bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visual feature tuning properties of stimulus-driven saccadic inhibition in macaque monkeys
Authors: Khademi Fatemeh , Zhang Tong , Baumann Matthias P. , Buonocore Antimo , Malevich Tatiana , Yu Yue , Hafed Ziad M. 
Published: July 2023

AbstractSaccadic inhibition refers to a short-latency transient cessation of saccade generation after visual sensory transients. This oculomotor phenomenon occurs with a latency that is consistent with a rapid influence of sensory responses, such as stimulus-induced visual bursts, on oculomotor control circuitry. However, the neural mechanisms underlying saccadic inhibition are not well understood. Here, we exploited the fact that macaque monkeys experience robust saccadic inhibition to test the hypothesis that inhibition time and strength exhibit systematic visual feature tuning properties to a multitude of visual feature dimensions commonly used in vision science. We measured saccades in three monkeys actively controlling their gaze on a target, and we presented visual onset events at random times. Across six experiments, the visual onsets tested size, spatial frequency, contrast, motion direction, and motion speed dependencies of saccadic inhibition. We also investigated how inhibition might depend on the behavioral relevance of the appearing stimuli. We found that saccadic inhibition starts earlier, and is stronger, for large stimuli of low spatial frequencies and high contrasts. Moreover, saccadic inhibition timing depends on motion direction, with earlier inhibition systematically occurring for horizontally than for vertically drifting gratings. On the other hand, saccadic inhibition is stronger for faster motions, and when the appearing stimuli are subsequently foveated. Besides documenting a range of feature tuning dimensions of saccadic inhibition on the properties of exogenous visual stimuli, our results establish macaque monkeys as an ideal model system for unraveling the neural mechanisms underlying a highly ubiquitous oculomotor phenomenon in visual neuroscience.New and noteworthyVisual onsets dramatically reduce saccade generation likelihood with very short latencies. Such latencies suggest that stimulus-induced visual responses, normally jumpstarting perceptual and scene analysis processes, can also directly impact the decision of whether to generate saccades or not, causing saccadic inhibition. Consistent with this, we found that changing the appearance of the visual onsets systematically alters the properties of saccadic inhibition. These results constrain neurally-inspired models of coordination between saccade generation and exogenous sensory stimulation.
Wall teichoic acid substitution with glucose governs phage susceptibility ofStaphylococcus epidermidis
Authors: Beck Christian , Krusche Janes , Notaro Anna , Walter Axel , Kränkel Lara , Vollert Anneli , Stemmler Regine , Wittmann Johannes , Schaller Martin , Slavetinsky Christoph , Mayer Christoph , De Castro Cristina , Peschel Andreas 
Published: July 2023

AbstractThe species- and clone-specific susceptibility ofStaphylococcuscells for bacteriophages is governed by the structures and glycosylation patterns of wall teichoic acid (WTA) glycopolymers. The glycocodes of phage-WTA interaction in the opportunistic pathogenStaphylococcus epidermidisand in other coagulase-negative staphylococci (CoNS) have remained unknown. We report a newS. epidermidisWTA glycosyltransferase TagE whose deletion confers resistance to siphoviruses such as ΦE72 but enables binding of otherwise unbound podoviruses.S. epidermidisglycerolphosphate WTA was found to be modified with glucose in atagE-dependent manner. TagE is encoded together with the enzymes PgcA and GtaB providing uridine diphosphate-activated glucose. ΦE72 transduced several other CoNS species encoding TagE homologs suggesting that WTA glycosylation via TagE is a frequent trait among CoNS that permits inter-species horizontal gene transfer. Our study unravels a crucial mechanism of phage-Staphylococcusinteraction and of horizontal gene transfer and it will help in the design of anti-staphylococcal phage therapies.ImportancePhages are highly specific for certain bacterial hosts, and some can transduce DNA even across species boundaries. How phages recognize cognate host cells remains incompletely understood. Phages infecting members of the genusStaphylococcusbind to wall teichoic acid (WTA) glycopolymers with highly variable structures and glycosylation patterns. How WTA is glycosylated in the opportunistic pathogenStaphylococcus epidermidisand in other coagulase-negativeStaphylococcus(CoNS) species has remained unknown. We describe thatS. epidermidisglycosylates its WTA backbone with glucose and we identify a cluster of three genes, responsible for glucose activation and transfer to WTA. Their inactivation strongly alters phage susceptibility patterns, yielding resistance to siphoviruses but susceptibility to podoviruses. Many different CoNS species with related glycosylation genes can exchange DNA via siphovirus ΦE72 suggesting that glucose-modified WTA is crucial for interspecies horizontal gene transfer. Our finding will help to develop antibacterial phage therapies and unravel routes of genetic exchange.
Comprehensive mapping of cell fates in microsatellite unstable cancer cells support dual targeting of WRN and ATR
Authors: Zong Dali , Koussa Natasha C. , Cornwell James A. , Pankajam Ajith V. , Kruhlak Michael J. , Wong Nancy , Chari Raj , Cappell Steven D. , Nussenzweig André 
Published: July 2023

AbstractAddiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN, knowledge that would be helpful for informing clinical development of WRN-targeting therapy, predicting possible resistance mechanisms, and identifying useful biomarkers of successful WRN inhibition. Here, we report the construction of an inducible ligand-mediated degradation system wherein the stability of endogenous WRN protein can be rapidly and specifically tuned, enabling us to track the complete sequence of cellular events elicited by acute loss of WRN function. We find that WRN degradation leads to immediate accrual of DNA damage in a replication-dependent manner that curiously did not robustly engage checkpoint mechanisms to halt DNA synthesis. As a result, WRN-degraded MSI-H cancer cells accumulate DNA damage across multiple replicative cycles and undergo successive rounds of increasingly aberrant mitoses, ultimately triggering cell death. Of potential therapeutic importance, we find no evidence of any generalized mechanism by which MSI-H cancers could adapt to near-complete loss of WRN. However, under conditions of partial WRN degradation, addition of low dose ATR inhibitor significantly increased their combined efficacy to levels approaching full inactivation of WRN. Overall, our results provided the first comprehensive view of molecular events linking upstream inhibition of WRN to subsequent cell death and suggested a potential therapeutical rationale for dual targeting of WRN and ATR.
A systematic comparison of computational methods for expression forecasting
Authors: Kernfeld Eric , Yang Yunxiao , Weinstock Joshua S. , Battle Alexis , Cahan Patrick 
Published: July 2023

AbstractExpression forecasting methods use machine learning models to predict how a cell will alter its transcriptome upon perturbation. Such methods are enticing because they promise to answer pressing questions in fields ranging from developmental genetics to cell fate engineering and because they are a fast, cheap, and accessible complement to the corresponding experiments. However, the absolute and relative accuracy of these methods is poorly characterized, limiting their informed use, their improvement, and the interpretation of their predictions. To address these issues, we created a benchmarking platform that combines a panel of 11 large-scale perturbation datasets with an expression forecasting software engine that encompasses or interfaces to a wide variety of methods. We used our platform to systematically assess methods, parameters, and sources of auxiliary data, finding that performance strongly depends on the choice of metric, and especially for simple metrics like mean squared error, it is uncommon for expression forecasting methods to out-perform simple baselines. Our platform will serve as a resource to improve methods and to identify contexts in which expression forecasting can succeed.
Irregularity of instantaneous gamma frequency in the motor control network characterize visuomotor and proprioceptive information processing
Authors: Ryu Jihye , Choi Jeong-woo , Niketeghad Soroush , Torres Elizabeth B. , Pouratian Nader 
Published: July 2023

AbstractBackgroundGoal-directed movements involve integrating proprioceptive and visuo-motor information. Although the neural correlates of such information processing are known, the details of how sensory-motor integration occurs are still largely unknown.ObjectiveThe study aims to characterize movements with different sensory goals, by contrasting the neural activity involved in processing proprioceptive and visuo-motor information. To accomplish this, we have developed a new methodology that utilizes the irregularity of the instantaneous gamma frequency parameter for characterization.ApproachIn this study, 8 essential tremor patients undergoing an awake deep brain stimulation (DBS) implantation surgery repetitively touched the clinician’s finger (forward visually-guided/FV movement) and then one’s own chin (backward proprioceptively-guided/BP movement). Neural electrocorticographic (ECoG) recordings from the motor (M1), somatosensory (S1), and posterior parietal cortex (PPC) were obtained and band-pass filtered in the gamma range (30-80Hz). The irregularity of the inter-event intervals (IEI; inverse of instantaneous gamma frequency) were examined as: 1) correlation between the amplitude and its proceeding IEI, and 2) auto-information of the IEI time series. We further explored the network connectivity after segmenting the FV and BP movements by periods of accelerating and decelerating forces, and applying the IEI parameter to transfer entropy methods.ResultsConceptualizing that the irregularity in IEI reflects active new information processing, we found the highest irregularity in M1 during BP movement, highest in PPC during FV movement, and the lowest during rest at all sites. Also, connectivity was the strongest from S1 to M1 and from S1 to PPC during FV movement with accelerating force and weakest during rest.SignificanceWe introduce a novel methodology that utilize the instantaneous gamma frequency (i.e., IEI) parameter in characterizing goal-oriented movements with different sensory goals, and demonstrate its use to inform the directional connectivity within the motor cortical network. This method successfully characterizes different movement types, while providing interpretations to the sensory-motor integration processes.
Heat stress induces a developmental shift from type-V to type-IV trichome dependent on jasmonate signaling in tomato
Authors: Säbel Robert , Brand Alejandro , Bergau Nick , Balcke Gerd U. , Syrowatka Frank , Püffeld-Raorane Mandy , Hause Bettina , Tissier Alain 
Published: July 2023

AbstractCultivated tomato (Solanum lycopersicum) and related wild species develop several types of trichomes, both glandular and non-glandular, on their aerial parts. Among these, type-IV trichomes are responsible for the synthesis and secretion of acylsugars, which act as defense compounds against herbivores. In contrast to related wild species such asS. pennellii, type-IV trichomes are present only in the juvenile stages of cultivated tomato plants and absent in later stages of development. By submitting tomato plants to high temperatures during the day (37 °C), we observe that non-glandular type-V trichomes are replaced by type-IV trichomes. This is accompanied by a massive increase in acylsugar production. On the other hand, heat treatment does not affect type VI-trichomes, which produce mono- and sesquiterpenes, but the production of monoterpenes is increased while that of sesquiterpenes is suppressed. Furthermore, tomatojai1mutants deficient in jasmonate (JA) perception do not exhibit this developmental switch from type-V to type-IV trichomes. The implication of JA signaling in this process was further supported by an increase in JA-isoleucine and in the expression of genes involved in JA-signalling within hours of heat stress application. These results establish a unique system to study how environmental factors affect developmental fate decisions in plants while opening opportunities to understand mechanisms controlling type-IV trichome initiation and development.
Hawkes process modeling quantifies complicated firing behaviors of cortical neurons during sleep and wakefulness
Authors: Kanda Takeshi , Aritake Toshimitsu , Ohyama Kaoru , Vogt Kaspar E. , Makino Yuichi , McHugh Thomas J. , Hino Hideitsu , Akaho Shotara , Murata Noboru 
Published: July 2023

AbstractDespite the importance of sleep to the cerebral cortex, how much sleep changes cortical neuronal firing remains unclear due to complicated firing behaviors. Here we quantified firing of cortical neurons using Hawkes process modeling that can model sequential random events exhibiting temporal clusters. “Intensity” is a parameter of Hawkes process that defines the probability of an event occurring. We defined the appearance of repetitive firing as the firing intensity corresponding to “intensity” in Hawkes process. Firing patterns were quantified by the magnitude of firing intensity, the time constant of firing intensity, and the background firing intensity. The higher the magnitude of firing intensity, the higher the likelihood that the spike will continue. The larger the time constant of firing intensity, the longer the repetitive firing lasts. The higher the background firing intensity, the more likely neurons fire randomly. The magnitude of firing intensity was inversely proportional to the time constant of firing intensity, and non-REM sleep increased the magnitude of firing intensity and decreased the time constant of firing intensity. The background firing intensity was not affected by the sleep/wake state. Our findings suggest that the cortex is organized such that neurons with a higher probability of repetitive firing have shorter repetitive firing periods. In addition, our results suggest that repetitive firing is ordered to become high frequency and short term during non-REM sleep, while unregulated components of firing are independent of the sleep/wake state in the cortex. Hawkes process modeling of firing will reveal novel properties of the brain.
Murine GMP- and MDP-derived classical monocytes have distinct functions and fates
Authors: Trzebanski Sébastien , Kim Jung-Seok , Larossi Niss , Raanan Ayala , Kancheva Daliya , Bastos Jonathan , Haddad Montaser , Solomon Aryeh , Sivan Ehud , Aizik Dan , Kralova Jarmila , Gross-Vered Mor , Boura-Halfon Sigalit , Lapidot Tsvee , Alon Ronen , Movahedi Kiavash , Jung Steffen 
Published: July 2023

AbstractMonocytes are short-lived myeloid immune cells that arise from adult hematopoiesis and circulate for a short time in the blood. They comprise two main subsets, in mice defined as classical Ly6Chighand non-classical Ly6Clowmonocytes (CM, NCM). Recent fate mapping and transcriptomic analyses revealed that CM themselves are heterogeneous. Here, we report surface markers that allow segregation of murine GMP- and MDP-derived CM in the BM and blood. Functional characterization, including fate definition following adoptive cell transfer, established that GMP-Mo and MDP-Mo could equal rise to homeostatic CM progeny, such as NCM in blood and gut macrophages, but differentially seeded selected other tissues. Specifically, GMP-Mo and MDP-Mo gave rise to distinct interstitial lung macrophages, thus linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide comprehensive evidence for the existence of two functionally distinct CM subsets in the mouse, which differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge. Our findings are indicative of impact of monocyte ontogeny onin situdifferentiation.
Evaluation of a BE-inactivated whole virus preparation using an encephalomyocarditis virus strain that was isolated from fatal infection in orangutans
Authors: Tong Cathlyn , Tan Boon-Huan , Sugrue Richard 
Published: July 2023

AbstractA novel Encephalomyocarditis virus (EMCV) of the group 3 cluster (EMCV-3) was first reported in 2002 to be responsible for the deaths of orang-utans in an outbreak in the Singapore Zoo. After this first outbreak, sporadic infections among the primate population caused by EMCV-3 continued to be reported, suggesting that the virus remains prevalent in Singapore. To prevent future infections, we constructed an experimental vaccine using binary ethylenimine (BE) to inactivate the EMCV-3 virus. The immunological performance of the BE-inactivated (BEI) virus was analysed in mice and the neutralising titre of the immune sera measured against the wild-type EMCV-3. The BEI virus showed a strong immunological response in BALB/c mice at 1: 40,960 titre, suggesting that it can be used as a promising experimental vaccine candidate to prevent EMCV-3 infections.
Brd4::Nutm1fusion gene initiates NUT carcinomain vivo
Authors: Zheng Dejin , Elnegiry Ahmed , Luo Chenxiang , Bendahou Mohammed Amine , Xie Liangqi , Bell Diana , Takahashi Yoko , Hanna Ehab , Mias George I. , Tsoi Mayra F. , Gu Bin 
Published: July 2023

AbstractNut carcinoma (NC) is an aggressive cancer with no effective treatment. The majority (70%) of NUT carcinoma is associated with chromosome translocation events that lead to the formation of aBRD4::NUTM1fusion gene. However, because theBRD4::NUTM1gene is unequivocally cytotoxic when ectopically expressed in cell lines, questions remain on whether the fusion gene can initiate NC. Here, we report the first genetically engineered mouse model (GEMM) for NUT carcinoma recapitulating the human mutation. By stochastically inducing a chromosome translocation mirroring the human event, we demonstrated that theBrd4::Nutm1fusion gene could induce aggressive carcinomas in mice. The tumors present histopathological and molecular features similar to human NC, with an enrichment of undifferentiated cells. Similar to the reports of human NC incidence,Brd4::Nutm1can induce NC from a broad range of tissues, demonstrating that its oncogenic potential is not lineage-restricted. The consistent induction of tumors of squamous phenotypes, even from ductal epithelial and mesenchymal tissues, demonstrated a strong reprogramming activity of BRD4::NUTM1. The new mouse model provided a critical preclinical model for NC and opens new opportunities for understanding the oncogenic mechanism and developing new therapies.
Upper Thermal Tolerance of the Endemic Freshwater StingrayPotamotrygon Magdalenaeand Inference on its Populations: An Endemic Potamotrygonid Resistant to High Temperatures Facing Thermal Changes
Authors: Gómez-Martínez Daniela , Londoño-Cruz Edgardo , Mejía-Falla Paola Andrea 
Published: July 2023

ABSTRACTKnowledge on thermal tolerance limits provide important clues to the capacity of a species to withstand acute thermal conditions. Climatic models predict the increase and intensification of events such as heat waves, therefore understanding the upper thermal limits that a species can tolerate, has become of utmost importance. We measure the upper thermal tolerance of the endemic freshwater stingrayPotamotrygon magdalenaeacclimated to experimental conditions, using the Critical Thermal Methodology (CTM). We also describe the behavior of individuals and infer the possible consequences of temperature increases in the habitats ofP. magdalenaepopulations. There were no significant differences between sexes in temperature tolerance or behavior. The Critical Thermal Maximum - CTMax (39ºC) was 5.9ºC above the maximum recorded temperature for the study area. AlthoughP. magdalenaewas tolerant to high temperature and currently is not living at its upper thermal limit, its survival in Guarinocito Pond will be threatened if the increasing trend in temperature conditions keeps growing over time.SUMMARY STATEMENTPotamotrygon magdalenaeshows tolerance to high temperatures regardless of sex and size; however, can be threatened in the future if the temperature in its habitat continues rising.
Elevator motion of chloride ion transporter SLC26A9 induced by STAS domain
Authors: Omori Satoshi , Hanazono Yuya , Nishi Hafumi , Kinoshita Kengo 
Published: July 2023

ABSTRACTThe anion exchanger SLC26A9, consisting of the transmembrane (TM) domain and the cytoplasmic STAS domain, plays an essential role in regulating chloride transport across cell membranes. Recent studies have indicated that C-terminal helices block the entrance of the putative ion transport pathway. However, the precise functions of the STAS domain and C-terminal helix, as well as the underlying molecular mechanisms governing the transport process, remain poorly understood. In this study, we performed molecular dynamics simulations of three distinct models of human SLC26A9: full-length (FL), STAS domain removal (ΔSTAS), and C-terminus removal (ΔC), to investigate their conformational dynamics and ion binding properties. Stable binding of ions to the binding sites was exclusively observed in the ΔC model in these simulations. Comparing the FL and ΔC simulations, the ΔC model displayed enhanced motion of the STAS domain. Furthermore, comparing the ΔSTAS and ΔC simulations, the ΔSTAS simulation failed to exhibit stable ion bindings to the sites despite the absence of the C-terminus blocking the ion transmission pathway in both systems. These results suggest that the removal of the C-terminus not only unblocks the access of ions to the permeation pathway but also triggers STAS domain motion, gating the TM domain to promote ions’ entry into their binding site. Further analysis revealed that the asymmetric motion of STAS domain leads to the expansion of the ion permeation pathway within the TM domain, resulting in the stiffening of the flexible TM12 helix near the ion binding site. This structural change in the TM12 helix stabilizes chloride ion binding, which is essential for SLC26A9 elevator motion. Overall, our study provides new insights into the molecular mechanisms of SLC26A9 transport and may pave the way for the development of novel treatments for diseases associated with dysregulated ion transport.SIGNIFICANCEWe explored the mechanism by which the human protein SLC26A9 transports chloride in the cell. SLC26A9 is a potential therapeutic target for patients with cystic fibrosis, as by targeting drugs to it, it may be possible to restore chloride ion transport in epithelial cells. To design therapeutic drugs, it is essential to understand how the protein works. Our findings support an elevator-type mechanism, in which chloride ions bind to SLC26A9 inside the cell and are then released by the protein to the extracellular environment. We find that the STAS domain of SLC26A9 has critical roles in binding chloride and induces conformational changes in the transmembrane domain that facilitate chloride transport.