bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the tumor micro-environment in ovarian cancer histotypes and tumor sites
Authors: Xie Bingqing , Olalekan Susan , Back Rebecca , Ashitey Naa Asheley , Eckart Heather , Basu Anindita 
Published: October 2023

AbstractOvarian cancer is a highly heterogeneous disease consisting of at least five different histological subtypes with varying clinical features, cells of origin, molecular composition, risk factors, and treatments. While most single-cell studies have focused on High grade serous ovarian cancer, a comprehensive landscape of the constituent cell types and their interactions within the tumor microenvironment are yet to be established in the different ovarian cancer histotypes. Further characterization of tumor progression, metastasis, and various histotypes are also needed to connect molecular signatures to pathological grading for personalized diagnosis and tailored treatment. In this study, we leveraged high-resolution single-cell RNA sequencing technology to elucidate the cellular compositions on 21 solid tumor samples collected from 12 patients with six ovarian cancer histotypes and both primary (ovaries) and metastatic (omentum, rectum) sites. The diverse collection allowed us to deconstruct the histotypes and tumor site-specific expression patterns of cells in the tumor and identify key marker genes and ligand-receptor pairs that are active in the ovarian tumor microenvironment. Our findings can be used in improving precision disease stratification and optimizing treatment options.
Distribution theories for genetic line of least resistance and evolvability measures
Authors: Watanabe Junya 
Published: October 2023

AbstractQuantitative genetic theory on multivariate character evolution predicts that a population’s response to directional selection tends to happen around the major axis of the genetic covariance matrixG—the so-called genetic line of least resistance. Inferences on the genetic constraints in this sense have traditionally been made by measuring the angle of deviation of evolutionary trajectories from the major axis, or more recently by calculating the amount of genetic variance—the Hansen–Houle evolvability—available along the trajectories. However, there have not been clear practical guidelines on how these quantities can be interpreted, especially in a high-dimensional space. This study summarizes pertinent distribution theories for relevant quantities, pointing out that they can be written as ratios of quadratic forms in evolutionary trajectory vectors by takingGas a parameter. For example, a beta distribution with appropriate parameters can be used as a null distribution for squared cosine of the angle of deviation from a major axis or subspace. More general cases can be handled with the probability distribution of ratios of quadratic forms in normal variables. Apart from its use in hypothesis-testing, this latter approach could potentially be used as a heuristic tool for looking into various selection scenarios like directional and/or correlated selection as parameterized with mean and covariance of selection gradients.
Effect of altered production and storage of dopamine on development and behavior inC. elegans
Authors: Lee Irene , Knickerbocker Ava C , Depew Charlotte Rose , Martin Elizabeth , Dicent Jocelyn , Miller Gary W , Bucher Meghan L 
Published: October 2023

AbstractThe nematode,Caenorhabditis elegans, is an advantageous model for studying developmental toxicology due to its homology to humans and well-defined developmental stages. Similarly to humans,C. elegansutilize dopamine as a neurotransmitter to regulate motor behavior. We have previously reported behavioral deficits in a genetic model ofC. elegans(OK411) that lack the neurotransmitter transporter necessary for packaging dopamine into synaptic vesicles. Anecdotally, we observed theseC. elegansappeared to have a smaller body size, which is supported by prior studies that observed a larger body size inC. elegansthat lack the enzyme that catalyzes dopamine synthesis, suggesting a complex regulatory system in which dopamine mediates body size inC. elegans. However, the question of whether body size abnormalities apparent inC. eleganswith disruptions to their dopamine system are developmental or purely based on body size remains unanswered. Here, we present data characterizing the effect of gene mutations in dopamine-related proteins on body size, development, and behavior. We analyzedC. elegansthat lack the ability to sequester dopamine (OK411), that overproduce dopamine (UA57), and a novel strain (MBIA) generated through crossing OK411 and UA57, which lacks the ability to sequester dopamine into vesicles and additionally endogenously overproduces dopamine. This novel strain was generated to address the hypothesis that an endogenous increase in production of dopamine can rescue deficits caused by a lack of vesicular dopamine sequestration. Compared to wild type, OK411 have shorter body lengths and behavioral deficits in early life stages. In contrast, the MBIA strain have similar body lengths to wild-type by early adulthood and display similar behavior to wild-type by early adulthood. Our data suggests that endogenously increasing the production of dopamine is able to mitigate deficits inC. eleganslacking the ability to package dopamine into synaptic vesicles. These results provide evidence that the dopamine system impacts development, growth, and reproduction inC. elegans.
Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy
Authors: Leylek Ozen , Honeywell Megan E. , Lee Michael J. , Hemann Michael T. , Ozcan Gulnihal 
Published: October 2023

AbstractThe rational combination of anticancer agents is critical to improving patient outcomes in cancer. Nonetheless, most combination regimens in the clinic result from empirical methodologies disregarding insight into the mechanism of action and missing the opportunity to improve therapy outcomes incrementally. Deciphering the genetic dependencies and vulnerabilities responsible for synergistic interactions is crucial for rationally developing effective anticancer drug combinations. Hence, we screened pairwise pharmacological interactions between molecular-targeted agents and conventional chemotherapeutics and examined the genome-scale genetic dependencies in gastric adenocarcinoma cell models. Since this type of cancer is mainly chemoresistant and incurable, clinical situations demand effective combination strategies. Our pairwise combination screen revealed SN38/erlotinib as the drug pair with the most robust synergism. Genome-wide CRISPR screening and a shRNA-based signature assay indicated that the genetic dependency/vulnerability signature of SN38/erlotinib is the same as SN38 alone. Additional investigation revealed that the enhanced cell death with improved death kinetics caused by the SN38/erlotinib combination is surprisingly due to erlotinib’s off-target effect that inhibits ABCG2 but not its on-target effect on EGFR. Our results confirm that a genetic dependency signature different from the single-drug application may not be necessary for the synergistic interaction of molecular-targeted agents with conventional chemotherapeutics in gastric adenocarcinoma. The findings also demonstrated the efficacy of functional genomics approaches in unveiling biologically validated mechanisms of pharmacological interactions.SignificanceFunctional genomics approaches efficiently demonstrated an off-target dependency of the synergistic interaction of erlotinib with SN38 in gastric adenocarcinoma cell models.
DIFFERENTIAL SCANNING CALORIMETRY: A SUITABLE METHODOLOGY TO PROBLEM THE BINDING PROPERTIES OF BCL-2 INHIBITORS
Authors: Dinc Bircan , Dogan Berna , Mavromoustakos Thomas , Durdagi Serdar 
Published: October 2023

AbstractThe Differential Scanning Calorimeter (DSC) technique is commonly used for quantitative analysis of protein stability, and it is one of the methods used to quantify protein-ligand interactions. DSC provides denaturation curves that can be a source of data on binding constants. B-cell leukemia/lymphoma-2 (BCL-2) is an antiapoptotic protein, one of the overexpressed proteins in cancer cells. Here, binding constants for BCL-2 of nine BCL-2 inhibitors were evaluated by utilization of DSC measurements. The binding free energies of suggested inhibitors of BCL-2 were measured by melting temperature, Tm,and heat capacity, Cp. Evaluated BCL-2 binding parameters of candidate molecules agreed with our previously reported biological assays and molecular simulations indicating that the DSC method could be applied for the determination of free energies of enzyme inhibitors with high accuracy. Therefore, our results showed that this fast and relatively cheap technique can be conducted in high throughput drug screening analyses to compare the binding affinity of a set of compounds against a specific target protein. BCL-2 and most of its inhibitors have hydrophobic cavities, and a definite percent of dimethyl sulfoxide (DMSO) was advised to increase the solubility. Our work also suggests that the presence of the recommended high concentration of DMSO as the solvent significantly changes the affinity of the inhibitors to BCL-2, revealing similar DSC curves for all inhibitors.
Structural Evolution of Trimeric Gamma-Type Retroviral Envelope Proteins
Authors: Hötzel Isidro 
Published: October 2023

AbstractThe envelope glycoproteins (Env) of retroviruses are highly diverse due to their relatively rapid evolution and the ancient origin of retroviruses. Sequence similarity among the Env of retroviruses is observed in the transmembrane subunit (TM) of Env mediating membrane fusion, whereas this similarity is more limited or absent in the surface subunit (SU) mediating receptor binding. Recent structural modeling of the SU of major retroviral groups identified a structurally conserved β-sheet domain in SU and the SU-equivalent of filoviruses, GP1, that is differentially expanded to generate the structural diversity observed in this protein family. Here, trimeric Env structures from three major exogenous and endogenous gamma-type retroviral Env classes were modeled with AlphaFold2 multimer to address the evolution of trimeric Env in the retroviruses. The models show a close structural relationship between the trimeric Env proteins of gammaretroviruses and alpharetroviruses and the trimeric filoviral spike protein, with an extended hydrophobic structure anchoring SU into TM in retroviral Env occluding the intersubunit disulfide bond. In addition, the murine leukemia virus (MLV) Env trimer model indicates that the type-C gammaretroviral receptor binding domains (RBD) are positioned on the side of the Env trimer pointing towards the viral envelope membrane, unlike those of the gammaretroviral RDR interference group, which are positioned closer to the apical end of the Env trimer. The trimeric MLV Env structural model, including RBD position, is consistent with previous trimeric MLV Env electron-density maps. The structural models provide insights into the structure, function and evolution of trimeric retroviral gamma-type Env.
Multi-omics analysis reveals novel interplays between intratumoral bacteria and glioma
Authors: Li Ting , Zhao Zhanyi , Peng Meichang , Wang Cheng , Luo Feiyang , Zeng Meiqin , Sun Kaijian , Fang Zhencheng , Luo Yunhao , Huang Qiyuan , Xie Yugu , Wang Jiaxuan , Huang Jian-Dong , Zhou Hongwei , Sun Haitao 
Published: October 2023

AbstractEmerging evidence highlights the potential impact of intratumoral microbiota on cancer. However, the microbial composition and function in glioma remains elusive. Consequently, our study aimed to investigate the microbial community composition in glioma tissues and elucidate its role in glioma development. We parallelly performed microbial profiling, transcriptome sequencing and metabolomics detection on tumor and adjacent normal brain tissues obtained from 50 glioma patients. We employed immunohistochemistry, multicolor immunofluorescence and FISH staining to observe the presence and location of bacteria. Furthermore, an animal model was employed to validate the impact of key bacteria on glioma development. Six genera were found to be significantly enriched in glioma tissues compared to its adjacent normal brain tissues, includingFusobacterium,Longibaculum,Intestinimonas,Pasteurella,LimosilactobacillusandArthrobacter. Both bacterial RNA and LPS were observed in glioma tissues. Multicolor immunofluorescence analysis showed higher bacterial LPS levels in tumor cells than in macrophages and in glioma tissue than in adjacent normal brain tissue. Integrated microbiomics, transcriptomics, and metabolomics revealed that genes associated with intratumoral microbes were enriched in multiple synapse-associated pathways and that metabolites associated with intratumoral microbes were (R)-N-methylsalsolinol, N-acetylaspartylglutamic acid, and N-acetyl-L-aspartic acid. Further mediation analysis suggested that intratumoral microbiome may affect the expression of neuron-related genes through bacteria-associated metabolites. In addition, a glioma mouse model suggested thatFusobacterium nucleatumpromoted glioma growth by increasing the levels of N-acetylneuraminic acid and the expression levels of CCL2, CXCL1, and CXCL2. In conclusion, our findings shed light on the intricate interplays between intratumoral bacteria and glioma.
The fitness cost of spurious phosphorylation
Authors: Bradley David , Hogrebe Alexander , Dandage Rohan , Dubé Alexandre K , Leutert Mario , Dionne Ugo , Chang Alexis , Villén Judit , Landry Christian R 
Published: October 2023

AbstractThe fidelity of signal transduction requires the binding of regulatory molecules to their cognate targets. However, the crowded cell interior risks off-target interactions between proteins that are functionally unrelated. How such off-target interactions impact fitness is not generally known, but quantifying this is required to understand the constraints faced by cell systems as they evolve. Here, we use the model organismS. cerevisiaeto inducibly express tyrosine kinases. Because yeast lacksbona fidetyrosine kinases, most of the resulting tyrosine phosphorylation is spurious. This provides a suitable system to measure the impact of artificial protein interactions on fitness. We engineered 44 yeast strains each expressing a tyrosine kinase, and quantitatively analysed their phosphoproteomes. This analysis resulted in ∼30,000 phosphosites mapping to ∼3,500 proteins. Examination of the fitness costs in each strain revealed a strong correlation between the number of spurious pY sites and decreased growth. Moreover, the analysis of pY effects on protein structure and on protein function revealed over 1000 pY events that we predict to be deleterious. However, we also find that a large number of the spurious pY sites have a negligible effect on fitness, possibly because of their low stoichiometry. This result is consistent with our evolutionary analyses demonstrating a lack of phosphotyrosine counter-selection in species withbona fidetyrosine kinases. Taken together, our results suggest that, alongside the risk for toxicity, the cell can tolerate a large degree of non-functional crosstalk as interaction networks evolve.
Climate warming suppresses soil abundant fungal taxa and reduces soil carbon efflux in a semi-arid grassland
Authors: Qiu Yunpeng , Zhang Kangcheng , Zhao Yunfeng , Zhao Yexin , Wang Bianbian , Wang Yi , He Tangqing , Xu Xinyu , Bai Tongshuo , Zhang Yi , Hu Shuijin 
Published: October 2023

AbstractThe abundance, diversity and activity of soil microorganisms critically control the fate of recent plant carbon (C) inputs as well as protecting soil organic C, regulating C-climate feedbacks. However, the effects of climate change drivers such as warming and precipitation change on soil microbial communities and C dynamics remain poorly understood. Utilizing a long-term field warming and precipitation manipulation in a semi-arid grassland on the Loess Plateau and a complementary incubation experiment, here we show that warming and rainfall reduction differentially affect the abundance and composition of bacteria and fungi, and soil C efflux. Warming significantly reduced the abundance of fungi but not bacteria, increasing the relative dominance of bacteria in the soil microbial community. In particular, warming shifted the community composition of abundant fungi in favor of oligotrophicCapnodialesandHypocrealesover potential saprotrophArchaeorhizomycetales. In contrast, precipitation reduction increased soil microbial biomass, but did not significantly affect either the abundance or diversity of bacteria. Furthermore, soil abundant, not rare, fungal community composition was significantly correlated with soil CO2efflux. Our findings suggest that alterations in the fungal community composition, in response to changes in soil C and moisture, dominate the microbial responses to climate change and thus control soil C dynamics in semi-arid grasslands.Impact statementSemi-arid grasslands play a critical role in global carbon (C) cycle and potential feedbacks to climate change. Understanding the responses of soil microorganisms to warming and rainfall change is key to evaluating and predicting semi-arid grassland soil C dynamics under future climate change scenarios. Our study showed that warming induced a shift in the abundant fungal community, favoring oligotrophic fungi (i.e.,CapnodialesandHypocreales) over the potential saprotrophicArchaeorhizomycetales,and reduced C efflux. These findings advance our understanding of soil microbial and C responses to climate change drivers and may help predict and possibly manage soil C sequestration in semi-arid grasslands.
Tissue Usage Preference and Intrinsically Disordered Region Remodeling of Alternative Splicing Derived Proteoforms in the Heart
Authors: Pandi Boomathi , Brenman Stella , Black Alexander , Ng Dominic C. M. , Lau Edward , Lam Maggie P. Y. 
Published: October 2023

AbstractA computational analysis of mass spectrometry data was performed to uncover alternative splicing derived protein variants across chambers of the human heart. Evidence for 216 non-canonical isoforms was apparent in the atrium and the ventricle, including 52 isoforms not documented on SwissProt and recovered using an RNA sequencing derived database. Among non-canonical isoforms, 29 show signs of regulation based on statistically significant preferences in tissue usage, including a ventricular enriched protein isoform of tensin-1 (TNS1) and an atrium-enriched PDZ and LIM Domain 3 (PDLIM3) isoform 2 (PDLIM3-2/ALP-H). Examined variant regions that differ between alternative and canonical isoforms are highly enriched in intrinsically disordered regions, and over two-thirds of such regions are predicted to function in protein binding and/or RNA binding. The analysis here lends further credence to the notion that alternative splicing diversifies the proteome by rewiring intrinsically disordered regions, which are increasingly recognized to play important roles in the generation of biological function from protein sequences.
DiffDec: Structure-Aware Scaffold Decoration with an End-to-End Diffusion Model
Authors: Xie Junjie , Chen Sheng , Lei Jinping , Yang Yuedong 
Published: October 2023

AbstractIn molecular optimization, one popular way is R-groups decoration on molecular scaffolds, and many efforts have been put to generate R-groups based on deep generative models. However, these methods mostly use information of known binding ligands, without fully utilizing target structure information. In this study, we proposed a new method, DiffDec, to involve three-dimensional pocket constraints by a modified diffusion technique for optimizing molecules through molecular scaffold decoration. For an end-to-end generation of R-groups with different sizes, we designed a novel fake atom mechanism. DiffDec was shown able to generate structure-aware R-groups, and simultaneously generate multiple R-groups for one scaffold on different growth anchors. The growth anchors could be provided by users or automatically determined by our model. DiffDec achieved R-group recovery rates of 69.67% and 45.34% in the single and multiple R-group decoration tasks, respectively, and these values were significantly higher than competing methods (37.33% and 26.85%). According to the molecular docking study, our decorated molecules obtained better average binding affinity than baseline methods. The docking pose analysis revealed that DiffDec could decorate scaffolds with R-groups that exhibited improved binding affinities and more favourable interactions with the pocket. These results demonstrated the potential and applicability of DiffDec in real-world scaffold decoration for molecular optimization.
Learning performance and GABAergic pathway link to deformed wing virus in the mushroom bodies of naturally infected honey bees
Authors: Szymański Szymon , Baracchi David , Dingle Lauren , Bowman Alan S. , Manfredini Fabio 
Published: October 2023

AbstractViral infections can be detrimental to the foraging ability of the Western honey beeApis mellifera. These include the deformed wing virus (DWV), which is the most common honey bee virus and has been proposed as a possible cause of learning and memory impairment. However, evidence for this phenomenon so far has come from artificially infected bees, while less is known about the implications of natural infections with the virus. Using the proboscis extension reflex (PER), we uncovered no significant association between a simple associative learning task and natural DWV loads. However, when assessed through a reversal associative learning assay, bees with higher DWV loads performed better in the reversal learning phase.DWV is able to replicate in the honey bee mushroom bodies, where the GABAergic signalling pathway has an antagonistic effect on associative learning but is crucial for reversal learning. Hence, we assessed the pattern of expression of several GABA-related genes in bees with different learning responses. Intriguingly, mushroom body expression of selected genes was positively correlated with DWV load, but only for bees with good reversal learning performance. We hypothesize that DWV might improve olfactory learning performance by enhancing the GABAergic inhibition of responses to unrewarded stimuli, which is consistent with the behavioural patterns that we observed.Our results suggest that previously reported DWV-driven learning deficits might be exclusive to acute, artificial infections and do not occur in naturally infected bees, stressing the importance of investigating more ecologically relevant scenarios when assessing host-parasite systems.Summary statementThis study describes a virus-associated increase in learning in honey bees and proposes a mechanism based on GABA to explain the interplay between infection and cognition in the insect brain.