Miracle-dz/UniFAR-FTUs huggingface dataset:
Ninjinyoeito Has a Protective Effect on the Auditory Nerve and Suppresses the Progression of Age-Related Hearing Loss in Mice

Currently, there are limited reports available regarding the treatment and prevention of progressive age-related hearing loss. This is because age-related hearing loss is not a critical disease with direct fatalities and has several well-established countermeasures such as hearing aids and cochlear implants. This study evaluated the efficacy of Ninjinyoeito (NYT) in the treatment of age-related hearing loss. C57BL/6J mice were divided into three groups: baseline group, untreated group, and NYT-treated group, with the latter receiving NYT treatment for 2 months. The mice were fed with NYT extract mixed with 4% mouse normal chow. Hearing loss was confirmed by a reduction in intact cell density of the auditory nerve from the age of 5–7 months. The suppression of hearing loss with aging and decrease in the intact cell density of the auditory nerve were significant in mice fed with NYT for 2 months. NYT has been reported to improve blood flow and enhance mitochondrial activity and may exert its protective effects on spiral neurons through these mechanisms. There was no decrease in the size of the stria vascularis from the age of 5–7 months in C57BL/6J mice. The present model failed to reveal the effect of NYT on atrophy of the stria vascularis of the cochlear duct. In conclusion, NYT appears to have a protective effect on the auditory nerve and suppress the progression of age-related hearing loss by reducing age-related auditory nerve degeneration.
Investigation of RNA metabolism through large-scale genetic interaction profiling in yeast

Gene deletion and gene expression alteration can lead to growth defects that are amplified or reduced when a second mutation is present in the same cells. We performed 154 genetic interaction mapping (GIM) screens with mutants related with RNA metabolism and measured growth rates of about 700 000 Saccharomyces cerevisiae double mutant strains. The screens used the gene deletion collection in addition to a set of 900 strains in which essential genes were affected by mRNA destabilization (DAmP). To analyze the results we developed RECAP, a strategy that validates genetic interaction profiles by comparison with gene co-citation frequency, and identified links between 1 471 genes and 117 biological processes. To validate specific results, we tested and confirmed a link between an inositol polyphosphate hydrolase complex and mRNA translation initiation. Altogether, the results and the newly developed analysis strategy should represent a useful resource for discovery of gene function in yeast.
Single-cell tracking reveals super-spreading cells with high persistence in invasive brain cancer

Cell migration is a fundamental characteristic of vital processes such as tissue morphogenesis, wound healing and immune cell homing to lymph nodes and inflamed or infected sites. Therefore, various brain defect diseases, chronic inflammatory diseases as well as tumor formation and metastasis are associated with aberrant or absent cell migration. With embedment of multicellular brain cancer spheroids in Matrigel™ and single-particle tracking, we extracted the paths of cells migrating away from the spheroids. We found that - in contrast to local invasion - single cell migration is independent of the mechanical load exerted by the environment and is characterized by high directionality and persistence. Furthermore, we identified a subpopulation of super-spreading cells with >200-fold longer persistence times than the majority of cells. These results highlight yet another aspect of between-cell heterogeneity in tumors.
Evidence and Urgency Related EEG Signals during Dynamic Decision-Making in Humans

A successful class of models link decision-making to brain signals by assuming that evidence accumulates to a decision threshold. These evidence accumulation models have identified neuronal activity that appears to reflect sensory evidence and decision variables that drive behavior. More recently, an additional evidence-independent and time-variant signal, called urgency, has been hypothesized to accelerate decisions in the face of insufficient evidence. However, most decision-making paradigms tested with fMRI or EEG in humans have not been designed to disentangle evidence accumulation from urgency. Here we use a face-morphing decision-making task in combination with EEG and a hierarchical Bayesian model to identify neural signals related to sensory and decision variables, and to test the urgency-gating model. Forty females and 34 males took part (mean age, 23.4 years). We find that an evoked potential time locked to the decision, the centroparietal positivity, reflects the decision variable from the computational model. We further show that the unfolding of this signal throughout the decision process best reflects the product of sensory evidence and an evidence-independent urgency signal. Urgency varied across subjects, suggesting that it may represent an individual trait. Our results show that it is possible to use EEG to distinguish neural signals related to sensory evidence accumulation, decision variables, and urgency. These mechanisms expose principles of cognitive function in general and may have applications to the study of pathologic decision-making such as in impulse control and addictive disorders. SIGNIFICANCE STATEMENT Perceptual decisions are often described by a class of models that assumes that sensory evidence accumulates gradually over time until a decision threshold is reached. In the present study, we demonstrate that an additional urgency signal impacts how decisions are formed. This endogenous signal encourages one to respond as time elapses. We found that neural decision signals measured by EEG reflect the product of sensory evidence and an evidence-independent urgency signal. A nuanced understanding of human decisions, and the neural mechanisms that support it, can improve decision-making in many situations and potentially ameliorate dysfunction when it has gone awry.
Personalized Sheet Music Search

This paper discusses a novel system for querying digital sheet music using musical metadata. Users select instruments and playable ranges for an ensemble using a custom note entry tool. From this ensemble profile, the system generates SQL queries to find matching compositions based on ranges rather than motifs. The system extracts metadata such as instrument ranges, keys, and meters from MusicXML and vectorized PDF documents. Metadata is extracted by a proprietary algorithm without recourse to optical music recognition (OMR), in concert with music21.
Flash properties of Gaussia Luciferase are the result of covalent inhibition after a limited number of cycles

Luciferases are widely used as reporters for gene expression and for sensitive detection systems. While luciferases from firefly and Renilla have long been used for analysis of intracellular expression, the luciferase (GLuc) from the marine copepod Gaussia princeps, has gained popularity, primarily because it is secreted and displays a very high light intensity. Firefly luciferase is characterized by kinetic behavior which is consistent with conventional steady-state Michaelis-Menten kinetics (termed “glow” kinetics). GLuc, conversely, displays what has been termed “flash” kinetics which signify a burst in light emission followed by a rapid decay. As the mechanistic background for this behavior is poorly characterized, we decided to decipher the mechanism in more detail. We show that decay in light signal is not due to depletion of substrate, but rather is caused by the irreversible inactivation of the enzyme. Inactivation takes place after between 10 and 200 reaction cycles, depending on substrate concentration. We found that the rate of inactivation is described by the sum of two exponentials with associated rate constants. The dominant of these of these increases linearly with substrate concentration while the minor is substrate-concentration independent. In terms of rate of initial luminescence reaction, this increases with the substrate concentration to the power of 1.53 and shows no signs of saturation up to 10 μM coelenterazine. Finally, we found that the inactivated form of the enzyme has a larger apparent size in both size exclusion chromatography and SDS-PAGE analysis and shows a fluorescence peak at 410 nm when excited at 333 nm. These findings indicate that the “flash” kinetics in Gaussia luciferase are caused by an irreversible covalent binding to a derivative of the substrate during the reaction.
Temporo-parietal cortex involved in modeling one’s own and others’ attention

In a traditional view, in social cognition, attention is equated with gaze and people track attention by tracking other people’s gaze. Here we used fMRI to test whether the brain represents attention in a richer manner. People read stories describing an agent (either oneself or someone else) directing attention to an object in one of two ways: either internally directed (endogenous) or externally induced (exogenous). We used multivoxel pattern analysis to examine how brain areas within the theory-of-mind network encoded attention type and agent type. Brain activity patterns in the left temporo-parietal junction (TPJ) showed significant decoding of information about endogenous versus exogenous attention. The left TPJ, left superior temporal sulcus (STS), precuneus, and medial prefrontal cortex (MPFC) significantly decoded agent type (self versus other). These findings show that the brain constructs a rich model of one’s own and others’ attentional state, possibly aiding theory of mind. Impact statement This study used fMRI to show that the human brain encodes other people’s attention in enough richness to distinguish whether that attention was directed exogenously (stimulus-driven) or endogenously (internally driven).
Distinct higher-order representations of natural sounds in human and ferret auditory cortex

Little is known about how neural representations of natural stimuli differ across species. Speech and music for example play a unique role in human hearing, but it is unclear how auditory representations of speech and music differ between humans and other animals. Using functional Ultrasound imaging, we measured responses in ferret auditory cortex to a set of natural and spectrotemporally-matched synthetic sounds previously tested in humans, as well as natural and synthetic ferret vocalizations. Ferrets showed similar frequency and modulation tuning to that observed in humans. But while humans showed selective responses to natural speech and music in non-primary auditory cortex, ferret responses to natural and synthetic sounds were closely matched throughout primary and non-primary regions, even when tested with ferret vocalizations. This finding suggests the unique demands of speech and music have substantially altered higher-order acoustic representations in human auditory cortex, while largely preserving lower-level tuning for frequency and modulation.
“A novel female-specific circadian clock mechanism regulating metabolism”

Circadian clocks enable organisms to predict and align their behaviors and physiologies to constant daily day-night environmental cycle. Because the ubiquitin ligase Siah2 has been identified as a potential regulator of circadian clock function in cultured cells, we have used Siah2-deficient mice to examine its function in vivo. Our experiments demonstrate a striking and unexpected sexually dimorphic effect of Siah2 deficiency on the regulation of rhythmically expressed genes. The absence of Siah2 in females, but not in males, altered the expression of core circadian clock genes and drastically remodeled the rhythmic hepatic transcriptome. Siah2 loss, only in females, increased the expression of 100’s of genes selectively at mid-day, resulting in a >50% increase in the number of rhythmically expressed genes, and shifted the expression of 100’s of other genes from a mid-night peak, to a mid-day peak. The combined result is a near inversion of overall rhythmicity in gene expression selectively in Siah2-deficient females. This dramatic reorganization created a substantial misalignment between rhythmic liver functions and feeding/behavioral rhythms, and consequently disrupted daily patterns of lipid/lipoprotein metabolism and metabolic responses to high-fat diet. Collectively, our results suggest that Siah2 is part of a female-specific circadian mechanism important for maintaining metabolic homeostasis and may play a key role in establishing sexual dimorphisms in metabolism, and broadly reveal that circadian clocks may drive rhythms using novel sex-specific transcriptional pathways.
Modulating the Blood-Brain Barrier by Light Stimulation of Molecular-Targeted Nanoparticles

The blood-brain barrier (BBB) tightly regulates the entry of molecules into the brain by tight junctions that seals the paracellular space and receptor-mediated transcytosis. It remains elusive to selectively modulate these mechanisms and to overcome BBB without significant neurotoxicity. Here we report that light stimulation of tight junction-targeted plasmonic nanoparticles selectively opens up the paracellular route to allow diffusion through the compromised tight junction and into the brain parenchyma. The BBB modulation does not impair vascular dynamics and associated neurovascular coupling, or cause significant neural injury. It further allows antibody and adeno-associated virus delivery into local brain regions. This novel method offers the first evidence of selectively modulating BBB tight junctions and opens new avenues for therapeutic interventions in the central nervous system. One Sentence Summary Gentle stimulation of molecular-targeted nanoparticles selectively opens up the paracellular pathway and allows macromolecules and gene therapy vectors into the brain.
The Phaeodactylum tricornutum Diaminopimelate Decarboxylase was Acquired via Horizontal Gene Transfer from Bacteria and Displays Substrate Promiscuity

Diatoms are predicted to synthesize certain amino acids within the chloroplast, including L-lysine via a diaminopimelate-dependent pathway. Herein, we report that the model diatom, Phaeodactylum tricornutum, possesses a chimeric lysine biosynthetic pathway, which coalesces bacterial and plant genes, and is terminated by a chloroplast-localized diaminopimelate decarboxylase (DAPDC, PtLYSA). We show that while RNAi ablation of PtLYSA is either synthetically lethal or concomitant with a slower growth rate, Cas9-mediated mutagenesis of PtLYSA results in recovery of heterozygous cells lines, suggesting that PtLYSA is an essential gene. Previously characterized DAPDCs are unique within the PLP-dependent decarboxylases where catalysis occurs at the D-stereocenter of the substrate and display a strict stereochemical preference for a (D,L)- or meso-substrate and not the D,D- or L,L-isomers of diaminopimelate (DAP) to synthesize L-lysine. Using decarboxylation assays and differential scanning calorimetry analyses, we validate that PtLYSA is a bona fide DAPDC and uncover its unexpected stereopromiscuous behavior in substrate specificity. The crystal structure of PtLYSA confirms the enzyme is an obligate homodimer in which both protomers reciprocally participate in the active site. The structure underscores features unique to the PtLYSA clan of DAPDC and provides structural insight into the determinants responsible for the substrate-promiscuity observed in PtLYSA.
Waves Out of the Korean Peninsula and Inter- and Intra-Species Replacements in Freshwater Fishes in Japan

The Japanese archipelago is located at the periphery of the continent of Asia. Rivers in the Japanese archipelago, separated from the continent of Asia about 17 Ma, have experienced an intermittent exchange of freshwater fish taxa through a narrow land bridge generated by lowered sea level. As the Korean Peninsula and Japanese archipelago were not covered by an ice sheet during glacial periods, phylogeographical analyses in this region can trace the history of biota for a long time beyond the last glacial maximum. In this study, we analyzed the phylogeography of four freshwater fish taxa, Hemibarbus longirostris, dark chub Nipponocypris temminckii, Tanakia ssp. and Carassius ssp. , whose distributions include both the Korean Peninsula and western Japan. We found for each taxon that a small component of diverse Korean clades of freshwater fishes migrated in waves into the Japanese archipelago to form the current phylogeographic structure of biota. Indigenous populations were replaced by succeeding migrants. We refer to this phenomenon as “waves out of the Korean Peninsula,” with parallels to “out of Africa” in humans.
Parametric Cognitive Load Reveals Hidden Costs in the Neural Processing of Perfectly Intelligible Degraded Speech

Speech is often degraded by environmental noise or hearing impairment. People can compensate for degradation, but this requires cognitive effort. Previous research has identified frontotemporal networks involved in effortful perception, but materials in these works were also less intelligible, and so it is not clear whether activity reflected effort or intelligibility differences. We used functional magnetic resonance imaging to assess the degree to which spoken sentences were processed under distraction and whether this depended on speech quality even when intelligibility of degraded speech was matched to that of clear speech (close to 100%). On each trial, male and female human participants either attended to a sentence or to a concurrent multiple object tracking (MOT) task that imposed parametric cognitive load. Activity in bilateral anterior insula reflected task demands; during the MOT task, activity increased as cognitive load increased, and during speech listening, activity increased as speech became more degraded. In marked contrast, activity in bilateral anterior temporal cortex was speech selective and gated by attention when speech was degraded. In this region, performance of the MOT task with a trivial load blocked processing of degraded speech, whereas processing of clear speech was unaffected. As load increased, responses to clear speech in these areas declined, consistent with reduced capacity to process it. This result dissociates cognitive control from speech processing; substantially less cognitive control is required to process clear speech than is required to understand even very mildly degraded, 100% intelligible speech. Perceptual and control systems clearly interact dynamically during real-world speech comprehension. SIGNIFICANCE STATEMENT Speech is often perfectly intelligible even when degraded, for example, by background sound, phone transmission, or hearing loss. How does degradation alter cognitive demands? Here, we use fMRI to demonstrate a novel and critical role for cognitive control in the processing of mildly degraded but perfectly intelligible speech. We compare speech that is matched for intelligibility but differs in putative control demands, dissociating cognitive control from speech processing. We also impose a parametric cognitive load during perception, dissociating processes that depend on tasks from those that depend on available capacity. Our findings distinguish between frontal and temporal contributions to speech perception and reveal a hidden cost to processing mildly degraded speech, underscoring the importance of cognitive control for everyday speech comprehension.
Social information use shapes the coevolution of sociality and virulence

Social contacts can facilitate the spread of both survival-related information and infectious diseases, but little is known about how these processes combine to shape host and parasite evolution. Here, we use a theoretical model that captures both infection and information transmission processes to investigate how host sociality (contact effort) and parasite virulence (disease-associated mortality rate) (co)evolve. We show that selection for sociality (and in turn, virulence) depends on both the intrinsic costs and benefits of social information and infection as well as their relative prevalence in the population. Specifically, greater sociality and lower virulence evolve when the risk of infection is either low or high and social information is neither very common nor too rare. Lower sociality and higher virulence evolve when the prevalence patterns are reversed. When infection and social information are both at moderate levels in the population, the direction of selection depends on the relative costs and benefits of being infected or informed. We also show that sociality varies inversely with virulence, and that parasites may be unable to prevent runaway selection for higher contact efforts. Together, these findings provide new insights for our understanding of group living and how apparently opposing ecological processes can influence the evolution of sociality and virulence in a range of ways.
Depressive-like behaviors induced by somatostatin-positive GABA neuron silencing are rescued by alpha 5 GABA-A receptor potentiation

Introduction Deficits in somatostatin-positive gamma-aminobutyric acid interneurons (“SST+ cells”) are associated with major depressive disorder (MDD) and a causal link between SST+ cell dysfunction and depressive-like deficits has been proposed, based on rodent studies showing that chronic stress induces a low SST+ GABA cellular phenotype across corticolimbic brain regions, that lowering Sst, SST+ cell, or GABA functions induces depressive-like behaviors, and that disinhibiting SST+ cell functions has antidepressant effects. Recent studies found that compounds preferentially potentiating receptors mediating SST+ cell functions with α5-GABA-A receptor positive allosteric modulators (α5-PAMs) achieved antidepressant-like effects. Together, evidence suggests that SST+ cells regulate mood and cognitive functions that are disrupted in MDD and that rescuing SST+ cell function may represent a promising therapeutic strategy. Methods We developed a mouse model with chemogenetic silencing of brain-wide SST+ cells and employed behavioral characterization 30 min after acute or sub-chronic silencing to identify contributions to behaviors related to MDD. We then assessed whether an α5-PAM, GL-II-73, could rescue behavioral deficits induced by SST+ cell silencing. Results Brain-wide SST+ cell silencing induced features of stress-related illnesses, including elevated neuronal activity and plasma corticosterone levels, increased anxiety- and anhedonia-like behaviors, and impaired short-term memory. GL-II-73 led to antidepressant-like improvements among all behavioral deficits induced by brain-wide SST+ cell silencing. Conclusion Our data validate SST+ cells as regulators of mood and cognitive functions, support a role for SST+ cell deficits in depressive-like behaviors, and demonstrate that bypassing low SST+ cell function via α5-PAM represents a targeted antidepressant strategy. Significance Statement Human and animal studies demonstrate somatostatin-positive GABAergic interneuron (“SST+ cell”) deficits as contributing factors to the pathology of major depressive disorder (MDD). These changes involve reduced SST and GABAergic markers, occurring across corticolimbic brain regions. Studies have identified roles for SST+ cells in regulating mood and cognitive functions, but employed genetic or region-specific ablation that is not representative of disease-related processes. Here, we developed a chemogenetic mouse model of brain-wide low SST+ cell function. This model confirmed a role for SST+ cells in regulating anxiety- and anhedonia-like behaviors, overall behavioral emotionality, and impaired working memory. We next showed that a positive allosteric modulator at α5-GABA-A receptors (α5-PAM, GL-II-73) rescued behavioral deficits induced by low SST+ cell function. These findings support a central role for brain-wide low SST+ cell function in MDD and validate targeting α5-GABA-A receptors as a therapeutic modality across MDD symptom dimensions.