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Porous structures by additive manufacturing have fascinating and compelling performance compared with solid structures. The stress‐related porous infill designs which could greatly mitigate the effects of the intrinsic high residual stress in additive manufacturing process have gained increasing attention. In the current work, we propose a promising Isogeometric Topology Optimization (ITO) method for porous infill structures with stress minimization to avoid the occurrence of stress concentrations in additive manufacturing. The IsoGeometric Analysis (IGA) and induced p‐norm aggregation are utilized to develop a stress‐minimization topology description model for infill design, which can remove the mesh dependency and offer benefits for improving numerical accuracy and convergence stability. We also introduced global volume constraints to easily control the usage of material and eliminate the over‐fine structures affecting the printing accuracy. Several numerical examples are performed to demonstrate the effectiveness and advantages of the proposed ITO method on porous infill designs with stress minimization. The laser powder bed fusion (LPBF) technique is employed to fabricate several prototypes, and the performance are evaluated by experiments. The advancements of our work are demonstrated effectively, which is adapted for additive manufacturing and practical application. [ABSTRACT FROM AUTHOR]

To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks1. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvlOXTR cells minimally respond to aggressor cues. During defeat, aVMHvlOXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvlOXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.In mice, the neural mechanisms underlying aversive social learning, specifically avoidance and fear after defeat, involve oxytocin signalling in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part. [ABSTRACT FROM AUTHOR]

In QoE fairness optimization of multiple video streams, a distributed video stream fairness scheduling strategy based on federated deep reinforcement learning is designed to address the problem of low bandwidth utilization due to unfair bandwidth allocation and the problematic convergence of distributed algorithms in cooperative control of multiple video streams. The proposed strategy predicts a reasonable bandwidth allocation weight for the current video stream according to its player state and the global characteristics provided by the server. Then the congestion control protocol allocates the proportion of available bandwidth, matching its bandwidth allocation weight to each video stream in the bottleneck link. The strategy trains a local predictive model on each client and periodically performs federated aggregation to generate the optimal global scheme. In addition, the proposed strategy constructs global parameters containing information about the overall state of the video system to improve the performance of the distributed scheduling algorithm. The experimental results show that the introduction of global parameters can improve the algorithm's QoE fairness and overall QoE efficiency by 10% and 8%, respectively. The QoE fairness and overall QoE efficiency are improved by 8% and 7%, respectively, compared with the latest scheme. [ABSTRACT FROM AUTHOR]

Social behaviors, such as mating, fighting, and parenting, are fundamental for survival of any vertebrate species. All members of a species express social behaviors in a stereotypical and species-specific way without training because of developmentally hardwired neural circuits dedicated to these behaviors. Despite being innate, social behaviors are flexible. The readiness to interact with a social target or engage in specific social acts can vary widely based on reproductive state, social experience, and many other internal and external factors. Such high flexibility gives vertebrates the ability to release the relevant behavior at the right moment and toward the right target. This maximizes reproductive success while minimizing the cost and risk associated with behavioral expression. Decades of research have revealed the basic neural circuits underlying each innate social behavior. The neural mechanisms that support behavioral plasticity have also started to emerge. Here we provide an overview of these social behaviors and their underlying neural circuits and then discuss in detail recent findings regarding the neural processes that support the flexibility of innate social behaviors. Social behaviors such as aggression are innate but flexible. In this review, Wei et al. summarize our current understanding of the neural circuits underlying social behaviors in rodents and the plasticity in the circuits that supports behavioral flexibility. [ABSTRACT FROM AUTHOR]

Background/Aims: Astragaloside (AGS) extracted from radix astragalin (Huangqi) has been considered to be beneficial to liver diseases. In this study, we examined the role played by AGS in alleviating hepatic fibrosis function via protease-activated receptor-2 (PAR2) mechanisms. We hypothesized that AGS affects PAR2 signaling pathway thereby improving hepatic function in rats with hepatic fibrosis induced by carbon tetrachloride (CCl4). We further hypothesized that AGS attenuates impaired hepatic function evoked by CCl4 to a greater degree in diabetic animals. Methods: ELISA and Western Blot analysis were used to examine PAR2 signaling pathway in diabetic CCl4-rats and non-diabetic CCl4-rats. Results: AGS inhibited the protein expression of PAR2 and its downstream pathway PKA and PKCɛ in CCl4-rats. Notably, the effects of AGS were greater in CCl4-rats with diabetes. AGS also significantly attenuated the CCl4-induced upregulations of pro-inflammatory cytokines, namely interleukin-1β, interleukin-6 and tumor necrosis factor-α accompanied with decreases of collagenic parameters such as hexadecenoic acid, laminin and hydroxyproline. Additionally, AGS improved the CCl4-induced exaggerations of liver index and functions including alanine aminotransferase, aspartate aminotransferase. Moreover, TGF-β1, a marker of hepatic fibrosis, was increased in CCl4-rats and AGS inhibited increases in TGF-β1 induced by CCl4. Conclusions: AGS alleviates hepatic fibrosis by inhibiting PAR2 signaling expression and its effects are largely enhanced in diabetic animals. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of hepatic fibrosis; and results of our study are likely to shed light on strategies for application of AGS because it has potentially greater therapeutic effectiveness for hepatic fibrosis in diabetes. [ABSTRACT FROM AUTHOR]

Although the ventromedial hypothalamus ventrolateral area (VMHvl) is now well established as a critical locus for the generation of conspecific aggression, its role is complex, with neurons responding during multiple phases of social interactions with both males and females. It has been previously unclear how the brain uses this complex multidimensional signal and coordinates a discrete action: the attack. Here, we find a hypothalamic-midbrain circuit that represents hierarchically organized social signals during aggression. Optogenetic-assisted circuit mapping reveals a preferential projection from VMHvlvGlut2 to lPAGvGlut2 cells, and inactivation of downstream lPAGvGlut2 populations results in aggression-specific deficits. lPAG neurons are selective for attack action and exhibit short-latency, time-locked spiking relative to the activity of jaw muscles during biting. Last, we find that this projection conveys male-biased signals from the VMHvl to downstream lPAGvGlut2 neurons that are sensitive to features of ongoing activity, suggesting that action selectivity is generated by a combination of pre- and postsynaptic mechanisms. • VMHvlvGlut2 neurons target lPAGvGlut2 neurons that project polysynaptically to the jaw • Inactivating lPAGvGlut2 neurons results in aggressive action-specific deficits • Single-unit lPAG activity is action specific and time locked to EMG-detected biting • VMHvl-lPAG projection relays male-biased signals to generate action selectivity Although stimulation of the hypothalamus has long been known to evoke attack, how these neurons organize aggressive action is unknown. Here, Falkner et al. describe an excitatory hypothalamic-midbrain circuit that transforms generalized social information into an action-specific neural code that is time locked to the bite during attack. [ABSTRACT FROM AUTHOR]

Winning increases the readiness to attack and the probability of winning, a widespread phenomenon known as the "winner effect." Here, we reveal a transition from target-specific to generalized aggression enhancement over 10 days of winning in male mice. This behavioral change is supported by three causally linked plasticity events in the ventrolateral part of the ventromedial hypothalamus (VMHvl), a critical node for aggression. Over 10 days of winning, VMHvl cells experience monotonic potentiation of long-range excitatory inputs, transient local connectivity strengthening, and a delayed excitability increase. Optogenetically coactivating the posterior amygdala (PA) terminals and VMHvl cells potentiates the PA-VMHvl pathway and triggers the same cascade of plasticity events observed during repeated winning. Optogenetically blocking PA-VMHvl synaptic potentiation eliminates all winning-induced plasticity. These results reveal the complex Hebbian synaptic and excitability plasticity in the aggression circuit during winning, ultimately leading to increased "aggressiveness" in repeated winners., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Peripheral sensitization is one of the primary mechanisms underlying the pathogenesis of chronic pain. However, candidate molecules involved in peripheral sensitization remain incompletely understood. We have shown that store-operated calcium channels (SOCs) are expressed in the dorsal root ganglion (DRG) neurons. Whether SOCs contribute to peripheral sensitization associated with chronic inflammatory pain is elusive. Here we report that global or conditional deletion of Orai1 attenuates Complete Freund's adjuvant (CFA)-induced pain hypersensitivity in both male and female mice. To further establish the role of Orai1 in inflammatory pain, we performed calcium imaging and patch-clamp recordings in wild-type (WT) and Orai1 knockout (KO) DRG neurons. We found that SOC function was significantly enhanced in WT but not in Orai1 KO DRG neurons from CFA- and carrageenan-injected mice. Interestingly, the Orai1 protein level in L3/4 DRGs was not altered under inflammatory conditions. To understand how Orai1 is modulated under inflammatory pain conditions, prostaglandin E2 (PGE2) was used to sensitize DRG neurons. PGE2-induced increase in neuronal excitability and pain hypersensitivity was significantly reduced in Orai1 KO mice. PGE2-induced potentiation of SOC entry (SOCE) was observed in WT, but not in Orai1 KO DRG neurons. This effect was attenuated by a PGE2 receptor 1 (EP1) antagonist and mimicked by an EP1 agonist. Inhibition of Gq/11, PKC, or ERK abolished PGE2-induced SOCE increase, indicating PGE2-induced SOCE enhancement is mediated by EP1-mediated downstream cascade. These findings demonstrate that Orai1 plays an important role in peripheral sensitization. Our study also provides new insight into molecular mechanisms underlying PGE2-induced modulation of inflammatory pain. Significance Statement Store-operated calcium channel (SOC) Orai1 is expressed and functional in dorsal root ganglion (DRG) neurons. Whether Orai1 contributes to peripheral sensitization is unclear. The present study demonstrates that Orai1-mediated SOC function is enhanced in DRG neurons under inflammatory conditions. Global and conditional deletion of Orai1 attenuates complete Freund's adjuvant (CFA)-induced pain hypersensitivity. We also demonstrate that prostaglandin E2 (PGE2) potentiates SOC function in DRG neurons through EP1-mediated signaling pathway. Importantly, we have found that Orai1 deficiency diminishes PGE2-induced SOC function increase and reduces PGE2-induced increase in neuronal excitability and pain hypersensitivity. These findings suggest that Orai1 plays an important role in peripheral sensitization associated with inflammatory pain. Our study reveals a novel mechanism underlying PGE2/EP1-induced peripheral sensitization. Orai1 may serve as a potential target for pathological pain., (Copyright © 2023 the authors.)

Objective: Microgravity contributes to ocular injury yet the underlying mechanism remains unclear. This study aims to elucidate the mechanism behind choroidal circulation disorder and outer retinal degeneration in rats with simulated weightlessness. Methods: Optical coherence tomography angiography (OCTA) was used to evaluate choroidal circulation and retinal morphological alterations in rats with weightlessness simulation. Electroretinogram and transmission electron microscopy were used to examine the ultrastructure and function of the choroid and outer retina. Furthermore, histological and terminal deoxynucleotidyl transferase deoxyuridine dUTP nick-end labeling (TUNEL) staining was used to monitor retinal morphology. Western blotting was performed to analyze the expressions of blood-retinal outer barrier function-related proteins (Cx43, ZO-1, and occludin). Results: The choroidal thickening was observed from the fourth week of simulated weightlessness ( p < 0.05), and choroidal capillary density started to decline by the fifth week ( p < 0.05). Transmission electron microscopy revealed that the choroidal vessels were open and operating well by the fourth week. However, most of the mitochondria within the vascular endothelium underwent mild swelling, and by the fifth week, the choroidal vessels had various degrees of erythrocyte aggregation, mitochondrial swelling, and apoptosis. Additionally, ERG demonstrated a decline in retinal function beginning in the fifth week ( p < 0.05). TUNEL staining revealed a significantly higher apoptotic index in the outer nuclear layer of the retina ( p < 0.05). At the sixth week weeks of simulated weightlessness, OCTA and hematoxylin and eosin (HE) staining of retinal sections revealed that the outer nuclear layer of the retina started to become thin ( p < 0.05). Results from western blotting revealed that Cx43, ZO-1, and occludin exhibited decreased expression ( p < 0.05). Conclusion: Based on our findings in a rat model of simulated weightlessness, choroidal circulation disturbance induced by choroidal congestion is the initial cause of outer retinal degeneration. Blood-retinal barrier disruption is significant in this process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mu, Wei, Yao, Xu, Li, Cao, Chen and Zhang.)

During the process of aging, the retina exhibits chronic oxidative stress (OS) damage. Our preliminary experiment showed that acetaldehyde dehydrogenase 2 (ALDH2) could alleviate retinal damage caused by OS. This study aimed to explore whether ALDH2 could inhibit mice retinal cell apoptosis and enhance the function of unfolded protein response in endoplasmic reticulum (UPR ER ) through reducing OS in aging process. Retinal function and structure in vivo and in vitro were examined in aged ALDH2+ overexpression mice and ALDH2 agonist Alda1-treated aged mice. Levels of ALDH2, endoplasmic reticulum stress (ERS), apoptosis and inflammatory cytokines were evaluated. Higher expression of ALDH2 was observed at the outer nuclear layer (ONL) and the inner nuclear layer (INL) in aged ALDH2+ overexpression and aged Alda1-treated mice. Moreover, aged ALDH2+ overexpression mice and aged Alda1-treated mice exhibited better retinal function and structure. Increased expression of glucose-regulated protein 78 (GRP78) and ERS-related protein phosphorylated eukaryotic initiation factor 2 (peIF2α) and decreased expression of apoptosis-related protein, including C/EBP homologous protein (CHOP), caspase12 and caspase9, and retinal inflammatory cytokines were detected in the retina of aged ALDH2+ overexpression mice and aged Alda1-treated mice. The expression of ALDH2 in the retina was decreased in aging process. ALDH2 could reduce retinal oxidative stress and apoptosis, strengthen UPR ER during the aging process to improve retinal function and structure.

Pathological pain is a common and debilitating condition that is often poorly managed. Central sensitization is an important mechanism underlying pathological pain. However, candidate molecules involved in central sensitization remain unclear. Store-operated calcium channels (SOCs) mediate important calcium signals in nonexcitable and excitable cells. SOCs have been implicated in a wide variety of human pathophysiological conditions, including immunodeficiency, occlusive vascular diseases, and cancer. However, the role of SOCs in CNS disorders has been relatively unexplored. Orai1, a key component of SOCs, is expressed in the human and rodent spinal cord dorsal horn, but its functional significance in dorsal horn neurons is poorly understood. Here we sought to explore a potential role of Orai1 in the modulation of neuronal excitability and A-type potassium channels involved in pain plasticity. Using both male and female Orai1 knock-out mice, we found that activation of Orai1 increased neuronal excitability and reduced A-type potassium channels via the protein kinase C-extracellular signal-regulated protein kinase (PKC-ERK) pathway in dorsal horn neurons. Orai1 deficiency significantly decreased acute pain induced by noxious stimuli, nearly eliminated the second phase of formalin-induced nociceptive response, markedly attenuated carrageenan-induced ipsilateral pain hypersensitivity and abolished carrageenan-induced contralateral mechanical allodynia. Consistently, carrageenan-induced increase in neuronal excitability was abolished in the dorsal horn from Orai1 mutant mice. These findings uncover a novel signaling pathway involved in the pain process and central sensitization. Our study also reveals a novel link among Orai1, ERK, A-type potassium channels, and neuronal excitability. SIGNIFICANCE STATEMENT Orai1 is a key component of store-operated calcium channels (SOCs) in many cell types. It has been implicated in such pathological conditions as immunodeficiency, autoimmunity, and cancer. However, the role of Orai1 in CNS disorders remains poorly understood. The functional significance of Orai1 in neurons is elusive. Here we demonstrate that activation of Orai1 modulates neuronal excitability and Kv4-containing A-type potassium channels via the protein kinase C-extracellular signal-regulated protein kinase (PKC-ERK) pathway. Genetic knock-out of Orai1 nearly eliminates the second phase of formalin-induced pain and markedly attenuates carrageenan-induced pain hypersensitivity and neuronal excitability. These findings reveal a novel link between Orai1 and neuronal excitability and advance our understanding of central sensitization., (Copyright © 2018 the authors 0270-6474/18/380887-14$15.00/0.)

Store-operated calcium channels (SOCs) are highly calcium-selective channels that mediate calcium entry in various cell types. We have previously reported that intraplantar injection of YM-58483 (a SOC inhibitor) attenuates chronic pain. A previous study has reported that the function of SOCs in dorsal root ganglia (DRG) is enhanced after nerve injury, suggesting that SOCs may play a peripheral role in chronic pain. However, the expression, functional distribution and significance of the SOC family in DRG neurons remain elusive and the key components that mediate SOC entry (SOCE) are still controversial. Here, we demonstrated that the SOC family (STIM1, STIM2, Orai1, Orai2, and Orai3) was expressed in DRGs and STIM1 was mainly present in small- and medium-sized DRG neurons. Using confocal live cell imaging, Ca 2+ imaging and electrophysiology techniques, we demonstrated that depletion of the endoplasmic reticulum Ca 2+ stores induced STIM1 and STIM2 translocation, and that inhibition of STIM1 or blockage of Orai channels with pharmacological tools attenuated SOCE and SOC currents. Using the small inhibitory RNA knockdown approach, we identified STIM1, STIM2, Orai1, and Orai3 as the key components of SOCs mediating SOCE in DRG neurons. Importantly, activation of SOCs by thapsigargin induced plasma membrane depolarization and increased neuronal excitability, which were completely abolished by inhibition of SOCs or double knockdown of Orai1 and Orai3. Our findings suggest that SOCs exert an excitatory action in DRG neurons and provide a potential peripheral mechanism for modulation of pain hypersensitivity by SOC inhibition.

JOURNAL/nrgr/04.03/01300535-202507000-00032/figure1/v/2024-09-09T124005Z/r/image-tiff A microgravity environment has been shown to cause ocular damage and affect visual acuity, but the underlying mechanisms remain unclear. Therefore, we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity. After 4 weeks of tail suspension, there were no notable alterations in retinal function and morphology, while after 8 weeks of tail suspension, significant reductions in retinal function were observed, and the outer nuclear layer was thinner, with abundant apoptotic cells. To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina, proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension. The results showed that the expression levels of fibroblast growth factor 2 (also known as basic fibroblast growth factor) and glial fibrillary acidic protein, which are closely related to Müller cell activation, were significantly upregulated. In addition, Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks, respectively, of simulated weightlessness. These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)