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Altered mitochondrial dynamics are commonly seen in tumors and Parkinson’s disease (PD), but the exact mechanism is unclear. We observed in tumor and PD flies, interference of mitochondrial fission or fusion reverses metabolic reprogramming and attenuates pathogenic phenotypes, indicating the rebalanced mitochondrial dynamics can re-establish cellular homeostasis. Surprisingly, we found Hsp22 is highly induced in tumor and PD flies. Hence, Hsp22 overexpression, not only suppressed RAS tumor flies, hepatocellular carcinoma mice, but also rescued PINK1B9 PD flies associating with restored mitochondrial homeostasis and reversing metabolic reprogramming. We speculate that mitochondrial dynamics is normally in a constant dynamic equilibrium, as if on a continually oscillating seesaw, tumor and PD are like the two extreme states of the seesaw which can be corrected by the promising target, Hsp22.One Sentence SummaryMitochondrial dynamics defects including tumor and PD lead to metabolic reprogramming accompanied with Hsp22 induction, vice versa, overexpression of Hsp22 reverses the mitochondrial dynamic dysfunction caused pathogenic metabolism.

There is an urgent need for vaccines and antiviral drugs to combat the COVID-19 pandemic. Encouraging progress has been made in developing antivirals targeting SARS-CoV-2, the etiological agent of COVID-19. Among the drug targets being investigated, the viral main protease (M (pro) ) is one of the most extensively studied drug targets. M (pro) is a cysteine protease that hydrolyzes the viral polyprotein at more than 11 sites and it is highly conserved among coronaviruses. In addition, M (pro) has a unique substrate preference for glutamine in the P1 position. Taken together, it appears that M (pro) inhibitors can achieve both broad-spectrum antiviral activity and a high selectivity index. Structurally diverse compounds have been reported as M (pro) inhibitors, with several of which also showed antiviral activity in cell culture. In this study, we investigated the mechanism of action of six previously reported M (pro) inhibitors, ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12 using a consortium of techniques including FRET-based enzymatic assay, thermal shift assay, native mass spectrometry, cellular antiviral assays, and molecular dynamics simulations. Collectively, the results showed that the inhibition of M (pro) by these six compounds is non-specific and the inhibition is abolished or greatly reduced with the addition of reducing reagent DTT. In the absence of DTT, these six compounds not only inhibit M (pro) , but also a panel of viral cysteine proteases including SARS-CoV-2 papain-like protease, the 2A (pro) and 3C (pro) from enterovirus A71 (EV-A71) and EV-D68. However, none of the compounds inhibits the viral replication of EV-A71 or EV-D68, suggesting that the enzymatic inhibition potency IC (50) values obtained in the absence of DTT cannot be used to faithfully predict their cellular antiviral activity. Overall, we provide compelling evidence suggesting that ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12 are non-specific SARS-CoV-2 M (pro) inhibitors, and urge the scientific community to be stringent with hit validation.

Adamantanes such as amantadine (1) and rimantadine (2) are FDA-approved anti-influenza drugs that act by inhibiting the wild-type M2 proton channel from influenza A viruses, thereby inhibiting the uncoating of the virus. Although adamantanes have been successfully used for more than four decades, their efficacy was curtailed by emerging drug resistance. Among the limited number of M2 mutants that confer amantadine resistance, the M2-V27A mutant was found to be the predominant mutant under drug selection pressure, thereby representing a high profile antiviral drug target. Guided by molecular dynamics simulations, we previously designed first-in-class M2-V27A inhibitors. One of the potent lead compounds, spiroadamantane amine (3), inhibits both the M2-WT and M2-V27A mutant with IC50 values of 18.7 and 0.3μM, respectively, in invitro electrophysiological assays. Encouraged by these findings, in this study we further examine the invitro and invivo antiviral activity of compound 3 in inhibiting both amantadine-sensitive and -resistant influenza A viruses. Compound 3 not only had single to sub-micromolar EC50 values against M2-WT- and M2-V27A-containing influenza A viruses in antiviral assays, but also rescued mice from lethal viral infection by either M2-WT- or M2-V27A-containing influenza A viruses. In addition, we report the design of two analogs of compound 3, and one was found to have improved invitro antiviral activity over compound 3. Collectively, this study represents the first report demonstrating the invivo antiviral efficacy of inhibitors targeting M2 mutants. The results suggest that inhibitors targeting drug-resistant M2 mutants are promising antiviral drug candidates worthy of further development.

The present study addressed the controversy around the effect of a working memory load and cognitive distraction, and more specifically the finding in past work that this load sometimes increases distraction, sometimes reduces it. SanMiguel et al. (2010) found that the effect of unexpected novel sounds on performance in a visual working memory task reduced when the task placed significant demands on executive processing by imposing a memory load approaching capacity limits. This load reduced the involuntary orienting of attention toward the sounds and, in turn, their impact (facilitation or distraction) on behavioral performance. In contrast, Lavie (2005) argues that a working memory load increases distraction because load competes for resources with executive control mechanism that attempt to inhibit prepotent responses towards distractors and help limit distraction. We argue that there are two important factors that might influence the deviance distraction: whether distractors are inhibited because they provide no relevant information for the task (e.g., when cueing targets with 50% validity), and whether a load depletes resources otherwise needed for this inhibition. We predicted deviance distraction when attentional resources are directed toward the distractors because they are informative and when a load monopolizes resources otherwise used to inhibit uninformative distractors. In our experiments, participants performed a two-alternative categorization task in which they indicated whether a target stimulus appeared above or below the vertical centre of a computer screen. These targets were preceded by a location cue and, shortly after, a bilateral auditory distractor (standard sound on most trials, deviant sound on the others). Across experiments we manipulated the degree of validity of the location cue (50% or 80%) and whether participants performed the task with a load (1-back task) or without. The location cue was uninformative (50% valid) in Experiments 1 and 2, and informative (80% valid) in Experiments 3 and 4. A load was introduced in Experiments 2 and 4 by use of a 1-back task in which participants responded to the previous trial instead of the current one. The results from Experiment 1 revealed no deviance distraction but longer response times for valid trials, suggesting the inhibition of the distractors. Remarkably, the introduction of a load in Experiment 2 led to observation of deviance distraction, suggesting that the load used resources no longer available for the executive control mechanisms inhibiting responses towards the distractors. In Experiment 3, where location cues were 80% valid, deviance distraction was observed in the absence of a load. Interestingly, it remained so in the presence of a load (Experiment 4). Our results demonstrate that with peripheral visual cues can mediate the extent to which auditory distractors are processed. Distraction seems to appear when attentional resources are available to be directed toward deviant sounds.

Although items matching the contents of visual object working memory(VOWM) could automatically capture attention,whether it is obligatory remains an opening question.With two experiments,we aimed to investigate whether this guidance effect could be affected by top-down inhibitory control.The participants were instructed to remember a visual object item for a change-detection test after a short delay.During the retention interval,the participants were required to seek a target stimulus among five distractors.One of the crucial manipulations was the presence or absence of distractors in the search array matching the memory items.In Experiment 1,we varied the proportion of matching trials across different experimental groups to induce different levels of inhibition incentive.As the memory item would never match the search target,it's highly likely that the participants would draw attention away from the memory-matching distractors.And this effect would be more pronounced in the condition of high inhibition incentive.In Experiment 2,we instructed different proportions of matching trials to different groups while keeping the actual proportion constant across groups to further ruled out the interference of practice.The main results showed,when the level of inhibition incentive was relatively low,search RTs were shorter in matching trials in comparison of that in control trials,demonstrating a classical memory-based attention capture effect by the memory-matching distractors.However,when the level of inhibition incentive was high enough,search RTs were faster in matching trials,suggesting a memory-based attention inhibition effect by the top-down control.Furthermore,the effects of the top-down inhibitory control were more in evidence and appeared earlier,when the inhibition incentive was extremely high.The results,thus,demonstrates:1) the VOWM guidance effect is not obligatory.Instead,it's a flexible mechanism that could be modulated by the top-down inhibitory control.And 2) this top-down control can be modulated by the level of inhibition incentive in terms of its effectiveness,efficiency and time course.

In this paper, a new approach of face recognition is presented on the basis of PCA face recognition algorithm. It constructs a new face recognition feature vector based on fusion algebraic features extracted from singular value decomposition and KL projection. In this method, singular value decomposition and KL transform are applied to the face image, then the main feature and SVD feature vector of KL projection are fused to form a new face recognition feature vector. The method can effectively eliminate the influence of the correlation between the face images and the recognition accuracy, which greatly improves the accuracy of face recognition.

In this paper, a parametric approach for longitudinal attitude control of a hypersonic vehicle is presented. Firstly, according to the complicated aerodynamics characteristic of a hypersonic vehicle, the model of the pitch channel is treated as an interval system in order to cope with parameter uncertainties. Secondly, by employing robust stability analysis and parametric control theory, a parameterization of state feedback controllers for the interval autopilot system is obtained. Thirdly, by appropriately optimizing the free parameters in the robust stabilizing controller, the H 2 norm of the disturbance-output transfer function is made sufficiently small over the system parameter intervals. A simulation example of the pitch channel of a hypersonic vehicle demonstrates that the system achieves good performance with external disturbance despite the aerodynamical parameters vary in a large scale.