bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arrested Agonist Paradigm For Selective Radiosensitization of Prostate Cancer
Authors: Coulter Jonathan B. , Haffner Michael C. , Zhang Yonggang , Zhou Haoming , Pham Minh-Tam , Chen Jiayu , Chikarmane Roshan , Mishra Alok , Mehl Maire S. , Kazibwe Stella , Choi Kirsten , Archey Ava , Valluri Sarayu , Lupold Shawn E. , Song Daniel , De Marzo Angelo , Nelson William G. , DeWeese Theodore L. , Yegnasubramanian Srinivasan 
Published: October 2023

AbstractAs a prototypical nuclear hormone receptor, the androgen receptor (AR) signals via a sequential cascade triggered by binding to androgenic ligands such as testosterone and dihydrotestosterone (DHT). This cascade includes dimerization of the ligand-receptor complex, nuclear translocation, chromatin binding to response elements, recruitment of TOP2B and co-activator complexes, and induction of an effector transcriptional program. In prostate cancers, this AR signaling cascade is an essential driver of growth and survival, yet its activity confers potential vulnerabilities through transient TOP2B-mediated DNA double strand breaks. We investigated the ability of non-steroidal AR ligands to activate initial steps of the AR signaling cascade up to the point of AR- and TOP2B-mediated double strand breaks, with subsequent arrest of the signaling cascade to prevent induction of pro-growth/survival transcriptional programs in prostate cancer cells. We identified hydroxyflutamide (FLU) as such an androgen receptor arrested agonist; in androgen-deprived conditions, FLU induced AR nuclear translocation, chromatin binding, and TOP2B-mediated double strand breaks, but failed to induce AR target gene expression and prostate cancer cell growth. The FLU-mediated arrest in the signaling cascade could be attributed to the inability of FLU to allow association of AR with SMARCD2, a critical component of the BAF chromatin remodeling complex required for androgen induced AR co-activation. Interestingly, the FLU-induced, AR- and TOP2B-mediated double strand breaks could be used to selectively sensitize AR-positive prostate cancer cells to ionizing radiationin vitroandin vivo. These findings support a novel arrested agonist paradigm for selective radiosensitization of prostate cancer cells without inducing AR-mediated pro-growth and survival transcriptional programs.
Puzzle cell shape emerges from the interaction of growth with mechanical constraints
Authors: Trozzi Nicola , Lane Brendan , Perruchoud Alice , Wang Yixuan , Hörmayer Lukas , Ansel Mylan , Mollier Corentin , Malivert Alice , Clark Frances , Reichgelt Tammo , Roeder Adrienne H.K. , Hamant Olivier , Boudaoud Arezki , Kwiatkowska Dorota , Runions Adam , Smith Richard S. , Majda Mateusz 
Published: October 2023

AbstractThe puzzle-shaped cells found in the shoot epidermis of many plant species are a fascinating example of complex cell shapes. Because biological form often follows function, the unique shape of these cells suggests that they must serve some adaptive purpose for the plant. We previously proposed that these intricate shapes provide an effective strategy for reducing mechanical stress on the cell wall when epidermal cells undergo growth in more than one direction. Here we analyze a large selection of living and paleo plant species and find that the ability to make puzzle cells is a shared feature across all plant species, although their presence can be hidden as it varies depending on the organ, developmental stage, and environmental conditions. Computational modeling ofArabidopsisand maize epidermal cells revealed that presence and patterning of lobes is a dynamic process that is intricately linked to the growth history and environmental context of the plant organ. Conversely, disrupted lobeyness in mutants or with drug treatments affects plant development and leads to compensatory strategies. We propose that the mechanism underlying the formation of puzzle-shaped cells is likely conserved among higher plants and is a response to a developmental constraint driven by growth and mechanical stress.
SaProt: Protein Language Modeling with Structure-aware Vocabulary
Authors: Su Jin , Han Chenchen , Zhou Yuyang , Shan Junjie , Zhou Xibin , Yuan Fajie 
Published: October 2023

AbstractLarge-scale protein language models (PLMs), such as the ESM family, have achieved remarkable performance in various downstream tasks related to protein structure and function by undergoing unsupervised training on residue sequences. They have become essential tools for researchers and practitioners in biology. However, a limitation of vanilla PLMs is their lack ofexplicitconsideration for protein structure information, which suggests the potential for further improvement. Motivated by this, we introduce the concept of a “structure-aware vocabulary” that integrates residue tokens with structure tokens. The structure tokens are derived by encoding the 3D structure of proteins using Foldseek. We then propose SaProt, a large-scale general-purpose PLM trained on an extensive dataset comprising approximately 40 million protein sequences and structures. Through extensive evaluation, our SaProt model surpasses well-established and renowned baselines across 10 significant downstream tasks, demonstrating its exceptional capacity and broad applicability. We have made the code1, pre-trained model, and all relevant materials available athttps://github.com/westlake-repl/SaProt.
ProxyTyper: Generation of Proxy Panels for Privacy-aware Outsourcing of Genotype Imputation
Authors: Zhi Degui , Jiang Xiaoqian , Harmanci Arif 
Published: October 2023

AbstractOne of the major challenges in genomic data sharing is protecting the privacy of participants. Numerous studies demonstrated that genetic data and related summary statistics can be used for identifying individuals. These studies led to a strong chilling effect on researchers that hindered collaborative data sharing. Consequently, population-level genetic databases are often siloed in central repositories with complex and burdensome data usage agreements. While cryptographic methods that are provably secure have been developed, these methods require high-level expertise in security and depend on large computational resources.To fill the methodological gap in this domain, we present ProxyTyper, a set of data protection mechanisms to generate “proxy-panels” from sensitive haplotype-level genetic datasets. ProxyTyper uses haplotype sampling, allele hashing, and anonymization to protect the genetic variant coordinates, genetic maps, and chromosome-wide haplotypes. These mechanisms can provide strong deterrence against honest-but-curious entities and well-known re-identification and linking attacks. The proxy panels can be used as input to existing tools without any modifications to the underlying algorithms. We focus on building proxy-panels for genotype imputation to protect typed and untyped variants. We demonstrate that proxy-based imputation provides protection against well-known attacks with a minor decrease of imputation accuracy for variants in wide range of allele frequencies.
A dicer-related helicase opposes the age-related pathology from SKN-1 activation in ASI neurons
Authors: Turner Chris D. , Stuhr Nicole L. , Ramos Carmen M. , Van Camp Bennett T. , Curran Sean P. 
Published: October 2023

ABSTRACTCoordination of cellular responses to stress are essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here we identify how SKN-1 activation in two ciliated ASI neurons inC. elegansresults in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of non-coding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a novel regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase,drh-1, in the intestine, can oppose the e2ffects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell non-autonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.SIGNIFICANCE STATEMENTUnlike activation, an understudied fundamental question across biological systems is how to deactivate a pathway, process, or enzyme after it has been turned on. The irony that the activation of a transcription factor that is meant to be protective can diminish health was first documented by us at the organismal level over a decade ago, but it has long been appreciated that chronic activation of the human ortholog of SKN-1, NRF2, could lead to chemo- and radiation resistance in cancer cells. A colloquial analogy to this biological idea is a sink faucet that has an on valve without a mechanism to shut the water off, which will cause the sink to overflow. Here, we define this off valve.
Implementing evidence ecosystems in the public health service: Development of a seven-step framework for designing tailored training programs
Authors: Arnold Laura , Bimczok Simon , Clemens Timo , Brand Helmut , Starke Dagmar 
Published: October 2023

AbstractThe COVID-19 pandemic has highlighted the importance of local evidence-ecosystems in which academia and practice in the Public Health Service (PHS) are interconnected. However, appropriate organizational structures and well-trained staff are lacking and evidence use in local public health decision-making has to be integrated into training programs in Germany. To address this issue, we developed a toolbox to conceptualize training programs designed to qualify public health professionals for working at the interface between academia and practice. We conducted a scoping review of training programs, key-informant interviews with public health experts, and a multi-professional stakeholder workshop and triangulated their output. The toolbox consists of four core elements, encompassing 15 parameters: (1) content-related aspects, (2) context-related aspects, (3) aspects relevant for determining the training format, and (4) aspects relevant for consolidation and further development. Guiding questions with examples supports the application of the toolbox. The developed seven-step frame-work aims to facilitate new training programs for knowledge-transfer at the academia-practice interface, equipping public health researchers and practitioners with relevant skills for needs-based PHS research. The joint development of training approaches can foster cross-institutional collaboration and enhance evidence utilization, resulting in long-term resource savings and a stronger evidence base for implementing complex public health measures on site. In this way, co-development of tailored solutions within the local evidence ecosystem has the potential to enhance both scientific and practical impact.
Assessment of brain-derived extracellular vesicle enrichment for blood biomarker analysis in age-related neurodegenerative diseases: An international overview
Authors: Badhwar AmanPreet , Hirschberg Yael , Tamayo Natalia Valle , Iulita M. Florencia , Udeh-Momoh Chinedu T. , Matton Anna , Tarawneh Rawan M. , Rissman Robert A. , Ledreux Aurélie , Winston Charisse N. , Haqqani Arsalan S. ,   Alzheimer’s Association International Society to Advance Alzheimer's Research and Treatment, BBB-EWG
Published: October 2023

ABSTRACTINTRODUCTIONBrain-derived extracellular vesicles (BEVs) in blood allows for minimally- invasive investigations of CNS-specific markers of age-related neurodegenerative diseases (NDDs). Polymer-based EV- and immunoprecipitation (IP)-based BEV-enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS-specificity of proteins associated with these protocols.METHODSNDD articles investigating BEVs in blood using polymer-based and/or IP-based BEV enrichment protocols were systematically identified, and protocols compared. Proteins used for BEV-enrichment and/or post-enrichment were assessed for CNS- and brain-cell-type- specificity; extracellular domains (ECD+); and presence in EV-databases.RESULTS82.1% of studies used polymer-based (ExoQuick) EV-enrichment, and 92.3% used L1CAM for IP-based BEV-enrichment. Centrifugation times differed across studies. 26.8% of 82 proteins systematically identified were CNS-specific: 50% ECD+, 77.3% were listed in EV- databases.DISCUSSIONWe identified protocol steps requiring standardization, and recommend additional CNS-specific proteins that can be used for BEV-enrichment or as BEV-biomarkers.
Next-Generation Breast Organoids Capture Human Organogenesis with High-Resolution Live Imaging
Authors: Rauner Gat , Traugh Nicole C. , Trepicchio Colin J. , Parrish Meadow E. , Mushayandebvu Kenan , Kuperwasser Charlotte 
Published: October 2023

AbstractOrganoids have emerged as a powerful tool for modeling tissue growth and diseases. In this study, we introduce a groundbreaking organotypic culture technique that replicates the morphology, scale, and heterogeneity of human breast tissue, and includes a mesenchymal-like stromal component. A standout feature of this approach is the use of long-term live imaging at high temporal resolution to directly observe stem cell dynamics during organogenesis, from single cells to mature organ tissue. The system is adaptable for high throughput applications and allows for genetic manipulation of the cells. Real-time imaging of ex-vivo tissue formation reveals a non-canonical process of ductal-lobular morphogenesis and branching, and de-novo generation of a supportive stroma. Incorporating patient-derived single cells from multiple donors offers an enhanced representation of the spectrum of individual responses and the impacts of distinct exposures. While developed for breast tissue, the principles of this technology can serve as a model for the development of similar systems in other tissues, where organoids do not merely reproduce the tissue, but where their regeneration can also be observed and studied. In addition, this model provides a quantitative experimental system to study mechanisms of embryogenesis, development, and tissue organization where biomechanics plays an important role.
Identification and structural characterization of small-molecule inhibitors of PINK1
Authors: Rasool Shafqat , Shomali Tara , Truong Luc , Croteau Nathalie , Veyron Simon , Trempe Jean-François 
Published: October 2023

AbstractMutations in PTEN-induced putative kinase 1 (PINK1) cause early-onset autosomal recessive Parkinson’s Disease (PD). PINK1 is a Ser/Thr protein kinase which functions as a mitochondrial damage sensor and initiates mitochondrial quality control by accumulating on the damaged organelle. There, it will autophosphorylate and then phosphorylate ubiquitin chains, which in turn will recruit and activate Parkin, and E3 ubiquitin ligase also implicated in PD. Ubiquitylation of mitochondrial proteins leads to the autophagic degradation of the damaged organelle. Pharmacological modulation of PINK1 constitutes an appealing avenue to study its physiological function and develop PD therapeutics. In this study, we used a thermal shift assay to identify small-molecule inhibitors of PINK1. In vitro kinase activity assays demonstrate that these molecules are ATP competitive inhibitors that block ubiquitin phosphorylation. PRT062607 (a SYK inhibitor) is the most potent inhibitor of PINK1 in our screen and has anIC50of 2 μM against insect PINK1 and 1 μM in HeLa cells expressing human PINK1. The crystal structures of PINK1 in complex with PRT062607 or CYC116 reveal how the compounds interact with the ATP-binding pocket. PRT062607 notably engages with the catalytic aspartate (type-1 inhibition) and causes a destabilization of insert-2 at the autophosphorylation dimer interface. Our findings provide a scaffold for the development of more selective and potent inhibitors of PINK1 that can be used as chemical probes.
Multiomics Analysis Revealed Anti-freezing Mechanism ofStaphylococcus aureusin Its Anti-freezing Strain
Authors: Youzhi Wu , Linjun Sun , Chunlei Shi , Xia Jiao Ling , Fuzhou Ye 
Published: October 2023

AbstractFrozen food is currently a common food type. However, the presence ofStaphylococcus aureuscontamination caused serious challenge to frozen food safety. In this study, we explored the differences between sensitive strains and anti-freeze strains through multiomics analysis such as proteomics, phosphorylated proteomics, and metabolomics studies to understand the anti-freezing mechanism ofS. aureus. This study compared the proteomics, phosphorylated proteomics and metabolomic differences between anti-freeze strains and sensitive strains before and after freezing. Before and after freezing, the differential protein-enriched channels changed from fructose-6-phosphate pathway, arachidonic acid metabolism pathway, atrazine degradation pathway to atrazine degradation pathway, starch and sucrose metabolism pathway, cysteine and methionine metabolism pathway, nitrogen metabolism pathway. In addition, this study inferred thatpgigene,ureA (urease subunit γ),ureB (urease subunit α),ureC (urease subunit β) gene,mtlD gene,fruB gene andasdgene could be crucial genes for the anti-freezing mechanism ofS. aureus, which needs further investigation. Furthermore, the experimental results showed that PfkA, DeoC and Fda proteins fromS. aureuswere the key proteins for anti-freezing. They correspondingly involved in carbon fixation, fructose and mannose metabolism, and glycolysis/gluconeogenesis pathways in photosynthetic organisms. Finally, important metabolic pathways involved in the anti-freezing mechanism, mainly ABC transport pathway, amino acid metabolism pathway and secondary metabolite anabolic pathway.
Cochlear tuning characteristics arise from temporal prediction of natural sounds
Authors: Trinh Freddy , King Andrew J , Willmore Ben D B , Harper Nicol 
Published: October 2023

AbstractThe cochlea decomposes incoming sound waveforms into different frequency components along the length of its basilar membrane. The receptor hair cells at the apical end of this resonant membrane are tuned to the lowest sound frequencies, with the preferred sound frequency of hair cell tuning increasing near-exponentially along the length of the membrane towards its basal end. This frequency composition of the sound is then transmitted to the brain by the auditory nerve fibers that innervate the inner hair cells. Hair cells respond to a sound impulse with a temporally asymmetric envelope and the sharpness of their tuning changes as the frequency to which they are most sensitive varies with their position along the basilar membrane. We ask if there is a normative explanation for why the cochlea decomposes sounds in this manner. Inspired by findings in the retina, we propose that cochlear tuning properties may be optimized for temporal prediction. This principle states that the sensory features represented by neurons are optimized to predict immediate future input from recent past input. We show that an artificial neural network optimized for temporal prediction of the immediate future of raw waveforms of natural sounds from their recent past produces tuning properties that resemble those observed in the auditory nerve. Specifically, the model captures the temporally asymmetric impulse responses, the tonotopic distribution and variation in tuning sharpness along the cochlea, and the frequency glide polarity of the impulse responses. These characteristics are not captured by a similar model optimized for compression of the sound waveform, rather than prediction. Given its success in accounting for the tuning properties at various processing levels in the auditory and visual systems, this finding for the cochlea provides further evidence that temporal prediction may be a general principle of sensory processing.
Inversions and integrations using CRISPR/Cas9 and a module-based plasmid construction kit for fission yeast
Authors: Berenguer Millanes Cristina , Nieuwenhuis Bart P.S. 
Published: October 2023

AbstractStructural variants (SV) are genetic alterations that involve large-scale changes in the structure of a genome. These variations can encompass deletions, duplications, inversions, translocations, or complex rearrangements. While smaller structural variants are relatively well studied, much is unknown about the prevalence and effect of larger SV. Genome sequencing methods that are able to find large reorganization in the genome, e.g. using mate pair or long-reads, have shown inversions and translocations are more common than was previously expected. Reduced recombination between regions with different structural organizations leads to the rise of variant specific alleles. Studying the effect of the SV in isolation is obscured by their independent evolutionary histories. Tools are needed to introduce SVs without introducing correlated alleles. Here we describe a method to introduce specific inversions and rearrangements in the fission yeastSchizosacchromyces pombeusing the modified CRISPR/Cas9 system SpEDIT to introduce multiple breakpoints with a single plasmid. Sequences for homologous recombination that guide repair resulting in the desired SVs are generated using an extended method for Golden Gate DNA shuffling forS. pombe. Our extension of the system from Kakui et al. is more efficient for integration, introduces more flexibility, and extends the system beyond single construct integrations. Additionally, we extend the set of promoters, tags, markers and terminators, specifically using DNA sequences from other fission yeast species, which avoid introduction of homologous sequences, thereby reducing the chance of non-allelic homologous recombination during sexual reproduction.