bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimal operation of parallel mini-bioreactors in bioprocess development using multi-stage MPC
Authors: Krausch Niels , Kim Jong Woo , Lucia Sergio , Groß Sebastian , Barz Tilman , Neubauer Peter , Cruz Bournazou Mariano N. 
Published: December 2021

AbstractBioprocess development is commonly characterized by long development times, especially in the early screening phase. After promising candidates have been pre-selected in screening campaigns, an optimal operating strategy has to be found and verified under conditions similar to production. Cultivating cells with pulse-based feeding and thus exposing them to oscillating feast and famine phases has shown to be a powerful approach to study microorganisms closer to industrial bioreactor conditions. In view of the large number of strains and the process conditions to be tested, high-throughput cultivation systems provide an essential tool to sample the large design space in short time. We have recently presented a comprehensive platform, consisting of two liquid handling stations coupled with a model-based experimental design and operation framework to increase the efficiency in High Throughput bioprocess development. Using calibrated macro-kinetic growth models, the platform has been successfully used for the development of scale-down fed-batch cultivations in parallel mini-bioreactor systems. However, it has also been shown that parametric uncertainties in the models can significantly affect the prediction accuracy and thus the reliability of optimized cultivation strategies. To tackle this issue, we implemented a multi-stage Model Predictive Control (MPC) strategy to fulfill the experimental objectives under tight constraints despite the uncertainty in the parameters and the measurements. Dealing with uncertainties in the parameters is of major importance, since constraint violation would easily occur otherwise, which in turn could have adverse effects on the quality of the heterologous protein produced. Multi-stage approaches build up scenario tree, based on the uncertainty that can be encountered and computing optimal inputs that satisfy the constrains despite of such uncertainties. Using the feedback information gained through the evolution along the tree, the control approach is significantly more robust than standard MPC approaches without being overly conservative. We show in this study that the application of multi-stage MPC can increase the number of successful experiments, by applying this methodology to a mini-bioreactor cultivation operated in parallel.
Insights from the IronTract challenge: optimal methods for mapping brain pathways from multi-shell diffusion MRI
Authors: Maffei Chiara , Girard Gabriel , Schilling Kurt G. , Aydogan Dogu Baran , Adluru Nagesh , Zhylka Andrey , Wu Ye , Mancini Matteo , Hamamci Andac , Sarica Alessia , Teillac Achille , Baete Steven H. , Karimi Davood , Yeh Fang-Cheng , Yildiz Mert E. , Gholipour Ali , Bihan-Poudec Yann , Hiba Bassem , Quattrone Andrea , Quattrone Aldo , Boshkovski Tommy , Stikov Nikola , Yap Pew-Thian , de Luca Alberto , Pluim Josien , Leemans Alexander , Prabhakaran Vivek , Bendlin Barbara B. , Alexander Andrew L. , Landman Bennett A. , Canales-Rodríguez Erick J. , Barakovic Muhamed , Rafael-Patino Jonathan , Yu Thomas , Rensonnet Gaëtan , Schiavi Simona , Daducci Alessandro , Pizzolato Marco , Fischi-Gomez Elda , Thiran Jean-Philippe , Dai George , Grisot Giorgia , Lazovski Nikola , Puch Santi , Ramos Marc , Rodrigues Paulo , Prchkovska Vesna , Jones Robert , Lehman Julia , Haber Suzanne N. , Yendiki Anastasia 
Published: December 2021

AbstractLimitations in the accuracy of brain pathways reconstructed by diffusion MRI (dMRI) tractography have received considerable attention. While the technical advances spearheaded by the Human Connectome Project (HCP) led to significant improvements in dMRI data quality, it remains unclear how these data should be analyzed to maximize tractography accuracy. Over a period of two years, we have engaged the dMRI community in the IronTract Challenge, which aims to answer this question by leveraging a unique dataset. Macaque brains that have received both tracer injections and ex vivo dMRI at high spatial and angular resolution allow a comprehensive, quantitative assessment of tractography accuracy on state-of-the-art dMRI acquisition schemes. We find that, when analysis methods are carefully optimized, the HCP scheme can achieve similar accuracy as a more time-consuming, Cartesian-grid scheme. Importantly, we show that simple pre- and post-processing strategies can improve the accuracy and robustness of many tractography methods. Finally, we find that fiber configurations that go beyond crossing (e.g., fanning, branching) are the most challenging for tractography. The IronTract Challenge remains open and we hope that it can serve as a valuable validation tool for both users and developers of dMRI analysis methods.
DOK1 and DOK2 regulate CD8+ T cell signaling and memory formation without affecting tumor cell killing
Authors: Laletin V. , Bernard P.-L. , Montersino C. , Yamanashi Y. , Olive D. , Castellano R. , Guittard G. , Nunès J. A. 
Published: December 2021

ABSTRACTTargeting intracellular inhibiting proteins is a promising strategy to improve CD8+ T cell anti-tumor efficacy. DOK1 and DOK2 are CD8+ T cell inhibitory proteins that are targeted in this study in order to improve the activation and cytotoxic capacities of these cells. To evaluate the role of DOK-1 and DOK-2 depletion in physiology and effector function of T CD8+ lymphocyte and in cancer progression, a transgenic T cell receptor mouse model specific to melanoma antigen hgp100 (pmel-1 TCR Tg) was established.Depletion of both Dok1 and Dok2 did not affect the development, proliferation, mortality, activation and cytotoxic function of naive CD8+ T cells. However, after an in vitro pre-stimulation Dok1/Dok2 DKO CD8+ T cells had higher percentage of effector memory T cells and showed an increase in levels of pAKT and pERK upon TCR stimulation. Despite this improved TCR signaling, pre-stimulated Dok1/Dok2 DKO CD8+ T cells did not show any increase in their activation or cytotoxicity capacities against melanoma cell line expressing hgp100 in vitro.Altogether we demonstrate here a novel aspect of the negative regulation by DOK1 and DOK2 proteins in CD8+ T cells. In conclusion, DOK1 and DOK2 have an inhibitory role following long term T cell stimulations.
Temporal in vivo platelet labelling in mice reveals age-dependent receptor expression and conservation of specific mRNAs
Authors: Armstrong Paul C , Allan Harriet E , Kirkby Nicholas S , Joshi Abhishek , Gutmann Clemens , Crescente Marilena , Mitchell Jane A , Mayr Manuel , Warner Timothy D 
Published: December 2021

AbstractThe proportion of young platelets, also known as newly formed or reticulated, within the overall platelet population has been clinically correlated with adverse cardiovascular outcomes. Our understanding of this is incomplete, however, because of limitations in the technical approaches available to study platelets of different ages. In this study we have developed and validated an in vivo ‘temporal labelling’ approach using injectable fluorescent anti-platelet antibodies to sub-divide platelets by age and assess differences in functional and molecular characteristics. With this approach we found that young platelets (<24h old) in comparison to older platelets respond to stimuli with greater calcium flux and degranulation, and contribute more to the formation of thrombi in vitro and in vivo. Sequential sampling confirmed this altered functionality to be independent of platelet size with no size differences or changes relative to the global population seen at any age. The age associated decrease in thrombotic function was accompanied by significant decreases in the surface expression of GPVI and CD31 (PECAM-1) and an increase in CD9. Platelet mRNA content also decreased with age but at different rates for individual mRNAs indicating apparent conservation of those encoding granule proteins. Our pulse-chase type approach to define circulating platelet age has allowed timely re-examination of commonly held beliefs regarding size and reactivity of young platelets whilst providing novel insights into the temporal regulation of receptor and protein expression. Overall, future application of this validated tool will inform on age-based platelet heterogeneity in physiology and disease.
“Heat waves” experienced during larval life have species-specific consequences on life-history traits and sexual development in anuran amphibians
Authors: Ujszegi János , Bertalan Réka , Ujhegyi Nikolett , Verebélyi Viktória , Nemesházi Edina , Mikó Zsanett , Kásler Andrea , Herczeg Dávid , Szederkényi Márk , Vili Nóra , Gál Zoltán , Hoffmann Orsolya I. , Bókony Veronika , Hettyey Attila 
Published: December 2021

AbstractExtreme temperatures during heat waves can induce mass-mortality events, but can also exert sublethal negative effects by compromising life-history traits and derailing sexual development. Ectothermic animals may, however, also benefit from increased temperatures via enhanced physiological performance and the suppression of cold-adapted pathogens. Therefore, it is crucial to address how the intensity and timing of naturally occurring or human-induced heat waves affect life-history traits and sexual development in amphibians, to predict future effects of climate change and to minimise risks arising from the application of elevated temperature in disease mitigation. We raised agile frog (Rana dalmatina) and common toad (Bufo bufo) tadpoles at 19 °C and exposed them to a simulated heat wave of 28 or 30 °C for six days during one of three ontogenetic periods (early, mid or late larval development). In agile frogs, exposure to 30 °C during early larval development increased mortality. Regardless of timing, all heat-treatments delayed metamorphosis, and exposure to 30 °C decreased body mass at metamorphosis. Furthermore, exposure to 30 °C during any period and to 28 °C late in development caused female-to-male sex reversal, skewing sex ratios strongly towards males. In common toads, high temperature only slightly decreased survival and did not influence phenotypic sex ratio, while it reduced metamorph mass and length of larval development. Juvenile body mass measured two months after metamorphosis was not adversely affected by temperature treatments in either species. Our results indicate that heat waves may have devastating effects on amphibian populations, and the severity of these negative consequences, and sensitivity can vary greatly between species and with the timing and intensity of heat. Finally, thermal treatments against cold-adapted pathogens have to be executed with caution, taking into account the thermo-sensitivity of the species and the life stage of animals to be treated.
MicroRNA-like snoRNA-derived RNAs (sdRNAs) promote castration resistant prostate cancer
Authors: Coley Alexander B. , Stahly Ashlyn N. , Kasukurthi Mohan V. , Barchie Addison A. , Hutcheson Sam B. , Houserova Dominika , Huang Yulong , Watters Brianna C. , King Valeria M. , Dean Meghan A. , Roberts Justin T. , DeMeis Jeffrey D. , McInnis Cameron H. , Godang Noel L. , Wright Ryan M. , Haider David F. , Piracha Neha B. , Brown Cana L. , Ijaz Zohaib M. , Li Shengyu , Xi Yaguang , McDonald Oliver G. , Huang Jingshan , Borchert Glen M. 
Published: December 2021

ABSTRACTWe have identified 38 specifically excised, differentially expressed snoRNA fragments (sdRNAs) in TCGA prostate cancer (PCa) patient samples as compared to normal prostate controls. SnoRNA-derived fragments sdRNA-D19b and -A24 emerged among the most differentially expressed and were selected for further experimentation. We found that overexpression of either sdRNA significantly increased PC3 (a well-established model of castration-resistant prostate cancer (CRPC)) cell proliferation, and that sdRNA-D19b overexpression also markedly increased the rate of PC3 cell migration. In addition, both sdRNAs provided drug-specific resistances with sdRNA-D19b levels correlating with paclitaxel resistance and sdRNA-24A conferring dasatinib resistance. In silico and in vitro analyses revealed that two established PCa tumor suppressor genes, CD44 and CDK12, represent targets for sdRNA-D19b and sdRNA-A24 respectively. This outlines a biologically coherent mechanism by which sdRNAs downregulate tumor suppressors in AR-PCa to enhance proliferative and metastatic capabilities and to encourage chemotherapeutic resistance. Aggressive proliferation, rampant metastasis, and recalcitrance to chemotherapy are core characteristics of CRPC that synergize to produce a pathology that ranks 2nd in cancer-related deaths for men. This study defines sdRNA-D19b and -A24 as contributors to AR-PCa potentially providing novel biomarkers and therapeutic targets of use in PCa clinical intervention.
Stimulus-induced changes in 1/f-like background activity in EEG
Authors: Gyurkovics Máté , Clements Grace M. , Low Kathy A. , Fabiani Monica , Gratton Gabriele 
Published: December 2021

AbstractResearch into the nature of 1/f-like, non-oscillatory electrophysiological activity has grown exponentially in recent years in cognitive neuroscience. The shape of this activity has been linked to the balance between excitatory and inhibitory neural circuits, which is thought to be important for information processing. However, to date, it is not known whether the presentation of a stimulus induces changes in the parameters of 1/f activity, which are separable from the emergence of event-related potentials (ERPs). Here, we analyze event-related broadband changes in scalp-recorded EEG both before and after removing ERPs to demonstrate their confounding effect, and to establish whether there are genuine stimulus-induced changes in 1/f. Using data from a passive and an active auditory task (n=23), we found that the shape of the post-event spectra differed significantly from the pre-event spectra even after removing the frequency-content of ERPs. Further, a significant portion of this difference could be accounted for by a rotational shift in 1/f activity, manifesting as an increase in low and a decrease in high frequencies. Importantly, the magnitude of this rotational shift was related to the attentional demands of the task. This change in 1/f is consistent with increased inhibition following the onset of a stimulus, and likely reflects a disruption of ongoing excitatory activity proportional to processing demands. Finally, these findings contradict the central assumption of baseline normalization strategies in time-frequency analyses, namely that background EEG activity is stationary across time. As such, they have far-reaching consequences that cut across several subfields of neuroscience.Significance statementInterest in the functional role of the 1/f-like background brain activity has been growing exponentially in neuroscience. Yet, no study to date has demonstrated a clear relationship between information processing and 1/f activity by investigating event-related effects on its parameters. Here, we demonstrate for the first time that stimuli induce rotational changes in 1/f activity, independent from the occurrence of event-related potentials. Not only do these findings suggest that the assumption of stationary background activity in the analysis of neural oscillations is untenable, but they also suggest the presence of large-scale inhibition following stimulus onset, the magnitude of which is dependent on the demands of the task. These findings have far-reaching consequences that cut across several subfields of neuroscience.
Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford Progeria Syndrome
Authors: Murtada S-I. , Mikush N. , Wang M. , Ren P. , Kawamura Y. , Ramachandra A.B. , Braddock D.T. , Tellides G. , Gordon L.B. , Humphrey J.D. 
Published: December 2021

ABSTRACTClinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved Zokinvy™ (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe end-stage cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, dual treatment with lonafarnib and rapamycin did not improve outcomes over that achieved with lonafarnib monotherapy.
Efficient Design of Peptide-Binding Polymers Using Active Learning Approaches
Authors: Rakhimbekova A. , Lopukov A. , Klyachko N. , Kabanov A. , Madzhidov T.I. , Tropsha A. 
Published: December 2021

AbstractActive learning (AL) has become a subject of active recent research both in industry and academia as an efficient approach for rapid design and discovery of novel chemicals, materials, and polymers. The key advantages of this approach relate to its ability to (i) employ relatively small datasets for model development, (ii) iterate between model development and model assessment using small external datasets that can be either generated in focused experimental studies or formed from subsets of the initial training data, and (iii) progressively evolve models toward increasingly more reliable predictions and the identification of novel chemicals with the desired properties. Herein, we first compared various AL protocols for their effectiveness in finding biologically active molecules using synthetic datasets. We have investigated the dependency of AL performance on the size of the initial training set, the relative complexity of the task, and the choice of the initial training dataset. We found that AL techniques as applied to regression modeling offer no benefits over random search, while AL used for classification tasks performs better than models built for randomly selected training sets but still quite far from perfect. Using the best performing AL protocol, we have assessed the applicability of AL for the discovery of polymeric micelle formulations for poorly soluble drugs. Finally, the best performing AL approach was employed to discover and experimentally validate novel binding polymers for a case study of asialoglycoprotein receptor (ASGPR).
Structure of Vibrio phage XM1, a simple contractile DNA injection machine
Authors: Wang Zhiqing , Fokine Andrei , Guo Xinwu , Jiang Wen , Rossmann Michael G. , Kuhn Richard J. , Luo Zhu-Hua , Klose Thomas 
Published: December 2021

AbstractAntibiotic resistance poses a growing risk to public health requiring new tools to combat pathogenic bacteria. Contractile injection systems, including bacteriophage tails, pyocins, and bacterial type VI secretion systems, can efficiently penetrate cell envelopes and become potential antibacterial agents. Bacteriophage XM1 is a dsDNA virus belonging to the Myoviridae family and infecting Vibrio bacteria. The XM1 virion, made of 18 different proteins, consists of an icosahedral head and a contractile tail, terminated with a baseplate. Here we report cryo-EM reconstructions of all components of the XM1 virion and describe atomic structures of 14 XM1 proteins. The XM1 baseplate is composed of a central hub surrounded by six wedge modules to which twelve spikes are attached. The XM1 tail contains a fewer number of smaller proteins compared with other reported phage baseplates, depicting the minimum requirements for building an effective cell-envelope-penetrating machine. We describe the tail sheath structure in the pre-infection post-infection states and its conformational changes during infection. In addition, we report, for the first time, the in situ structure of the phage neck region to near-atomic resolution. Based on these structures, we propose mechanisms of virus assembly and infection.
Metabolic Processing of Selenium-based Bioisostere of meso-diaminopimelic Acid in Live Bacteria
Authors: Apostolos Alexis J. , Koyasseril-Yehiya Thameez M. , Santamaria Carolina , Silva José Rogério A. , Lameira Jerônimo , Alves M. Cláudio N. , Siegrist M. Sloan , Pires Marcos M. 
Published: December 2021

AbstractThe bacterial cell wall supports cell shape and prevents lysis due to internal turgor pressure. A primary component of all known bacterial cell walls is the peptidoglycan (PG) layer, which is comprised of repeating units of sugars connected to short and unusual peptides. The various steps within PG biosynthesis are often the target of antibiotics as they are essential for cellular growth and survival. Synthetic mimics of PG have proven to be indispensable tools to study bacterial cell growth and remodeling. Yet, a common component of PG, meso-diaminopimelic acid (m-DAP) at the third position of the stem peptide, remains challenging to build synthetically and is not commercially available. Here, we describe the synthesis and metabolic processing of a selenium-based bioisostere of a m-DAP analogue, selenolanthionine. We show that selenolanthionine is installed within the PG of live bacteria by the native cell wall crosslinking machinery in several mycobacteria species. We envision that this probe will supplement the current methods available for investigating PG crosslinking in m-DAP containing organisms.
Global cerebrospinal fluid circulation mapping using gold nanoparticle enhanced X-ray microtomography reveals region-specific brain and spinal cord CSF pathways
Authors: Pan Shelei , DeFreitas Dakota , Ramagiri Sruthi , Bayguinov Peter , Hacker Carl D. , Snyder Abraham Z. , Wilborn Jackson , Huang Hengbo , Yang Peter H. , Raval Dhvanii K. , Svben Sanja , Achilefu Samuel , Tang Rui , Haller Gabriel , Quirk James D. , Fitzpatrick James A. , Esakky Prabagaran , Strahle Jennifer M. 
Published: December 2021

AbstractCerebrospinal fluid (CSF) movement within the brain interstitium is essential for the development and functioning of the brain. However, the interstitium has largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with CSF. Here, we developed a novel technique for CSF tracking, gold nanoparticle enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF pathways during development. Using this method and subsequent histological analysis, we map global CSF pathways and present novel particle size-dependent circulation patterns through the CNS. We identify an intraparenchymal CSF circulation that targets stem cell-rich and cholinergic neuronal populations. CSF solute distribution to these areas is mediated by CSF flow along projections from the basal cisterns which is altered in posthemorrhagic hydrocephalus. Our study uncovers region-specific patterns in a biologically driven CSF circulation that has implications for normal brain development and the pathophysiology of hydrocephalus and neurodegenerative disorders.