Integration of Prior Expectations and Suppression of Prediction Errors During Expectancy-Induced Pain Modulation: The Influence of Anxiety and Pleasantness.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.

Creep and Shrinkage Properties of Nano-SiO2-Modified Recycled Aggregate Concrete.

The poor performance of recycled concrete aggregate (RCA) leads to greater creep in recycled aggregate concrete (RAC) compared to natural aggregate concrete (NAC). To enhance the quality of RCA, this paper utilizes a 2% concentration of a nano-SiO2 (NS) solution for pre-soaking RCA. This study aims to replace natural aggregate (NA) with NS-modified recycled aggregate (SRCA) and investigate the creep and shrinkage properties of NS-modified recycled aggregate concrete (SRAC) at various SRCA replacement rates. Subsequently, the creep and shrinkage strains of NAC, SRAC, and RAC are simulated using the finite element method. Finally, a comparative analysis is conducted with the predicted creep and shrinkage strains from CEB-FIP, ACI, B3, and GL2000 models. The experimental results indicate that the creep and shrinkage deformation of SRAC increases with the SRCA replacement rate. Compared to NAC, the creep and shrinkage deformation of SRAC at replacement rates of 30%, 50%, 70%, and 100% increased by 2%, 7%, 13%, and 30%, respectively. However, when 100% of the natural aggregate is replaced with SRCA, the creep and shrinkage deformation decreases by 7% compared to RAC. Moreover, the CEB-FIP and ACI models can predict the creep and shrinkage deformation of concrete reasonably well.

Cyclic Behavior and Stress-Strain Model of Nano-SiO2-Modified Recycled Aggregate Concrete.

Recycled aggregate concrete (RAC) possesses different mechanical properties than ordinary concrete because of inherent faults in recycled aggregates (RAs), such as the old interfacial transition zone (ITZ). However, the application of nano-SiO2 presents an effective methodology to enhance the quality of RA. In this study, nano-SiO2-modified recycled aggregate (SRA) was used to replace natural aggregate (NA), and the stress-strain relationships and cyclic behavior of nano-SiO2-modified recycled aggregate concrete (SRAC) with different SRA replacement rates were investigated. After evaluating the skeleton curve of SRAC specimens, the existing constitutive models were compared. Additionally, the study also proposed a stress-strain model designed to predict the mechanical behavior of concrete in relation to the SRA replacement rate. The results show that compared with RAC, the axial compressive strength of SRAC specimens showed increases of 40.27%, 29.21%, 26.55%, 16.37%, and 8.41% at specific SRA replacement rates of 0%, 30%, 50%, 70%, and 100%, respectively. Moreover, the study found that the Guo model's calculated results can accurately predict the skeleton curves of SRAC specimens.

Investigating the therapeutic effects of novel compounds targeting inflammatory IL-1ß and IL-6 signaling pathways in spinocerebellar ataxia type 3.

At least seven dominantly inherited spinocerebellar ataxias (SCA) are caused by expansions of polyglutamine (polyQ)-encoding CAG repeat. The misfolded and aggregated polyQ-expanded proteins increase reactive oxygen species (ROS), cellular toxicity, and neuroinflammation in the disease pathogenesis. In this study, we evaluated the anti-inflammatory potentials of coumarin derivatives LM-021, LMDS-1, LMDS-2, and pharmacological chaperone tafamidis using mouse BV-2 microglia and SCA3 ataxin-3 (ATXN3)/Q75-GFP SH-SY5Y cells. The four tested compounds displayed anti-inflammatory activity by suppressing nitric oxide (NO), interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α production, and CD68 antigen (CD68) and histocompatibility-2 (MHCII) expression in lipopolysaccharides (LPS)/interferon (IFN)-γ-stimulated BV-2 microglia. In retinoic acid-differentiated ATXN3/Q75-GFP-expressing SH-SY5Y cells inflamed with LPS/IFN-γ-primed BV-2 conditioned medium, treatment with test compounds mitigated the increased caspase 1 activity and lactate dehydrogenase release, reduced ROS and ATXN3/Q75 aggregation, and promoted neurite outgrowth. Examination of IL-1ß and IL-6-mediated signaling pathways revealed that LM-021, LMDS-1, LMDS-2, and tafamidis decreased NLR family pyrin domain containing 1 (NLRP1), c-Jun N-terminal kinase/c-Jun proto-oncogene (JNK/JUN), inhibitor of kappa B (IκBα)/P65, mitogen-activated protein kinase 14/signal transducer and activator of transcription 1 (P38/STAT1), and/or Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling. The study results suggest the potential of LM-021, LMDS-1, LMDS-2, and tafamidis in treating SCA3 and probable other polyQ diseases.

Application of Nanohybrid Substrates with Layer-by-Layer Self-Assembling Properties to High-Sensitivity Surface-Enhanced Raman Scattering Detection.

The present study was conducted to prepare and investigate large-area, high-sensitivity surface-enhanced Raman scattering (SERS) substrates. Organic/inorganic nanohybrid dispersants consisting of an amphiphilic triblock copolymer (hereafter referred to simply as "copolymer") and graphene oxide (GO) were used to stabilize the growth and size of gold nanoparticles (AuNPs). Ion-dipole forces were present between the AuNPs and copolymer dispersants, while the hydrogen bonds between GO and the copolymer prevented the aggregation of GO, thereby stabilizing the AuNP/GO nanohybrids. Transmission electron microscopy (TEM) revealed that the AuNPs had particle sizes of 25-35 nm and a relatively uniform size distribution. The AuNP/GO nanohybrids were deposited onto the glass substrate by using the solution drop-casting method and employed for SERS detection. The self-assembling properties of two-dimensional sheet-like GO led to a regular lamellar arrangement of AuNP/GO nanohybrids, which could be used for the preparation of large-area SERS substrates. Following removal of the copolymer by annealing at 300 °C for 2 h, measurements were obtained under scanning electron microscopy. The results confirmed that 2D GO nanosheets were capable of stabilizing AuNPs, with the final size reaching approximately 40 nm. These AuNPs were adsorbed on both sides of the GO nanosheets. Because the GO nanosheets were merely 5 nm-thick, a good three-dimensional hot-junction effect was generated along the z-axis of the AuNPs. Lastly, the prepared material was used for the SERS detection of rhodamine 6G (R6G), a commonly used highly fluorescent dye. An enhancement factor (EF) of up to 3.5 × 106 was achieved, and the limit of detection was approximately 10-10 M. Detection limits of 10-10 M and < 10-10 M were also observed with the detection of Direct Blue 200 and the biological molecule adenine. It is therefore evident that AuNP/copolymer/GO nanohybrids are large-area flexible SERS substrates that hold great potential in environmental monitoring and biological system detection applications.

Cadherin-responsive hydrogel combined with dental pulp stem cells and fibroblast growth factor 21 promotes diabetic scald repair via regulating epithelial-mesenchymal transition and necroptosis.

Diabetes causes a loss of sensation in the skin, so diabetics are prone to burns when using heating devices. Diabetic scalded skin is often difficult to heal due to the microenvironment of high glucose, high oxidation, and low blood perfusion. The treatment of diabetic scald mainly focuses on three aspects: 1) promote the formation of the epithelium; 2) promote angiogenesis; and 3) maintain intracellular homeostasis. In response to these three major repair factors, we developed a cadherin-responsive hydrogel combined with FGF21 and dental pulp stem cells (DPSCs) to accelerate epithelial formation by recruiting cadherin to the epidermis and promoting the transformation of N cadherin to E cadherin; promoting angiogenesis to increase wound blood perfusion; regulating the stability of lysosomal and activating autophagy to maintain intracellular homeostasis in order to comprehensively advance the recovery of diabetic scald.

The antagonistic role of an E3 ligase pair in regulating plant NLR-mediated autoimmunity and fungal pathogen resistance.

Plant immune homeostasis is achieved through a balanced immune activation and suppression, enabling effective defense while averting autoimmunity. In Arabidopsis, disrupting a mitogen-activated protein (MAP) kinase cascade triggers nucleotide-binding leucine-rich-repeat (NLR) SUPPRESSOR OF mkk1/2 2 (SUMM2)-mediated autoimmunity. Through an RNAi screen, we identify PUB5, a putative plant U-box E3 ligase, as a critical regulator of SUMM2-mediated autoimmunity. In contrast to typical E3 ligases, PUB5 stabilizes CRCK3, a calmodulin-binding receptor-like cytoplasmic kinase involved in SUMM2 activation. A closely related E3 ligase, PUB44, functions oppositely with PUB5 to degrade CRCK3 through monoubiquitylation and internalization. Furthermore, CRCK3, highly expressed in roots and conserved across plant species, confers resistance to Fusarium oxysporum, a devastating soil-borne fungal pathogen, in both Arabidopsis and cotton. These findings demonstrate the antagonistic role of an E3 ligase pair in fine-tuning kinase proteostasis for the regulation of NLR-mediated autoimmunity and highlight the function of autoimmune activators in governing plant root immunity against fungal pathogens.

Paeonol Derivative, 6'-Methyl Paeonol, Attenuates Aß-Induced Pathophysiology in Cortical Neurons and in an Alzheimer's Disease Mice Model.

Herbs themselves and various herbal medicines are great resources for discovering therapeutic drugs for various diseases, including Alzheimer's disease (AD), one of the common neurodegenerative diseases. Utilizing mouse primary cortical neurons and DiBAC4(3), a voltage-sensitive indicator, we have set up a drug screening system and identified an herbal extraction compound, paeonol, obtained from Paeonia lactiflora; this compound is able to ameliorate the abnormal depolarization induced by Aß42 oligomers. Our aim was to further find effective paeonol derivatives since paeonol has been previously studied. 6'-Methyl paeonol, one of the six paeonol derivatives surveyed, is able to inhibit the abnormal depolarization induced by Aß oligomers. Furthermore, 6'-methyl paeonol is able to alleviate the NMDA- and AMPA-induced depolarization. When a molecular mechanism was investigated, 6'-methyl paeonol was found to reverse the Aß-induced increase in ERK phosphorylation. At the animal level, mice injected with 6'-methyl paeonol showed little change in their basic physical parameters compared to the control mice. 6'-Methyl paeonol was able to ameliorate the impairment of memory and learning behavior in J20 mice, an AD mouse model, as measured by the Morris water maze. Thus, paeonol derivatives could provide a structural foundation for developing and designing an effective compound with promising clinical benefits.

Hierarchical global and local auxin signals coordinate cellular interdigitation in Arabidopsis.

The development of multicellular tissues requires both local and global coordination of cell polarization, however, the mechanisms underlying their interplay are poorly understood. In Arabidopsis, leaf epidermal pavement cells (PC) develop a puzzle-piece shape locally coordinated through apoplastic auxin signaling. Here we show auxin also globally coordinates interdigitation by activating the TIR1/AFB-dependent nuclear signaling pathway. This pathway promotes a transient maximum of auxin at the cotyledon tip, which then moves across the leaf activating local PC polarization, as demonstrated by locally uncaged auxin globally rescuing defects in tir1;afb1;afb2;afb4;afb5 mutant but not in tmk1;tmk2;tmk3;tmk4 mutants. Our findings show that hierarchically integrated global and local auxin signaling systems, which respectively depend on TIR1/AFB-dependent gene transcription in the nucleus and TMK-mediated rapid activation of ROP GTPases at the cell surface, control PC interdigitation patterns in Arabidopsis cotyledons, revealing a mechanism for coordinating a local cellular process with the development of whole tissues.