bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual experience has opposing influences on the quality of stimulus representation in adult primary visual cortex
Authors: Jeon Brian B. , Fuchs Thomas , Chase Steven M. , Kuhlman Sandra J.
Published: May 2022

Transient dark exposure, typically 7-10 days in duration, followed by light reintroduction is an emerging treatment for improving the restoration of vison in amblyopic subjects whose occlusion is removed in adulthood. Dark exposure initiates homeostatic mechanisms that together with light-induced changes in cellular signaling pathways result in the re-engagement of juvenile-like plasticity in the adult such that previously deprived inputs can gain cortical territory. It is possible that dark exposure itself degrades visual responses, and this could place constraints on the optimal duration of dark exposure treatment. To determine whether eight days of dark exposure has a lasting negative impact on responses to classic grating stimuli, neural activity was recorded before and after dark exposure in awake head-fixed mice using 2-photon calcium imaging. Neural discriminability, assessed using classifiers, was transiently reduced following dark exposure; a decrease in response reliability across a broad range of spatial frequencies accounted for the disruption. Both discriminability and reliability recovered. Fixed classifiers were used to demonstrated that stimulus representation rebounded to the original, pre-deprivation state, thus DE did not appear to have a lasting negative impact on visual processing. Unexpectedly, we found that dark exposure significantly stabilized orientation preference and signal correlation. Our results reveal that natural vision exerts a disrupting influence on the stability of stimulus preference for classic grating stimuli, and at the same time improves neural discriminability for both low and high spatial frequency stimuli.
Zygotic genome activation by the totipotency pioneer factor Nr5a2
Authors: Gassler Johanna , Kobayashi Wataru , Gáspár Imre , Ruangroengkulrith Siwat , Kümmecke Maximilian , Kravchenko Pavel , Zaczek Maciej , Vallot Antoine , Hernandez Laura Gomez , Rico Laura Cuenca , Ladstätter Sabrina , Tachibana Kikuë
Published: May 2022

Life begins with a switch in genetic control from the maternal to the embryonic genome during zygotic genome activation (ZGA) in totipotent embryos. Despite its importance, the essential regulators of ZGA remain largely unknown in mammals. Based on de novo motif searches, we identified the orphan nuclear receptor Nr5a2 as a key activator of major ZGA in mouse embryos. Nr5a2 binds to its motif within a subtype of SINE B1/Alu transposable elements found in cis-regulatory regions of ZGA genes. Chemical inhibition suggests that 72% of ZGA genes are regulated by Nr5a2 and potentially other orphan nuclear family receptors. Consistent with a role in ZGA, Nr5a2 is required for progression beyond the 2-cell stage. Nr5a2 promotes chromatin accessibility during ZGA and binds to entry/exit sites of nucleosomal DNA in vitro. We conclude that Nr5a2 is an essential pioneer factor that distinctly regulates totipotency and pluripotency during mammalian development.

One-Sentence Summary

Nr5a2 is an essential pioneer transcription factor that activates expression of zygotic genes in mouse embryos.
Limited Cross-Species Virus Transmission in a Spatially Restricted Coral Reef Fish Community
Authors: Costa Vincenzo A. , Bellwood David R. , Mifsud Jonathon C.O. , Geoghegan Jemma L. , Holmes Edward C. , Harvey Erin
Published: May 2022

The Great Barrier Reef (GBR) – the largest coral reef ecosystem in the world – supports over 1200 fish species with some of the highest population densities and diversities seen in vertebrates, offering a high potential for virus transmission among species. As such, the GBR represents an exceptional natural ecosystem to determine the impact of host community diversity on virus evolution and emergence. In recent decades the GBR has also experienced significant threats of extinction, making it one of the most vulnerable ecosystems on the planet. However, our understanding of virus diversity and connectivity in tropical reef fishes remains poor. Here, we employed metatranscriptomic sequencing to reveal the viromes of 61 reef fish species. This identified a total of 132 viruses, 38 of which were vertebrate-associated and therefore likely infecting the fish, including a novel isolate ofSantee-cooper ranavirus(Iridoviridae). Notably, we found little evidence for virus transmission between fish species living within a very restricted geographical space – a 100 m2coral reef ecosystem – suggesting that there might be important host genetic barriers to successful cross-species transmission despite regular exposure. We also identified differences in virome composition between reef fish families, such that cryptobenthic reef fishes – characterized by small body sizes and short life-spans – exhibited greater virome richness compared to large reef fishes. This study suggests that there are important barriers to cross-species transmission, and that successful emergence in a reef fish community likely requires active host adaptation, even among closely related host species.
Lipidomic profiling reveals concerted temporal patterns of functionally related lipids inAedes aegyptifemales following blood feeding
Authors: Lau Meng-Jia , Nie Shuai , Yang Qiong , Harshman Lawrence G. , Mao Cungui , Williamson Nicholas A. , Hoffmann Ary A.
Published: May 2022

We conducted a lipidomic analysis of the whole body of femaleAedes aegyptimosquitoes at different time points over the course of feeding and reproduction. There were temporal biphasic increases of more than 80% of lipids identified at the time of feeding and from 16 h to 30 h post blood meal. During these two increases, the abundance of many lipids dropped while body weight remained stable, probably reflecting blood lipid digestion and the synthesis of vitellogenin in this period. A concerted temporal pattern was particularly strong at the second peak for membrane and signalling lipids such as PE, PI, CL, HexCer and LPA. Lyso-glycerophospholipids showed three distinct change patterns which are functionally related: LPE and LPC, which are membrane lipids, showed little change; LPA, a signalling lipid, showed a dramatic increase from 16 to 30 h PBM; LPI, a bioactive lipid, and both LPG and LPS which are bacterial membrane lipids, showed one significant increase from the time of feeding to 16 hours post blood meal. The result of our study on the anautogenous insectAe. aegyptipoint to specific lipids likely to be important in the reproductive process with a role in the formation and growth of ovarian follicles.
Mating disrupts morning anticipation inDrosophila melanogasterfemales
Authors: Riva Sabrina , Ispizua Juan Ignacio , Breide María Trinidad , Polcowñuk Sofía , Lobera José Ricardo , Ceriani M. Fernanda , Risau Gusman Sebastian , Franco D. Lorena
Published: May 2022

After mating, the physiology ofDrosophilafemales undergoes several important changes, some of which are reflected in their rest-activity cycles. To explore the hypothesis that mating modifies the temporal organization of locomotor activity patterns, we recorded the fly activity by a video tracking method. Monitoring rest-activity patterns under light/dark (LD) cycles indicated that mated females lose their ability to anticipate the night-day transition, in stark contrast to males and virgins; this postmating response is mediated by the sex peptide (SP) acting mainly onpickpocket(ppk) expressing neurons, since reducing expression of the SP receptor (SPR) in these neurons restores the ability to anticipate the LD transition in mated females. We further provide evidence of connectivity between PPK+ neurons and the pigment-dispersing factor (PDF)-positive ventral lateral neurons (sLNv), which play a central role in the temporal organization of daily activity. Since PDF has been associated to the generation of the morning activity peak, we hypothesized that the mating signal could modulate PDF levels. Indeed, mated females have reduced PDF levels at the dorsal protocerebrum; moreover, SPR downregulation in PPK+ neurons mimics PDF levels observed in males. In sum, our results are consistent with a model whereby mating-triggered signals reaches clock neurons in the fly central nervous system to modulate the temporal organization of circadian behavior according to the needs of the new status.

Author Summary

After mating,Drosophilafemales undergoes striking behavioral changes, specially in their activity patterns. Despite some of the circuits that deliver mating signals to the female brain are known the connection with the circadian network has not been explored in detail. Here, we show that mating changes the onset of daily activity, masking a central function of the clock. This modulation is mediated by the sex peptide (transferred during courtship) acting on PPK+ neurons, which, in turn, directly contact PDF+ neurons, responsible for the increase of the activity that precedes dawn. Thus, our work identifies a postmating response directly related to the circadian clock, and begins to unravel the underlying neuronal circuit.
Collective directional migration drives the formation of heteroclonal cancer cell clusters
Authors: Palmiero Miriam , Di Blasio Laura , Monica Valentina , Peracino Barbara , Primo Luca , Puliafito Alberto
Published: May 2022

Metastasisation occurs through the acquisition of invasive and survival capabilities that allow tumour cells to colonise distant sites. While the role of multicellular aggregates in cancer dissemination is acknowledged, the mechanisms that drive the formation of multi-clonal cell aggregates are not fully elucidated. Here we show that cancer cells of different tissue of origins can perform collective directional migration and can actively form heteroclonal aggregates in 3D, through a proliferation-independent mechanism. Coalescence of distant cell clusters is mediated by subcellular actin-rich protrusions and multicellular outgrowths that extend towards neighbouring aggregates. Coherently, perturbation of cytoskeletal dynamics impairs collective migration while myosin II activation is necessary for multicellular movements. We put forward the hypothesis that cluster attraction is mediated by secreted soluble factors consistently with the abrogation of aggregation by inhibition of PI3K/AKT/mTOR and MEK/ERK, with evidence that conditioned culture media act as chemoattractant and corroborated by a wide screening on secreted proteins. Our results present a novel collective migration model and shed light on the mechanisms of formation of heteroclonal aggregates in cancer.
Analysis of proteome adaptation reveals a key role of the bacterial envelope in starvation survival
Authors: Schink Severin , Ammar Constantin , Chang Yu-Fang , Zimmer Ralf , Basan Markus
Published: May 2022

Bacteria reorganize their physiology upon entry to stationary phase. What part of this reorganization improves starvation survival is a difficult question, because the change in physiology includes a global reorganization of the proteome, envelope and metabolism of the cell. In this work, we used several trade-offs between fast growth and long survival to statistically score over 2000E. coliproteins for their global correlation with death rate. The combined ranking allowed us to narrow down the set of proteins that positively correlate with survival and validate the causal role of a subset of proteins. Remarkably, we found that important survival genes are related to the cell envelope, i.e., periplasm and outer membrane, because maintenance of envelope integrity ofE. coliplays a crucial role during starvation. Our results uncover a new protective feature of the outer membrane that adds to the growing evidence that the outer membrane is not only a barrier that prevents abiotic substances from reaching the cytoplasm, but essential for bacterial proliferation and survival.

Standfirst text

A trade-off between the two major modes of bacterial lifestyle, growth and starvation can be explained by bacteria investing resources into the cell envelope to make it impermeable to ions, which improves their lifespan but comes at the expense of slowing down growth.

Highlights

A trade-off between growth rate and death rate confines fitness of bacteria across environments.

Analysis of proteome signatures in 126 conditions across five independent perturbations reveals the cell envelope as a key determinant of death rate.

The trade-off can be abolished by changing environment to a low-salt, but osmo-balanced medium where cell envelope integrity is not limiting.
Dysfunction of transfer RNA modifications in inflammatory bowel disease
Authors: Zhang Jilei , Zhang Yongguo , Xia Yinglin , Sun Jun
Published: May 2022

Backgrounds and aims

Transfer RNA (tRNA) is the most extensively modified RNA in cells. Queuosine (Q)-modification is a fundamental process for fidelity and efficiency of translation from RNA to proteins. In eukaryotes, tRNA-Q-modification relies on the intestinal microbial product queuine. However, the roles and potential mechanisms of Q-tRNA modifications in IBD are unknown.

Methods

We explored the Q-tRNA modifications and expression of Q tRNA ribosyltransferase catalytic subunit 1 (QTRT1) in patients with IBD by investigating human biopsies and reanalyzing datasets. We used colitis models, organoids, and cultured cells for loss- and gain-of-function studies to investigate the molecular mechanisms of Q-tRNA modifications in intestinal inflammation.

Results

QTRT1 expression was significantly downregulated in ulcerative colitis and Crohn’s disease patients. The four Q-tRNA-related tRNA synthetases (asparaginyl-aspartyl-, histidyl-, and tyrosyl-tRNA synthetase) were decreased in IBD patients. This reduction was further confirmed in DSS-induced colitis and IL10-deficient mice. Reduced QTRT1 was significantly correlated with cell proliferation and intestinal junctions, including downregulated β-catenin and Claudin-5 and upregulated Claudin-2. These alterations were confirmed in vitro by deleting QTRT1 from cells. Queuine treatment significantly enhanced cell proliferation and junction functions in cell lines and human colonoids. Queuine treatment also reduced inflammation in epithelial cells. Moreover, altered QTRT1-related metabolites were found in human IBD.

Conclusion

tRNA modifications play an unexplored novel role in the pathogenesis of intestinal inflammation by altering epithelial proliferation and junctions. Investigations on tRNA modification will uncover novel molecular mechanisms for potential prevention and therapy for IBD.
A 512-ch dual-mode microchip for simultaneous measurements of electrophysiological and neurochemical activities
Authors: Mulberry Geoffrey , White Kevin A. , Kim Brian N.
Published: May 2022

In the study of the brain, large and high-density microelectrode arrays have been widely used to study the behavior of neurotransmission. CMOS technology has facilitated these devices by enabling the integration of high-performance amplifiers directly on-chip. Usually, these large arrays measure only the voltage spikes resulting from action potentials traveling along firing neuronal cells. However, at synapses, communication between neurons occurs by the release of neurotransmitters, which cannot be measured on typical CMOS electrophysiology devices. Development of electrochemical amplifiers has resulted in the measurement of neurotransmitter exocytosis down to the level of a single vesicle. To effectively monitor the complete picture of neurotransmission, measurement of both action potentials and neurotransmitter activity is needed. Current efforts have not resulted in a device that is capable of the simultaneous measurement of action potential and neurotransmitter release at the same spatiotemporal resolution needed for a comprehensive study of neurotransmission. In this paper, we present a true dual-mode CMOS device that fully integrates 256-ch electrophysiology amplifiers and 256-ch electrochemical amplifiers, along with an on-chip 512 electrode microelectrode array capable of simultaneous measurement from all 512 channels. Electrochemical amplifiers achieve a noise level of 4.51 pARMS with a bandwidth of 10.3 kHz. Electrophysiology amplifiers exhibit 24.9 μVRMS noise in the action potential band and a total usable bandwidth from 0.2 Hz to 10 kHz.
Precision motor timing via scalar input fluctuations
Authors: Pang Rich , Duffy Alison , Bell David , Torok Zsofia , Fairhall Adrienne
Published: May 2022

Complex motor skills like playing piano require precise timing over long periods, without errors accumulating between subprocesses like the left and right hand movements. While biological models can produce motor-like sequences, how the brain quenches timing errors is not well understood. Motivated by songbirds, where the left and right brain nuclei governing song sequences do not connect but may receive low-dimensional thalamic input, we present a model where timing errors in an autonomous sequence generator are continually corrected by one-dimensional input fluctuations. We show in a spiking neural network model how such input can rapidly correct temporal offsets in a propagating spike pulse, recapitulating the precise timing seen in songbird brains. In a reduced, more general model, we show that such timing correction emerges when the spatial profile of the input over the sequence sufficiently reflects its temporal fluctuations, yielding time-locking attractors that slow advanced sequences and hasten lagging ones, up to the input timescale. Unlike models without fluctuating input, our model predicts anti-correlated durations of adjacent segments of the output sequence, which we verify in recorded zebra finch songs. This work provides a bioplausible picture of how temporal precision could arise in extended motor sequences and generally how low-dimensional input could continuously coordinate time-varying output signals.

Significance

Complex motor skills like playing piano require precision timing over long periods, often among multiple components like left and right muscle groups. Although brain-like network models can produce motor-like outputs, timing regulation is not well understood. We introduce a model, inspired by songbird brains, where imprecise timing in a cortical-like system is corrected by a single thalamic input regulating the sequential propagation, or tempo, of cortical activity. This model illuminates a relation between the input’s spatial structure and temporal variation that lets lagging activity hasten and advanced activity slow, which makes a prediction about output timing that we verify in real birdsong. This work reveals a simple, neuroplausible mechanism that may play a role in precision cortical or motor timing.
Dynamic Structure Of Motor Cortical Neuron Co-Activity Carries Behaviorally Relevant Information
Authors: Sundiang Marina , Hatsopoulos Nicholas G. , MacLean Jason N.
Published: May 2022

Skillful, voluntary movements are underpinned by computations performed by networks of interconnected neurons in the primary motor cortex (M1). Computations are reflected by patterns of co-activity between neurons. Using spike time correlations, co-activity can be represented as functional networks (FNs). Here, we show that the structure of FNs constructed from instructed-delay reach trials in non-human primates are behaviorally specific: low dimensional embedding and graph alignment scores show that FNs constructed from closer target reach distances are also closer in network space. We next constructed temporal FNs using short intervals across a trial. We find that temporal FNs traverse a low-dimensional subspace in a reach-specific trajectory. Alignment scores show that FNs become separable and correspondingly, decodable shortly after the instruction cue. Finally, we observe that reciprocal connections in FNs transiently decrease following the instruction cue, suggesting the network momentarily switches from a recurrent system to one that is more feedforward.
Heterogeneity in killing efficacy of individual effector CD8+ T cells against Plasmodium liver stages
Authors: Bera Soumen , Amino Rogerio , Cockburn Ian A. , Ganusov Vitaly V.
Published: May 2022

Vaccination strategies in mice inducing high numbers of memory CD8+ T cells specific to a single epitope are able to provide sterilizing protection against infection with Plasmodium sporozoites. We have recently found that Plasmodium-specific CD8+ T cells cluster around sporozoite-infected hepatocytes but whether such clusters are important in elimination of the parasite remains incompletely understood. Here we used our previously generated data in which we employed intravital microscopy to longitudinally image 32 GFP-expressing Plasmodium yoelii parasites in livers of mice that had received activated Plasmodium-specific CD8+ T cells after sporozoite infection. We found significant heterogeneity in the dynamics of the normalized GFP signal from the parasites (termed “vitality index” or VI) that was weakly correlated with the number of T cells near the parasite. We also found that a simple model assuming mass-action, additive killing by T cells well describes the VI dynamics for most parasites and predicts a highly variable killing efficacy by individual T cells. Given our estimated median per capita kill rate ofk= 0.031/h we predict that a single T cell is typically incapable to kill a parasite within the 48 hour lifespan of the liver stage in mice. Stochastic simulations of T cell clustering and killing of the liver stage also suggested that 1) three or more T cells per infected hepatocyte are required to ensure sterilizing protection; 2) both variability in killing efficacy of individual T cells and resistance to killing by individual parasites may contribute to the observed variability in VI decline, and 3) the stable VI of some clustered parasites cannot be explained by measurement noise. Taken together, our analysis for the first time provides estimates of efficiency at which individual CD8+ T cells eliminate intracellular parasitic infection in vivo.
Chemoproteomics-Enabled Discovery of a Covalent Molecular Glue Degrader Targeting NF-κB
Authors: King Elizabeth A. , Cho Yoojin , Dovala Dustin , McKenna Jeffrey M. , Tallarico John A. , Schirle Markus , Nomura Daniel K.
Published: May 2022

Targeted protein degradation using heterobifunctional Proteolysis-Targeting Chimeras (PROTACs) or molecular glues has arisen as a powerful therapeutic modality for degrading disease targets. While PROTAC design is becoming more modular and straightforward, the discovery of novel molecular glue degraders has been more challenging. While several recent studies have showcased phenotypic screening and counter-screening approaches to discover new molecular glue degraders, mechanistically elucidating the ternary complex induced by the small-molecule that led to the initial phenotype—i.e. identifying the degraded target and relevant components of the ubiquitin-proteasome system—has remained cumbersome and laborious. To overcome these obstacles, we have coupled the screening of a covalent ligand library for anti-proliferative effects in leukemia cells with quantitative proteomic and chemoproteomic approaches to rapidly discover both novel covalent molecular glue degraders and their associated ternary complex components and anti-proliferative mechanisms. We have identified a cysteine-reactive covalent ligand EN450 that impairs leukemia cell viability in a NEDDylation and proteasome-dependent manner. Chemoproteomic profiling revealed covalent interaction of EN450 with an allosteric C111 in the E2 ubiquitin ligase UBE2D. Follow-up quantitative proteomic profiling revealed the proteasome-mediated degradation of the oncogenic transcription factor NFKB1 as a putative degradation target. Subsequent validation studies demonstrated that EN450 induced the ternary complex formation between UBE2D and NFKB1 and that both UBE2D and NFKB1 were important for the anti-proliferative mechanisms of EN450. Our study thus puts forth the discovery of a novel molecular glue degrader that uniquely induced the proximity of an E2 ligase with a transcription factor to induce its degradation and anti-proliferative effects in cancer cells. Taken more broadly, our study showcases a rapid and modular approach for discovering novel covalent molecular glue degraders and their respective ternary complex components in an unbiased fashion.
Allosteric Inhibition of PTP1B by a Nonpolar Terpenoid
Authors: Friedman Anika J. , Liechty Evan T. , Kramer Levi , Sarkar Ankur , Fox Jerome M. , Shirts Michael R.
Published: May 2022

Protein tyrosine phosphatases (PTPs) are promising drug targets for treating a wide range of diseases such as diabetes, cancer, and neurological disorders, but their conserved active sites have complicated the design of selective therapeutics. This study examines the allosteric inhibition of PTP1B by amorphadiene (AD), a terpenoid hydrocarbon that is an unusually selective inhibitor. Molecular dynamics (MD) simulations carried out in this study suggest that AD can stably sample multiple neighboring sites on the allosterically influential C-terminus of the catalytic domain. Binding to these sites requires a disordered α7 helix, which stabilizes the PTP1B-AD complex and may contribute to the selectivity of AD for PTP1B over TCPTP. Intriguingly, the binding mode of AD differs from that of the most well-studied allosteric inhibitor of PTP1B. Indeed, biophysical measurements and MD simulations indicate that the two molecules can bind simultaneously. Upon binding, both inhibitors destabilize the α7 helix and disrupt hydrogen bonds that facilitate closure of the catalytically essential WPD loop. These findings indicate that AD is a promising scaffold for building allosteric inhibitors of PTP1B and illustrate, more broadly, how unfunctionalized terpenoids can engage in specific interactions with protein surfaces.
Brain-muscle connectivity during gait: corticomuscular coherence as quantification of the cognitive reserve
Authors: Caffi L. , Boccia S. , Longatelli V. , Guanziroli E. , Molteni F. , Pedrocchi A.
Published: May 2022

A detailed comprehension of the central and peripheral processes underlying walking is essential to develop effective therapeutic interventions to slow down gait decline with age, and rehabilitation strategies to maximize motor recovery for patients with damages at the central nervous system. The combined use of electromyography (EMG) and electroencephalography (EEG), in the framework of coherence analysis, has recently established for neuromotor integrity/impairment assessment. In this study, we propose corticomuscular (EEG-EMG) and inter/intramuscular (EMG-EMG) coherences as measures of the cognitive reserve, i.e., the process whereby a wider repertoire of cognitive strategies, as well as more flexible and efficient strategies, can moderate the manifestation of brain disease/damage. We recorded EEG signals from the main brain source locations and superficial EMG signals from the main leg muscles involved in gait in 16 healthy young adults (age ≤30 years) and 13 healthy elderly (age ≥65 years) during three different overground walking conditions (i.e., spontaneous walking, walking with cognitive dual-task, and walking with targets drawn on the floor). In all conditions, we calculated corticomuscular and inter/intramuscular coherences. We observed higher corticomuscular and inter/intramuscular coherences during targeted walking compared to spontaneous walking in both groups, even if the increase was greater in young people. Considering dual-task walking compared to spontaneous walking, only corticomuscular coherence in the elderly increased. These results suggest age-related differences in cognitive reserve that reflect different abilities to perform complex cognitive or motor tasks during gait. This study demonstrates the feasibility, repeatability, and effectiveness of the proposed method to investigate brain-to-muscle connectivity during different gait conditions, to study the related changes with age, and to quantify the cognitive reserve.
Spatiotemporal dynamics of membrane surface charge regulates cell polarity and migration
Authors: Banerjee Tatsat , Biswas Debojyoti , Pal Dhiman Sankar , Miao Yuchuan , Iglesias Pablo A. , Devreotes Peter N.
Published: May 2022

During cell migration and polarization, hundreds of signal transduction and cytoskeletal components self-organize to generate localized protrusions. Although biochemical and genetic analyses have delineated many specific interactions, how the activation and localization of so many different molecules are spatiotemporally orchestrated at the subcellular level has remained unclear. Here we show that the regulation of negative surface charge on the inner leaflet of the plasma membrane plays an integrative role in the molecular interactions. Surface charge, or zeta potential, is transiently lowered at new protrusions and within cortical waves of Ras/PI3K/TORC2/F-actin network activation. Rapid alterations of inner leaflet anionic phospholipids, such as PI(4,5)P2, PI(3,4)P2, phosphatidylserine, and phosphatidic acid, collectively contribute to the surface charge changes. Abruptly reducing the surface charge by recruiting positively charged optogenetic actuators was sufficient to trigger the entire biochemical network, initiate de novo protrusions, and abrogate pre-existing polarity. These effects were blocked by genetic or pharmacological inhibitions of key signaling components such as Akt and PI3K/TORC2. Conversely, increasing the negative surface deactivated the network and locally suppressed chemoattractant-induced protrusions or subverted EGF-induced ERK activation. Computational simulations involving excitable biochemical networks demonstrated that slight changes in feedback loops, induced by recruitment of the actuators, could lead to outsized effects on system activation. We propose that key signaling network components act on, and are in turn acted upon, by surface charge, closing feedback loops which bring about the global-scale molecular self-organization required for spontaneous protrusion formation, cell migration, and polarity establishment.
Comprehensive analysis of the effect of mRNA sequences on translation efficiency and accuracy
Authors: Umemoto S. , Kondo T. , Fujino T. , Hayashi G. , Murakami H.
Published: May 2022

Messenger ribonucleic acid (mRNA) sequences influence the translation efficiency and accuracy. To increase our knowledge of how mRNA sequences affect ribosome translation and apply the obtained information to improve the mRNA display method, we conducted a comprehensive analysis of the effect of mRNA sequences on the translation. Translation efficiency depended strongly on the three codons following the start codon. Furthermore, the codons at the ribosomal E- and P-sites strongly influence the misreading of the A-site blank codon by near-cognate transfer RNA. The purine base after the blank codon also induced a higher misread rate than that with a pyrimidine base. Based on these findings, we demonstrated construction of highly diverse monobody and macrocyclic peptide libraries that would be useful in developing functional peptides and proteins in the future.
Spatiotemporal organization of human sensorimotor beta burst activity
Authors: Zich Catharina , Quinn Andrew J , Bonaiuto James J , O’Neill George , Mardell Lydia C , Ward Nick S , Bestmann Sven
Published: May 2022

Beta oscillations in human sensorimotor cortex are hallmark signatures of healthy and pathological movement. In single trials, beta oscillations include bursts of intermittent, transient periods of high-power activity. These burst events have been linked to a range of sensory and motor processes, but their precise spatial, spectral, and temporal structure remains unclear. Specifically, a role for beta burst activity in information coding and communication suggests spatiotemporal patterns, or travelling wave activity, along specific anatomical gradients. We here show in human magnetoencephalography recordings that burst activity in sensorimotor cortex occurs in planar spatiotemporal wave-like patterns that dominate along two axes either parallel or perpendicular to the central sulcus. Moreover, we find that the two propagation directions are characterised by distinct anatomical and physiological features. Finally, our results suggest that sensorimotor beta bursts occurring before and after a movement share the same generator but can be distinguished by their anatomical, spectral and spatiotemporal characteristics, indicating distinct functional roles.
Lipopolysaccharide synthesis and traffic in the envelope of the pathogen Brucella abortus
Authors: Servais Caroline , Vassen Victoria , Verhaeghe Audrey , Küster Nina , Carlier Elodie , Phégnon Léa , Mayard Aurélie , De Bolle Xavier
Published: May 2022

Lipopolysaccharide is essential for most Gram-negative bacteria as it is a main component of the outer membrane. In the pathogen Brucella abortus, smooth lipopolysaccharide containing the O-antigen is required for virulence. Being part of the Rhizobiales, Brucella spp. display unipolar growth and lipopolysaccharide was shown to be incorporated at the active growth sites, i.e. the new pole and the division site. By localizing proteins involved in the lipopolysaccharide transport across the cell envelope, from the inner to the outer membrane, we show that the lipopolysaccharide incorporation sites are determined by the inner membrane complex of the lipopolysaccharide transport system. Moreover, we identify the main O-antigen ligase of Brucella spp involved in smooth lipopolysaccharide synthesis. Altogether, our data highlight a new layer of spatiotemporal organization of the lipopolysaccharide biosynthesis pathway and identify a new class of bifunctional O-antigen ligases.
Oriented evening flight behaviour in the Bogong moth revealed through automated video tracking
Authors: Wallace Jesse R A , Dreyer David , Zeil Jochen , Warrant Eric J
Published: May 2022

During their period of summer dormancy, Australian Bogong mothsAgrotis infusaundertake seemingly random evening flights, filling the air with densities in the dozens per cubic metre. The purpose of these flights is unknown, but they may serve an important role in Bogong moth navigation, which remarkably enables them to return to the same exact summer sites— generation after generation—after migrating around 1000 km, and with no opportunity to learn their route or destination from prior generations. The recent development of the camera-based insect monitoring method, Camfi, enables quantitative observations of Bogong moth behaviour at an unprecedented scale. To gain a better understanding of the summer evening flights of Bogong moths, we have extended Camfi to facilitate automated video tracking of flying insects, taking the already-high throughput of the method to a new level. We used this new method to record the evening flight behaviour of Bogong moths in two elevational transects below the summit of Mt. Kosciuszko, NSW, on a single night in February 2021, and found that these flights were not random, but were systematically oriented in directions relative to the azimuth of the summit of the mountain. These results stimulate interesting and plausible hypotheses relating to previously unexplained summer evening flight behaviour of Bogong moths, and the mechanisms of their long-distance navigation.
Stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses
Authors: Bączyńska E. , Zaręba-Kozioł M. , Ruszczycki B. , Krzystyniak A. , Wójtowicz T. , Bijata K. , Pochwat B. , Magnowska M. , Roszkowska M. , Figiel I. , Masternak J. , Pytyś A. , Dzwonek J. , Worch R. , Olszyński K.H. , Wardak A.D. , Szymczak P. , Labus J. , Radwańska K. , Jahołkowski P. , Hogendorf A. , Ponimaskin E. , Filipkowski R.K. , Szewczyk B. , Bijata M. , Włodarczyk J
Published: May 2022

Stress resilience is the ability of neuronal networks to maintain their function despite the stress exposure. Using a mouse model we here investigate stress resilience phenomenon. To assess the resilient and anhedonic behavioral phenotypes developed after the induction of chronic unpredictable stress, we quantitatively characterized the structural and functional plasticity of excitatory synapses in the hippocampus using a combination of proteomic, electrophysiological, and imaging methods. Our results indicate that stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses. We reveal that chronic stress influences palmitoylation of synaptic proteins, whose profiles differ between resilient and anhedonic animals. The changes in palmitoylation are predominantly related with the glutamate receptor signaling thus affects synaptic transmission and associated structures of dendritic spines. We show that stress resilience is associated with structural compensatory plasticity of the postsynaptic parts of synapses in CA1 subfield of the hippocampus.

One Sentence Summary

Compensatory remodeling of dendritic spines at the structural and molecular levels underlies stress resilience.
Reproducing extracellular matrix adverse remodelling of non-ST myocardial infarction in a large animal model
Authors: Contessotto Paolo , Spelat Renza , Vysockas Vaidas , Krivickienė Aušra , Jin Chunsheng , Chantepie Sandrine , Chinello Clizia , Pauza Audrys G. , Rackauskas Mindaugas , Zigmantaitė Vilma , Magni Fulvio , Papy-Garcia Dulce , Karlsson Niclas G. , Ereminienė Eglė , Pandit Abhay , Da Costa Mark
Published: May 2022

The rising incidence of non-ST-segment elevation myocardial infarction (NSTEMI) and associated long-term high mortality constitutes an urgent clinical issue. Unfortunately, the study of possible interventions to treat this pathology lacks a reproducible pre-clinical model. Indeed, currently adopted small and large animal models of MI mimic only full-thickness, ST-segment-elevation (STEMI) infarcts, and hence cater only for investigation into therapeutics and interventions directed at this subset of MI. Thus, we developed an ovine model of NSTEMI by ligating the myocardial muscle at precise intervals parallel to the left anterior descending coronary artery. After validating the presented model both by histology and functional analysis with clinical data, further omics analyses highlighted the distinctive features of post-NSTEMI tissue remodelling. Here, by looking at the transcriptome and proteome-derived pathways emerging at acute (7 days) and late (28 days) post-surgery timepoints, we discovered specific alterations in cardiac post-ischaemic extracellular matrix (ECM). Together with the rise of well-known markers of inflammation and fibrosis, NSTEMI ischaemic regions showed distinctive patterns in the expression of complex N-glycans and glycosaminoglycans in cellular membranes and ECM. Identifying such changes in molecular moieties accessible to infusible and intra-myocardial injectable drugs sheds light on the development of targeted pharmacological solutions to contrast adverse fibrotic remodelling.
Gene expression profiling reveals B cells are highly educated by the pancreatic environment during autoimmune diabetes
Authors: Boldison Joanne , Hopkinson Jessica , Davies Joanne , Pearson James A , Leete Pia , Richardson Sarah , Morgan Noel G , Wong F. Susan
Published: May 2022

B cells play an important role in driving the development of type 1 diabetes, however, it remains unclear how they contribute to local beta-cell destruction during disease progression. Using gene expression profiling of B cell subsets in the pancreas and pancreatic lymph nodes, we reveal that B cells are highly modified by the inflamed pancreatic tissue and can be distinguished by their transcriptional profile from those in the lymph node. We identified both a discrete and a core shared gene expression profile in islet CD19+CD138- and CD19+CD138+ B cell subsets, the latter known to have enriched autoreactivity during diabetes development. Upon localisation to pancreatic islets, CD138+ B cells overexpressed genes associated with adhesion molecules and growth factors compared to CD138- B cells. Their shared signature displayed gene expression changes related to the differentiation of antibody-secreting cells and gene regulatory networks associated with interferon signalling pathways, pro-inflammatory cytokines and toll-like receptor activation. Finally, abundant TLR7 expression was detected in islet B cells, and was enhanced specifically in CD138+ B cells. Our study, therefore, provides a detailed transcriptional analysis of islet B cells identifying specific gene signatures and interaction networks that point towards a functional role for B cells in driving autoimmune diabetes.
Humans parsimoniously represent auditory sequences by pruning and completing the underlying network structure
Authors: Benjamin Lucas , Fló Ana , Roumi Fosca Al , Dehaene-Lambertz Ghislaine
Published: May 2022

Successive auditory inputs are rarely independent, their relationships ranging from local transitions between elements to hierarchical and nested representations. In many situations, humans retrieve these dependencies even from limited datasets. However, this learning at multiple scale levels is poorly understood. Here We used the formalism proposed by network science to study the representation of local and higher order structures, and their interaction, in auditory sequences. We show that human adults exhibited biases in their perception of local transitions between elements, which made them sensitive to high-order structures such as network communities. This behavior is consistent with the creation of a parsimonious simplified model from the evidence they receive, achieved by pruning and completing relationships between network elements. This observation suggests that the brain does not rely on exact memories but compressed representations of the world. Moreover, this bias can be analytically modeled by a memory/efficiency trade-off. This model correctly account for previous findings, including local transition probabilities as well as high order network structures, unifying statistical learning across scales. We finally propose putative brain implementations of such bias.
Bisected graph matching improves automated pairing of bilaterally homologous neurons from connectomes
Authors: Pedigo Benjamin D. , Winding Michael , Priebe Carey E. , Vogelstein Joshua T.
Published: May 2022

Graph matching algorithms attempt to find the best correspondence between the nodes of two networks. These techniques have been used to match individual neurons in nanoscale connectomes – in particular, to find pairings of neurons across hemispheres. However, since graph matching techniques deal with two isolated networks, they have only utilized the ipsilateral (same hemisphere) subgraphs when performing the matching. Here, we present a modification to a state-of-the-art graph matching algorithm which allows it to solve what we call the bisected graph matching problem. This modification allows us to leverage the connections between the brain hemispheres when predicting neuron pairs. Via simulations and experiments on real connectome datasets, we show that this approach improves matching accuracy when sufficient edge correlation is present between the contralateral (between hemisphere) subgraphs. We also show how matching accuracy can be further improved by combining our approach with previously proposed extensions to graph matching, which utilize edge types and previously known neuron pairings. We expect that our proposed method will improve future endeavors to accurately match neurons across hemispheres in connectomes, and be useful in other applications where the bisected graph matching problem arises.
Quantitative Characterization of Duodenal Gastrinoma Autofluorescence using Multi-photon Microscopy
Authors: Knapp Thomas G. , Duan Suzann , Merchant Juanita L. , Sawyer Travis W.
Published: May 2022

Duodenal gastrinomas (DGASTs) are neuroendocrine tumors that develop in the submucosa of the duodenum and produce the hormone gastrin. Surgical resection of DGASTs is complicated by the small size of these tumors and the tendency for them to develop diffusely in the duodenum. Endoscopic mucosal resection of DGASTS is an increasingly popular method for treating this disease due to its low complication rate but suffers from poor rates of pathologically negative margins. Multiphoton microscopy (MPM) is capable of capturing high-resolution images of biological tissue with contrast generated from endogenous fluorescence (autofluorescence) through two-photon excited fluorescence (2PEF). Second harmonic generation (SHG) is another popular method of generating image contrast with MPM and is a light-scattering phenomenon that occurs predominantly from structures such as collagen in biological samples. Some molecules that contribute to autofluorescence change in abundance from processes related to the cancer disease process (e.g., metabolic changes, oxidative stress, angiogenesis). MPM was used to image 12 separate patient samples of formalin-fixed and paraffinized DGAST slides with a SHG channel 4 2PEF channels, each tuned to capture fluorescence from NADH, FAD, lipofuscin, and porphyrin. We found that there was a significant difference in the relative abundance of signal generated in the 2PEF in comparison to the neighboring tissues of the duodenum. Texture extraction was used to create linear discriminant classifiers for tumor vs all other tissue classes before and after principal component analysis (PCA) of the texture feature dataset. PCA improved the classifier accuracy and reduced the number of features required to achieve maximum accuracy of the classifier. The LDA classifier after PCA distinguished between tumor and other tissue types with an accuracy of 90.6 - 93.8%. These results suggest that MPM 2PEF and SHG imaging is a promising label-free method for discriminating between DGAST tumors and normal duodenal tissue which has implications for future applications of in vivo assessment of resection margins with endoscopic MPM.
Di-tert-butyltin(IV)–hydroxide–iodide,
t
Bu2Sn(OH)I, the last missing member in the series of pure di-tert-butyltin(IV)–hydroxide–halides
Authors: Reuter Hans
Published: May 2022

The crystal structure of di-tert-butylhydroxidoiodidotin(IV), [Sn(C4H9)2I(OH)] or
t
Bu2Sn(OH)I, consists of dimeric, centrosymmetric molecules exhibiting the typical structural features of diorganotin(IV)-hydroxide-halides, R
2Sn(OH)Hal. Two trigonal–bipyramidally coordinated tin(IV) atoms are bridged via two hydroxyl groups, resulting in a planar, four-membered {Sn—O}2 ring of rhombic shape, with acute angles at tin, obtuse angles at oxygen and two different Sn—O distances depending whether the oxygen atom adopts an axial or equatorial position at the tin(IV) atom. In contrast to its fluorine, chlorine and bromine homologues, no hydrogen bonds between the OH group and the halide atom exist, confining the intermolecular interactions to van der Waals forces.
Crystal structure and void analysis of tris(2-amino-1-methylbenzimidazolium) hexakis(nitrato-κ2
O,O′)lanthanate(III)
Authors: Ruzieva Bakhtigul , Kunafiev Rishad , Kadirova Zukhra , Daminova Shahlo
Published: May 2022

The organic–inorganic complex salt, (C8H10N3)3[La(NO3)6], comprises a network of N-protonated 2-amino-1-methylbenzimidazolium cations and hexakis(nitrato)lanthanate(III) anions. The LaIII atom is twelve-coordinate within a distorted icosahedral environment. In the unit cell, each pair of the LaIII atoms lie nearly on one of the crystallographic glide planes. In the crystal structure, there are several N—H...O hydrogen-bonding interactions between the cations and terminal oxygen atoms from the nitrate moieties of the [La(NO3)6]3– anion. Additional weak C—H...O hydrogen bonds between the cations and anions consolidate the three-dimensional arrangement of the structure. A packing analysis was performed to check the strength of the crystal packing.