bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interaction between random and systematic visual stimulation and infraslow quasiperiodic spatiotemporal patterns of whole brain activity
Authors: Xu Nan , Smith Derek M. , Jeno George , Seeburger Dolly T. , Schumacher Eric H. , Keilholz Shella D. 
Published: December 2022

AbstractOne prominent feature of the infraslow BOLD signal during rest or task is quasi-periodic spatiotemporal pattern (QPP) of signal changes that involves an alternation of activity in key functional networks and propagation of activity across brain areas, and that is known to tie to the infraslow neural activity involved in attention and arousal fluctuations. This ongoing whole-brain pattern of activity might potentially modify the response to incoming stimuli or be modified itself by the induced neural activity. To investigate this, we presented checkerboard sequences flashing at 6Hz to subjects. This is a salient visual stimulus that is known to produce a strong response in visual processing regions. Two different visual stimulation sequences were employed, a systematic stimulation sequence in which the visual stimulus appeared every 20.3 secs and a random stimulation sequence in which the visual stimulus occurred randomly every 14~62.3 secs. Three central observations emerged. First, the two different stimulation conditions affect the QPP waveform in different aspects, i.e., systematic stimulation has greater effects on its phase and random stimulation has greater effects on its magnitude. Second, the QPP was more frequent in the systematic condition with significantly shorter intervals between consecutive QPPs compared to the random condition. Third, the BOLD signal response to the visual stimulus across both conditions was swamped by the QPP at the stimulus onset. These results provide novel insights into the relationship between intrinsic patterns and stimulated brain activity.
Quantitative mapping of autophagic cargo during nutrient stress reveals YIPF3-YIPF4 as membrane receptors for Golgiphagy
Authors: Hickey Kelsey L. , Swarup Sharan , Smith Ian R. , Paoli Julia C. , Paulo Joao A. , Harper J. Wade 
Published: December 2022

ABSTRACTDuring nutrient stress, macroautophagy is employed to degrade cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodeling the proteome. While the machinery responsible for initiation of macroautophagy is well characterized, our understanding of the extent to which individual proteins, protein complexes and organelles are selected for autophagic degradation, and the underlying targeting mechanisms is limited. Here, we use orthogonal proteomic strategies to provide a global molecular inventory of autophagic cargo during nutrient stress in mammalian cell lines. Through prioritization of autophagic cargo, we identify a heterodimeric pair of membrane-embedded proteins, YIPF3 and YIPF4, as receptors for Golgiphagy. During nutrient stress, YIPF4 is mobilized into ATG8-positive vesicles that traffic to lysosomes as measured via Golgiphagy flux reporters in a process that requires the VPS34 and ULK1-FIP200 arms of the autophagy system. Cells lacking YIPF3 or YIPF4 are selectively defective in elimination of Golgi membrane proteins during nutrient stress. By merging absolute protein abundance with autophagic turnover, we create a global protein census describing how autophagic degradation maps onto protein abundance and subcellular localization. Our results, available via an interactive web tool, reveal that autophagic turnover prioritizes membrane-bound organelles (principally Golgi and ER) for proteome remodeling during nutrient stress.One-Sentence SummaryDuring nutrient stress, macroautophagy uses organelle-phagy receptors to prioritize recycling of Golgi and ER membrane proteins.
Molecular mechanisms regulating the pH-dependent pr/E interaction in yellow fever virus
Authors: Crampon E. , Covernton E. , Vaney M.C. , Dellarole M. , Sharma A. , Haouz A. , England P. , Lepault J. , Duquerroy S. , Rey F.A. , Barba-Spaeth G. 
Published: December 2022

ABSTRACTFlavivirus particles bud in the ER of infected cells as immature virions composed of 180 heterodimers of glycoproteins prM and E, associated as 60 (prM/E)3trimeric spikes. Exposure to the mildly acidic pH of the TGN results in dissociation of the trimeric spikes followed by reassociation of the prM/E protomers into 90 dimers organized in a characteristic herringbone pattern. The furin site in prM is exposed in the dimers for maturation of prM into M and pr. For flaviviruses such as the tick-borne encephalitis virus (TBEV) as well as for dengue virus, it was shown that at neutral pH pr loses affinity for E, such that it dissociates from the mature particle as soon as it reaches the external milieu, which is at neutral pH. Using a soluble recombinant form of E (sE) and pr from yellow fever virus (YFV), we show here that the affinity of pr for recombinant E protein remains high even at neutral pH. The X-ray structure of YFV pr/sE shows more extensive inter-chain hydrogen bonding than does the dengue or TBEV, and also that it retains the charge complementarity between the interacting surfaces of the two proteins even at neutral pH. We further show that pr blocks sE flotation with liposomes when exposed at low pH at a 1:1 stoichiometry, yet in the context of the virus particle, an excess of 10:1 pr:E ratio is required to block virus/liposome fusion. In aggregate, our results show that the paradigm obtained from earlier studies of other flaviviruses does not apply to yellow fever virus, the flavivirus type species. A mechanism that does not rely solely in a change in the environmental pH is thus required for the release of pr from the mature particles upon release from infected cells. These results open up new avenues to understand the activation mechanism that yields mature, infectious YFV particles.
Burst firing is required for induction of Hebbian LTP at lateral perforant path to hippocampal granule cell synapses
Authors: Kim Yoonsub , Kim Sooyun , Ho Won-Kyung , Lee Suk-Ho 
Published: December 2022

AbstractHigh frequency burst firing is critical in summation of back-propagating action potentials (APs) in dendrites, which may greatly depolarize dendritic membrane potential. The physiological significance of burst firings of hippocampal dentate GCs in synaptic plasticity remains unknown. We found that GCs with low input resistance could be categorized into regular-spiking (RS) and burst-spiking (BS) cells based on their initial firing frequency (Finit) upon somatic rheobase current injection, and investigated how two types of GCs differ in long-term potentiation (LTP) induced by high-frequency lateral perforant pathway (LPP) inputs. Induction of Hebbian LTP at LPP synapses required at least three postsynaptic APs at Finithigher than 100 Hz, which was met in BS but not in RS cells. The synaptically evoked burst firing was critically dependent on persistent Na+current, which was larger in BS than RS cells. The Ca2+source for Hebbian LTP at LPP synapses was primarily provided by L-type calcium channels. In contrast, Hebbian LTP at medial PP synapses was mediated by T-type calcium channels, and could be induced regardless of cell types or Finitof postsynaptic APs. These results suggest that intrinsic firing properties affect synaptically driven firing patterns, and that bursting behavior differentially affects Hebbian LTP mechanisms depending on the synaptic input pathway.
Single-cell transcriptome analysis illuminating the characteristics of species-specific innate immune responses against viral infections
Authors: Aso Hirofumi , Ito Jumpei , Ozaki Haruka , Kashima Yukie , Suzuki Yutaka , Koyanagi Yoshio , Sato Kei 
Published: December 2022

AbstractBats harbor various viruses without severe symptoms and act as their natural reservoirs. The tolerance of bats against viral infections is assumed to originate from the uniqueness of their immune system. However, how immune responses vary between primates and bats remains unclear. Here, we characterized differences in the immune responses by peripheral blood mononuclear cells to various pathogenic stimuli between primates (humans, chimpanzees, and macaques) and bats (Egyptian fruit bats) using single-cell RNA sequencing. We show that the induction patterns of key cytosolic DNA/RNA sensors and antiviral genes differed between primates and bats. A novel subset of monocytes induced by pathogenic stimuli specifically in bats was identified. Furthermore, bats robustly respond to DNA virus infection even though major DNA sensors are dampened in bats. Overall, our data suggest that immune responses are substantially different between primates and bats, presumably underlying the difference in viral pathogenicity among the mammalian species tested.
Regional genetic correlations highlight relationships between neurodegenerative diseases and the immune system
Authors: Lona-Durazo Frida , Reynolds Regina H. , Scholz Sonja W. , Ryten Mina , Taliun Sarah A. Gagliano 
Published: December 2022

AbstractNeurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Lewy body dementia (LBD) and amyotrophic lateral sclerosis (ALS), are devastating complex diseases that result in a physical and psychological burden to patients and their families. There have been significant efforts to understand the genetic basis of neurodegenerative diseases resulting in the identification of disease risk-associated variants involved in several molecular mechanisms, including those that influence immune-related pathways. Regional genetic correlations, in contrast to genome-wide correlations, between pairs of immune and neurodegenerative traits have not been comprehensively explored, but such a regional assessment could shed light on additional immune-mediated risk-associated loci. Here, we systematically assessed the potential role of the immune system in five neurodegenerative diseases, by estimating regional genetic correlations between neurodegenerative diseases and immune-cell-derived single-cell expression quantitative trait loci (sc-eQTLs), using the recently developed method of Local Analysis of [co]Variant Association (LAVA). We used the most recently published genome-wide association studies (GWASes) for five neurodegenerative diseases and publicly available sc-eQTLs derived from 982 individuals from the OneK1K Consortium, capturing aspects of the innate and adaptive immune systems. Additionally, we tested GWASes from well-established immune-mediated diseases, Crohn’s disease (CD) and ulcerative colitis (UC), the immune-mediated neurodegenerative disease, multiple sclerosis (MS) and a well-powered GWAS with strong signal in the HLA region, schizophrenia (SCZ), as positive controls. Finally, we also performed regional genetic correlations between diseases and protein levels. We observed significant (FDR < 0.01) regional genetic correlations between sc-eQTLs and neurodegenerative diseases across 151 unique genes, spanning both the innate and adaptive immune systems, across most diseases tested (except for frontotemporal dementia (FTD) and LBD). Colocalization analyses on followed-up regional correlations highlighted immune-related candidate causal risk genes associated with neurodegenerative diseases. We also observed significant regional correlations with protein levels across 156 unique proteins, across all diseases tested, except for FTD. The outcomes of this study will improve our understanding of the immune component of neurodegeneration, which can be potentially used to repurpose existing immunotherapies used in clinical care for other immune-mediated diseases, to slow the progression of neurodegenerative diseases.
The relationship between maternal psychopathology and offspring incontinence and constipation at school age: a prospective cohort study
Authors: Sawyer Gemma , Heron Jon , Joinson Carol 
Published: December 2022

AbstractBackgroundMaternal depression and anxiety may increase the risk of offspring incontinence; however, current evidence is unable to draw causal inferences. This study aimed to examine prospective associations between maternal psychopathology and offspring incontinence/constipation and examine evidence for causal intra-uterine effects.MethodsThe study used data from 6,489 children from the Avon Longitudinal Study of Parents and Children. Mothers provided data on depression and anxiety (antenatal and postnatal) and their child’s incontinence (daytime wetting, bedwetting, soiling) and constipation at age 7. We used multivariable logistic regression to examine evidence for independent effects of maternal depression/anxiety on offspring incontinence/constipation and explore a critical/sensitive period of exposure. A negative control design was utilised to examine evidence causal intra-uterine effects.ResultsPostnatal maternal psychopathology was associated with an increased risk of offspring incontinence and constipation (e.g. postnatal anxiety and daytime wetting OR: 1.53; 95% CI: 1.21-1.94), and data were consistent with a critical period model. There was evidence for an independent effect of maternal anxiety. Antenatal maternal psychopathology was associated with constipation (e.g. antenatal anxiety OR: 1.57; 95% CI: 1.25-1.98), but there was no evidence for a causal intra-uterine effect.LimitationsAttrition and maternal reports without use of established diagnostic criteria for incontinence/constipation are potential limitations.ConclusionsChildren exposed to maternal postnatal psychopathology had a greater risk of incontinence/constipation, and maternal anxiety had stronger associations than depression.
Species and condition shape the mutational spectrum in experimentally evolved biofilms
Authors: Hu Guohai , Wang Yue , Liu Xin , Strube Mikael Lenz , Wang Bo , Kovács Ákos T. 
Published: December 2022

AbstractLaboratory experimental evolution provides a powerful tool for studying microbial adaptation to different environments. To understand the differences and similarities of the dynamic evolutionary landscapes of two model species from theBacillusgenus as they adapt to abiotic and biotic surfaces, we revived the archived population samples from our four previous experimental evolution studies and performed longitudinal whole-population genome sequencing. Surprisingly, higher number of mutations, higher genotypic diversity, and higher evolvability were detected in the biotic conditions with smaller population size. Different adaptation strategies were observed in different environments within each species, with more diversified mutational spectrum detected in biotic conditions. The insertion sequences ofBacillus thuringiensisare critical for its adaptation to the plastic bead-attached biofilm environment, but insertion sequence mobility was a general phenomenon in this species independent of the selection condition. Additionally, certain parallel evolution has been observed across species and environments, particularly when two species adapt to the same environment at the same time. Further, our results suggest that the population size might be an important driver of evolution. Together, these results provide the first comprehensive mutational landscape of two bacterial species’ biofilms that is adapted to an abiotic and biotic surface.ImportanceBiofilm formation is a vital factor for the survival and adaptation of bacteria in diverse environmental niches. Experimental evolution combined with the advancement of whole-population genome sequencing provides us a powerful tool to understand the genomic dynamic of evolutionary adaptation to different environments, such as during biofilm development. Previous studies described the genetic and phenotypic changes of selected clones from experimentally evolvedBacillus thuringiensisandBacillus subtilisthat were adapted under abiotic and biotic biofilm conditions. However, the full understanding of the dynamic evolutionary landscapes was lacking. Further, the differences and similarities of adaptive mechanisms inB. thuringiensisandB. subtiliswere not identified. To overcome these limitations, we performed longitudinal whole-population genome sequencing to study the underlying genetic dynamics at high resolution. Our study provides the first comprehensive mutational landscape of two bacterial species’ biofilms that is adapted to an abiotic and biotic surface.
Optogenetic activation of visual thalamus generates artificial visual percepts
Authors: Wang Jing , Azimi Hamid , Zhao Yilei , Kaeser Melanie , Sánchez Pilar Vaca , Harvey Michael , Rainer Gregor 
Published: December 2022

AbstractThe lateral geniculate nucleus (LGN), a retinotopic relay center where visual inputs from the retina are processed and relayed to the visual cortex, has been proposed as a potential target for artificial vision. At present, it is unknown whether optogenetic LGN stimulation is sufficient to elicit behaviorally relevant percepts and the properties of LGN neural responses relevant for artificial vision have not been thoroughly characterized. Here, we demonstrate that tree shrews pretrained on a visual detection task can detect optogenetic LGN activation using an AAV2-CamKIIα-ChR2 construct and readily generalize from visual to optogenetic detection. We also characterize how amplitude and frequency of optogenetic stimulation affect behavioral performance. Given the importance of temporal stimulation parameters, we also study tree shrew behavioral ability to discriminate among pairs of visual flicker frequencies and demonstrate performance transfer among related discrimination problems as well as limitations. Neural recordings in LGN and primary visual cortex (V1) examining two flicker discriminations reveal that while LGN neurons multiplex information about temporal stimulation discriminations, V1 neurons explicitly encode information about one or the other discriminations but not both. Our findings confirm the LGN as a potential target for visual prosthetics and introduce a distinction in stimulus encoding between thalamic and cortical representations that could be of fundamental importance in artificial vision.
Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration after peripheral nerve injury
Authors: Fuentes-Flores Andrés , Geronimo-Olvera Cristian , Ñecuñir David , Patel Sandip Kumar , Bons Joanna , Wright Megan C. , Geschwind Daniel , Hoke Ahmet , Gomez-Sanchez Jose A. , Schilling Birgit , Campisi Judith , Court Felipe A. 
Published: December 2022

AbstractAfter peripheral nerve injuries, successful axonal growth and functional recovery requires the reprogramming of Schwann cells into a reparative phenotype, a process dependent on the activation of the transcription factor c-Jun. Nevertheless, axonal regeneration is greatly impaired in aged organisms or after chronic denervation leading to important clinical problems. This regenerative failure has been associated to a diminished c-Jun expression by Schwann cells, but whether the inability of these cells to maintain a repair state is associated to the transition into a phenotype inhibitory for axonal growth, has not been evaluated so far. We find that repair Schwann cells transitions into a senescent phenotype, characterized by diminished c-Jun expression and secretion of factor inhibitory for axonal regeneration in both aging and chronic denervation. In both conditions, elimination of senescent Schwann cells by systemic senolytic drug treatment or genetic targeting improves nerve regeneration and functional recovery in aging and chronic denervation, associated with an upregulation of c-Jun expression and a decrease in nerve inflammation. This work provides the first characterization of senescent Schwann cells and their impact over axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration, and functional recovery after peripheral nerve injuries.
Expanding the HDAC druggable landscape beyond enzymatic activity
Authors: Olivet Julien , Choi Soon Gang , Sierra Salvador , O’Grady Tina M. , de la Fuente Revenga Mario , Laval Florent , Botchkarev Vladimir V. , Gorgulla Christoph , Coote Paul W. , Blavier Jérémy , Geffken Ezekiel A. , Lakhani Jimit , Song Kijun , Yeoh Zoe C. , Hu Bin , Varca Anthony C. , Bruyr Jonathan , Ibrahim Samira , Jivanjee Tasneem , Bromley Joshua D. , Nyquist Sarah K. , Richardson Aaron , Yue Hong , Wang Yang , Calonghi Natalia , Stefan Alessandra , Spirohn Kerstin , Vertommen Didier , Baietti Maria F. , Lemmens Irma , Seo Hyuk-Soo , Dozmorov Mikhail G. , Willems Luc , Tavernier Jan , Das Kalyan , Leucci Eleonora , Hochkoeppler Alejandro , Sun Zhen-Yu Jim , Calderwood Michael A. , Hao Tong , Shalek Alex K. , Hill David E. , Boeszoermenyi Andras , Arthanari Haribabu , Buhrlage Sara J. , Dhe-Paganon Sirano , González-Maeso Javier , Dequiedt Franck , Twizere Jean-Claude , Vidal Marc 
Published: December 2022

ABSTRACTEnzymatic pockets such as those of histone deacetylases (HDACs) are among the most favored targets for drug development. However, enzymatic inhibitors often exhibit low selectivity and high toxicity due to targeting multiple enzyme paralogs, which are often involved in distinct multisubunit complexes. Here, we report the discovery and characterization of a non-enzymatic small molecule inhibitor of HDAC transcriptional repression functions with comparable anti-tumor activity to the enzymatic HDAC inhibitor Vorinostat, and anti-psychedelic activity of anHDAC2knockoutin vivo. We highlight that these phenotypes are achieved while modulating the expression of 20- and 80-fold fewer genes than enzymatic and genetic inhibition in the respective models. Thus, by achieving the same biological outcomes as established therapeutics while impacting a dramatically smaller number of genes, inhibitors of protein-protein interactions can offer important advantages in improving the selectivity of epigenetic modulators.GRAPHICAL ABSTRACT
Mega-scale movie-fields in the mouse visuo-hippocampal network
Authors: Purandare Chinmay S. , Mehta Mayank R. 
Published: December 2022

AbstractNatural experience often involves a continuous series of related images while the subject is immobile. How does the cortico-hippocampal circuit process this information? The hippocampus is crucial for episodic memory1–3, but most rodent single unit studies require spatial exploration4–6or active engagement7. Hence, we investigated neural responses to a silent, isoluminant, black and white movie in head-fixed mice without any task or locomotion demands, or rewards, from the Allen Brain Observatory. The activity of most neurons (97%, 6554/6785) in the thalamo-cortical visual areas was significantly modulated by the 30s long movie clip. Surprisingly, a third (33%, 3379/10263) of hippocampal –dentate gyrus, CA1 and subiculum– neurons showed movie-selectivity, with elevated firing in specific movie sub-segments, termed movie-fields. Movie-tuning remained intact when mice were immobile or ran spontaneously. On average, a tuned cell had more than 5 movie-fields in visual areas, but only 2 in hippocampal areas. The movie-field durations in all brain regions spanned an unprecedented 1000-fold range: from 0.02s to 20s, termed mega-scale coding. Yet, the total duration of all the movie-fields of a cell was comparable across neurons and brain regions. We hypothesize that hippocampal responses show greater continuous-sequence encoding than visual areas, as evidenced by fewer and broader movie-fields than in visual areas. Consistent with this hypothesis, repeated presentation of the movie images in a fixed, scrambled sequence virtually abolished hippocampal but not visual-cortical selectivity. The enhancement of continuous movie tuning compared to the scrambled sequence was eight-fold greater in hippocampal than visual areas, further supporting episodic-sequence encoding. Thus, all mouse-brain areas investigated encoded segments of the movie. Similar results are likely to hold in primates and humans. Hence, movies could provide a unified way to probe neural mechanisms of episodic information processing and memory, even in immobile subjects, across brain regions, and species.