bluuebunny/crossref_metadata_2025_split huggingface dataset:
Out-of-equilibrium gene expression fluctuations in presence of extrinsic noise
Authors: Biondo Marta , Singh Abhyudai , Caselle Michele , Osella Matteo 
Published: February 2023

AbstractCell-to-cell variability in protein concentrations is strongly affected by extrinsic noise, especially for highly expressed genes. Extrinsic noise can be due to fluctuations of several possible cellular factors connected to cell physiology and to the level of key enzymes in the expression process. However, how to identify the predominant sources of extrinsic noise in a biological system is still an open question. This work considers a general stochastic model of gene expression with extrinsic noise represented as colored fluctuations of the different model rates, and focuses on the out-of-equilibrium expression dynamics. Combining analytical calculations with stochastic simulations, we fully characterize how extrinsic noise shapes the protein variability during gene activation or inactivation, depending on the prevailing source of extrinsic variability, on its intensity and timescale. In particular, we show that qualitatively different noise profiles can be identified depending on which are the fluctuating parameters. This indicates an experimentally accessible way to pinpoint the dominant sources of extrinsic noise using time-coarse experiments.Author summaryGenetically identical cells living in the same environment may differ in their phenotypic traits. These differences originate from the inherent stochasticity in all cellular processes, starting from the basic process of gene expression. At this level, large part of the variability comes from cell-to-cell differences in the rates of the molecular reactions due to stochasticity in the level of key enzymes or in physiological parameters such as cell volume or growth rate. Which expression rates are predominantly affected by these so-called “extrinsic” fluctuations and how they impact the level of protein concentration are still open research questions. In this work, we tackle the protein fluctuation dynamics while approaching a steady state after gene activation or repression in presence of extrinsic noise. Our analytical results and simulations show the different consequences of alternative dominant sources of extrinsic noise, thus providing an experimentally-accessible way to distinguish them in specific systems.
Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders
Authors: Li Yen-Der , Ma Michelle W. , Hassan Muhammad Murtaza , Hunkeler Moritz , Teng Mingxing , Puvar Kedar , Lumpkin Ryan , Sandoval Brittany , Jin Cyrus Y. , Ficarro Scott B. , Wang Michelle Y. , Xu Shawn , Groendyke Brian J. , Sigua Logan H. , Tavares Isidoro , Zou Charles , Tsai Jonathan M. , Park Paul M. C. , Yoon Hojong , Majewski Felix C. , Marto Jarrod A. , Qi Jun , Nowak Radosław P. , Donovan Katherine A. , Słabicki Mikołaj , Gray Nathanael S. , Fischer Eric S. , Ebert Benjamin L. 
Published: February 2023

AbstractSmall molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics1-3. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs4-6. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define atrans-labeling covalent molecular glue mechanism, which we term “template-assisted covalent modification”. We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 Å cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16Cys58covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2revealed that the loop conformation around BRD4His437, rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes “template-assisted covalent modification” as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology.
Comparisons of paternity success for resident and non-resident males and their influences on paternal sibling cohorts in Japanese macaques on Shodoshima Island
Authors: Ishizuka Shintaro , Inoue Eiji 
Published: February 2023

AbstractIn group-living mammals, reproductive success can be attributed to both resident and non-resident males. However, the reproductive success of non-resident males has rarely been investigated at an individual level. As male reproductive success is highly skewed towards specific males, often the most dominant males, the percentage of similar-aged paternal siblings within groups is expected to increase. However, the extent to which each male contributes to the production of cohorts of paternal siblings remains unclear. Here we examined the paternity of 46 offspring born over five consecutive years in a group of Japanese macaquesMacaca fuscataon Shodoshima Island. We quantitatively assessed paternity success for males, including both resident and non-resident males, and the percentages of paternal sibling dyads in the same age cohorts produced by those males. Non-resident males sired neither higher nor lower percentage of offspring compared to resident males, indicating that various males, including non-resident males, usually partake in the within-group breeding of macaque groups. These are possibly because female preference of mating partners can change over time. Subadult males had a lower percentage of paternity success, which may be because females may not prefer the physically immature subadult males. Various males, including non-resident males, contributed to the creation of paternal sibling in the same age cohort. The overall results suggest that not only resident but also non-resident males play an important role in shaping within-group kin structures. Future studies are required to examine how paternal siblings interact with each other.
Pharmacological PINK1 activation ameliorates Pathology in Parkinson’s Disease models
Authors: Chin Randall M. , Rakhit Rishi , Ditsworth Dara , Wang Chengzhong , Bartholomeus Johan , Liu Song , Mody Akash , Laishu Alex , Eastes Andrea , Tai Chao , Kim Roy Y. , Li Jessica , Hansberry Steven , Khasnavis Saurabh , Rafalski Victoria , Herendeen Donald , Garda Virginia , Phung Jennie , de Roulet Daniel , Ordureau Alban , Harper J. Wade , Johnstone Shawn , Stöhr Jan , Hertz Nicholas T. 
Published: February 2023

SummaryPINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinson’s disease (PD) and Parkinsonism, respectively. We demonstrate that pathological α-synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction and impairs mitophagy, driving accumulation of the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. We synthesized MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance of α-synuclein pathology in PFF seeding models in vitro and in vivo and reduces pUb. We developed an ultrasensitive assay to quantify pUb levels in plasma and observed an increase in pUb in PD subjects that correlates with disease progression, paralleling our observations in PD models. Our combined findings from preclinical PD models and patient biofluids suggest that pharmacological activation of PINK1 is worthy of further study as a therapeutic strategy for disease modification in PD.HighlightsDiscovery of a plasma Parkinson’s Disease biomarker candidate, pS65-Ubiquitin (pUb)Plasma pUb levels correlate with disease status and progression in PD patients.Identification of a potent, brain penetrant PINK1 activator, MTK458MTK458 selectively activates PINK1 by stimulating dimerization and stabilization of the PINK1/TOM complexMTK458 drives clearance of α-synuclein pathology and normalizes pUb in in vivo Parkinson’s models
Maribacter halichondrissp. nov., isolated from the marine spongeHalichondria panicea
Authors: Steiner Leon X. , Wiese Jutta , Rahn Tanja , Borchert Erik , Slaby Beate M. , Hentschel Ute 
Published: February 2023

AbstractA new member of the familyFlavobacteriaceae(termed Hal144T) was isolated from the marine breadcrumb spongeHalichondria panicea. Sponge material was collected in 2018 at Schilksee which is located in the Kiel Fjord (Baltic Sea, Germany). Phylogenetic analysis of the full-length Hal144T16S rRNA gene sequence revealed similarities from 94.3% - 96.6% to the nearest type strains of the genusMaribacter. The phylogenetic tree depicted a cluster of strain Hal144Twith its closest relativesMaribacter aestuariiGY20T(96.6%) andMaribacter thermophilusHT7-2T(96.3%). Genome comparisons of strain Hal144TwithMaribacterspp. type strains exhibited average nucleotide identities in the range of 75% - 76% and digital DNA-DNA hybridization values in the range of 13.1% - 13.4%. Strain Hal144Twas determined to be Gram-negative, mesophilic, strictly aerobic, flexirubin positive, resistant to aminoglycoside antibiotics, and able to utilize N-acetyl-β-D-glucosamine. Optimal growth occurred at 25 – 30 °C, within a salinity range of 2 - 6% sea salt, and a pH range between 5 - 8. The major fatty acids identified were C17:03-OH, iso-C15:0, and iso-C15:1G. The DNA G+C content of strain Hal144Twas 41.4 mol%. Based on the polyphasic approach, strain Hal144Trepresents a novel species of the genusMaribacter, and we propose the nameMaribacter halichondrissp. nov.. The type strain is Hal144T(= DSM 114563T= LMG 32744T).
Rice Gene Index (RGI): a comprehensive pan-genome database for comparative and functional genomics of Asian rice
Authors: Yu Zhichao , Chen Yongming , Zhou Yong , Zhang Yulu , Li Mengyuan , Ouyang Yidan , Chebotarov Dmytro , Mauleon Ramil , Zhao Hu , Xie Weibo , McNally Kenneth L. , Wing Rod A. , Guo Weilong , Zhang Jianwei 
Published: February 2023

AbstractTo integrate the genomic information of the rice pan-genome, we performed comparative analyses and established a user-friendly Rice Gene Index (RGI,https://riceome.hzau.edu.cn) platform with 16 platinum standard reference genomes and supplementary transcriptome data. To logically organize and scientifically the index of 744,233 genes among rice accessions, we detected 112,658 Ortholog Gene Indices, and provide ‘GeneCard’ pages to query genomic, transcriptomic, and homology information for each gene. The RGI allows users to search for relationships and comprehensive information of genes in keyword-based, sequence-based, and relationship-based ways. Furthermore, users can visualize these relationships at local and global scales corresponding to ‘Microcollinearity’ and ‘Macrocollinearity’ modules.
A closer look at high-energy X-ray-induced bubble formation during soft tissue imaging
Authors: Xian R. Patrick , Brunet Joseph , Huang Yuze , Wagner Willi L. , Lee Peter D. , Tafforeau Paul , Walsh Claire L. 
Published: February 2023

AbstractImproving the scalability of tissue imaging throughput with bright, coherent X-rays requires identifying and mitigating artifacts resulting from the interactions between X-rays and matter. At synchrotron sources, long-term imaging of soft tissues in solution can result in gas bubble formation or cavitation, which dramatically compromises image quality and integrity of the samples. By combining in-line phase-contrast cineradiography withoperandogas chromatography, we were able to track the onset and evolution of high-energy X-ray-induced gas bubbles in ethanol-embedded soft tissue samples for tens of minutes (2 to 3 times the typical scan times). We demonstrate quantitatively that vacuum degassing of the sample during preparation can significantly delay bubble formation, offering up to a twofold improvement in dose tolerance, depending on the tissue type. However, once nucleated, bubble growth is faster in degassed than undegassed samples, indicating their distinct metastable states at bubble onset. Gas chromatography analysis shows increased solvent vaporization concurrent with bubble formation, yet the quantities of dissolved gases remain unchanged. Coupling features extracted from the radiographs with computational analysis of bubble characteristics, we uncover dose-controlled kinetics and nucleation site-specific growth. These hallmark signatures provide quantitative constraints on the driving mechanisms of bubble formation and growth. Overall, the observations highlight bubble formation as a critical, yet often overlooked hurdle in upscaling X-ray imaging for biological tissues and soft materials and we offer an empirical foundation for their understanding and imaging protocol optimization. More importantly, our approaches establish a top-down scheme to decipher the complex, multiscale radiation-matter interactions in these applications.Significance statementBetter probing the X-ray radiation dose limit of bubble formation in biological tissue and developing mitigation methods is essential for improving imaging techniques involving X-ray, such as synchrotron X-ray tomography or crystallography. Here, we combinedoperandogas chromatography with in-line X-ray phase-contrast radiography on human lung and brain tissue to investigate bubble formation under high-energy X-ray irradiation. We demonstrate that vacuum degassing delays bubble nucleation up to a factor two, depending on the tissue type. Gas chromatography analysis showed increased solvent vaporization during bubble formation; however, the quantities of dissolved gases remained unchanged. Moreover, depending on the nucleation site, bubble growth can be geometrically constrained by sample microstructure, which influence its dynamics.
Spectral methods for prediction uncertainty quantification in Systems Biology
Authors: Deneer Anna , Molenaar Jaap , Fleck Christian 
Published: February 2023

AbstractUncertainty is ubiquitous in biological systems. These uncertainties can be the result of lack of knowledge or due to a lack of appropriate data. Additionally, the natural variability of biological systems caused by intrinsic noise, e.g. in stochastic gene expression, leads to uncertainties. With the help of numerical simulations the impact of these uncertainties on the model predictions can be assessed, i.e. the impact of the propagation of uncertainty in model parameters on the model response can be quantified. Taking this into account is crucial when the models are used for experimental design, optimisation, or decision-making, as model uncertainty can have a significant effect on the accuracy of model predictions. We focus here on spectral methods to quantify prediction uncertainty based on a probabilistic framework. Such methods have a basis in, e.g., computational mathematics, engineering, physics, and fluid dynamics, and, to a lesser extent, systems biology. In this chapter, we highlight the advantages these methods can have for modelling purposes in systems biology and do so by providing a novel and intuitive scheme. By applying the scheme to an array of examples we show its power, especially in challenging situations where slow converge due to high-dimensionality, bifurcations, and spatial discontinuities play a role.
Tertiary Lymphoid Structures Sustain Cutaneous B cell Activity in Hidradenitis Suppurativa
Authors: Lowe Margaret M. , Cohen Jarish N. , Moss Madison I. , Clancy Sean , Adler James , Yates Ashley , Naik Haley B. , Pauli Mariela , Taylor Ian , McKay Austin , Harris Hobart , Kim Esther , Hansen Scott L. , Rosenblum Michael D. , Moreau Joshua M. 
Published: February 2023

Structured AbstractBackgroundHidradenitis suppurativa (HS) skin lesions are highly inflammatory and characterized by a large immune infiltrate. While B cells and plasma cells comprise a major component of this immune milieu the biology and contribution of these cells in HS pathogenesis is unclear.ObjectiveWe aimed to investigate the dynamics and microenvironmental interactions of B cells within cutaneous HS lesions.MethodsWe combined histological analysis, single-cell RNA-sequencing (scRNAseq), and spatial transcriptomic profiling of HS lesions to define the tissue microenvironment relative to B cell activity within this disease.ResultsOur findings identify tertiary lymphoid structures (TLS) within HS lesions and describe organized interactions between T cells, B cells, antigen presenting cells and skin stroma. We find evidence that B cells within HS TLS actively undergo maturation, including participation in germinal center reactions and class switch recombination. Moreover, skin stroma and accumulating T cells are primed to support the formation of TLS and facilitate B cell recruitment during HS.ConclusionOur data definitively demonstrate the presence of TLS in lesional HS skin and point to ongoing cutaneous B cell maturation through class switch recombination and affinity maturation during disease progression in this inflamed non-lymphoid tissue.
Targeted protein degradation via intramolecular bivalent glues
Authors: Hsia Oliver , Hinterndorfer Matthias , Cowan Angus D. , Iso Kentaro , Ishida Tasuku , Sundaramoorthy Ramasubramanian , Nakasone Mark A. , Imrichova Hana , Schätz Caroline , Rukavina Andrea , Husnjak Koraljka , Wegner Martin , Correa-Sáez Alejandro , Craigon Conner , Casement Ryan , Maniaci Chiara , Testa Andrea , Kaulich Manuel , Dikic Ivan , Winter Georg E. , Ciulli Alessio 
Published: February 2023

AbstractTargeted protein degradation is a pharmacological modality based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via bifunctional compounds (PROTACs) composed of two separate warheads that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target1–4. Using orthogonal genetic screening, biophysical characterization, and structural reconstitution, we investigate the mode of action of bifunctional BRD2/4 degraders (IBG1-4) and find that – instead of connecting target and ligasein transas PROTACs do – they simultaneously engage two adjacent domains of the target proteinin cis. This conformational change glues BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target-ligase affinities which, albeit pre-existing, do not translate to BRD4 degradation in absence of compound. Structural insights into the ternary BRD4:IBG1:DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, termed intramolecular bivalent glues (IBGs), which work by bridging protein domains to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.
Dephosphorylation of 4EBP1/2 Induces Prenatal Neural Stem Cell Quiescence
Authors: Geben Laura C. , Brockman Asa A. , Chalkley Mary Bronwen L. , Sweet Serena R. , Gallagher Julia E. , Scheuing Alexandra L. , Simerly Richard B. , Ess Kevin C. , Irish Jonathan M. , Ihrie Rebecca A. 
Published: February 2023

AbstractA limiting factor in the regenerative capacity of the adult brain is the abundance and proliferative ability of neural stem cells (NSCs). Adult NSCs are derived from a subpopulation of embryonic NSCs that temporarily enter quiescence during mid-gestation and remain quiescent until postnatal reactivation. Here we present evidence that the mechanistic/mammalian target of rapamycin (mTOR) pathway regulates quiescence entry in embryonic NSCs of the developing forebrain. Throughout embryogenesis, two downstream effectors of mTOR, p-4EBP1/2 T37/46 and p-S6 S240/244, were mutually exclusive in NSCs, rarely occurring in the same cell. While 4EBP1/2 was phosphorylated in stem cells undergoing mitosis at the ventricular surface, S6 was phosphorylated in more differentiated cells migrating away from the ventricle. Phosphorylation of 4EBP1/2, but not S6, was responsive to quiescence induction in cultured embryonic NSCs. Further, inhibition of p-4EBP1/2, but not p-S6, was sufficient to induce quiescence. Collectively, this work offers new insight into the regulation of quiescence entry in embryonic NSCs and, thereby, correct patterning of the adult brain. These data suggest unique biological functions of specific posttranslational modifications and indicate that the preferential inhibition of such modifications may be a useful therapeutic approach in neurodevelopmental diseases where NSC numbers, proliferation, and differentiation are altered.
A thin line between conflict and reaction time effects on EEG and fMRI brain signals
Authors: Beldzik Ewa , Ullsperger Markus 
Published: February 2023

AbstractThe last two decades of electrophysiological and neuroimaging research converged that the activity in the medial frontal cortex plays a pivotal role in cognitive control processes. Notably, the midfrontal theta (MFT) oscillatory EEG power, as well as activity in the anterior midcingulate cortex (aMCC) or pre-supplementary motor area (preSMA), were consistently proclaimed as markers of conflict processing. However, these brain signals are strongly correlated with response time (RT) variability in various non-conflict tasks, which overshadows the true nature of their involvement. Our previous study (Beldzik et al., 2022) successfully identified these brain signals during a simultaneous EEG-fMRI experiment implementing Stroop and Simon tasks. Based on the assumption that overcoming the habitual prepotent response during high interference trials require additional neural resources beyond simple decision variable represented in RTs, here we aim to verify if these markers exhibit a congruency effect beyond RT variations. Furthermore, we explored if these brain signals represent either proactive or reactive cognitive control mechanisms by investigating two widely known behavioral phenomena observed in conflict tasks: proportion congruency and congruency sequence effects. The results revealed partially null findings for MFT activity, yet a distinct cognitive control specialization between aMCC and preSMA. Our study provides novel evidence that the former is involved in proactive control mechanisms, possibly contingency learning, whereas the latter reflects reactive control mechanisms by exhibiting a strong congruency effect regardless of RT variation and responding to adaptive behavior.