bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity
Authors: Park Jae Woo , Park Se Eun , Koh Wuhyun , Jang Won Hee , Choi Jong Han , Roh Eun , Kang Gil Myoung , Kim Seong Jun , Lim Hyo Sun , Park Chae Beom , Jeong So Yeon , Moon Sang Yun , Lee Chan Hee , Kim Sang Yeob , Choi Hyung Jin , Min Se Hee , Lee C. Justin , Kim Min-Seon
Published: March 2024

Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.
DeepETPicker: Fast and accurate 3D particle picking for cryo-electron tomography using weakly supervised deep learning
Authors: Liu Guole , Niu Tongxin , Qiu Mengxuan , Zhu Yun , Sun Fei , Yang Ge
Published: March 2024

To solve three-dimensional structures of biological macromolecules in situ, large numbers of particles often need to be picked from cryo-electron tomograms. However, adoption of automated particle-picking methods remains limited because of their technical limitations. To overcome the limitations, we develop DeepETPicker, a deep learning model for fast and accurate picking of particles from cryo-electron tomograms. Training of DeepETPicker requires only weak supervision with low numbers of simplified labels, reducing the burden of manual annotation. The simplified labels combined with the customized and lightweight model architecture of DeepETPicker and accelerated pooling enable substantial performance improvement. When tested on simulated and real tomograms, DeepETPicker outperforms the competing state-of-the-art methods by achieving the highest overall accuracy and speed, which translate into higher authenticity and coordinates accuracy of picked particles and higher resolutions of final reconstruction maps. DeepETPicker is provided in open source with a user-friendly interface to support cryo-electron tomography in situ.
Pla2g12b drives expansion of triglyceride-rich lipoproteins
Authors: Thierer James H. , Foresti Ombretta , Yadav Pradeep Kumar , Wilson Meredith H. , Moll Tabea O. C. , Shen Meng-Chieh , Busch-Nentwich Elisabeth M. , Morash Margaret , Mohlke Karen L. , Rawls John F. , Malhotra Vivek , Hussain M. Mahmood , Farber Steven A.
Published: March 2024

Vertebrates transport hydrophobic triglycerides through the circulatory system by packaging them within amphipathic particles called Triglyceride-Rich Lipoproteins. Yet, it remains largely unknown how triglycerides are loaded onto these particles. Mutations in Phospholipase A2 group 12B (PLA2G12B) are known to disrupt lipoprotein homeostasis, but its mechanistic role in this process remains unclear. Here we report that PLA2G12B channels lipids within the lumen of the endoplasmic reticulum into nascent lipoproteins. This activity promotes efficient lipid secretion while preventing excess accumulation of intracellular lipids. We characterize the functional domains, subcellular localization, and interacting partners of PLA2G12B, demonstrating that PLA2G12B is calcium-dependent and tightly associated with the membrane of the endoplasmic reticulum. We also detect profound resistance to atherosclerosis in PLA2G12B mutant mice, suggesting an evolutionary tradeoff between triglyceride transport and cardiovascular disease risk. Here we identify PLA2G12B as a key driver of triglyceride incorporation into vertebrate lipoproteins.
Epigenetic profiling reveals key genes and cis-regulatory networks specific to human parathyroids
Authors: Jung Youngsook Lucy , Zhao Wenping , Li Ian , Jain Dhawal , Epstein Charles B. , Bernstein Bradley E. , Parangi Sareh , Sherwood Richard , Robinson-Cohen Cassianne , Hsu Yi-Hsiang , Park Peter J. , Mannstadt Michael
Published: March 2024

In all terrestrial vertebrates, the parathyroid glands are critical regulators of calcium homeostasis and the sole source of parathyroid hormone (PTH). Hyperparathyroidism and hypoparathyroidism are clinically important disorders affecting multiple organs. However, our knowledge regarding regulatory mechanisms governing the parathyroids has remained limited. Here, we present the comprehensive maps of the chromatin landscape of the human parathyroid glands, identifying active regulatory elements and chromatin interactions. These data allow us to define regulatory circuits and previously unidentified genes that play crucial roles in parathyroid biology. We experimentally validate candidate parathyroid-specific enhancers and demonstrate their integration with GWAS SNPs for parathyroid-related diseases and traits. For instance, we observe reduced activity of a parathyroid-specific enhancer of the Calcium Sensing Receptor gene, which contains a risk allele associated with higher PTH levels compared to the wildtype allele. Our datasets provide a valuable resource for unraveling the mechanisms governing parathyroid gland regulation in health and disease.
Single-cell profiling identifies IL1Bhi macrophages associated with inflammation in PD-1 inhibitor-induced inflammatory arthritis
Authors: Zhou Ziyue , Zhou Xiaoxiang , Jiang Xu , Yang Bo , Lu Xin , Fei Yunyun , Zhao Lidan , Chen Hua , Zhang Li , Si Xiaoyan , Liang Naixin , Wang Yadong , Yang Dan , Peng Yezi , Yang Yiying , Yao Zhuoran , He Yangzhige , Wu Xunyao , Zhang Wen , Wang Min , Yang Huaxia , Zhang Xuan
Published: March 2024

Inflammatory arthritis (IA) is a common rheumatic adverse event following immune checkpoint inhibitors treatment. The clinical disparities between IA and rheumatoid arthritis (RA) imply disease heterogeneity and distinct mechanisms, which remain elusive. Here, we profile CD45+ cells from the peripheral blood or synovial fluid (SF) of patients with PD-1-induced IA (PD-1-IA) or RA using single-cell RNA sequencing. We report the predominant expansion of IL1Bhi myeloid cells with enhanced NLRP3 inflammasome activity, in both the SF and peripheral blood of PD-1-IA, but not RA. IL1Bhi macrophages in the SF of PD-1-IA shared similar inflammatory signatures and might originate from peripheral IL1Bhi monocytes. Exhausted CD8+ T cells (Texs) significantly accumulated in the SF of patients with PD-1-IA. IL1Bhi myeloid cells communicated with CD8+ Texs possibly via the CCR1-CCL5/CCL3 and CXCL10-CXCR3 axes. Collectively, these results demonstrate different cellular and molecular pathways in PD-1-IA and RA and highlight IL1Bhi macrophages as a possible therapeutic target in PD-1-IA.
Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency
Authors: Gardner Scott , Jin Yibo , Fyfe Paul K. , Voisin Tomas B. , Bellón Junel Sotolongo , Pohler Elizabeth , Piehler Jacob , Moraga Ignacio , Bubeck Doryen
Published: March 2024

IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains. However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.
Fast topographic optical imaging using encoded search focal scan
Authors: Vilar Narcís , Artigas Roger , Duocastella Martí , Carles Guillem
Published: March 2024

A central quest in optics is to rapidly extract quantitative information from a sample. Existing topographical imaging tools allow non-contact and three-dimensional measurements at the micro and nanoscales and are essential in applications including precision engineering and optical quality control. However, these techniques involve acquiring a focal stack of images, a time-consuming process that prevents measurement of moving samples. Here, we propose a method for increasing the speed of topographic imaging by orders of magnitude. Our approach involves collecting a reduced set of images, each integrated during the full focal scan, whilst the illumination is synchronously modulated during exposure. By properly designing the modulation sequence for each image, unambiguous reconstruction of the object height map is achieved using far fewer images than conventional methods. We describe the theoretical foundations of our technique, characterise its performance, and demonstrate sub-micrometric topographic imaging over 100 µm range of static and dynamic systems at rates as high as 67 topographies per second, limited by the camera frame rate. The high speed of the technique and its ease of implementation could enable a paradigm shift in optical metrology, allowing the real-time characterisation of large or rapidly moving samples.
Malaria blood stage infection suppresses liver stage infection via host-induced interferons but not hepcidin
Authors: Patel Hardik , Minkah Nana K. , Kumar Sudhir , Zanghi Gigliola , Schepis Antonino , Goswami Debashree , Armstrong Janna , Abatiyow Biley A. , Betz Will , Reynolds Laura , Camargo Nelly , Sheikh Amina A. , Kappe Stefan H. I.
Published: March 2024

Malaria-causing Plasmodium parasites first replicate as liver stages (LS), which then seed symptomatic blood stage (BS) infection. Emerging evidence suggests that these stages impact each other via perturbation of host responses, and this influences the outcome of natural infection. We sought to understand whether the parasite stage interplay would affect live-attenuated whole parasite vaccination, since the efficacy of whole parasite vaccines strongly correlates with their extend of development in the liver. We thus investigated the impact of BS infection on LS development of genetically attenuated and wildtype parasites in female rodent malaria models and observed that for both, LS infection suffered severe suppression during concurrent BS infection. Strikingly and in contrast to previously published studies, we find that the BS-induced iron-regulating hormone hepcidin is not mediating suppression of LS development. Instead, we demonstrate that BS-induced host interferons are the main mediators of LS developmental suppression. The type of interferon involved depended on the BS-causing parasite species. Our study provides important mechanistic insights into the BS-mediated suppression of LS development. This has direct implications for understanding the outcomes of live-attenuated Plasmodium parasite vaccination in malaria-endemic areas and might impact the epidemiology of natural malaria infection.
Bioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2
Authors: Lee Dongtak , Jung Hyo Gi , Park Dongsung , Bang Junho , Cheong Da Yeon , Jang Jae Won , Kim Yonghwan , Lee Seungmin , Lee Sang Won , Lee Gyudo , Kim Yeon Ho , Hong Ji Hye , Hwang Kyo Seon , Lee Jeong Hoon , Yoon Dae Sung
Published: March 2024

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has evoked a worldwide pandemic. As the emergence of variants has hampered the neutralization capacity of currently available vaccines, developing effective antiviral therapeutics against SARS-CoV-2 and its variants becomes a significant challenge. The main protease (Mpro) of SARS-CoV-2 has received increased attention as an attractive pharmaceutical target because of its pivotal role in viral replication and proliferation. Here, we generated a de novo Mpro-inhibitor screening platform to evaluate the efficacies of Mpro inhibitors based on Mpro cleavage site-embedded amyloid peptide (MCAP)-coated gold nanoparticles (MCAP-AuNPs). We fabricated MCAPs comprising an amyloid-forming sequence and Mpro-cleavage sequence, mimicking in vivo viral replication process mediated by Mpro. By measuring the proteolytic activity of Mpro and the inhibitory efficacies of various drugs, we confirmed that the MCAP-AuNP-based platform was suitable for rapid screening potential of Mpro inhibitors. These results demonstrated that our MCAP-AuNP-based platform has great potential for discovering Mpro inhibitors and may accelerate the development of therapeutics against COVID-19.
Bet hedging in a unicellular microalga
Authors: Tang Si , Liu Yaqing , Zhu Jianming , Cheng Xueyu , Liu Lu , Hammerschmidt Katrin , Zhou Jin , Cai Zhonghua
Published: March 2024

Understanding how organisms have adapted to persist in unpredictable environments is a fundamental goal in biology. Bet hedging, an evolutionary adaptation observed from microbes to humans, facilitates reproduction and population persistence in randomly fluctuating environments. Despite its prevalence, empirical evidence in microalgae, crucial primary producers and carbon sinks, is lacking. Here, we report a bet-hedging strategy in the unicellular microalga Haematococcus pluvialis. We show that isogenic populations reversibly diversify into heterophenotypic mobile and non-mobile cells independently of environmental conditions, likely driven by stochastic gene expression. Mobile cells grow faster but are stress-sensitive, while non-mobile cells prioritise stress resistance over growth. This is due to shifts from growth-promoting activities (cell division, photosynthesis) to resilience-promoting processes (thickened cell wall, cell enlargement, aggregation, accumulation of antioxidant and energy-storing compounds). Our results provide empirical evidence for bet hedging in a microalga, indicating the potential for adaptation to current and future environmental conditions and consequently conservation of ecosystem functions.
bacLIFE: a user-friendly computational workflow for genome analysis and prediction of lifestyle-associated genes in bacteria
Authors: Guerrero-Egido Guillermo , Pintado Adrian , Bretscher Kevin M. , Arias-Giraldo Luisa-Maria , Paulson Joseph N. , Spaink Herman P. , Claessen Dennis , Ramos Cayo , Cazorla Francisco M. , Medema Marnix H. , Raaijmakers Jos M. , Carrión Víctor J.
Published: March 2024

Bacteria have an extensive adaptive ability to live in close association with eukaryotic hosts, exhibiting detrimental, neutral or beneficial effects on host growth and health. However, the genes involved in niche adaptation are mostly unknown and their functions poorly characterized. Here, we present bacLIFE (https://github.com/Carrion-lab/bacLIFE) a streamlined computational workflow for genome annotation, large-scale comparative genomics, and prediction of lifestyle-associated genes (LAGs). As a proof of concept, we analyzed 16,846 genomes from the Burkholderia/Paraburkholderia and Pseudomonas genera, which led to the identification of hundreds of genes potentially associated with a plant pathogenic lifestyle. Site-directed mutagenesis of 14 of these predicted LAGs of unknown function, followed by plant bioassays, showed that 6 predicted LAGs are indeed involved in the phytopathogenic lifestyle of Burkholderia plantarii and Pseudomonas syringae pv. phaseolicola. These 6 LAGs encompassed a glycosyltransferase, extracellular binding proteins, homoserine dehydrogenases and hypothetical proteins. Collectively, our results highlight bacLIFE as an effective computational tool for prediction of LAGs and the generation of hypotheses for a better understanding of bacteria-host interactions.
RNA compaction and iterative scanning for small RNA targets by the Hfq chaperone
Authors: Małecka Ewelina M. , Woodson Sarah A.
Published: March 2024

RNA-guided enzymes must quickly search a vast sequence space for their targets. This search is aided by chaperones such as Hfq, a protein that mediates regulation by bacterial small RNAs (sRNAs). How RNA binding proteins enhance this search is little known. Using single-molecule Förster resonance energy transfer, we show that E. coli Hfq performs a one-dimensional scan in which compaction of the target RNA delivers sRNAs to sites distant from the location of Hfq recruitment. We also show that Hfq can transfer an sRNA between different target sites in a single mRNA, favoring the most stable duplex. We propose that compaction and segmental transfer, combined with repeated cycles of base pairing, enable the kinetic selection of optimal sRNA targets. Finally, we show that RNA compaction and sRNA transfer require conserved arginine patches. We suggest that arginine patches are a widespread strategy for enabling the movement of RNA across protein surfaces.
Cholesterol-modified sphingomyelin chimeric lipid bilayer for improved therapeutic delivery
Authors: Wang Zhiren , Li Wenpan , Jiang Yanhao , Park Jonghan , Gonzalez Karina Marie , Wu Xiangmeng , Zhang Qing-Yu , Lu Jianqin
Published: March 2024

Cholesterol (Chol) fortifies packing and reduces fluidity and permeability of the lipid bilayer in vesicles (liposomes)-mediated drug delivery. However, under the physiological environment, Chol is rapidly extracted from the lipid bilayer by biomembranes, which jeopardizes membrane stability and results in premature leakage for delivered payloads, yielding suboptimal clinic efficacy. Herein, we report a Chol-modified sphingomyelin (SM) lipid bilayer via covalently conjugating Chol to SM (SM-Chol), which retains membrane condensing ability of Chol. Systemic structure activity relationship screening demonstrates that SM-Chol with a disulfide bond and longer linker outperforms other counterparts and conventional phospholipids/Chol mixture systems on blocking Chol transfer and payload leakage, increases maximum tolerated dose of vincristine while reducing systemic toxicities, improves pharmacokinetics and tumor delivery efficiency, and enhances antitumor efficacy in SU-DHL-4 diffuse large B-cell lymphoma xenograft model in female mice. Furthermore, SM-Chol improves therapeutic delivery of structurally diversified therapeutic agents (irinotecan, doxorubicin, dexamethasone) or siRNA targeting multi-drug resistant gene (p-glycoprotein) in late-stage metastatic orthotopic KPC-Luc pancreas cancer, 4T1-Luc2 triple negative breast cancer, lung inflammation, and CT26 colorectal cancer animal models in female mice compared to respective FDA-approved nanotherapeutics or lipid compositions. Thus, SM-Chol represents a promising platform for universal and improved drug delivery.
Selenium substitution for dielectric constant improvement and hole-transfer acceleration in non-fullerene organic solar cells
Authors: He Xinjun , Qi Feng , Zou Xinhui , Li Yanxun , Liu Heng , Lu Xinhui , Wong Kam Sing , Jen Alex K.-Y. , Choy Wallace C. H.
Published: March 2024

Dielectric constant of non-fullerene acceptors plays a critical role in organic solar cells in terms of exciton dissociation and charge recombination. Current acceptors feature a dielectric constant of 3-4, correlating to relatively high recombination loss. We demonstrate that selenium substitution on acceptor central core can effectively modify molecule dielectric constant. The corresponding blend film presents faster hole-transfer of ~5 ps compared to the sulfur-based derivative (~10 ps). However, the blends with Se-acceptor also show faster charge recombination after 100 ps upon optical pumping, which is explained by the relatively disordered stacking of the Se-acceptor. Encouragingly, dispersing the Se-acceptor in an optimized organic solar cell system can interrupt the disordered aggregation while still retain high dielectric constant. With the improved dielectric constant and optimized fibril morphology, the ternary device exhibits an obvious reduction of non-radiative recombination to 0.221 eV and high efficiency of 19.0%. This work unveils heteroatom-substitution induced dielectric constant improvement, and the associated exciton dynamics and morphology manipulation, which finally contributes to better material/device design and improved device performance.
Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis
Authors: Liu Chunxiao , Wang Hui , Han Lu , Zhu Yifan , Ni Shurui , Zhi Jingke , Yang Xiping , Zhi Jiayi , Sheng Tian , Li Huanqiu , Hu Qinghua
Published: March 2024

Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y14R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y14R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y14R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y14R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y14R deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1, inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2Y14R antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y14R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.
CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression
Authors: Cai Huiqiang , Zhang Bin , Ahrenfeldt Johanne , Joseph Justin V. , Riedel Maria , Gao Zongliang , Thomsen Sofie K. , Christensen Ditte S. , Bak Rasmus O. , Hager Henrik , Vendelbo Mikkel H. , Gao Xin , Birkbak Nicolai , Thomsen Martin K.
Published: March 2024

Metastatic prostate cancer (PCa) poses a significant therapeutic challenge with high mortality rates. Utilizing CRISPR-Cas9 in vivo, we target five potential tumor suppressor genes (Pten, Trp53, Rb1, Stk11, and RnaseL) in the mouse prostate, reaching humane endpoint after eight weeks without metastasis. By further depleting three epigenetic factors (Kmt2c, Kmt2d, and Zbtb16), lung metastases are present in all mice. While whole genome sequencing reveals few mutations in coding sequence, RNA sequencing shows significant dysregulation, especially in a conserved genomic region at chr5qE1 regulated by KMT2C. Depleting Odam and Cabs1 in this region prevents metastasis. Notably, the gene expression signatures, resulting from our study, predict progression-free and overall survival and distinguish primary and metastatic human prostate cancer. This study emphasizes positive genetic interactions between classical tumor suppressor genes and epigenetic modulators in metastatic PCa progression, offering insights into potential treatments.
Frequency-selective perovskite photodetector for anti-interference optical communications
Authors: Min Liangliang , Sun Haoxuan , Guo Linqi , Wang Meng , Cao Fengren , Zhong Jun , Li Liang
Published: March 2024

Free-space coupling, essential for various communication applications, often faces significant signal loss and interference from ambient light. Traditional methods rely on integrating complex optical and electronic systems, leading to bulkier and costlier communication equipment. Here, we show an asymmetric 2D–3D–2D perovskite structure device to achieve a frequency-selective photoresponse in a single device. By combining two electromotive forces of equal magnitude in the opposite directions, the device output is attenuated to zero under constant light illumination. Because these reverse photodiodes have different response speeds, the device only responds near a certain frequency, which can be tuned by manipulating the 2D perovskite components. The target device achieves an ultrafast response of 19.7/18.3 ns in the frequency-selective photoresponse range 0.8–9.7 MHz. This anti-interference photodetector can accurately transmit character and video data under strong light interference with a source intensity of up to 454 mW cm−2.
A SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer
Authors: Szczepanski Aileen , Tsuboyama Natsumi , Lyu Huijue , Wang Ping , Beytullahoglu Oguzhan , Zhang Te , Singer Benjamin David , Yue Feng , Zhao Zibo , Wang Lu
Published: March 2024

Recent studies have identified a previously uncharacterized protein C11orf53 (now named POU2AF2/OCA-T1), which functions as a robust co-activator of POU2F3, the master transcription factor which is critical for both normal and neoplastic tuft cell identity and viability. Here, we demonstrate that POU2AF2 dictates opposing transcriptional regulation at distal enhance elements. Loss of POU2AF2 leads to an inhibition of active enhancer nearby genes, such as tuft cell identity genes, and a derepression of Polycomb-dependent poised enhancer nearby genes, which are critical for cell viability and differentiation. Mechanistically, depletion of POU2AF2 results in a global redistribution of the chromatin occupancy of the SWI/SNF complex, leading to a significant 3D genome structure change and a subsequent transcriptional reprogramming. Our genome-wide CRISPR screen further demonstrates that POU2AF2 depletion or SWI/SNF inhibition leads to a PTEN-dependent cell growth defect, highlighting a potential role of POU2AF2-SWI/SNF axis in small cell lung cancer (SCLC) pathogenesis. Additionally, pharmacological inhibition of SWI/SNF phenocopies POU2AF2 depletion in terms of gene expression alteration and cell viability decrease in SCLC-P subtype cells. Therefore, impeding POU2AF2-mediated transcriptional regulation represents a potential therapeutic approach for human SCLC therapy.
Exploring the frontiers of condensed-phase chemistry with a general reactive machine learning potential
Authors: Zhang Shuhao , Makoś Małgorzata Z. , Jadrich Ryan B. , Kraka Elfi , Barros Kipton , Nebgen Benjamin T. , Tretiak Sergei , Isayev Olexandr , Lubbers Nicholas , Messerly Richard A. , Smith Justin S.
Published: March 2024

Atomistic simulation has a broad range of applications from drug design to materials discovery. Machine learning interatomic potentials (MLIPs) have become an efficient alternative to computationally expensive ab initio simulations. For this reason, chemistry and materials science would greatly benefit from a general reactive MLIP, that is, an MLIP that is applicable to a broad range of reactive chemistry without the need for refitting. Here we develop a general reactive MLIP (ANI-1xnr) through automated sampling of condensed-phase reactions. ANI-1xnr is then applied to study five distinct systems: carbon solid-phase nucleation, graphene ring formation from acetylene, biofuel additives, combustion of methane and the spontaneous formation of glycine from early earth small molecules. In all studies, ANI-1xnr closely matches experiment (when available) and/or previous studies using traditional model chemistry methods. As such, ANI-1xnr proves to be a highly general reactive MLIP for C, H, N and O elements in the condensed phase, enabling high-throughput in silico reactive chemistry experimentation.
One-stage versus two-stage bilateral implantable collamer lens implantation: a comparison of efficacy and safety
Authors: Lorger Anna , Luft Nikolaus , Mayer Wolfgang J. , Priglinger Siegfried G. , Dirisamer Martin
Published: March 2024

Implantable collamer lens implantation (ICL) represents a safe and effective treatment for myopia and myopic astigmatism. To compare the outcomes of a bilateral one-stage same day approach to a two-stage approach, the databases of the University Eye Hospital Munich, Ludwig Maximilians-University and Smile Eyes Linz, Austria were screened for eyes that had undergone ICL implantation. Two-stage surgery was performed at an interval of 1 day (17 patients), 2 days (19 patients) and 1 week (2 patients). Variables analyzed were preoperative, 1-day and last follow-up uncorrected distance (UDVA) and corrected distance visual acuity (CDVA), manifest refraction, refractive spherical equivalent (SEQ), astigmatism, age, endothelial cell count (ECD), intraocular pressure (IOP) and ICL vaulting. In total, 178 eyes (100 eyes one-stage, 78 eyes two-stage) of 89 patients were included in this study. Mean follow-up was 1.1 ± 0.8 and 1.3 ± 0.5 years. Mean preoperative SEQ was − 7.9 ± 2.6 diopters (D) in the one-stage and − 8.0 ± 1.7 D in the two-stage group (p = 0.63) and improved to 0.00 ± 0.40 and − 0.20 ± 0.40 D at end of follow-up, showing slightly better stability in the one-stage group (p = 0.004). There was no difference in the efficacy (1.1 vs. 1.2, p = 0.06) and the safety index (1.2 vs. 1.2, p = 0.60) between the two groups. No eye (0%) in either group lost 2 lines or more of UDVA (p > 0.99). Refraction within ± 0.50 D and ± 1.00 D around target was achieved comparably often (89 vs. 86%, p = 0.65; 99 vs. 99%, p > 0.99). Endothelial cell loss was slightly higher in the two-stage group (1.3 vs. 4.3%). Vaulting at the final follow up was higher in the one-stage group (373.8 ± 205.4 µm vs. 260.3 ± 153.5 µm, p = 0.00007). There were no serious intraoperative complications in either group. In conclusion, this study demonstrates that both the one- and two-stage approaches are equally effective, predictable and safe. Regarding endothelial cell loss, vaulting and SEQ stability, the one-stage group showed slightly better outcomes, but these results are clinically questionable because they are so small. Larger studies are needed to quantitatively evaluate a potential benefit.
Sex-specific epigenetics drive low GPER expression in gastrointestinal smooth muscles in type 2 diabetic mice
Authors: Muhammad Aliyu , Hixon Juanita C. , Pharmacy Yusuf Abdurrahman , Rivas Zarete Jatna I. , Johnson India , Miller Jamial , Adu-Addai Benjamin , Yates Clayton , Mahavadi Sunila
Published: March 2024

Type 2 diabetes mellitus (T2D) causes gastroparesis, delayed intestinal transit, and constipation, for unknown reasons. Complications are predominant in women than men (particularly pregnant and postmenopausal women), suggesting a female hormone-mediated mechanism. Low G-protein coupled estrogen receptor (GPER) expression from epigenetic modifications may explain it. We explored sexually differentiated GPER expression and gastrointestinal symptoms related to GPER alterations in wild-type (WT) and T2D mice (db/db). We also created smooth muscle-specific GPER knockout (GPER KO) mice to phenotypically explore the effect of GPER deficiency on gastrointestinal motility. GPER mRNA and protein expression, DNA methylation and histone modifications were measured from stomach and colon samples of db/db and WT mice. Changes in gut motility were also evaluated as daily fecal pellet production patterns. We found that WT female tissues have the highest GPER mRNA and protein expressions. The expression is lowest in all db/db. GPER downregulation is associated with promoter hypermethylation and reduced enrichment of H3K4me3 and H3K27ac marks around the GPER promoter. We also observed sex-specific disparities in fecal pellet production patterns of the GPER KO mice compared to WT. We thus, conclude that T2D impairs gut GPER expression, and epigenetic sex-specific mechanisms matter in the downregulation.
A comparative analysis of RCC and composite buildings using the new plastic deformation (PD) method
Authors: Qing Zhang Qing , Na Zhang Li
Published: March 2024

Low computational efficiency and non-linearity behaviour make the simulation of the overall building structure problematic to attain with a single dynamic or static method. Thus, this paper uses a plastic deformation (PD) method based on concrete plasticity theory (CPT) for comparative analysis of multi-storey reinforcement cement concrete (RCC) and composite buildings under common and rare earthquake loads. For this purpose, a 15-storey tall building was selected for analysis using ABAQUS software. At first, a possible building model was created and then plastic deformation analysis was performed using the new PD method under both common and rare earthquakes. After that, a nonlinear time history analysis was conducted, and the results of plastic strain distribution, lateral displacement, peak acceleration, storey stiffness, shear force, storey drift, normalised shear, and top deflection of the RCC and composite buildings were studied deeply. The fundamental time period of the RCC model was found to be 5.2 s while the fundamental time period of the composite model was 6 s. Under common and rare earthquake leads, the peak acceleration of the RCC building was 19% and 22% higher than composite buildings, respectively. Under common and rare seismic loads, the top deflections of the composite building were 33% and 36% higher than those of RCC buildings, respectively. In the case of the RCC building, it was found in this study that higher peak acceleration (PA) of the ground motion led to higher storey top displacement, storey drift, shear force and top deflection under both ground motions. Numerical results suggested that the use of composite structure is more durable than RCC structure. It was also concluded that the PD method could also be effectively used for the analysis of RCC and composite buildings under dynamic loads.
Data-driven assisted real-time optimal control strategy of submerged arc furnace via intelligent energy terminals considering large-scale renewable energy utilization
Authors: Zheng Bowen , Pan Mingming , Liu Qixin , Xu Xu , Liu Chang , Wang Xuchen , Chu Wen , Tian Shiming , Yuan Jindou , Xu Yuting , Xu Zishang , Li Yongjun
Published: March 2024

This study presents a data-driven assisted real-time optimization model which is an innovative approach to address the challenges posed by integrating Submerged Arc Furnace (SAF) systems with renewable energy sources, specifically photovoltaic (PV) and wind power, with modern intelligent energy terminals. Specifically, the proposed method is divided into two stages. The first stage is related to data-driven prediction for addressing local time-varying renewable energy and electricity market prices with predicted information, and the second stage uses an optimization model for real-time SAF dispatch. Connections between intelligent energy terminals, demand-side devices, and load management systems are established to enhance local renewable resource utilization. Additionally, mathematical formulations of the operating resistance in SAF are explored, and deep neuron networks are employed and modified for dynamic uncertainty prediction. The proposed approach is validated through a case study involving an intelligent energy terminal with a 12.5 MVA SAF system and 12 MW capacity renewable generators in an electricity market with fluctuating prices. The findings of this research underscore the efficacy of the proposed optimization model in reducing operational costs and enhancing the utilization of localized renewable energy generation. By integrating four distinct dissatisfaction coefficients into the optimization framework, we demonstrate the model's adaptability and efficiency. The application of the optimization strategy delineated herein results in the SAF system's profitability oscillating between $111 and $416 across various time intervals, contingent upon the coefficient settings. Remarkably, an aggregate daily loss recovery amounting to $1,906.84 can be realized during the optimization period. Such outcomes not only signify considerable economic advantages but also contribute to grid stability and the diminution of renewable energy curtailment, thereby underscoring the dual benefits of economic efficiency and sustainability in energy management practices.
Structure and tethering mechanism of dynein-2 intermediate chains in intraflagellar transport
Authors: Mukhopadhyay Aakash G , Toropova Katerina , Daly Lydia , Wells Jennifer N , Vuolo Laura , Mladenov Miroslav , Seda Marian , Jenkins Dagan , Stephens David J , Roberts Anthony J
Published: March 2024

Dynein-2 is a large multiprotein complex that powers retrograde intraflagellar transport (IFT) of cargoes within cilia/flagella, but the molecular mechanism underlying this function is still emerging. Distinctively, dynein-2 contains two identical force-generating heavy chains that interact with two different intermediate chains (WDR34 and WDR60). Here, we dissect regulation of dynein-2 function by WDR34 and WDR60 using an integrative approach including cryo-electron microscopy and CRISPR/Cas9-enabled cell biology. A 3.9 Å resolution structure shows how WDR34 and WDR60 use surprisingly different interactions to engage equivalent sites of the two heavy chains. We show that cilia can assemble in the absence of either WDR34 or WDR60 individually, but not both subunits. Dynein-2-dependent distribution of cargoes depends more strongly on WDR60, because the unique N-terminal extension of WDR60 facilitates dynein-2 targeting to cilia. Strikingly, this N-terminal extension can be transplanted onto WDR34 and retain function, suggesting it acts as a flexible tether to the IFT “trains” that assemble at the ciliary base. We discuss how use of unstructured tethers represents an emerging theme in IFT train interactions.
Strain-induced charge ordering above room temperature in rare-earth manganites
Authors: Samoshkina Yu. , Rautskii M. , Neznakhin D. , Stepanova E. , Andreev N. , Chichkov V. , Zaikovskii V. , Chernichenko A.
Published: March 2024

Polycrystalline films of Pr1−xSrxMnO3 (x = 0.2 and 0.4) and La0.7Sr0.3MnO3 deposited on YSZ substrates represent a special case for the formation of the AFM-CO phase in manganite at temperatures close to and above room temperature.
Dietary intake of different ratios of ARA/DHA in early stages and its impact on infant development
Authors: Fan Lijiao , Wang Xincen , Szeto Ignatius Man-Yau , Liu Biao , Sinclair Andrew J. , Li Duo
Published: March 2024

This article systematically reviewed the proportion of ARA and DHA in breast milk and formula among regions and lactation periods, and their impact on infant development and health.
Unveiling the nature of room-temperature-fabricated p-type SnO thin films: the critical role of intermediate phases, lattice disorder, and oxygen interstitials
Authors: Januar Mochamad , Lu Cheng-Yu , Lin Horng-Chih , Huang Tsung-Yu , Yang Chia-Ming , Liu Kuo-Kang , Liu Kou-Chen
Published: March 2024

This study showcases the use of ion-beam-assisted deposition for fabricating p-type SnO thin films at room temperature, which reveals crucial links between Hall mobility and lattice disorder, and between hole concentration and the relative content of interstitial oxygen.
A new thermoelectric Ag8SiSe6argyrodite for room temperature application: sensitivity of thermoelectric performance to cooling conditions
Authors: Wang Bo , Li Suwei , Luo Yubo , Yang Junyou , Ye Haitao , Liu Yong , Jiang Qinghui
Published: March 2024

Ag8SiSe6is a promising n-type thermoelectric material for near-room temperature applications. We reveal the pronounced relationship between the cooling conditions (including quenching parameters) and thermoelectric properties of Ag8SiSe6compounds.
Copper single-site engineering in MOF-808 membranes for improved water treatment
Authors: del Castillo-Velilla Isabel , Romero-Muñiz Ignacio , Marini Carlo , Montoro Carmen , Platero-Prats Ana Eva
Published: March 2024

Copper meets MOF-808 for water remediation: our innovative mixed-matrix membranes incorporating Cu–MOF-808 offer a sustainable solution for efficiently removing endocrine-disrupting compounds from water sources with minimal metal leaching.
Carbon dots on LAPONITE® hybrid nanocomposites: solid-state emission and inter-aggregate energy transfer
Authors: Onishi Bruno S. D. , Carneiro Neto Albano N. , Bortolleto-Santos Ricardo , Masterlaro Valmor R. , Carlos Luís D. , Ferreira Rute A. S. , Ribeiro Sidney J. L.
Published: March 2024

Solid-state and aquous emission by hybrids nanocomposites based on carbon dots/LAPONITE® – energy transfer (ET) between aggregates.
An innovative experimental and mathematical approach in electrochemical sensing for mapping a drug sensor landscape
Authors: Madhavan Madheswaran , Shobana Babu , Pandiaraja Duraisamy , Prakash Periakaruppan
Published: March 2024

Our study delves into the examination of an electrochemical sensor through both experimentation and mathematical analysis.
On the engineering of reductase-based-monooxygenase activity in CYP450 peroxygenases
Authors: Yadav Shalini , Shaik Sason , Dubey Kshatresh Dutta
Published: March 2024

Recent bioengineering of CYP450OleT shows that peroxide-based CYP450OleT can be converted to a reductase-based self-sufficient enzyme, which is capable of showing efficient hydroxylation and decarboxylation activity for a wide range of substrates.
Fluorotelomer ethoxylates cause developmental toxicity in mice
Authors: Steeves Katherine L. , Hanrahan Jenna , Harvey Nikita E. , Jobst Karl J. , Cahill Lindsay S.
Published: March 2024

Maternal exposure to environmentally relevant concentrations of fluorotelomer ethoxylates, an unregulated group of poly- and perfluoroalkyl substances, results in placental insufficiency and fetal distress in mice.
Diverse thermal desorption combined with self-aspirating corona discharge ionization for direct mass spectrometry analysis of complex samples
Authors: Shi Qinhao , Yu Xiaohua , Sun Shuang , Wu Weilong , Shi Wenyan , Yu Quan
Published: March 2024

The thermal desorption (TD) technique is widely employed in modern mass spectrometry to facilitate the detection of non-volatile analytes.
Quantification of rifampicin loaded into inhaled polymeric nanoparticles by reversed phase high-performance liquid chromatography in pulmonary nonphagocytic cellular uptake
Authors: Scolari Ivana Romina , De La Cruz-Thea Benjamín , Musri Melina Mara , Granero Gladys Ester
Published: March 2024

The intracellular concentration of rifampicin (RIF) loaded into chitosan (CS)/Tween 80 (T80)-coated alginate nanoparticles determined by a validated RP-HPLC method and fluorescence microscopy studies demonstrated that the nanoparticles promote the cellular internalization of RIF.
DeepSPInN – deep reinforcement learning for molecular structure prediction from infrared and 13C NMR spectra
Authors: Devata Sriram , Sridharan Bhuvanesh , Mehta Sarvesh , Pathak Yashaswi , Laghuvarapu Siddhartha , Varma Girish , Priyakumar U. Deva
Published: March 2024

DeepSPInI is a deep reinforcement learning method that predicts the molecular structure when given infrared and 13C nuclear magnetic resonance spectra with an accuracy of 91.5%.
Sonochemically synthesized black phosphorus nanoparticles: a promising candidate for piezocatalytic antibacterial activity with enhanced dielectric properties
Authors: Halder Piyali , Mondal Indrajit , Bag Neelanjana , Pal Alapan , Biswas Somen , Sau Souvik , Paul Biplab Kumar , Mondal Dheeraj , Chattopadhyay Brajadulal , Das Sukhen
Published: March 2024

Overview of the eradication of pathogenic bacteria using few-layer black phosphorus piezo catalyst under mechanical stimuli, along with the exploration of temperature dependent dielectric properties.
An immunogenic anti-cancer stem cell bi-nuclear copper(ii)-flufenamic acid complex
Authors: Li Yue , Fang Jiaxin , Singh Kuldip , Ortu Fabrizio , Suntharalingam Kogularamanan
Published: March 2024

An asymmetric bi-nuclear copper(ii) complex with both cytotoxic and immunogenic activity towards breast cancer stem cells (CSCs) is reported.
Selective removal of Cr2O72− in aqueous solution by nonporous pure crystals of cucurbit[6]uril
Authors: Xu Jing , Li Bin , Zhang Xiu-Du , Wu Dong , Zhao Jiang-Lin , Chen Kai
Published: March 2024

Nonporous pure crystals of cucurbit[6]uril could serve as a highly selective absorbent for the toxic anion Cr2O72− in aqueous solution, even in the presence of other common interfering anions.
Regulating electrode/electrolyte interfacial chemistry enables 4.6 V ultra-stable fast charging of commercial LiCoO2
Authors: Zhang Anping , Bi Zhihong , Wang Gongrui , Liao Shihao , Das Pratteek , Lin Hu , Li Mingrun , Yu Yan , Feng Xinliang , Bao Xinhe , Wu Zhong-Shuai
Published: March 2024

A schematic diagram of the mechanism of our fluorinated “cocktail electrolyte” stabilizing electrode/electrolyte interfaces in 4.6 V LCO batteries.
Cross-polymerization between bio-oil and polyaniline: synergistic effects on pore development in subsequent activation and adsorption of phenol
Authors: Li Baihong , Li Chao , Li Dianqiang , Zhang Lijun , Zhang Shu , Wang Yi , Hu Song , Xiang Jun , Gholizadeh Mortaza , Hu Xun
Published: March 2024

The preparation of nitrogen-containing porous carbon by cross-polymerization of polyaniline and bio-oil during activation process for phenol adsorption.
High-performance polyethylene elastomers using a hybrid steric approach in α-diimine nickel precatalysts
Authors: Saeed Hassan , Mahmood Qaiser , Yuan Rongyan , Wang Yizhou , Zou Song , Tahir Kainat Fatima , Ma Yanping , Liang Tongling , Sun Wen-Hua
Published: March 2024

In this study, hybrid steric hindrance was introduced into the α-diimine structure to prepare a set of nickel complexes, aiming to enhance catalytic performance and polyethylene properties simultaneously for ethylene polymerization.
Multifaceted nucleic acid probing with a rationally upgraded molecular rotor
Authors: Kha Tuan-Khoa , Shi Qi , Pandya Nirali , Zhu Ru-Yi
Published: March 2024

A rationally designed molecular rotor CCVJ-H shows superior performances than CCVJ-1 in a range of nucleic acid sensing applications, including nucleic acid detection, DNA glycosylase assay, and nucleic acid-small molecule interaction profiling.
Enhanced synthesis of multiblock copolymers via acid-triggered RAFT polymerization
Authors: Antonopoulou Maria-Nefeli , Truong Nghia P. , Anastasaki Athina
Published: March 2024

This study employs acid in RAFT polymerization to enhance multiblock copolymer synthesis, achieving near-quantitative monomer conversion, while suppressing low molecular weight tailing, and maintaining dispersity constant.