bluuebunny/crossref_metadata_2025_split huggingface dataset:
Benchmarking solutions to the T-cell receptor epitope prediction problem: IMMREP22 workshop report
Authors: Meysman Pieter , Barton Justin , Bravi Barbara , Cohen-Lavi Liel , Karnaukhov Vadim , Lilleskov Elias , Montemurro Alessandro , Nielsen Morten , Mora Thierry , Pereira Paul , Postovskaya Anna , Martínez María Rodríguez , Fernandez-de-Cossio-Diaz Jorge , Vujkovic Alexandra , Walczak Aleksandra M. , Weber Anna , Yin Rose , Eugster Anne , Sharma Virag 
Published: October 2022

AbstractMany different solutions to predicting the cognate epitope target of a T-cell receptor (TCR) have been proposed. However several questions on the advantages and disadvantages of these different approaches remain unresolved, as most methods have only been evaluated within the context of their initial publications and data sets. Here, we report the findings of the first public TCR-epitope prediction benchmark performed on 23 prediction models in the context of the ImmRep 2022 TCR-epitope specificity workshop. This benchmark revealed that the use of paired-chain alpha-beta, as well as CDR1/2 or V/J information, when available, improves classification obtained with CDR3 data, independent of the underlying approach. In addition, we found that straight-forward distance-based approaches can achieve a respectable performance when compared to more complex machine-learning models. Finally, we highlight the need for a truly independent follow-up benchmark and provide recommendations for the design of such a next benchmark.
An exploratory study of a simple approach for evaluating drug solubility in milk related vehicles
Authors: Li Sean , Gabriel Justin J. , Martinez Marilyn N. , Longstaff David G. , Coffey Martin J. , Zhao Fang 
Published: October 2022

AbstractMilk related materials are frequently used as a vehicle for drug product administration. Therefore, drug solubility information in milk related vehicles is desirable for prediction of how they may influencein vivodrug release and bioavailability. However, there are very limited data published on this topic. This study explored a practical method to address the key challenges associated with solubility assessment in milk, including the sample equilibration time and cleanup procedures. Amitriptyline, acetaminophen, dexamethasone, nifedipine, piroxicam, and prednisolone were selected as model drugs to represent a wide range of physicochemical properties. Their solubilities were determined at room temperature in pH 6.8 phosphate buffer, skim milk, whole milk, reconstituted whole milk powder, and unprocessed raw milk. The overall results confirmed that milk greatly improves the solubility of poorly water-soluble drugs. However, the extent of improvement and mechanism of solubilization appeared unique for each drug, highlighting the importance of evaluating milk solubility experimentally. The method used in this exploratory study can be applied in future investigations of a broader range of drugs and milk-related vehicles.
Optogenetic closed-loop feedback control of the unfolded protein response optimizes protein production
Authors: Benisch Moritz , Benzinger Dirk , Kumar Sant , Hu Hanrong , Khammash Mustafa 
Published: October 2022

AbstractIn biotechnological protein production processes, the onset of protein unfolding at high gene expression levels leads to diminishing production yields and reduced efficiency. Here we show thatin silicoclosed-loop optogenetic feedback control of the unfolded protein response (UPR) clamps gene expression rates at intermediate near-optimal values, leading to significantly improved product titers. Specifically, in a fully-automated custom-built 1L-photobioreactor, we used a cybergenetic control system to steer the level of UPR in yeast to a desired set-point by optogenetically modulating the expression of a hard-to-fold protein based on real-time feedback measurements of the UPR, resulting in 60% higher product titers. This proof-of-concept study paves the way for advanced optimal biotechnology production strategies that diverge from and complement current strategies employing constitutive overexpression or genetically hardwired circuits.
Chromosome-scale genome assemblies of five differentBrassica oleraceamorphotypes provide insights in intraspecific diversification
Authors: Cai Chengcheng , Bucher Johan , Finkers Richard , Bonnema Guusje 
Published: October 2022

AbstractBrassica oleraceais an economically important vegetable and fodder crop species that includes many morphotypes exhibiting enormous phenotypic variations. Previously, a pan-genome study based on short reads mapping approach has shown extensive structural variations betweenB. oleraceamorphotypes. Here, to capture more complete genome sequences ofB. oleracea, we report new chromosome-scale genome assemblies for five different morphotypes, namely broccoli, cauliflower, kale, kohlrabi and white cabbage, which were created by combining long-read sequencing data and Bionano DLS optical maps. The five assemblies are the most continuous and completeB. oleraceagenomes to date (contig N50 > 10 Mb). Comparative analysis revealed both highly syntenic relationships and extensive structural variants among the five genomes. Dispensable and specific gene clusters accounted for ~38.19% of total gene clusters based on a pan-genome analysis including our five newly assembled genomes and four previously reported genomes. Using the pan-genome ofB. oleraceaandB. rapa, we revealed their different evolutionary dynamics of LTR-RTs. Furthermore, we inferred the ancestral genome ofB. oleraceaand the common ancestral genome ofB. oleraceaandB. rapavia a pan-genome approach. We observed faster WGT-derived gene loss inB. rapathan inB. oleraceabefore intraspecific diversification. We also revealed continuing gene loss bias during intraspecific diversification of the two species and a strong bias towards losing only one copy among the three paralogous genes. This study provides valuable genomic resources forB. oleraceaimprovement and insights towards understanding genome evolution during the intraspecific diversification ofB. oleraceaandB. rapa.
Repurposing the CRISPR-Cas9 System for Targeted Chromatin O-linked β-N-acetylglucosamine Editing
Authors: Parker Matthew P. , Dias Wagner B. , Brautman Will , Lowe Nick , Fedosyuk Halyna , Peterson Kenneth R. , Slawson Chad 
Published: October 2022

AbstractEukaryotic gene transcription is controlled by many proteins, including the basal transcription machinery, epigenetic chromatin remodeling complexes, and transcription cofactors. Chromatin and genome-mapping consortia identifiedO-linked β-N-acetylglucosamine (O-GlcNAc) as an abundant chromatin post-translational modification involved in numerous transcriptional processes, including RNA polymerase function, epigenetic dynamics, and transcription factor activity. Thus, O-GlcNAc regulation ofcis-regulatory elements is essential for proper gene expression. O-GlcNAc is a single N-acetylglucosamine sugar attached to serine or threonine residues in nuclear, cytoplasmic, or mitochondrial proteins. Two enzymes cycle O-GlcNAc on or off protein; O-GlcNAc transferase (OGT) adds the modification, and O-GlcNAcase (OGA) removes it. O-GlcNAcylation responds to inputs from multiple metabolic and stress pathways including glucose, amino acid, fatty acid, and nucleotide metabolism. Therefore, O-GlcNAc acts as a sensor of cellular homeostasis able to link environmental conditions with gene transcription; however, decoding the precise function of millions of O-GlcNAc regulated elements remains challenging. Technologies to readily manipulate O-GlcNAcylation at specificcis-regulatory elements for functional analysis without pleiotropic consequences are lacking. We have employed novel CRISPR-based gene targeting tools to probe the function of O-GlcNAc regulatedcis-elements. First, we developed a programmable CRISPR-Cas9-based targeting system. This was accomplished by fusing a catalytically dead Cas9 (dCas9) to O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA), which allows for highly specific O-GlcNAc manipulation at chromatincis-regulatory elements. Previously, we demonstrated that O-GlcNAc plays a role in regulating humanAγ-globin gene expression by regulating CHD4 function and the formation of the NuRD (Nucleosome Remodeling and Deacetylase) complex at the -566 GATA repressor-binding site. Thus, as a proof of principle and to further explore the function of O-GlcNAc inγ-globin gene transcription, we targeted both dCas9-OGT and -OGA fusion proteins to theAγ-globin gene promoter. When dCas9-OGT or dCas9-OGA was targeted to the -566 GATA silencer site of theAγ-globin promoter, gene expression decreased or increased, respectively. This data strongly correlates with our previous findings and implicates O-GlcNAc cycling inγ-globin gene regulation. Importantly, this method can be employed to investigate O-GlcNAc events known to exist within the eukaryotic genome in a highly specific manner. Together, this tool will be fundamental in elucidating the function of O-GlcNAc in gene transcription.
Cell-specific expression of key mitochondrial enzymes precludes OXPHOS in astrocytes of the adult human neocortex and hippocampal formation
Authors: Dobolyi Arpad , Bago Attila G , Stepanova Anna , Paal Krisztina , Lee Jeonghyoun , Palkovits Miklos , Chinopoulos Christos 
Published: October 2022

AbstractThe astrocyte-to-neuron lactate shuttle hypothesis entails that glycolytically derived pyruvate in astrocytes is converted to lactate instead of being catabolized in mitochondria. The mechanism of this metabolic rewiring is unclear. Here we show that astrocytes of the adult human neocortex and hippocampal formation do not express mitochondrial proteins critical for performing oxidative phosphorylation (OXPHOS) to a detectable degree, including cytochrome c and complex IV. Without OXPHOS, human brain astrocytes are bound to produce lactate to avoid interruption of glycolysis.
The circadian clock conveys thermal and photoperiodic cues to modulate EYES ABSENT via the neuropeptide PDF to regulate seasonal physiology
Authors: Hidalgo Sergio , Anguiano Maribel , Tabuloc Christine A. , Chiu Joanna C. 
Published: October 2022

AbstractOrganisms adapt to seasonal changes in photoperiod and temperature to survive; however, the mechanisms by which these signals are integrated in the brain are poorly understood. We previously reported that EYES ABSENT (EYA) inDrosophilashows higher levels in cold temperature or short photoperiod, and genetic ablation ofeyain the fly brain inhibits reproductive dormancy, suggesting that EYA promotes winter physiology. Nevertheless, the mechanisms by which EYA senses seasonal cues are unclear. Pigment-Dispersing Factor (PDF) is a neuropeptide important for photoentrainment and regulation of circadian output rhythms. Interestingly, PDF also regulates reproductive dormancy, suggesting that it may mediate the function of the circadian clock in modulating seasonal physiology. In this study, we investigated the role of PDF signaling in mediating the impact of EYA on seasonal biology. First, we subjected flies to different photoperiodic and temperature regimes and observed that PDF abundance is lower in cold and short days, compared to warm and long days. Interestingly, the response of PDF to seasonal cues is opposite of what was observed for EYA. We then determined the potential for PDF to convey seasonal cues and modulate EYA function in seasonality by assessing coexpression of EYA and PDF receptor. Our results indicated that PDF receptor (PDFR) is indeed coexpressed with EYA in the fly brain, including in the circadian clock neuronal network and neurons in thepars intercerebralis. We then manipulated PDF signaling ineya+ cells to show that PDF modulates seasonal adaptations in daily activity rhythm and ovary development via EYA-dependent and independent mechanisms. At the molecular level, manipulating PDF signaling impacted EYA protein abundance. Specifically, we showed that protein kinase A (PKA), an effector of PDF signaling, phosphorylates EYA and promotes its degradation. This explains the opposite responses of PDF and EYA abundance to changes in seasonal cues. In summary, our results support a model in which PDF signaling negatively modulates EYA levels to regulate seasonal physiology, linking the circadian clock to the modulation of seasonal adaptations.
Equalizing epigenetically imprinted centromeres in early mammalian embryos
Authors: Manske Gabriel , Jorgensen Kelsey , Ma Binbin , Aboelenain Mansour , Tower Catherine , Chakraborty Saikat , Ranjan Rajesh , Das Arunika , Lampson Michael A. , Black Ben E. , Schindler Karen , Chen Xin , Hammoud Saher Sue 
Published: October 2022

SummaryThe CENP-A histone variant epigenetically defines centromeres, where its levels and locations are precisely maintained through mitotic cell divisions. However, differences in centromere CENP-A propagation in soma versus female/male germline remains poorly understood. Here, we generated CenpamScarletmice and followed CENP-A dynamics in gametes, zygotes, and embryos. We found that, unlike somatic cells, progenitor female and male germ cells carry high centromeric CENP-A levels that decrease upon terminal differentiation. The reduction in CENP-A is differentially regulated between sexes, resulting in a ten-fold higher level in oocytes compared to sperm. In the zygote, the parent-of-origin CENP-A asymmetry is equalized prior to initial S-phase by redistribution of nuclear CENP-A from maternal to paternal chromosomes. Redistribution of CENP-A requires both CDK1/2 and PLK1 centromeric machinery. These experiments provide direct evidence for resetting of epigenetically imprinted centromeres in early pronuclear stage embryos and imply a mechanism to sense the non-equivalency of parental chromosomes.HighlightsIncreased CENP-A density at centromeres is a conserved property of germline stem cells while CENP-A reduction is coincident with germ cell differentiationPaternal and maternal CENP-A containing nucleosomes are intergenerationally inheritedCENP-A density at centromeres differs between male and female mature gametesUpon fertilization, maternal nuclear CENP-A is redistributed to equalize with parental CENP-ACENP-C and MIS18BP1 are asymmetrically enriched in the parental pronuclei in accordance with CENP-A asymmetry.Licensing for centromere equalization begins before zygotic DNA replication
Tocilizumab treatment leads to early resolution of lymphopenia and myeloid dysregulation in patients hospitalized with COVID-19
Authors: Shivram Haridha , Hackney Jason A. , Rosenberger Carrie M , Teterina Anastasia , Qamra Aditi , Onabajo Olusegun , McBride Jacqueline , Cai Fang , Bao Min , Tsai Larry , Regev Aviv , Rosas Ivan O. , Bauer Rebecca N. 
Published: October 2022

AbstractHigh interleukin (IL)-6 levels are associated with more severe clinical manifestations in patients hospitalized with COVID-19, but the complex role of IL-6 in antiviral and inflammatory processes has made it difficult to decipher its involvement in the disease. IL-6 receptor blockade by tocilizumab (anti-IL6R; Actemra) is used globally for the treatment of severe COVID-19, yet a molecular understanding of the therapeutic benefit remains unclear. We characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial that assessed the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysregulation, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab in addition to identifying novel pharmacodynamic biomarkers. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysregulation associated with severe COVID-19, indicating greater anti-inflammatory activity relative to standard of care and potentially leading to faster recovery in patients hospitalized with COVID-19.One sentence summaryInterleukin-6 receptor blockade with tocilizumab accelerated resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19
How predictable is rapid evolution?
Authors: Behrman Emily L. , Schmidt Paul 
Published: October 2022

AbstractAlthough evolution is historically considered a slow, gradual process, it is now clear that evolution can occur rapidly over generational timescales. It remains unclear both how predictable rapid evolution is and what timescales are ecologically relevant due to a paucity of longitudinal studies. We use a common garden approach to measure genetic-based change in complex, fitness-associated traits that are important for climatic adaptation in wildDrosophilaover multiple timescales: an estimated 1-16 generations within each year and 48-89 generations over five consecutive years. Evolution is fast and pervasive with parallel patterns of rapid evolution in three distinct locations that span 4º latitude. Developmental time evolves consistently across seasons with flies collected in spring developing faster than those collected in autumn. The evolutionary trajectory of stress traits (heat knockdown and starvation) depends on the severity of the preceding winter: harsh winters result in a predictable evolutionary trajectory with high stress tolerance in spring flies that declines in the subsequent generations across the summer. Flies collected after mild winters do not evolve in a predictable pattern but may utilize an alternative strategy as plasticity for chill coma recovery and starvation evolves across seasons. Overall, winter severity determines the predictability of rapid seasonal evolution, but there are also long-term shifts in the phenotypic correlations and allele frequencies that indicate long-term population changes that have broader implications for how organisms respond to the changing climate.Significance StatementAdaptive tracking may result in rapid evolution over short timescales, but the repeatability and predictability of rapid adaptation is less well resolved without long-term, multi-year analyses. Here, we collect wild flies at regular intervals across five years to determine what traits evolve consistently over seasons and which environmental variables predict this rapid evolution. Traditional temperate seasonal patterns of harsh winters are crucial for normal selection patterns, although independently changing phenotypic and genetic correlations help the populations respond to long-term shifts over years, particularly in response to heat stress. This has the implication that populations may be flexible within certain genetic constraints to adapt to changing climatic temperatures.
Natural heteroclitic-like peptides are generated by SARS-CoV-2 mutations
Authors: Tiezzi Camilla , Vecchi Andrea , Rossi Marzia , Cavazzini Davide , Bolchi Angelo , Laccabue Diletta , Sacchelli Luca , Brillo Federica , Meschi Tiziana , Ticinesi Andrea , Nouvenne Antonio , Donofrio Gaetano , Zanelli Paola , Benecchi Magda , Giuliodori Silvia , Fisicaro Paola , Montali Ilaria , Urbani Simona , Pedrazzi Giuseppe , Missale Gabriele , Telenti Amalio , Corti Davide , Ottonello Simone , Ferrari Carlo , Boni Carolina 
Published: October 2022

ABSTRACTMutations carried by SARS-CoV-2 spike protein variants may promote viral escape from immune protection. Humoral immunity is sensitive to evasion by SARS-CoV-2 mutants, but the impact of viral evolution on the interplay between virus and host CD8 T cell reactivity remains uncertain. By a systematic functional analysis of 30 spike variant mutations, we show that in vaccinated as well as convalescent subjects, mutated epitopes can have not only a neutral or abrogating effect on the recognition by CD8 T cells but can also enhance or even generate de novo CD8 T cell responses. Large pools of peptides spanning the entire spike sequence and comprising previously identified CD8 T cell epitopes were then used in parallel with variant peptides to define strength and multispecificity of total anti-spike CD8 responses. In some individuals, CD8 cells were narrowly focused on a few epitopes indicating that in this context of weak and oligospecific responses the overall antiviral protection can likely benefit of the function enhancing effect of heteroclitic-like mutations. In conclusion, appearance of mutated stimulatory epitopes likely reflects an epiphenomenon of SARS-CoV-2 evolution driven by antibody evasion and increased transmissibility, that might bear clinical relevance in a subset of individuals with weak and oligospecific CD8 T cell responses.
Car-following traffic model based on PID control: modelling and simulation
Authors: Han Shuang , Zhang Jing , Yang Quanyue , Yuan Zijian , Li Shubin , Cui Fengying , Zhang Chuntang , Wang Tao 
Published: October 2022

PurposeThe performance of the classical car-following system is easily affected by external disturbances. To enhance the performance of the classical car-following model under sudden external disturbances, a novel car-following model is established to smooth traffic flow.Design/methodology/approachThis paper proposed a Proportion Integration Differentiation (PID) control strategy based on classical control theory and developed a novel car-following model. The linear system theory and Laplace transform are used to derive a closed-loop transfer function. Then, the stability condition is obtained by using the Routh stability criterion and the small gain theorem. Finally, the validity and feasibility of the PID control strategy is proved by numerical simulations.FindingsThe analytic results and the numerical simulation results show that both the integration part and the differential part have the positive effect to suppress traffic oscillation efficiently; the collaboration of these two parts has more power to improve the stability of traffic flow. It means that the proposed model integrated with the PID control strategy has the ability of anti-interference and smooth traffic compared with the classical car-following model.Originality/valueThis paper introduces the PID control strategy into the classical car-following system, which enhances the stability of the system and also provides an efficient method for optimizing the traffic flow system.
An integrated method of automated layout design and optimization for modular construction
Authors: Zheng Zihao , Li Yuanqi , Torres Jaume 
Published: October 2022

PurposeThis paper aims to propose a generative design method combined with meta-heuristic algorithm for automating and optimizing the floor layout of modular buildings using typical standardized module units, which are the room module, the corridor module and the stair module.Design/methodology/approachThe integrated framework involves the generative design method and optimization for modular construction. The generative rules are provided by geometric relationships and functionalities of the module units. An evaluation function of the generated floor plans is also presented by the combination of project cost and cost penalties for the geometric features. The multi-population genetic algorithm (MPGA) method is provided for the optimization of the combination of costs.FindingsThe proposed MPGA method is demonstrated fast and efficient at discovering the globally optimal solution. The results indicate that when the unit price of modules is high, the transportation distance is long, or the land cost is high, the layout cost, which related to the symmetry, the compactness and the energy is tend to be lower, making the optimal layout economical.Originality/valueThis paper presented an integrated framework of generative floor layout and optimization for modular construction by using typical module units. It fulfills the need for automated layout generation with repetitive units and corresponding assessment during the early design stage.