bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure to temporal randomness promotes subsequent adaptation to new temporal regularities
Authors: Shdeour Orit , Tal-Perry Noam , Glickman Moshe , Yuval-Greenberg Shlomit 
Published: June 2023

AbstractNoise is intuitively thought to interfere with perceptual learning; However, human and machine learning studies suggest that, in certain contexts, variability may reduce overfitting and improve generalizability. Whereas previous studies have examined the effects of variability in learned stimuli or tasks, it is hitherto unknown what are the effects of variability in the temporal environment. Here, we examined this question in two groups of adult participants (N=40) presented with visual targets at either random or fixed temporal routines and then tested on the same type of targets at a new nearly-fixed temporal routine. Findings reveal that participants of the random group performed better and adapted quicker following a change in the timing routine, relative to participants of the fixed group. Corroborated with eye-tracking and computational modeling, these findings suggest that prior exposure to temporal randomness promotes the formation of new temporal expectations and enhances generalizability in a dynamic environment. We conclude that noise plays an important role in promotion perceptual learning in the temporal domain: rather than interfering with the formation of temporal expectations, noise enhances them. This counterintuitive effect is hypothesized to be achieved through eliminating overfitting and promoting generalizability.
Methoxsalen inhibited the acquisition of nicotine self-administration: attenuation by cotinine replacement in rats
Authors: Ding Zheng-Ming , Neslund Elizabeth M. , Sun Dongxiao , Tan Xiaoying 
Published: June 2023

AbstractCigarette smoking remains the leading preventable cause of disease and death. Nicotine is the primary reinforcing ingredient in cigarettes sustaining addiction. Cotinine is the major metabolite of nicotine that produces a myriad of neurobehavioral effects. Cotinine supported self-administration and rats with a history of intravenous self-administration of cotinine exhibited relapse-like drug-seeking behavior, suggesting cotinine may also be reinforcing. To date, a potential contribution of cotinine to nicotine reinforcement remains unknown. Nicotine metabolism is mainly catalyzed by hepatic CYP2B1 enzyme in the rat and methoxsalen is a potent CYP2B1 inhibitor. The study tested the hypothesis that methoxsalen inbibits nicotine metabolism and self-administration, and that cotinine replacement attenuates the inhibitory effects of methoxsalen. Acute methoxsalen decreased plasma cotinine levels and increased nicotine levels following subcutaneous nicotine injection. Repeated methoxsalen reduced the acquisition of nicotine self-administration, leading to fewer nicotine infusions, disruption of lever differentiation, smaller total nicotine intake, and lower plasma cotinine levels. On the other hand, methoxsalen did not alter nicotine self-administration during the maintenance phase despite great reduction of plasma cotinine levels. Cotinine replacement by mixing cotinine with nicotine for self-administration dose-dependently increased plasma cotinine levels, counteracted effects of methoxsalen, and enhanced the acquisition of self-administration. Neither basal nor nicotine-induced locomotor activity was altered by methoxsalen. These results indicate that methoxsalen depressed cotinine formation from nicotine and the acquisition of nicotine self-administration, and that replacement of plasma cotinine attenuated the inhibitory effects of methoxsalen, suggesting that cotinine may contribute to the development of nicotine reinforcement.
Discovering the mechanics of artificial and real meat
Authors: St. Pierre Skyler R. , Rajasekharan Divya , Darwin Ethan C. , Linka Kevin , Levenston Marc E. , Kuhl Ellen 
Published: June 2023

AbstractArtificial meat is an eco-friendly alternative to real meat that is marketed to have a similar taste and feel. The mechanical properties of artificial meat significantly influence our perception of taste, but how precisely the mechanics of artificial meat compare to real meat remains insufficiently understood. Here we perform mechanical tension, compression, and shear tests on isotropic artificial meat (Tofurky® Plant-Based Deli Slices), anisotropic artificial meat (Daring™ Chick’n Pieces) and anisotropic real meat (chicken) and analyze the data using constitutive neural networks and automated model discovery. Our study shows that, when deformed by 10%, artificial and real chicken display similar maximum stresses of 21.0 kPa and 21.8 kPa in tension, -7.2 kPa and -16.4 kPa in compression, and 2.4 kPa and 0.9 kPa in shear, while the maximum stresses for tofurky were 28.5 kPa, -38.3 kP, and 5.5 kPa. To discover the mechanics that best explain these data, we consulted two constitutive neural networks of Ogden and Valanis-Landel type. Both networks robustly discover models and parameters to explain the complex nonlinear behavior of artificial and real meat for individual tension, compression, and shear tests, and for all three tests combined. When constrained to the classical neo Hooke, Blatz Ko, and Mooney Rivlin models, both networks discover shear moduli of 94.4 kPa for tofurky, 35.7 kPa for artificial chick’n, and 21.4 kPa for real chicken. Our results suggests that artificial chicken succeeds in re-producing the mechanical properties of real chicken across all loading modes, while tofurky does not, and is about three times stiffer. Strikingly, all three meat products display shear softening and their resistance to shear is about an order of magnitude lower than their resistance to tension and compression. We anticipate our study to inspire more quantitative, mechanistic comparisons of artificial and real meat. Our automated-model-discovery based approach has the potential to inform the design of more authentic meat substitutes with an improved perception of taste, with the ultimate goal to reduce environmental impact, improve animal welfare, and mitigate climate change, while still offering the familiar taste and texture of traditional meat.Our source code, data, and examples will be available athttps://github.com/LivingMatterLab/CANNs.
MAT2A inhibition in AML unveils therapeutic potential of combining DNA demethylating agents with UPR targeting
Authors: Zeka Keti , Taylor Alice V. , Samarista Ralph , Ragusa Denise , Suen Chun-Wai , Cyran Oliwia W. , Domingues Ana Filipa , Meduri Eshwar , Huntly Brian JP , Forte Dorian , Curti Antonio , Pina Cristina 
Published: June 2023

ABSTRACTAcute Myeloid Leukaemia (AML) is a heterogeneous disease of dismal prognosis, with vulnerabilities in epigenetic and metabolic regulation. DNA demethylating agents, e.g. azacytidine (AZA), are used as first-line therapy in AML patients unable to tolerate intensive chemotherapy regimens, often in combination with BCL-2 inhibitor venetoclax. However, the impact on survival is limited, indicating the need for alternative therapeutic strategies. Methyl-group usage for epigenetic modifications depends on methionine availability and MAT2A-driven conversion to S-adenosyl-methionine. Methyl-group production is a vulnerability in multiple tumours, including AML, and has been variably linked to impairment of different histone methyl-modifications. In contrast, we herein align MAT2A effects in AML with DNA methylation and proteostasis. We show that MAT2A inhibition can be mimicked by combining AZA with unfolded protein response (UPR) activation through targeting of valosin-containing protein (VCP)/P97. Combined AZA and P97 inhibition exceeded AZA-driven restriction of human AML cell expansion, and specifically impaired colony-formation and maintenance of CD34+ patient blasts, suggesting targeting of AML stem/progenitor-like cells. Overall, our data support combined targeting of DNA methylation and the UPR as a promising therapeutic strategy in AML.
CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid carcinomas
Authors: Pita Jaime M. , Raspé Eric , Coulonval Katia , Decaussin-Petrucci Myriam , Tarabichi Maxime , Dom Geneviève , Libert Frederick , Craciun Ligia , Andry Guy , Wicquart Laurence , Leteurtre Emmanuelle , Trésallet Christophe , Marlow Laura A. , Copland John A. , Durante Cosimo , Maenhaut Carine , Cavaco Branca M. , Dumont Jacques E. , Costante Giuseppe , Roger Pierre P. 
Published: June 2023

AbstractDespite overall good prognosis associated to thyroid cancer (TC), poorly differentiated carcinomas (PDTC) and anaplastic carcinomas (ATC, one of the most lethal human malignancies) represent major clinical challenges. We have shown that the presence of active T172-phosphorylated CDK4 predicts sensitivity to CDK4/6 inhibitory drugs (CDK4/6i) including palbociclib. Here, CDK4 phosphorylation was detected in all well-differentiated TC (n=29), 19/20 PDTC, 16/23 ATC, and 18/21 TC cell lines including 11 ATC-derived ones. The cell lines lacking CDK4 phosphorylation were insensitive to CDK4/6i. RNA-sequencing and immunohistochemistry revealed that tumors and cell lines without phosphorylated CDK4 presented very high p16CDKN2Alevels that were associated with proliferative activity. NoRB1mutations were found in 5 of these 7 tumors. p16/KI67 immunohistochemistry and a previously developed 11-gene signature identified the likely insensitive tumors lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib, completely and irreversibly arresting proliferation. The combined drugs prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes. Our study supports the evaluation of CDK4/6i for ATC/PDTC treatment, including in combination with MEK/BRAF inhibitors.
Aeroplane wing, a new recessive autosomal phenotypic marker in malaria vector,Anopheles stephensiListon
Authors: Ghosh Chaitali , Soumya M , Kumar Naveen , Chethan Kumar R , Joshi Soumya Gopal , Kumar Sampath , Subramani Suresh , Swain Sunita 
Published: June 2023

AbstractA novel and distinct mutant, with an aeroplane wing (ae) phenotype, is reported for the first time in the urban malaria vector,Anopheles stephensi. The mutant mosquitoes exhibit extended wings that are easily visible to naked eyes in both sexes. This mutant was first observed in a nutritionally stressed experimental isofemale line and characterized for its genetic inheritance and other related parameters. Meticulous and strategic genetic crosses revealed that theaegene is an autosomal, recessive, non-sex-linked and monogenic trait with full penetrance and uniform expression in the adult stage. Cytogenetic study of the ovarian polytene chromosome revealed an inversion on the 3L chromosome (3Li) in both theaemutant and its parent line. No significant differences in wing venation and other parameters were observed inaemutants compared to their normal parental lines. Thisaemutant would be an excellent marker that can be used by researchers to study the function of related genes within the genome.Author summaryIn the present study, we have established and describe the inheritance of an unusual novel aeroplane (ae) winged mutant inAnopheles stephensi, an urban malaria vector in India. Theaemutant lines exhibit three open-wing orientations in both the sexes of adults viz. left (LW), right (RW) and double wing (DW) during its resting phase. Through various inbreeding crosses we demonstrated the mode of inheritance of theaegene to be autosomal, recessive and monogenic in nature. The morphometric studies of eggs and wings revealed that mutant lines are on par with their parental lines. Cytogenetic study of polytene chromosome ofaemutant revealed the presence of heterogenic inversion on the 3L chromosome arm, which might help in adaptation mechanism. We strongly believe thataephenotypic markers have great applications bridging both basic and applied genetic research such as constructing linkage maps, identifying loci of quantitative and/or qualitative traits and as guides for insect transformation studies.
Recurrent pattern completion drives the neocortical representation of sensory inference
Authors: Shin Hyeyoung , Ogando Mora B. , Abdeladim Lamiae , Durand Severine , Belski Hannah , Cabasco Hannah , Loefler Henry , Bawany Ahad , Hardcastle Ben , Wilkes Josh , Nguyen Katrina , Suarez Lucas , Johnson Tye , Han Warren , Ouellette Ben , Grasso Conor , Swapp Jackie , Ha Vivian , Young Ahrial , Caldejon Shiella , Williford Ali , Groblewski Peter , Olsen Shawn , Kiselycznyk Carly , Lecoq Jerome , Adesnik Hillel 
Published: June 2023

AbstractWhen sensory information is incomplete or ambiguous, the brain relies on prior expectations to infer perceptual objects. Despite the centrality of this process to perception, the neural mechanism of sensory inference is not known. Illusory contours (ICs) are key tools to study sensory inference because they contain edges or objects that are implied only by their spatial context. Using cellular resolution, mesoscale two-photon calcium imaging and multi-Neuropixels recordings in the mouse visual cortex, we identified a sparse subset of neurons in the primary visual cortex (V1) and higher visual areas that respond emergently to ICs. We found that these highly selective ‘IC-encoders’ mediate the neural representation of IC inference. Strikingly, selective activation of these neurons using two-photon holographic optogenetics was sufficient to recreate IC representation in the rest of the V1 network, in the absence of any visual stimulus. This outlines a model in which primary sensory cortex facilitates sensory inference by selectively strengthening input patterns that match prior expectations through local, recurrent circuitry. Our data thus suggest a clear computational purpose for recurrence in the generation of holistic percepts under sensory ambiguity. More generally, selective reinforcement of top-down predictions by pattern-completing recurrent circuits in lower sensory cortices may constitute a key step in sensory inference.
Theta phase precession at encoding predicts subsequent memory of sensory-driven vector fields, & occurs in memory-dependent fields at retrieval
Authors: Poulter Steven , de Cothi William , Barry Caswell , Lever Colin 
Published: June 2023

AbstractTheta phase precession is thought to confer key computational advantages (e.g. temporal compression suiting spike-timing related plasticity, cognitive relations as phase distances, and population-level coding for directions and sequences). However, direct evidence speaking to: 1) its widely-theorised role in enhancing memorability; 2) its dependence upon sensory input, is lacking. We leveraged the Vector trace cell (VTC) phenomenon to examine these issues. VTCs in subiculum show a simple, unambiguous memory correlate: VTCs remember the distance and direction to a cue after the cue is removed, with a new ‘trace field’ which was not present before the cue was inserted. Regarding memorability, here we show that subsequently-remembered cue fields (those which become trace fields) exhibit higher levels of phase precession than subsequently-forgotten cue fields (those which produce no trace). Thus, phase precession does appear to enhance memorability, consistent with long-established theory. The second issue concerns the extent of phase precession in sensory-elicited vs memory-dependent firing. Phase precession in CA1 is strongly disrupted following deprivation of its Entorhinal, but not CA3, inputs; this could indicate that theta phase precession is largely sensory-driven and absent in memory-dependent fields. Here, however, we show that phase precession is robust in subicular VTC trace fields, i.e. when the cue that originally elicited the new vector field is no longer present. Thus, the much-theorised benefits of phase precession likely apply to memory-dependent fields. These findings have wide implications for oscillatory-based models of memory.
Plant geographic distribution influences chemical defenses in native and introducedPlantago lanceolatapopulations
Authors: Medina-van Berkum Pamela , Schmöckel Eric , Bischoff Armin , Carrasco-Farias Natalia , Catford Jane A. , Feldmann Reinart , Groten Karin , Henry Hugh A. L. , Bucharova Anna Lampei , Hänniger Sabine , Luong Justin C. , Meis Julia , Oetama Vincensius S.P. , Pärtel Meelis , Power Sally A. , Villellas Jesus , Welk Erik , Wingler Astrid , Rothe Beate , Gershenzon Jonathan , Reichelt Michael , Roscher Christiane , Unsicker Sybille B. 
Published: June 2023

AbstractPlants growing outside their native range may be confronted by new regimes of herbivory, but how this affects plant chemical defense profiles has rarely been studied. UsingPlantago lanceolataas a model species, we investigated whether introduced populations show significant differences from native populations in several growth and chemical defense traits.Plantago lanceolata(ribwort plantain) is an herbaceous plant species native to Europe and Western Asia that has been introduced to numerous countries worldwide. We sampled seeds from nine native and ten introduced populations that covered a broad geographic and environmental range and performed a common garden experiment in a greenhouse, in which we infested half of the plants in each population with caterpillars of the generalist herbivoreSpodoptera littoralis. We then measured size-related and resource-allocation traits as well as the levels of constitutive and induced chemical defense compounds in roots and shoots ofP. lanceolata. When we considered the environmental characteristics of the site of origin, our results revealed that populations from introduced ranges were characterized by an increase of chemical defense compounds without compromising plant biomass. The concentrations of iridoid glycosides and verbascoside, the major anti-herbivore defense compounds ofP. lanceolata, were higher in introduced populations than in native populations. In addition, introduced populations exhibited greater rates of herbivore-induced volatile organic compound emission and diversity, and similar chemical diversity based on untargeted analyses of leaf methanol extracts. In general, the geographic origin of the populations had a significant influence on morphological and chemical plant traits, suggesting thatP. lanceolatapopulations are not only adapted to different environments in their native range, but also in their introduced range.
Deformable Cell-Like Microlasers for Real-Time Mechanical Quantification in Organoids
Authors: Fang Guocheng , Chen Yu-Cheng 
Published: June 2023

AbstractMechanical stress in multicellular environments plays a critical role in a wide range of tissue function and drug delivery. However, conventional methods are incapable of quantifying internal solid stressin situ, which is the hallmark of the 3D multicellular mechanical environment. To overcome the limitations, here we developed hollow-core structured microsphere lasers to realize all-optical direct recording of cellular stress in organoids and spheroids with cellular resolution. The deformations of whispering-gallery-mode laser can therefore be transduced into the change of the laser spectrum to reflect deformation within two-hundred nanometers in deep tissue environment. Our findings demonstrate the capability to quantify internal solid stress in different types of human tumor spheroids in real time. We also explored its potential in mechano-responded drug screening. Dynamic monitoring of contractile stress inside human embryonic stem cell-derived cardiac organoids was also obtained. This method may bring new opportunities to mechanobiology with multicellular resolution and accelerate high-throughput drug screening in human organoids.
Data-driven recombination detection in viral genomes
Authors: Alfonsi Tommaso , Bernasconi Anna , Chiara Matteo , Ceri Stefano 
Published: June 2023

AbstractRecombination is a key molecular mechanism for the evolution and adaptation of viruses. The first recombinant SARS-CoV-2 genomes were recognized in 2021; as of today, more than ninety SARS-CoV-2 lineages are designated as recombinant. In the wake of the COVID-19 pandemic, several methods for detecting recombination in SARS-CoV-2 have been proposed; however, none could faithfully confirm manual analyses by experts in the field.We hereby present RecombinHunt, a novel, automated method for the identification of recombinant/mosaic genomes purely based on a data-driven approach. RecombinHunt compares favorably with other state-of-the-art methods and recognizes recombinant SARS-CoV-2 genomes (or lineages) with one or two breakpoints with high accuracy, within reduced turn-around times and small discrepancies with respect to the expert manually-curated standard nomenclature.Strikingly, applied to the complete collection of viral sequences from the recent monkeypox epidemic, RecombinHunt identifies recombinant viral genomes in high concordance with manually curated analyses by experts, suggesting that our approach is robust and can be applied to any epidemic/pandemic virus.In conclusion, RecombinHunt represents a breakthrough in the detection of recombinant viral lineages in pandemic/epidemic scenarios and could substantially improve/advance community-based approaches for the detection of recombinant viral genomes based on phylogenetic analyses.
Activation of Multiple Eph Receptors on Neuronal Membranes Correlates with The Onset of Traumatic Optic Neuropathy
Authors: Strong Thomas A. , Esquivel Juan , Wang Qikai , Ledon Paul J. , Wang Hua , Gaidosh Gabriel , Tse David , Pelaez Daniel 
Published: June 2023

ABSTRACTBackgroundOptic neuropathy (ON) is a major cause of irreversible blindness, yet the molecular determinants that contribute to neuronal demise have not been fully elucidated. Several studies have identified ‘ephrin signaling’ as one of the most dysregulated pathways in the early pathophysiology of ON with varied etiologies. Developmentally, gradients in ephrin signaling coordinate retinotopic mapping via repulsive modulation of cytoskeletal dynamics in neuronal membranes. Little is known about the role ephrin signaling played in the post-natal visual system and its correlation with the onset of optic neuropathy.MethodsPostnatal mouse retinas were collected for mass spectrometry analysis for Eph receptors. Optic nerve crush (ONC) model was employed to induce optic neuropathy, and proteomic changes during the acute phase of neuropathic onset were analyzed. Confocal and super-resolution microscopy determined the cellular localization of activated Eph receptors after ONC injury. Eph receptor inhibitors assessed the neuroprotective effect of ephrin signaling modulation.ResultsMass spectrometry revealed expression of seven Eph receptors (EphA2, A4, A5, B1, B2, B3, and B6) in postnatal mouse retinal tissue. Immunoblotting analysis indicated a significant increase in phosphorylation of these Eph receptors 48 hours after ONC. Confocal microscopy demonstrated the presence of both subclasses of Eph receptors in the inner retinal layers. STORM super-resolution imaging combined with optimal transport colocalization analysis revealed a significant co-localization of activated Eph receptors with injured neuronal processes, compared to uninjured neuronal and/or injured glial cells, 48 hours post-ONC. Eph receptor inhibitors displayed notable neuroprotective effects after 6 days of ONC injury.ConclusionsOur findings demonstrate the functional presence of diverse Eph receptors in the postnatal mammalian retina, capable of modulating multiple biological processes. Pan-Eph receptor activation contributes to the onset of neuropathy in ONs, with preferential activation of Eph receptors on neuronal processes in the inner retina following optic nerve injury. Notably, Eph receptor activation precedes neuronal loss. We observed neuroprotective effects upon inhibiting Eph receptors. Our study highlights the importance of investigating this repulsive pathway in early optic neuropathies and provides a comprehensive characterization of the receptors present in the developed retina of mice, relevant to both homeostasis and disease processes.