieved by enzymatic catalysis methods to date.

Association of carotid duplex ultrasonography screening with stroke and mortality among patients undergoing coronary artery bypass grafting.

OBJECTIVE: Selection criteria for carotid duplex ultrasonography screening (DUS) before coronary artery bypass grafting (CABG) is primarily based on limited observational analysis, and the risks associated with carotid artery stenosis (CAS) detected by this approach to preoperative DUS are uncertain. This study aimed to determine the association of carotid DUS with stroke and mortality among patients undergoing CABG. METHODS: Adult patients with coronary artery disease who underwent isolated CABG or CABG with concomitant valvular or congenital procedure were identified. CHA2DS2-VASc score was assessed before CABG, and patients were recorded as high risk if they had a score of 3 or higher. The primary outcomes were stroke and all-cause mortality. Secondary outcomes included ischemic stroke, non-ischemic stroke, transient ischemic attack, and cardiovascular mortality. RESULTS: Among 8958 patients who underwent CABG, 70.9% (n = 6347) received carotid DUS preoperatively (low-risk, 57.3%; high-risk, 42.7%). In the low-risk cohort, there was no significant difference in the risk of stroke (20.7 per 1000 patient-years for CAS vs 13.1 per 1000 patient-years for no CAS; adjusted hazard ratio [aHR], 1.14; 95% confidence interval [CI], 0.78-1.68) or mortality (20.5 per 1000 patient-years for CAS vs 16.8 per 1000 patient-years for no CAS; aHR, 1.33; 95% CI, 0.97-1.83) at 15 years. In the high-risk cohort, CAS was associated with significantly higher risks of stroke at 30 days (433.2 vs 279.5 per 1000 patient-years; aHR, 1.92; 95% CI, 1.00-3.70) and mortality at 15 years (38.4 vs 32.7 per 1000 patient-years; aHR, 1.25; 95% CI, 1.01-1.57) compared with no CAS. CONCLUSIONS: CAS did not impact the incidence of stroke or mortality in the low-risk cohort who underwent CABG. However, in the high-risk cohort, CAS was associated with a significant increase in the risks of 30-day stroke and 15-year mortality, indicating selective carotid DUS is necessarily recommended for these patients.

A retinal vessel segmentation network with multiple-dimension attention and adaptive feature fusion.

The incidence of blinding eye diseases is highly correlated with changes in retinal morphology, and is clinically detected by segmenting retinal structures in fundus images. However, some existing methods have limitations in accurately segmenting thin vessels. In recent years, deep learning has made a splash in the medical image segmentation, but the lack of edge information representation due to repetitive convolution and pooling, limits the final segmentation accuracy. To this end, this paper proposes a pixel-level retinal vessel segmentation network with multiple-dimension attention and adaptive feature fusion. Here, a multiple dimension attention enhancement (MDAE) block is proposed to acquire more local edge information. Meanwhile, a deep guidance fusion (DGF) block and a cross-pooling semantic enhancement (CPSE) block are proposed simultaneously to acquire more global contexts. Further, the predictions of different decoding stages are learned and aggregated by an adaptive weight learner (AWL) unit to obtain the best weights for effective feature fusion. The experimental results on three public fundus image datasets show that proposed network could effectively enhance the segmentation performance on retinal blood vessels. In particular, the proposed method achieves AUC of 98.30%, 98.75%, and 98.71% on the DRIVE, CHASE_DB1, and STARE datasets, respectively, while the F1 score on all three datasets exceeded 83%. The source code of the proposed model is available at https://github.com/gegao310/VesselSeg-Pytorch-master.

BDE-47-induced damage prevented by melatonin in grass carp hepatocytes (L8824).

Polybrominated diphenyl ethers (PBDEs) are toxic to organisms with melatonin (MT) providing protection for tissues and cells against these. This study investigates the mechanism of damage of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and the cellular protection of MT on grass carp hepatocytes. Grass carp hepatocytes were exposed to 25 µmol/L BDE-47 and/or 40 µmol/L MT for 24 h before testing. Acridine orange/ethidium bromide (AO/EB) double fluorescence staining results showed that BDE-47 could induce cell apoptosis. The expression levels of the endoplasmic reticulum (ER) stress-related genes ire1, atf4, grp78, perk, and chop were also significantly up-regulated (P < 0.01). The levels of the apoptosis-related genes caspase3, bax, and caspase9 were significantly up-regulated (P < 0.0001), while the level of bcl-2 was significantly down-regulated (P < 0.01). Compared with the BDE-47 group, the BDE-47 + MT group showed reduced levels of ER and apoptosis of hepatocytes, while the expression of the ER stress-related genes ire1, atf4, grp78, perk, and chop and the apoptosis-related genes caspase3, bax, and caspase9 were down-regulated (P < 0.05), and the level of bcl-2 was up-regulated (P < 0.01). In conclusion, BDE-47 can activate ER and apoptosis in grass carp hepatocytes, while MT can reduce these responses.

Rifampicin-Loaded Polyelectrolyte Complex Eliminates Intracellular Bacteria through Thiol-Mediated Cellular Uptake and Oxidative Stress Enhancement.

The poor accumulation of antibiotics in the cytoplasm leads to the poor eradication of intracellular bacteria. Herein, a polyelectrolyte complex (PECs@Rif) allowing direct cytosolic delivery of rifampicin (Rif) was developed for the treatment of intracellular infections by complexation of poly(α-lipoic acid) (pLA) and oligosaccharide (COS) in water and loading Rif. Due to the thiol-mediated cellular uptake, PECs@Rif delivered 3.9 times higher Rif into the cytoplasm than that of the free Rif during 8 h of incubation. After entering cells, PECs@Rif released Rif by dissociating pLA into dihydrolipoic acid (DHLA) in the presence of intracellular thioredoxin reductase (TrxR). Notably, DHLA could reduce endogenous Fe(III) to Fe(II) and provide a catalyst for the Fenton reaction to produce a large amount of reactive oxygen species (ROS), which would assist Rif in eradicating intracellular bacteria. In vitro assay showed that PECs@Rif reduced almost 2.8 orders of magnitude of intracellular bacteria, much higher than 0.7 orders of magnitude of free Rif. The bacteremia-bearing mouse models showed that PECs@Rif reduced bacterial levels in the liver, spleen, and kidney by 2.2, 3.7, and 2.3 orders of magnitude, respectively, much higher than free Rif in corresponding tissues. The direct cytosolic delivery in a thiol-mediated manner and enhanced oxidative stress proposed a feasible strategy for treating intracellular bacteria infection.

OfBFT genes play an essential role in the proliferate flower formation of Osmanthus fragrans.

Floral organ development is one of the most vital events in flowering plants and is closely related to ornamental properties. The proliferate flower (a new branch or flower occurring in the centre of a flower) in plants is an interesting type, while the specific molecular mechanism remains largely unknown. Osmanthus fragrans 'Tianxiang Taige' has two different flower morphologies: normal flower and proliferate flower. Phenotypic observation suggested that a normal flower was composed of calyx, petal, stamen and pistil (reduced to leaf-like carpel). While in proliferate flower, the leaf-like carpel continued to grow and was replaced by a new branch. Paraffin section indicated that the re-growth of leaf carpels might be the main reason for proliferate flower formation. Transcriptome sequencing of normal and proliferate flower was performed, and the expression levels of related genes were analysed. Among the differentially expressed genes, OfBFT-a and OfBFT-b had differential expression during the proliferate flower formation process. The expression patterns revealed that both OfBFT-a and OfBFT-b were highly accumulated in carpels, and were significantly downregulated during the proliferate flower development process. Subcellular localization indicated that OfBFT-a and OfBFT-b proteins were located in the nucleus. Functional studies in 'Tianxiang Taige' and Arabidopsis showed that OfBFT-a and OfBFT-b had important roles in floral organ development, especially the proliferate flower formation process by downregulating the accumulation of AG and SEP3 homologous genes. These results may shed new light on the study of proliferate flower formation and flower morphology breeding in flowering plants.

Development of a Serum-Based MicroRNA Signature for Early Detection of Pancreatic Cancer: A Multicenter Cohort Study.

BACKGROUND: A grim prognosis of pancreatic cancer (PCa) was attributed to the difficulty in early diagnosis of the disease. AIMS: Identifying novel biomarkers for early detection of PCa is thus urgent to improve the overall survival rates of patients. METHODS: The study was performed firstly by identification of candidate microRNAs (miRNAs) in formalin-fixed, paraffin-embedded tissues using microarray profiles, and followed by validation in a serum-based cohort study to assess clinical utility of the candidates. In the cohorts, a total of 1273 participants from four centers were retrospectively recruited as two cohorts including training and validation cohort. The collected serum specimens were analyzed by real-time polymerase chain reaction. RESULTS: We identified 27 miRNAs expressed differentially in PCa tissues as compared to the benign. Of which, the top-four was selected as a panel whose diagnostic efficacy was fully assessed in the serum specimens. The panel exhibited superior to CA19-9, CA125, CEA and CA242 in discriminating patients with early stage PCa from healthy controls or non-PCa including chronic pancreatitis as well as pancreatic cystic neoplasms, with the area under the curves (AUC) of 0.971 (95% CI 0.956-0.987) and 0.924 (95% CI 0.899-0.949), respectively. Moreover, the panel eliminated interference from other digestive tumors with a specificity of 90.2%. CONCLUSIONS: A panel of four serum miRNAs was developed showing remarkably discriminative ability of early stage PCa from either healthy controls or other pancreatic diseases, suggesting it may be developed as a novel, noninvasive approach for early screening of PCa in clinic.

Three-in-One Peptide Prodrug with Targeting, Assembly and Release Properties for Overcoming Bacterium-Induced Drug Resistance and Potentiating Anti-Cancer Immune Response.

The presence of bacteria in tumor results in chemotherapeutic drug resistance and weakens the immune response in colorectal cancer. To overcome bacterium-induced chemotherapeutic drug resistance and potentiate antitumor immunity, herein a novel molecule Biotin-Lys(SA-Cip-OH)-Lys(SA-CPT)-Phe-Phe-Nap (Biotin-Cip-CPT-Nap) is rationally designed containing four functional motifs (i.e., a biotin motif for targeting, Phe-Phe(-Nap) motif for self-assembly, ciprofloxacin derivative (Cip-OH) motif for antibacterial effect, and camptothecin (CPT) motif for chemotherapy). Using the designed molecule, a novel strategy of intracellular enzymatic nanofiber formation and synergistic antibacterium-enhanced chemotherapy and immunotherapy is achieved. Under endocytosis mediated by highly expressed biotin receptor in colorectal cancer cell membrane and the catalysis of highly expressed carboxylesterase in the cytoplasm, this novel molecule can be transformed into Biotin-Nap, which self-assembled into nanofibers. Meanwhile, antibiotic Cip-OH and chemotherapeutic drug CPT are released, overcoming bacterium-induced drug resistance and enhancing the therapeutic efficacy of immunotherapy towards colorectal cancer. This work offers a feasible strategy for the design of novel multifunctional prodrugs to improve the efficiency of colorectal cancer treatment.