bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractMalaria-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

AbstractThe 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

AbstractUnderstanding 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

AbstractBacteria 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

AbstractRNA-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

AbstractCholesterol (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

AbstractDielectric 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

AbstractPurinergic 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

AbstractMetastatic 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

AbstractFree-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

AbstractRecent 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

AbstractAtomistic 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

AbstractImplantable 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

AbstractType 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.