The deubiquitinase USP28 maintains the expression of the transcription factor MYCN and is essential in neuroblastoma cells.

Neuroblastoma (NB) is one of the most common extracranial solid tumors in children. MYCN gene amplification is highly associated with poor prognosis in high-risk NB patients. In non-MYCN-amplified high-risk NB patients, the expression of c-MYC (MYCC) and its target genes is highly elevated. USP28 as a deubiquitinase is known to regulate the stability of MYCC. We show here USP28 also regulates the stability of MYCN. Genetic depletion or pharmacologic inhibition of the deubiquitinase strongly destabilizes MYCN and stops the growth of NB cells that overexpress MYCN. In addition, MYCC could be similarly destabilized in non-MYCN NB cells by compromising USP28 function. Our results strongly suggest USP28 as a therapeutic target for NB with or without MYCN amplification/overexpression.

Iron metabolism and ferroptosis in nonalcoholic fatty liver disease: what is our next step?

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increasing prevalence worldwide. NAFLD could develop from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), NASH-related fibrosis, cirrhosis, and even hepatocellular carcinoma. However, the mechanism of NAFLD development has not yet been fully defined. Recently, emerging evidence shows that the dysregulated iron metabolism marked by elevated serum ferritin, and ferroptosis are involved in the NAFLD. Understanding iron metabolism and ferroptosis can shed light on the mechanisms of NAFLD development. Here, we summarized studies on iron metabolism and the ferroptosis process involved in NAFLD development to highlight potential medications and therapies for treating NAFLD.

Complete chloroplast genome of the Malus baccata var. gracilis provides insights into the evolution and phylogeny of Malus species.

Malus baccata (L.) var. gracilis (Rehd.) has high ornamental value and breeding significance, and comparative chloroplast genome analysis was applied to facilitate genetic breeding for desired traits and resistance and provide insight into the phylogeny of this genus. Using data from whole-genome sequencing, a tetrameric chloroplast genome with a length of 159,992 bp and a total GC content of 36.56% was constructed. The M. baccata var. gracilis chloroplast genome consists of a large single-copy sequence (88,100 bp), a short single-copy region (19,186 bp), and two inverted repeat regions, IRa (26,353 bp) and IRb (26,353 bp). This chloroplast genome contains 112 annotated genes, including 79 protein-coding genes (nine multicopy), 29 tRNA genes (eight multicopy), and four rRNA genes (all multicopy). Calculating the relative synonymous codon usage revealed a total of 32 high-frequency codons, and the codons exhibited a biased usage pattern towards A/U as the ending nucleotide. Interspecific sequence comparison and boundary analysis revealed significant sequence variation in the vast single-copy region, as well as generally similar expansion and contraction of the SSC and IR regions for 10 analyzed Malus species. M. baccata var. gracilis and Malus hupehensis were grouped together into one branch based on phylogenetic analysis of chloroplast genome sequences. The chloroplast genome of Malus species provides an important foundation for species identification, genetic diversity analysis, and Malus chloroplast genetic engineering. Additionally, the results can facilitate the use of pendant traits to improve apple tree shape.

Asthma prediction via affinity graph enhanced classifier: a machine learning approach based on routine blood biomarkers.

BACKGROUND: Asthma is a chronic respiratory disease affecting millions of people worldwide, but early detection can be challenging due to the time-consuming nature of the traditional technique. Machine learning has shown great potential in the prompt prediction of asthma. However, because of the inherent complexity of asthma-related patterns, current models often fail to capture the correlation between data samples, limiting their accuracy. Our objective was to use our novel model to address the above problem via an Affinity Graph Enhanced Classifier (AGEC) to improve predictive accuracy. METHODS: The clinical dataset used in this study consisted of 152 samples, where 24 routine blood markers were extracted as features to participate in the classification due to their ease of sourcing and relevance to asthma. Specifically, our model begins by constructing a projection matrix to reduce the dimensionality of the feature space while preserving the most discriminative features. Simultaneously, an affinity graph is learned through the resulting subspace to capture the internal relationship between samples better. Leveraging domain knowledge from the affinity graph, a new classifier (AGEC) is introduced for asthma prediction. AGEC's performance was compared with five state-of-the-art predictive models. RESULTS: Experimental findings reveal the superior predictive capabilities of AGEC in asthma prediction. AGEC achieved an accuracy of 72.50%, surpassing FWAdaBoost (61.02%), MLFE (60.98%), SVR (64.01%), SVM (69.80%) and ERM (68.40%). These results provide evidence that capturing the correlation between samples can enhance the accuracy of asthma prediction. Moreover, the obtained [Formula: see text] values also suggest that the differences between our model and other models are statistically significant, and the effect of our model does not exist by chance. CONCLUSION: As observed from the experimental results, advanced statistical machine learning approaches such as AGEC can enable accurate diagnosis of asthma. This finding holds promising implications for improving asthma management.

A high concentrate diet inhibits forkhead box protein A2 expression, and induces oxidative stress, mitochondrial dysfunction and mitochondrial unfolded protein response in the liver of dairy cows.

High-concentrate diet induce subacute ruminal acidosis (SARA) and cause liver damage in ruminants. It has been reported that forkhead box protein A2 (FOXA2) can enhance mitochondrial membrane potential but its function in mitochondrial dysfunction induced by high concentrate diets is still unknown. Therefore, the aim of this study was to elucidate the effect of high-concentrate (HC) diet on hepatic FOXA2 expression, mitochondrial unfolded protein response (UPRmt), mitochondrial dysfunction and oxidative stress. A total of 12 healthy mid-lactation Holstein cows were selected and randomized into 2 groups: the low concentrate (LC) diet group (concentrate:forage = 4:6) and HC diet group (concentrate:forage = 6:4). The trial lasted 21 d. The rumen fluid, blood and liver tissue were collected at the end of the experiment. The results showed that the rumen fluid pH level was reduced in the HC group and the pH was lower than 5.6 for more than 4 h/d, indicating that feeding HC diets successfully induced SARA in dairy cows. Both FOXA2 mRNA and protein abundance were significantly reduced in the liver of the HC group compared with the LC group. The activity of antioxidant enzymes (CAT, G6PDH, T-SOD, Cu/Zn SOD, Mn SOD) and mtDNA copy number in the liver tissue of the HC group decreased, while the level of H2O2 significantly increased, this increase was accompanied by a decrease in oxidative phosphorylation (OXPHOS). The balance of mitochondrial division and fusion was disrupted in the HC group, as evidenced by the decreased mRNA level of OPA1, MFN1, and MFN2 and increased mRNA level of Drp1, Fis1, and MFF. At the same time, HC diet downregulated the expression level of SIRT1, SIRT3, PGC-1α, TFAM, and Nrf 1 to inhibit mitochondrial biogenesis. The HC group induced UPRmt in liver tissue by upregulating the mRNA and protein levels of CLPP, LONP1, CHOP, Hsp10, and Hsp60. In addition, HC diet could increase the protein abundance of Bax, CytoC, Caspase 3 and Cleaved-Caspase 3, while decrease the protein abundance of Bcl-2 and the Bcl-2/Bax ratio. Overall, our study suggests that the decreased expression of FOXA2 may be related to UPRmt, mitochondrial dysfunction, oxidative stress, and apoptosis in the liver of dairy cows fed a high concentrate diet.

Nonlinear photonic crystals for completely independent asymmetric holographic imaging.

Nonlinear photonic crystals (NPCs) are microstructures characterized by a spatially modulated second-order nonlinear coefficient that have been extensively used for the generation and beam-shaping of coherent light at new frequencies. NPCs for asymmetric optical transmission have a significant impact on novel and multifunction photonic devices. However, nonreciprocal NPCs capable of completely independent asymmetric holographic imaging for the opposite propagation directions have not been reported. Here, we propose a holographic combiner for a different independent image generation at the second-harmonic (SH) wavelength when illuminated from opposite sides of NPCs. The design of the holographic combiner is based on a 3D nonlinear detour phase holography and an orbital angular momentum (OAM) multiplexing nonlinear holography. This work achieves completely independent asymmetric holographic imaging at the SH frequency by using NPCs, which may have potential applications in classical and quantum optical devices.

Two-Phase Electrosynthesis of Dihydroxycoumestans: Discovery of a New Scaffold for Topoisomerase I Poison.

Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9-dihydroxycoumestans via two-electrode constant current electrolysis was developed. The application of a two-phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o-benzoquinone intermediates from over-oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1-targeted antitumor agent.

Multi-omics analysis reveals the biosynthesis of flavonoids during the browning process of Malus sieversii explants.

Malus sieversii is a precious apple germplasm resource. Browning of explants is one of the most important factors limiting the survival rate of plant tissue culture. In order to explore the molecular mechanism of the browning degree of different strains of Malus sieversii, we compared the dynamic changes of Malus sieversii and Malus robusta Rehd. during the whole browning process using a multi-group method. A total of 44 048 differentially expressed genes (DEGs) were identified by transcriptome analysis on the DNBSEQ-T7 sequencing platform. KEGG enrichment analysis showed that the DEGs were significantly enriched in the flavonoid biosynthesis pathway. In addition, metabonomic analysis showed that (-)-epicatechin, astragalin, chrysin, irigenin, isoquercitrin, naringenin, neobavaisoflavone and prunin exhibited different degrees of free radical scavenging ability in the tissue culture browning process, and their accumulation in different varieties led to differences in the browning degree among varieties. Comprehensive transcriptome and metabonomics analysis of the data related to flavonoid biosynthesis showed that PAL, 4CL, F3H, CYP73A, CHS, CHI, ANS, DFR and PGT1 were the key genes for flavonoid accumulation during browning. In addition, WGCNA analysis revealed a strong correlation between the known flavonoid structure genes and the selected transcriptional genes. Protein interaction predictions demonstrated that 19 transcription factors (7 MYBs and 12 bHLHs) and 8 flavonoid structural genes had targeted relationships. The results show that the interspecific differential expression of flavonoid genes is the key influencing factor of the difference in browning degree between Malus sieversii and Malus robusta Rehd., providing a theoretical basis for further study on the regulation of flavonoid biosynthesis.

Enantioselective formal total synthesis of dihydrospirotryprostatin B.

Spirotryprostatins are representative members of medicinally interesting bioactive molecules of the spirooxindole natural products. In this communication, we present a novel enantioselective total synthesis of the spirooxindole alkaloid dihydrospirotryprostatin B. The synthesis takes advantage of copper-catalyzed tandem reaction of o-iodoanilide chiral sulfinamide derivatives with alkynone to rapidly construct the key quaternary carbon stereocenter of the natural product dihydrospirotryprostatin B.

[Research progress on chemical constituents from Kadsura genus and its pharmacological activities and clinical application].

The 29 plant species in the Kadsura genus of the Schisandraceae family are mainly distributed in eastern and southeas-tern Asia. Ten species of plants in this genus are distributed in China, some of which are folk medicinal plants with activating blood circulation, relieving pain, dispelling wind, and dehumidifying effects. Their main constituents are lignans and triterpenes. The current pharmacology and clinical studies have shown that their extracts and constituents have anti-rheumatoid arthritis, liver protection, antioxidation, anti-inflammatory, and other biological activities. The rheumatologic and liver diseases can also be treated with the plants in the clinic. The new chemical constituents reported in the last decade(2012 to date) from the plants of Kadsura genus in China, as well as their pharmacological effects and clinical applications in recent years were reviewed, so as to provide a theoretical basis for further research on the genus.

Mutation spectrum of FLT3 and significance of non-canonical FLT3 mutations in haematological malignancy.

Fms-like tyrosine kinase 3 (FLT3) is frequently mutated in haematological malignancies. Although canonical FLT3 mutations including internal tandem duplications (ITDs) and tyrosine kinase domains (TKDs) have been extensively studied, little is known about the clinical significance of non-canonical FLT3 mutations. Here, we first profiled the spectrum of FLT3 mutations in 869 consecutively newly diagnosed acute myeloid leukaemia (AML), myelodysplastic syndrome and acute lymphoblastic leukaemia patients. Our results showed four types of non-canonical FLT3 mutations depending on the affected protein structure: namely non-canonical point mutations (NCPMs) (19.2%), deletion (0.7%), frameshift (0.8%) and ITD outside the juxtamembrane domain (JMD) and TKD1 regions (0.5%). Furthermore, we found that the survival of patients with high-frequency (>1%) FLT3-NCPM in AML was comparable to those with canonical TKD. In vitro studies using seven representative FLT3-deletion or frameshift mutant constructs showed that the deletion mutants of TKD1 and the FLT3-ITD mutant of TKD2 had significantly higher kinase activity than wild-type FLT3, whereas the deletion mutants of JMD had phosphorylation levels comparable with wild-type FLT3. All tested deletion mutations and ITD were sensitive to AC220 and sorafenib. Collectively, these data enrich our understanding of FLT3 non-canonical mutations in haematological malignancies. Our results may also facilitate prognostic stratification and targeted therapy of AML with FLT3 non-canonical mutations.

Gastrodin relieves cognitive impairment by regulating autophagy via PI3K/AKT signaling pathway in vascular dementia.

Vascular dementia (VaD), the second most common type of dementia, is attributed to lower cerebral blood flow. To date, there is still no available clinical treatment for VaD. The phenolic glucoside gastrodin (GAS) is known for its neuroprotective effects, but the role and mechanisms of action on VD remains unclear. In this study, we aim to investigate the neuroprotective role and underlying mechanisms of GAS on chronic cerebral hypoperfusion (CCH)-mediated VaD rats and hypoxia-induced injury of HT22 cells. The study showed that GAS relieved learning and memory deficits, ameliorated hippocampus histological lesions in VaD rats. Additionally, GAS down-regulated LC3II/I, Beclin-1 levels and up-regulated P62 level in VaD rats and hypoxia-injured HT22 cells. Notably, GAS rescued the phosphorylation of PI3K/AKT pathway-related proteins expression, which regulates autophagy. Mechanistic studies verify that YP-740, a PI3K agonist, significantly resulted in inhibition of excessive autophagy and apoptosis with no significant differences were observed in the YP-740 and GAS co-treatment. Meantime, we found that LY294002, a PI3K inhibitor, substantially abolished GAS-mediated neuroprotection. These results revealed that the effects of GAS on VaD are related to stimulating PI3K/AKT pathway-mediated autophagy, suggesting a potentially beneficial therapeutic strategy for VaD.

Asymmetric wavefront shaping with nonreciprocal 3D nonlinear detour phase hologram.

Asymmetric control of light with nonlinear material is of great significance in the design of novel micro-photonic components, such as asymmetric imaging devices and nonreciprocal directional optical filters. However, the use of nonlinear photonic crystals for asymmetric optical transmission, to the best of our knowledge, is still an untouched area of research. Herein we propose the 3D nonlinear detour phase holography for realizing asymmetric SH wavefront shaping by taking advantage of the dependence of the SH phase on the propagation direction of the excitation beam. With the proposed method, the designed nonreciprocal 3D nonlinear detour phase hologram yields SH phases with opposite signs for the forward and backward transmission situations. Moreover, the quasi-phase-matching scheme and orbital angular momentum conservation in the asymmetric SH wavefront shaping process are also discussed. This study conceptually extends the 2D nonlinear detour phase holography into 3D space to build the nonreciprocal 3D nonlinear detour phase hologram for achieving SH twin-image elimination and asymmetric SH wavefront shaping, offering new possibilities for the design of nonreciprocal optical devices.

Large mode-area all-solid anti-resonant fiber based on chalcogenide glass for mid-infrared transmission.

A large mode-area chalcogenide all-solid anti-resonant fiber has been designed and successfully prepared for the first time. The numerical results show that the high-order mode extinction ratio of the designed fiber can reach 6000, and the maximum mode-area is 1500 um2. The fiber possesses a calculated low bending loss of less than 10-2 dB/m as the bending radius is larger than 15 cm. In addition, there is a low normal dispersion of -3 ps/nm/km at 5 µm, which is beneficial for the transmission of high power mid-infrared laser. Finally, a completely structured all-solid fiber was prepared by the precision drilling and two-stage rod-in-tube methods. The fabricated fibers transmit in the mid-infrared spectral range from 4.5 to 7.5 µm with the lowest loss of 7 dB/m @ 4.8 µm. Modeling suggests that the theoretical loss of the optimized structure is consistent with that of the prepared structure in the long wavelength band.

Chalcogenide GRIN glasses with high refractive index and large refractive index difference for LWIR imaging.

Gradient refractive index (GRIN) materials utilize an internally tailored refractive index in combination with the designed curvature of the optical element surface, providing the optical designer with additional freedom for correcting chromatic and spherical aberrations. In this paper, new GRIN materials suitable for the second (3-5 µm) and third (8-12 µm) atmospheric windows were successfully developed by the thermal diffusion method based on Ge20As20Se60-xTex series high refractive index glasses, where the maximum refractive index difference (Δn) at 4 µm and 10.6 µm were 0.281 and 0.277, respectively. The diffusion characteristics and refractive index distribution of the GRIN glass were analyzed by Raman characterization. Furthermore, the performance of GRIN singlet and homogeneous singlet in the LWIR band (8 µm, 10.6 µm (primary wavelength), 12 µm) was compared, and the results showed that the GRIN singlet had better chromatic aberration correction and unique dispersion characteristics.

Low-loss chalcogenide microstructured optical fibers prepared by eliminating interfaces defects.

The loss of chalcogenide microstructured optical fibers (ChG-MOFs) is generally higher than that of step fibers, mainly due to the immature fiber preform preparation method and strong waveguide defect scattering. Chemical polishing is used to polish mechanically drilled preforms to prepare ChG-MOFs with low defect scattering. Firstly, the scattering loss caused by the defective layer of ChG-MOFs is studied theoretically and experimentally. Then, a single-mode photonic crystal fiber (PCF) was prepared to verify the effect of chemical polishing on reducing fiber loss. The experimental results show that the PCF average loss is reduced from more than 8 dB/m to less than 2 dB/m, and the minimum loss reaches 0.8 dB/m @ 2.7 µm. At the same time, the bending strength of the PCF after chemical polishing is also significantly improved.

Compact reconfigurable on-chip polarization beam splitters enabled by phase change material.

In this paper, we present the design of a compact reconfigurable polarization beam splitter (PBS) enabled by ultralow-loss phase-changing Sb2Se3. By harnessing the phase-change-mediated mode coupling in a directional coupler (DC), guided light with different polarizations could be routed into different paths and this routing could be dynamically switched upon the phase change of Sb2Se3. With an optimized DC region, the proposed PBS demonstrates efficient polarization splitting with crosstalk less than -21.3 dB and insertion loss less than 0.16 dB at 1550 nm for both phase states of Sb2Se3, and features energy efficient property benefitting from the nonvolatile phase change of Sb2Se3, which holds great potentials for on-chip applications involving polarization control, including polarization-division multiplexing system, quantum photonics, microwave photonics, etc.

Design and fabrication of large-mode-area multicore chalcogenide fiber with low bending loss.

Multicore fiber (MCF) has a larger mode-area (LMA) compared to traditional single-core fiber, making it easy to get a mode area of more than 3000 µm2 with an optimized MCF structure. Here, a fine-structured 19-core fiber based on chalcogenide glass was fabricated using a combined method involving extrusion, drilling, and rod-in-tube for the first time. The fiber has a minimum transmission loss of 1.8 dB/m at 6.7 µm. When the bending radius exceeds 6 cm, a low bending loss of about 0.6 dB appears, and the experimental data are in good agreement with the simulation results. In addition, the supermode characteristics of the 19-core fiber are analyzed from both perspectives of simulation and experiment, and these results are perfectly in good agreement. We believe it opens a new way to develop high-power and bend-resisting fiber with such kind of multicore structure.

Silencing of IRF7 ameliorates osteoarthritis by inhibiting chondrocyte pyroptosis via targeting FGF21.

Osteoarthritis (OA) is the most common joint disease which can lead to serious disability. Interferon regulatory factor 7 (IRF7) is a member of the interferon regulatory factor family. This study aimed to explore the function and potential mechanism of IRF7 in OA. Our results found that IRF7 was increased in LPS-stimulated C28/I2 chondrocytes and in OA mice established with medial menisco-tibial ligament (MMTL) transection. IRF7 silencing enhanced cell viability, reduced IL-18 and IL-1ß levels and suppressed cell apoptosis. IRF7 knockdown decreased ROS and LDH levels, and inhibited pyroptosis in LPS-treated chondrocytes. IRF7 negatively regulated FGF21 expression. FGF21 overexpression alleviated pyroptosis in LPS-stimulated chondrocytes. Knockdown of IRF7 improved OA injury in mice. In conclusion, our study demonstrates that silencing of IRF7 alleviates OA by inhibiting chondrocyte pyroptosis via upregulation of FGF21.

A simplified mid-infrared anti-resonant chalcogenide fiber with fewest resonant peaks.

High-power laser delivery in the mid-infrared via hollow-core fibers is attractive, but it is too difficult to be fabricated using chalcogenide glasses. Here, we designed a mid-infrared hollow-core anti-resonant chalcogenide fiber (HC-ARCF) with a simplified Kagome cladding micro-structure for the first time. Then, the fiber was firstly fabricated through a precision mechanical drilling and pressured fiber drawing method. Ultra-thin walls of 2µm in the fiber lead to the fewest resonance peaks in the 2-5µm among all reported HC-ARCFs. All the fundamental mode, the second-order mode, tube mode and node mode in the fiber were excited and observed at 1550 nm. The power and spectral properties of the core and cladding of HC-ARCF are studied for the first time. The fiber can deliver high-power of 4.84 W without damage with core-coupling, while the threshold of the node in the cladding is only 3.5 W. A broadening of the output spectrum from 1.96 to 2.41µm due to the high nonlinearity at the node was successfully observed under short-pulse laser pumping at 2µm. The potentials of the fiber used for mid-infrared high-power laser delivery via core, or nonlinear laser generation via node, were thus demonstrated.