bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer
Authors: DeAngelo Stephen L. , Zhao Liang , Dziechciarz Sofia , Shin Myungsun , Solanki Sumeet , Balia Andrii , El-Derany Marwa O , Castillo Cristina , Qin Yao , Das Nupur K. , Bell Hannah Noelle , Paulo Joao A. , Zhang Yuezhong , Rossiter Nicholas J. , McCulla Elizabeth C. , He Jianping , Talukder Indrani , Ng Billy Wai-Lung , Schafer Zachary T. , Neamati Nouri , Mancias Joseph D. , Koutmos Markos , Shah Yatrik M. 
Published: April 2024

AbstractFerroptosis is a non-apoptotic form of cell death resulting from the iron-dependent accumulation of lipid peroxides. Colorectal cancer (CRC) cells accumulate high levels of intracellular iron and reactive oxygen species (ROS) and are thus particularly sensitive to ferroptosis. The compound (S)-RSL3 ([1S,3R]-RSL3) is a commonly used ferroptosis inducing compound that is currently characterized as a selective inhibitor of the selenocysteine containing enzyme (selenoprotein) Gluathione Peroxidase 4 (GPx4), an enzyme that utilizes glutathione to directly detoxify lipid peroxides. However, through chemical controls utilizing the (R) stereoisomer of RSL3 ([1R,3R]-RSL3) that does not bind GPx4, combined with inducible genetic knockdowns of GPx4 in CRC cell lines, we revealed that GPx4 dependency does not always align with (S)-RSL3 sensitivity, questioning the current characterization of GPx4 as the central regulator of ferroptosis. Utilizing affinity pull-down mass spectrometry with chemically modified (S)-RSL3 probes we discovered that the effects of (S)-RSL3 extend far beyond GPx4 inhibition, revealing that (S)-RSL3 is a broad and non-selective inhibitor of selenoproteins. To further investigate the therapeutic potential of broadly disrupting the selenoproteome as a therapeutic strategy in CRC, we employed additional chemical and genetic approaches. We found that the selenoprotein inhibitor auranofin, an FDA approved gold-salt, chemically induced oxidative cell death and ferroptosis in bothin-vitroandin-vivomodels of CRC. Consistent with these data, we found that AlkBH8, a tRNA-selenocysteine methyltransferase required for the translation of selenoproteins, is essential for thein-vitrogrowth and xenograft survival of CRC cell lines. In summary, these findings recharacterize the mechanism of action of the most commonly used ferroptosis inducing molecule, (S)-RSL3, and reveal that broad inhibition of selenoproteins is a promising novel therapeutic angle for the treatment of CRC.
Non-invasive neuromodulation of cerebello-hippocampal volume-behavior relationships
Authors: Magalhães Thamires N. C. , Maldonado Ted , Jackson T. Bryan , Hicks Tracey H. , Herrejon Ivan A. , Rezende Thiago J. R. , Symm Abigail C. , Bernard Jessica A. 
Published: April 2024

AbstractThe study here explores the link between transcranial direct current stimulation (tDCS) and brain-behavior relationships. We propose that tDCS may indirectly influence the complex relationships between brain volume and behavior. We focused on the dynamics between the hippocampus (HPC) and cerebellum (CB) in cognitive processes, a relationship with significant implications for understanding memory and motor skills. Seventy-four young adults (mean age: 22±0.42 years, mean education: 14.7±0.25 years) were randomly assigned to receive either anodal, cathodal, or sham stimulation. Following stimulation, participants completed computerized tasks assessing working memory and sequence learning in a magnetic resonance imaging (MRI) environment. We investigated the statistical interaction between CB and HPC volumes. Our findings showed that individuals with larger cerebellar volumes had shorter reaction times (RT) on a high-load working memory task in the sham stimulation group. In contrast, the anodal stimulation group exhibited faster RTs during the low-load working memory condition. These RT differences were associated with the cortical volumetric interaction between CB-HPC. Literature suggests that anodal stimulation down-regulates the CB and here, those with larger volumes perform more quickly, suggesting the potential need for additional cognitive resources to compensate for cerebellar downregulation. This new insight suggests that tDCS can aid in revealing structure-function relationships, due to greater performance variability, especially in young adults. It may also reveal new targets of interest in the study of aging or in diseases where there is also greater behavioral variability.
NMR study of the interaction between MinC and FtsZ and modeling of the FtsZ:MinC complex
Authors: Machado Luciana E. S. F. , Castellen Patricia , Blasios Valdir , Ribeiro Filho Helder Veras , Bisson-Filho Alexandre W. , Benites-Pariente Jhonatan S. , Nogueira Maria Luiza Caldas , Sforça Mauricio , Honorato Rodrigo Vargas , de Oliveira Paulo Sérgio Lopes , Salinas Roberto K. , Zeri Ana Carolina de Mattos , Gueiros-Filho Frederico J. 
Published: April 2024

AbstractThe Min system is a key spatial regulator of cell division in rod-shaped bacteria and the first FtsZ negative modulator to be recognized. Nevertheless, despite extensive genetic and in vitro studies, the molecular mechanism used by MinC to inhibit Z-ring formation remains incompletely understood. The crystallization of FtsZ in complex with other negative regulators such as SulA and MciZ has provided important structural information to corroborate in vitro experiments and establish the mechanism of Z-ring antagonism by these modulators. However, MinC and FtsZ have so far eluded co-crystallization, probably because their complex is too unstable to be crystallized. To gain structural insight into the mechanism of action of MinC, we determined the solution structure of the N-terminal domain ofB. subtilisMinC, and through NMR titration experiments and mutagenesis identified the binding interfaces involved in the MinCN-FtsZ interaction. By using our experimental results as restraints in docking, we also constructed a molecular model for the FtsZ:MinCNcomplex and validated it by molecular dynamics. The model shows that MinCNbinding overlaps with the FtsZ polymerization interface on the C-terminal globular subdomain of FtsZ and, thus, provides a structural basis for MinCNinhibition of FtsZ filament formation. Given that the C-terminal polymerization interface of FtsZ corresponds to the plus end of FtsZ filaments, we propose that capping is the main mechanism employed by MinC to antagonize FtsZ polymerization.
A single strand-based library preparation method for unbiased virome characterization
Authors: Zhai Xichuan , Gobbi Alex , Kot Witold , Krych Lukasz , Nielsen Dennis Sandris , Deng Ling 
Published: April 2024

ABSTRACTThe gut virome is an integral component of the gut microbiome, playing a crucial role in maintaining gut health. However, accurately depicting the entire gut virome is challenging due to the inherent limitations and biases associated with current sequencing library preparation methods. To overcome these problems, we repurposed the ligation-based single-stranded library (SSLR) preparation method for virome studies. We demonstrate that the SSLR method exhibits exceptional efficiency in quantifying viral DNA genomes (both dsDNA and ssDNA) and outperforms existing double-stranded (Nextera) and single-stranded (xGen, MDA+Nextera) library preparation approaches in terms of minimal amplification bias, evenness of coverage, and integrity of assembling viral genomes. The SSLR method can be utilized for the simultaneous library preparation of both DNA and RNA viral genomes. Furthermore, the SSLR method showed its ability to capture highly modified phage genomes, which were often lost using other library preparation approaches.
User Preferences on Long-Acting Pre-Exposure Prophylaxis for HIV Prevention in Sub-Saharan Africa: A Scoping Review
Authors: Pfau Brian , Saravis BA Arden , Cox Sarah N. , Wu Linxuan , Wittenauer Rachel , Callen Emily , Arrouzet Cory , Sharma Monisha 
Published: April 2024

Structured AbstractBackgroundNovel formulations for PrEP such as injectables, implants, and intravaginal rings are emerging as long-acting alternatives to daily pills for the prevention of HIV. Sub-Saharan Africa has the highest HIV burden as well as the highest PrEP coverage globally. As long-acting formulations continue to become available, it is crucial to understand the product preferences of potential users.ObjectiveTo conduct a scoping review focused on the region of Sub-Saharan Africa to understand which PrEP products, especially long-acting formulations, different patients and demographic groups prefer as well as the factors that influence their preferences.DesignWe identified 34 publications published between 2014 and 2024 that assessed preferences regarding at least one long-acting PrEP product in the region of Sub-Saharan Africa.ResultsParticipants preferred longer-acting products over oral pills when given the choice in almost all studies. On-demand PrEP was commonly preferred over daily dosing, and long-acting products were preferred over on-demand dosing. A majority of studies found injectables to be most commonly preferred compared to daily oral PrEP, implants, and rings. This preference was observed across a range of demographics including men and women, youth, men who have sex with men, and female sex workers. Duration, efficacy, and discretion were the three most important factors influencing participants’ choices.ConclusionsLong-acting products, especially injectables, are acceptable for a wide range of individuals at risk of HIV in Sub-Saharan Africa and tend to be preferred over daily oral pills. Participants expressed a diversity of values and opinions regarding preferences, emphasizing the benefit of providing multiple formulations to maximize coverage over heterogeneous populations.Strength and Limitations of this StudySome key populations, such as transgender women, were underrepresented in the literature. With most studies published before long-acting products became widely available, the hypothetical preferences of non-experienced users may differ from preferences in practice.
Engineering probioticEscherichia coliNissle 1917 to block transfer of multiple antibiotic resistance genes by exploiting a type I CRISPR-Cas system
Authors: Fang Mengdie , Zhang Ruiting , Wang Chenyu , Liu Zhizhi , Fei Mingyue , Tang Biao , Yang Hua , Sun Dongchang 
Published: April 2024

AbstractMany multidrug-resistant (MDR) bacteria evolved through accumulation of antibiotic-resistance genes (ARGs). Although the potential risk of probiotics as reservoirs of ARGs has been recognized, strategies for blocking transfer of ARGs while using probiotics have rarely been explored. The probioticEscherichia coliNissle 1917 (EcN) has long been used for treating intestinal diseases. Here, we showed frequent transfer of ARGs into EcN bothin vitroandin vivo, raising its potential risk of accumulating antibiotic resistance. Given that no CRISPR-Cas system is found in natural EcN, we integrated the endogenous type I-E CRISPR-Cas system derived fromE. coliBW25113 into EcN, and showed that the engineered EcN was able to efficiently cleave multiple ARGs (i.e.,mcr-1,blaNDM-1andtet(X)). By co-incubation of EcN expressing Cas3-Cascade and that expressing Cas9, we showed that the growth of the former strain outcompeted the latter strain, demonstrating better clinical application prospect of EcN expressing the type I-E CRISPR-Cas system. Finally, the engineered EcN exhibited immunity against transfer of targeted ARGs in the intestine of a model animal (i.e. zebrafish). Our work provides a new strategy for restricting transfer of ARGs in EcN, paving the way for safe use of this probiotic and development of probiotics as living therapeutics.
rRNA Operon Improves Species-Level Classification of Bacteria and Microbial Community Analysis Compared to 16S rRNA
Authors: Won Sohyoung , Cho Seoae , Kim Heebal 
Published: April 2024

ABSTRACTPrecise identification of species is fundamental in microbial genomics, crucial for understanding the microbial communities. While the 16S rRNA gene, particularly its V3-V4 regions, has been extensively employed for microbial identification, however has limitations in achieving species-level resolution. Advancements in long-read sequencing technologies have highlighted the rRNA operon as a more accurate marker for microbial classification and analysis than the 16S rRNA gene. This study aims to compare the accuracy of species classification and microbial community analysis using the rRNA operon versus the 16S rRNA gene. We evaluated the species classification accuracy of the rRNA operon,16S rRNA gene, and 16S rRNA V3-V4 region using a BLAST based method and ak-mer matching based method with public data available from NCBI. We further preformed simulations to model microbial community analysis. We accessed the performance using each marker in community composition estimation and differential abundance analysis. Our findings demonstrate that the rRNA operon offers an advantage over the 16S rRNA gene and its V3-V4 region for species-level classification within genus. When applied to microbial community analysis, the rRNA operon enables a more accurate determination of composition. Using the rRNA operon yielded more reliable results in differential abundance analysis as well.IMPORTANCEWe quantitatively demonstrated that the rRNA operon outperformed the 16S rRNA and its V3-V4 regions in accuracy, for both individual species identification and species-level microbial community analysis. Our findings can provide guidelines for selecting appropriate markers in the field of microbial research.
MutLα suppresses error-prone DNA mismatch repair and preferentially protects noncoding DNA from mutations
Authors: Kadyrova Lyudmila Y. , Mieczkowski Piotr A. , Kadyrov Farid A. 
Published: April 2024

ABSTRACTThe DNA mismatch repair (MMR) system promotes genome stability and protects humans from certain types of cancer. Its primary function is the correction of DNA polymerase errors. MutLα is an important eukaryotic MMR factor. We have examined the contributions of MutLα to maintaining genome stability. We show here that loss of MutLα in yeast increases the genome-wide mutation rate by ∼130-fold and generates a genome-wide mutation spectrum that consists of small indels and base substitutions. We also show that loss of yeast MutLα leads to error-prone MMR that produces T>C base substitutions in 5’-ATA-3’ sequences. In agreement with this finding, our examination of human whole genome DNA sequencing data has revealed that loss of MutLα in induced pluripotent stem cells triggers error-prone MMR that leads to the formation of T>C mutations in 5’-NTN-3’ sequences. Our further analysis has shown that MutLα-independent MMR plays a role in suppressing base substitutions in N3homopolymeric runs. In addition, we describe that MutLα preferentially defends noncoding DNA from mutations. Our study defines the contributions of MutLα-dependent and independent mechanisms to genome-wide MMR.
Anti-EGFR aptamer exhibits direct anti-cancer effects in NSCLC cells harboring EGFR L858R mutations
Authors: Thomas Brian J. , Awan Sania Z. , Joshi Trupti , Daniels Mark A. , Porciani David , Burke Donald H. 
Published: April 2024

AbstractNon-small cell lung cancer (NSCLC) adenocarcinoma (LUAD) is a leading cause of death worldwide. Activating mutations in the tyrosine kinase domain of the oncogene epidermal growth factor receptor (EGFR) are responsible for ∼10-50% of all LUAD cases. Although EGFR tyrosine kinase inhibitors (TKIs) have been effective in prolonging NSCLC patient survival and quality of life, acquired resistance mechanisms and disease progression are inevitable. Contemporary second- and third-line treatments, such as immunotherapy, remain ineffective for these patients, presenting a clear and unmet need for alternative or adjuvant therapeutics for the treatment of mutant EGFR positive NSCLC. Here we show that an anti-EGFR aptamer (EGFRapt) decreases viability of NSCLC cell lines harboring the L858R ± T790M mutation in EGFR but not cell lines harboring wild-type or exon 19 deletions. In a humanized xenograft mouse model of NSCLC,EGFRaptdecreased tumor burden compared to controls when delivered intratumorally over multiple doses. To elucidate the mechanism by whichEGFRaptexerts these effects, we monitored cellular processes associated with kinase-dependent and kinase-independent mechanisms and found that the anti-cancer effects ofEGFRaptare cell line dependent, inhibiting cellular proliferation in one cell line and inducing cell death in another. Post hoc transcriptomics analysis supported these findings and provided additional mechanistic insights. Overall, these data establish thatEGFRapthas direct anti-cancer activity in mutant EGFR positive NSCLC via targetable mechanisms that are independent of existing approaches, and they provide a foundation for further development of nucleic acid-based therapies that target EGFR.
Pseudocobalamin production and use in marineSynechococcuscultures and communities
Authors: Bannon Catherine C. , Soto Maria A. , Rowland Elden , Chen Nan , Gleason Anna , Devred Emmanuel , LaRoche Julie , Bertrand Erin M. 
Published: April 2024

AbstractCobalamin influences marine microbial communities because an exogenous source is required by most eukaryotic phytoplankton, and demand can exceed supply. Pseudocobalamin is a cobalamin analog that is produced and used by most cyanobacteria but is not directly available to eukaryotic phytoplankton. Some microbes can remodel pseudocobalamin into cobalamin, but a scarcity of pseudocobalamin measurements impedes our ability to evaluate its importance for marine cobalamin production. Here, we perform simultaneous measurements of pseudocobalamin and methionine synthase (MetH), the key protein that uses it as a co-factor, inSynechococcuscultures and communities. InSynechococcussp. WH8102, pseudocobalamin quota decreases in low temperature (17 °C) and low N:P, while MetH did not. Pseudocobalamin and MetH quotas were influenced by culture methods and growth phase. Despite the variability present in cultures, we found a comparably consistent quota of 300 ± 100 pseudocobalamin molecules per cyanobacterial cell in the Northwest Atlantic Ocean, suggesting that cyanobacterial cell counts may be sufficient to estimate pseudocobalamin inventories in this region. This work offers insights into cellular pseudocobalamin metabolism, and the environmental and physiological conditions that may influence it, and provides environmental measurements to further our understanding of when and how pseudocobalamin can influence marine microbial communities.
Large-scale statistical mapping of T-cell receptorβsequences to Human Leukocyte Antigens
Authors: Zahid H. Jabran , Taniguchi Ruth , Ebert Peter , Chow I-Ting , Gooley Chris , Lv Jinpeng , Pisani Lorenzo , Rusnak Mikaela , Elyanow Rebecca , Takamatsu Hiroyuki , Zhou Wenyu , Greissl Julia , Robins Harlan , Carlson Jonathan M. 
Published: April 2024

AbstractT-cell receptors (TCRs) interacting with peptides presented by human leukocyte antigens (HLAs) are the foundation of the adaptive immune system but population-level analysis of TCR-HLA interactions is lacking. Here we statistically associate∼106public TCRs to specific HLAs using the TCRβrepertoires sampled from 4,144 HLA-genotyped subjects. The TCRs we associate are specific to unique HLA allotypes, not allelic groups, and to the pairedα-βheterodimer of class II HLAs though exceptions are observed. This specificity permits highly accurate imputation of 248 class I and II HLAs from the TCRβrepertoire. Notably, 45 HLA-DP and -DQ heterodimers lack associated TCRs because they likely arise from non-functional trans-complementation. The public class I and II HLA-associated TCRs we identify are primarily expressed on CD8+and CD4+memory T cells, respectively, which are responding to various common antigens. Our results recapitulate fundamental biology, provide insights into the functionality of HLAs and demonstrate the power and potential of population-level TCR repertoire sequencing.
A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes
Authors: Sharma Sorabh , Cheema Manjinder , Tennant Kelly A. , Boghozian Roobina , Cota Ana Paula , Brosschot Tara P. , Fitzpatrick Rachael D. , Körbelin Jakob , Reynolds Lisa A. , Brown Craig E. 
Published: April 2024

AbstractVascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes, but precisely how capillary flow is affected and the underlying mechanisms remain elusive. Here we show that capillaries in the diabetic mouse brain are prone to stalling, with blocks composed primarily of erythrocyte plugs in branches off penetrating venules. Increased capillary obstructions were evident in both sexes and only partially reversed by insulin. Screening for circulating inflammatory cytokines revealed persistently high levels of interleukin-10 (IL-10) in diabetic mice. Contrary to expectation, stimulating IL-10 signalling increased capillary obstructions, whereas inhibiting IL-10 receptors with neutralizing antibodies or endothelial specific knockdown in diabetic mice, reversed these impairments. Chronic IL-10R blocking antibody treatment in diabetic mice also improved stimulus evoked cerebral blood flow, increased capillary widths in lower-order branches and reversed cognitive deficits. These data suggest IL-10 signalling plays an unexpected pathogenic role in cerebral microcirculatory defects and cognitive impairment.
Nonreciprocal Dissipation Engineering via Strong Coupling with a Continuum of Modes
Authors: Zhou Yishu , Ruesink Freek , Gertler Shai , Cheng Haotian , Pavlovich Margaret , Kittlaus Eric , Starbuck Andrew L. , Leenheer Andrew J. , Pomerene Andrew T. , Trotter Douglas C. , Dallo Christina , Musick Katherine M. , Garcia Eduardo , Reyna Robert , Holterhoff Andrew L. , Gehl Michael , Kodigala Ashok , Bowers John , Eichenfield Matt , Otterstrom Nils T. , Lentine Anthony L. , Rakich Peter 
Published: April 2024

Optical nonreciprocity plays a key role in almost every optical system, directing light flow and protecting optical components from backscattered light. Controllable forms of on-chip nonreciprocity are needed for the robust operation of increasingly sophisticated photonic integrated circuits (PICs) in the context of classical and quantum computation, networking, communications, and sensing. However, it has been challenging to achieve wideband, low-loss optical nonreciprocity on-chip. In this paper, we demonstrate strong coupling and Rabi-like energy exchange between photonic bands, possessing a continuum of modes, to unlock nonreciprocity and frequency translation over wide optical bandwidths in silicon. Using a traveling-wave phonon field to drive indirect interband photonic transitions, we demonstrate band hybridization that enables an intriguing form of nonreciprocal dissipation engineering. Using the converted mode to create a nonreciprocal dissipation channel, we demonstrate a frequency-neutral, low-loss (less than 1 dB) isolator with high nonreciprocal contrast (more than 14 dB) and broad operating bandwidth (more than 59 GHz). Additionally, through the implementation of complete interband conversion, we demonstrate a high extinction (more than 55 dB) optical frequency translation operation with near-unity efficiency.

Published by the American Physical Society
2024