Temporal variation in production performance, biochemical and oxidative stress markers, and gut microbiota in Pekin ducks during the late growth stage.

In the late growth stage of commercial Pekin ducks, a significant increase in feed intake and a decline in body weight gain have been observed, leading to impaired feed conversion efficiency. To address this issue, we investigated alterations in production performance, blood biochemical indices, ileum tissue architecture, and microbial community structure in Pekin ducks. The primary objective was to provide robust data supporting the improvement of meat duck production efficiency during the late growth stage (28-42-days-old). Forty 28-day-old Pekin ducks were randomly assigned to 8 replicates, with five ducks per replicate. The rearing period lasted 14 days, with feed and water provided ad libitum. Our findings indicated a significant increase in Pekin duck body and heart weights with advancing age (P < 0.05). Moreover, serum antioxidant enzyme and high-density lipoprotein concentrations significantly increased, whereas triglyceride levels decreased (P < 0.05). Notably, the height of the ileal villi was significantly reduced (P < 0.05). The microbial community structure of the ileum exhibited significant changes as ducks aged, accompanied by a substantial increase in microbial flora diversity, particularly with the formation of more tightly connected microbial network modules. Time-dependent enrichment was observed in microbial gene functions related to energy metabolism pathways. At the genus level, Sphingomonas and Subdoligranulum have emerged as crucial players in microbial differential functional pathways and network formation. These bacteria likely serve as the key driving factors in the dynamic microbial changes that occur in Pekin ducks over time. Overall, our findings suggest a potential decline in the absorption function of the small intestine and fat deposition performance of Pekin ducks during later growth stages, which may be attributed to the maturation and proliferation of the gut microbial community.

Clinically amyopathic dermatomyositis: Clinical, laboratory, and histopathological features.

BACKGROUND: Despite the advancements in the categorization of clinically amyopathic dermatomyositis (CADM), the classification and diagnosis of its subtypes are still challenging. The aim of our study was to describe the clinicopathological features of CADM and assess the differences between amyopathic dermatomyositis (ADM) and hypomyopathic dermatomyositis (HDM). METHODS: This retrospective study included 43 patients with CADM diagnosed at our institution from 2016 to 2020. Patients were subclassed into ADM (n = 30) and HDM (n = 13) groups to assess their clinicopathological differences. RESULTS: All included patients had characteristic cutaneous manifestations of dermatomyositis; 67.4% had myositis-associated auto-antibodies, including ANA (32.6%), RNP (14.0%), anti-Ro52 (9.3%), anti-p155/140 (7.0%), rheumatoid factor (7.0%), anti-NXP-2 (4.7%), anti-MDA5 (2.3%), and anti-Jo-1 (2.3%) antibodies. One patient had associated interstitial lung disease, and another patient had oral squamous cell carcinoma. The histopathological findings included mucin deposition (69.8%), telangiectasia (65.1%), lymphocytic infiltrate (48.8%), vacuolar interface dermatitis (46.5%), and epidermal atrophy (14.0%). Compared to patients with HDM, ADM patients were significantly less likely to have epidermal atrophy, 3.3% versus 38.5% (p = 0.006), and more likely to have mucin deposition, 80.0% versus 46.2% (p = 0.028). CONCLUSION: We described the clinicopathological features of CADM and highlighted the distinctions between ADM and HDM dermatopathologic findings. This information may prove helpful in diagnosing ambiguous lesions.

Clinicopathologic and Molecular Characterization of Inflammatory Bowel Disease-Associated Neuroendocrine Carcinomas and Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms.

The pathogenesis of neuroendocrine carcinoma (NEC) and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) in the gastrointestinal tract remains poorly understood. This study seeks to characterize the clinicopathologic and molecular features of NEC/MiNEN in patients with inflammatory bowel disease (IBD). Eighteen surgically resected IBD-associated intestinal carcinomas with a minimum of 30% neuroendocrine component were collected from 6 academic centers and compared to a control group of 12 IBD-associated carcinomas lacking neuroendocrine differentiation. Both groups exhibited a male predominance and similar age distribution. The NEC/MiNEN group was more likely to have a higher percentage of Crohn's disease (9/18 vs. 1/12, P=0.024), occur in the rectum (9/18 vs. 3/12) and small intestine (4/18 vs. 0/12) (P<0.01), be diagnosed on resection without a preceding biopsy (6/18 vs. 0/12, P=0.057), and have unidentifiable precursor lesions (10/18 vs. 1/12, P=0.018) than the control group. Synchronous carcinoma, advanced tumor stage (pT3 and pT4), and lymph node metastasis occurred at similar rates; however, the NEC/MiNEN group had a higher incidence of angiovascular invasion (14/18 vs. 4/12, P=0.024), distant metastasis (8/18 vs. 1/12, P=0.049), mortality (8/18 vs. 2/12, P=0.058), and worse survival (Kaplan-Meier, P=0.023) than the control group. All tested cases were mismatch repair proficient. A Ki-67 proliferation index ranged from 25% to 100%. Next-generation sequencing in 11 NEC/MiNEN cases revealed low tumor mutational burdens but complex genetic abnormalities commonly involving TP53 (9/11, 82%), FBXW7 (4/11, 36%), and APC (3/11, 27%), with the other genetic alterations randomly occurring in one or two cases. The neuroendocrine component, which shared similar molecular alterations as the non-neuroendocrine component, was subcategorized into intermediate (G3a)- and high-grade (G3b); the higher-grade correlated with more genetic alterations. In conclusion, IBD-associated NEC/MiNEN shows diverse histologic features, variable precursor lesions, intricate genetic abnormalities, and aggressive biologic behavior. The classification and grading of GI-NEC/MiNEN may be refined for better clinical management.

Effector Protein Serine Carboxypeptidase FgSCP Is Essential for Full Virulence in F. graminearum and Is Involved in Modulating Plant Immune Responses.

Fusarium head blight (FHB) caused by Fusarium graminearum is a significant pathogen affecting wheat crops. During the infection process, effector proteins are secreted to modulate plant immunity and promote infection. The toxin deoxynivalenol (DON) is produced in infected wheat grains, posing a threat to human and animal health. Serine carboxypeptidases (SCPs) belong to the α/ß hydrolase family of proteases and are widely distributed in plant and fungal vacuoles as well as animal lysosomes. Research on SCPs mainly focuses on the isolation, purification of a small number of fungi as well as their study in plants.However, their functions in F. graminearum, a fungal pathogen, remain relatively unknown. In this study, the biological functions of the FgSCP gene in F. graminearum were investigated. The study revealed that mutations in FgSCP affected nutritional growth, sexual reproduction, and stress tolerance of F. graminearum. Furthermore, the deletion of FgSCP resulted in reduced pathogenicity and hindered the biosynthesis of DON. The upregulation of FgSCP expression three days after infection indicated its involvement in host invasion, possibly acting as a "smokescreen" to deceive the host and suppress the expression of host defensive genes. Subsequently, we confirmed the secretion ability of FgSCP and its ability to inhibit the cell death induced by INF1 in Nicotiana. benthamiana cells, indicating its potential role as an effector protein in suppressing plant immune responses and promoting infection. In summary, we have identified FgSCP as an essential effector protein in F. graminearum, playing critical roles in growth, virulence, secondary metabolism, and host invasion.

Association between immune-inflammation-based prognostic index and depression: An exploratory cross-sectional analysis of NHANES data.

BACKGROUND: Immune-inflammatory mediators influence numerous immune and inflammatory pathways, elevating the likelihood of depression. The systemic immune-inflammation index (SII) emerges as an innovative prognostic indicator, integrating various peripheral blood immune cell subpopulations, specifically neutrophils, platelets, and lymphocytes. This exploratory study aims to examine the correlation between SII and depression. METHODS: Data from the 2005-2020 National Health and Nutrition Examination Survey (NHANES) were utilized. Depression was diagnosed with a Patient Health Questionnaire score of 10 or higher. The relationship between log2-SII and depression incidence was analyzed using a restricted cubic spline (RCS). Logistic regression was employed to calculate the odds ratio of depression concerning log2-SII. In cases of non-linearity, piecewise linear models with change points were applied to assess the associations in both the overall population and specific subgroups. Additionally, subgroup analyses were conducted to determine the applicability of the findings to particular populations. RESULTS: A total of 42,133 participants were included in the study, comprising 49.32 % men and 50.68 % women, with an average age of 47.02 ± 17.45 years. RCS analysis demonstrated a J-shaped non-linear relationship between log2-SII and depression incidence. When log2-SII was ≥8.50, SII showed a positive association with depression incidence, even after adjusting for covariates. Additionally, each unit increase in log2-SII corresponded to an 18 % rise in depression incidence (OR = 1.18, 95 % CI: 1.10-1.27). Subgroup analysis further revealed that the association between SII and depression incidence varied across different populations. LIMITATIONS: Due to the cross-sectional nature of NHANES, causality or long-term implications cannot be inferred. Further research is needed to ascertain if a longitudinal relationship exists between SII and depression. CONCLUSION: Our findings suggest a significant and complex non-linear association between SII and depression. However, further basic and prospective studies are necessary to explore SII's impact on depression and clarify its underlying mechanisms. Additionally, these studies will provide a foundation for personalized interventions targeting the immune-inflammatory processes in patients with depression and elevated SII.

The impact of extreme precipitation on water use efficiency along vertical vegetation belts in Hengduan Mountain during 2001 and 2020.

In the context of climate change, extreme precipitation events are continuously increasing and impact the water­carbon coupling of ecosystems. The vertical vegetation zonation, as a characteristic of mountain ecosystems, reflects the differences in vegetation response to climate change at different elevations. In this study, we used the water use efficiency (WUE) as an indicator to evaluate the water­carbon relationship. By using MODIS data, we analyzed the spatiotemporal patterns of gross primary productivity (GPP), evapotranspiration (ET), and WUE from 2001 to 2020, as well as the responses of WUE to extreme wetness factor Number of precipitation days (R0.1), extreme dryness factor Consecutive dry days (CDD), and meteorological factors under the vertical vegetation zonation. Our results showed that annual GPP and ET displayed a significant increasing trend between 2001 and 2020, whereas WUE showed a weak decreasing trend. Spatially, GPP and WUE decreased with increasing elevation. Analyzing the WUE of mountainous ecosystems as a unified whole may not precisely capture the reactions of vegetation to severe rainfall occurrences. In fact, across different vegetation belts in mountainous areas, there exists a negative correlation between WUE and R0.1, and a positive correlation with CDD. In terms of meteorological factors, the temporal variation of GPP was primarily associated with vapor pressure deficit (VPD) and temperature (Ta), while those of ET was mainly related to soil water content (SWC). WUE was affected by a combination of meteorological factors and had a certain degree of variation between different altitude intervals. These findings contribute to a better understanding and prediction of the relationship between extreme rainfall climate and water­carbon coupling in mountainous areas.

Reversible Mechanical Switching of Ferroelastic Stripe Domains in Multiferroic Thin Films.

The application potential of ferroelectric thin films largely relies on the controllability of their domain structure. Among the various proposed strategies, mechanical switching is being considered as a potential alternative to replace electrical switching for control of the domain structure of ferroelectric thin films via, e.g., the flexoelectric effect. So far, studies on mechanical switching are confined to out-of-plane polarization switching in ferroelectric thin films, which are in pristine or prepoled single-domain states. In this work, we report reversible in-plane mechanical switching of the monoclinic phase (MC phase) stripe domains in BiFeO3 thin films can be realized by scanning tip force. Via controlling the fast scan direction of the scanning probe microscopy tip and the magnitude of the tip force, the effective trailing field induced by the local tip force can be rotated to consequently switch the net in-plane polarization of the two-variant stripe domain patterns by either 90° or 180°. Moreover, the monoclinic to rhombohedral (MC-R) phase transition occurs during mechanical switching with the distribution of R-phase domains dependent on the switching paths. These results extend our current understanding of the mechanical switching behavior in ferroelectric thin films and should be instructive for their future applications.

Hidden Charge Order and Multiple Electronic Instabilities in EuTe4.

The rare-earth telluride compound EuTe4 exhibits a charge density wave (CDW) and an unconventional thermal hysteresis transition. Herein, we report a comprehensive study of the CDW states in EuTe4 by using low-temperature scanning tunneling microscopy. Two types of charge orders are observed at 4 K, including a newly discovered spindle-shaped pattern and a typical stripe-like pattern. As an exotic charge order, the spindle-shaped CDW is off-axis and barely visible at 77 K, indicating that it is a hidden order developed at low temperature. Based on our first-principles calculations, we reveal the origins of the observed electronic instabilities. The spindle-shaped charge order stems from a subsequent transition based on the stripe-like CDW phase. Our work demonstrates that the competition and cooperation between multiple charge orders can generate exotic quantum phases.

Selective intrafascicular stimulation of myelinated and unmyelinated nerve fibers through a longitudinal electrode: A computational study.

Carbon nanotube (CNT) fiber electrodes have demonstrated exceptional spatial selectivity and sustained reliability in the context of intrafascicular electrical stimulation, as evidenced through rigorous animal experimentation. A significant presence of unmyelinated C fibers, known to induce uncomfortable somatosensory experiences, exists within peripheral nerves. This presence poses a considerable challenge to the excitation of myelinated Aß fibers, which are crucial for tactile sensation. To achieve nuanced tactile sensory feedback utilizing CNT fiber electrodes, the selective stimulation of Aß sensory afferents emerges as a critical factor. In confronting this challenge, the present investigation sought to refine and apply a rat sciatic-nerve model leveraging the capabilities of the COMSOL-NEURON framework. This approach enables a systematic evaluation of the influence exerted by stimulation parameters and electrode geometry on the activation dynamics of both myelinated Aß and unmyelinated C fibers. The findings advocate for the utilization of current pulses featuring a pulse width of 600 µs, alongside the deployment of CNT fibers characterized by a diminutive diameter of 10 µm, with an exclusively exposed cross-sectional area, to facilitate reduced activation current thresholds. Comparative analysis under monopolar and bipolar electrical stimulation conditions revealed proximate activation thresholds, albeit with bipolar stimulation exhibiting superior fiber selectivity relative to its monopolar counterpart. Concerning pulse waveform characteristics, the adoption of an anodic-first biphasic stimulation modality is favored, taking into account the dual criteria of activation threshold and fiber selectivity optimization. Consequently, this investigation furnishes an efficacious stimulation paradigm for the selective activation of touch-related nerve fibers, alongside provisioning a comprehensive theoretical foundation for the realization of natural tactile feedback within the domain of prosthetic hand applications.

Faecalibacterium prausnitzii Supplementation Prevents Intestinal Barrier Injury and Gut Microflora Dysbiosis Induced by Sleep Deprivation.

Sleep deprivation (SD) leads to impaired intestinal barrier function and intestinal flora disorder, especially a reduction in the abundance of the next generation of probiotic Faecalibacterium prausnitzii (F. prausnitzii). However, it remains largely unclear whether F. prausnitzii can ameliorate SD-induced intestinal barrier damage. A 72 h SD mouse model was used in this research, with or without the addition of F. prausnitzii. The findings indicated that pre-colonization with F. prausnitzii could protect against tissue damage from SD, enhance goblet cell count and MUC2 levels in the colon, boost tight-junction protein expression, decrease macrophage infiltration, suppress pro-inflammatory cytokine expression, and reduce apoptosis. We found that the presence of F. prausnitzii helped to balance the gut microbiota in SD mice by reducing harmful bacteria like Klebsiella and Staphylococcus, while increasing beneficial bacteria such as Akkermansia. Ion chromatography analysis revealed that F. prausnitzii pretreatment increased the fecal butyrate level in SD mice. Overall, these results suggested that incorporating F. prausnitzii could help reduce gut damage caused by SD, potentially by enhancing the intestinal barrier and balancing gut microflora. This provides a foundation for utilizing probiotics to protect against intestinal illnesses.

Relationship of Day-by-Day Blood Pressure Variability and Admission Stroke Severity in Acute Ischemic Stroke.

OBJECTIVES: Research on the association between stroke severity and day-by-day blood pressure variability (BPV) in acute ischemic stroke (AIS) is rare as the majority focus on the blood pressure (BP) or the short-term BPV. Our study aims to explore the exact roles of daily BPV through the 7-day commencement on stroke severity in AIS. METHODS: The study included 633 patients with AIS, defining AIS as the time from the beginning of symptom up to 7 days with recording BP twice a day as well as calculating the daily BPV, and then matching them to the stroke severity. The logistic regression models were used to evaluate associations between stroke severity and day-by-day BPV. We used the smooth curve fitting to identify whether there was a nonlinear association. In addition, the subgroup analyses were performed using the logistic regression. RESULTS: According to the modified National Institutes of Health Stroke Scale score, 301 (47.5%) patients were allocated to the mild stroke group and 332 (52.5%) to the moderate-to-severe stroke group. In terms of stroke categories, we found no significant difference between BP at admission or mean BP. However, the moderate-to-severe stroke group exhibited higher daily BPV. The multiple logistic regression analysis indicated that day-by-day BPV was positively correlated to stroke severity [odds ratio (OR)=1.05, 95% CI:1.01-1.1, P=0.03 for SBP-SD; OR=1.08, 95% CI:1.01-1.15, P=0.03 for SBP-CV; OR=1.04, 95% CI:1.01-1.07, P=0.015 for SBP-SV). CONCLUSIONS: High day-by-day BPV in AIS was associated with more severe stroke independent of BP levels.

Effects of nitrate- and ammonium- nitrogen on anatomical and physiological responses of Catalpa bungei under full and partial root-zone drought.

Catalpa bungei is a precious timber species distributed in North China where drought often occurs. To clarify adaptive responses of C. bungei to partial- and full- root-zone drought under the influence of nitrogen forms, a two-factor experiment was conducted in which well-watered (WW), partial root-zone drought in horizontal direction (H-PRD) and in vertical direction (V-PRD), and full root-zone drought (FRD) were combined with nitrate-nitrogen (NN) and ammonium-nitrogen (AN) treatments. C. bungei responded to FRD by sharply closing stomata, decreasing gas exchange rate and increasing leaf instantaneous water use efficiency (WUEi). Under FRD condition, the growth of seedlings was severely inhibited and the effect of N forms was covered up by the drastic drought effect. In comparison, stomata conductance and gas exchanges were moderately inhibited by PRDs. WUEi in V-PRD treatment was superior to H-PRD due to the active stomata regulation resulting from a higher ABA level and active transcription of genes in abscisic acid (ABA) signaling pathway under V-PRD. Under both PRDs and FRD, nitrate benefited antioxidant defense, stomata regulation and leaf WUEi. Under V-PRD, WUEi in nitrate treatment was superior to that in ammonium treatment due to active stomata regulation by signaling network of nitric oxide (NO), Ca2+ and ABA. Under FRD, WUEi was higher in nitrate treatment due to the favoring photosynthetic efficiency resulting from active NO signal and antioxidant defense. The interactive effect of water and N forms was significant on wood xylem development. Superoxide dismutase (SOD) and catalase (CAT) largely contributes to stress tolerance and xylem development.

Dynamic lymphocyte-CRP ratio as a predictor: a single-centre retrospective study on disease severity and progression in adult COVID-19 patients.

OBJECTIVE: To assess the efficacy of dynamic changes in lymphocyte-C-reactive protein ratio (LCR) on differentiating disease severity and predicting disease progression in adult patients with Coronavirus disease 2019 (COVID-19). METHODS: This single-centre retrospective study enrolled adult COVID-19 patients categorized into moderate, severe and critical groups according to the Diagnosis and Treatment of New Coronavirus Pneumonia (ninth edition). Demographic and clinical data were collected. LCR and sequential organ failure assessment (SOFA) score were calculated. Lymphocyte count and C-reactive protein (CRP) levels were monitored on up to four occasions. Disease severity was determined concurrently with each LCR measurement. RESULTS: This study included 145 patients assigned to moderate (n = 105), severe (n = 33) and critical groups (n = 7). On admission, significant differences were observed among different disease severity groups including age, comorbidities, neutrophil proportion, lymphocyte count and proportion, D-Dimer, albumin, total bilirubin, direct bilirubin, indirect bilirubin, CRP and SOFA score. Dynamic changes in LCR showed significant differences across different disease severity groups at different times, which were significantly inversely correlated with disease severity of COVID-19, with correlation coefficients of -0.564, -0.548, -0.550 and -0.429 at four different times. CONCLUSION: Dynamic changes in LCR can effectively differentiate disease severity and predict disease progression in adult COVID-19 patients.

Predictive and Prognostic Potentials of Lymphocyte-C-Reactive Protein Ratio Upon Hospitalization in Adult Patients with Acute Pancreatitis.

Purpose: In this study, our objective was to investigate the potential utility of lymphocyte-C-reactive protein ratio (LCR) as a predictor of disease progression and a screening tool for intensive care unit (ICU) admission in adult patients with acute pancreatitis (AP). Methods: We included a total of 217 adult patients with AP who were admitted to the First Affiliated Hospital of Harbin Medical University between July 2019 and June 2022. These patients were categorized into three groups: mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP), based on the presence and duration of organ dysfunction. Various demographic and clinical data were collected and compared among different disease severity groups. Results: Height, diabetes, lymphocyte count (LYMPH), lymphocyte percentage (LYM%), platelet count (PLT), D-Dimer, albumin (ALB), blood urea nitrogen (BUN), serum creatinine (SCr), glucose (GLU), calcium ion (Ca2+), C-reactive protein (CRP), procalcitonin (PCT), hospitalization duration, ICU admission, need for BP, LCR, sequential organ failure assessment (SOFA) score, bedside index for severity in AP (BISAP) score, and modified Marshall score showed significant differences across different disease severity groups upon hospitalization. Notably, there were significant differences in LCR between the MAP group and the MSAP and SAP combined group, and the MAP and MSAP combined group and the SAP group, and adult AP patients with ICU admission and those without ICU admission upon hospitalization. Conclusion: In summary, LCR upon hospitalization can be utilized as a simple and reliable predictor of disease progression and a screening tool for ICU admission in adult patients with AP.

Identification and sex expression profiles of candidate chemosensory genes from Atherigona orientalis via the antennae and leg transcriptome analysis.

Atherigona orientalis Schiner (1868) is an acknowledged agricultural pest owing to its feeding habits and breeding locations. This insect is a tropical and subtropical pest in fruits and vegetables, in which >50 varieties of fruits and vegetables in 26 families, such as Capsicum annuum, Lycopersicon esculentum, and Cucumis melo have been attacked. Moreover, A. orientalis may also develop in rotten crops and feces or insect carcasses, which are also considered one kind of sanitary pest and medical insect. At present, the invasion ranges of A. orientalis are still increasing and more preventive and management measures are to be processed. To gain a better understanding of the molecular mechanisms involved in olfactory reception in A. orientalis, the transcriptome of male and female antennae and legs was systematically analyzed. In total, 131 chemosensory-related genes, including 63 odorant receptors (ORs), 20 gustatory receptors (GRs), 18 ionotropic receptors (IRs), 27 odorant binding proteins (OBPs), 1 chemosensory protein (CSP), and 2 sensory neuron membrane proteins (SNMPs), were identified. The analysis focused on obtaining expression information of candidate olfactory genes at the transcriptomic level by examining the differentially expressed genes (DEGs) in all samples. Totally, 41 DEGs were identified between male antennae (MA) and female antennae (FA), including 32 ORs, 5 OBPs, 1 IR, 2 GRs and 1 SNMP. In MA versus male legs (ML), 78 DEGs were identified (45 ORs, 18 OBPs, 6 GRs, 6 IRs, 1 CSP and 2 SNMPs). In FA and female legs (FL), 96 DEGs were identified (51 ORs, 21 OBPs, 9 GRs, 12 IRs, 1 CSP and 2 SNMPs). For ML and FL, 3 DEGs were identified, including 2 ORs and 1 SNMP. Our results supplement valuable insights for future research on the chemoreception mechanisms in A. orientalis.

METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2.

Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether N6-methyladenosine (m6A) specifically modified by methyltransferase-like 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-d-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4-L6 DRG neurons in CINP in a DBP/METTL14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment.

The open gate of the AMPA receptor forms a Ca2+ binding site critical in regulating ion transport.

Alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are cation-selective ion channels that mediate most fast excitatory neurotransmission in the brain. Although their gating mechanism has been studied extensively, understanding how cations traverse the pore has remained elusive. Here we investigated putative ion and water densities in the open pore of Ca2+-permeable AMPARs (rat GRIA2 flip-Q isoform) at 2.3-2.6 Å resolution. We show that the ion permeation pathway attains an extracellular Ca2+ binding site (site-G) when the channel gate moves into the open configuration. Site-G is highly selective for Ca2+ over Na+, favoring the movement of Ca2+ into the selectivity filter of the pore. Seizure-related N619K mutation, adjacent to site-G, promotes channel opening but attenuates Ca2+ binding and thus diminishes Ca2+ permeability. Our work identifies the importance of site-G, which coordinates with the Q/R site of the selectivity filter to ensure the preferential transport of Ca2+ through the channel pore.

Allosteric Activation of α7 Nicotinic Acetylcholine Receptors by Novel 2-Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice.

Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives 6-9 that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of α7 current with an EC50 of 1.3 µM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 µM). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 µM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.

Chitosan entrapping of sodium alginate / Lycium barbarum polysaccharide gels for the encapsulation, protection and delivery of Lactiplantibacillus plantarum with enhanced viability.

To preserve the viability of probiotics during digestion and storage, encapsulation techniques are necessary to withstand the challenges posed by adverse environments. A core-shell structure has been developed to provide protection for probiotics. By utilizing sodium alginate (SA) / Lycium barbarum polysaccharide (LBP) as the core material and chitosan (CS) as the shell, the probiotic load reached 9.676 log CFU/mL. This formulation not only facilitated continuous release in the gastrointestinal tract but also enhanced thermal stability and storage stability. The results obtained from Fourier transform infrared spectroscopy and thermogravimetric analysis confirmed that the addition of LBP and CS affected the microstructure of the gel by enhancing the hydrogen bond force, so as to achieve controlled release. Following the digestion of the gel within the gastrointestinal tract, the released amount was determined to be 9.657 log CFU/mL. The moisture content and storage stability tests confirmed that the encapsulated Lactiplantibacillus plantarum maintained good activity for an extended period at 4 °C, with an encapsulated count of 8.469 log CFU/mL on the 28th day. In conclusion, the newly developed core-shell gel in this study exhibits excellent probiotic protection and delivery capabilities.