The FBXW7-binding sites on FAM83D are potential targets for cancer therapy.

Increasing evidence shows the oncogenic function of FAM83D in human cancer, but how FAM83D exerts its oncogenic function remains largely unclear. Here, we investigated the importance of FAM83D/FBXW7 interaction in breast cancer (BC). We systematically mapped the FBXW7-binding sites on FAM83D through a comprehensive mutational analysis together with co-immunoprecipitation assay. Mutations at the FBXW7-binding sites on FAM83D led to that FAM83D lost its capability to promote the ubiquitination and proteasomal degradation of FBXW7; cell proliferation, migration, and invasion in vitro; and tumor growth and metastasis in vivo, indicating that the FBXW7-binding sites on FAM83D are essential for its oncogenic functions. A meta-evaluation of FAM83D revealed that the prognostic impact of FAM83D was independent on molecular subtypes. The higher expression of FAM83D has poorer prognosis. Moreover, high expression of FAM83D confers resistance to chemotherapy in BCs, which is experimentally validated in vitro. We conclude that identification of FBXW7-binding sites on FAM83D not only reveals the importance for FAM83D oncogenic function, but also provides valuable insights for drug target.

Genetic landscape of human mitochondrial genome using whole-genome sequencing.

Increasing evidences suggest that mitochondrial dysfunction is implicated in diseases and aging, and whole-genome sequencing (WGS) is the most unbiased method in analyzing the mitochondrial genome (mtDNA). However, the genetic landscape of mtDNA in the Chinese population has not been fully examined. Here, we described the genetic landscape of mtDNA using WGS data from Chinese individuals (n = 3241). We identified 3892 mtDNA variants, of which 3349 (86%) were rare variants. Interestingly, we observed a trend toward extreme heterogeneity of mtDNA variants. Our study observed a distinct purifying selection on mtDNA, which inhibits the accumulation of harmful heteroplasmies at the individual level: (1) mitochondrial dN/dS ratios were much <1; (2) the dN/dS ratio of heteroplasmies was higher than homoplasmies; (3) heteroplasmies had more indels and predicted deleterious variants than homoplasmies. Furthermore, we found that haplogroup M (20.27%) and D (20.15%) had the highest frequencies in the Chinese population, followed by B (18.51%) and F (16.45%). The number of variants per individual differed across haplogroup groups, with a higher number of homoplasmies for the M lineage. Meanwhile, mtDNA copy number was negatively correlated with age but positively correlated with the female sex. Finally, we developed an mtDNA variation database of Chinese populations called MTCards (http://genemed.tech/mtcards/) to facilitate the query of mtDNA variants in this study. In summary, these findings contribute to different aspects of understanding mtDNA, providing a better understanding of the genetic basis of mitochondrial-related diseases.

CYP eicosanoid pathway mediates colon cancer-promoting effects of dietary linoleic acid.

Human and animal studies support that consuming a high level of linoleic acid (LA, 18:2ω-6), an essential fatty acid and key component of the human diet, increases the risk of colon cancer. However, results from human studies have been inconsistent, making it challenging to establish dietary recommendations for optimal LA intake. Given the importance of LA in the human diet, it is crucial to better understand the molecular mechanisms underlying its potential colon cancer-promoting effects. Using LC-MS/MS-based targeted lipidomics, we find that the cytochrome P450 (CYP) monooxygenase pathway is a major pathway for LA metabolism in vivo. Furthermore, CYP monooxygenase is required for the colon cancer-promoting effects of LA, since the LA-rich diet fails to exacerbate colon cancer in CYP monooxygenase-deficient mice. Finally, CYP monooxygenase mediates the pro-cancer effects of LA by converting LA to epoxy octadecenoic acids (EpOMEs), which have potent effects on promoting colon tumorigenesis via gut microbiota-dependent mechanisms. Overall, these results support that CYP monooxygenase-mediated conversion of LA to EpOMEs plays a crucial role in the health effects of LA, establishing a unique mechanistic link between dietary fatty acid intake and cancer risk. These results could help in developing more effective dietary guidelines for optimal LA intake and identifying subpopulations that may be especially vulnerable to LA's negative effects.

GGC expansions in NOTCH2NLC contribute to Parkinson disease and dopaminergic neuron degeneration.

BACKGROUND AND PURPOSE: The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN. METHODS: A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat-primed PCR and GC-rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno-associated virus (AAV)-mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection. RESULTS: Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p-value = 0.29). Skin biopsy showed P62-positive intranuclear NOTCH2NLC-polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa-NOTCH2NLC-(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN. CONCLUSIONS: Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons.

Metallic and Dimensional Optimization of Metal-Organic Frameworks for High-Performance Lithium-Sulfur Batteries.

Lithium-sulfur batteries (LSBs) have been considered as one of the most promising energy storage systems owing to their high theoretical energy density and abundant sulfuric resources. However, their commercial application is limited by rapid capacity decline and low Coulombic efficiency. Metal-organic frameworks (MOFs) made of metallic nodes and organic ligands can suppress polysulfide shuttling and promote redox kinetics. In this paper, the effects of crystallographic dimensions and metallic categories on chemical performance of LSBs have been meticulously explored electrochemical performance. As a result, exposed Ni active sites in a lamellar Ni-MOF was found to deliver a superior electrochemical performance. The as-assembled LSBs with 2D-Ni-MOF/CNTs cathode deliver a much superior initial discharge capacity, (820 mAh g-1 at 0.5 C), and exhibit excellent cycling stability over 550 cycles than those analogues of 3D stereoscopic Ni-MOF and 2D lamellar Co-MOF. This work proposed a perspective in elevating LSBs performance through synergistic optimization of the MOFs dimensions and the metallic nuclei in the cathodes.

Tunable Luminescence of Silver Nanoclusters Confined in SOD/FAU Zeolites and Selective Sensing for Organic Amine.

A series of Ag-zeolite luminescent composites are prepared based on SOD and FAUY zeolites, and the effect of zeolite host particle size on their dynamic luminescent emission properties was discussed for the first time. The relationship between zeolite particle size and the nucleation of silver nanoclusters (AgNCs) is revealed. With the increase of zeolite particle size from nanometers to microns, the luminescent color of both Ag-SOD and Ag-Y composites shows significant blue shift. The observed tunable luminescence can be accounted for the slower nucleation rate of AgNCs in micron-scale zeolites with longer channels, resulting in smaller nuclearity of AgNCs within large-size zeolites, through the characterization of extended X-ray absorption fine structure, implying the important roles played by the zeolite themselves in determining the luminescence properties. Moreover, the composites prepared by us feature simple signal transduction, fast response (30 s), and excellent selectivity and sensitivity for discriminative luminescence detection of triethylamine and ethylamine, and they have good reversible luminescence response after sensing HAc gas, which might imply the potential applications in the volatile organic amine detection and information encryption field.

Stable and Highly Luminescent Silver Nanoclusters in the 13X Zeolite Enabled by Mg2+ Doping and Their Luminescence Tuning by Heating Temperature.

Zeolite-confined silver nanoclusters (Ag-zeolite) have aroused vast interest due to their remarkable luminescence. The countercations within a zeolite play critical roles in determining the luminescent properties of the resulting Ag-zeolite. We observed, in this work, that introducing Mg2+ enabled the Ag-13X zeolite a stable and bright yellow emission with a high PLQY of 94.6%, the first report on the luminescence enhancement of the Ag-13X zeolite by Mg2+, to the best of our knowledge. The formation of specific internal electric fields inside 13X and the structural contraction of the zeolite framework due to the high charge density and the small ionic radius of Mg2+ are believed to be responsible for the enhanced stable and bright yellow emission. The stabilization effect of Mg2+ is removed by increasing the heating temperature above 700 °C, which leads to the variation of silver nanoclusters as a result of the framework collapse of the zeolite. The Ag-zeolite synthesized by us, featured with a broad emission band, a high PLQY of 94.6%, and good thermal stability, can be considered a suitable candidate to replace the traditional commercial yellow-emitting phosphor YAG:Ce3+ for light-based applications. This work contributes to a valuable reference for the rational design of silver nanoclusters confined in zeolites with promising new functionalities and stimulates potential applications as novel phosphors for near-ultraviolet light-emitting diodes (NUV-LEDs).

Mesoporous Surface-Sulfurized Fe-Co3O4 Nanosheets Integrated with N/S Co-Doped Graphene as a Robust Bifunctional Electrocatalyst for Oxygen Evolution and Reduction Reactions.

Playing a significant role in electrochemical energy conversion and storage systems, heteroatom-doped transition metal oxides are key materials for oxygen-involving reactions. Herein, mesoporous surface-sulfurized Fe-Co3O4 nanosheets integrated with N/S co-doped graphene (Fe-Co3O4-S/NSG) were designed as composite bifunctional electrocatalysts for the oxygen evolution reaction (OER) and the oxygen reduction reaction (ORR). Compared with the Co3O4-S/NSG catalyst, it exhibited superior activity in the alkaline electrolytes by delivering an OER overpotential of 289 mV at 10 mA cm-2 and an ORR half-wave potential of 0.77 V vs. RHE. Additionally, Fe-Co3O4-S/NSG kept stable at 4.2 mA cm-2 for 12 h without significant attenuation to render robust durability. This work not only demonstrates the satisfactory effect of the transition-metal cationic modification represented by iron doping on the electrocatalytic performance of Co3O4, but it also provides a new insight on the design of OER/ORR bifunctional electrocatalysts for efficient energy conversion.

Association of rare PPARGC1A variants with Parkinson's disease risk.

BACKGROUND: Recent researches on Parkinson's disease (PD) pathogenesis discovered the correlation between PD and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) dysfunction and reduction of PPARGC1A gene expression. Hence, we detected PPARGC1A rare variants to clarify their effect on PD risk in a large population of PD patients in mainland China. METHODS: We applied whole-exome sequencing (WES) to 1917 patients with early-onset or familial PD and 1652 controls (WES cohort), and whole-genome sequencing (WGS) to 1962 patients with sporadic late-onset PD and 1279 controls (WGS cohort). To identify PPARGC1A rare variants, we used burden analysis to assess the relationship between PPARGC1A rare variants and PD susceptibility. RESULTS: 30 rare missense variants in the cohort WES and 21 missense variants in the cohort WGS have been detected in the study and PPARGC1A missense variants are significantly associated with early-onset and familial PD susceptibility in our study (P = 0.012), which supports evidence that PPARGC1A rare variants are involved in the onset of early-onset and familial PD. CONCLUSIONS: The study suggested that PPARGC1A rare variants may contribute to the risk of early-onset and familial PD.

CcMYB12 Positively Regulates Flavonoid Accumulation during Fruit Development in Carya cathayensis and Has a Role in Abiotic Stress Responses.

Flavonoid, an important secondary metabolite in plants, is involved in many biological processes. Its synthesis originates from the phenylpropane metabolic pathway, and it is catalyzed by a series of enzymes. The flavonoid biosynthetic pathway is regulated by many transcription factors, among which MYB transcription factors are thought to be key regulators. Hickory (Carya cathayensis) is an economic forest tree species belonging to the Juglandaceae family, and its fruit is rich in flavonoids. The transcriptome of exocarp and seed of hickory has previously been sequenced and analyzed by our team, revealing that CcMYB12 (CCA0691S0036) may be an important regulator of flavonoid synthesis. However, the specific regulatory role of CcMYB12 in hickory has not been clarified. Through a genome-wide analysis, a total of 153 R2R3-MYB genes were identified in hickory, classified into 23 subclasses, of which CcMYB12 was located in Subclass 7. The R2R3-MYBs showed a differential expression with the development of hickory exocarp and seed, indicating that these genes may regulate fruit development and metabolite accumulation. The phylogenetic analysis showed that CcMYB12 is a flavonol regulator, and its expression trend is the same as or opposite to that of flavonol synthesis-related genes. Moreover, CcMYB12 was found to be localized in the nucleus and have self-activation ability. The dual-luciferase reporter assay demonstrated that CcMYB12 strongly bonded to and activated the promoters of CcC4H, CcCHS, CcCHI, and CcF3H, which are key genes of the flavonoid synthesis pathway. Overexpression of CcMYB12 in Arabidopsis thaliana could increase the content of total flavonoids and the expression of related genes, including PAL, C4H, CHS, F3H, F3'H, ANS, and DFR, in the flavonoid synthesis pathway. These results reveal that CcMYB12 may directly regulate the expression of flavonoid-related genes and promote flavonoid synthesis in hickory fruit. Notably, the expression level of CcMYB12 in hickory seedlings was significantly boosted under NaCl and PEG treatments, while it was significantly downregulated under acid stress, suggesting that CcMYB12 may participate in the response to abiotic stresses. The results could provide a basis for further elucidating the regulation network of flavonoid biosynthesis and lay a foundation for developing new varieties of hickory with high flavonoid content.

The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.

This study aimed to determine the mutational spectrum of familial Parkinson's disease and sporadic early-onset Parkinson's disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson's disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson's disease, 242 probands from families with autosomal-dominant Parkinson's disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson's disease-associated genes occurred more frequently in the autosomal-recessive Parkinson's disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson's disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson's disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson's disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson's disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson's disease-associated genes. Our data highlight the importance of genetic testing in Parkinson's disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

A gadolinium(III)-porphyrin based coordination polymer for colorimetric and fluorometric dual mode determination of ferric ions.

A coordination polymer (CP) based nanoprobe is described for colorimetric and fluorometric (dual mode) determination of ferric ion. The method is making use of a nanosized Gd(III)-5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin coordination polymer that was prepared by a single-step hydrothermal procedure. The nanoprobe is monodisperse and has uniform size and good water solubility. It also exhibits strong fluorescence and magnetic resonance response. On exposure to Fe(III), the color of the solution changes from red to brown as the concentration of Fe(III) exceed 5 µM. Similarly, the red fluorescence of the probe (with excitation/emission peaks at 420/675 nm) decreases as concentrations of Fe(III) increase from 0.5 to 100 µM. The limit of detection is 98 nM in the fluorometric mode. The assay was applied to the determination of Fe(III) in fetal bovine serum samples. Graphical abstract Schematic presentation of the synthesis and application of lanthanide-porphyrin based coordination polymer for ferric ion detection in colorimetric and fluorometric dual modes.

Ammonia-Responsive Luminescence of Ln3+-ß-diketonate Complex Encapsulated within Zeolite Y.

Assembling Ln3+(HPBAn) (Ln = Eu or Tb, HPBA = N-(2-pyridinyl)benzoylacetamide) in the cavities of zeolite Y (ZY) via the "ship-in-a-bottle" strategy leads to the formation of novel luminescent composite, Ln(HPBAn)@ZY, whose luminescence can be easily modulated by ammonia on the basis of the energy level variation of HPBA after deprotonation process. Additionally the bimetallic complex doping sample, Eu0.5Tb0.5(HPBAn)@ZY, show great potential as self-referencing luminescent sensor for detecting low ammonia concentration of 10-12⁻0.25 wt%.

Reversible Phase Transition of Robust Luminescent Hybrid Hydrogels.

We report herein on remote control over a reversible phase transition of robust luminescent hybrid hydrogels as enabled by the rational selection and incorporation of photoswitches. Azobenzene units functionalized with a guanidinium group were utilized as the photoswitches and incorporated through a host-guest inclusion method involving α-cyclodextrins functionalized with 2,6-pyridinedicarboxylic acid (PDA) groups. While the guanidinium functional groups bind to the negatively charged Laponite matrix surface to connect organic and inorganic components, the PDA groups enable simultaneous coordination with different lanthanide metal ions, thus rendering the hydrogel broadly luminescent. Owing to its conformation-dependent binding behavior with α-cyclodextrin, the isomerization of azobenzene induced association or dissociation of the inclusion complexes and thus lead to a reversible photocontrolled sol↔gel phase transition of the luminescent hybrid hydrogels.

Preparation and Properties of Transparent Ultrathin Lanthanide-Complex Films.

Highly transparent ultrathin films (UTFs) based on alternative layer-by-layer assembly of Eu- and Tb-based lanthanide complexes (LCs) and Mg-Al-layered double hydroxide (LDH) nanosheets are reported herein. UV-visible absorption and fluorescence spectroscopy showed an orderly growth of the two types of ultrathin films upon increasing the number of deposition cycles. AFM and SEM measurements indicate that the films feature periodic layered structures as well as uniform surface morphology. Luminescent investigations reveal that (LCs/LDH)n UTFs can detect Fe(3+) with relative selectivity and high sensitivity (Stern-Volmer constant KSV =8.43×10(3)  L mol(-1) ); this suggests that (LCs/LDH)n UTFs could be a promising luminescent probe for selectively sensing Fe(3+) ion.

Temperature-dependent luminescence properties of lanthanide(III) ß-diketonate complex-doped LAPONITE®.

In this work, by doping the lanthanide(III)-hexafluoroacetylacetone complex into LAPONITE®, we obtained a lanthanide-based organic-inorganic hybrid material. The resulting hybrid materials were fully characterized with elementary analysis, scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD) techniques. The Ln(3+) and HFA loadings were experimentally determined to be roughly 0.3 per u.c. and 0.72 per u.c. by analyzing the supernatant (titration against EDTA) and elemental analysis, respectively. XRD patterns suggest that at least partial complexes are intercalated within the interlayers of the LAPONITE®. The in situ formation of luminescent Ln(3+) complexes is confirmed by the luminescence data. Furthermore, the emission intensity ratio of the (5)D4→(7)F5 transition (Tb(3+)) to the (5)D0→(7)F2 transition (Eu(3+)) of the hybrid material containing both Eu(3+) and Tb(3+) can be linearly related to temperature in the range from 197 K to 287 K (temperature sensitivity: 1.107% per K), which will be an appealing alternative for in situ and real time detection of temperature in many special areas. This strategy presents new opportunities for the development of highly sensitive and stable thermo sensors.

Reversible On-Off Luminescence Switching in Self-Healable Hydrogels.

We present herein an easy way to prepare novel responsive hydrogels by simply doping lanthanide complexes into a polymer hydrogel, poly(2-acrylamido-2-methyl-1-propanesulfonicacid) (PAMPSA). The resulting hybrid hydrogels can be readily processed into a range of shapes. Both the on-off luminescence switching and the healable properties are simultaneously achieved in the resulting responsive hybrid hydrogels. They exhibit effectively self-healing performance without any external stimulus and reversible "on-off" luminescence switching triggered by exposure to acid-base vapor. The key to this on-off luminescence switching behavior is that the protonation of the organic ligands compete with full coordination to Ln(3+) and that incomplete coordination affects the luminescence yield. The high proton strength in the resulting hydrogels makes the doped lanthanide complexes unstable, and ammonia (or triethylamine) vapor can dramatically decrease the proton strength through neutralization, driving the full coordination of the ligand to Ln(3+).