Biocompatible Folic-Acid-Strengthened Ag-Ir Quantum Dot Nanozyme for Cell and Plant Root Imaging of Cysteine/Stress and Multichannel Monitoring of Hg2+ and Dopamine.

To boost the enzyme-like activity, biological compatibility, and antiaggregation effect of noble-metal-based nanozymes, folic-acid-strengthened Ag-Ir quantum dots (FA@Ag-Ir QDs) were developed. Not only did FA@Ag-Ir QDs exhibit excellent synergistic-enhancement peroxidase-like activity, high stability, and low toxicity, but they could also promote the lateral root propagation of Arabidopsis thaliana. Especially, ultratrace cysteine or Hg2+ could exclusively strengthen or deteriorate the inherent fluorescence property with an obvious "turn-on" or "turn-off" effect, and dopamine could alter the peroxidase-like activity with a clear hypochromic effect from blue to colorless. Under optimized conditions, FA@Ag-Ir QDs were successfully applied for the turn-on fluorescence imaging of cysteine or the stress response in cells and plant roots, the turn-off fluorescence monitoring of toxic Hg2+, or the visual detection of dopamine in aqueous, beverage, serum, or medical samples with low detection limits and satisfactory recoveries. The selective recognition mechanisms for FA@Ag-Ir QDs toward cysteine, Hg2+, and dopamine were illustrated. This work will offer insights into constructing some efficient nanozyme sensors for multichannel environmental analyses, especially for the prediagnosis of cysteine-related diseases or stress responses in organisms.

Object weight can be rapidly predicted, with low cognitive load, by exploiting learned associations between the weights and locations of objects.

Weight prediction is critical for dexterous object manipulation. Previous work has focused on lifting objects presented in isolation and has examined how the visual appearance of an object is used to predict its weight. Here we tested the novel hypothesis that when interacting with multiple objects, as is common in everyday tasks, people exploit the locations of objects to directly predict their weights, bypassing slower and more demanding processing of visual properties to predict weight. Using a three-dimensional robotic and virtual reality system, we developed a task in which participants were presented with a set of objects. In each trial a randomly chosen object translated onto the participant's hand and they had to anticipate the object's weight by generating an equivalent upward force. Across conditions we could control whether the visual appearance and/or location of the objects were informative as to their weight. Using this task, and a set of analogous web-based experiments, we show that when location information was predictive of the objects' weights participants used this information to achieve faster prediction than observed when prediction is based on visual appearance. We suggest that by "caching" associations between locations and weights, the sensorimotor system can speed prediction while also lowering working memory demands involved in predicting weight from object visual properties.NEW & NOTEWORTHY We use a novel object support task using a three-dimensional robotic interface and virtual reality system to provide evidence that the locations of objects are used to predict their weights. Using location information, rather than the visual appearance of the objects, supports fast prediction, thereby avoiding processes that can be demanding on working memory.

Global, Low-Amplitude Cortical State Predicts Response Outcomes in a Selective Detection Task in Mice.

Spontaneous neuronal activity strongly impacts stimulus encoding and behavioral responses. We sought to determine the effects of neocortical prestimulus activity on stimulus detection. We trained mice in a selective whisker detection task, in which they learned to respond (lick) to target stimuli in one whisker field and ignore distractor stimuli in the contralateral whisker field. During expert task performance, we used widefield Ca2+ imaging to assess prestimulus and post-stimulus neuronal activity broadly across frontal and parietal cortices. We found that lower prestimulus activity correlated with enhanced stimulus detection: lower prestimulus activity predicted response versus no response outcomes and faster reaction times. The activity predictive of trial outcome was distributed through dorsal neocortex, rather than being restricted to whisker or licking regions. Using principal component analysis, we demonstrate that response trials are associated with a distinct and less variable prestimulus neuronal subspace. For single units, prestimulus choice probability was weak yet distributed broadly, with lower than chance choice probability correlating with stronger sensory and motor encoding. These findings support low amplitude and low variability as an optimal prestimulus cortical state for stimulus detection that presents globally and predicts response outcomes for both target and distractor stimuli.

Canagliflozin Inhibited the Activity of Hemolysin and Reduced the Inflammatory Response Caused by Streptococcus suis.

Highly virulent Streptococcus suis (S. suis) infections can cause Streptococcal toxic shock-like syndrome (STSLS) in pigs and humans, in which an excessive inflammatory response causes severe damage. Hemolysin (SLY) is a major virulence factor of S. suis serotype 2 that produces pores in the target cell membrane, leading to cytoplasmic K+ efflux and activation of the NLRP3 inflammasome, ultimately causing STSLS. The critical aspect of hemolysin in the pathogenesis of S. suis type 2 makes it an attractive target for the development of innovative anti-virulence drugs. Here, we use the S. suis toxin protein (SLY) as a target for virtual screening. A compound called canagliflozin, a hypoglycemic agent, was identified through screening. Canagliflozin significantly inhibits the hemolytic activity of hemolysin. The results combined with molecular dynamics simulation, surface plasmon resonance, and nano differential scanning fluorimetry show that canagliflozin inhibits the hemolytic activity of SLY by binding to SLY. In addition, canagliflozin markedly reduced the release of SC19-induced inflammatory factors at the cellular level and in mice. Importantly, the combination of canagliflozin and ampicillin had a 90% success rate in mice, significantly greater than the therapeutic effect of ampicillin. The findings suggest that canagliflozin may be a promising new drug candidate for S. suis infections.

Mitochondrial regulation in spermatogenesis.

The classic roles of mitochondria in energy production, metabolism, and apoptosis have been well defined. However, a growing body of evidence suggests that mitochondria are also active players in regulating stem cell fate decision and lineage commitment via signaling transduction, protein modification, and epigenetic modulations. This is particularly interesting for spermatogenesis, during which germ cells demonstrate changing metabolic requirements across various stages of development. It is increasingly recognized that proper male fertility depends on exquisitely controlled plasticity of mitochondrial features, activities, and functional states. The unique role of mitochondria in germ cell ncRNA processing further adds another layer of complexity to mitochondrial regulation during spermatogenesis. In this review, we will discuss potential regulatory mechanisms of how mitochondria swiftly reshape their features, activities, and functions to support critical germ cell fate transitions during spermatogenesis. In addition, we will also review recent findings of how mitochondrial regulators coordinate with germline proteins to participate in germ cell-specific activities.

Functional Localization of an Attenuating Filter within Cortex for a Selective Detection Task in Mice.

An essential feature of goal-directed behavior is the ability to selectively respond to the diverse stimuli in one's environment. However, the neural mechanisms that enable us to respond to target stimuli while ignoring distractor stimuli are poorly understood. To study this sensory selection process, we trained male and female mice in a selective detection task in which mice learn to respond to rapid stimuli in the target whisker field and ignore identical stimuli in the opposite, distractor whisker field. In expert mice, we used widefield Ca2+ imaging to analyze target-related and distractor-related neural responses throughout dorsal cortex. For target stimuli, we observed strong signal activation in primary somatosensory cortex (S1) and frontal cortices, including both the whisker region of primary motor cortex (wMC) and anterior lateral motor cortex (ALM). For distractor stimuli, we observed strong signal activation in S1, with minimal propagation to frontal cortex. Our data support only modest subcortical filtering, with robust, step-like attenuation in distractor processing between mono-synaptically coupled regions of S1 and wMC. This study establishes a highly robust model system for studying the neural mechanisms of sensory selection and places important constraints on its implementation.SIGNIFICANCE STATEMENT Responding to task-relevant stimuli while ignoring task-irrelevant stimuli is critical for goal-directed behavior. However, the neural mechanisms involved in this selection process are poorly understood. We trained mice in a detection task with both target and distractor stimuli. During expert performance, we measured neural activity throughout cortex using widefield imaging. We observed responses to target stimuli in multiple sensory and motor cortical regions. In contrast, responses to distractor stimuli were abruptly suppressed beyond sensory cortex. Our findings localize the sites of attenuation when successfully ignoring a distractor stimulus and provide essential foundations for further revealing the neural mechanism of sensory selection and distractor suppression.

Back to reality: differences in learning strategy in a simplified virtual and a real throwing task.

Virtual environments have been widely used in motor neuroscience and rehabilitation, as they afford tight control of sensorimotor conditions and readily afford visual and haptic manipulations. However, typically, studies have only examined performance in the virtual testbeds, without asking how the simplified and controlled movement in the virtual environment compares to behavior in the real world. To test whether performance in the virtual environment was a valid representation of corresponding behavior in the real world, this study compared throwing in a virtual set-up with realistic throwing, where the task parameters were precisely matched. Even though the virtual task only required a horizontal single-joint arm movement, similar to many simplified movement assays in motor neuroscience, throwing accuracy and precision were significantly worse than in the real task that involved all degrees of freedom of the arm; only after 3 practice days did success rate and error reach similar levels. To gain more insight into the structure of the learning process, movement variability was decomposed into deterministic and stochastic contributions. Using the tolerance-noise-covariation decomposition method, distinct stages of learning were revealed: While tolerance was optimized first in both environments, it was higher in the virtual environment, suggesting that more familiarization and exploration was needed in the virtual task. Covariation and noise showed more contributions in the real task, indicating that subjects reached the stage of fine-tuning of variability only in the real task. These results showed that while the tasks were precisely matched, the simplified movements in the virtual environment required more time to become successful. These findings resonate with the reported problems in transfer of therapeutic benefits from virtual to real environments and alert that the use of virtual environments in research and rehabilitation needs more caution.NEW & NOTEWORTHY This study compared human performance of the same throwing task in a real and a matched virtual environment. With 3 days' practice, subjects improved significantly faster in the real task, even though the arm and hand movements were more complex. Decomposing variability revealed that performance in the virtual environment, despite its simplified hand movements, required more exploration. Additionally, due to fewer constraints in the real task, subjects could modify the geometry of the solution manifold, by shifting the release position, and thereby simplify the task.

Nanoparticle-Aided Nanoreactor for Nanoproteomics.

Large-scale bottom-up proteomics of few even single cells is crucial for a better understanding of the roles played by cell-to-cell heterogeneity in disease and development. Novel proteomic methodologies with extremely high sensitivity are required for few even single-cell proteomics. Sample processing with high recovery and no contaminants is one key step. Here we developed a nanoparticle-aided nanoreactor for nanoproteomics (Nano3) technique for processing low-nanograms of mammalian cell proteins for proteome profiling. The Nano3 technique employed nanoparticles packed in a capillary channel to form a nanoreactor (≤30 nL) for concentrating, cleaning, and digesting proteins originally in a lysis buffer containing sodium dodecyl sulfate (SDS), followed by nanoRPLC-MS/MS analysis. The Nano3 method identified a 40-times higher number of proteins based on MS/MS from 2-ng mouse brain protein samples compared to the SP3 (single-pot solid-phase-enhanced sample preparation) method, which performed the sample processing using the nanoparticles in a 10 µL solution in an Eppendorf tube. The data indicates a drastically higher sample recovery of the Nano3 compared to the SP3 method for processing mass-limited proteome samples. In this pilot study, the Nano3 method was further applied in processing 10-1000 HeLa cells for bottom-up proteomics, producing 441 ± 263 (n = 4) (MS/MS) and 983 ± 292 (n = 4) [match between runs (MBR)+MS/MS] protein identifications from only 10 HeLa cells using a Q-Exactive HF mass spectrometer. The preliminary results render the Nano3 method a useful approach for processing few mammalian cells for proteome profiling.

Protective Effects of Baicalin on Peritoneal Tight Junctions in Piglets Challenged with Glaesserella parasuis.

Glaesserella parasuis (G. parasuis) causes inflammation and damage to piglets. Whether polyserositis caused by G. parasuis is due to tight junctions damage and the protective effect of baicalin on it have not been examined. Therefore, this study aims to investigate the effects of baicalin on peritoneal tight junctions of piglets challenged with G. parasuis and its underlying molecular mechanisms. Piglets were challenged with G. parasuis and treated with or without baicalin. RT-PCR was performed to examine the expression of peritoneal tight junctions genes. Immunofluorescence was carried out to detect the distribution patterns of tight junctions proteins. Western blot assays were carried out to determine the involved signaling pathways. Our data showed that G. parasuis infection can down-regulate the tight junctions expression and disrupt the distribution of tight junctions proteins. Baicalin can alleviate the down-regulation of tight junctions mRNA in peritoneum, prevent the abnormalities and maintain the continuous organization of tight junctions. Our results provide novel evidence to support that baicalin has the capacity to protect peritoneal tight junctions from G. parasuis-induced inflammation. The protective mechanisms of baicalin could be associated with inhibition of the activation of PKC and MLCK/MLC signaling pathway. Taken together, these data demonstrated that baicalin is a promising natural agent for the prevention and treatment of G. parasuis infection.

The primacy of rhythm: how discrete actions merge into a stable rhythmic pattern.

This study examined how humans spontaneously merge a sequence of discrete actions into a rhythmic pattern, even when periodicity is not required. Two experiments used a virtual throwing task, in which subjects performed a long sequence of discrete throwing movements, aiming to hit a virtual target. In experiment 1, subjects performed the task for 11 sessions. Although there was no instruction to perform rhythmically, the variability of the interthrow intervals decreased to a level comparable to that of synchronizing with a metronome; furthermore, dwell times shortened or even disappeared with practice. Floquet multipliers and decreasing variability of the arm trajectories estimated in state space indicated an increasing degree of dynamic stability. Subjects who achieved a higher level of periodicity and stability also displayed higher accuracy in the throwing task. To directly test whether rhythmicity affected performance, experiment 2 disrupted the evolving continuity and periodicity by enforcing a pause between successive throws. This discrete group performed significantly worse and with higher variability in their arm trajectories than the self-paced group. These findings are discussed in the context of previous neuroimaging results showing that rhythmic movements involve significantly fewer cortical and subcortical activations than discrete movements and therefore may pose a computationally more parsimonious solution. Such emerging stable rhythms in neuromotor subsystems may serve as building blocks or dynamic primitives for complex actions. The tendency for humans to spontaneously fall into a rhythm in voluntary movements is consistent with the ubiquity of rhythms at all levels of the physiological system. NEW & NOTEWORTHY When performing a series of throws to hit a target, humans spontaneously merged successive actions into a continuous approximately periodic pattern. The degree of rhythmicity and stability correlated with hitting accuracy. Enforcing irregular pauses between throws to disrupt the rhythm deteriorated performance. Stable rhythmic patterns may simplify control of movement and serve as dynamic primitives for more complex actions. This observation reveals that biological systems tend to exhibit rhythmic behavior consistent with a plethora of physiological processes.

Exploiting the geometry of the solution space to reduce sensitivity to neuromotor noise.

Throwing is a uniquely human skill that requires a high degree of coordination to successfully hit a target. Timing of ball release appears crucial as previous studies report required timing accuracies as short as 1-2ms, which however appear physiologically challenging. This study mathematically and experimentally demonstrates that humans can overcome these seemingly stringent timing requirements by shaping their hand trajectories to create extended timing windows, where ball releases achieve target hits despite temporal imprecision. Subjects practiced four task variations in a virtual environment, each with a distinct geometry of the solution space and different demands for timing. Model-based analyses of arm trajectories revealed that subjects first decreased timing error, followed by lengthening timing windows in their hand trajectories. This pattern was invariant across solution spaces, except for a control case. Hence, the exquisite skill that humans evolved for throwing is achieved by developing strategies that are less sensitive to temporal variability arising from neuromotor noise. This analysis also provides an explanation why coaches emphasize the "follow-through" in many ball sports.

Neuromotor Noise Is Malleable by Amplifying Perceived Errors.

Variability in motor performance results from the interplay of error correction and neuromotor noise. This study examined whether visual amplification of error, previously shown to improve performance, affects not only error correction, but also neuromotor noise, typically regarded as inaccessible to intervention. Seven groups of healthy individuals, with six participants in each group, practiced a virtual throwing task for three days until reaching a performance plateau. Over three more days of practice, six of the groups received different magnitudes of visual error amplification; three of these groups also had noise added. An additional control group was not subjected to any manipulations for all six practice days. The results showed that the control group did not improve further after the first three practice days, but the error amplification groups continued to decrease their error under the manipulations. Analysis of the temporal structure of participants' corrective actions based on stochastic learning models revealed that these performance gains were attained by reducing neuromotor noise and, to a considerably lesser degree, by increasing the size of corrective actions. Based on these results, error amplification presents a promising intervention to improve motor function by decreasing neuromotor noise after performance has reached an asymptote. These results are relevant for patients with neurological disorders and the elderly. More fundamentally, these results suggest that neuromotor noise may be accessible to practice interventions.

Perceptual error based on Bayesian cue combination drives implicit motor adaptation.

The sensorimotor system can recalibrate itself without our conscious awareness, a type of procedural learning whose computational mechanism remains undefined. Recent findings on implicit motor adaptation, such as over-learning from small perturbations and fast saturation for increasing perturbation size, challenge existing theories based on sensory errors. We argue that perceptual error, arising from the optimal combination of movement-related cues, is the primary driver of implicit adaptation. Central to our theory is the increasing sensory uncertainty of visual cues with increasing perturbations, which was validated through perceptual psychophysics (Experiment 1). Our theory predicts the learning dynamics of implicit adaptation across a spectrum of perturbation sizes on a trial-by-trial basis (Experiment 2). It explains proprioception changes and their relation to visual perturbation (Experiment 3). By modulating visual uncertainty in perturbation, we induced unique adaptation responses in line with our model predictions (Experiment 4). Overall, our perceptual error framework outperforms existing models based on sensory errors, suggesting that perceptual error in locating one's effector, supported by Bayesian cue integration, underpins the sensorimotor system's implicit adaptation.

ABA inhibits in vitro shoot regeneration by affecting H3K9ac modification of WUS in Arabidopsis.

The phytohormone abscisic acid (ABA) is an important regulator of plant growth, but its potential participation in the process of in vitro shoot regeneration has not to date been reported. Here, we found that ABA appeared to inhibit in vitro shoot regeneration. ABA represses the formation of stem cell niches, thereby reducing the shoot regeneration by localizing the expression of WUSCHEL (WUS). During in vitro shoot regeneration, enrichment of H3K9ac in the specific region of WUS is a necessary event for its activation which could be inhibited by exogenous ABA. These findings reveal the potential function, as well as the possible way of ABA in regulating de novo shoot regeneration in Arabidopsis.

Discovery of Salifungin as a Repurposed Antibiotic against Methicillin-Resistant Staphylococcus aureus with Limited Resistance Development.

Exploring novel antimicrobial drugs and strategies has become essential to the fight MRSA-associated infections. Herein, we found that membrane-disrupted repurposed antibiotic salifungin had excellent bactericidal activity against MRSA, with limited development of drug resistance. Furthermore, adding salifungin effectively decreased the minimum inhibitory concentrations of clinical antibiotics against Staphylococcus aureus. Evaluations of the mechanism demonstrated that salifungin disrupted the level of H+ and K+ ions using hydrophilic and lipophilic groups to interact with bacterial membranes, causing the disruption of bacterial proton motive force followed by impacting on bacterial the function of the respiratory chain and adenosine 5'-triphosphate, thereby inhibiting phosphatidic acid biosynthesis. Moreover, salifungin also significantly inhibited the formation of bacterial biofilms and eliminated established bacterial biofilms by interfering with bacterial membrane potential and inhibiting biofilm-associated gene expression, which was even better than clinical antibiotics. Finally, salifungin exhibited efficacy comparable to or even better than that of vancomycin in the MRSA-infected animal models. In conclusion, these results indicate that salifungin can be a potential drug for treating MRSA-associated infections.

EvfG is a multi-function protein located in the Type VI secretion system for ExPEC.

The Type VI secretion system (T6SS) functions as a protein transport nanoweapon in several stages of bacterial life. Even though bacterial competition is the primary function of T6SS, different bacteria exhibit significant variations. Particularly in Extraintestinal pathogenic Escherichia coli (ExPEC), research into T6SS remains relatively limited. This study identified the uncharacterized gene evfG within the T6SS cluster of ExPEC RS218. Through our experiments, we showed that evfG is involved in T6SS expression in ExPEC RS218. We also found evfG can modulate T6SS activity by competitively binding to c-di-GMP, leading to a reduction in the inhibitory effect. Furthermore, we found that evfG can recruit sodA to alleviate oxidative stress. The research shown evfG controls an array of traits, both directly and indirectly, through transcriptome and additional tests. These traits include cell adhesion, invasion, motility, drug resistance, and pathogenicity of microorganisms. Overall, we contend that evfG serves as a multi-functional regulator for the T6SS and several crucial activities. This forms the basis for the advancement of T6SS function research, as well as new opportunities for vaccine and medication development.

Motor cortex gates distractor stimulus encoding in sensory cortex.

Suppressing responses to distractor stimuli is a fundamental cognitive function, essential for performing goal-directed tasks. A common framework for the neuronal implementation of distractor suppression is the attenuation of distractor stimuli from early sensory to higher-order processing. However, details of the localization and mechanisms of attenuation are poorly understood. We trained mice to selectively respond to target stimuli in one whisker field and ignore distractor stimuli in the opposite whisker field. During expert task performance, optogenetic inhibition of whisker motor cortex increased the overall tendency to respond and the detection of distractor whisker stimuli. Within sensory cortex, optogenetic inhibition of whisker motor cortex enhanced the propagation of distractor stimuli into target-preferring neurons. Single unit analyses revealed that whisker motor cortex (wMC) decorrelates target and distractor stimulus encoding in target-preferring primary somatosensory cortex (S1) neurons, which likely improves selective target stimulus detection by downstream readers. Moreover, we observed proactive top-down modulation from wMC to S1, through the differential activation of putative excitatory and inhibitory neurons before stimulus onset. Overall, our studies support a contribution of motor cortex to sensory selection, in suppressing behavioral responses to distractor stimuli by gating distractor stimulus propagation within sensory cortex.

Multiple Temporal and Object-Based Strategies Across Learning for a Selective Detection Task in Mice.

Goal-directed behavior paradigms inevitably involve temporal processes, such as anticipation, expectation, timing, waiting, and withholding. And yet, amongst the vast use of object-based task paradigms, characterizations of temporal features are often neglected. Here, we longitudinally analyzed mice from naïve to expert performance in a somatosensory selective detection task. In addition to tracking standard measures from signal detection theory, we also characterized learning of temporal features. We find that mice transition from general sampling strategies to stimulus detection and stimulus discrimination. During these transitions, mice learn to wait as they anticipate an expected stimulus presentation and to time their response after a stimulus presentation. By establishing and implementing standardized measures, we show that the development of waiting and timing in the task overlaps with learning of stimulus detection and discrimination. We also investigated sex differences in temporal and object-based trajectories of learning, finding that males learn strategies idiosyncratically and that females learn strategies more sequentially and stereotypically. Overall, our findings emphasize multiple temporal strategies in learning for an object-based task and highlight the importance of considering diverse temporal and object-based features when characterizing behavioral and neuronal aspects of learning.