bluuebunny/crossref_metadata_2025_split huggingface dataset:
Latent Diffusion for Conditional Generation of Molecules
Authors: Kaufman Benjamin , Williams Edward C. , Pederson Ryan , Underkoffler Carl , Panjwani Zahid , Wang-Henderson Miles , Mardirossian Narbe , Katcher Matthew H. , Strater Zack , Grandjean Jean-Marc , Lee Bryan , Parkhill John 
Published: August 2024

AbstractDesigning a small molecule therapeutic is a challenging multi-parameter optimization problem. Key properties, such as potency, selectivity, bioavailability, and safety must be jointly optimized to deliver an effective clinical candidate. We present COATI-LDM, a novel application of latent diffusion models to the conditional generation of property-optimized, drug-like small molecules. Diffusive generation of latent molecular encodings, rather than direct diffusive generation of molecular structures, offers an appealing way to handle the small and mismatched datasets that are common for molecular properties. We benchmark various diffusion guidance schemes and sampling methods against a pre-trained autoregressive transformer and genetic algorithms to evaluate control over potency, expert preference, and various physicochemical properties. We show that conditional diffusion allows control over the properties of generated molecules, with practical and performance advantages over competing methods. We also apply the recently introduced idea of particle guidance to enhance sample diversity. We prospectively survey a panel of medicinal chemists and determine that we can conditionally generate molecules that align with their preferences via a learned preference score. Finally, we present a partial diffusion method for the local optimization of molecular properties starting from a seed molecule. Conditional generation of small molecules using latent diffusion models on molecular encodings provides a highly practical and flexible alternative to prior molecular generation schemes.
Large-scale manipulation of radial positioning does not affect most aspects of genome organization
Authors: Guetta Mor , Kariti Hagai , Sherman Liora , Israitel Lena , Tel-Paz Moran , Avidan Nili , Shemer Revital , Kaplan Noam 
Published: August 2024

AbstractAlthough the spatial organization of the genome is closely linked to biological function, genome structure is highly stochastic. Within this heterogeneity, specific function-associated structural elements must be maintained, even when the nucleus is deformed due to physiological physical constraints. The radial positioning of genomic loci - their distance from the nuclear periphery - has long been considered an important feature of genome organization which is correlated with both structural elements and genomic activity.In the current study, we developed an experimental system for manipulating the radial positioning of the genome, by expressing the sperm-specific protein Prm1 in somatic cells. By microscopy, we observe that initial Prm1 nuclear foci develop within 72 hours into a large Prm1 focus occupying most of the nuclear interior, while the entire genome is driven towards the nuclear periphery, resulting in a 3-5 fold reduction in the volume that the genome occupies. Noting that this system enables isolation of a pure population of cells with reorganized nuclei, we then used Hi-C to study the effects of this perturbation. Remarkably, we find that interaction patterns are largely robust to this major nuclear reorganization, with minor changes which mostly reflect a strengthening of heterochromatin self-interactions.Our experimental system provides means for manipulating nuclear organization in a reproducible manner, potentially allowing to examine radial positioning decoupled from other features of genome organization. Highlighting the complementary nature of microscopic and genomic methods, our work further suggests a remarkable resilience of genome structure such that large-scale nuclear changes, including chromosome compression and changes in radial positioning, can occur without extensive alteration of functional genome organization.
Flexibility and hydration of the Qosite determine multiple pathways for proton transfer in cytochromebc1
Authors: Camilo Sofia R. G. , Arantes Guilherme M. 
Published: August 2024

AbstractThe detailed catalytic activity of cytochromebc1(or respiratory complex III) and the molecular mechanism of the Q cycle remain elusive. At the Qosite, the cycle begins with oxidation of the coenzyme-Q substrate (quinol form) in a bifurcated two-electron transfer to the iron-sulfur (FeS) cluster and the hemebLcenter. The uptake of the two protons released during quinol oxidation is less understood, with one proton likely delivered to the histidine side chain attached to the FeS cluster. Here, we present extensive molecular dynamics simulations with enhanced sampling of side-chain torsions at the Qosite and analyze available sequences and structures of severalbc1homologues to probe the interactions of quinol with potential proton acceptors and identify viable pathways for proton transfer. Our findings reveal that side chains at the Qosite are highly flexible and can adopt multiple conformations. Consequently, the quinol head is also flexible, adopting three distinct binding modes. Two of these modes are proximal to the hemebLand represent reactive conformations capable of electron and proton transfer, while the third, more distal mode likely represents a pre-reactive state, consistent with recent cryo-EM structures ofbc1with bound coenzyme-Q. The Qosite is highly hydrated, with several water molecules bridging interactions between the quinol head and the conserved side chains Tyr147, Glu295, and Tyr297 in cytochromeb(numbering according toR. sphaeroides), facilitating proton transfer. A hydrogen bond network and at least five distinct proton wires are established and possibly transport protons via a Grotthuss mechanism. Asp287 and propionate-A of hemebLin cytochromebare in direct contact with external water and are proposed as the final proton acceptors. The intervening water molecules in these proton wires exhibit low mobility, and some have been resolved in recent experimental structures. These results help to elucidate the intricate molecular mechanism of the Q-cycle and pave the way to a detailed understanding of chemical proton transport in several bioenergetic enzymes that catalyze coenzyme-Q redox reactions.
Inhibiting EZH2 complements steroid effects in Duchenne muscular dystrophy
Authors: Jeon Eun Young , Kwak Yejin , Kang Hyeji , Jin Se Young , Park Soojin , Kim Ryeo Gyeong , Ko Dayoung , Won Jae-Kyung , Cho Anna , Jung Inkyung , Lee Chul-Hwan , Park Jeongbin , Kim Hyun-Young , Chae Jong-Hee , Choi Murim 
Published: August 2024

AbstractDuchenne muscular dystrophy (DMD) is a devastating X-linked disorder caused by mutations in the dystrophin gene. Despite recent advances in understanding the disease etiology and applying emerging treatment methodologies, glucocorticoid derivatives remain the only general therapeutic option that can slow disease development. However, the precise molecular mechanism of glucocorticoid action remains unclear, and there is still need for additional remedies to complement the treatment. Here, using single-nucleus RNA-sequencing and spatial transcriptome analyses of human and mouse muscles, we investigated pathogenic features in DMD patients and palliative effects of glucocorticoids. Our approach further illuminated the importance of proliferating satellite cells, and revealed increased activity of a signal transduction pathway involving EZH2 in the patient cells. Subsequent administration of EZH2 inhibitors toDmdmutant mice resulted in improved muscle phenotype through maintaining the immune-suppressing effect but overriding the muscle weakness and fibrogenic effects exerted by glucocorticoids. Our analysis reveals pathogenic mechanisms that can be readily targeted by extant therapeutic options for DMD.TeaserA survey of DMD tissues in human and mouse suggests EZH2 as a critical factor in DMD satellite cells; its inhibition resulted in better prognosis.
A convenient single-cell newly synthesized transcriptome assay reveals gene expression dynamics during early-stage T-cell activation
Authors: Lyu Jun , Xu Xiaoyan , Chen Chongyi 
Published: August 2024

AbstractSequencing newly synthesized transcriptome alongside regular transcriptome in single cells enables the study of gene expression temporal dynamics during rapid chromatin and gene regulation processes. However, existing assays to profile single-cell newly synthesized transcriptome require in-house technical expertise to achieve high cellular throughput, limiting their widespread application. Here, we developed NOTE-seq, a method that simultaneously profiles regular and newly synthesized transcriptomes in single cells. NOTE-seq integrates 4-thiouridine labeling of newly synthesized RNA, thiol-alkylation-based chemical conversion, and a streamlined workflow on the 10X Genomics platform, offering high cellular throughput that is accessible and convenient for regular biology laboratories without specialized single-cell expertise. Using NOTE-seq, we characterized the temporal dynamics of gene expression during early-stage T-cell activation in Jurkat and naïve T cells, identified transcription factors and regulons, and discoveredFli-1as a master transcription factor for gene regulation upon T-cell stimulation. Interestingly, chemotherapeutic topoisomerase inhibitor affectsFli-1level in T cells, indicating potential complications for the immune system.
VRS5 (HvTB1) binds to the promoter of tillering and floral homeotic genes to regulate their expression
Authors: Winkelmolen T. , Colleoni P. , Moscou M. , Hoseinzadeh P. , Oldach K. , Schmidt R.C. , Immink R. , van Esse G.W. 
Published: August 2024

AbstractVariation in shoot architecture, or tillering, is an important adaptive trait targeted during the domestication of crops. A well-known regulatory factor in shoot architecture is TEOSINTE BRANCHED 1 (TB1). TB1 and its orthologs have a conserved function in integrating environmental signals to regulate axillary branching, or tillering in cereals. The barley ortholog of TB1,VULGARE ROW-TYPE SIX 5(VRS5) does not only regulate tillering, but is also involved in regulating row-type by inhibiting lateral spikelet development. These discoveries predominantly come from genetic studies, but how VRS5 regulates these processes on a molecular level remains largely unknown. By combining transcriptome analysis betweenvrs5and wild type at different developmental stages and DAP-sequencing to locate the genome-wide DNA binding sites of VRS5, we identifiedbona fidetargets of VRS5. We found that VRS5 targets abscisic acid related genes, potentially to inhibit tillering in a conserved way. While later in inflorescence development, row-type geneVRS1and several known floral development genes, like MIKCc type MADS-box genes, are targeted. This study identifies several significant genes for mutational analysis, representing a selection ofbona fidetargets that will contribute to a deeper understanding of the VRS5 network and its role in shaping barley development.
Variant-to-function mapping of late-onset Alzheimer’s disease GWAS signals in human microglial cell models implicatesRTFDC1at theCASS4locus
Authors: Burton Elizabeth A. , Argenziano Mariana , Cook Kieona , Ridler Molly , Lu Sumei , Su Chun , Manduchi Elisabetta , Littleton Sheridan H. , Leonard Michelle E. , Hodge Kenyaita M. , Wang Li-San , Schellenberg Gerard D. , Johnson Matthew E. , Pahl Matthew C. , Pippin James A. , Wells Andrew D. , Anderson Stewart A. , Brown Christopher D. , Grant Struan F.A. , Chesi Alessandra 
Published: August 2024

ABSTRACTLate-onset Alzheimer’s disease (LOAD) research has principally focused on neurons over the years due to their known role in the production of amyloid beta plaques and neurofibrillary tangles. In contrast, recent genomic studies of LOAD have implicated microglia as culprits of the prolonged inflammation exacerbating the neurodegeneration observed in patient brains. Indeed, recent LOAD genome-wide association studies (GWAS) have reported multiple loci near genes related to microglial function, includingTREM2,ABI3, andCR1. However, GWAS alone cannot pinpoint underlying causal variants or effector genes at such loci, as most signals reside in non-coding regions of the genome and could presumably confer their influence frequently via long-range regulatory interactions. We elected to carry out a combination of ATAC-seq and high-resolution promoter-focused Capture-C in two human microglial cell models (iPSC-derived microglia and HMC3) in order to physically map interactions between LOAD GWAS-implicated candidate causal variants and their corresponding putative effector genes. Notably, we observed consistent evidence that rs6024870 at the GWASCASS4locus contacted the promoter of nearby gene,RTFDC1. We subsequently observed a directionallly consistent decrease inRTFDC1expression with the the protective minor A allele of rs6024870 via both luciferase assays in HMC3 cells and expression studies in primary human microglia. Through CRISPR-Cas9-mediated deletion of the putative regulatory region harboring rs6024870 in HMC3 cells, we observed increased pro-inflammatory cytokine secretion and decreased DNA double strand break repair related, at least in part, toRTFDC1expression levels. Our variant-to-function approach therefore reveals that the rs6024870-harboring regulatory element at the LOAD ‘CASS4’GWAS locus influences both microglial inflammatory capacity and DNA damage resolution, along with cumulative evidence implicatingRTFDC1as a novel candidate effector gene.
3D scanning measurement method for seed size research
Authors: Málik-Roffa Hajnalka , Málik Tamás , Tőzsér Dávid , Tóthmérész Béla 
Published: August 2024

AbstractPremiseTraditionally used seed size and surface area calculation techniques are often inaccurate or destructive. This is especially relevant for organisms with irregular shapes. It is believed that three-dimensional (3D) printing and scanning could also be disruptive technologies. However, these methods hold immense potential for ecology and evolution sciences, which have a longstanding tradition of inventing and creating objects for research, education, and outreach.Methods and ResultsWe describe how to 3D scan seeds reproducible on an inexpensive structured light based commodity 3D scanner. We then compared novel 3D and traditional 2D approaches by reproducibility and timing.ConclusionsThis study demonstrates how 3D scanning methods are easily applicable to the quantification of seed shape and providing an easy entry into it.
Automatic crystal identification for crystallography:a comparison between direct methods and artificial intelligence strategies
Authors: Lages Camila F A , Nicoleti Vitoria Y , Correa Maicon R , Mausbach Paulo , Ramos Felipe C , de Araujo Evandro A , Nascimento Andrey Z , Miqueles Eduardo X 
Published: August 2024

AbstractCrystallography is an important, and well-established technique for assessing crystalline atomic structure of a wide variety of materials. An auxiliary optical microscope instrument is used to perform the data acquisition at the manaca beamline, a crystallography experimental station from sirius (the 4th generation Brazilian synchrotron). The importance of detecting these crystals in the auxiliary image is to define the best order in which each crystal will be measured by the incident beam since each one of them must be measured only once; improving beamtime and maximizing user experience at the facility. Detecting rough crystal positions from these auxiliary images is a scientific computing task, which could benefit from some open artificial intelligence tools. This manuscript compares a real-time object detection interface (Yolo) with a new, simple and effective strategy obtained from a particular partial differential equation.
Generation of humanized mouse models to support therapeutic development for SYNGAP1 and STXBP1 disorders
Authors: Felix Alex J. , Wilson Taryn , Randell Rani , Marotta Nicolas , Uchida Keita , Boland Michael J. , Davidson Beverly L. , Prosser Benjamin L. 
Published: August 2024

AbstractHeterozygous variants inSYNGAP1andSTXBP1lead to distinct neurodevelopmental disorders caused by haploinsufficient levels of post-synaptic SYNGAP1 and pre-synaptic STXBP1, which are critical for normal synaptic function. While several gene-targeted therapeutic approaches have proven efficaciousin vitro, these often target regions of the human gene that are not conserved in rodents, hindering the pre-clinical development of these compounds and their transition to the clinic. To overcome this limitation, here we generate and characterizeSyngap1andStxbp1humanized mouse models in which we replaced the mouseSyngap1andStxbp1gene, respectively, with the human counterpart, including regulatory and non-coding regions. Fully humanizedSyngap1mice present normal viability and can be successfully crossed with currently availableSyngap1haploinsufficiency mouse models to generateSyngap1humanized haploinsufficient mice.Stxbp1mice were successfully humanized, yet exhibit impaired viability (particularly males) and reduced STXBP1 protein abundance. Mouse viability could be improved by outcrossing this model to other mouse strains, whileStxbp1humanized females and hybrid mice can be used to evaluate target engagement of human-specific therapeutics. Overall, these humanized mouse models represent a broadly available tool to further pre-clinical therapeutic development for SYNGAP1 and STXBP1 disorders.
Regulation of angiogenesis by signal sequence-derived peptides
Authors: Ghim Mean , Wei Linyan , Jung Jae-Joon , The Erlinda , Kukreja Gunjan , Neishabouri Afarin , Ahmad Azmi A. , Raza M. Zawwad , Golbazi Arvene , Hedayatyanfard Keshvad , Nie Lei , Zhang Jiasheng , Sadeghi Mehran M. 
Published: August 2024

ABSTRACTBackgroundThe neuropilin-like, Discoidin, CUB and LCCL domain containing 2 (DCBLD2) is a transmembrane protein with an unusually long signal sequence (SS) composed of N-terminal (N) and C-terminal (C) subdomains, separated by a transition (tra) subdomain. DCBLD2 interacts with VEGFR-2 and regulates VEGF-induced endothelial cell signaling, proliferation and migration, as well as angiogenesis. The exact mechanisms by which DCBLD2 interacts with VEGFR2 to modulate VEGF signaling remain unclear.MethodsSearching for VEGFR2 interacting DCBLD2 domains, we generated various constructs containing different DCBLD2 domain combinations and conducted co-immunoprecipitation and signaling studies in HEK 293T and endothelial cells. Several peptides were synthesized based on the identified domain, and their effect on VEGF signaling was assessed in vitro in cell culture and in vivo using matrigel plug and corneal micropocket assays. The effect of the lead peptide was further evaluated using a murine hindlimb ischemia model.ResultsDCBLD2 SS interacted with VEGFR2 and promoted VEGF signaling. SS was not cleaved in the mature DCBLD2 and its hydrophobic transmembrane ‘traC’ segment, but not the ‘N’ subdomain, was involved in DCBLD2-VEGFR2 interaction. The smallest unit in DCBLD2 SS that interacts with VEGFR2 was the L5VL5 sequence. Even after the central valine was removed, the L10 sequence mimicked the DCBLD2 SS traC’s effect on VEGF-signaling, while shorter or longer poly-leucine sequences were less effective. Finally, a synthetic traC peptide enhanced VEGF signaling in vitro, promoted VEGF-induced angiogenesis in vivo, and improved blood flow recovery following hindlimb ischemia.ConclusionDCBLD2 SS along with its derivative peptides can promote VEGFR2 signaling and angiogenesis. Synthetic peptides based on DCBLD2 SS hold promise as therapeutic agents for regulating angiogenesis. Importantly these findings refine the traditional view of signal sequences as mere targeting elements, revealing a role in cellular signaling. This opens new avenues for research and therapeutic strategies.
Detecting behavioural oscillations with increased sensitivity: A modification of Brookshire’s (2022) AR-surrogate method
Authors: Harris Anthony M. , Beale Henry A. 
Published: August 2024

AbstractA core challenge of cognitive neuroscience is to understand how cognition changes over time within the same individual. For example, the tendency for behavioural responses in a range of cognitive domains to oscillate over time has been studied extensively. Recently, however, the phenomenon of behavioural oscillations has been called into question by indications that past findings might reflect aperiodic temporal structure rather than true oscillations. Brookshire (2022) proposed methods to control for aperiodic temporal structure while examining oscillations in behavioural time-courses and found no evidence of behavioural oscillations in reanalyses of four published datasets. However, Brookshire’s (2022) method has been criticised for having low sensitivity to detect effects of realistic magnitude, so it is currently unclear whether these findings suggest that behavioural oscillations are not present in these and perhaps many other datasets, or whether they are false negatives. Here, we present a modification of Brookshire’s (2022) AR-surrogate method with increased sensitivity to detect effects of realistic magnitude, adequate control of false positives, and other desirable properties such as the ability to increase statistical power by adding more participants. Using this method, we reanalyse the same publicly available datasets and show significant behavioural oscillations in each of them, suggesting oscillations in behaviour are a robust phenomenon upon which to draw theoretical inferences. The participant-level AR-surrogate method is currently the most sensitive method available for analysing behavioural oscillations while controlling for the contribution of aperiodic data fluctuations.
RNA quality control by CCR4 safeguards chromatin integrity and centromere function inArabidopsis
Authors: Shimada Atsushi , Saze Hidetoshi 
Published: August 2024

SummaryThe centromere is a pivotal chromatin domain that ensures accurate chromosome segregation during cell division. However, the epigenome regulation of the centromere and its impact on centromere function remain largely elusive. Here in the model plantArabidopsis, we show that CCR4, the catalytic subunit of the RNA deadenylation complex CCR4-NOT, is essential for maintenance of the centromere epigenome and chromosome integrity. We demonstrate that CCR4 is involved in shortening of the poly(A) tails of transcripts originated from centromeric transposons and repeats, thereby promoting the production of small interfering RNAs (siRNAs). The CCR4-dependent siRNAs guide non-CG DNA methylation at centromere repeats, and CCR4 cooperates with canonical DNA methylation pathways to enhance centromeric H3K9 methylation and ensure mitotic chromosome stability. Our study illustrates the crucial role of RNA quality control in RNA interference and reveals the elaborate mechanism that safeguards plant centromeres through epigenomic regulation.