Plasmodium vivax is responsible for most malaria cases in Latin America and Southeast Asia and can cause severe manifestations. Prevention strategies such as vaccines, have been hampered by the complexity of the parasite's life cycle, especially in the liver stages. The P. vivax-Liver-Specific Protein 2 (Pv_LISP-2) has been described as essential for intrahepatic development, but its antigenicity has not yet been explored. Thus, in this study we evaluate the naturally acquired humoral response against two regions of Pv_LISP-2 in populations from the Brazilian Amazon exposed to P. vivax infection. Plasma samples were collected from infected individuals in Manaus (Amazonas state) and Boa Vista (Roraima state). Two structural regions of Pv_LISP-2 (Pv_L.seq1 and Pv_L.seq2) were expressed in E. coli, purified, and applied in ELISA assays to detect total IgM, IgG, and IgG subclasses antibodies. Furthermore, longitudinal follow-up was conducted for up to 180 days in part of the Manaus cohort. Pv_LISP-2 fragments were recognized by antibodies of P. vivax-infected individuals. During the acute phase, the response was characterized by high levels of IgM, followed by the induction of IgG, especially against Pv_L.seq1. The cytophilic subclasses IgG1 and IgG3 were the predominant subclasses. IgM responses correlated with parasitemia and days of symptoms but showed a negative association with hematological parameters (hemoglobin, hematocrit, and erythrocytes). This is the first study to evaluate naturally acquired antibodies against this liver-stage antigen of P. vivax, we showed that Pv_LISP-2 is naturally antigenic in individuals exposed to vivax malaria. While the functional implications of these responses remain to be fully elucidated, our findings support further investigation of Pv_LISP-2 as a potential vaccine candidate targeting the liver stage of P. vivax.
Despite significant improvements in contemporary machine learning, symbolic methods currently outperform artificial neural networks on tasks that involve compositional reasoning, such as goal-directed planning and logical inference. This illustrates a computational explanatory gap between cognitive and neurocomputational algorithms that obscures the neurobiological mechanisms underlying cognition and impedes progress toward human-level artificial intelligence. Because of the strong relationship between cognition and working memory control, we suggest that the cognitive abilities of contemporary neural networks are limited by biologically-implausible working memory systems that rely on persistent activity maintenance and/or temporal nonlocality. Here we present NeuroLISP, an attractor neural network that can represent and execute programs written in the LISP programming language. Unlike previous approaches to high-level programming with neural networks, NeuroLISP features a temporally-local working memory based on itinerant attractor dynamics, top-down gating, and fast associative learning, and implements several high-level programming constructs such as compositional data structures, scoped variable binding, and the ability to manipulate and execute programmatic expressions in working memory (i.e., programs can be treated as data). Our computational experiments demonstrate the correctness of the NeuroLISP interpreter, and show that it can learn non-trivial programs that manipulate complex derived data structures (multiway trees), perform compositional string manipulation operations (PCFG SET task), and implement high-level symbolic AI algorithms (first-order unification). We conclude that NeuroLISP is an effective neurocognitive controller that can replace the symbolic components of hybrid models, and serves as a proof of concept for further development of high-level symbolic programming in neural networks.
Access to palliative care is a right recognized in France since 1999. Various care systems are present in the field of palliative care, and in particular the Identified Palliative Care Beds (LISP), which aim to promote the deployment of the palliative culture and approach in care services regularly confronted with palliative situations and whose organizational reference framework is mentioned in DHOS/O2/2008/99 of 25 March 2008. Although the system is widely deployed in hospitals, there is still some uncertainty about the actual functioning of LISPs and the impact of the system on these initial objectives. The LISP study thus proposes to question the contribution of LISPs to the deployment of culture and palliative care in healthcare services. The investigation method used for this qualitative survey is based on semi-directive interviews in 6 establishments in the Bourgogne Franche Comté region. At the end of our study, we note that in half of the services surveyed, the system has clearly contributed to the gradual emergence of a palliative culture and approach. A number of measures necessary for its efficiency are emerging, which could give rise to avenues of reflection articulated in 3 axes: making the system less abstract, in particular by identifying LISPs at the level of services and strengthening the information transmitted with regard to the system, developing support by EMSPs, and questioning the means to be allocated to enable efficient operation.
By adding prestressed reinforcements and designing the cross-section of steel pipe-concrete beams, a prestressed unequal-walled rectangular concrete-filled steel beam (PURCFSB) was proposed, which solves the problem of underutilizing the strength of the material due to the large deformation of the beams in large spans. In order to study the flexural performance of PURCFSB beams, a four-point bending test of 10 rectangular steel box-concrete beams was designed to analyze the effects of prestressing level and concrete filling rate on the flexural performance of the beams.The beams were categorized into high and low prestress groups. Each group covered five concrete filling ratios (a = 0, 1/3, 1/2, 2/3, 1). L = 3000 mm, b = 150 mm, h = 200 mm, t1 = 8 mm, t2 = 10 mm, tw = 5 mm, hp = 162 mm. Test results reveal that applying prestress can dramatically boost the cracking moment (by as much as 108.3%), while increasing the concrete filling rate improves the ultimate moment by up to 50.5%. Higher prestress levels consistently lead to greater cracking resistance. Building on these findings, the study develops theoretical formulas to predict both cracking and ultimate moments, along with exploring optimal cross-section designs. Concrete remains crack-free during service when the filling rate stays under 60%. Interestingly, the beam achieves peak load-bearing capacity at a 41% filling rate when partition plate thickness is disregarded. The research highlights how PURCFSB beams excel at controlling deformations and strengthening bending resistance in large-span structures.
IDyOM (Information Dynamics of Music) is the statistical model of music the most used in the community of neuroscience of music. It has been shown to allow for significant correlations with EEG (Marion, 2021), ECoG (Di Liberto, 2020) and fMRI (Cheung, 2019) recordings of human music listening. The language used for IDyOM -Lisp- is not very familiar to the neuroscience community and makes this model hard to use and more importantly to modify. IDyOMpy is a new Python re-implementation and extension of IDyOM. This new model allows for computing the information content and entropy for each melody note after training on a corpus of melodies. In addition to those features, two new features are presented: probability estimation of silences and enculturation modeling. We first describe the mathematical details of the implementation. We extensively compare the two models and show that they generate very similar outputs. We also support the validity of IDyOMpy by using its output to replicate previous EEG and behavioral results that relied on the original Lisp version (Gold, 2019; Di Liberto, 2020; Marion, 2021). Finally, it reproduced the computation of cultural distances between two different datasets as described in previous studies (Pearce, 2018). Our model replicates the previous behaviors of IDyOM in a modern and easy-to-use language -Python. In addition, more features are presented. We deeply think this new version will be of great use to the community of neuroscience of music.
The P2Y6 receptor (P2Y6R) is implicated in neuroinflammation and synaptic plasticity, but its role in depression remains unclear. This study reveals a crucial role for the P2Y6 receptor (P2Y6R) in depression. Using a chronic restraint stress (CRS) mouse model, we found reduced hippocampal P2Y6R expression. Pharmacological inhibition of P2Y6R with MRS2578 (MRS) induced robust depressive-like behaviors in mice, including anhedonia and behavioral despair, accompanied by decreased hippocampal serotonin and norepinephrine. At the molecular level, MRS disrupted synaptic integrity, evidenced by reduced expression of key synaptic proteins (PSD95, synaptophysin, SNAP25, mature BDNF) and impaired associated signaling pathways. Our multi-omics analysis further showed that P2Y6R inhibition profoundly disrupted neuronal autophagic flux and metabolic homeostasis. The late-stage autophagy inhibitor chloroquine was more effective than the early-stage inhibitor 3-methyladenine in attenuating MRS-induced depressive symptoms and restoring synaptic protein expression. This suggests that lysosomal dysfunction is a key contributor to the pathology. We identified that MRS disrupts neuronal autophagy primarily through the P2Y6R-Oxidative stress axis, as evidenced by dysregulated antioxidant defences and increased oxidative damage markers, including protein carbonyls (PC), 3-nitrotyrosine (3-NT), and the lipid peroxidation product 4-hydroxynonenal (4-HNE). Crucially, antioxidant intervention with N-acetylcysteine (NAC) rescued MRS-induced depressive behaviors, synaptic deficits, and normalized oxidative stress and autophagy dynamics. Validation with P2Y6R agonists confirmed that the observed effects were specific to P2Y6R inhibition. These findings establish the P2Y6R-Oxidative stress-autophagy axis as a novel and promising therapeutic target for Major Depressive Disorder, offering new avenues for more effective treatments.
Friedreich's ataxia (FA) is a progressive autosomal recessive neurodegenerative disorder caused by frataxin (FXN) deficiency, resulting in mitochondrial dysfunction, oxidative stress, defective autophagy, and progressive motor impairment. Despite extensive efforts, effective disease-modifying therapies for FA remain lacking. Here, we investigate the therapeutic efficacy and underlying mechanisms of UA-36, a novel water-soluble and bioavailable derivative of urolithin A, in cellular and animal models of FA. In Fxn-knockdown N2a cells, UA-36 significantly restored FXN protein levels, enhanced autophagic flux, improved mitochondrial function, and attenuated oxidative stress-induced damage. In vivo, oral administration of UA-36 for eight weeks in YG8R transgenic mice, a well-established FA model, markedly improved motor coordination, gait performance, and skeletal muscle strength. Histological and ultrastructural analyses revealed substantial protection against cerebellar Purkinje cell loss and iron deposition, cardiac hypertrophy, and the degree of skeletal muscle atrophy and fibrosis. Proteomic analysis of cerebellar tissue demonstrated that UA-36 robustly reprograms the FA-associated molecular landscape by upregulating pathways related to autophagy, mitochondrial biogenesis, oxidative phosphorylation, and redox homeostasis, while suppressing apoptosis and neuroinflammatory signaling. Together, these findings identify UA-36 as a promising lead compound and provide compelling evidence that therapeutic enhancement of autophagy and mitochondrial quality control represents a viable, mechanism-based strategy for the treatment of FA.
Neuroinflammation is increasingly recognized as a critical factor in the pathogenesis of depression. SARM1, a dual-function enzyme involved in immune responses and neuronal degeneration, has been implicated in neurodegenerative conditions. However, its role in depression-related neuroinflammation remains unclear. This study investigated the association between SARM1 deficiency and depressive symptoms, elucidating the underlying inflammatory mechanisms. Using SARM1 knockout (KO) mice, we found that SARM1 deficiency induces depressive symptoms, including anhedonia and behavioral despair, as well as selective synaptic impairment characterized by a decline in PSD95 and mature BDNF levels in the reduced hippocampal tissue of SARM1 KO mice. Concurrently, these mice displayed increased phosphorylation of JNK, ERK, p38, and NF-κB, elevated NLRP3 and HO-1 expression, reduced SOD2, and a marked activation of the cGAS-STING-TBK1 pathway in the hippocampus. Similar inflammatory changes and cGAS-STING-TBK1 upregulation were observed in SARM1 KD HT22 cells and primary neurons. Importantly, treatment of SARM1 KD mice with SP600125 significantly alleviated depressive-like behaviors, reduced hippocampal ROS and IL-1β levels, suppressed p-p38, p-NF-κB, and NLRP3, and unexpectedly downregulated p-STING and p-TBK1, while increasing PSD95 expression. Furthermore, Pharmacological inhibition of JNK with SP600125 in SARM1 knockdown mice effectively alleviated depressive-like behaviors, reduced hippocampal ROS and IL-1β, suppressed p-p38/p-NF-κB/NLRP3, and unexpectedly downregulated p-STING/p-TBK1 while improving PSD95 levels. These findings suggest that SARM1 deficiency drives neuroinflammation and depressive phenotypes through dysregulated JNK/STING/TBK1 signaling, highlighting this pathway as a potential therapeutic target for neuroinflammation-associated depression.
Chronic stress increases the risk of developing depression. However, the neurological mechanism by which chronic stress elicits depression remains largely unknown. Here, we identify that somatostatin-positive neurons in the zona incerta (ZISST neurons) regulate chronic restraint stress response and are involved in regulating depression-like behaviors. Activation of the ZISST neurons produces antidepressant-like behaviors, which is triggered by the direct input from the vesicular glutamate transporter 2-positive neurons in the anterior cingulate cortex (ACC). Inactivation of ZISST neurons produces depression-like behaviors by activating neurons in the lateral habenula (LHb). Interestingly, (2 R,6 R)-hydroxynorketamine (HNK) alleviates chronic restraint stress-induced depression-like behaviors through the activation of ZISST neurons. Collectively, these findings reveal a critical role of ZISST neurons in encoding chronic stress-induced depression and suggest that activating ZISST neurons may offer a new strategy for treating depression.
Phosphodiesterase 7 A (PDE7A) is a key regulator of cyclic adenosine monophosphate (cAMP) signaling, expressed prominently in brain regions associated with reward and addiction. Despite its strategic localization within reward-related neurocircuitry, the functional contribution of PDE7A to substance use disorders remains poorly defined. We investigated the role of PDE7A in morphine-induced behavioral plasticity using a combination of genetic deletion (Nestin-Cre-mediated neuronal PDE7A knockout) and pharmacological inhibition (BRL-50481) in male C57BL/6J mice (8-10 weeks of age). Behavioral assessments included conditioned place preference (CPP) and locomotor sensitization. Biochemical analyses (ELISA, Western blotting, co-immunoprecipitation) were performed on striatal tissue to assess dopamine levels, cAMP levels, and signaling pathways (AKT/GSK3β, D2R-β-arrestin2 complex). Mice with neuronal PDE7A deficiency failed to develop morphine-induced CPP, highlighting a critical requirement for PDE7A in drug-associated memory formation. Consistently, administration of the PDE7 inhibitor BRL-50,481 (10 mg/kg, i.p.) significantly disrupted established drug memories and attenuated morphine-induced behavioral sensitization in wild-type mice. Mechanistically, PDE7A deletion led to a hyper-dopaminergic state in the striatum, characterized by elevated dopamine levels and D1 receptor expression, yet a paradoxical impairment in downstream signaling. Specifically, the behavioral effects of PDE7 inhibition were reversed by the D2 receptor antagonist haloperidol and the AKT inhibitor oridonin, suggesting a reliance on the D2R-AKT-GSK3β axis. Biochemical analyses further revealed that PDE7A deficiency suppresses the AKT/GSK3β signaling pathway, a defect validated through pharmacological manipulation of PDE7, D2R, and AKT. Collectively, these findings identify PDE7A as a pivotal modulator of morphine-induced addiction and suggest that targeting the PDE7A-D2R-AKT signaling cascade represents a novel therapeutic strategy for managing substance use disorders.
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To verify changes in phonetic, nasometric and aerodynamic aspects of speech in individuals with cleft lip and palate and the influence of occlusion on these variables, before and after orthognathic surgery (OC) for maxillary advancement. Retrospective, observational, cross-sectional and analytical study. Fifty-one patients with previously repaired cleft lip and palate participated, 26 men and 25 women (x̅=31 years), who underwent maxillary advancement OC. The following were performed: assessment of phonetic and occlusal aspects, nasometry and aerodynamic assessment of velopharyngeal function (flow-pressure technique), before and after OC. The phonetic aspects were evaluated by 3 experienced judges. There was high intra and inter judge agreement. There was a significant improvement in phonetic production after OC: in tongue interposition ([d], [t], [l], [n], [ʎ]), distortion ([f], [v]) and anterior lisp ([s], [z], [ʃ]). In the occlusal aspects, the overjet reached, on average, the normal values after the OC and there was an occlusal improvement in the anterior crossbite, openbite and overbite. Nasalance values were within the normal range after CO for the nasal text and there was an increase in nasalance, suggestive of hypernasality, in the oral text. There was no change in velopharyngeal closure, in the production of the word "rampa", suggestive of adequate velopharyngeal closure. Occlusion did not influence nasalance and velopharyngeal closure before or after maxillary advancement OC. There was a significant improvement in phonetic, occlusal and nasometric aspects after OC. However, none of the phones obtained 100% adequacy,reinforcing the importance of speech therapy after OC. Verificar as modificações dos aspectos fonéticos, nasométricos e aerodinâmicos da fala em indivíduos com fissura labiopalatina e a influência da oclusão sobre essas variáveis, antes e após a cirurgia ortognática (CO) de avanço de maxila. Estudo retrospectivo, observacional, transversal e analítico. Participaram 51 pacientes com fissura labiopalatina previamente reparada, 26 homens e 25 mulheres (x̅=31 anos), submetidos à CO de avanço maxilar. Foram realizados: avaliação dos aspectos fonéticos e oclusais, nasometria e avaliação aerodinâmica da função velofaríngea (técnica fluxo-pressão), antes e após a CO. Os aspectos fonéticos foram avaliados por 3 juízes experientes. Houve alta concordância intra e inter juízes. Observou-se melhora significativa na produção fonética, após a CO: na interposição de língua ([d], [t], [l], [n], [ʎ]), distorção ([f], [v]) e ceceio anterior ([s], [z], [ʃ]). Nos aspectos oclusais, o trespasse horizontal atingiu, em média, os valores de normalidade após a CO e houve melhora oclusal da mordida cruzada anterior, mordida aberta e sobremordida. Os valores de nasalância encontraram-se dentro dos valores de normalidade após CO para o texto nasal e houve aumento da nasalância, sugestiva de hipernasalidade, no texto oral. Não houve modificação no fechamento velofaríngeo, na produção do vocábulo “rampa”, sugestivo de adequado fechamento velofaríngeo. A oclusão não influenciou a nasalância e o fechamento velofaríngeo antes ou após a CO de avanço de maxila. Houve melhora significativa dos aspectos fonéticos, oclusais e nasométricos após a CO. Entretanto, em nenhum fone se obteve 100% de adequação, reforçando a importância da fonoterapia após a CO. Verificar as modificações dos aspectos fonéticos, nasométricos e aerodinâmicos da fala em indivíduos com fissura labiopalatina e a influência da oclusão sobre essas variáveis, antes e após a cirurgia ortognática (CO) de avanço de maxila. Estudo retrospectivo, observacional, transversal e analítico. Participaram 51 pacientes com fissura labiopalatina previamente reparada, 26 homens e 25 mulheres (x̅=31 anos), submetidos à CO de avanço maxilar. Foram realizados: avaliação dos aspectos fonéticos e oclusais, nasometria e avaliação aerodinâmica da função velofaríngea (técnica fluxo-pressão), antes e após a CO. Os aspectos fonéticos foram avaliados por 3 juízes experientes. Houve alta concordância intra e inter juízes. Observou-se melhora significativa na produção fonética, após a CO: na interposição de língua ([d], [t], [l], [n], [ʎ]), distorção ([f], [v]) e ceceio anterior ([s], [z], [ʃ]). Nos aspectos oclusais, o trespasse horizontal atingiu, em média, os valores de normalidade após a CO e houve melhora oclusal da mordida cruzada anterior, mordida aberta e sobremordida. Os valores de nasalância encontraram-se dentro dos valores de normalidade após CO para o texto nasal e houve aumento da nasalância, sugestiva de hipernasalidade, no texto oral. Não houve modificação no fechamento velofaríngeo, na produção do vocábulo “rampa”, sugestivo de adequado fechamento velofaríngeo. A oclusão não influenciou a nasalância e o fechamento velofaríngeo antes ou após a CO de avanço de maxila. Houve melhora significativa dos aspectos fonéticos, oclusais e nasométricos após a CO. Entretanto, em nenhum fone se obteve 100% de adequação, reforçando a importância da fonoterapia após a CO.
This study set out to identify the factors and combinations of factors associated with the individual's premature death, using data from the Finnish Longitudinal Study on Ageing Municipal Employees (FLAME) which involved 6,257 participants over a 29-year follow-up period. Exact dates of death were obtained from the Finnish population register. Premature death was defined as a death occurring earlier than the age- and sex-specific actuarial life expectancy indicated by life tables for 1981, as the baseline, with the threshold period of nine months. Explanatory variables encompassed sociodemographic characteristics, health and functioning, health behaviors, subjective experiences, working conditions, and work abilities. Data were mined using the General Unary Hypothesis Automaton (GUHA) method, implemented with LISp-Miner software. GUHA involves an active dialogue between the user and the LISp-Miner software, with parameters tailored to the data and user interests. The parameters used are not absolute but depend on the data to be mined and the user's interests. Over the follow-up period, 2,196 deaths were recorded, of which 70.4% were premature. Seven single factors and 67 sets of criteria (paths) were statistically significantly associated with premature mortality, passing the one-sided Fisher test. Single predicates of premature death included smoking, consuming alcohol a few times a month or once a week, poor self-rated fitness, incompetence to work and poor assured workability in two years' time, and diseases causing work disability. Notably, most of the factors selected as single predicates of premature mortality did not appear in the multi-predicate paths. Factors appearing in the paths were smoking more than 20 cigarettes a day, symptoms that impaired functioning, past smoking, absence of musculoskeletal diseases, poor self-rated health, having pain, male sex, being married, use of medication, more physical strain compared to others, and high life satisfaction, intention to retire due to reduced work ability caused by diseases and demanding work. Sex-specific analysis revealed similar findings. The findings indicate that associations between single predictors and premature mortality should be interpreted with caution, even when adjusted for a limited number of other factors. This highlights the complexity of premature mortality and the need for comprehensive models considering multiple interacting factors.
This study presents a graph-based approach to investigate the steady-state kinetics of the preferential CO oxidation process in H2 (PROX) occurring on a MnO2 model fragment with manganese centers at varying oxidation states, simulating the surface Mn(IV) active sites of a composite MnO2-CeO2 catalyst previously used in experimental applications. A novel modeling approach, termed DFT graph-based kinetic analysis (DFT-GKA), is introduced. It utilizes free activation energy (ΔG⧧) values to characterize linear elementary events, supposed at pseudosteady-state, in this complex reaction system, as determined through density functional theory (DFT) integrated by thermochemical calculations. The implementation of this model is achieved using a homemade Common Lisp code, specifically designed for efficient manipulation of long lists essential for the analysis. Finally, the comprehensive ab initio DFT kinetic descriptors related to the CO/H2 PROX catalytic process on the manganese oxide fragments are discussed, highlighting their significance for future research and applications.
The paper introduces PAVSig: Polish Audio-Visual child speech dataset for computer-aided diagnosis of Sigmatism (lisp). The study aimed to gather data on articulation, acoustics, and visual appearance of the articulators in different child speech patterns, particularly in sigmatism. The data was collected in 2021-2023 in six kindergarten and school facilities in Poland during the speech and language therapy examinations of 201 children aged 4-8. The diagnosis was performed simultaneously with data recording, including 15-channel spatial audio signals and a dual-camera stereovision stream of the speaker's oral region. The data record comprises audiovisual recordings of 51 words and 17 logotomes containing all 12 Polish sibilants and the corresponding speech and language therapy diagnoses from two independent speech and language therapy experts. In total, we share 66,781 audio-video segments, including 12,830 words and 53,951 phonemes (12,576 sibilants).
The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPRmt modulator, fipp-1/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, highlighting its translational relevance. Overall, our dataset (https://lisp-lms.shinyapps.io/RIAILs_Dox/) serves as a unique resource to dissect lifespan and mitochondrial stress response modulators in a large genetic reference population.
When long-span beams undergo large, the strength of the beam material cannot be fully utilized. To solve this problem, a prestressed unequal-walled rectangular concrete-filled steel box (PURCFSB) beam is proposed in this paper. The prestressing is added to the concrete-filled steel tubular (CFST) beam and the section is designed. This beam is an improved concrete-filled steel tubular (CFST) beam with flanges of unequal thickness; the upper part of the steel box contains concrete, and the lower part is fitted with prestressed steel bars. Bending tests on ten PURCFSB beams with different concrete filling ratios and prestress levels revealed that prestressing can increase the yield bending moment and delay the cracking of concrete. The appropriate filling ratio can improve the structure's yield moment and ultimate bearing capacity and reduce its self-weight while avoiding concrete cracking within the scope of work. Finite element analysis of the whole bending process of PURCFSB beams, carried out using ABAQUS software, yields results that are in good agreement with the experimental results. Parametric analysis (based on the validated finite element model) of the effects of the filling ratio and prestress level on the bending performance revealed that PURCFSB beams have good bearing capacity and deformation performance.
Mitochondrial dysfunction is a hallmark of many psychiatric disorders, and SIRT1 signaling plays a critical role in regulating mitochondrial dynamics, function, and autophagy. This study investigated the interplays between erythropoietin (EPO), mitochondrial protection, and SIRT1 signaling in depression. Chronic restraint stress (CRS)- induced depression mouse model and CORT-treated HT22 cells were employed, which were subsequently treated with EPO. CRS mice exhibited depressive-like behaviors, which were alleviated by EPO treatment, as evidenced by decreased immobility and increased sucrose preference. EPO also enhanced mitochondrial function by stimulating mitophagy and improving mitochondrial homeostasis, as indicated by elevated ATP levels, reduced nitric oxide, and restored expression of mitochondrial-related genes in both the hippocampus of CRS mice and CORT-treated HT22 cells. Additionally, EPO restored suppressed SIRT1 expression, promoted dendritic spine density and synaptic gene expression in the hippocampus, increased p-STAT5 phosphorylation, and increased NAMPT expression and NAD + levels. Notably, pharmacological inhibition of SIRT1 via EX-527 counteracted EPO effects, exacerbating depressive symptoms and mitochondrial homeostasis. Furthermore, EX-527 treatment decreased ATP levels and mitochondrial DNA copy numbers in CRS + EPO-treated mice and reduced ATG5 expression. However, EX-527 did not significantly impact BNIP3, Parkin, PINK1, LC3B-II, Ace-FOXO1, or FOXO1 expression. EX-527 exposure significantly increased Ac-LC3B precipitation in the hippocampus of CRS + EPO-treated mice and the COXIV/LAMP1 ratio in the HT22 cells. In summary, these results suggested that EPO antidepressant effects were mediated through SIRT1 regulation, which influenced LC3B deacetylation, improving CRS-induced mitochondrial dysfunction and autophagy impairment.
Sterile Alpha and TIR Motif Containing 1 (SARM1) are proteins implicated in various neurological processes; however, their role in depression remains unexplored. This study investigated the contribution of SARM1 to depressive-like behaviors in a chronic stress-induced depression model and SARM1 knockout (KO) mice. Depressive-like behaviors were assessed using a battery of behavioral tests, including the Open Field Test (OFT), the Forced Swim Test (FST), the Sucrose Preference Test (SPT), and the Tail Suspension Test (TST). Mitochondrial energy metabolism alteration, cytokine level changes, and other related molecular signaling protein expression were evaluated using ELISA and western blotting techniques to investigate the underlying mechanisms. Behavioral assessments (OFT, FST, SPT, TST) revealed depressive-like phenotypes in SARM1 KO mice, accompanied by altered mitochondrial energy metabolism (NAD+, ATP) in the cortex. Intriguingly, SARM1 depletion led to peripheral inflammation, as evidenced by elevated cytokine levels in plasma but not in brain regions (cortex). In addition, we found dysregulated energy metabolism, AMPK signaling, and synaptic plasticity in the cortex of SARM1 KO mice. Notably, AICAR (Acadesine), an AMPK activator, ameliorated depressive-like behaviors and synaptic dysfunction, while Compound C, an AMPK inhibitor, reversed these effects. Additionally, NH125, an eEF2 kinase inhibitor, improved depressive-like behaviors in SARM1 KO mice. These findings demonstrate that SARM1 is critical in regulating depressive-like behaviours through the AMPKα/p-eEF2 signaling pathway. Targeting AMPK signaling and synaptic function may offer novel therapeutic avenues for depression.