The circadian clock affects starvation resistance through the pentose phosphate pathway in silkworm, Bombyx mori.

Disruption of the circadian clock can affect starvation resistance, but the molecular mechanism is still unclear. Here, we found that starvation resistance was significantly reduced in the core gene BmPer deficient mutant silkworms (Per-/-), but the mutant's starvation resistance increased with larval age. Under natural physiological conditions, the weight of mutant 5th instar larvae was significantly increased compared to wild type, and the accumulation ability of triglycerides and glycogen in the fat bodies was upregulated. However, under starvation conditions, the weight consumption of mutant larvae was increased and cholesterol utilization was intensified. Transcriptome analysis showed that beta-oxidation was significantly upregulated under starvation conditions, fatty acid synthesis was inhibited, and the expression levels of genes related to mitochondrial function were significantly changed. Further investigations revealed that the redox balance, which is closely related to mitochondrial metabolism, was altered in the fat bodies, the antioxidant level was increased, and the pentose phosphate pathway, the source of reducing power in cells, was activated. Our findings suggest that one of the reasons for the increased energy burden observed in mutants is the need to maintain a more robust redox balance in metabolic tissues. This necessitates the diversion of more glucose into the pentose phosphate pathway to ensure an adequate supply of reducing power.

Structural Causes of Brittleness Changes in Aluminosilicate Glasses with Different Cooling Rates.

Numerous sources have already demonstrated that varying annealing rates can result in distinct toughness and brittleness in glass. To determine the underlying mechanisms driving this phenomenon, molecular dynamic (MD) simulations were employed to investigate the microstructure of aluminosilicate glasses under different cooling rates, and then uniaxial stretching was performed on them under controlled conditions. Results indicated that compared with short-range structure, cooling rate has a greater influence on the medium-range structure in glass, and it remarkably affects the volume of voids. Both factors play a crucial role in determining the brittleness of the glass. The former adjusts network connectivity to influence force transmission by manipulating the levels of bridging oxygen (BO) and non-bridging oxygen (NBO), and the latter accomplishes the objective of influencing brittleness by modifying the environmental conditions that affect the changes in BO and NBO content. The variation in the void environment results in differences in the strategies of the changes in BO and NBO content during glass stress. These findings stem from the excellent response of BO and NBO to the characteristic points of stress-strain curves during stretching. This paper holds importance in understanding the reasons behind the effect of cooling rates on glass brittleness and in enhancing our understanding of the ductile/brittle transition (DTB) in glass.

Bruceantinol works as a CDK2/4/6 inhibitor to inhibit the growth of breast cancer cells.

Bruceantinol (BOL), isolated from the dried fruit of the Brucea javanica (L.) Merr., exhibits cytotoxic effects on breast cancer cells. However, the underlying mechanism remains to be fully addressed. In this paper, the MCF-7 and MDA-MB-231 human breast cancer cell lines were used as experimental models to uncover how BOL inhibits breast cancer cell growth. The effects of BOL on cell growth, proliferation, the cell cycle, and apoptosis were investigated using the MTT assays, EdU incorporation assays, and flow cytometry, respectively. Bioinformatics techniques were applied to predict the key targets of BOL in breast cancer. Subsequent validation of these targets and the anti-breast cancer mechanism of BOL was conducted through Western blotting, RT-PCR, siRNA transfection, and molecular docking analysis. The results demonstrated that BOL dose- and time-dependently reduced the growth of both cell lines, impeded cell proliferation, disrupted the cell cycle, and induced necrosis in MCF-7 cells and apoptosis in MDA-MB-231 cells. Furthermore, CDK2/4/6 were identified as BOL targets, and their knockdown reduced cell sensitivity to BOL. BOL was found to potentially bind with CDK2/4/6 to facilitate protein degradation through the proteasome pathway. Additionally, BOL activated ERK in MDA-MB-231 cells, and this activation was required for BOL's functions in these cells. Collectively, BOL may act as an inhibitor of CDK2/4/6 to exert anti-breast cancer effects. Its effects on cell growth and CDK2/4/6 expression may also depend on ERK activation in HRs-HER2- breast cancer cells. These results suggest the potential of using BOL for treating breast cancer.

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease.

We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (MPro), a highly conserved protease among various CoVs, is essential for viral replication and pathogenesis, making it a prime target for antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 MPro. Among them, MPD2 was demonstrated to effectively reduce MPro protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing MPro protein levels in SARS-CoV-2-infected A549-ACE2 cells. MPD2 also displayed potent antiviral activity against various SARS-CoV-2 strains and exhibited enhanced potency against nirmatrelvir-resistant viruses. Overall, this proof-of-concept study highlights the potential of targeted protein degradation of MPro as an innovative approach for developing antivirals that could fight against drug-resistant viral variants.

Leveraging a Phage-Encoded Noncanonical Amino Acid: A Novel Pathway to Potent and Selective Epigenetic Reader Protein Inhibitors.

Epigenetic reader proteins interpret histone epigenetic marks to regulate gene expression. Given their vital roles and the link between their dysfunction and various diseases, these proteins present compelling targets for therapeutic interventions. Nevertheless, designing selective inhibitors for these proteins poses significant challenges, primarily due to their unique properties such as shallow binding sites and similarities with homologous proteins. To overcome these challenges, we propose an innovative strategy that uses phage display with a genetically encoded noncanonical amino acid (ncAA) containing an epigenetic mark. This ncAA guides binding to the reader protein's active site, allowing the identification of peptide inhibitors with enhanced affinity and selectivity. In this study, we demonstrate this novel approach's effectiveness by identifying potent inhibitors for the ENL YEATS domain that plays a critical role in leukemogenesis. Our strategy involved genetically incorporating Nε-butyryl-l-lysine (BuK), known for its binding to ENL YEATS, into a phage display library for enriching the pool of potent inhibitors. One resultant hit was further optimized by substituting BuK with other pharmacophores to exploit a unique π-π-π stacking interaction with ENL YEATS. This led to the creation of selective ENL YEATS inhibitors with a KD value of 2.0 nM and a selectivity 28 times higher for ENL YEATS than its close homologue AF9 YEATS. One such inhibitor, tENL-S1f, demonstrated robust cellular target engagement and on-target effects to inhibit leukemia cell growth and suppress the expression of ENL target genes. As a pioneering study, this work opens up extensive avenues for the development of potent and selective peptidyl inhibitors for a broad spectrum of epigenetic reader proteins.

Efficient Solar-Driven Interfacial Water Evaporator using Hydrogel Modified Carbon-Based Biomass with Abundant Microchannels.

The conventional sea water desalination technologies are not yet adopted worldwide, especially in the third world countries due to their high capital cost as well as large energy requirement. To solve this issue in a sustainable way an interfacial solar water evaporation device is designed and proposed in this article using the branches of Prunus serrulata (PB). The PB has abundant microchannels and shows excellent photothermal conversion capability after carbonization. Moreover, the easy access to raw materials and the facile fabrication process makes the solar water evaporating device very cost effective for seawater desalination application. Experiments show that in the presence of the fabricated evaporator the evaporation rate of water can reach 3.5 kg m-2  h-1 under 1 sun, which is superior to many similar experimental devices. In addition, its advantages, such as effective sewage purification capability, low cost, and environmental friendliness, make this evaporator highly competitive in the extensive promotion of this technology and can be considered as a new sustainable solution for seawater desalination with great application potential and prospects.

Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors.

The main protease (MPro) of SARS-CoV-2, the causative agent of COVID-19, is a pivotal nonstructural protein critical for viral replication and pathogenesis. Its protease function relies on three active site pockets for substrate recognition and a catalytic cysteine for enzymatic activity. To develop potential SARS-CoV-2 antivirals, we successfully synthesized a diverse range of azapeptide inhibitors with various covalent warheads to target MPro's catalytic cysteine. Our characterization identified potent MPro inhibitors, including MPI89 that features an aza-2,2-dichloroacetyl warhead with a remarkable EC50 value of 10 nM against SARS-CoV-2 infection in ACE2+ A549 cells and a selective index of 875. MPI89 is also remarkably selective and shows no potency against SARS-CoV-2 papain-like protease and several human proteases. Crystallography analyses demonstrated that these inhibitors covalently engaged the catalytic cysteine and used the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 stands as one of the most potent MPro inhibitors, suggesting the potential for further exploration of azapeptides and the aza-2,2-dichloroacetyl warhead for developing effective therapeutics against COVID-19.

Effects of Habitual Dietary Change on the Gut Microbiota and Health of Silkworms.

Diet plays a crucial role in shaping the gut microbiota and overall health of animals. Traditionally, silkworms are fed fresh mulberry leaves, and artificial diets do not support good health. The aim of this study was to explore the relationship between the dietary transition from artificial diets to mulberry leaves and the effects on the gut microbiota and physiological changes in silkworms as a model organism. With the transition from artificial diets to mulberry leaves, the diversity of the silkworm gut microbiota increased, and the proportion of Enterococcus and Weissella, the dominant gut bacterial species in silkworms reared on artificial diets, decreased, whereas the abundance of Achromobacter and Rhodococcus increased. Dietary transition at different times, including the third or fifth instar larval stages, resulted in significant differences in the growth and development, immune resistance, and silk production capacity of silkworms. These changes might have been associated with the rapid adaptation of the intestinal microbiota of silkworms to dietary transition. This study preliminarily established a dietary transition-gut microbial model in silkworms based on the conversion from artificial diets to mulberry leaves, thus providing an important reference for future studies on the mechanisms through which habitual dietary changes affect host physiology through the gut microbiome.

Dual heterogeneous interfaces enhance X-ray excited persistent luminescence for low-dose 3D imaging.

Lanthanide-doped fluoride nanoparticles (NPs) showcase adjustable X-ray-excited persistent luminescence (XEPL), holding significant promise for applications in three-dimensional (3D) imaging through the creation of flexible X-ray detectors. However, a dangerous high X-ray irradiation dose rate and complicated heating procedure are required to generate efficient XEPL for high-resolution 3D imaging, which is attributed to a lack of strategies to significantly enhance the XEPL intensity. Here we report that the XEPL intensity of a series of lanthanide activators (Dy, Pr, Er, Tm, Gd, Tb) is greatly improved by constructing dual heterogeneous interfaces in a double-shell nanostructure. Mechanistic studies indicate that the employed core@shell@shell structure could not only passivate the surface quenchers to lower the non-radiative relaxation possibility, but also reduce the interfacial Frenkel defect formation energy leading to increase the trap concentration. By employing a NPs containing flexible film as the scintillation screen, the inside 3D electrical structure of a watch was clearly achieved based on the delayed XEPL imaging and 3D reconstruction procedure. We foresee that these findings will promote the development of advanced X-ray activated persistent fluoride NPs and offer opportunities for safer and more efficient X-ray imaging techniques in a number of scientific and practical areas.

BRD4354 Is a Potent Covalent Inhibitor against the SARS-CoV-2 Main Protease.

Numerous organic molecules are known to inhibit the main protease (MPro) of SARS-CoV-2, the pathogen of Coronavirus Disease 2019 (COVID-19). Guided by previous research on zinc-ligand inhibitors of MPro and zinc-dependent histone deacetylases (HDACs), we identified BRD4354 as a potent inhibitor of MPro. The in vitro protease activity assays show that BRD4354 displays time-dependent inhibition against MPro with an IC50 (concentration that inhibits activity by 50%) of 0.72 ± 0.04 µM after 60 min of incubation. Inactivation follows a two-step process with an initial rapid binding step with a KI of 1.9 ± 0.5 µM followed by a second slow inactivation step, kinact,max of 0.040 ± 0.002 min-1. Native mass spectrometry studies indicate that a covalent intermediate is formed where the ortho-quinone methide fragment of BRD4354 forms a covalent bond with the catalytic cysteine C145 of MPro. Based on these data, a Michael-addition reaction mechanism between MPro C145 and BRD4354 was proposed. These results suggest that both preclinical testing of BRD4354 and structure-activity relationship studies based on BRD4354 are warranted to develop more effective anti-COVID therapeutics.

Nonsteaming method improves the nutritional value and utilization efficiency of silkworm artificial diets.

Artificial diets for silkworms overcome the seasonal limitations of traditional rearing methods with fresh mulberry leaves. However, the current wet artificial diets, steamed at high temperatures, are not favored by silkworms, and they are cumbersome and challenging to preserve. These conditions adversely affected the development of artificial diet-based sericulture production. In this study, we disinfected dry powder diets with radiation and added distilled water without steaming before use. Then, the nutritional value of finished diets and their impact on silkworm development was assessed. Compared with steamed diets, nonsteamed diets were more attractive to silkworms. Chemical assays showed significantly more essential nutrients for silkworms, including l-ascorbic acid, vitamin B1, vitamin B2, and urease in nonsteamed diets than in steamed diets. Feeding fifth-instar silkworm larvae with nonsteamed diets significantly improved the ammonia utilization efficiency of the diet and increased the cocoon shell rate and diet/silk protein conversion efficiency by 5.9% and 13.3%, respectively. When fed with nonsteamed diets, the abundance of aerobic microorganisms in silkworm intestines increased and the abundance of pathogenic bacteria decreased. Furthermore, the vitality of the silkworm, measured by the dead worm cocoon rate, significantly improved by 16.90%. In summary, preparing sterile wet diets without high-temperature steaming effectively improved the nutritional value of the diet and enhanced silkworm growth.

Tunable afterglow Ca1 - xSrxAl2O4:Eu2+, Nd3+ phosphors with dependence of an excitation wavelength.

In the emerging field of high-capacity information encryption, multicolor, multitemporal, and multimodal luminescence inorganic materials are of great significance. However, conventional inorganic materials lack the flexibility to dynamically adjust the photon transition path, resulting in unicolor luminescence of the sample and reducing the reading and decoding levels. Herein, we elaborately designed the components for constructing dual-phase crystal fields for Eu2+ in phosphors based on a high temperature solid-state method. Specifically, SrAl2O4:Eu2+ crystal with a bright green afterglow and CaAl2O4:Eu2+ crystal with a blue afterglow were obtained in phosphors at the same time. As a result, a tunable afterglow behavior from blue to white was achieved due to the 4f65d1 → 4f7 transition of Eu2+ at different crystal field sites. Finally, the color tunable afterglow sample was used to explore the encryption and decryption processes of information, and the results showed that the prepared material has a good anti-counterfeiting performance, which is promising for the development of long persistent luminescent materials.

Multi-omics integrative analysis revealed characteristic changes in blood cell immunity and amino acid metabolism in a silkworm model of hyperproteinemia.

Hyperproteinemia is a serious metabolic disease of both humans and animals characterized by an abnormally high plasma protein concentration (HPPC). Although hyperproteinemia can cause an imbalance in blood cell homeostasis, the functional changes to blood cells remain unclear. Here, a HPPC silkworm model was used to assess changes to the chromatin accessibility and transcript levels of genes related to blood cell metabolism and immune function. The results showed that HPPC enhanced phagocytosis of blood cells, increased chromatin accessibility and transcript levels of genes involved in cell phagocytosis, proliferation, stress, and programmed death, while genes associated with aromatic amino acid metabolism, and antibacterial peptide synthesis were inhibited in blood cells. Further analysis of the chromatin accessibility of the promoter region found that the high chromatin accessibility of genes sensitive to HPPC, was related to histone modifications, including tri-methylation of lysine residue 4 of histone H3 and acetylation of lysine residue 27 of histone H3. Changes to the chromatin accessibility and transcript levels of genes related to immune function and amino acid metabolism in the blood cells of the HPPC silkworm model provided useful references for future studies of the mechanisms underlying epigenomic regulation mediated by hyperproteinemia.

Enhanced blue afterglow in Ce-doped boroaluminate glass modified by Na.

The alkali metal Na+ is commonly applied as a charge compensator to optimize afterglow performance but rarely reported as a structural regulator to modify afterglow behavior in long afterglow glass materials. In this paper, by preparing the Na + -modified Ce-doped boroaluminate glasses under a high-temperature reducing atmosphere, super-five times brighter blue-violet afterglow lasting up to 30 min was obtained. Results show that appropriate Na+ doping loosens the glass structure and widens the bandgap, thereby regulating most of the electron capture-release modes. This work provides new insights into the behavior of afterglow enhancement in alkali metal-doped glasses.

Broadband La2LiSbO6: Cr3+ Phosphors with Double Luminescent Centers for NIR pc-LEDs.

The La2LiSbO6: xCr3+ phosphors were synthesized by means of a high-temperature solid-phase method. Based on the differences in ionic radius, valence state, and formation energy, the substitution sites of Cr3+ ions are discussed in detail. The optimized doping concentration of Cr3+ is determined to be 0.01. Under 517 nm excitation, the La2LiSbO6: 0.01Cr3+ phosphor presents a wide emission band (from 700 to 1350 nm) with a peak centered at 952 nm. Additionally, its corresponding full width at half-maximum is 155 nm, and the internal quantum efficiency reaches 62.4%. Meanwhile, the emission intensity of the La2LiSbO6: 0.01Cr3+ phosphor at 373 K is about 63.7% of that at room temperature, exhibiting good thermal stability. Aiming to fabricate a near-infrared phosphor-converted light-emitting diode device, the La2LiSbO6: 0.01Cr3+ phosphor is mixed with epoxy adhesive and cured on a green light-emitting diode chip. Under the irradiation of the fabricated light-emitting diode device, fruits and writing in the dark environment can be captured by a near-infrared camera. Hence, the La2LiSbO6: 0.01Cr3+ phosphor is promising for night vision.

Rapid ultra-sensitive nucleic acid detection using plasmonic fiber-optic spectral combs and gold nanoparticle-tagged targets.

Nucleic acid (NA) is a widely-used biomarker for viruses. Accurate quantification of NA can provide a reliable basis for point-of-care diagnosis and treatment. Here, we propose a tilted fiber Bragg grating (TFBG)-based plasmonic fiber-optic spectral comb for fast response and ultralow limit NA detection. The TFBG is coated with a gold film which enables excitation of surface plasmon resonance (SPR), and single-stranded probe NAs with known base sequences are assembled on the gold film. To enhance sensitivity of refractive index (RI) for sensing a chosen combination of probe and target NAs around the TFBG surface, gold nanoparticles (AuNPs) are bonded to the target NA molecules as "RI-labels". The NA combination-induced aggregation of AuNPs induces significant spectral responses in the TFBG that would be below the detection threshold for the NAs in the absence of the AuNPs. The proposed TFBG-SPR NA sensor shows a fast response time of 30 s and an ultra-wide NA detection range from 1 × 10-18 mol/L to 1 × 10-7 mol/L. In the NA concentration range of 1 × 10-12 mol/L (1 pM) to 105 pM, an ultra-high sensitivity of 1.534 dB/lg(pM) is obtained. The sensor achieves an ultra-low limit of detection down to 1.0 × 10-18 mol/L (1 aM), which is more than an order of magnitude lower than the previous reports. The proposed sensor not only shows potentials in practical applications of NA detection, but also provides a new way for TFBG-SPR biochemical sensors to achieve higher RI sensitivity.

Continuous electroproduction of formate via CO2 reduction on local symmetry-broken single-atom catalysts.

Atomic-level coordination engineering is an efficient strategy for tuning the catalytic performance of single-atom catalysts (SACs). However, their rational design has so far been plagued by the lack of a universal correlation between the coordination symmetry and catalytic properties. Herein, we synthesised planar-symmetry-broken CuN3 (PSB-CuN3) SACs through microwave heating for electrocatalytic CO2 reduction. Remarkably, the as-prepared catalysts exhibited a selectivity of 94.3% towards formate at -0.73 V vs. RHE, surpassing the symmetrical CuN4 catalyst (72.4% at -0.93 V vs. RHE). In a flow cell equipped with a PSB-CuN3 electrode, over 90% formate selectivity was maintained at an average current density of 94.4 mA cm-2 during 100 h operation. By combining definitive structural identification with operando X-ray spectroscopy and theoretical calculations, we revealed that the intrinsic local symmetry breaking from planar D4h configuration induces an unconventional dsp hybridisation, and thus a strong correlation between the catalytic activity and microenvironment of metal centre (i.e., coordination number and distortion), with high preference for formate production in CuN3 moiety. The finding opens an avenue for designing efficient SACs with specific local symmetries for selective electrocatalysis.

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease.

We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (M Pro ) is a highly conserved and essential protease that plays key roles in viral replication and pathogenesis among various CoVs, representing one of the most attractive drug targets for antiviral drug development. Traditional antiviral drug development strategies focus on the pursuit of high-affinity binding inhibitors against M Pro . However, this approach often suffers from issues such as toxicity, drug resistance, and a lack of broad-spectrum efficacy. Targeted protein degradation represents a promising strategy for developing next-generation antiviral drugs to combat infectious diseases. Here we leverage the proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 M Pro . Our previously developed M Pro inhibitors MPI8 and MPI29 were used as M Pro ligands to conjugate a CRBN E3 ligand, leading to compounds that can both inhibit and degrade SARS-CoV-2 M Pro . Among them, MDP2 was demonstrated to effectively reduce M Pro protein levels in 293T cells (DC 50 = 296 nM), relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing M Pro protein levels in SARS-CoV-2-infected A549-ACE2 cells, concurrently demonstrating potent anti-SARS-CoV-2 activity (EC 50 = 492 nM). This proof-of-concept study highlights the potential of PROTAC-mediated targeted protein degradation of M Pro as an innovative and promising approach for COVID-19 drug discovery.

Engineering the crystal facets of α-MnO2 nanorods for electrochemical energy storage: experiments and theory.

Crystal facet engineering is an effective strategy for precisely regulating the orientations and electrochemical properties of metal oxides. However, the contribution of each crystal facet to pseudocapacitance is still puzzling, which is a bottleneck that restricts the specific capacitance of metal oxides. Herein, α-MnO2 nanorods with different exposed facets were synthesized through a hydrothermal route and applied to pseudocapacitors. XRD and TEM results verified that the exposure ratio of active crystal facets was significantly increased with the assistance of the structure-directing agents. XPS analysis showed that there was more adsorbed oxygen and Mn3+ on the active crystal facets, which can provide strong kinetics for the electrochemical reaction. Consequently, the α-MnO2 nanorods with {110} and {310} facets exhibited much higher pseudocapacitances of 120.0 F g-1 and 133.0 F g-1 than their α-MnO2-200 counterparts (67.5 F g-1). The theoretical calculations proved that the {310} and {110} facets have stronger adsorption capacity and lower diffusion barriers for sodium ions, which is responsible for the enhanced pseudocapacitance of MnO2. This study provides a strategy to enhance the electrochemical performance of metal oxide, based on facet engineering.

Efficient and tunable emission CsPbClxBr3-x quantum dot glass for overcoming the lack of cyan gap in WLED.

Recently, the photoluminescence (PL) performance and stability of cyan emission perovskite quantum dot (PQD) were found to be inferior to other color emitting PQDs, which greatly limits their practical applications. In this Letter, CsPbClxBr3-x PQD glass with excellent hydrothermal stability is successfully synthesized by a high-temperature melting method. Results review that the vacancy defects in [PbBr6]4- octahedra can be effectively compensated by excessive halogen doping, resulting in an improvement in the photoluminescence quantum yield (PLQY) of PQDs from 24.73% to 65.62%. In addition, compared to white light emitting diode (WLED) synthesized with commercial fluorescent powders, the introduction of CsPbCl2Br1 PQD glass effectively fills the cyan gap. Moreover, the WLED displays the color-rendering index (CRI) of 87 at correlated color temperature (CCT) of 5257 K, and the color gamut area reaches 126% of the National Television System Committee (NTSC). This work provides an effective way for improving the PL performance of PQDs and brings CsPbClxBr3-x PQD glass significant prospect in the optoelectronic applications.