Unmasking the silent culprit: recurrent exercise-induced acute kidney injury in a Chinese adolescent with renal hypouricemia.

Primary renal hypouricemia (RHUC) is a rare autosomal recessive disorder with a mean duration of end-stage acute kidney injury (EIAKI) of 14 days. The pathogenesis of EIAKI in patients with RHUC remains unclear. Several hypotheses have been proposed, including those related to the renal vasoconvulsive effect and the elevating effect of xanthine oxidase (XO). The effect of xanthine oxidase (XO) is most often observed following strenuous anaerobic exercise, which is frequently accompanied by low back pain, nausea, and acute kidney injury (AKI). Consequently, we postulate that EIAKI could be prevented by avoiding strenuous exercise, thus preventing the onset and recurrence of EIAKI. In this paper, we present a case of recurrent EIAKI in a patient with RHUC and a mutation in the SLC2A9 gene.

Discovery of Selective and Potent ATR Degrader for Exploration its Kinase-Independent Functions in Acute Myeloid Leukemia Cells.

ATR has emerged as a promising target for anti-cancer drug development. Several potent ATR inhibitors are currently undergoing various stages of clinical trials, but none have yet received FDA approval due to unclear regulatory mechanisms. In this study, we discovered a potent and selective ATR degrader. Its kinase-independent regulatory functions in acute myeloid leukemia (AML) cells were elucidated using this proteolysis-targeting chimera (PROTAC) molecule as a probe. The ATR degrader, 8 i, exhibited significantly different cellular phenotypes compared to the ATR kinase inhibitor 1. Mechanistic studies revealed that ATR deletion led to breakdown in the nuclear envelope, causing genome instability and extensive DNA damage. This would increase the expression of p53 and triggered immediately p53-mediated apoptosis signaling pathway, which was earlier and more effective than ATR kinase inhibition. Based on these findings, the in vivo anti-proliferative effects of ATR degrader 8 i were assessed using xenograft models. The degrader significantly inhibited the growth of AML cells in vivo, unlike the ATR inhibitor. These results suggest that the marked anti-AML activity is regulated by the kinase-independent functions of the ATR protein. Consequently, developing potent and selective ATR degraders could be a promising strategy for treating AML.

Oncogenic SIRT7 inhibits GATA4 transcriptional activity and activates the Wnt signaling pathway in ovarian cancer.

OBJECTIVE: Sirtuin-7 (SIRT7) is a class III histone deacetylase that plays an important role in cancer development and frequently overexpressed in carcinomas. In this study, the tumor-supporting role and underlying mechanisms of SIRT7 were characterized in ovarian cancer (OC) aggressiveness. METHODS: SIRT7 expression was examined in OC tissues and cells. Interactions among SIRT7, GATA4, Wnt signaling pathway were explored by bioinformatics tools and experimental validations. The effect of SIRT7 and GATA4 on malignant phenotypes of OC cells were examined with gain- and loss-of-function experiments. A nude mouse model of OC was developed to verify the in vitro findings. RESULTS: It was noted that SIRT7 was highly expressed in OC tissues and cells. Cell lines with higher SIRT7 expression (OVCAR-3 and OVCAR-8) were used for subsequent in vitro experiments. The experimental data indicated that silencing of SIRT7 suppressed the OC cell proliferation, colony formation, migration, and invasion, and promoted cell senescence, which could be abolished by GATA4 knockdown. Mechanistically, SIRT7 promoted deacetylation of GATA4 and consequently inhibited the transcriptional activity of GATA4. In addition, GATA4 induced OC cell senescence by inhibiting Wnt signaling pathway. Further in vivo experiments substantiated that SIRT7 knockdown or overexpressed GATA4 could effectively inhibit tumor growth of nude mice. CONCLUSION: Taken together, our findings indicated that SIRT7 enhanced development of OC by suppressing GATA4 and activating Wnt signaling pathway, suggesting the potential of SIRT7/GATA4/Wnt axis as a therapeutic target for OC.

Structure optimization and discovery of novel compound for the treatment of insertion mutations within exon 20 of EGFR and HER2.

In previous decades, patients with the most active EGFR mutations in non-small cell lung cancer (NSCLC) have significantly benefited from EGFR tyrosine kinase inhibitors (TKIs). However, a minority with EGFR and HER2 exon 20 mutations are inherently resistant to treatment. Several molecular TKIs (such as TAK788 and Poziotinib) were recently discovered and demonstrated as effective inhibitors against the most prevalent HER2 or EGFR exon 20 mutations. However, low clinical efficiency and uncertain adverse reaction indicated that the development of effective therapies is still demanded. In the present work, we designed several hybrid compounds learning from 3D modeling of kinase structure. One lead compound (compound 56) was found to be the most potent compound with IC50 value of 0.027 nM against EGFR D770-N771 ins NPG and reduced binding affinity with hERG protein. In vitro and in vivo biological results suggested that compound 56 demonstrated good oral bioavailability, and it was significantly capable of inhibiting the growth of tumor cells with a variety of HER2 exon 20 mutations and EGFR mutants with negligible toxic effects. It was identified that compound 56 might be considered a potential drug candidate for NSCLC target therapy.

Design and discovery of new selective and potent VEGF receptor 2 tyrosine kinase inhibitors.

A series of novel substituted 4-anilinoquinazolines and their related compounds were designed and prepared by 3D modeling as potential inhibitors of VEGFR-2. Evaluation of VEGFR inhibitory activities suggested that compound I10 was a more potent (IC50 = 0.11 nM) VEGFR-2 inhibitor than most of the listed drugs. Kinase panel assays demonstrated that compound I10 was the selective VEGFR-2 inhibitor. The prediction of 3D modeling unveiled a unique binding mode of this lead compound to VEGFR-2. Compound I10 exhibited remarkable anti-angiogenesis and anti-proliferation in HUVEC at low nanomolar concentrations. PK studies indicated that the lead compound possessed adequate oral bioavailability in various species. In vivo subcutaneous tumor model demonstrated that oral administration of I10 demonstrated potent efficacy in inhibiting tumor growth and angiogenesis. All these results suggested compound I10 is a potential drug candidate for cancer treatment.

A stable and highly luminescent 3D Eu(III)-organic framework for the detection of colchicine in aqueous environment.

The metal-organic framework materials have an important application as sensors. In this work, a microporous three-dimensional (3D) Eu(III)-organic framework (Eu-MOF), [Eu2(3,5-bct)(phen)2(ox)2(H2O)]·H2O, was constructed from 3,5-bis(3'-carboxyphenyl)-1,2,4-triazole (3,5-H2bct), oxalate (ox) and 1,10-phenanthroline (phen) as a luminescent sensor. The free volume was found to be 15.7% per unit volume ignoring the free water molecules. The Eu-MOF showed bright red light due to the emission at 622 nm (5D0 → 7F2 transition) of the Eu(III) with high quantum yield (QY, 52.51%). The Eu-MOF exerted high luminescence stability in common organic solvents as well as aqueous solutions within a wide pH range from 4 to 11. Based on the luminescent Eu-MOF, the sensing behavior for colchicine in the aqueous environment was studied. Highly selective and sensitive detection (LOD = 2.43 × 10-5 mol L-1) of colchicine was observed by the Eu-MOF even in the presence of potential interfering components. The sensing mechanism for colchicine was investigated by experimental and theoretical results. It is worth noting that a film (Film@Eu-MOF) prepared by loading Eu-MOF showed intense characteristic red light emission under UV light. The luminescence color changed immediately from red to colorless when the Film@Eu-MOF came in contact with colchicine. Highly sensitive and rapid detection of colchicine in wastewater was achieved using this Film@Eu-MOF, which could be identified by the naked eye. The experimental results suggest that the synthesized Eu-MOF has potential application as a luminescent sensing material for pollutants in the environmental system.

MicroRNA-1915-3p inhibits cell migration and invasion by targeting SET in non-small-cell lung cancer.

BACKGROUND: MicroRNAs (miRNAs) have been reported to play significant roles in non-small-cell lung cancer (NSCLC). However, the roles of microRNA (miR)-1915-3p in NSCLC remain unclear. In this study, we aimed to explore the biological functions of miR-1915-3p in NSCLC. METHODS: The expression of miR-1915-3p and SET nuclear proto-oncogene (SET) in NSCLC tissues were examined by quantitative real-time PCR (qRT-PCR). Migratory and invasive abilities of lung cancer were tested by wound healing and transwell invasion assay. The direct target genes of miR-1915-3p were measured by dual-luciferase reporter assay and western blot. Finally, the regulation between METTL3/YTHDF2/KLF4 axis and miR-1915-3p were evaluated by qRT-PCR, promoter reporter assay and chromatin immunoprecipitation (CHIP). RESULTS: miR-1915-3p was downregulated in NSCLC tissues and cell lines, and inversely associated with clinical TNM stage and overall survival. Functional assays showed that miR-1915-3p significantly suppressed migration, invasion and epithelial-mesenchymal transition (EMT) in NSCLC cells. Furthermore, miR-1915-3p directly bound to the 3'untranslated region (3'UTR) of SET and modulated the expression of SET. SET inhibition could recapitulate the inhibitory effects on cell migration, invasion and EMT of miR-1915-3p, and restoration of SET expression could abrogate these effects induced by miR-1915-3p through JNK/Jun and NF-κB signaling pathways. What's more, miR-1915-3p expression was regulated by METTL3/YTHDF2 m6A axis through transcription factor KLF4. CONCLUSIONS: These findings demonstrate that miR-1915-3p function as a tumor suppressor by targeting SET and may have an anti-metastatic therapeutic potential for lung cancer treatment.

A novel epigenetic drug conjugating flavonoid and HDAC inhibitor confer suppression of acute myeloid leukemogenesis.

Epigenetic dysregulation has long been identified as a key driver of leukemogenesis in acute myeloid leukemia (AML). However, epigenetic drugs such as histone deacetylase inhibitors (HDACis) targeting epigenetic alterations in AML have obtained only limited clinical efficiency without clear mechanism. Fortunately, we screened out a novel epigenetic agent named Apigenin-Vorinostat-Conjugate (AVC), which provides us a possibility to handle the heterogeneous malignancy. Its inhibition on HDACs was presented by HDACs expression, enzyme activity, and histone acetylation level. Its efficacy against AML was detected by cell viability assay and tumor progression of AML mouse model. Apoptosis is the major way causing cell death. We found that AVC efficiently suppresses leukemogenesis while sparing the normal human cells. Kasumi-1 cells are at least 20-fold higher sensitive to AVC (IC50 = 0.024 µM) than vorinostat (IC50 = 0.513 µM) and Ara-C (IC50 = 0.4366 µM). Furthermore, it can efficiently regress the tumorigenesis in AML mouse model while keeping the pivotal organs safe, demonstrating a feasibility and favorable safety profile in treatment of AML. Collectively, these preclinical data suggest a promising potential utilizing flavonoid-HDACi-conjugate as a next-generation epigenetic drug for clinical therapy against AML.

A sensitive photothermometric biosensor based on redox reaction-controlled nanoprobe conversion from Prussian blue to Prussian white.

As a new low-cost photothermal nanoprobe, Prussian blue nanoparticles (PB NPs) have been demonstrated to have more potential in photothermometric-based point-of-care testing (POCT) application. However, most of the existing PB NP-based photothermometric sensors were constructed mainly relying on in situ generation of PB NPs or their combination with antigens and antibodies, therefore usually suffering from the inherent defects like complicated preparation and cumbersome surface process as well as high-cost modification. To break this limitation of PB NP-based photothermometric POCT, we proposed an ingenious redox reaction-controlled nanoprobe conversion strategy and successfully applied to photothermometric detection of ascorbate oxidase (AAO). In this design, the heat of PB NP photothermal system under 808-nm laser irradiation dramatically decreased with the addition of AA, due to a unique AA-induced Prussian blue to Prussian white (PB-to-PW) conversion. Upon AAO addition, the heat of reaction system increased because of the enzymatic catalytic reaction between AAO and AA, which led to a significant reduction of AA and resultantly inhibited PB-to-PW conversion. Such target-mediated nanoprobe conversion resulted in an obvious temperature change that could be easily detected by a common thermometer and exhibited good linear ranges from 0.25 to 14 mU/mL with a detection limit as low as 0.21 mU/mL for POCT analysis of AAO. This facile, convenient, and portable photothermometric sensing platform provides an innovative route for the design of PB NP nanoprobe-based photothermometric detection methods. A sensitive photothermometric AAO sensor based on a redox reaction-controlled nanoprobe conversion strategy from Prussian blue to Prussian white.

In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC).

Immunotherapy via immune checkpoints blockade has aroused the attention of researchers worldwide. Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has been one of the most promising immunotherapy strategies. Several neutralizing antibodies targeting this interaction have been developed, which have already achieved considerable clinical success. Additionally, numerous pharmaceutical companies have been committed to develop small molecules which could block the interaction between PD-1 and PD-L1. In this study, a novel PROTAC molecule 21a was developed, and effectively induced the degradation of PD-L1 protein in various malignant cells in a proteasome-dependent manner. Moreover, compound 21a could significantly reduce PD-L1 protein levels of MC-38 cancer cells in vivo, by which promoted the invasion of CD8+ T cells and inhibited the growth of MC-38 in vivo. This PROTAC molecule could be used as a novel and alternative strategy for cancer immunotherapy.

Factors controlling the CO intercalation of h-BN overlayers on Ru(0001).

The space between a two-dimensional (2D) material overlayer and a metal surface can be regarded as a nanoreactor, in which molecule adsorption and surface reaction may occur. In this work, we present CO intercalation under a hexagonal boron nitride (h-BN) overlayer on Ru(0001) at room temperature, observed using X-ray photoelectron spectroscopy, ultraviolet photoelectron spectroscopy, and scanning tunneling microscopy. Critical factors influencing the interfacial process have been investigated, including CO partial pressure, h-BN coverage, and oxygen pre-adsorption on the Ru surface. It has been identified that CO adsorption on the bare Ru surface region plays an important role in CO intercalation. Comparative studies of CO intercalation at h-BN/Ru(0001) and graphene/Ru(0001) interfaces indicate that CO starts to intercalate h-BN overlayers more easily than graphene. Temperature-programmed CO desorption experiments from h-BN/CO/Ru(0001) and graphene/CO/Ru(0001) surfaces reveal a similar confinement effect of the 2D cover on CO adsorption, which results in a more abrupt and quick CO desorption in comparison with the CO/Ru(0001) surface.

Hexagonal boron nitride cover on Pt(111): a new route to tune molecule-metal interaction and metal-catalyzed reactions.

In heterogeneous catalysis molecule-metal interaction is often modulated through structural modifications at the surface or under the surface of the metal catalyst. Here, we suggest an alternative way toward this modulation by placing a two-dimensional (2D) cover on the metal surface. As an illustration, CO adsorption on Pt(111) surface has been studied under 2D hexagonal boron nitride (h-BN) overlayer. Dynamic imaging data from surface electron microscopy and in situ surface spectroscopic results under near ambient pressure conditions confirm that CO molecules readily intercalate monolayer h-BN sheets on Pt(111) in CO atmosphere but desorb from the h-BN/Pt(111) interface even around room temperature in ultrahigh vacuum. The interaction of CO with Pt has been strongly weakened due to the confinement effect of the h-BN cover, and consequently, CO oxidation at the h-BN/Pt(111) interface was enhanced thanks to the alleviated CO poisoning effect.

[Cytomegalovirus reactivation and steroid refractory are the independent risk factors for colonic surgery in ulcerative colitis].

OBJECTIVE: To explore the risk factors of surgery in patients with ulcerative colitis (UC). METHODS: Patients with UC, hospitalized from January 2005 to October 2012 were retrospectively enrolled in this study. Univariate and multivariate analyses were used to reveal the risk factors of colon surgery, including demographic features, clinical manifestations, laboratory examinations and medication. RESULTS: A total of 273 UC patients were enrolled in this study with 39 (14.3%) patients receiving colon surgery. Compared with the flare group, patients in surgery group 71.8% (28/39) had more proportion with severe disease (P=0.008), higher prevalence of active cytomegalovirus (CMV) infection [47.6% (10/21) vs 10.9% (11/101), P<0.001], higher ratio of steroid resistance [60.0% (15/25) vs 10.7% (18/168), P<0.001], more receiving cyclosporine A [28.2% (11/39) vs 7.3% (17/234), P<0.001], and lesser with 5-aminosalicylic acid [82.1% (32/39) vs 95.3% (223/234), P=0.007]. Based on multivariate logistic regression analyses, active CMV infection and steroid resistance were two independent risk factors of colon surgery in UC patients (P=0.006 and 0.030, OR=6.040 and 17.928). CONCLUSION: Active CMV infection and steroid resistance are independent risk factors of colon surgery in UC.

Characterization of coal porosity for naturally tectonically stressed coals in Huaibei coal field, China.

The enrichment of coalbed methane (CBM) and the outburst of gas in a coal mine are closely related to the nanopore structure of coal. The evolutionary characteristics of 12 coal nanopore structures under different natural deformational mechanisms (brittle and ductile deformation) are studied using a scanning electron microscope (SEM) and low-temperature nitrogen adsorption. The results indicate that there are mainly submicropores (2~5 nm) and supermicropores (<2 nm) in ductile deformed coal and mesopores (10~100 nm) and micropores (5~10 nm) in brittle deformed coal. The cumulative pore volume (V) and surface area (S) in brittle deformed coal are smaller than those in ductile deformed coal which indicates more adsorption space for gas. The coal with the smaller pores exhibits a large surface area, and coal with the larger pores exhibits a large volume for a given pore volume. We also found that the relationship between S and V turns from a positive correlation to a negative correlation when S > 4 m(2)/g, with pore sizes <5 nm in ductile deformed coal. The nanopore structure (<100 nm) and its distribution could be affected by macromolecular structure in two ways. Interconversion will occur among the different size nanopores especially in ductile deformed coal.

Characterisation and comparison of enzymatically prepared donkey milk whey protein hydrolysates.

This study evaluated the structural characteristics, processing properties, and antioxidant properties of hydrolysates prepared from donkey milk (DM) whey protein using different proteases (Alcalase, Neutrase, papain, and Flavourzyme). The results showed that enzymatic hydrolysis significantly increased hydrolysate solubility and reduced average particle size compared to those of DM whey protein. Neutrase and Flavourzyme hydrolysates exhibited higher degrees of hydrolysis (DH), along with elevated emulsification properties and surface hydrophobicity. The choice of protease influenced secondary and tertiary protein structures and amino acid composition. Enzymatic hydrolysis led to decreased molecular weight of DM whey proteins. Moreover, all hydrolysates exhibited higher fluorescence intensity at λmax compared to DM whey protein, implying distinct properties due to the varied impacts of the four proteases on DM whey protein structure. The preparation of hydrolysates from DM whey proteins using proteases contributes to the development of integrated-value DM products.

Phosphate-rich cellulose beads for efficient cesium extraction from aqueous solutions: a novel approach for cellulose utilization.

In this work, phosphate-rich cellulose beads (CBPs) were first used for cesium extraction from aqueous solutions. These green, abundant, cheap, and renewable CBPs demonstrated a high adsorption capacity and fast absorption rate. Besides, the CBPs also exhibited excellent stability and recycling performance, as well as good selectivity. This study presents the promising application potential of cellulose for efficient cesium extraction from aqueous media.

Structural, antioxidant activity, and stability studies of jellyfish collagen peptide-calcium chelates.

The aim of this study was to prepare and characterize jellyfish collagen peptide (JCP)-calcium chelates (JCP-Ca) using peptides with different molecular weights. Further analysis revealed that the low-molecular-weight jellyfish collagen peptide (JCP1) had a higher chelation rate. Structural characterization showed that functional groups such as N-H, C[bond, double bond]O, and -COO were involved in the formation of JCP-Ca, which shifted towards a more ordered and regular structure, and smaller-molecular-weight peptides were more likely to form a denser structure. In addition, JCPs chelated with calcium ions showed excellent antioxidant capacity. JCP-Ca showed good stability in heat-treated and gastrointestinal environments, whereas the antioxidant activity was significantly reduced under highly acidic conditions. The present study addresses the knowledge gap regarding the physicochemical properties of JCP-Ca and establishes a solid research foundation for its associated products.

Two-Dimensional Lanthanide Metal-Organic Framework Heterostructures for Noninvasively Photoresponsive High-Security Photonic Barcodes.

Stimuli-responsive micro/nanoscale photonic barcodes show great capacity for encryption and anticounterfeiting technologies due to multiple authentications, yet their application is commonly restricted by invasive stimuli. Herein, we report noninvasive light-stimulated high-security photonic barcodes based on spatially assembled photoresponsive two-dimensional (2D) 1,3,5-benzenetribenzoate (BTB)@Ln-MOF host-guest heterostructures. The photoluminescence (PL) spectra information on BTB@Ln-MOF heterostructures could be precisely controlled by the different wavelengths of ultraviolet (UV) light trigger. By using the PL properties and 2D heterostructures as cryptographic primitives, spatially resolved smart photonic barcodes based on both spectral and graphical coding are realized in BTB@Ln-MOF host-guest materials. These results will pave an avenue for the development of smart stimuli-responsive photonic barcodes for anticounterfeiting applications.

Bioaerosols in the coastal region of Qingdao: Community diversity, impact factors and synergistic effect.

Atmospheric bioaerosols are influenced by multiple factors, including physical, chemical, and biotic interactions, and pose a significant threat to the public health and the environment. The nonnegligible truth however is that the primary driver of the changes in bioaerosol community diversity remains unknown. In this study, putative biological association (PBA) was obtained by constructing an ecological network. The relationship between meteorological conditions, atmospheric pollutants, water-soluble inorganic ions, PBA and bioaerosol community diversity was analyzed using random forest regression (RFR)-An ensemble learning algorithm based on a decision tree that performs regression tasks by constructing multiple decision trees and integrating the predicted results, and the contribution of different rich species to PBA was predicted. The species richness, evenness and diversity varied significantly in different seasons, with the highest in summer, followed by autumn and spring, and was lowest in winter. The RFR suggested that the explanation rate of alpha diversity increased significantly from 73.74 % to 85.21 % after accounting for the response of the PBA to diversity. The PBA, temperature, air pollution, and marine source air masses were the most crucial factors driving community diversity. PBA, particularly putative positive association (PPA), had the highest significance in diversity. We found that under changing external conditions, abundant taxa tend to cooperate to resist external pressure, thereby promoting PPA. In contrast, rare taxa were more responsive to the putative negative association because of their sensitivity to environmental changes. The results of this research provided scientific advance in the understanding of the dynamic and temporal changes in bioaerosols, as well as support for the prevention and control of microbial contamination of the atmosphere.

Heterozygosity analysis of spontaneous 2n female gametes and centromere mapping of the diploid Hevea brasiliensis based on full-sib triploid populations.

KEY MESSAGE: Unreduced megagametophytes via second-division restitution were confirmed through heterozygosity analysis, and four candidate physical centromeres of rubber were located for the first time. The evaluation of maternal heterozygosity restitution (MHR) is vital in identifying the mechanism of 2n gametogenesis and assessing the utilization value of 2n gametes. In this study, three full-sib triploid populations were employed to evaluate the MHR of 2n female gametes of rubber tree clone GT1 and to confirm their genetic derivation. The 2n female gametes of GT1 were derived from second-division restitution (SDR) and transmitted more than half of the parental heterozygosity. In addition, low recombination frequency markers were developed, and four candidate physical centromeres of rubber tree were located for the first time. The confirmation that 2n female gametes of rubber tree clone GT1 are derived from SDR provides insights into the molecular mechanisms of 2n gametogenesis. In addition, the identified centromere location will aid in the development of centromeric markers for the rapid identification of the 2n gametogenesis mechanism.