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Entropy (Basel, Switzerland) Nov 2023Living organisms are active open systems far from thermodynamic equilibrium. The ability to behave actively corresponds to dynamical metastability: minor but... (Review)
Review
Living organisms are active open systems far from thermodynamic equilibrium. The ability to behave actively corresponds to dynamical metastability: minor but supercritical internal or external effects may trigger major substantial actions such as gross mechanical motion, dissipating internally accumulated energy reserves. Gaining a selective advantage from the beneficial use of activity requires a consistent combination of sensual perception, memorised experience, statistical or causal prediction models, and the resulting favourable decisions on actions. This information processing chain originated from mere physical interaction processes prior to life, here denoted as structural information exchange. From there, the self-organised transition to symbolic information processing marks the beginning of life, evolving through the novel purposivity of trial-and-error feedback and the accumulation of symbolic information. The emergence of symbols and prediction models can be described as a ritualisation transition, a symmetry-breaking kinetic phase transition of the second kind previously known from behavioural biology. The related new symmetry is the neutrally stable arbitrariness, conventionality, or code invariance of symbols with respect to their meaning. The meaning of such symbols is given by the structural effect they ultimately unleash, directly or indirectly, by deciding on which actions to take. The early genetic code represents the first symbols. The genetically inherited symbolic information is the first prediction model for activities sufficient for survival under the condition of environmental continuity, sometimes understood as the "final causality" property of the model.
PubMed: 38136476
DOI: 10.3390/e25121596 -
Current Opinion in Structural Biology Oct 2023Sirtuins are NAD-dependent protein lysine deacylases and mono-ADP-ribosylases whose activity regulates different pathways, including DNA damage repair, cell survival and... (Review)
Review
Sirtuins are NAD-dependent protein lysine deacylases and mono-ADP-ribosylases whose activity regulates different pathways, including DNA damage repair, cell survival and metabolism, reactive oxygen species (ROS) detoxification, inflammation, cardiac function, and neuronal signaling. Considering the beneficial effects of specific sirtuin isoforms on health and lifespan, the past two decades have seen a mounting interest in the development of sirtuin activators. The availability of enzyme-activator co-crystal structures has proven significant throughout the years for elucidating the mechanisms of action of activators and designing more potent and selective molecules. In this review, we highlight the most interesting examples of sirtuin activators and provide comprehensive coverage of the role that structural biology played in their discovery and characterization.
Topics: Sirtuins; Enzyme Activators; Protein Isoforms; Biology
PubMed: 37542908
DOI: 10.1016/j.sbi.2023.102666 -
Cancer Metastasis Reviews Jun 2024Hepatocellular carcinoma (HCC) is an increasing burden on global public health and is associated with enhanced lipogenesis, fatty acid uptake, and lipid metabolic... (Review)
Review
Hepatocellular carcinoma (HCC) is an increasing burden on global public health and is associated with enhanced lipogenesis, fatty acid uptake, and lipid metabolic reprogramming. De novo lipogenesis is under the control of the transcription factor sterol regulatory element-binding protein 1 (SREBP-1) and essentially contributes to HCC progression. Here, we summarize the current knowledge on the regulation of SREBP-1 isoforms in HCC based on cellular, animal, and clinical data. Specifically, we (i) address the overarching mechanisms for regulating SREBP-1 transcription, proteolytic processing, nuclear stability, and transactivation and (ii) critically discuss their impact on HCC, taking into account (iii) insights from pharmacological approaches. Emphasis is placed on cross-talk with the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) axis, AMP-activated protein kinase (AMPK), protein kinase A (PKA), and other kinases that directly phosphorylate SREBP-1; transcription factors, such as liver X receptor (LXR), peroxisome proliferator-activated receptors (PPARs), proliferator-activated receptor γ co-activator 1 (PGC-1), signal transducers and activators of transcription (STATs), and Myc; epigenetic mechanisms; post-translational modifications of SREBP-1; and SREBP-1-regulatory metabolites such as oxysterols and polyunsaturated fatty acids. By carefully scrutinizing the role of SREBP-1 in HCC development, progression, metastasis, and therapy resistance, we shed light on the potential of SREBP-1-targeting strategies in HCC prevention and treatment.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Sterol Regulatory Element Binding Protein 1; Animals; Signal Transduction; Gene Expression Regulation, Neoplastic; Molecular Targeted Therapy
PubMed: 38036934
DOI: 10.1007/s10555-023-10156-5 -
Frontiers in Endocrinology 2023Type 2 diabetes mellitus (T2DM) is a leading cause of disability-adjusted life years (DALY). Physical exercise is an effective non-pharmacological intervention to...
BACKGROUND
Type 2 diabetes mellitus (T2DM) is a leading cause of disability-adjusted life years (DALY). Physical exercise is an effective non-pharmacological intervention to promote glycaemic control in T2DM. However, the optimal exercise parameters for glycemic control in individuals with T2DM remain unclear.
OBJECTIVE
This study aimed to analyze the relationship between physical training variables - frequency, intensity, type, duration, volume, and progression - and glycemic control in individuals with T2DM.
METHODS
A rapid systematic literature review was conducted on PubMed and LILACS databases. The PICOT strategy was employed to define the inclusion criteria. Eligible studies had to assess the impact of exercise parameters (frequency, intensity, type, duration, volume, and progression) on glycemic control indicators, primarily glycosylated hemoglobin (HbA1c). Randomized and non-randomized clinical trials were included in the review. The methodological quality of each study was assessed using the PEDro scale (PROSPERO - CRD 42021262614).
RESULTS
Out of 1188 papers initially identified, 18 reports met the inclusion criteria and were included in the analysis. A total of 1,228 participants with T2DM (1086 in exercise groups) were included in the selected studies. Among these studies, 16 (88.9%) were RCTs and 2 (11.1%) were nRCTs. The age of participants ranged from 43.1 and 68.9 years, and the average intervention duration was 16.8 weeks. Data on adherence to the intervention, adverse events, detailed intervention protocol, and its impacts on glycaemic control, lipid profile, blood pressure, anthropometric measures, medication, body composition, and physical fitness are reported.
CONCLUSION
The evidence supports the safety and effectiveness of physical exercises as non-pharmacological interventions for glycemic control. Aerobic, resistance and combined training interventions were associated with reductions in HbA1c and fasting glucose. The diversity of the physical exercise intervention protocols investigated in the studies included in this review is an important limitation to generalizing evidence-based practice. The call for action is mandatory to implement large-scale education programs on the prevention of diabetes and public health policies aimed to include well-planned and supervised exercise programs as an essential part of the primary prevention of type 2 diabetes.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, identifier (CRD42021262614).
Topics: Humans; Adult; Infant; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Exercise; Physical Fitness; Fasting
PubMed: 37842305
DOI: 10.3389/fendo.2023.1233906 -
JAMA Pediatrics Nov 2023The beneficial effects of increasing outdoor physical activity time on children's myopia onset and physical well-being are widely acknowledged. However, in countries... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The beneficial effects of increasing outdoor physical activity time on children's myopia onset and physical well-being are widely acknowledged. However, in countries with competitive educational systems, such as China, parents and school administrators may be relatively reluctant to increase the extracurricular physical activity time for children due to concerns that this action will compromise children's academic performance.
OBJECTIVE
To investigate whether additional extracurricular physical activity time after school compromises the academic performance of schoolchildren.
DESIGN, SETTING, AND PARTICIPANTS
This cluster randomized clinical trial was conducted from October 2020 to June 2021 in Yudu, Jiangxi, China. Eligible children in grades 3 and 4 from 24 elementary schools were randomized to the intervention or control group. Primary analysis was conducted in the full sample using the intention-to-treat principle.
INTERVENTIONS
The intervention group received 2 hours of after-school physical activity time outdoors on school days. The control group was free to arrange their after-school activity.
MAIN OUTCOMES AND MEASURES
The primary outcome was the between-group mean difference in mathematics test scores at the end of 1 academic year, with a noninferiority margin of -3.3 points. Standardized mathematics tests, physical fitness assessments (in reference to the 2018 National Physical Fitness Survey Monitoring Programme in China), and cycloplegic autorefraction were performed at baseline and the end of 1 academic year. Myopia was defined as a cycloplegic spherical equivalent refraction of -0.5 diopters or less in either eye.
RESULTS
A total of 2032 children (mean [SD] age, 9.22 [0.62] years; 1040 girls [51.2%]) from 24 schools were randomized to the intervention group (12 schools; 1012 children) or control group (12 schools; 1020 children). The mean (SD) mathematics score at the end of 1 academic year was 78.01 (17.56) points in the intervention group and 77.70 (17.29) points in the control group. The adjusted between-group mean difference was 0.65 points (95% CI, -2.85 to 4.15). The adjusted between-group mean difference in physical fitness score was 4.95 points (95% CI, 3.56-6.34; P < .001) and -1.90% (95% CI, -18.72% to 14.91%; P > .99) in myopia incidence.
CONCLUSIONS AND RELEVANCE
Results of this trial indicate that, compared with the control practice of free play after school, adding 2 hours of extracurricular physical activity outdoors after school was noninferior in academic performance and had superior efficacy in improving physical fitness.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04587765.
Topics: Child; Female; Humans; Mydriatics; Schools; Exercise; Academic Performance; Myopia
PubMed: 37721735
DOI: 10.1001/jamapediatrics.2023.3615 -
The Journal of Neuroscience : the... Nov 2023Because the sophistication of tool use is vastly enhanced in humans compared with other species, a rich understanding of its neural substrates requires neuroscientific...
Because the sophistication of tool use is vastly enhanced in humans compared with other species, a rich understanding of its neural substrates requires neuroscientific experiments in humans. Although functional magnetic resonance imaging (fMRI) has enabled many studies of tool-related neural processing, surprisingly few studies have examined real tool use. Rather, because of the many constraints of fMRI, past research has typically used proxies such as pantomiming despite neuropsychological dissociations between pantomimed and real tool use. We compared univariate activation levels, multivariate activation patterns, and functional connectivity when participants used real tools (a plastic knife or fork) to act on a target object (scoring or poking a piece of putty) or pantomimed the same actions with similar movements and timing. During the Execute phase, we found higher activation for real versus pantomimed tool use in sensorimotor regions and the anterior supramarginal gyrus, and higher activation for pantomimed than real tool use in classic tool-selective areas. Although no regions showed significant differences in activation magnitude during the Plan phase, activation patterns differed between real versus pantomimed tool use and motor cortex showed differential functional connectivity. These results reflect important differences between real tool use, a closed-loop process constrained by real consequences, and pantomimed tool use, a symbolic gesture that requires conceptual knowledge of tools but with limited consequences. These results highlight the feasibility and added value of employing natural tool use tasks in functional imaging, inform neuropsychological dissociations, and advance our theoretical understanding of the neural substrates of natural tool use. The study of tool use offers unique insights into how the human brain synthesizes perceptual, cognitive, and sensorimotor functions to accomplish a goal. We suggest that the reliance on proxies, such as pantomiming, for real tool use has (1) overestimated the contribution of cognitive networks, because of the indirect, symbolic nature of pantomiming; and (2) underestimated the contribution of sensorimotor networks necessary for predicting and monitoring the consequences of real interactions between hand, tool, and the target object. These results enhance our theoretical understanding of the full range of human tool functions and inform our understanding of neuropsychological dissociations between real and pantomimed tool use.
Topics: Humans; Psychomotor Performance; Tool Use Behavior; Brain Mapping; Brain; Neuroimaging; Magnetic Resonance Imaging
PubMed: 37722847
DOI: 10.1523/JNEUROSCI.0068-23.2023 -
Proceedings of the National Academy of... Aug 2023Loss-of-function mutations in the (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks,...
Loss-of-function mutations in the (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by mutations has been clinically approved. Here, we uncovered that niflumic acid (NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation-induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a mouse model of EA1 and restored the neuromuscular transmission and climbing ability in (Kv1.1) mutant flies (). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule-based therapeutic agent for EA1 and serves as a valuable model for drug discovery.
Topics: Animals; Mice; Myokymia; Drosophila melanogaster; Ataxia; Drosophila; Kv1.2 Potassium Channel
PubMed: 37487086
DOI: 10.1073/pnas.2207978120 -
Scientific Reports Nov 2023During social interactions, we continuously integrate current and previous information over varying timescales to infer other people's action intentions. Motor cognition...
During social interactions, we continuously integrate current and previous information over varying timescales to infer other people's action intentions. Motor cognition theories argue for a hierarchical organization of goal-directed actions based on temporal scales. Accordingly, transient motor primitives are represented at lower levels of the hierarchy, a combination of primitives building motor sequences at subordinate levels, and more stable overarching action goals at superordinate levels. A neural topography of hierarchal timescales for information accumulation was previously shown in the visual and auditory domains. However, whether such a temporal hierarchy can also account for observed goal-directed action representations in motor pathways remains to be determined. Thus, the current study examined the neural architecture underlying the processing of observed goal-directed actions using inter-subject correlation (ISC) of fMRI activity. Observers (n = 24) viewed sequential hand movements presented in their intact order or piecewise scrambled at three timescales pertaining to goal-directed action evolution (Primitives: ± 1.5 s, Sub-Goals: ± 4 s, and High-Goals: ± 10 s). The results revealed differential intrinsic temporal capacities for integrating goal-directed action information across brain areas engaged in action observation. Longer timescales (> ± 10 s) were found in the posterior parietal and dorsal premotor compared to the ventral premotor (± 4 s) and anterior parietal (± 1.5 s) cortex. Moreover, our results revealed a hemispheric bias with more extended timescales in the right MT+, primary somatosensory, and early visual cortices compared to their homotopic regions in the left hemisphere. Our findings corroborate a hierarchical neural mapping of observed actions based on temporal scales of goals and provide further support for a ubiquitous time-dependent neural organization of information processing across multiple modalities.
Topics: Humans; Goals; Psychomotor Performance; Brain Mapping; Cerebral Cortex; Brain; Magnetic Resonance Imaging
PubMed: 37952024
DOI: 10.1038/s41598-023-46917-z -
Journal of Experimental Child Psychology Aug 2023From early in life, children learn to perform actions on the objects in their environments. Although children learn from observing others' actions, actively engaging...
From early in life, children learn to perform actions on the objects in their environments. Although children learn from observing others' actions, actively engaging with the material to be learned can be important for learning. This study tested whether instruction that included opportunities for children to be active supported toddlers' action learning. In a within-participants design, 46 22- to 26-month-old toddlers (average age = 23.3 months; 21 male) were introduced to target actions for which instruction was either active or observed (instruction order counterbalanced across children). During active instruction, toddlers were coached to perform a set of target actions. During observed instruction, toddlers saw a teacher perform the actions. Toddlers were then tested on their action learning and generalization. Surprisingly, action learning and generalization did not differ between instruction conditions. However, toddlers' cognitive maturity supported their learning from both types of instruction. One year later, children from the original sample were tested on their long-term memory for information learned from active and observed instructions. Of this sample, 26 children provided usable data for the follow-up memory task (average age = 36.7 months, range = 33-41; 12 male). Children demonstrated better memory for information learned from active instruction than for information learned from observed instruction (odds ratio = 5.23) 1 year after instruction. Active experience during instruction appears to be pivotal for supporting children's long-term memory.
Topics: Child, Preschool; Humans; Infant; Male; Cognition; Learning; Child Development; Female
PubMed: 36972644
DOI: 10.1016/j.jecp.2023.105670 -
Biomedicine & Pharmacotherapy =... Dec 2023Protein posttranslational modification regulates synaptic protein stability, sorting and trafficking, and is involved in emotional disorders. Yet the molecular...
Protein posttranslational modification regulates synaptic protein stability, sorting and trafficking, and is involved in emotional disorders. Yet the molecular mechanisms regulating emotional disorders remain unelucidated. Here we report unknown roles of protein palmitoylation/nitrosylation crosstalk in regulating anxiety-like behaviors in rats. According to the percentages of open arm duration in the elevated plus maze test, the rats were divided into high-, intermediate- and low-anxiety groups. The palmitoylation and nitrosylation levels were detected by acyl-biotin exchange assay, and we found low palmitoylation and high nitrosylation levels in the basolateral amygdala (BLA) of high-anxiety rats. Furthermore, we observed that 2-bromopalmitate (2-BP), a palmitoylation inhibitor, induced anxiety-like behaviors, accompanied with decreased amplitude and frequency of mEPSCs and mIPSCs in the BLA. Additionally, we also found that inhibiting nNOS activity with 7-nitroindazole (7-NI) in the BLA caused anxiolytic effects and reduced the synaptic transmission. Interestingly, diazepam (DZP) rapidly elevated the protein palmitoylation level and attenuated the protein nitrosylation level in the BLA. Specifically, similar to DZP, the voluntary wheel running exerted DZP-like anxiolytic action, and induced high palmitoylation and low nitrosylation levels in the BLA. Lastly, blocking the protein palmitoylation with 2-BP induced an increase in protein nitrosylation level, and attenuating the nNOS activity by 7-NI elevated the protein palmitoylation level. Collectively, these results show a critical role of protein palmitoylation/nitrosylation crosstalk in orchestrating anxiety behavior in rats, and it may serve as a potential target for anxiolytic intervention.
Topics: Rats; Animals; Basolateral Nuclear Complex; Anti-Anxiety Agents; Lipoylation; Motor Activity; Anxiety; Diazepam
PubMed: 37948993
DOI: 10.1016/j.biopha.2023.115859