bluuebunny/crossref_metadata_2025 huggingface dataset:
Optogenetic stimulation of the locus coeruleus enhances appetitive extinction in rats
Authors: Lui Simon , Brink Ashleigh , Corbit Laura
Published: June 2023

Extinction is a specific example of learning where a previously reinforced stimulus or response is no longer reinforced, and the previously learned behaviour is no longer necessary and must be modified. Current theories suggest extinction is not the erasure of the original learning but involves new learning that acts to suppress the original behaviour. Evidence for this can be found when the original behaviour recovers following the passage of time (spontaneous recovery), or reintroduction of the reinforcement (i.e., reinstatement). Recent studies have shown that pharmacological manipulation of noradrenaline (NA) or its receptors can influence appetitive extinction, however, the role and source of endogenous NA in these effects is unknown. Here, we examined the role of the locus coeruleus (LC) in appetitive extinction. Specifically, we tested whether optogenetic stimulation of LC neurons during extinction of a food-seeking behaviour would enhance extinction evidenced by reduced spontaneous recovery in future tests. LC stimulation during extinction trials did not change the rate of extinction but did serve to reduce subsequent spontaneous recovery suggesting that stimulation of the LC can augment reward-related extinction. Optogenetic inhibition of the LC during extinction trials reduced responding during the trials where it was applied, but no long-lasting changes in the retention of extinction were observed. Since not all LC cells expressed halorhodopisn, is possible that more complete LC inhibition or pathway-specific targeting would be more effective at suppressing extinction learning. These results provide further insight into the neural basis of appetitive extinction, and in particular the role of the LC. A deeper understanding of the physiological bases of extinction can aid development of more effective extinction-based therapies.
Alpha-band frequency and temporal windows in perception: A review and living meta-analysis of 27 experiments (and counting)
Authors: Samaha Jason , Romei Vincenzo
Published: June 2023

Temporal windows in perception refer to windows of time within which distinct stimuli interact to influence perception. A simple example is two temporally proximal stimuli fusing into a single percept. It has long been hypothesized that the human alpha rhythm (an 8-13 Hz neural oscillation maximal over posterior cortex) is linked to temporal windows, with higher frequencies corresponding to shorter windows and finer-grained temporal resolution. This hypothesis has garnered support from studies demonstrating a correlation between individual differences in alpha frequency (IAF) and behavioral measures of temporal processing. However, non-significant effects have also been reported. Here, we review and meta-analyze 27 experiments correlating IAF with measures of visual and audio-visual temporal processing. Our results estimate the true correlation in the population to be between 0.39 to 0.53, a medium-to-large effect. The effect held when considering visual or audio-visual experiments separately, when examining different IAF estimation protocols (i.e., eyes-open and eyes-closed), and when using analysis choices that favor a null result. Our review shows that 1) effects have been internally and independently replicated 2) several positive effects are based on larger sample sizes than the null effects and 3) many reported null effects are actually in the direction predicted by the hypothesis. A free interactive web-app was developed to allow users to replicate our meta-analysis and change or update the study selection at will, making this a “living” meta-analysis (https://randfxmeta.streamlit.app). We discuss possible factors underlying null reports, design recommendations, and open questions for future research
Communication between wolf and domestic dog revealed from experimental scent marking
Authors: Stępniak Kinga M. , Diserens Tom A. , Szewczyk Maciej , Mysłajek Robert W. , Kuijper Dries P.J.
Published: June 2023

The European grey wolf (Canis lupus) and the domestic dog (Canis lupus familiaris) share not only a common origin but also many similarities in their behavior. Due to the implementation of protection wolves repopulated large parts of Europe. The increase of wolves in human-dominated landscapes also leads to a growing potential for interactions between wolves and domestic dogs. However, these interactions between wolves and dogs are still poorly understood. Scent marking is one of the main forms of communication in canids, as is crucial for territorial marking, synchronization of reproduction, establishment of hierarchies in groups, and formation of new breeding pairs. We hypothesized that the presence of scent markings by domestic dogs in wolf territories elicits a behavioral response of wolves and therefore may interfere with natural wolf behavior. To test this, we experimentally scent-marked objects within known wolf home-ranges in the Kampinos National Park (Poland) to simulate the presence of “unknown dogs” (dog urine from outside the area) and water as a control. To test whether and how the behavioral response differs between domestic dogs and wolves we additionally created scent marks of “unknown wolves” (wolf urine from outside the area). By means of camera traps we studied the behavioral repones of local wolf families exposed simultaneously to all three scent stimuli. Our study showed that wolves (breeding pair) reacted to scent marking from “unknown dog” in 16% of cases, while an average juvenile reacted in 27% of cases. In 33% of cases, the breeding pair overmarked stimuli from an “unknown dog” and in 27% of cases mark them by ground scratching. Wolves spend significantly more time exploring and sniffing scent marks of “unknown wolves” than “unknown dogs”.

Our result indicates that domestic dog scent marks trigger a behavioral response in wild wolves showing that it does affect their behavior. The longer time that wolves spend on responding to wolf scent marks compared to dog scent marks indicates they can distinguish between wolf and dog scent marks, but especially inexperienced juveniles spend much time exploring dog scent marks. This suggests that the increasing occurrence of dogs inside wolf territories could affect and potentially disturb the scent-marking behavior of wolves.
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

Noise 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

Cigarette 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

Artificial 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

Acute 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

Despite 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.
The long term effects of uncoupling interventions as a therapy for dementia in humans
Authors: Holt Alan G , Davies Adrian M
Published: June 2023

In this paper we use simulation methods to study a hypothetical uncoupling agent as a therapy for dementia. We simulate the proliferation of mitochondrial deletion mutants amongst a population of wild-type in human neurons. Mitochondria play a key role in ATP generation. Clonal expansion can lead to the wild-type being overwhelmed by deletions such that a diminished population can no longer fulfill a cell's energy requirement, eventually leading its demise. The intention of uncoupling is to reduce the formation of deletion mutants by reducing mutation rate. However, a consequence of uncoupling is that the energy production efficacy is also reduced which in turn increases wild-type copy number in order to compensate for the energy deficit. The results of this paper showed that uncoupling reduced the severity of dementia, however, there was some increase in cognitive dysfunction pre-onset of dementia. The effectiveness of uncoupling was dependent upon the timing of intervention relative to the onset of dementia and would necessitate predicting its onset many years in advance.
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

A 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 summary

In 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

When 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

Theta 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

Plants 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

Mechanical 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

Recombination 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

Background

Optic 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.

Methods

Postnatal 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.

Results

Mass 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.

Conclusions

Our 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.
Early and selective subcortical Tau pathology within the human Papez circuit
Authors: Sárkány Barbara , Dávid Csaba , Hortobágyi Tibor , Gombás Péter , Somogyi Peter , Acsády László , Viney Tim J.
Published: June 2023

The Papez circuit comprises several interconnected brain areas important for spatial navigation and orientation. An early symptom of dementia is disorientation, suggesting that brain regions responsible for providing a sense of direction are adversely affected. We examinedpost-mortemhuman tissue from cases with no cognitive impairment, mild cognitive impairment, and Alzheimer’s disease. A key part of the Papez circuit, the anterodorsal thalamic nucleus (ADn), contained a high density of misfolded pathological Tau (pTau) at all disease stages, including in control cases. Moreover, pTau preferentially accumulated in calretinin-expressing neurons. At the subcellular level, we detected pTau filaments in ADn cell bodies, dendrites, and in specialized presynaptic terminals. Large vesicular-glutamate-transporter-2-containing terminals from the lateral mammillary nucleus, rather than corticothalamic terminals, preferentially contained pTau, suggesting that Tau crosses specific synapses within the Papez circuit. As the ADn contains a high density of head direction cells, pTau may degrade the processing of orientation signals, explaining why people become disorientated years-to-decades before memory deficits emerge.
Atypical Chemokine Receptor 1 (Ackr1)-deficient Mice Resist Lethal SARS-CoV-2 Challenge
Authors: Majumdar Shamik , Weaver Joseph D. , Pontejo Sergio M. , Minai Mahnaz , Georgia-Clark Shalamar , Gao Ji-Liang , Lu Xinping , Zhang Hongwei , Lackemeyer Nicole , Burdette Tracey , Johnson Reed , Kelsall Brian L. , Farber Joshua M. , Alves Derron A. , Murphy Philip M.
Published: June 2023

High pro-inflammatory chemokine levels have been reported in blood and lung in patients with COVID-19. To investigate specific roles in pathogenesis, we studied the regulation of chemokine ligands and receptors in the lungs of 4-6-month-old wild type C57BL/6 mice infected with the MA10 mouse-adapted strain of SARS-CoV-2. We found that atypical chemokine receptor 1 (Ackr1, also known as Duffy antigen receptor for chemokines/DARC) was the most highly upregulated chemokine receptor in infected lung, where it localized to endothelial cells of veins and arterioles. In a screen of 7 leukocyte chemoattractant or chemoattractant receptor knockout mouse lines,Ackr1-/-mice were unique in having lower mortality after SARS-CoV-2 infection, particularly in males. ACKR1 is a non-signaling chemokine receptor that in addition to endothelium is also expressed on erythrocytes and Purkinje cells of the cerebellum. It binds promiscuously to both inflammatory CC and CXC chemokines and has been reported to control chemokine availability which may influence the shape of chemotactic gradients and the ability of leukocytes to extravasate and produce immunopathology. Of note, erythrocyte ACKR1 deficiency is fixed in sub-Saharan African populations where COVID-19 has been reported to result in low mortality compared to worldwide data. Our data suggest the possibility of a causal contribution of ACKR1 deficiency to low sub-Saharan COVID-19 mortality and identify ACKR1 as a possible drug target in the disease.
The human Y and inactive X chromosomes similarly modulate autosomal gene expression
Authors: San Roman Adrianna K. , Skaletsky Helen , Godfrey Alexander K. , Bokil Neha V. , Teitz Levi , Singh Isani , Blanton Laura V. , Bellott Daniel W. , Pyntikova Tatyana , Lange Julian , Koutseva Natalia , Hughes Jennifer F. , Brown Laura , Phou Sidaly , Buscetta Ashley , Kruszka Paul , Banks Nicole , Dutra Amalia , Pak Evgenia , Lasutschinkow Patricia C. , Keen Colleen , Davis Shanlee M. , Lin Angela E. , Tartaglia Nicole R. , Samango-Sprouse Carole , Muenke Maximilian , Page David C.
Published: June 2023

Somatic cells of human males and females have 45 chromosomes in common, including the “active” X chromosome. In males the 46thchromosome is a Y; in females it is an “inactive” X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex-chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors –ZFXandZFY– encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.
Evaluation of haplotype-aware long-read error correction with hifieval
Authors: Guo Yujie , Feng Xiaowen , Li Heng
Published: June 2023

The PacBio High-Fidelity (HiFi) sequencing technology produces long reads of>99% in accuracy. It has enabled the development of a new generation ofde novosequence assemblers, which all have sequencing error correction as the first step. As HiFi is a new data type, this critical step has not been evaluated before. Here, we introduced hifieval, a new command-line tool for measuring over- and under-corrections produced by error correction algorithms. We assessed the accuracy of the error correction components of existing HiFi assemblers on the CHM13 and the HG002 datasets and further investigated the performance of error correction methods in challenging regions such as homopolymer regions, centromeric regions, and segmental duplications. Hifieval will help HiFi assemblers to improve error correction and assembly quality in the long run.

Availability and implementation

The source code is available athttps://github.com/magspho/hifieval

Contact

hli@ds.dfci.harvard.edu

Supplementary information

Supplementary data are available atBioinformaticsonline.
Loss ofOsARF18confers glufosinate ammonium herbicide resistance in rice
Authors: Xia Jin-Qiu , He Da-Yu , Liang Qin-Yu , Zhang Zheng-Yi , Wu Jie , Zhang Zi-Sheng , Zhang Jing , Zhao Ping-Xia , Xiang Cheng-Bin
Published: June 2023

Weed is one of the major biotic stresses that causes severe loss of crop yield. Herbicide is one of the most cost-effective ways to control weeds. Thus, the development of herbicide-resistant crops is critical for the application of herbicides. To isolate new glufosinate ammonium resistance loci, we screened a rice ethyl methyl sulfonate-mutagenized library and obtained theglufosinateammonium-resistant mutantgar1-1.GAR1encodes auxin response factor 18 (OsARF18). A G-to-A substitution in the coding region ofOsARF18results in loss of function ofOsARF18and thereby enhances glufosinate ammonium resistance ofgar1-1, which was confirmed by three additional CRISPR/Cas9-editedgar1alleles.GLUTAMINE SYNTHETASE 1;1(OsGS1;1) andGLUTAMINE SYNTHETASE 1;2(OsGS1;2) were upregulated ingar1-1upon glufosinate ammonium treatment, directly contributing to increased GS activity that enhances glufosinate ammonium herbicide resistance. We further show that OsARF18 suppressesOsGS1;1andOsGS1;2expression.

Comparative transcriptomic analyses reveal a huge shift in the gene expression profile involved in stress tolerance and growth. A large number of detoxification-related genes are enriched ingar1-1, which may also contribute to enhanced herbicide resistance. Moreover, stress tolerance-related genes are upregulated and growth-related genes are downregulated ingar1-1, consistent with the improved tolerance to salt and osmotic stress ofgar1mutants. Taken together, our study demonstrates thatOsARF18is a negative regulator of glufosinate ammonium resistance as well as salt and osmotic stress tolerance, suggesting a role in balancing the stress response and growth.
Not all movements are equal: Differences in variability of trunk motor behavior between people with and without low back pain - A Systematic Review
Authors: Bakar Florian Abu , Staal J. Bart , van Cingel Robert , Saito Hiroki , Ostelo Raymond , van Dieën Jaap H.
Published: June 2023

Background

In treatment of low-back pain (LBP), motor control exercises have shown to be superior to minimal interventions, but not to any other form of exercise therapy. Knowledge about variability in trunk motor behavior may help to identify patients that may be more likely to benefit from motor control exercises.

Objective

This systematic review aims to answer the question: Is variability of trunk motor behavior different between people with and without LBP and if so, do people with LBP show more or less variability? Furthermore, we addressed the question whether the results are dependent on characteristics of the patient group, the task performed and the type of variability measure.

Methods

This study was registered in PROSPERO (CRD42020180003). Studies were eligible if they (1) included a LBP group and a control group, (2) included adults with non-specific low back pain of any duration and (3) measured kinematic variability, EMG variability and/or kinetic variability. Risk of Bias was evaluated and a descriptive synthesis was performed.

Results

Thirty-nine studies were included, thirty-one of which were included in the descriptive synthesis. In most studies and experimental conditions, variability did not significantly differ between groups. When significant differences were found, less variability in patients with LBP was more frequently reported than more variability, especially in gait-related tasks.

Conclusions

Given the considerable risk of bias of the included studies and the clinical characteristics of the participants with low severity scores for pain, disability and psychological measures, there is insufficient evidence to draw firm conclusions.
Improved Seizure Onset-Zone Lateralization in Temporal Lobe Epilepsy using 7T Resting-State fMRI: A Direct Comparison with 3T
Authors: Lucas Alfredo , Cornblath Eli J. , Sinha Nishant , Caciagli Lorenzo , Hadar Peter , Tranquille Ashley , Stein Joel M. , Das Sandhitsu , Davis Kathryn A.
Published: June 2023

Objective:Resting-state functional magnetic resonance imaging (rs-fMRI) at ultra high-field strengths (≥7T) is known to provide superior signal-to-noise and statistical power than comparable acquisitions at lower field strengths. In this study, we aim to provide a direct comparison of the seizure onset-zone (SOZ) lateralizing ability of 7T rs-fMRI and 3T rs-fMRI.

Methods:We investigated a cohort of 70 temporal lobe epilepsy (TLE) patients. A paired cohort of 19 patients had 3T and 7T rs-fMRI acquisitions for direct comparison between the two field strengths. Forty-three patients had only 3T, and 8 patients had only 7T rs-fMRI acquisitions. We quantified the functional connectivity between the hippocampus and other nodes within the default mode network (DMN) using seed-to-voxel connectivity, and measured how hippocampo-DMN connectivity could inform SOZ lateralization at 7T and 3T field strengths.

Results:Differences between hippocampo-DMN connectivity ipsilateral and contralateral to the SOZ were significantly higher at 7T (pFDR=0.008) than at 3T (pFDR=0.80) when measured in the same subjects. We found that our ability to lateralize the SOZ, by distinguishing subjects with left TLE from subjects with right TLE, was superior at 7T (AUC = 0.97) than 3T (AUC = 0.68). Our findings were reproduced in extended cohorts of subjects scanned at either 3T or 7T. Our rs-fMRI findings at 7T, but not 3T, are consistent and highly correlated (Spearman Rho=0.65) with clinical FDG-PET lateralizing hypometabolism.

Significance:We show superior SOZ lateralization in TLE patients when using 7T relative to 3T rs-fMRI, supporting the adoption of high-field strength functional imaging in the epilepsy presurgical evaluation.
Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study
Authors: Sharkey Rachel J. , Bacon Chelsea , Peterson Zeru , Rootes-Murdy Kelly , Salvador Raymond , Pomarol-Clotet Edith , Karuk Andriana , Homan Philipp , Ji Ellen , Omlor Wolfgang , Homan Stephanie , Georgiadis Foivos , Kaiser Stefan , Kirschner Matthias , Ehrlich Stefan , Dannlowski Udo , Grotegerd Dominik , Goltermann Janik , Meinert Susanne , Kircher Tilo , Stein Frederike , Brosch Katharina , Krug Axel , Nenadić Igor , Sim Kang , Spalletta Gianfranco , Piras Fabrizio , Banaj Nerisa , Sponheim Scott R , Demro Caroline , Ramsay Ian S , King Margaret , Quidé Yann , Green Melissa J. , Nguyen Dana , Preda Adrian , Calhoun Vince D. , Turner Jessica A. , van Erp Theo G.M. , Nickl-Jockschat Thomas
Published: June 2023

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.
Early acquisition of S-specific Tfh clonotypes after SARS-CoV-2 vaccination is associated with the longevity of anti-S antibodies
Authors: Lu Xiuyuan , Hayashi Hiroki , Ishikawa Eri , Takeuchi Yukiko , Dychiao Julian Vincent Tabora , Nakagami Hironori , Yamasaki Sho
Published: June 2023

SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) αβ sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). In donors exhibiting sustained anti-S antibody titers (designated as “sustainers”), S-reactive T cell clonotypes detected immediately after 2nd vaccination polarized to follicular helper T (Tfh)-like cells, which was less obvious in “decliners”. Even before vaccination, S-reactive CD4+T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic bacteria. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly-responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest thatde novoacquisition of memory Tfh-like cells upon vaccination contributes to the longevity of anti-S antibody titers.