Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System

Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of age. Homozygous Cln3Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12–13 week old homozygous Cln3Δex7/8mice, which were also seen to a lesser extent in heterozygous Cln3Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15–16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV), and reticulocyte counts were reproducibly increased in homozygous Cln3Δex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3Δex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3Δex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3Δex7/8 mice that merit further study for JNCL biomarker development

Revisiting Lattice Thermal Conductivity of Cscl: the Crucial Role of Quartic Anharmonicity

Thermal conductivity plays a critical role in thermal management applications. Usually, crystals with simpler structures exhibit higher due to fewer phonon scatterings. However, cesium chloride (CsCl) presents an anomaly, demonstrating an unexpectedly low of 1.0 W m−1 K−1 at 300 K, as observed in Professor Iversen\u27s experimental measurement despite its simple structure. This prompts a need for understanding anomalous low and matching theory with experimental observations. Our study brings forth several findings for CsCl: (i) relying solely on three-phonon scattering inadequately captures ⁠. (ii) Anharmonic phonon renormalization significantly contributes to increased ⁠. (iii) Coherent phonons align temperature-dependent closely with the experiment. This work not only enhances understanding of anomalous in CsCl but also provides an approach to bridge the gap between experiment and theory in other crystals

Structural basis for two metal-ion catalysis of DNA cleavage by Cas12i2

Cas12i, class 2 type V CRISPR-Cas system protein, uses a single RuvC domain for cleavage of both strands of target DNA. Structures of Cas12i2–crRNA–DNA complexes not only provide insight into the mechanism of DNA recognition and cleavage by Cas12i2, but also the DNA cleavage mechanism by RuvC-containing Cas proteins

Cudraflavone B induces human glioblastoma cells apoptosis via ER stress-induced autophagy

Abstract Background Glioblastoma (GBM) is the most common malignant intracranial tumor with a low survival rate. However, only few drugs responsible for GBM therpies, hence new drug development for it is highly required. The natural product Cudraflavone B (CUB) has been reported to potentially kill a variety of tumor cells. Currently, its anit-cancer effect on GBM still remains unknown. Herein, we investigated whether CUB could affect the proliferation and apoptosis of GBM cells to show anti-GBM potential. Results CUB selectively inhibited cell viability and induced cell apoptosis by activating the endoplasmic reticulum stress (ER stress) related pathway, as well as harnessing the autophagy-related PI3K/mTOR/LC3B signaling pathway. Typical morphological changes of autophagy were also observed in CUB treated cells by microscope and scanning electron microscope (SEM) examination. 4-Phenylbutyric acid (4-PBA), an ER stress inhibitor, restored the CUB-caused alteration in signaling pathway and morphological change. Conclusions Our finding suggests that CUB impaired cell growth and induced cell apoptosis of glioblastoma through ER stress and autophagy-related signaling pathways, and it might be an attractive drug for treatment of GBM

Morusin Enhances Temozolomide Efficiency in GBM by Inducing Cytoplasmic Vacuolization and Endoplasmic Reticulum Stress

Glioblastoma multiforme (GBM) is an aggressive brain tumor with high risks of recurrence and mortality. Chemoradiotherapy resistance has been considered a major factor contributing to the extremely poor prognosis of GBM patients. Therefore, there is an urgent need to develop highly effective therapeutic agents. Here, we demonstrate the anti-tumor effect of morusin, a typical prenylated flavonoid, in GBM through in vivo and in vitro models. Morusin showed selective cytotoxicity toward GBM cell lines without harming normal human astrocytes when the concentration was less than 20 µM. Morusin treatment significantly induced apoptosis of GBM cells, accompanied by the activation of endoplasmic reticulum (ER) stress, and the appearance of cytoplasmic vacuolation and autophagosomes in cells. Then, we found the ER stress activation and cytotoxicity of morusin were rescued by ER stress inhibitor 4-PBA. Furthermore, morusin arrested cell cycle at the G1 phase and inhibited cell proliferation of GBM cells through the Akt–mTOR–p70S6K pathway. Dysregulation of ERs and cell cycle in morusin exposed GBM cells were confirmed by RNA-seq analysis. Finally, we demonstrated the combination of morusin and TMZ remarkably enhanced ER stress and displayed a synergistic effect in GBM cells, and suppressed tumor progression in an orthotopic xenograft model. In conclusion, these findings reveal the toxicity of morusin to GBM cells and its ability to enhance drug sensitivity to TMZ, suggesting the potential application value of morusin in the development of therapeutic strategies for human GBM

Sulfidation of ZIF-Derived Core-Shell NiCo LDH/Ni MOF Heterostructure toward Supercapacitor Electrodes with Enhanced Performance

Developing electrodes in a reasonable structure is essential to boost the performance of supercapacitors. Self-supporting heterostructures enriched active sites are promising as binder-free electrodes for supercapacitors. Here, core-shell layered double hydroxide (LDH)/Metal organic frame (MOF) heterostructure was directly grown on carbon cloth (CC) substrate derived from L-Co ZIF NWAs. Subsequently, the composite was treated with a sulfidation process to optimize its electrical conductivity. Thanks to its unique network structure, it facilitates active site exposure and efficient charge transfer, together with the synergetic effect between NiCo double hydroxide and Ni MOF nanosheets. This hybrid electrode possesses an excellent specific capacity (1200 F g−1 at 1 A g−1) and stable cycle performance with 86% capacity maintained after 4000 cycles, indicating its potential superiority for use in high-efficiency electrochemical capacitors

The Relation Between the Atomic Mass Ratio and Quartic Anharmonicity in Alkali Metal Hydrides

Phonons play a crucial role in understanding various aspects of solid-state physics, including thermal expansion, phase transition, interfacial thermal resistance, and lattice thermal conductivity (κL). Usually, the three-phonon (3ph) scattering processes have been considered the dominant mechanism governing thermal transport in solids. However, recent studies have revealed that quartic anharmonicity can fill the gap between theoretical calculations based on 3ph interactions and experimental values in a range of materials, such as BAs, perovskite CsPbBr3, and thermoelectric PbTe. Typically, the vibration frequency of phonons is proportional to the inverse square root of the atomic mass. Some semiconductors with heavy atoms have a big mass ratio which leads to a gap between acoustic and optical phonon modes. This phenomenon concurrently suppresses 3ph scattering. The influence of 4ph scattering on κL becomes more important. We investigate the relation between the atomic mass ratio and quartic anharmonicity using rocksalt alkali metal hydrides XH (X = Li, Na, K, Rb, Cs). Our finding reveals a positive correlation between the atomic mass ratio and quartic anharmonicity

Sulfidation of ZIF-Derived Core-Shell NiCo LDH/Ni MOF Heterostructure toward Supercapacitor Electrodes with Enhanced Performance

Developing electrodes in a reasonable structure is essential to boost the performance of supercapacitors. Self-supporting heterostructures enriched active sites are promising as binder-free electrodes for supercapacitors. Here, core-shell layered double hydroxide (LDH)/Metal organic frame (MOF) heterostructure was directly grown on carbon cloth (CC) substrate derived from L-Co ZIF NWAs. Subsequently, the composite was treated with a sulfidation process to optimize its electrical conductivity. Thanks to its unique network structure, it facilitates active site exposure and efficient charge transfer, together with the synergetic effect between NiCo double hydroxide and Ni MOF nanosheets. This hybrid electrode possesses an excellent specific capacity (1200 F g−1 at 1 A g−1) and stable cycle performance with 86% capacity maintained after 4000 cycles, indicating its potential superiority for use in high-efficiency electrochemical capacitors

Fast mapping of a chlorophyll b synthesis-deficiency gene in barley (Hordeum vulgare L.) via bulked-segregant analysis with reduced-representation sequencing

Bulked-segregant analysis coupled with next-generation sequencing (BSA-seq) has emerged as an efficient tool for genetic mapping of single genes or major quantitative trait loci controlling (agronomic) traits of interest. However, such a mapping-by-sequencing approach usually relies on deep sequencing and advanced statistical methods. Application of BSA-Seq based on construction of reduced-representation libraries and allele frequency analysis permitted anchoring the barley pale-green (pg) gene on chromosome 3HL. With further marker-assisted validation, pg was mapped to a 3.9 Mb physical-map interval. In the pg mutant a complete deletion of chlorophyllide a oxygenase (HvCAO) gene was identified. Because the product of this gene converts Chl a to Chl b, the pg mutant is deficient in Chl b. An independent Chl b-less mutant line M4437_2 carried a nonsynonymous substitution (F263L) in the C domain of HvCAO. The study demonstrates an optimized pooling strategy for fast mapping of agronomically important genes using a segregating population. Keywords: Barley, BSA-seq, Reduced representative sequencing, Pale-green, Chlorophyllide a oxygenas