Exchange of subtelomeric regions between chromosomes 4q and 10q reverts the FSHD genotype and phenotype.

The most common form of facioscapulohumeral dystrophy (FSHD1) is caused by a partial loss of the D4Z4 macrosatellite repeat array in the subtelomeric region of chromosome 4. Patients with FSHD1 typically carry 1 to 10 D4Z4 repeats, whereas nonaffected individuals have 11 to 150 repeats. The ~150-kilobyte subtelomeric region of the chromosome 10q exhibits a ~99% sequence identity to the 4q, including the D4Z4 array. Nevertheless, contractions of the chr10 array do not cause FSHD or any known disease, as in most people D4Z4 array on chr10 is flanked by the nonfunctional polyadenylation signal, not permitting the DUX4 expression. Here, we attempted to correct the FSHD genotype by a CRISPR-Cas9-induced exchange of the chr4 and chr10 subtelomeric regions. We demonstrated that the induced t(4;10) translocation can generate recombinant genotypes translated into improved FSHD phenotype. FSHD myoblasts with the t(4;10) exhibited reduced expression of the DUX4 targets, restored PAX7 target expression, reduced sensitivity to oxidative stress, and improved differentiation capacity.

Residual networks without pooling layers improve the accuracy of genomic predictions.

KEY MESSAGE: Residual neural network genomic selection is the first GS algorithm to reach 35 layers, and its prediction accuracy surpasses previous algorithms. With the decrease in DNA sequencing costs and the development of deep learning, phenotype prediction accuracy by genomic selection (GS) continues to improve. Residual networks, a widely validated deep learning technique, are introduced to deep learning for GS. Since each locus has a different weighted impact on the phenotype, strided convolutions are more suitable for GS problems than pooling layers. Through the above technological innovations, we propose a GS deep learning algorithm, residual neural network for genomic selection (ResGS). ResGS is the first neural network to reach 35 layers in GS. In 15 cases from four public data, the prediction accuracy of ResGS is higher than that of ridge-regression best linear unbiased prediction, support vector regression, random forest, gradient boosting regressor, and deep neural network genomic prediction in most cases. ResGS performs well in dealing with gene-environment interaction. Phenotypes from other environments are imported into ResGS along with genetic data. The prediction results are much better than just providing genetic data as input, which demonstrates the effectiveness of GS multi-modal learning. Standard deviation is recommended as an auxiliary GS evaluation metric, which could improve the distribution of predicted results. Deep learning for GS, such as ResGS, is becoming more accurate in phenotype prediction.

In Situ Prelithiation by Direct Integration of Lithium Mesh into Battery Cells.

Silicon (Si)-based anodes are promising for next-generation lithium (Li)-ion batteries due to their high theoretical capacity (∼3600 mAh/g). However, they suffer quantities of capacity loss in the first cycle from initial solid electrolyte interphase (SEI) formation. Here, we present an in situ prelithiation method to directly integrate a Li metal mesh into the cell assembly. A series of Li meshes are designed as prelithiation reagents, which are applied to the Si anode in battery fabrication and spontaneously prelithiate Si with electrolyte addition. Various porosities of Li meshes tune prelithiation amounts to control the degree of prelithiation precisely. Besides, the patterned mesh design enhances the uniformity of prelithiation. With an optimized prelithiation amount, the in situ prelithiated Si-based full cell shows a constant >30% capacity improvement in 150 cycles. This work presents a facile prelithiation approach to improve battery performance.

Identification of aged-rice adulteration based on near-infrared spectroscopy combined with partial least squares regression and characteristic wavelength variables.

The long-term storage of rice will inevitably be involved in the deterioration of edible quality, and aged rice poses a great threat to food safety and human health. The acid value can be employed as a sensitive index for the determination of rice quality and freshness. In this study, near-infrared spectra of three kinds of rice (Chinese Daohuaxiang, southern japonica rice, and late japonica rice) mixed with different proportions of aged rice were collected. The partial least squares regression (PLSR) model with different preprocessing was constructed to identify the aged rice adulteration. Meanwhile, a competitive adaptive reweighted sampling (CARS) algorithm was used to extract the optimization model of characteristic variables. The constructed CARS-PLSR model method could not only reduce greatly the number of characteristic variables required by the spectrum but also improve the identification accuracy of three kinds of aged-rice adulteration. As above, this study proposed a rapid, simple, and accurate detection method for aged-rice adulteration, providing new clues and alternatives for the quality control of commercial rice.

High-strength and machinable load-bearing integrated electrochemical capacitors based on polymeric solid electrolyte.

Load bearing/energy storage integrated devices (LEIDs) allow using structural parts to store energy, and thus become a promising solution to boost the overall energy density of mobile energy storage systems, such as electric cars and drones. Herein, with a new high-strength solid electrolyte, we prepare a practical high-performance load-bearing/energy storage integrated electrochemical capacitors with excellent mechanical strength (flexural modulus: 18.1 GPa, flexural strength: 160.0 MPa) and high energy storage ability (specific capacitance: 32.4 mF cm-2, energy density: 0.13 Wh m-2, maximum power density: 1.3 W m-2). We design and compare two basic types of multilayered structures for LEID, which significantly enhance the practical bearing ability and working flexibility of the device. Besides, we also demonstrate the excellent processability of the LEID, by forming them into curved shapes, and secondarily machining and assembling them into complex structures without affecting their energy storage ability.

Heat Conductor-Insulator Transition in Electrochemically Controlled Hybrid Superlattices.

Designing materials with ultralow thermal conductivity has broad technological impact, from thermal protection to energy harvesting. Low thermal conductivity is commonly observed in anharmonic and strongly disordered materials, yet a microscopic understanding of the correlation to atomic motion is often lacking. Here we report that molecular insertion into an existing two-dimensional layered lattice structure creates a hybrid superlattice with extremely low thermal conductivity. Vibrational characterization and ab initio molecular dynamics simulations reveal strong damping of transverse acoustic waves and significant softening of longitudinal vibrations. Together with spectral correlation analysis, we demonstrate that the molecular insertion creates liquid-like atomic motion in the existing lattice framework, causing a large suppression of heat conduction. The hybrid materials can be transformed into solution-processable coatings and used for thermal protection in wearable electronics. Our work provides a generic mechanism for the design of heat insulators and may further facilitate the engineering of heat conduction based on understanding atomic correlations.

A Morphologically Stable Li/Electrolyte Interface for All-Solid-State Batteries Enabled by 3D-Micropatterned Garnet.

Morphological degradation at the Li/solid-state electrolyte (SSE) interface is a prevalent issue causing performance fading of all-solid-state batteries (ASSBs). To maintain the interfacial integrity, most ASSBs are operated under low current density with considerable stack pressure, which significantly limits their widespread usage. Herein, a novel 3D-micropatterned SSE (3D-SSE) that can stabilize the morphology of the Li/SSE interface even under relatively high current density and limited stack pressure is reported. Under the pressure of 1.0 MPa, the Li symmetric cell using a garnet-type 3D-SSE fabricated by laser machining shows a high critical current density of 0.7 mA cm-2 and stable cycling over 500 h under 0.5 mA cm-2 . This excellent performance is attributed to the reduced local current density and amplified mechanical stress at the Li/3D-SSE interface. These two effects can benefit the flux balance between Li stripping and creep at the interface, thereby preventing interfacial degradation such as void formation and dendrite growth.

Analysis of genes regulated by DUX4 via oxidative stress reveals potential therapeutic targets for treatment of facioscapulohumeral dystrophy.

Muscles of patients with facioscapulohumeral dystrophy (FSHD) are characterized by sporadic DUX4 expression and oxidative stress which is at least partially induced by DUX4 protein. Nevertheless, targeting oxidative stress with antioxidants has a limited impact on FSHD patients, and the exact role of oxidative stress in the pathology of FSHD, as well as its interplay with the DUX4 expression, remain unclear. Here we set up a screen for genes that are upregulated by DUX4 via oxidative stress with the aim to target these genes rather than the oxidative stress itself. Immortalized human myoblasts expressing DUX4 (MB135-DUX4) have an increased level of reactive oxygen species (ROS) and exhibit differentiation defects which can be reduced by treating the cells with classic (Tempol) or mitochondria-targeted antioxidants (SkQ1). The transcriptome analysis of antioxidant-treated MB135 and MB135-DUX4 myoblasts allowed us to identify 200 genes with expression deregulated by DUX4 but normalized upon antioxidant treatment. Several of these genes, including PITX1, have been already associated with FSHD and/or muscle differentiation. We confirmed that PITX1 was indeed deregulated in MB135-DUX4 cells and primary FSHD myoblasts and revealed a redox component in PITX1 regulation. PITX1 silencing partially reversed the differentiation defects of MB135-DUX4 myoblasts. Our approach can be used to identify and target redox-dependent genes involved in human diseases.

Discovery of Novel Inhibitor for WNT/ß-Catenin Pathway by Tankyrase 1/2 Structure-Based Virtual Screening.

Aberrant activation of the WNT/ß-catenin signaling pathway is implicated in various types of cancers. Inhibitors targeting the Wnt signaling pathway are intensively studied in the current cancer research field, the outcomes of which remain to be determined. In this study, we have attempted to discover novel potent WNT/ß-catenin pathway inhibitors through tankyrase 1/2 structure-based virtual screening. After screening more than 13.4 million compounds through molecular docking, we experimentally verified one compound, LZZ-02, as the most potent inhibitor out of 11 structurally representative top hits. LiCl-induced HEK293 cells containing TOPFlash reporter showed that LZZ-02 inhibited the transcriptional activity of ß-catenin with an IC50 of 10 ± 1.2 µM. Mechanistically, LZZ-02 degrades the expression of ß-catenin by stabilizing axin 2, thereby diminishing downstream proteins levels, including c-Myc and cyclin D1. LZZ-02 also inhibits the growth of colonic carcinoma cell harboring constitutively active ß-catenin. More importantly, LZZ-02 effectively shrinks tumor xenograft derived from colonic cell lines. Our study successfully identified a novel tankyrase 1/2 inhibitor and shed light on a novel strategy for developing inhibitors targeting the WNT/ß-catenin signaling axis.

The SEACIT complex is involved in the maintenance of vacuole-mitochondria contact sites and controls mitophagy.

The major signaling pathway that regulates cell growth and metabolism is under the control of the target of rapamycin complex 1 (TORC1). In Saccharomyces cerevisiae the SEA complex is one of the TORC1 upstream regulators involved in amino acid sensing and autophagy. Here, we performed analysis of the expression, interactions and localization of SEA complex proteins under different conditions, varying parameters such as sugar source, nitrogen availability and growth phase. Our results show that the SEA complex promotes mitochondria degradation either by mitophagy or by general autophagy. In addition, the SEACIT subcomplex is involved in the maintenance of the vacuole-mitochondria contact sites. Thus, the SEA complex appears to be an important link between the TORC1 pathway and regulation of mitochondria quality control.

mTORC1 pathway in DNA damage response.

Living organisms have evolved various mechanisms to control their metabolism and response to various stresses, allowing them to survive and grow in different environments. In eukaryotes, the highly conserved mechanistic target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals and serves as a central regulator of cellular metabolism, proliferation and survival. A growing body of evidence indicates that mTOR signaling is closely related to another cellular protection mechanism, the DNA damage response (DDR). Many factors important for the DDR are also involved in the mTOR pathway. In this review, we discuss how these two pathways communicate to ensure an efficient protection of the cell against metabolic and genotoxic stresses. We also describe how anticancer therapies benefit from simultaneous targeting of the DDR and mTOR pathways.

Tumor suppressor NPRL2 induces ROS production and DNA damage response.

The SEA/GATOR complex is an essential regulator of the mTORC1 pathway. In mammals the GATOR1 complex is composed of the proteins DEPDC5, NPRL2 and NPRL3. GATOR1 serves as an mTORC1 inhibitor and activates the mTORC1-modulating RagA GTPase. However, several GATOR members have mTORC1 independent functions. Here we characterize mammalian cells overexpressing the GATOR1 component NPRL2. We demonstrate that, in the cells with active p53, ectopic expression of NPRL2 induces NOX2-dependent production of reactive oxygen species and DNA damage. Overexpressed NPRL2 accumulates in the nucleus, together with apoptosis-inducing factor (AIF). These events are accompanied by phosphorylation of p53, activation of a DNA-damage response and cell cycle arrest in G1 phase, followed by apoptosis. In the cells negative for active p53, NPRL2 ectopic expression leads to activation of CHK1 or CHK2 kinases and cell cycle arrest in S or G2/M phases. Combined, these results demonstrate a new role for the NPRL2, distinct from its function in mTORC1 regulation.

PMS1077 sensitizes TNF-α induced apoptosis in human prostate cancer cells by blocking NF-κB signaling pathway.

Our previous studies have demonstrated that PMS1077, a platelet-activating factor (PAF) antagonist, could induce apoptosis of Raji cells. However, the mechanism of action has not yet been determined. The nuclear transcription factor-kappa B (NF-κB) signaling pathway plays a critical role in tumor cell survival, proliferation, invasion, metastasis, and angiogenesis, so we determined the effects of PMS1077 and its structural analogs on tumor necrosis factor-α (TNF-α) induced activation of NF-κB signaling. In this study, we found that PMS1077 inhibited TNF-α induced expression of the NF-κB regulated reporter gene in a dose dependent manner. Western blot assay indicated that PMS1077 suppressed the TNF-α induced inhibitor of κB-α (IκB-α) phosphorylation, IκB-α degradation, and p65 phosphorylation. PMS1077 consistently blocked TNF-α induced p65 nuclear translocation as demonstrated in the immunofluorescence assay used. Docking studies by molecular modeling predicted that PMS1077 might interact directly with the IκB kinase-ß (IKK-ß) subunit. These results suggested that PMS1077 might suppress the activation of NF-κB by targeting IKK-ß involved in the NF-κB signaling pathway. Finally, we showed that PMS1077 sensitized cells to TNF-α induced apoptosis by suppressing the expression of NF-κB regulated anti-apoptotic genes. Our results reveal a novel function of PMS1077 on the NF-κB signaling pathway and imply that PMS1077 can be considered as an anti-tumor lead compound.

Optical refocusing three-dimensional wide-field fluorescence lifetime imaging microscopy.

Three-dimensional fluorescence lifetime microscopy is achieved by combining wide-field fluorescence lifetime imaging with a remote optical refocusing method. As required for some applications in dynamic research for physics, chemistry, or biology, it is thereby not necessary to move the sample, i.e., the specimen is not disturbed during measurement. Using a fluorescent microsphere the performance of the system has been tested successfully with respect to three-dimensional fluorescence lifetime microscopy as well as time-resolved fluorescence spectroscopy.