bluuebunny/crossref_metadata_2025 huggingface dataset:
Can large language models help predict results from a complex behavioural science study?
Authors: Lippert Steffen , Dreber Anna , Johannesson Magnus , Tierney Warren , Cyrus-Lai Wilson , Uhlmann Eric Luis ,   Emotion Expression Collaboration, Pfeiffer Thomas
Published: September 2024

We tested whether large language models (LLMs) can help predict results from a complex behavioural science experiment. In study 1, we investigated the performance of the widely used LLMs GPT-3.5 and GPT-4 in forecasting the empirical findings of a large-scale experimental study of emotions, gender, and social perceptions. We found that GPT-4, but not GPT-3.5, matched the performance of a cohort of 119 human experts, with correlations of 0.89 (GPT-4), 0.07 (GPT-3.5) and 0.87 (human experts) between aggregated forecasts and realized effect sizes. In study 2, providing participants from a university subject pool the opportunity to query a GPT-4 powered chatbot significantly increased the accuracy of their forecasts. Results indicate promise for artificial intelligence (AI) to help anticipate—at scale and minimal cost—which claims about human behaviour will find empirical support and which ones will not. Our discussion focuses on avenues for human–AI collaboration in science.
Accounting for extinction dynamics unifies the geological and biological histories of Indo-Australian Archipelago
Authors: Herrera-Alsina Leonel , Lancaster Lesley T. , Algar Adam C. , Bocedi Greta , Papadopulos Alexander S. T. , Gubry-Rangin Cecile , Osborne Owen G. , Mynard Poppy , Creer Simon , Villegas-Patraca Rafael , Made Sudiana I. , Fahri Fahri , Lupiyaningdyah Pungki , Nangoy Meis , Iskandar Djoko T. , Juliandi Berry , Burslem David F. R. P. , Travis Justin M. J.
Published: September 2024

Biogeographical reconstructions of the Indo-Australian Archipelago (IAA) have suggested a recent spread across the Sunda and Sahul shelves of lineages with diverse origins, which appears to be congruent with a geological history of recent tectonic uplift in the region. However, this scenario is challenged by new geological evidence suggesting that the Sunda shelf was never submerged prior to the Pliocene, casting doubt on the interpretation of recent uplift and the correspondence of evidence from biogeography and geology. A mismatch between geological and biogeographical data may occur if analyses ignore the dynamics of extinct lineages, because this may add uncertainty to the timing and origin of clades in biogeographical reconstructions. We revisit the historical biogeography of multiple IAA taxa and explicitly allow for the possibility of lineage extinction. In contrast to models assuming zero extinction, we find that all of these clades, including plants, invertebrates and vertebrates, have a common and widespread geographic origin, and each has spread and colonized the region much earlier than previously thought. The results for the eight clades re-examined in this article suggest that they diversified and spread during the early Eocene, which helps to unify the geological and biological histories of IAA.
The fetal specific geneLIN28Bis essential for human fetal B-lymphopoiesis and initiation of KMT2A::AFF1 infant leukemia
Authors: Ling Rebecca , Jackson Thomas , Elliott Natalina , Cross Joe , Hamer Lucy , Wuppalapati Arundhati , Smith Alastair , Chahrour Catherine , Sevim Okan , Iskander Deena , Wang Guanlin , Rice Siobhan , O’Byrne Sorcha , Harman Joe , Psaila Bethan , Morgan Rhys , Roberts Irene , Milne Thomas A. , Roy Anindita
Published: September 2024

Infant ALL (iALL) is initiatedin utero, most often by rearrangement of theKMT2Agene (KMT2Ar). It carries a very poor prognosis despite a lack of additional oncogenic driver mutations common in childhood ALL. Here, we aimed to identify specific properties of human fetal hematopoietic stem/progenitor cells (HSPC) that promote leukemic transformation inKMT2AriALL using molecular, functional andin vivoassays. First, by comparing transcriptomes of human fetal HSPC to adult HSPC we derived a fetal-specific gene signature and identified the fetal oncogeneLIN28Band its downstream effectors among the top hits. These genes were also expressed in iALL. Functional assays revealed thatLIN28Bwas essential in human fetal liver (FL) CD34+ cells to maintain proliferation and stemness, and support B- and NK-lymphopoiesis. To interrogate the role ofLIN28Bin iALL, we utilised a human FL-derived CRISPR-Cas9 KMT2A::AFF1 model. In this model,LIN28B-expressing leukemias were more proliferativein vitroandin vivo, with this advantage being lost uponLIN28Bknockdown. Mechanistic studies showed that LIN28B acts by stabilizing key early B-lymphoid genes, epigenetic regulators, and cell cycle and anti-apoptotic genes. Finally, In the absence ofLIN28B, human FL CD34+ cells fail to transform upon induction of KMT2A::AFF1 translocation. Thus,LIN28Bhas an essential role in normal human fetal B-lymphopoiesis, and is necessary for the initiation ofKMT2A::AFF1iALL in fetal cells in the absence of co-operating mutations. It has a role in making leukemias more aggressive, suggesting it is a potential target inLIN28B-expressing leukemias.
The TMRCA of general genealogies in populations of variable size
Authors: Wences Alejandro H. , Peñaloza Lizbeth , Steinrücken Matthias , Siri-Jégousse Arno
Published: September 2024

We study the time to the most recent common ancestor of a sample of finite size in a wide class of genealogical models for populations with variable size. This is made possible by recently developed results on inhomogeneous phase-type random variables, allowing us to obtain the density and the moments of the TMRCA of time-dependent coalescent processes in terms of matrix formulas. We also provide matrix simplifications permitting a more straightforward calculation. With these results, the TMRCA provides an explicative variable to distinguish different evolutionary scenarios.
Liberality is More Explainable than PCA of Transcriptome for Vertebrate Embryo Development
Authors: Ogata Norichika
Published: September 2024

Dimensional reduction approaches of genome scale data are widely used. Liberality is one of the approaches which is a quantitative index of cellular differentiation and dedifferentiation. Here, we analyzed a trend of liberality of time course transcriptome data on vertebrate embryo development. Historically annotated embryo developmental stages matched changes in the trend of liberality. Analyzing liberality of various biological phenomena would be beneficial.
In Situ UNIversal Orthogonal Network (UNION) Bioink Deposition for Direct Delivery of Corneal Stromal Stem Cells to Corneal Wounds
Authors: Brunel Lucia G. , Cai Betty , Hull Sarah M. , Han Uiyoung , Wungcharoen Thitima , Fernandes-Cunha Gabriella Maria , Seo Youngyoon Amy , Johansson Patrik K. , Heilshorn Sarah C. , Myung David
Published: September 2024

The scarcity of human donor corneal graft tissue worldwide available for corneal transplantation necessitates the development of alternative therapeutic strategies for treating patients with corneal blindness. Corneal stromal stem cells (CSSCs) have the potential to address this global shortage by allowing a single donor cornea to treat multiple patients. To directly deliver CSSCs to corneal defects within an engineered biomatrix, we developed a UNIversal Orthogonal Network (UNION) collagen bioink that crosslinksin situwith a bioorthogonal, covalent chemistry. This cell-gel therapy is optically transparent, stable against contraction forces exerted by CSSCs, and permissive to the efficient growth of corneal epithelial cells. Furthermore, CSSCs remain viable within the UNION collagen gel precursor solution under standard storage and transportation conditions. This approach promoted corneal transparency and re-epithelialization in a rabbit anterior lamellar keratoplasty model, indicating that the UNION collagen bioink serves effectively as anin situ-forming, suture-free therapy for delivering CSSCs to corneal wounds.

TEASER.Corneal stem cells are delivered within chemically crosslinked collagen as a transparent, regenerative biomaterial therapy.
Mechanistic insights into Rho/MRTF inhibition-induced apoptotic events and prevention of drug resistance in melanoma: Implications for the involvement of pirin
Authors: Foda Bardees M. , Baker Annika E. , Joachimiak Łukasz , Mazur Marzena , Neubig Richard R.
Published: September 2024

Aim

Overcoming therapy resistance is critical for effective melanoma control. Upregulation of Rho/MRTF signaling in human and mouse melanomas causes resistance to targeted therapies. Inhibition of this pathway by MRTFi, CCG-257081 resensitized resistant melanomas to BRAF and MEK inhibitors. It also prevented the development of resistance to vemurafenib (Vem). Here, we investigate the role of apoptosis and the protein pirin in CCG-257081-mediated suppression of drug resistance.

Methods

Using naïve and resistant mouse YUMMER melanoma cells, we studied the effect of the BRAF inhibitor Vem with or without CCG-257081 on real-time growth and apoptosis (activation of caspase, Propidium iodide (PI) staining, and PARP cleavage). The effects of CCG-257081 on proliferation (Ki67) and caspase-3 activation were assessed in resistant YUMMER_R tumorsin vivo. Finally, two CCG-257081 enantiomers were tested for pirin binding, inhibition of the Rho/MRTF-mediated activation of ACTA2 gene expression in fibroblasts, and the prevention of Vem resistance development by YUMMER_P cells.

Results

Vem reduced growth of parental but not resistant cells, while CCG-257081 inhibited both. The combination was more effective than Vem alone. CCG-257081, but not Vem, induced activation of caspase-3 and -7 in resistant cells and increased PARP cleavage and PI staining. CCG-257081 reduced proliferation and activated caspase-3 in YUMMER_R melanoma tumors. Both CCG-257081 enantiomers robustly suppressed development of Vem-resistant colonies with the S isomer being more potent (1 μM IC50).

Conclusion

CCG-257081 appears to target pre-resistant cells and Vem-induced resistant cells through enhanced apoptosis. Inhibition of pirin or the Rho/MRTF pathway can be employed to prevent melanoma resistance.
Innate immune epigenomic landscape following controlled human influenza virus infection
Authors: Thistlethwaite William , Vangeti Sindhu , Cheng Wan-Sze , Agarwal Pankaj , Cappuccio Antonio , Wang Wenliang , Wei Bei , Myers Rachel , Rubenstein Aliza B. , Chawla Daniel , Hariharan Manoj , McClain Micah T. , Burke Thomas W. , Kleinstein Steven H. , Ecker Joseph R. , Woods Christopher W. , Greenleaf William J. , Chen Xi , Ramos Irene , Zaslavsky Elena , Evans Thomas G. , Troyanskaya Olga G. , Sealfon Stuart C.
Published: September 2024

Viral infections can induce changes in innate immunity that persist after virus clearance. Here, we used blood samples from a human influenza H3N2 challenge study to perform comprehensive multi-omic analyses. We detected remodeling of immune programs in innate immune cells after resolution of the infection that was proportional in magnitude to the level of prior viral load. We found changes associated with suppressed inflammation including decreased cytokine and AP-1 gene expression as well as decreased accessibility at AP-1 targets and interleukin-related gene promoter regions. We also found decreased histone deacetylase gene expression, increased MAP kinase gene expression, and increased accessibility at interferon-related gene promoter regions. Genes involved in inflammation and epigenetic-remodeling showed modulation of gene-chromatin site regulatory circuit activity. These results reveal a coordinated rewiring of the epigenetic landscape in innate immune cells induced by mild influenza virus infection.
An Open Quantum System Approach to Bicoid Gradient Dynamics
Authors: Lone Irfan
Published: September 2024

A prototypical morphogen gradient that plays a key role in the early embryonic development of fruit flies, by providing positional information to cells, is that of the transcription factor Bicoid (Bcd). Recently a one-dimensional quantum walk model has been utilised to explain its multiple dynamic modes observed through fluorescence correlation spectroscopy (FCS) studies using a closed quantum system approach. In this work we use an open quantum system approach to the dynamics of the Bcd gradient formation and show that exactly the same dynamics are obtained through this more rigorous analysis. We then use the thus obtained expression for the fast dynamic modes to explain the Bcd transcription factor search times for binding to the promoter regions along the DNA. Specifically, we find that the large values of diffusivity allowed by quantum mechanics can avoid the paradox of faster-than-diffusion association rates without any need for the transcription factor to constantly alternate between 1D and 3D diffusion-based search processes. This might help explain the fast and precise transcriptional response elicited by such factors. We conclude that, since many transcription factors share a common search strategy for target gene regulatory regions, our mechanism may have a wide range of applicability.
CAR Treg synergy with anti-CD154 mediates infectious tolerance to dictate heart transplant outcomes
Authors: Durgam Samarth S , Rosado-Sánchez Isaac , Yin Dengping , Speck Madeleine , Mojibian Majid , Sayin Ismail , Hynes Grace E , Alegre Maria Luisa , Levings Megan K , Chong Anita S
Published: September 2024

Successful allograft specific tolerance induction would eliminate the need for daily immunosuppression and improve post-transplant quality of life. Adoptive cell therapy with regulatory T cells expressing donor-specific Chimeric Antigen Receptors (CAR-Tregs) is a promising strategy, but as monotherapy, cannot prolong the survival with allografts with multiple MHC mismatches. Using an HLA-A2-transgenic haplo-mismatched heart transplantation model in immunocompetent C57Bl/6 recipients, we show that HLA-A2-specific (A2) CAR Tregs was able to synergize with low dose of anti-CD154 to enhance graft survival. Using haplo-mismatched grafts expressing the 2W-OVA transgene and tetramer-based tracking of 2W- and OVA-specific T cells, we showed that in mice with accepted grafts, A2.CAR Tregs inhibited endogenous non-A2 donor- specific T cell, B cell and antibody responses, and promoted a significant increase in endogenous FoxP3+Tregs with indirect donor-specificity. By contrast, in mice where A2.CAR Tregs failed to prolong graft survival, FoxP3negA2.CAR T cells preferentially accumulated in rejecting allografts and endogenous donor-specific responses were not controlled. This study therefore provides the first evidence for synergy between A2.CAR Tregs and CD154 blockade to promote infectious tolerance in immunocompetent recipients of haplo-mismatched heart grafts and defines features of A2.CAR Tregs when they fail to reshape host immunity towards allograft tolerance.
Probing visual literacy skills reveals unexpected student conceptions of chromosomes
Authors: Uminski Crystal , Newman Dina L. , Wright L. Kate
Published: September 2024

Molecular biology can be challenging for undergraduate students because it requires visual literacy skills to interpret abstract representations of submicroscopic concepts, structures and processes. The Conceptual-Reasoning-Mode framework suggests that visual literacy relies on applying conceptual knowledge to appropriately reason with the different ways of representing concepts in molecular biology. We used this framework to specifically explore visual literacy related to chromosomes. We conducted 35 semi-structured interviews with students who had taken at least a year of college-level biology courses, and we asked them to sketch chromosomes, interpret an abstract representation of chromosomes, and use the abstract representation to answer a multiple-choice question about meiosis. While many participants used the correct vocabulary to describe chromosome structure and function, probing their visual literacy skills revealed gaps in their understanding. Notably, 97% of participants (34 of 35) held conceptual errors related to chromosome structure and function, which were often only revealed in their sketches or explanations of their sketches. Our findings highlight the importance of scaffolding visual literacy skills into instruction by teaching with a variety of visual models and engaging students in using and interpreting the conventions of abstract representations of chromosomes.
Machine Learning Driven Simulations of SARS-CoV-2 Fitness Landscape
Authors: Durumeric Aleksander E. P. , Koehler Jonas , Elez Katarina , Raich Luis , Suriana Patricia A , Sztain Terra
Published: September 2024

SARS-CoV-2 infection is mediated by interactions between the receptor binding domain (RBD) of viral spike proteins and host cell angiotensin converting enzyme 2 (ACE2) receptors. Mutations in the spike protein are the primary cause for neutralizing antibody escape leading to breakthrough infections. We characterize the fitness landscape underpinning future variants of concern by combining supervised machine learning and Markov Chain Monte Carlo. Leveraging deep mutational scanning (DMS) data characterizing the binding affinity between RBD mutants to the ACE2 receptor, we predict variants of concern not seen in the training data and sample statistics of the fitness landscape. These simulations provide insight into the relationship between RBD sequence elements and offer a new perspective on utilizing DMS to predict emerging viral strains.
Seasonality and inter-annual stability in the population genetic structure of Batrachospermum gelatinosum (Rhodophyta)
Authors: Shainker-Connelly Sarah , Stoeckel Solenn , Vis Morgan L. , Crowell Roseanna M. , Krueger-Hadfield Stacy
Published: September 2024

Temporal population genetic studies have investigated evolutionary processes, but few have characterized the temporal patterns of reproductive system variation. Yet, temporal sampling may improve our understanding of reproductive system evolution through assessing the relative rates of selfing, outcrossing, and clonality. In this study, we focus on the monoicous, haploid-diploid freshwater red algaBatrachospermum gelatinosum.This species has a perennial, microscopic diploid phase (chantransia) that produces an ephemeral, macroscopic haploid phase (gametophyte). Recent work focusing on single time point genotyping suggested high rates of intragametophytic selfing, though there was variation among sites. We expand on this work by genotyping 191 gametophytes from four sites with reproductive system variation at multiple time points within and among years. Intra-annual data suggest shifts in gametophytic genotypes present throughout the gametophytic season. We hypothesize this pattern is likely due to the seasonality of the life cycle and the timing of meiosis among the chantransia. Inter-annual patterns were characterized by consistent genotypic and genetic composition, indicating stability in the prevailing reproductive system through time. Yet, our study identified limits to which available theoretical predictions and analytical tools can resolve reproductive system variation using haploid data. There is a need to develop better tools to understand the evolution of sex by expanding our ability to characterize the spatiotemporal variation in reproductive systems across diverse life cycles.
snCED-seq: High-fidelity cryogenic enzymatic dissociation of nuclei for single-nucleus RNA-seq of FFPE tissues
Authors: Guo Yunxia , Ma Junjie , Qi Ruicheng , Ma Xiaoying , Xu Jitao , Ye Kaiqiang , Huang Yan , Yang Xi , Wang Guang-zhong , Zhao Xiangwei
Published: September 2024

Profiling cellular heterogeneity in formalin-fixed paraffin-embedded (FFPE) tissues is key to characterizing clinical specimens for biomarkers, therapeutic targets, and drug responses. Recent advancements in single-nucleus RNA sequencing (snRNA-seq) techniques tailored for FFPE tissues have demonstrated their feasibility. However, isolation of high-quality nuclei from FFPE tissue with current methods remains challenging due to RNA cross-linking. We, therefore, proposed a novel strategy for the preparation of high-fidelity nuclei from FFPE samples, cryogenic enzymatic dissociation (CED) method, and performed snRandom-seq (snCED-seq) for polyformaldehyde (PFA)-fixed and FFPE brains to verify its applicability. The method is compatible with both PFA-based and FFPE brains or other organs with less hands-on time and lower reagent costs, and produced 10 times more nuclei than the homogenate method, without secondary degradation of RNA, and maximized the retention of RNA molecules within nuclei. snCED-seq shows 1.5-2 times gene and UMI numbers per nucleus, higher gene detection sensitivity and RNA coverage, and a minor rate of mitochondrial and ribosomal genes, compared with the nuclei from traditional method. The correlation gene expression of nucleus from the post-fixed and the frozen sample can be up to 94 %, and the gene expression of our nuclei was more abundant. Moreover, we applied snCED-seq to cellular heterogeneity study of the specimen on Alzheimer’s Disease (AD) to demonstrate a pilot application. Scarce Cajal Retzius cells in older mice were robustly detected in our data, and we successfully identified two subpopulations of disease-associated in astrocytes, microglia and oligodendrocytes, respectively. Meanwhile, we found that most cell types are affected at the transcriptional level by AD pathology, and there is a disease susceptibility gene set that affects these cell types similarly. Our method provides powerful nuclei for snRNA-seq studies for FFPE specimens, and even helps to reveal multi-omics information of clinical samples.
The efficacy and safety of Acupoint herbal patching in treating peptic ulcer: protocol for a systematic review and meta-analysis
Authors: Wang He , Jiang Yuxin , Sun Qiaoyue , Zhao Jinying , zhang Qi , Wang Fuchun
Published: September 2024

Introduction

Peptic ulcer (PU) is prone to recurrence and can have a prolonged course, significantly impacting patients’ quality of life. Clinical treatment commonly involves combating Helicobacter pylori(HP), reducing gastric acid secretion, and promoting gastric mucosal protection. Nevertheless, Western medicine often entails various adverse effects and long-term use. Consequently, numerous scholars have redirected their focus towards traditional Chinese medicine (TCM) for external treatments of PU due to its minimal toxicity, fewer side effects, and lower recurrence rates. This study aims to assess the efficacy and safety of Acupoint herbal patching (AHP) in treating PU, offering a foundation for future clinical investigations.

Methods and analysis

The computer will conduct a comprehensive search for relevant studies on the utilization of AHP in the management of PU from the inception of the database in various scholarly platforms including China Journal Network, Wanfang Database, Chongqing Wipo Database, China Biomedical Literature Database, PubMed, and Cochrane Library. Eligible literature will undergo meticulous scrutiny based on predefined criteria, with data extraction and quality assessment executed independently by two researchers. Meta-analysis utilizing RevMan 5.4.1 software will be employed to synthesize the collected data. The study will focus on the TCM Symptom Score Scale as the primary outcome measure, while secondary outcomes will encompass serum inflammatory factors, endoscopic findings, quality of life, recurrence rate, and adverse events. Furthermore, assessments on effectiveness, cure rate, and potential publication bias will be carried out. This investigation aims to assess the efficacy of AHP in the treatment of PU and its impact on enhancing the well-being of patients.

Ethics and dissemination

Since the present work constitutes a literature review, it is important to note that ethical approval is deemed unnecessary. The outcomes of this investigation are intended for dissemination in a scholarly periodical subject to peer review.

PROSPERO registration number

CRD42023456995

STRENGTHS AND LIMITATIONS OF THIS STUDY

A thorough examination of the literature will be undertaken across six electronic databases in both Chinese and English languages.

The methodology will adhere to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Evaluation of the studies’ quality will be conducted utilizing the updated Cochrane Risk of Bias 2.0 tool.

Variations in patch locations and treatment protocols may introduce significant heterogeneity, posing challenges to the synthesis of data.
Ocean carbon export can be predicted from ocean color-based phytoplankton communities
Authors: Kramer Sasha J. , Jones Erin L. , Estapa Margaret L. , Paul Nicola L. , Rynearson Tatiana A. , Santoro Alyson E. , Sudek Sebastian , Durkin Colleen A.
Published: September 2024

Carbon flux to the deep sea can be dictated by surface ocean phytoplankton community composition, but translating surface ocean observations into quantitative predictions of carbon export requires additional consideration of the underlying ecosystem drivers. Here, we used genetic tracers of phytoplankton detected in surface seawater and within sinking particles collected in the mesopelagic ocean to identify mechanistic links between surface communities and carbon export in the North Pacific and North Atlantic Oceans. Phytoplankton 18S rRNA sequences were sampled over a one-month period in surface seawater and within bulk-collected and individually-isolated sinking particles using mesopelagic sediment traps (100-500m). Nearly all phytoplankton amplicon sequence variants (ASVs) exported from the surface were packaged in large (>300 µm) particles. Individually, these particles contained only a few distinct phytoplankton ASVs, but collectively, large particles transported about half of the surface taxonomic diversity into the mesopelagic. The relative sequence abundances of the surface community detected within particles were quantitatively related to measured POC fluxes: a linear model based on the relative sequence abundance of just two pigment-based phytoplankton taxa, diatoms and photosynthetic Hacrobia, was predictive of POC flux magnitude. These two taxa were also enriched within the ecologically-distinct particle classes that had the greatest influence on carbon export magnitude. As global, hyperspectral ocean color satellites begin to quantify these taxonomic groups in the surface ocean, the relationship of these taxa to carbon fluxes demonstrated here may help generate more accurate global estimates of export.
Dietary specialization drives adaptation, convergence, and integration across the cranial and appendicular skeleton in Waterfowl (Anseriformes)
Authors: Chatterji Ray , Heath Tracy A. , James Helen F. , Hofman Courtney , Sorenson Michael D. , Buckner Janet C.
Published: September 2024

Convergence provides strong evidence for adaptive evolution as it reflects shared adaptive responses to the same selection pressures. The waterfowl (order Anseriformes) are an ideal group in which to study convergent evolution as they have repeatedly evolved morphotypes putatively correlated with diet (i.e., dabbler, grazer, diver). Here, we construct the most robust evolutionary hypothesis to date for waterfowl and reveal widespread morphological convergence across the order. We quantified the shape of the skull and hindlimb elements (femur, tibiotarsus, and tarsometatarsus) of 118 species of extant waterfowl using geometric morphometrics. Multivariate generalized evolutionary models provide strong support for a relationship between dietary ecology and skull shape, and evidence for convergent evolution across lineages that share dietary niches. Foraging behavior better explained the evolution of hindlimb shape, but diet still contributed significantly. We also find preliminary evidence for integration across all three measured hindlimb elements with each other and with the skull. We demonstrate that dietary ecology drives morphological convergence within waterfowl, that this convergent evolution involves multiple integrated skeletal structures, and that morphological changes are associated with shifts in the rate of phenotypic evolution.
AlphaMut: a deep reinforcement learning model to suggest helix-disrupting mutations
Authors: Bhargav Prathith , Mukherjee Arnab
Published: September 2024

1

Helices are important secondary structural motifs within proteins and are pivotal in numerous physiological processes. While amino acids (AA) such as alanine and leucine are known to promote helix formation, proline and glycine disfavor it. Helical structure formation, however, also depends on its environment, and hence, prior prediction of a mutational effect on a helical structure is difficult. Here, we employ a reinforcement learning algorithm to develop a predictive model for helix-disrupting mutations. We start with a toy model consisting of helices with only 30 AA and train different models. Our results show that only a few mutations lead to a drastic disruption of the target helix. We further extend our approach to helices in proteins and validate the results using rigorous free energy calculations. Our strategy identifies amino acids crucial for maintaining structural integrity and predicts key mutations that could alter protein function. Through our work, we present a new use case for reinforcement learning in protein structure disruption.
Mechanical regulation of cuboidal-to-squamous epithelial transition in theDrosophiladeveloping wing
Authors: Harmansa Stefan , Lecuit Thomas
Published: September 2024

Growing tissues are constantly exposed to mechanical stresses that lead to deformations at the cell and tissue scale. In epithelial organs, cells form monolayers whose thickness can change dramatically during development. Here, we address how cell shape changes in the peripodial epithelium of theDrosophilawing disc emerge from the interplay of basement membrane properties with tissue-extrinsic mechanical stress. We show that tissue-extrinsic stress arising from disc proper bending elastically deforms central peripodial cells and induces a cuboidal-to-squamous epithelial transition. In contrast, a rigid basement membrane shields peripheral hinge cells from this bending stress and causes a cuboidal-to-columnar transition. These inverse shape transitions are further amplified by selective shearing of central cells due to coupling via the apical extracellular matrix protein Dumpy. These findings point to a pivotal role of the basement membrane and inter-tissue coupling in the emergence of stress patterns and cell deformations during organ growth.
What does AlphaFold3 learn about antigen and nanobody docking, and what remains unsolved?
Authors: Hitawala Fatima N. , Gray Jeffrey J.
Published: September 2024

Antibody therapeutic development is a major focus in healthcare. To accelerate drug development, significant efforts have been directed towards thein silicodesign and screening of antibodies for which high modeling accuracy is necessary. To probe AlphaFold3’s (AF3) capabilities and limitations, we tested AF3’s ability to capture the fine details and interplay between antibody structure prediction and antigen docking accuracy. With one seed, AF3 achieves an 11.0% and 11.4% high-accuracy docking success rate for antibodies and nanobodies, respectively, and a median unbound CDR H3 RMSD accuracy of 2.73 Å and 2.30 Å. CDR H3 accuracy boosts complex prediction accuracy, with antigen context improving CDR H3 accuracy, particularly for loops longer than 15 residues. Combining I-pLDDT with ΔGBimproves discriminative power for correctly docked complexes. However, AF3’s 60% failure rate for antibody and nanobody docking (with single seed sampling) demonstrates necessary refinement to improve antibody design endeavors.
Explore the mechanism of Zigui Yichong Formula in reducing the apoptosis of ovarian granulosa cells in premature ovarian insufficiency based on network pharmacology, molecular docking and cell experiments
Authors: Zhang Xin-Miao , Xi Hong-Yan , Gao Tian-Yu , Liu Shu-Peng , Li Rong-Xia
Published: September 2024

Objective

This research is conducted with the objective of exploring the underlying mechanism by which the Zigui Yichong Formula (ZGYCF) diminishes granulosa cell apoptosis in the context of premature ovarian insufficiency (POI), utilizing network pharmacology, molecular docking, and cellular experimentation approaches.

Methods

The active constituents and potential therapeutic targets of the 12 medicinal herbs in ZGYCF, which include Rehmannia glutinosa, Cervus nippon, Cornus officinalis, Ligustrum lucidum, Lycium barbarum, Paeonia lactiflora, Astragalus membranaceus, Codonopsis pilosula, Atractylodes macrocephala, Angelica sinensis, Cyperus rotundus, and Glycyrrhiza uralensis, were identified through searches in the TCMSP, BATMAN, HERB, and ETCM databases. Targets associated with the POI condition were gathered from the OpenTargets, DrugBank, and GeneCards databases. Subsequently, a Venn diagram illustrating the compound-target-disease interaction was generated to derive a set of common targets that bridge the gap between pharmacological and pathological targets. A drug-component-target-disease network diagram was created using Cytoscape 3.9.1. Additionally, protein-protein interaction (PPI) networks were built utilizing the STRING database and visualized with Cytoscape to pinpoint key targets within the overlapping target set. Functional annotation and pathway enrichment analyses, including GO and KEGG pathway analyses, were performed using the clusterProfiler package in R 4.2.1 to investigate the underlying mechanisms by which the drug may influence the disease state. The molecular docking of pivotal active constituents with central targets was carried out using AutoDock Tools. Following this, in vitro studies were executed to corroborate the anticipated mechanisms of action of ZGYCF on POI that were inferred from the network pharmacology analysis.

Results

The selected active components include quercetin, kaempferol, andβ-sitosterol. The core targets identified are Tp53, Bcl-2, and Caspase-3. GO functional and KEGG enrichment analyses indicate that these core targets are primarily enriched in the p53 signaling pathway. Molecular docking results show that quercetin, kaempferol, andβ-sitosterol have good binding affinity with TP53, Bcl-2, and Caspase-3. Additionally, in vitro experiments demonstrate that ZGYCF medicated serum can reduce ACR-induced apoptosis in KGN cells, increase Bcl-2 expression, and decrease the expression of p53, Bax, Caspase-3, and the Bcl-2/Bax ratio.

Conclusion

ZGYCF exerts therapeutic effects on POI through multiple targets and pathways, and it may reduce ACR-induced apoptosis in KGN cells by modulating the p53 signaling pathway.

Graphical abstract
From spots to cells: Cell segmentation in spatial transcriptomics with BOMS
Authors: Kamboj Ocima , Park Jeongbin , Stegle Oliver , Hamprecht Fred A.
Published: September 2024

Imaging-based Spatial Transcriptomics methods enable the study of gene expression and regulation in complex tissues at subcellular resolution. However, inaccurate cell segmentation procedures lead to misassignment of mRNAs to individual cells which can introduce errors in downstream analysis. Current methods estimate cell boundaries using auxiliary DAPI/Poly(A) stains. These stains can be difficult to segment, thus requiring manual tuning of the method, and not all mRNA molecules may be assigned to the correct cells. We describe a new method, based on mean shift, that segments the cells based on the spatial locations and the gene labels of the mRNA spots without requiring any auxiliary images. We evaluate the performance of BOMS across various publicly available datasets and demonstrate that it achieves comparable results to the best existing method while being simple to implement and significantly faster in execution. Open-source code is available athttps://github.com/sciai-lab/boms.
The conversion of forests to agricultural land reduced the content of soil black carbon fractions in a karst rocky desertification area of Southwest China
Authors: Zhang Denan , Teng Qiumei , Huang Kechao , Shen Yuyi , Sun Yingjie , Lyu Shihong , Xu Guangping , Zhang Yanzhao
Published: September 2024

Understanding the effects of land use on soil black carbon (BC) is critical for correctly interpreting the role of BC in the carbon cycle of karst areas. This study investigated the distribution characteristics of organic carbon (OC), BC, char, and soot and soil physicochemical properties of the soil profiles (0–40 cm) of secondary forest, shrub, farmland, and wasteland in a rocky desertification area of Guangxi Province, a typical karst rocky desertification area in Southwest China. We used a combination of soot/char and δ13CBCisotope analysis to identify the source of BC of these soils. The average value of soil BC was the highest in secondary forest, followed by shrub, farmland, and wasteland in the 0–40 cm soil layer. BC had a positive correlation with OC, char, soot,soil nitrogen, phosphorus and potassium, showed a negative correlation with bulk density. In the black carbon component, char occupies a greater proportion than soot, with the heavy fraction OC exhibiting a higher concentration of BC than the light fraction OC. Conclusively, the BC content was mainly due to C3 plant burning, vehicle exhaust emissions, and fossil fuel utilization.Vegetation restoration improved the soil BC content associated with OC sequestration in the typical karst rocky desertification mountainous area of Southwest Guangxi.
Accurate Multiple Sequence Alignment of Ultramassive Genome Sets
Authors: Lai Xiao , Luan Haixin , Tian Pu
Published: September 2024

With ever increasing sequencing efficiency, there is a pressing need to tackle a presently intractable task of accurate multiple sequence alignment (MSA) for ultramassive genome sets of millions and beyond. Additionally, efficient graph and probabilistic representations for downstream analysis are in dire lack. In light of these challenges, we develop a set of linearly scalable algorithms, including that for constructing directed acyclic graphs, for training profile hidden Markov models and for conducting alignment on such graphs. The astounding power of these algorithms is demonstrated by both significantly improved accuracy and tremendous acceleration of SAR-CoV-2 MSA bythree observed to five projected orders of magnitudefor genome set sizes ranging from 40,000 to more than 4 million when compared with widely utilized MAFFT. Future application to other viral species and extension to more complex genomes will prove this algorithm set as a cornerstone for the coming era of ultramassive genome sets.
Perceived stress exacerbates psoriasis in human skinin vivo: Insights from a humanized psoriasis mouse model
Authors: Zeltzer Assaf A , Keren Aviad , Shinnawi Samieh , Bertolini Marta , Paus Ralf , Gilhar Amos
Published: September 2024

Introduction

The widely held belief that psychoemotional stress triggers or exacerbates psoriatic skin lesions lacks sufficient scientific evidence. This study investigated this concept using a psoriasis humanized mouse model.

Methods

Healthy human skin was grafted onto SCID/beige mice (n=25), and one month later, psoriatic lesions were induced by intradermal injection of autologous, in vitro IL-2- preactivated PBMCs. Following lesion development, topical dexamethasone (DEX) was applied to induce lesion remission. After lesions disappeared, the mice were exposed to either sonic or sham stress for 24 hours.

Results

Sonic stress led to the relapse of psoriatic lesions in all human skin xenografts within 14 days. This relapse was associated with significant changes in psoriasis-related skin characteristics: increased epidermal thickness, K16 expression, keratinocyte proliferation, antimicrobial peptide expression (S100A7, hβ2-defensin), and immune activation markers (HLA-DR, ICAM-1, CD1d, MICA-NKG2D). Additionally, epidermal and dermal immune cells (CD3+, CD8+, CD11c+, CD56+, ILC3, c-KIT+ or tryptase+ cells) and psoriasis-associated pro-inflammatory mediators (CXCL10, IL-22, IL-15, IL-17A/F, IFN-γ, and TNFα) were found to be increased. Neurogenic inflammation biomarkers (NGF, NK1-R, and substance P) were also significantly upregulated in stressed mice. Treatment with the FDA-approved neurokinin-1 receptor antagonist, aprepitant, prevented stress-induced psoriatic relapses in 4 out of 5 mice and normalized most inflammatory and neurobiological markers.

Conclusions

These findings provide novel, conclusive evidence that perceived stress can trigger psoriatic lesions in human skin xenografts in vivo and highlight the role of substance P-dependent neurogenic inflammation in this process.
Tumor-induced endothelial RhoA activation mediates tumor cell transendothelial migration and metastasis
Authors: Sajib Md Sanaullah , Zahra Fatema Tuz , Lamprou Margarita , Akwii Racheal Grace , Park Jee Hyun , Osorio Manuel , Tullar Paul , Doci Colleen L. , Zhang Chonghe , Huveneers Stephan , Van Buul Jaap D. , Wang Ming-Hai , Markiewski Maciej M. , Srivastava Sanjay K. , Zheng Yi , Gutkind J. Silvio , Hu Junhao , Bickel Ulrich , Maeda Dean Y. , Zebala John A. , Lionakis Michail S. , Trasti Scott , Mikelis Constantinos M.
Published: September 2024

Abstract/Summary

The endothelial barrier plays an active role in transendothelial tumor cell migration during metastasis, however, the endothelial regulatory elements of this step remain obscure. Here we show that endothelial RhoA activation is a determining factor during this process. Breast tumor cell-induced endothelial RhoA activation is the combined outcome of paracrine IL-8-dependent and cell-to-cell contact β1integrin-mediated mechanisms, with elements of this pathway correlating with clinical data. Endothelial-specific RhoA blockade orin vivodeficiency inhibited the transendothelial migration and metastatic potential of human breast tumor and three murine syngeneic tumor cell lines, similar to the pharmacological blockade of the downstream RhoA pathway. These findings highlight endothelial RhoA as a potent, universal target in the tumor microenvironment for anti-metastatic treatment of solid tumors.
Engineering CD3 Subunits with Endoplasmic Reticulum Retention Signal Facilitates Allogeneic CAR T Cell Production
Authors: Ebrahimiyan Hamidreza , Sayadmanesh Ali , Hesaraki Mahdi , Ebrahimi Marzieh , Baharand Hossein , Basiri Mohsen
Published: September 2024

The success of autologous CAR T cell therapies has driven interest in developing off-the-shelf allogeneic CAR T cells as a scalable and readily available option for broader patient access. Most of the current approaches involve the knockout of T cell receptor (TCR) subunits via genome editing for preventing graft-versus-host disease (GvHD). However, clinical translation of these methods faces challenges due to manufacturing complexities and emerging safety concerns like unintended long deletions and chromosomal loss. In this study, we explored an alternative approach by engineering synthetic CD3 subunits containing an endoplasmic reticulum retention (ERR) signal to suppress TCR surface expression by disrupting its trafficking to the plasma membrane. We screened multiple CD3-ERR candidate designs to identify the construct with the highest efficacy in TCR downregulation. The selected candidate, CD3ζ-ERR, was further characterized, demonstrating its ability to minimize TCR-mediated activation and alloreactivity without affecting T cell phenotype, cell cycle and cytokine-induced expansion. Subsequent assays revealed that CD3ζ-ERR CD19 CAR T cells retained their CAR-mediated cytotoxic function against CD19+malignant cells. This study presents an alternative approach for TCR downregulation that circumvents genome editing. By using a transgene compatible with conventional viral vector delivery, this approach holds promise for scalable clinical-grade manufacturing of allogeneic CAR T cell therapies.

Translational Impact Statement

Our study introduces a scalable method to engineer allogeneic CAR T cells by reducing TCR expression without genome editing, thereby minimizing the risk of immune rejection (GvHD) while maintaining antitumor efficacy. This approach offers a practical and clinically translatable solution for producing “off-the-shelf” CAR T cell therapies, potentially broadening access to these life-saving treatments and streamlining their integration into existing clinical manufacturing processes.
Peasants at the queen’s table?: The microbiome’s dynamics throughout swarming preparation in honey bees (Apis mellifera)
Authors: Kolasa Michał. R. , Molasy Bartłomiej , Strachecka Aneta , Michalik Anna
Published: September 2024

The intricate relationship between hosts and bacterial symbionts was crucial for the evolution of multiple insect clades. Western honey bees(Apis mellifera)have distinctive and highly stable microbiomes in terms of bacterial taxonomic composition. However, despite the significant development of molecular techniques observed in recent decades, we still are far from understanding much about the dynamics of honey bees’ microbiomes in terms of their strain diversity and quantities. The overall stable composition of their microbiome and complex behavior make honey bees a perfect model species for studying the gut-brain axis, where the gut microbiome can efficiently influence the host’s behavior. Here, by implementing high-throughput amplicon sequencing of bacterial 16S rRNA V4 and V1V2 hypervariable regions alongside a cutting-edge quantification approach, we aimed to describe the dynamic in honey bee young workers’ microbiome composition and quantity throughout swarming preparation.

Our results show no changes in microbial absolute abundances throughout the swarming preparation among young worker bees. The V4 and V1V2 datasets congruently reconstructed microbial composition with some notable exceptions, and differential abundance analysis indicated thatBombellaandBartonellasignificantly changed over batches.
Identification of potential inhibitors against Inosine 5'-Monophosphate Dehydrogenase of Cryptosporidium parvum through an integrated in silico approach
Authors: Al-Mamun Abdullah , Hossain Shah Imran , Moin Abu Tayab , Rakib Md Shafiqul Islam , Hasan Md Mahedi , Yousuf Eshma Binte , Powshi Shams Nur , Islam Enayetul , Tumpa Nasrin Jahan Salma , Hosna Asmaul , Chowdhury Dil Umme Salma , Hossain Mohabbat , Alam Sabrina Shameen , Islam Nazneen
Published: September 2024

The protozoan parasite Cryptosporidium, found in many vertebrate species, including humans, is the source of the global infection known as cryptosporidiosis, which manifests as acute gastroenteritis, abdominal pain, and diarrhea. Although infections in certain individuals have been linked to other species, Cryptosporidium parvum is the main cause of illnesses in humans. Lactate Dehydrogenase, Inosine 5'-Monophosphate Dehydrogenase (IMPDH), and several other targets have been identified by the genome sequencing of C. parvum. Bioactive phytochemicals derived from nature have enormous potential as anti-cryptosporidiosis agents. The study aimed to identify new anti-cryptosporidial agents that work against the IMPDH of the parasite by using integrated in silico approaches. In this study, a total of 24 bioactive phytochemicals were screened virtually through molecular docking and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses. Four lead compounds were identified, including Brevelin A (-8.9 kcal/mol), Vernodalin (-8.7 kcal/mol), Luteolin (-8.6 kcal/mol), and Pectolinarigenin (-8.1 kcal/mol), against the IMPDH protein (PDB ID: 4IXH) from the parasite. All the lead compounds were found to possess favorable pharmacokinetic and pharmacodynamic properties. The toxicity analysis showed satisfactory results with no major side effects. All of the selected compounds showed no violation of Lipinski's rules of five, indicating the possibility of oral bioavailability as potential drug candidates. Target class prediction unveiled enzymes in most of the cases, and some experimental and investigational drugs were found to be structurally similar to the lead compounds. With significant biochemical interactions, all of the targeted phytochemical compounds have demonstrated excellent pharmacokinetics and good bioavailabilities. The findings strongly recommend in vitro experimental studies to aid in the development of novel therapeutics against Cryptosporidium parvum.