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.

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.

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.

Repurposing an Antioxidant to Kill Mycobacterium tuberculosis by Targeting the 50S Subunit of the Ribosome.

Tuberculosis and drug-resistant TB remain serious threats to global public health. It is urgent to develop novel anti-TB drugs in order to control it. In addition to redesigning and developing new anti-TB drugs, drug repurposing is also an innovative way to develop antibacterial drugs. Based on this method, we discovered SKQ-1 in the FDA-approved drug library and evaluated its anti-TB activity. In vitro, we demonstrated that SKQ-1 engaged in bactericidal activity against drug-sensitive and -resistant Mtb and confirmed the synergistic effects of SKQ1 with RIF and INH. Moreover, SKQ-1 showed a significant Mtb-killing effect in macrophages. In vivo, both the SKQ-1 treatment alone and the treatment in combination with RIF were able to significantly reduce the bacterial load and improve the survival rate of G. mellonella infected with Mtb. We performed whole-genome sequencing on screened SKQ-1-resistant strains and found that the SNP sites were concentrated in the 50S ribosomal subunit of Mtb. Furthermore, we proved that SKQ-1 can inhibit protein translation. In summary, from the perspective of drug repurposing, we discovered and determined the anti-tuberculosis effect of SKQ-1, revealed its synergistic effects with RIF and INH, and demonstrated its mechanism of action through targeting ribosomes and disrupting protein synthesis, thus making it a potential treatment option for DR-TB.

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.

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.

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.

Corrigendum: Comparative genomic analysis reveals cellulase plays an important role in the pathogenicity of Setosphaeria turcica f. sp. zeae.

[This corrects the article DOI: 10.3389/fmicb.2022.925355.].

Effect of 2,4-dichlorophenol on the production of methane from anaerobic granular sludge during anaerobic digestion through spectroscopy analysis.

Chlorophenols in urban high organic wastewater increases, which plays an inhibitory role in the process of anaerobic fermentation and methanogenesis. The release rules of extracellular polymers (EPS) and soluble microbial products (SMP) and the production of methane from anaerobic granular sludge were evaluated by spectroscopic analysis. The methane production was reduced by 21.6%, 41.4% and 50.5% respectively by adding 2,4-DCP of different concentrations (25, 50 and 100 mg/L). Activity tests of methanogenic functional enzymes indicated that F420 was more susceptible to the toxic of 2, 4-DCP than Acetyl-CoA and NADH. The decrease in methane production was due to the reduction in the activity of conversion enzymes rather than the loss of crucial precursors for methanogenesis. 2,4-DCP disintegrated the protein 'shell' of anaerobic granular sludge by destroying α-helix and ß-sheet structures. After the protein 'shell' in EPS was destroyed, 2, 4-DCP entered the interior of granular, which inhibited the activity of functional enzymes and affected the process of acidogenesis and methanogenesis. At the same time, due to the partial rupture of the cells after being affected by the toxicity of 2,4-DCP, the protein material could be dissolved into the aqueous phase and complexed with 2,4-DCP to reduce the toxic effect of 2,4-DCP.

Comparative genomic analysis reveals cellulase plays an important role in the pathogenicity of Setosphaeria turcica f. sp. zeae.

Setosphaeria turcica f. sp. zeae and S. turcica f. sp. sorghi, the two formae speciales of S. turcica, cause northern leaf blight disease of corn and sorghum, respectively, and often cause serious economic losses. They have obvious physiological differentiation and show complete host specificity. Host specificity is often closely related to pathogen virulence factors, including secreted protein effectors and secondary metabolites. Genomic sequencing can provide more information for understanding the virulence mechanisms of pathogens. However, the complete genomic sequence of S. turcica f. sp. sorghi has not yet been reported, and no comparative genomic information is available for the two formae speciales. In this study, S. turcica f. sp. zeae was predicted to have fewer secreted proteins, pathogen-host interaction (PHI) genes and carbohydrate-active enzymes (CAZys) than S. turcica f. sp. sorghi. Fifteen and 20 polyketide synthase (PKS) genes were identified in S. turcica f. sp. zeae and S. turcica f. sp. sorghi, respectively, which maintained high homology. There were eight functionally annotated effector protein-encoding genes specifically in S. turcica f. sp. zeae, among which the encoding gene StCEL2 of endo-1, 4-ß-D-glucanase, an important component of cellulase, was significantly up-regulated during the interaction process. Finally, gluconolactone inhibited cellulase activity and decreased infection rate and pathogenicity, which indicates that cellulase is essential for maintaining virulence. These findings demonstrate that cellulase plays an important role in the pathogenicity of S. turcica f. sp. zeae. Our results also provide a theoretical basis for future research on the molecular mechanisms underlying the pathogenicity of the two formae speciales and for identifying any associated genes.

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.

Enhancing 2,6-dichlorophenol degradation and nitrate removal in the nano-zero-valent iron (nZVI) solid-phase denitrification system.

Nano-zero-valent iron (nZVI), as a typical nano-material, has been recently used in wastewater treatment and combination with bioreactors. Using nZVI coupled denitrification system research the effect and influence of nZVI enhanced denitrification sludge on the degradation of toxic compounds and system performance. The nZVI coupled denitrification system showed better resistance to 2,6-DCP impact, and the concentrations of effluent NO2- and NO3- were below 2.0 mg/L. At the same time, the addition of nZVI enabled the denitrification system to quickly adapt to the toxic environment of 2,6-DCP within 15 days, and the degradation efficiency of 2,6-DCP reached 99.9%. The released SMP reduced after nZVI coupled with denitrification sludge in 2,6-DCP environment, which could improve the effluent water quality. Nuclear magnetic resonance spectroscopy showed that the addition of nZVI would change the structure of EPS in denitrification sludge. After 90 days of operation, the dominant bacteria in the denitrifying sludge have undergone great changes. Moreover, Thauera was responsible as the dominant bacteria for degrading 2,6-DCP in the denitrification system. The increased in the proportion of functional bacteria with nitrate_reduction, nitrogen_respiration, nitrate_respiration and nitrite_respiration in the presence of NZVI further reveals the mechanism of enhanced denitrification.

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.

Motor memories of object dynamics are categorically organized.

The ability to predict the dynamics of objects, linking applied force to motion, underlies our capacity to perform many of the tasks we carry out on a daily basis. Thus, a fundamental question is how the dynamics of the myriad objects we interact with are organized in memory. Using a custom-built three-dimensional robotic interface that allowed us to simulate objects of varying appearance and weight, we examined how participants learned the weights of sets of objects that they repeatedly lifted. We find strong support for the novel hypothesis that motor memories of object dynamics are organized categorically, in terms of families, based on covariation in their visual and mechanical properties. A striking prediction of this hypothesis, supported by our findings and not predicted by standard associative map models, is that outlier objects with weights that deviate from the family-predicted weight will never be learned despite causing repeated lifting errors.

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.

Baicalin Protects Vascular Tight Junctions in Piglets During Glaesserella parasuis Infection.

Glaesserella parasuis (G. parasuis) can cause Glässer's disease and severely affect swine industry worldwide. This study is an attempt to address the issue of the capability of G. parasuis to damage the vascular barrier and the effects of baicalin on vascular tight junctions (TJ) in order to investigate the interactions between the pathogen and the porcine vascular endothelium. Piglets were challenged with G. parasuis and treated with or without baicalin. The expressions of vascular TJ genes were examined using RT-PCR. The distribution patterns of TJ proteins were detected by immunofluorescence. The involved signaling pathways were determined by Western blot assays on related proteins. G. parasuis can downregulate TJ expression and disrupt the distribution of TJ proteins. Baicalin can alleviate the downregulation of vascular TJ mRNA, maintain the distribution, and prevent the abnormalities of TJ. These results provide ample evidence that baicalin has the capacity to protect vascular TJ damaged by G. parasuis through inhibiting PKC and MLCK/MLC pathway activation. As a result, baicalin is a promising candidate for application as a natural agent for the prevention and control of G. parasuis infection.

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.