Walking and falling: Using robot simulations to model the role of errors in infant walking.

What is the optimal penalty for errors in infant skill learning? Behavioral analyses indicate that errors are frequent but trivial as infants acquire foundational skills. In learning to walk, for example, falling is commonplace but appears to incur only a negligible penalty. Behavioral data, however, cannot reveal whether a low penalty for falling is beneficial for learning to walk. Here, we used a simulated bipedal robot as an embodied model to test the optimal penalty for errors in learning to walk. We trained the robot to walk using 12,500 independent simulations on walking paths produced by infants during free play and systematically varied the penalty for falling-a level of precision, control, and magnitude impossible with real infants. When trained with lower penalties for falling, the robot learned to walk farther and better on familiar, trained paths and better generalized its learning to novel, untrained paths. Indeed, zero penalty for errors led to the best performance for both learning and generalization. Moreover, the beneficial effects of a low penalty were stronger for generalization than for learning. Robot simulations corroborate prior behavioral data and suggest that a low penalty for errors helps infants learn foundational skills (e.g., walking, talking, and social interactions) that require immense flexibility, creativity, and adaptability. RESEARCH HIGHLIGHTS: During infant skill acquisition, errors are commonplace but appear to incur a low penalty; when learning to walk, for example, falls are frequent but trivial. To test the optimal penalty for errors, we trained a simulated robot to walk using real infant paths and systematically manipulated the penalty for falling. Lower penalties in training led to better performance on familiar, trained paths and on novel untrained paths, and zero penalty was most beneficial. Benefits of a low penalty were stronger for untrained than for trained paths, suggesting that discounting errors facilitates acquiring skills that require immense flexibility and generalization.

Treosulfan Versus Busulfan-based Conditioning in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-analysis.

It is unclear whether there is a difference in outcomes with treosulfan or busulfan-based conditioning in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). We reviewed the evidence on this topic through a systematic review and meta-analysis, the comparison between treosulfan and busulfan-based conditioning in pediatric patients undergoing HSCT for instance. Six studies were included. Meta-analysis showed that there was no difference in the incidence of acute graft versus host disease (odds ratio [OR]: 0.96; 95% CI: 0.57, 1.61), grade II to IV acute graft versus host disease (OR: 1.19; 95% CI: 0.83, 1.72), chronic GVHD (OR: 1.18; 95% CI: 0.70, 2.00), and veno-occlusive disease (OR: 0.92; 95% CI: 0.22, 3.85) between treosulfan and busulfan groups. Pooled analysis indicated marginally better survival with treosulfan-based conditioning (OR: 1.57; 95% CI: 1.00, 2.44), however, these results were unstable on sensitivity analysis. A meta-analysis found no difference in transplant-related mortality (OR: 0.70; 95% CI: 0.34, 1.42) between the two groups. Retrospective data from a heterogenous population indicates that there is no difference in the rate of GVHD after treosulfan versus busulfan-based conditioning for pediatric HSCT. A marginal improvement in survival was noted with treosulfan but the results remained unstable. Future randomized controlled trials are needed to provide better evidence.

From description to generalization, or there and back again.

In his target article, Yarkoni prescribes descriptive research as a potential antidote for the generalizability crisis. In our commentary, we offer four guiding principles for conducting descriptive research that is generalizable and enduring: (1) prioritize context over control; (2) let naturalistic observations contextualize structured tasks; (3) operationalize the target phenomena rigorously and transparently; and (4) attend to individual data.

MiR-16-5p suppresses breast cancer proliferation by targeting ANLN.

BACKGROUND: In recent years, gene expression-based analysis has been used for disease biomarker discovery, providing ways for better diagnosis, leading to improvement of clinical treatment efficacy. This study aimed to explore the role of miR-16-5p and ANLN in breast cancer (BC). METHODS: Cohort datasets of BC were obtained from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) and analyzed by bioinformatics tools. qRT-PCR and western blotting were applied to validate ANLN and its protein expression. A dual-luciferase reporter assay was used to prove the regulatory relationship of miR-16-5p and ANLN. Finally, MTT, wound healing, Transwell invasion and flow cytometry analyses of the cell cycle and apoptosis were performed to assess cell proliferation, migration, invasion, cell cycle and apoptosis, respectively. RESULTS: A total of 195 differentially expressed genes (DEGs) and 50 overlapping microRNAs (miRNAs) were identified. Among these DEGs and miRNAs, ANLN, associated with poor overall survival in BC, overlapped in the GSE29431, GSE42568, TCGA and GEPIA2 databases. Moreover, ANLN was highly expressed, while miR-16-5p was lower in BC cells than in breast epithelial cells. Then, we confirmed that ANLN was directly targeted by miR-16-5p in BC cells. Over-expression of miR-16-5p and knock-down of ANLN remarkably inhibited cell proliferation and migration as well as cell invasion, arrested the cells in G2/M phase and induced apoptosis in BC cells. CONCLUSIONS: These findings suggest that miR-16-5p restrains proliferation, migration and invasion while affecting cell cycle and promotes apoptosis by regulating ANLN, thereby providing novel candidate biomarkers for the diagnosis and treatment of BC.

The impact of errors in infant development: Falling like a baby.

What is the role of errors in infants' acquisition of basic skills such as walking, skills that require immense amounts of practice to become flexible and generative? Do infants change their behaviors based on negative feedback from errors, as suggested by "reinforcement learning" in artificial intelligence, or do errors go largely unmarked so that learning relies on positive feedback? We used falling as a model system to examine the impact of errors in infant development. We examined fall severity based on parent reports of prior falls and videos of 563 falls incurred by 138 13- to 19-month-old infants during free play in a laboratory playroom. Parent reports of notable falls were limited to 33% of infants and medical attention was limited to 2% of infants. Video-recorded falls were typically low-impact events. After falling during free play in the laboratory, infants rarely fussed (4% of falls), caregivers rarely showed concern (8% of falls), and infants were back at play within seconds. Impact forces were mitigated by infants' effective reactive behaviors, quick arrest of the fall before torso or head impact, and small body size. Moreover, falling did not alter infants' subsequent behavior. Infants were not deterred from locomotion or from interacting with the objects and elevations implicated in their falls. We propose that a system that discounts the impact of errors in early stages of development encourages infants to practice basic skills such as walking to the point of mastery.

Assessment of 2-allyl-4,5-dimethoxyphenol safety and attractiveness to mature males of Bactrocera dorsalis (Hendel).

Males of the Oriental fruit fly Bactrocera dorsalis (Hendel) are highly attracted to, and compulsively feed, on methyl eugenol (ME). ME is converted into 2-allyl-4,5-dimethoxyphenol (DMP) and (E)-coniferyl alcohol (E-CF), which are temporarily sequestered in the fly's rectal gland prior to being released at dusk. Previous research initially confirmed that DMP is a relatively strong lure to B. dorsalis males. However, the characteristics of males' response to DMP and toxicology of DMP remains largely unclear. In our study, we demonstrated that DMP was more attractive to sexually mature males than E-CF tested in laboratory bioassays. Interestingly, the responsiveness of mature males to DMP was not uniform throughout the day, eliciting the highest response during the day and dropping to a low level at night. Furthermore, there were no significant differences between the olfactory responses of virgin and mated mature males to DMP. No obvious signs of toxic symptom and deaths were observed in mice during a 14-day acute oral toxicity testing. Further, toxicologically significant changes were not observed in body weight, water intake, food consumption, and absolute and relative organ weights between control and treated groups, implying DMP could be regarded as nontoxic. Lastly, the cytotoxicity data of DMP on cells showed that it exhibited no significant cytotoxicity to normal human and mouse cells. Taken together, results from both the acute and cellular toxicity experiments demonstrated the nontoxic nature of DMP. In conclusion, DMP shows promise as an effective and eco-friendly lure for B. dorsalis males, and may contribute to controlling B. dorsalis in the flied.

Look before you fit: The real-time planning cascade in children and adults.

Goal-directed actions involve problem solving-how to coordinate perception and action to get the job done. Whereas previous work focused on the ages at which children succeed in problem solving, we focused on how children solve motor problems in real time. We used object fitting as a model system to understand how perception and action unfold from moment to moment. Preschoolers (N = 25) and adults (N = 24) inserted three-dimensional objects into their corresponding openings in a "shape-sorting" box. We applied a new combination of real-time methods to the problem of object fitting-head-mounted eye tracking to record looking behaviors, video microcoding to record adjustments in object orientation between reach and insertion, and real-time analysis techniques (recurrent quantification analysis and Granger causality) to test the timing relations between visual and manual actions. Children, like adults, solved the problem successfully. However, adults outperformed children in terms of their speed of fitting, and speed depended on when adjustments of object orientation occurred. Adults adjusted object orientation during transport, whereas children adjusted object orientation after arriving at the box. Children's delays in adjustment resulted from delays in looking at the target shape and its corresponding aperture. Findings show that planning is a real-time cascade of perception and action, and looking provides the basis for planning actions prospectively. We suggest that developmental improvements in problem solving are driven by real-time changes in the instigation of the planning cascade and the timing of its components.

Cloning, expression, and characterization of a novel nitrilase, PaCNit, from Pannonibacter carbonis Q4.6.

OBJECTIVE: Identification of a heavy metal ion-stimulated nitrilase with broad-spectrum substrate specificity. RESULTS: A novel nitrilase, PaCNit, was identified from Pannonibacter carbonis Q4.6 and its enzymatic properties were investigated. The maximum activity of PaCNit was observed at 65 °C and pH 7.0. PaCNit showed broad substrate specificity towards aliphatic, aromatic, and heterocyclic nitriles, and was tolerant to different organic solvents. Remarkably, PaCNit activity was highly stimulated by metal ions, particularly by Ag+ and Hg2+. CONCLUSION: PaCNit nitrilase has a broad range of substrate specificity and can be activated by heavy metal ions. This specific characteristic makes it have a great potential for industrial application.

Pitfall or pratfall? Behavioral differences in infant learning from falling.

Researchers routinely infer learning and other unobservable psychological functions based on observable behavior. But what behavioral changes constitute evidence of learning? The standard approach is to infer learning based on a single behavior across individuals, including assumptions about the direction and magnitude of change (e.g., everyone should avoid falling repeatedly on a treacherous obstacle). Here we illustrate the benefits of an alternative "multiexpression, relativist, agnostic, individualized" approach. We assessed infant learning from falling based on multiple behaviors relative to each individual's baseline, agnostic about the direction and magnitude of behavioral change. We tested infants longitudinally (10.5-15 months of age) over the transition from crawling to walking. At each session, infants were repeatedly encouraged to crawl or walk over a fall-inducing foam pit interspersed with no-fall baseline trials on a rigid platform. Our approach revealed two learning profiles. Like adults in previous work, "pit-avoid" infants consistently avoided falling. In contrast, "pit-go" infants fell repeatedly across trials and sessions. However, individualized comparisons to baseline across multiple locomotor, exploratory, and social-emotional behaviors showed that pit-go infants also learned at every session. But they treated falling as an unimpactful "pratfall" rather than an aversive "pitfall." Pit-avoid infants displayed enhanced learning across sessions and partial transfer of learning from crawling to walking, whereas pit-go infants displayed neither. Thus, reliance on a predetermined, "one-size-fits-all" behavioral expression of a psychological function can obscure different behavioral profiles and lead to erroneous inferences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Real-time processes in the development of action planning.

Across species and ages, planning multi-step actions is a hallmark of intelligence and critical for survival. Traditionally, researchers adopt a "top-down" approach to action planning by focusing on the ability to create an internal representation of the world that guides the next step in a multi-step action. However, a top-down approach does not inform on underlying mechanisms, so researchers can only speculate about how and why improvements in planning occur. The current study takes a "bottom-up" approach by testing developmental changes in the real-time, moment-to-moment interplay among perceptual, neural, and motor components of action planning using simultaneous video, motion-tracking, head-mounted eye tracking, and electroencephalography (EEG). Preschoolers (n = 32) and adults (n = 22) grasped a hammer with their dominant hand to pound a peg when the hammer handle pointed in different directions. When the handle pointed toward their non-dominant hand, younger children ("nonadaptive planners") used a habitual overhand grip that interfered with wielding the hammer, whereas adults and older children ("adaptive planners") used an adaptive underhand grip. Adaptive and nonadaptive children differed in when and where they directed their gaze to obtain visual information, neural activation of the motor system before reaching, and straightness of their reach trajectories. Nonadaptive children immediately used a habitual overhand grip before gathering visual information, leaving insufficient time to form a plan before acting. Our novel bottom-up approach transcends mere speculation by providing converging evidence that the development of action planning depends on a real-time "tug of war" between habits and information gathering and processing.

Children do not distinguish efficient from inefficient actions during observation.

Observation is a powerful way to learn efficient actions from others. However, the role of observers' motor skill in assessing efficiency of others is unknown. Preschoolers are notoriously poor at performing multi-step actions like grasping the handle of a tool. Preschoolers (N = 22) and adults (N = 22) watched video-recorded actors perform efficient and inefficient tool use. Eye tracking showed that preschoolers and adults looked equally long at the videos, but adults looked longer than children at how actors grasped the tool. Deep learning analyses of participants' eye gaze distinguished efficient from inefficient grasps for adults, but not for children. Moreover, only adults showed differential action-related pupil dilation and neural activity (suppressed oscillation power in the mu frequency) while observing efficient vs. inefficient grasps. Thus, children observe multi-step actions without "seeing" whether the initial step is efficient. Findings suggest that observer's own motor efficiency determines whether they can perceive action efficiency in others.

Lithium chloride inhibits cell survival, overcomes drug resistance, and triggers apoptosis in multiple myeloma via activation of the Wnt/ß-catenin pathway.

Multiple myeloma (MM) is an extremely malignant plasma cell disease, which is still incurable due to its drug resistance. Lithium chloride (LiCl) functions in many pathological processes, including bipolar disorder, acute brain injuries, and chronic neurodegenerative diseases, but its antagonistic role in MM progression has not been reported thus far. In this study, we found that LiCl inhibited MM cell proliferation and induced MM cell cycle G2/M phase arrest in a dose-dependent manner. Moreover, LiCl overcomes bortezomib (BTZ)-mediated resistance in MM cells and induces apoptosis in BTZ-resistant cells. Our data preliminarily indicate that LiCl induces MM cell apoptosis via activating the Wnt/ß-catenin signaling pathway. Overall, our results define LiCl as an inducer of MM cell apoptosis and unveil a crosstalk between BTZ and LiCl in facilitating cell apoptosis.

[Effects of HDAC Inhibitor Scriptaid on IM9 Cell Line and Its Mechanism].

OBJECTIVE: To study the effect of HDAC inhibitor Scriptaid on multiple myeloma IM9 cells and preliminarily clarify the mechanism of Scriptaid-induced cell apoptosis. METHODS: The cell viability, cell cycle and cell apoptosis were measured by CCK8 assay and flow cytometry respectively, the relative target gene expression levels were detected by RT-PCR, the effect of Scriptaid on p21 promoter activity was detected by using luciferase reporter assay. RESULTS: Scriptaid inhibited IM9 cell viability in a dose-dependent manner. Scriptaid induced IM9 cell cycle arrest at G2/M phase in a dose-dependent manner. Scriptaid triggered IM9 cell apoptosis was obviously, the mRNA levels of apoptosis-related proteins Caspase 9, Caspase 3 and PARP1 were also activated. The apoptosis-associated factors BAD, PTEN and p21 increased following treatment with different dose of Scriptaid, meanwhile, p21 promoter activity was also activated significantly. CONCLUSION: HDAC inhibitor Scriptaid can promote IM9 cell apoptosis by transcriptional activation of p21 promoter in concentration-dependent manner.

Lysines 207 and 325 methylation of WDR5 catalyzed by SETD6 promotes breast cancer cell proliferation and migration.

Accumulating evidence has revealed that the methylation of lysines on nonhistones by histone lysine methyltransferases (HMTs) is crucial for regulating tumo-rigenesis and metastasis. However, whether the methy-lation of lysines on HMT complex components occurs and has functions in cancer progression is less well understood. WD repeat domain 5 (WDR5) is a core component of an HMT complex named mixed lineage leukemia (MLL)/Suppressor of Variegation, Enhancer of Zeste, and Trithorax 1 (SET1). In the present study, it was reported that lysines 207 and 325 (K207 and K325, respectively) of WDR5 were monomethylated by SET­domain­containing protein methyltransferase 6. Disrupting the methylation of K207/K325 via a K207R/K325R double­site mutation attenuated the WDR5 promotion of breast cancer cell proliferation and migration. Methylation of K207/K325 on WDR5 partially contributed to maintaining global histone tri­methylation of lysine 4 on histone H3 levels, but did not affect MLL/SET1 complex assembly. These results further understanding of a potential post­translational modification of WDR5, and imply that the methylation of lysines on HMT complex components is crucial for regulating human carcinogenesis.

Scriptaid inhibits cell survival, cell cycle, and promotes apoptosis in multiple myeloma via epigenetic regulation of p21.

Multiple myeloma (MM) is an extremely serious plasma cell malignancy. Despite the recent introduction of chemotherapies such as bortezomib and lenalidomide, it remains an incurable disease due to the high rate of relapse and the development of drug resistance. Epigenetic regulation is closely related to MM progression, but the epigenetic modification mechanism of MM cell apoptosis has remained unclear. As a novel histone deacetylase inhibitor (HDACi), Scriptaid's possible roles in MM progression have not been explored. Herein, we found that Scriptaid decreased several human MM cell viabilities in a dose-dependent manner. Scriptaid was also able to dose dependently and significantly induce MM cell cycle arrest at the G2/M phase. Moreover, Scriptaid facilitates p21 transcriptional activities by mediating H3Ac gene-activated modification, eventually leading to MM cell apoptosis. Overall, our results show that Scriptaid is an inducer of MM cell death, suggesting the possibility for Scriptaid-mediated therapeutics to cure refractory/relapsed MM.

Histone deacetylase inhibitor NaBut suppresses cell proliferation and induces apoptosis by targeting p21 in multiple myeloma.

Multiple myeloma (MM) is an extremely serious hematological malignancy that remains incurable due to chemotherapy resistance. Epigenetic regulation is closely associated with progression of MM. Histone deacetylase inhibitor NaBut functions in various physiologic processes, including inflammation and differentiation. Its' possible roles in MM progression have not been explored. In this report, NaBut decreased survival of several human MM cell lines in a dose- and time-dependent manner. NaBut could also lead to cell cycle arrest at the G2/M phase in a dose-dependent manner. NaBut inhibited bortezomib-resistant cell proliferation in dose- and time-dependent manners, and NaBut was likely to induce partly bortezomib-resistant MM cell death. Moreover, NaBut induced MM cell apoptosis via transcriptional activation of p21. Overall, our results implicate NaBut as a potential therapeutic drug for MM.