bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sample-efficient Antibody Design through Protein Language Model for Risk-aware Batch Bayesian Optimization
Authors: Wang Yanzheng , Wang Boyue , Shi Tianyu , Fu Jie , Zhou Yi , Zhang Zhizhuo 
Published: November 2023

AbstractAntibody design is a time-consuming and expensive process that often requires extensive experimentation to identify the best candidates. To address this challenge, we propose an efficient and risk-aware antibody design framework that leverages protein language models (PLMs) and batch Bayesian optimization (BO). Our framework utilizes the generative power of protein language models to predict candidate sequences with higher naturalness and a Bayesian optimization algorithm to iteratively explore the sequence space and identify the most promising candidates. To further improve the efficiency of the search process, we introduce a risk-aware approach that balances exploration and exploitation by incorporating uncertainty estimates into the acquisition function of the Bayesian optimization algorithm. We demonstrate the effectiveness of our approach through experiments on several benchmark datasets, showing that our framework outperforms state-of-the-art methods in terms of both efficiency and quality of the designed sequences. Our framework has the potential to accelerate the discovery of new antibodies and reduce the cost and time required for antibody design.
Poisoning scientific knowledge using large language models
Authors: Yang Junwei , Xu Hanwen , Mirzoyan Srbuhi , Chen Tong , Liu Zixuan , Ju Wei , Liu Luchen , Zhang Ming , Wang Sheng 
Published: November 2023

AbstractBiomedical knowledge graphs constructed from scientific literature have been widely used to validate biological discoveries and generate new hypotheses. Recently, large language models (LLMs) have demonstrated a strong ability to generate human-like text data. While most of these text data have been useful, LLM might also be used to generate malicious content. Here, we investigate whether it is possible that a malicious actor can use LLM to generate a malicious paper that poisons scientific knowledge graphs and further affects downstream biological applications. As a proof-of-concept, we develop Scorpius, a conditional text generation model that generates a malicious paper abstract conditioned on a promoting drug and a target disease. The goal is to fool the knowledge graph constructed from a mixture of this malicious abstract and millions of real papers so that knowledge graph consumers will misidentify this promoting drug as relevant to the target disease. We evaluated Scorpius on a knowledge graph constructed from 3,818,528 papers and found that Scorpius can increase the relevance of 71.3% drug disease pairs from the top 1000 to the top 10 by only adding one malicious abstract. Moreover, the generation of Scorpius achieves better perplexity than ChatGPT, suggesting that such malicious abstracts cannot be efficiently detected by humans. Collectively, Scorpius demonstrates the possibility of poisoning scientific knowledge graphs and manipulating downstream applications using LLMs, indicating the importance of accountable and trustworthy scientific knowledge discovery in the era of LLM.
On the limits of 16S rRNA gene-based metagenome prediction and functional profiling
Authors: Matchado Monica Steffi , Rühlemann Malte , Reimeiter Sandra , Kacprowski Tim , Frost Fabian , Haller Dirk , Baumbach Jan , List Markus 
Published: November 2023

AbstractMolecular profiling techniques such as metagenomics, metatranscriptomics or metabolomics offer important insights into the functional diversity of the microbiome. In contrast, 16S rRNA gene sequencing, a widespread and cost-effective technique to measure microbial diversity, only allows for indirect estimation of microbial function. To mitigate this, tools such as PICRUSt2, Tax4Fun2, PanFP and MetGEM infer functional profiles from 16S rRNA gene sequencing data using different algorithms. Prior studies have cast doubts on the quality of these predictions, motivating us to systematically evaluate these tools using matched 16S rRNA gene sequencing, metagenomic datasets, and simulated data. Our contribution is threefold: (i) using simulated data, we investigate if technical biases could explain the discordance between inferred and expected results; (ii) considering human cohorts for type 2 diabetes, colorectal cancer and obesity, we test if health-related differential abundance measures of functional categories are concordant between 16S rRNA gene-inferred and metagenome-derived profiles and; (iii) since 16S rRNA gene copy number is an important confounder in functional profiles inference, we investigate if a customised copy number normalisation with the rrnDB database could improve the results. Our results show that 16S rRNA gene-based functional inference tools generally do not have the necessary sensitivity to delineate health-related functional changes in the microbiome and should thus be used with care. Furthermore, we outline important differences in the individual tools tested and offer recommendations for tool selection.
The saccadic repertoire of larval zebrafish reveals kinematically distinct saccades that are used in specific behavioural contexts
Authors: Dowell Charles K. , Lau Joanna Y. N. , Bianco Isaac H. 
Published: November 2023

SummarySaccades are rapid eye movements that are used by all species with good vision. They have been extensively studied, especially in vertebrates, and are understood to be controlled by a conserved brainstem circuit. However, despite the fact that saccades play important roles during diverse visually guided behaviours, little is known about whether their properties, including the manner in which they are coordinated with head/body movements, vary in the context of different visuomotor tasks. Here, we characterise the saccadic repertoire of larval zebrafish and identify five saccade types, defined by systematic differences in kinematics and binocular coordination. Each type was differentially expressed during visually guided behaviours. Conjugate saccades form a large group that are used in at least four contexts: Fast phases of the optokinetic nystagmus, visual scanning in stationary animals, and to shift or maintain gaze during locomotion. Convergent saccades play a specialised role during hunting and are coordinated with body movements to foveate prey. Furthermore, conjugate and convergent saccades follow distinct velocity main sequence relationships and show differences in the millisecond coordination of the eyes and body, pointing to differences in underlying neurophysiology. In summary, this study reveals unexpected diversity in horizontal saccades and predicts saccade type-specific neural activity patterns.HighlightsKinematic analysis of thousands of rapid eye movements reveals five saccade types.Conjugate saccades have at least four identifiable visual functions.Convergent saccades are coordinated with body movements to foveate prey.Timing, kinematics and main sequence relationships indicate saccade type-specific neural control.
Self Fourier shell correlation: properties and application to cryo-ET
Authors: Verbeke Eric J. , Aurèle Gilles Marc , Bendory Tamir , Singer Amit 
Published: November 2023

AbstractThe Fourier shell correlation (FSC) is a measure of the similarity between two signals computed over corresponding shells in the frequency domain and has broad applications in microscopy. In structural biology, the FSC is ubiquitous in methods for validation, resolution determination, and signal enhancement. Computing the FSC usually requires two independent measurements of the same underlying signal, which can be limiting for some applications. Here, we analyze and extend on an approach proposed by Koho et al. [1] to estimate the FSC from a single measurement. In particular, we derive the necessary conditions required to estimate the FSC from downsampled versions of a single noisy measurement. These conditions reveal additional corrections which we implement to increase the applicability of the method. We then illustrate two applications of our approach, first as an estimate of the global resolution from a single 3-D structure and second as a data-driven method for denoising tomographic reconstructions in electron cryo-tomography. These results provide general guidelines for computing the FSC from a single measurement and suggest new applications of the FSC in microscopy.
Multi-modal microvascular cerebral blood flow velocity mapping with 14T single-vessel MRI and optical microscopy in the mouse brain
Authors: Miller D. R. , Zhou X. A. , Liang S. , Xie Z. , Fu B. , Shin P. , Pian Q. , Jiang Y. , Liu A. , Tang J. , Devor A. , Yu X. , Sakadzic S. 
Published: November 2023

AbstractIn this study, we imaged the same penetrating cortical vessels in a mouse using ultrahigh field single-vessel MRI at 14 T and high-resolution optical microscopy imaging. The optical imaging was performed through a chronic sealed cranial window, while the single-vessel MRI was facilitated by a custom-designed, chronically implanted radiofrequency coil surrounding the window. The MRI and optical imaging were performed sequentially focused on the same penetrating cortical arterioles and surfacing venules within the whisker barrel cortex. With MRI, we obtained high-resolution multi-gradient echo (MGE) images and single-vessel phase contrast (PC) velocity maps. With optical imaging, we acquired microvascular angiograms using 2-Photon Microscopy (2PM) and Optical Coherence Tomography (OCT) and measured the blood flow velocity using Dynamic Light Scattering OCT (DLS-OCT). The MGE images, PC-based MRI velocity maps, OCT angiograms, and DLS-OCT velocity maps were coregistered with the 2PM microvascular angiograms. Using these tools, we cross-validated blood flow velocity in the penetrating cortical arterioles and surfacing venules measured by single-vessel MRI and OCT at rest. Our novel method demonstrates the possibility of combining ultrahigh field single-vessel MRI and high-resolution optical methods (e.g., 2PM and OCT) for studying brain structure and function with single microvessel precision.
NLRP3 Cys126 palmitoylation by ZDHHC7 Promotes Inflammasome Activation
Authors: Yu Tao , Hou Dan , Zhao Jiaqi , Lu Xuan , Greentree Wendy K. , Zhao Qian , Yang Min , Conde Don-Gerard , Linder Maurine E. , Lin Hening 
Published: November 2023

AbstractNACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) mediates inflammasome activation in response to multiple pathogen and damage-associated molecular patterns in macrophages. Hyperactivation of NLRP3 inflammasome contributes to many human chronic inflammatory diseases. Understanding how NLRP3 inflammasome is regulated can potentially provide new strategies to treat inflammatory diseases. Here, we demonstrated that NLRP3 is palmitoylated on Cys126 by palmitoyl-acyltransferase ZDHHC7 in macrophages, which is critical for NLRP3-mediated inflammasome activation. Perturbating NLRP3 Cys126 palmitoylation by ZDHHC7 knockout, pharmacological inhibition, or modification site mutation, diminishes NLRP3 activation and the consequential Caspase-1 and Gasdermin D (GSDMD) cleavage, and IL-1β and IL-18 secretion in mouse primary macrophages and human macrophages. Furthermore, NLRP3 Cys126 palmitoylation is vital for inflammasome activationin vivo, asZdhhc7knockout, pharmacological inhibition, or NLRP3 C126A mutation protects mice from LPS-induced endotoxic shock and monosodium urate (MSU)-induced peritonitis. Mechanistically, ZDHHC7-mediated NLRP3 Cys126 palmitoylation promotes resting NLRP3 localizing on thetrans-Golgi network (TGN) and activated NLRP3 on the dispersed TGN (dTGN), which is indispensable for the recruitment and oligomerization of adaptor protein ASC after inflammasome activation. The activation of NLRP3 by ZDHHC7-mediated Cys126 palmitoylation is different from the previously reported inhibitory effect by ZDHHC12-mediated Cys841 palmitoylation, highlighting the versatile regulatory roles ofS-palmitoylation. Therefore, our study identifies a new regulatory mechanism of NLRP3 activation and suggests targeting ZDHHC7 or NLRP3 Cys126 residue as a potential therapeutic strategy to treat NLRP3-related human disorders.HighlightsNLRP3 Cys126 is palmitoylated by ZDHHC7.ZDHHC7 promotes NLRP3 activation in macrophages, which can be inhibited by ZDHHCs inhibitors, 2-bromopalmitate and MY-D4.Cys126 palmitoylation of NLRP3 is critical for NLRP3 activation.NLRP3 TGN/dTGN localization depends on ZDHHC7-mediated Cys126 palmitoylation, which is crucial for ASC recruitment and inflammasome assembly.NLRP3 inflammasome activation by ZDHHC7 differs from ZDHHC12-mediated NLRP3 inhibition.
Feasibility assessment of LI-RADS based ultrasonic screening and CT diagnosis for hepatocellular carcinoma in low middle income setting: observation from a small study
Authors: Malindi Ephranzia Chao , Mutala Timothy Musila , Ayo Stephen Onyango , Ogaro Roseline Kerubo 
Published: November 2023

AbstractIn our cross-sectional study, we assessed the feasibility of using the ACR LI-RADS screening and diagnostic pathway for Hepatocellular Carcinoma (HCC) in a low-middle-income setting. HCC develops in a well-defined high-risk population, but many countries in this income category lack HCC screening and surveillance guidelines. The ACR’s practical approach through LI-RADS provides a valuable solution. Our study showed that 5.66% of patients had positive ultrasound findings, and significant lesions were detected on multiphasic CT scans. Out of these, 1.89% were diagnosed with definite HCC (LR-5 lesions). We conclude that HCC screening and diagnosis using ACR LI-RADS algorithms are feasible in such settings. However, success hinges on knowledge, skills, and technical capacity building, and it is vital to consider the downstream effects of the screening and surveillance program during the design process.SummaryHCC screening and diagnosis using the ACR LI-RADS algorithms are feasible in low-middle-income settings, making it applicable and recommendable for even lower-income countries. However, successful implementation requires a focus on knowledge, skills, and technical capacity building.Key pointsEligible patients for hepatocellular carcinoma screening and surveillance programs are easily identifiable in low middle income countries.American College of Radiology’s Liver Imaging Reporting and Data Systems algorithm provides a practical approach to hepatocellular carcinoma screening and surveillance.With proper knowledge, skills, and technical capacity, this algorithm is feasible in a low middle income setting, factoring tiered levels of care and referral systems.
A systematic review and meta-analysis of the risk of hepatitis B virus (HBV) genotypic resistance in people treated with entecavir or tenofovir
Authors: Lumley Sheila F , Delphin Marion , Mokaya Jolynne F , Tan Cedric CS , Martyn Emily , Anderson Motswedi , Li Ka Chun , Waddilove Elizabeth , Sukali Gloria , Downs Louise O , Said Khadija , Okanda Dorcas , Campbell Cori , Harriss Eli , Shimakawa Yusuke , Matthews Philippa C 
Published: November 2023

AbstractBackgroundAs nucleos/tide analogue (NA) therapy for chronic Hepatitis B virus (HBV) infection becomes more widely indicated and available, understanding drug resistance is essential. We performed a systematic review and meta-analysis to estimate the risk of genotypic resistance to tenofovir and entecavir.MethodsWe searched nine databases up to 29-Aug-23. We included studies of HBV infection featuring >10 individuals, written in English, reporting tenofovir or entecavir treatment ≥48 weeks, with assessment of HBV genotypic resistance. Data were analysed according to prior exposure history to NA, and treatment with tenofovir or entecavir. Analyses were performed in R.Results62 studies involving a total of 12,358 participants were included. For tenofovir, pooled resistance risk was 0.0% at all time points, whether previously NA naive (11 studies; 3778 individuals) or experienced (19 studies; 2059 individuals). For entecavir, in treatment-naive individuals (22 studies; 4326 individuals), risk of resistance increased over time to 0.9% at ≥5 years (95%CI 0.1-2.3%). Entecavir resistance was increased in NA-experienced individuals (18 studies;1112 individuals), to 20.1% (95%CI 1.6-50.1%) at ≥5 years. There was a lack of consistent definitions, poor global representation and insufficient metadata to support subgroup analysis.DiscussionBased on existing data, tenofovir has an excellent resistance profile. More resistance is seen with entecavir, particularly in treatment-experienced groups. Due to data gaps, we may have under-estimated the true risk of resistance. Robust prospective data collection is crucial as treatment is rolled out more widely.
Skeletal muscle energetics explain the sex disparity in mobility impairment in the Study of Muscle, Mobility and Aging (SOMMA)
Authors: Kramer Philip A. , Coen Paul M. , Cawthon Peggy M. , Distefano Giovanna , Cummings Steven R. , Goodpaster Bret H. , Hepple Russell T. , Kritchevsky Stephen B. , Shankland Eric G. , Marcinek David J. , Toledo Frederico G. S. , Duchowny Kate A. , Ramos Sofhia V. , Harrison Stephanie , Newman Anne B. , Molina Anthony J. A. 
Published: November 2023

AbstractThe age-related decline in muscle mitochondrial energetics contributes to the loss of mobility in older adults. Women experience a higher prevalence of mobility impairment compared to men, but it is unknown whether sex-specific differences in muscle energetics underlie this disparity. In the Study of Muscle, Mobility and Aging (SOMMA), muscle energetics were characterized using in vivo phosphorus-31 magnetic resonance spectroscopy and high-resolution respirometry of vastus lateralis biopsies in 773 participants (56.4% women, age 70-94 years). A Short Physical Performance Battery score ≤ 8 was used to define lower-extremity mobility impairment. Muscle mitochondrial energetics were lower in women compared to men (e.g. Maximal Complex I&II OXPHOS: Women=55.06 +/− 15.95; Men=65.80 +/− 19.74; p<0.001) and in individuals with mobility impairment compared to those without (e.g., Maximal Complex I&II OXPHOS in women: SPPB≥9=56.59 +/− 16.22; SPPB≤8=47.37 +/− 11.85; p<0.001). Muscle energetics were negatively associated with age only in men (e.g., Maximal ETS capacity: R=-0.15, p=0.02; age/sex interaction, p=0.04), resulting in muscle energetics measures that were significantly lower in women than men in the 70-79 age group but not the 80+ age group. Similarly, the odds of mobility impairment were greater in women than men only in the 70-79 age group (70-79 age group, ORage-adjusted=1.78, 95% CI=1.03, 3.08, p=0.038; 80+ age group, ORage-adjusted=1.05, 95% CI=0.52, 2.15, p=0.89). Accounting for muscle energetics attenuated up to 75% of the greater odds of mobility impairment in women. Women had lower muscle mitochondrial energetics compared to men, which largely explain their greater odds of lower-extremity mobility impairment.
Bioprocess optimization enables enhanced protopanaxadiol production in yeast
Authors: Qiu Shangkun , Gilani Mariam Dianat Sabet , Müller Conrad , Liebal Ulf , Blank Lars M. 
Published: November 2023

AbstractGinsenosides are the primary active metabolites of ginseng and have been used in traditional herbal medicine in Asia for more than 4,000 years. Protopanaxadiol (PPD) is the precursor of dammarane-type ginsenosides, exhibiting different pharmacological activities. However, extraction of PPD from plant material is cumbersome because of its low concentration. Precision fermentation using recombinant yeast is a promising alternative strategy to produce PPD. For increasing PPD production, the medium and fermentation conditions were optimized by a Design of Experiment (DoE) approach. PPD production increased by 7.5-fold in the final cultivation condition compared to the reference condition. The PPD titer reached 1.2 g/L during simple 500 mL shake flask cultivations, the highest PPD production in shake flasks to date. The protocol presented facilitates parallel evaluation of recombinant yeast, thereby contributing to the much-needed sustainable synthesis of the versatile molecule class of triterpenoids.
ChatGPT usage in the Reactome curation process
Authors: Tiwari Krishna , Matthews Lisa , May Bruce , Shamovsky Veronica , Orlic-Milacic Marija , Rothfels Karen , Ragueneau Eliot , Gong Chuqiao , Stephan Ralf , Li Nancy , Wu Guanming , Stein Lincoln , D’Eustachio Peter , Hermjakob Henning 
Published: November 2023

AbstractAppreciating the rapid advancement and ubiquity of generative AI, particularly ChatGPT, a chatbot using large language models like GPT, we endeavour to explore the potential application of ChatGPT in the data collection and annotation stages within the Reactome curation process. This exploration aimed to create an automated or semi-automated framework to mitigate the extensive manual effort traditionally required for gathering and annotating information pertaining to biological pathways, adopting a Reactome “reaction-centric” approach. In this pilot study, we used ChatGPT/GPT4 to address gaps in the pathway annotation and enrichment in parallel with the conventional manual curation process. This approach facilitated a comparative analysis, where we assessed the outputs generated by ChatGPT against manually extracted information. The primary objective of this comparison was to ascertain the efficiency of integrating ChatGPT or other large language models into the Reactome curation workflow and helping plan our annotation pipeline, ultimately improving our protein-to-pathway association in a reliable and automated or semi-automated way. In the process, we identified some promising capabilities and inherent challenges associated with the utilisation of ChatGPT/GPT4 in general and also specifically in the context of Reactome curation processes. We describe approaches and tools for refining the output given by ChatGPT/GPT4 that aid in generating more accurate and detailed output.
Spatial organization of bacterial sphingolipid synthesis enzymes
Authors: Uchendu Chioma G. , Klein Eric A. 
Published: November 2023

AbstractSphingolipids are produced by nearly all eukaryotes where they play significant roles in cellular processes such as cell growth, division, programmed cell death, angiogenesis, and inflammation. While it was previously believed that sphingolipids were quite rare among bacteria, bioinformatic analysis of the recently identified bacterial sphingolipid synthesis genes suggests that these lipids are likely to be produced by a wide range of microbial species. The sphingolipid synthesis pathway consists of three critical enzymes. Serine palmitoyltransferase catalyzes the condensation of serine with palmitoyl-CoA (or palmitoyl-acyl carrier protein), ceramide synthase adds the second acyl chain, and a reductase reduces the ketone present on the long-chain base. While there is general agreement regarding the identity of these bacterial enzymes, the precise mechanism and order of chemical reactions for microbial sphingolipid synthesis is more ambiguous. Two mechanisms have been proposed. First, the synthesis pathway may follow the well characterized eukaryotic pathway in which the long-chain base is reduced prior to the addition of the second acyl chain. Alternatively, our previous work suggests that addition of the second acyl chain precedes the reduction of the long-chain base. To distinguish between these two models, we investigated the subcellular localization of these three key enzymes. We found that serine palmitoyltransferase and ceramide synthase are localized to the cytoplasm whereas the ceramide reductase is in the periplasmic space. This is consistent with our previously proposed model wherein the second acyl chain is added in the cytoplasm prior to export to the periplasm where the lipid molecule is reduced.