Search

MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy. SIGNIFICANCE: This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy.See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818.

Passive antibody therapies, typically administered via parenteral routes, have played a crucial role in the initial response to the COVID-19 pandemic. However, the ongoing evolution of SARS-CoV-2 has revealed significant limitations of this approach, primarily due to mutational escape and the inadequate delivery of antibodies to the upper respiratory tract. To overcome these challenges, we propose a novel prophylactic strategy involving the intranasal delivery of an antibody in combination with an Fc-binding nanodisc. This nanodisc, engineered to specifically bind to the Fc regions of IgG antibodies, served two key functions: extending the antibody's half-life in the larynx and trachea, and enhancing its neutralization efficacy. Notably, Sotrovimab, an FDA-approved monoclonal antibody that has experienced a significant decline in neutralizing potency due to viral evolution, exhibited robust antiviral activity when complexed with the nanodisc against all tested Omicron variants. Furthermore, the Fc-binding nanodisc significantly boosted the antiviral efficacy of the soluble angiotensin-converting enzyme 2 (sACE2) Fc fusion protein, which possesses broad but modest antiviral activity. In ACE2 transgenic mice, the Fc-binding nanodisc protected better than sACE2-Fc alone with two more log reduction in lung viral titer. Therefore, the intranasal Fc-binding nanodisc offers a promising and powerful approach to counteract the diminished antiviral activity of neutralizing antibodies caused by mutational escape, effectively restoring antiviral efficacy against various evolving SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]

The protein therapeutics market, including antibody and fusion proteins, has experienced steady growth over the past decade, underscoring the importance of optimizing amino acid sequences. In our previous study, we developed a fusion protein, R31, which combines retinol-binding protein (RBP) with albumin domains IIIA and IB, linked by a sequence (AAAA), and includes an additional disulfide bond (N227C-V254C) in IIIA. This fusion protein effectively inhibited hepatic stellate cell activation. In this study, we further optimized the sequence. The G176K mutation at the C-terminus of RBP altered the initiation site of the first α-helix in domain IIIA, shifting it from P182 to K176, and promoted polar interactions between K176 and adjacent residues, enhancing the rigidity of the RBP/IIIA interface. The introduction of an additional disulfide bond (V231C/Y250C) connecting helices 3 and 4 in IIIA resulted in a three-fold increase in productivity and a 2 °C improvement in thermal stability compared to R31. Furthermore, combining the G176K mutation with V231C/Y250C further enhanced both productivity and anti-fibrotic activity. These findings suggest that the enhanced stability of domain IIIA, conferred by V231C/Y250C, along with the increased rigidity of the RBP/IIIA interface, optimizes interdomain distance and alignment, facilitating proper protein folding. [ABSTRACT FROM AUTHOR]

In p–i–n perovskite solar cells (PSCs), fullerene derivatives are predominantly used as an electron transport material (ETM) despite their disadvantages, such as parasitic absorption in the short wavelength range and high cost. State‐of‐the‐art n‐i‐p PSCs are fabricated using SnO2 as the ETM due to their high charge transfer ability, transparency, and low cost. However, in p–i–n PSCs, dispersing SnO2 nanoparticles in a solvent that does not damage the perovskite and forming a uniform layer is challenging. Herein, a strategy of directly depositing SnO2 quantum dots (QDs) on perovskite using ethylenediamine (EDA) for high‐performance applications is reported, which involves a SnO2 QD solution designed with a damage‐free cosolvent. Treating the SnO2 QD layer with the EDA strategy creates a conformal SnO2 QD layer and improves charge transport. This strategy achieves a high power conversion efficiency (PCE) of 18.9% in PSCs with a 1.77 eV bandgap, which is the highest PCE reported for wide bandgap p–i–n PSCs using an inorganic ETM. The top SnO2 layer enables ITO deposition without sputtering damage and achieves a bifacial factor of 99% due to the high transmittance of SnO2 QD. The resulting four‐terminal all‐perovskite tandem exhibited a PCE of 27.0%. [ABSTRACT FROM AUTHOR]

This study presents the fabrication and characterization of a dual-functional Pt/Ga2O3/Pt optoelectronic synaptic device, capable of operating as both a memristor and a memcapacitor. We detail the optimized radio frequency (RF) sputtering parameters, including a base pressure of 8.7 × 10−7 Torr, RF power of 100 W, working pressure of 3 mTorr, and the use of high-purity Ga2O3 and Pt targets. These precisely controlled conditions facilitated the formation of an amorphous Ga2O3 thin film, as confirmed by XRD and AFM analyses, which demonstrated notable optical and electrical properties, including light absorption properties in the visible spectrum. The device demonstrated distinct resistive and capacitive switching behaviors, with memory characteristics highly dependent on the wavelength of the applied light. Ultraviolet (365 nm) exposure facilitated long-term memory retention, while visible light (660 nm) supported short-term memory behavior. Paired-pulse facilitation (PPF) measurements revealed that capacitance showed slower decay rates than EPSC, suggesting a more stable memory performance due to the dynamics of carrier trapping and detrapping at the insulator interface. Learning simulations further highlighted the efficiency of these devices, with improved memory retention upon repeated exposure to UV light pulses. Visual encoding simulations on a 3 × 3 pixel array also demonstrated effective multi-level memory storage using varying light intensities. These findings suggest that Ga2O3-based memristor and memcapacitor devices have significant potential for neuromorphic applications, offering tunable memory performance across various wavelengths from ultraviolet to red. [ABSTRACT FROM AUTHOR]

Three new depsipeptides, homiamides A–C (1–3), were isolated from a marine sediment-derived strain of Streptomyces sp., ROA-065. The planar structures of homiamides A–C (1–3) were elucidated using mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopic data. The absolute configurations of 1–3 were deduced from the application of the Marfey's method and GC-MS analysis after formation of the O-trifluoroacetylated (S)-(+)-methyl-2-butyl ester derivatives of amino acids. Compounds 1–3 exhibited weak anti-bacterial activities against both Gram-positive bacteria and Gram-negative bacteria, with compound 1 showing MIC values of 32–64 μg/mL. In antifouling assays, compounds 1 and 2 displayed moderate activity against Micrococcus luteus KCTC 3063, while compound 3 exhibited weak activity against all tested bacteria. [ABSTRACT FROM AUTHOR]

The effects of the parasitic gate capacitance and gate resistance (Rg) on the radiofrequency (RF) performance are investigated in LG = 0.15 μm GaN high‐electron‐mobility transistors with T‐gate head size ranging from 0.83 to 1.08 μm. When the device characteristics are compared, the difference in DC characteristics is negligible. The RF performance in terms of the current‐gain cut‐off frequency (fT) and maximum oscillation frequency (fmax) substantially depend on the T‐gate head size. For clarifying the T‐gate head size dependence, small‐signal modeling is conducted to extract the parasitic gate capacitance and Rg. When the T‐gate head size is reduced from 1.08 to 0.83 μm, Rg increases by 82%, while fT and fmax improve by 27% and 26%, respectively, because the parasitic gate–source and gate–drain capacitances reduce by 19% and 43%, respectively. Therefore, minimizing the parasitic gate capacitance is more effective that reducing Rg in our transistor design and fabrication, leading to improved RF performance when reducing the T‐gate head size. [ABSTRACT FROM AUTHOR]

Dunaliella salina, a halophilic unicellular chlorophyte, produces bioactive compounds and biofuels applicable to various industries. Despite its industrial significance, comprehensive studies on the morphological, physiological, and biochemical characteristics of the genus Dunaliella remain challenging. In this study, we characterized an axenically isolated green alga from a salt pond in Taean, Republic of Korea, and assessed its industrially relevant traits. The morphological characteristics were typical of D. salina, and molecular phylogenetic analysis of the SSU, ITS1-5.8S-ITS, LSU regions of rDNA, and rbcL gene confirmed the isolate as D. salina strain DSTA20. The optimal temperature, salinity, and photon flux density required for its growth were determined to be 21 °C, 0.5 M NaCl, and 88 µmol m−2 s−1, respectively. Dried biomass analysis revealed 42.87% total lipids, with major fatty acids, including α-linolenic acid (31.55%) and palmitic acid (21.06%). The alga produced high-value carotenoids, including β-carotene (2.47 mg g−1 dry weight (DW)) and lutein (1.39 mg g−1 DW), with peak levels at 0.25 M salinity. Glucose (195.5 mg g−1 DW) was the predominant monosaccharide. These findings highlight the potential of D. salina DSTA20 for biodiesel production and as a source of ω-3 fatty acids, carotenoids, and glucose. Morphological traits provide insights relevant to the industrial potential of the species. [ABSTRACT FROM AUTHOR]

The increasing burden on shipowners and shipping companies due to environmental regulations imposed by the International Maritime Organization (IMO) has led to the adoption of various compliance strategies, including the use of low-sulfur fuel, installation of scrubbers, and the use of liquefied natural gas (LNG) as an alternative fuel. LNG is particularly prevalent in dual-fuel propulsion ships, with the IMO Type C tank being the most commonly used storage facility. The structure of the IMO Type C tank comprises a pressure vessel and supporting saddles, which can be integrated or separate systems. Despite being manufactured within specified tolerances, welding-induced deformation of the tank and saddle is inevitable since the saddle is welded directly onto the hull. In integrated tank–saddle systems, this deformation can lead to cracks in the epoxy resin, which has lower strength and stiffness, as well as burn damage to the resin and wooden blocks from welding heat. In separate tank–saddle systems, installation difficulties can arise due to interference between the fuel tank system and adjacent structures, such as insulation or the fuel preparation room (FPR), resulting from saddle deformation caused by welding. This study analyzes the sensitivity of all weld lines involved in saddle installation using the direct inherent strain (DIS) method. Based on this analysis, the initial welding deformations are evaluated in relation to the welding direction and sequence. Finally, an optimized method for saddle installation is proposed to minimize deformation. [ABSTRACT FROM AUTHOR]

The nutritional quality of a colony significantly affects its health and strength, particularly because it is required for population growth in the early spring. We investigated the impact of various artificial pollen substitute diets on colony performance in the Republic of Korea during early spring, a critical period for colony health and growth. The colonies were provided with different diets, including the commercial product Megabee (positive control), our developed diet Test A, and four upgraded versions (Diet 1, Diet 2, Diet 3, and Diet 4) of Test A. The negative control group received no supplementary feed. Over 63 days, we observed 24 experimental colonies and assessed various parameters at the colony and individual levels. The results revealed that Diet 2 had the highest consumption and had the most positive impact on population growth, the capped brood area, colony weight, honey bees’ weight, and vitellogenin levels. These findings suggested that Diet 2 is most attractive to honey bees and thus holds great promise for improving colony maintenance and development during the crucial early spring period.

Anithiactin D (1), a 2-phenylthiazole class of natural products, was isolated from marine mudflat-derived actinomycetes Streptomyces sp. 10A085. The chemical structure of 1 was elucidated based on the interpretation of NMR and MS data. The absolute configuration of 1 was determined by comparing the experimental and calculated electronic circular dichroism (ECD) spectral data. Anithiactin D (1) significantly decreased cancer cell migration and invasion activities at a concentration of 5 μM via downregulation of the epithelial-to-mesenchymal transition (EMT) markers in A549, AGS, and Caco-2 cell lines. Moreover, 1 inhibited the activity of Rho GTPases, including Rac1 and RhoA in the A549 cell line, suppressed RhoA in AGS and Caco-2 cell lines, and decreased the mRNA expression levels of some matrix metalloproteinases (MMPs) in AGS and Caco-2 cell lines. Thus 1, which is a new entity of the 2-phenylthiazole class of natural products with a unique aniline-indole fused moiety, is a potent inhibitor of the motility of cancer cells.

Honeybees (Apis mellifera) are pollinating agents of economic importance. The role of the gut microbiome in honeybee health has become increasingly evident due to its relationship with immune function, growth, and development. Although their dynamics at various developmental stages have been documented, their dynamics during the era of colony collapse disorder and immunogenic potential, which are connected to the antagonistic immune response against pathogens, need to be elucidated. Using 16S rRNA gene Illumina sequencing, the results indicated changes in the gut microbiota with the developmental stage. The bacterial diversity of fifth stage larva was significantly different among the other age groups, in which Fructobacillus, Escherichia-Shigella, Bombella, and Tyzzerella were unique bacteria. In addition, the diversity of the worker bee microbiome was distinct from that of the younger microbiome. Lactobacillus and Gilliamella remained conserved throughout the developmental stages, while Bifidobacterium colonized only worker bees. Using an in silico approach, the production potential of lipopolysaccharide-endotoxin was predicted. Forager bees tend to have a higher abundance rate of Gram-negative bacteria. Our results revealed the evolutionary importance of some microbiome from the larval stage to the adult stage, providing insight into the potential dynamics of disease response and susceptibility. This finding provides a theoretical foundation for furthering the understanding of the function of the gut microbiota at various developmental stages related to probiotic development and immunogenic potential.

Honey bees play a significant role in ecology, producing biologically active substances used to promote human health. However, unlike humans, the molecular markers indicating honey bee health remain unknown. Unfortunately, numerous reports of honey bee collapse have been documented. To identify health markers, we analyzed ten defense system genes in Apis mellifera ligustica honey bees from winter (Owb) and spring (Fb for foragers and Nb for newly emerged) populations sampled in February and late April 2023, respectively. We focused on colonies free from SBV and DWV viruses. Molecular profiling revealed five molecular markers of honey bee health. Of these, two seasonal molecular markers—domeless and spz genes—were significantly downregulated in Owb compared to Nb and Fb honey bees. One task-related marker gene, apid-1, was identified as being downregulated in Owb and Nb compared to Fb honey bees. Two recommended general health markers, SOD and defensin-2, were upregulated in honey bees. These markers require further testing across various honey bee subspecies in different climatic regions. They can diagnose bee health without colony intervention, especially during low-temperature months like winter. Beekeepers can use this information to make timely adjustments to nutrients or heating to prevent seasonal losses.

PurposeWe estimated whether amyloid involvement in subcortical regions may predict cognitive impairment, and established an amyloid staging scheme based on degree of subcortical amyloid involvement.MethodsData from 240 cognitively normal older individuals, 393 participants with mild cognitive impairment, and 126 participants with Alzheimer disease were acquired at Alzheimer's Disease Neuroimaging Initiative sites. To assess subcortical involvement, we analyzed amyloid deposition in amygdala, putamen, and caudate nucleus. We staged participants into a 3-stage model based on cortical and subcortical amyloid involvement: 382 with no cortical or subcortical involvement as stage 0, 165 with cortical but no subcortical involvement as stage 1, and 203 with both cortical and subcortical involvement as stage 2.ResultsAmyloid accumulation was first observed in cortical regions and spread down to the putamen, caudate nucleus, and amygdala. In longitudinal analysis, changes in MMSE, ADAS-cog 13, FDG PET SUVR, and hippocampal volumes were steepest in stage 2 followed by stage 1 then stage 0 (p value