Miracle-dz/UniFAR-FTUs huggingface dataset:
Separate Functional Subnetworks of Excitatory Neurons Show Preference to Periodic and Random Sound Structures

Auditory cortex (ACX) neurons are sensitive to spectro-temporal sound patterns and violations in patterns induced by rare stimuli embedded within streams of sounds. We investigate the auditory cortical representation of repeated presentations of sequences of sounds with standard stimuli (common) with an embedded deviant (rare) stimulus in two conditions, Periodic (Fixed deviant position) or Random (Random deviant position). We used extracellular single-unit and two-photon Ca2+ imaging recordings in layer 2/3 neurons of the mouse (Mus musculus) ACX of either sex. Population single-unit average responses increased over repetitions in the Random condition and were suppressed or did not change in the Periodic condition, showing general irregularity preference. A subset of neurons showed the opposite behavior, indicating regularity preference. Furthermore, pairwise noise correlations were higher in the Random condition than in the Periodic condition, suggesting a role of recurrent connections in the observed differential adaptation. Functional two-photon Ca2+ imaging showed that excitatory (EX), and inhibitory (IN) neurons [parvalbumin-positive (PV) and somatostatin-positive (SOM)] also had different categories of long-term adaptation as observed with single-units. However, examination of functional connectivity between pairs of neurons of different categories showed that EX-PV connected pairs behaved opposite to the EX-EX and EX-SOM pairs, with more connections outside category in Random condition than Periodic condition. Finally, considering Regularity, Irregularity, and no preference of connected pairs of neurons showed that EX-EX and EX-SOM pairs were in largely separate functional subnetworks with different preferences, not EX-PV pairs. Thus, separate subnetworks underlie coding of periodic and random sound sequences. SIGNIFICANCE STATEMENT Studying how the auditory cortex (ACX) neurons respond to streams of sound sequences help us understand the importance of changes in dynamic acoustic noisy scenes around us. Humans and animals are sensitive to regularity and its violations in sound sequences. Psychophysical tasks in humans show that the auditory brain differentially responds to Periodic and Random structures, independent of the listener's attentional states. Here, we show that mouse ACX L2/3 neurons detect changes and respond differently to patterns over long-time scales. The differential functional connectivity profile obtained in response to two different sound contexts suggests the vital role of recurrent connections in the auditory cortical network. Furthermore, the excitatory-inhibitory neuronal interactions can contribute to detecting the changing sound patterns.
Hierarchical reactivation of transcription during mitosis-to-G1 transition by Brn2 and Ascl1 in neural stem cells

During mitosis, chromatin condensation is accompanied by a global arrest of transcription. Recent studies suggest transcriptional reactivation upon mitotic exit occurs in temporally coordinated waves, but the underlying regulatory principles have yet to be elucidated. In particular, the contribution of sequence-specific transcription factors (TFs) remains poorly understood. Here we report that Brn2, an important regulator of neural stem cell identity, associates with condensed chromatin throughout cell division, as assessed by live-cell imaging of proliferating neural stem cells. By contrast, the neuronal fate determinant Ascl1 dissociates from mitotic chromosomes. ChIP-seq analysis reveals that Brn2 mitotic-chromosome binding does not result in sequence-specific interactions prior to mitotic exit, relying mostly on electrostatic forces. Nevertheless, surveying active transcription using single-molecule RNA-FISH against immature transcripts, indicates the differential presence of TF near chromatin when exiting mitosis is associated with early (anaphase) versus late (early G1) reactivation of key targets of Brn2 and Ascl1, respectively. Moreover, by using a mitotic-specific dominant negative approach, we show that competing with Brn2 binding during mitotic exit reduces the transcription of its target gene Nestin. Our study shows an important role for differential binding of TFs to mitotic chromosomes, governed by their electrostatic properties, in defining the temporal order of transcriptional reactivation during mitosis-to-G1 transition.
Effect of aging-related network changes on unimanual sensorimotor learning – a simultaneous EEG-fMRI study

Sensorimotor coordination requires orchestrated network activity mediated by inter- and intra-hemispheric, excitatory and inhibitory neuronal interactions. Aging-related structural changes may alter these interactions. Disbalancing strength and timing of excitation and inhibition may limit motor performance. This is particularly true during motor coordination tasks that have to be learned through practice. To investigate this, we simultaneously acquired electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) in two groups of healthy adults (young N=13: 20-25y and elderly N=14: 59-70y), while they were practicing a unimanual motor task. Both groups learned the task during brain scanning, which was confirmed by a 24h follow-up retention test. On average, quality of performance of older participants stayed significantly below that of the younger ones. Accompanying decreases in motor-event-related EEG-source beta band power (β, 15-30 Hz) were lateralized in both groups towards the contralateral side, albeit more so in younger participants. In the latter, the mean β-power during motor learning in bilateral pre-motor cortex (PM1) was significantly higher than in the older group. Combined EEG/fMRI analysis revealed positive correlations between fMRI signals and source-reconstructed β-amplitude time courses in contralateral and ipsilateral M1, and negative correlations in bilateral PM1 for both groups. The β-positive fMRI response in bilateral M1 might be explained by an increased cross-talk between hemispheres during periods of pronounced β-activity. During learning, the Rolandic β-power relative to rest was higher in bilateral PM1 in younger participants, suggesting less task-related beta band desynchronization in this (better performing) group. We also found positive correlations between Rolandic β-amplitude and fMRI-BOLD in bilateral M1 and negative correlations bilateral in PM1. This indicates that increased β-amplitudes are associated with increased M1 “activity” (positive BOLD response) and decreased PM1 “activity” (negative BOLD response). Our results point at decreased pre-motor inhibitory inputs to M1 as possible source for increased interhemispheric crosstalk and an aging-related decline in motor performance. Highlights Sensorimotor coordination performance decreases with increasing age. During motor learning the β-power in pre-motor areas is reduced with age. EEG/fMRI points at less effective inhibitory inputs from PM1 to ipsilateral M1 in older adults.
Characterizing white matter alterations in drug-naïve de novo Parkinson’s disease with diffusion MRI

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by a range of motor and non-motor symptoms, often with the motor dysfunction initiated unilaterally. Knowledge regarding disease-related alterations in white matter pathways can effectively help improve the understanding of the disease and propose targeted treatment strategies. Microstructural imaging techniques, including diffusion tensor imaging (DTI), allows inspection of white matter integrity to study the pathogenesis of various neurological conditions. Previous voxel-based analyses with DTI measures, such as fractional anisotropy and mean diffusivity have uncovered changes in brain regions that are associated with PD, but the conclusions were inconsistent, partially due to small patient cohorts and the lack of consideration for clinical laterality onset, particularly in early PD. Fixel-based analysis (FBA) is a recent framework that offers tract-specific insights regarding white matter health, but very few FBA studies on PD exist. We present a study that reveals strengthened and weakened white matter integrity that is subject to symptom laterality in a large drug-naïve de novo PD cohort using complementary DTI and FBA measures. The findings suggest that the disease gives rise to both functional degeneration and the creation of compensatory networks in the early stage.
A systems-level analysis of dynamic total-body PET data reveals complex skeletal energy metabolism networks in vivo

Bone is now regarded to be a key regulator of a number of metabolic processes, in addition to the regulation of mineral metabolism. However, our understanding of complex bone metabolic interactions at a systems level remains rudimentary, limiting our ability to assess systemic mechanisms underlying diseases and develop novel therapeutics. In vitro molecular biology and bioinformatics approaches have frequently been used to understand the mechanistic changes underlying disease at the cell level, however, these approaches lack the capability to interrogate dynamic multi-bone metabolic interactions in vivo. Here we present a novel and integrative approach to understand complex bone metabolic interactions in vivo using total-body positron emission tomography (PET) network analysis of murine 18F-FDG scans, as a biomarker of glucose metabolism signature in bones. In this report we show that different bones within the skeleton have a unique glucose metabolism and form a complex metabolic network. These data could have important therapeutic implications in the management of the metabolic syndrome and skeletal disease. The application of our approach to clinical and preclinical total-body PET studies promises to reveal further physiological and pathological tissue interactions, which simplistic PET standard uptake values analysis fail to interrogate, extending beyond skeletal metabolism, due to the diversity of PET radiotracers available and under development as well as the advent of clinical total-body PET systems. One Sentence Summary Bones form a complex metabolic network.
Deletion of Small Ubiquitin-like Modifier-1 Attenuates Behavioral and Anatomical Deficits by Enhancing Functional Autophagic Activities in Huntington Disease

Mutant HTT (mHTT) associated with Huntington disease (HD) affects the central nervous system by prominent atrophy in the striatum and promotes psychiatric, cognitive, and choreiform movements, although the exact mechanism remains obscure. Previous studies have shown that SUMO1 (Small Ubiquitin-like Modifier-1) modification of mHTT promotes cellular toxicity, but the in vivo role and functions of SUMO1 in HD pathogenesis are unclear. Here, we report that SUMO1 deletion in Q175DN HD-het knock-in mice (HD mice) prevented age-dependent HD-like motor and neurological impairments and suppressed the striatal atrophy and inflammatory response. SUMO1 deletion caused a drastic reduction in soluble mHtt levels and nuclear and extracellular mHtt inclusions, while increasing cytoplasmic inclusions in the striatum of HD mice. SUMO1 deletion also enhanced autophagic activity, characterized by augmented interactions between mHTT inclusions and a lysosomal marker (LAMP1), increased LC3B/LAMP1 interaction, and decreased sequestosome-1 (p62) and mHTT and diminished p62/LAMP1 interactions in DARPP-32–positive medium spiny neurons (MSNs) in HD mice. Depletion of SUMO1 in an HD cell model also diminished the mHtt levels and enhanced autophagy flux. In addition, the SUMOylation inhibitor ginkgolic acid strongly enhanced autophagy and diminished mHTT levels in human HD fibroblasts. These results indicate that SUMO is a critical therapeutic target in HD and that blocking SUMO may ameliorate HD pathogenesis by improving autophagy activities.
Laminar dynamics of beta bursts in human motor cortex

Modulation of motor cortical activity in the beta frequency range is one of the strongest and most studied movement-related neural signals. At the single trial level, beta band activity is often characterized by transient bursting events rather than slowly modulating oscillations, suggesting a more rapid, information-encoding functional role than previously believed. Insight into how beta bursts are generated in sensorimotor circuits can provide important constraints to theories about their functional role for movement control. To this end, we leverage and extend recent developments in high precision MEG for temporally resolved laminar analysis of burst activity, combined with a neocortical circuit model that simulates the biophysical generators of the electrical currents which drive beta bursts. This approach pinpoints the generation of beta bursts in human motor cortex to distinct excitatory synaptic inputs to deep and superficial cortical layers, which drive current flow in opposite directions. These laminar dynamics of beta bursts in motor cortex align with prior invasive animal recordings within the somatosensory cortex, and suggest a conserved mechanism for somatosensory and motor cortical beta bursts. More generally, we demonstrate the ability for uncovering the laminar dynamics of event-related neural signals in human non-invasive recordings.
ID4 Is Required for Normal Ependymal Cell Development

Ependymal cells are radial glia-derived multiciliated cells lining the lateral ventricles of the brain and spinal cord. Correct development and coordinated cilia beating is essential for proper cerebrospinal fluid flow (CSF) and neurogenesis modulation. Dysfunctions of ependymal cells were associated with transcription factor deregulation. Here we provide evidence that the transcriptional regulator Id4 is involved in ependymal cell development and maturation. We observed that Id4-deficient mice display altered ependymal cytoarchitecture, decreased ependymal cell number, altered CSF flow and enlarged ventricles. Our findings open the way for a potential role of Id4 in ependymal cell development and/or motor cilia function.
Transcriptional and Translational Responsiveness of the Neisseria gonorrhoeae Type IV Secretion System to Conditions of Host Infections

The type IV secretion system of Neisseria gonorrhoeae translocates single-stranded DNA into the extracellular space, facilitating horizontal gene transfer and initiating biofilm formation. Expression of this system has been observed to be low under laboratory conditions, and multiple levels of regulation have been identified. ABSTRACT The type IV secretion system of Neisseria gonorrhoeae translocates single-stranded DNA into the extracellular space, facilitating horizontal gene transfer and initiating biofilm formation. Expression of this system has been observed to be low under laboratory conditions, and multiple levels of regulation have been identified. We used a translational fusion of lacZ to traD, the gene for the type IV secretion system coupling protein, to screen for increased type IV secretion system expression. We identified several physiologically relevant conditions, including surface adherence, decreased manganese or iron, and increased zinc or copper, which increase gonococcal type IV secretion system protein levels through transcriptional and/or translational mechanisms. These metal treatments are reminiscent of the conditions in the macrophage phagosome. The ferric uptake regulator, Fur, was found to repress traD transcript levels but to also have a second role, acting to allow TraD protein levels to increase only in the absence of iron. To better understand type IV secretion system regulation during infection, we examined transcriptomic data from active urethral infection samples from five men. The data demonstrated differential expression of 20 of 21 type IV secretion system genes during infection, indicating upregulation of genes necessary for DNA secretion during host infection.
Dynamic association of IκBα to chromatin is regulated by acetylation and cleavage of histone H4

IκBs exert a principal function as cytoplasmic inhibitors of the NF-kB transcription factors. Additional functions for IκB homologues have been described including association to chromatin and transcriptional regulatioin. Phosphorylated and SUMOylated IκBα (pS-IκBα) binds histones H2A and H4 in the stem and progenitor compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unstudied. We here show that serine 32-36 phosphorylation of IκBα favors its binding with nucleosomes and demonstrated that p-IκBα association to H4 is favored by acetylation at specific H4 lysine residues. N-terminal tail of H4 is lost during intestinal cell differentiation by proteolytic cleavage at residues 17-19 imposed ny trypsin or chymotrypsin, which interferes p-IκBα binding. Paradoxically, inhibition of trypsin and chymotrypsin activity in HT29 cells increased p-IκBα chromatin binding and impaired goblet cell differentiation, comparable to IκBα deletion. Together our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular base for the restricted nuclear distribution of p-IκBα at specific stem cell compartments.
Monoclonal antibodies targeting the influenza virus N6 neuraminidase

Influenza A viruses are a diverse species that include 16 hemagglutinin (HA) subtypes and 9 neuraminidase (NA) subtypes. While the antigenicity of many HA subtypes is reasonably well studied, less is known about NA antigenicity, especially when it comes to non-human subtypes that only circulate in animal reservoirs. The N6 NA subtypes are mostly found in viruses infecting birds. However, they have also been identified in viruses that infect mammals, such as swine and seals. More recently, highly pathogenic H5N6 subtype viruses have caused rare infections and mortality in humans. Here, we generated murine mAbs to the N6 NA, characterized their breadth and antiviral properties in vitro and in vivo and mapped their epitopes by generating escape mutant viruses. We found that the antibodies had broad reactivity across the American and Eurasian N6 lineages, but relatively little binding and inhibition of the H5N6 NA. Several of the antibodies exhibited strong NA inhibition activity and some also showed activity in the antibody dependent cellular cytotoxicity reporter assay and neutralization assay. In addition, we generated escape mutant viruses for six monoclonal antibodies and found mutations on the lateral ridge of the NA. Lastly, we observed variable protection in H4N6 and H5N6 mouse challenge models when the antibodies were given prophylactically. Importance The N6 NA has recently gained prominence due to the emergence of highly pathogenic H5N6 viruses. Currently, there is limited characterization of the antigenicity of avian N6 neuraminidase. Our data is an important first step towards a better understanding of the N6 NA antigenicity.
dioxin-like polychlorinated biphenyls (PCBs) in zebrafish larvae

1 Department of Biology, Woods Hole Oceanographic Institution, Woods Hole, MA, USA 5 2 School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan 6 Road, Shanghai 200240, China 7 3 Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China 8 4 Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological 9 Laboratory, Woods Hole, MA, USA 10 5 A.N. Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences, Moscow, Russia 11 12
Crystallinity and resistivity of ZnO thin films with indium implantation and postannealing

Ion implantation experiments of indium (In) into sputter-deposited undoped ZnO films were carried out to control the resistivity for n+-ZnO layers of electronic device. Improvement of ZnO crystallinity after the ion implantation was revealed by x-ray diffraction patterns including a shift of lattice parameter, enhancement of peak intensity, and a decrease in full width at half maximum in 2θ. In-implanted ZnO crystallinity was greatly improved compared to results of the Ga and Al-implanted ZnO experiments. The resistivity of 1×1016ions∕cm2 implanted ZnO film was decreased with over 11 orders of magnitude to 5.1×10−2Ωcm with postimplantation annealing at 400°C. The ratio of resistivity between unimplanted ZnO and In-implanted one at 1×1015ions∕cm2 was seven orders of magnitude after annealing at 300°C. The In-implanted ZnO would be suitable for fabricating source and drain regions of ZnO thin film transistors.
Polarity-reversal catalysis of hydrogen-atom abstraction reactions: concepts and applications in organic chemistry

The rates and selectivities of the hydrogen-atom abstraction reactions of electrically-neutral free radicals are known to depend on polar effects which operate in the transition state. Thus, an electrophilic species such as an alkoxyl radical abstracts hydrogen much more readily from an electron-rich C–H bond than from an electron-deficient one of similar strength. The basis of polarity-reversal catalysis (PRC) is to replace a single-step abstraction, that is slow because of unfavourable polar effects, with a two-step process in which the radicals and substrates are polarity-matched. This review explores the concept of PRC and describes its application in a variety of situations relevant to mechanistic and synthetic organic chemistry.
In Situ Quantitative Measurement of Rare Earth Elements in Uranium Oxides by Laser Ablation‐Inductively Coupled Plasma‐Mass Spectrometry

Advances in the quantification of rare earth elements (REE) at the micrometric scale in uranium oxides by laser ablation‐inductively coupled plasma‐mass spectrometry are described. The determination of the best analytical conditions was tested using a uranium oxide (Mistamisk) the concentrations of REE in which were previously estimated by other techniques. Comparison between the use of U or Pb as an internal standard clearly showed a diameter‐dependent fractionation effect related to Pb at small crater diameters (16 and 24 μm), which was not found for U. The quantification of REE contents in uranium oxide samples using both matrix‐matched (uranium oxide) and non‐matrix‐matched (NIST SRM 610 certified glass) external calibrators displayed no significant difference, demonstrating a limited matrix effect for REE determination by LA‐ICP‐MS. Moreover, no major interferences on REEs were detected. The proposed methodology (NIST SRM 610 as external calibrator and U as internal standard) was applied to samples from uranium deposits from around the world. The results showed that LA‐ICP‐MS is a suitable analytical technique to determine REE down to the μg g−1 level in uranium oxides at the micrometre scale and that this technique can provide significant insights into uranium metallogeny.