Representations and generalization in artificial and brain neural networks.

Humans and animals excel at generalizing from limited data, a capability yet to be fully replicated in artificial intelligence. This perspective investigates generalization in biological and artificial deep neural networks (DNNs), in both in-distribution and out-of-distribution contexts. We introduce two hypotheses: First, the geometric properties of the neural manifolds associated with discrete cognitive entities, such as objects, words, and concepts, are powerful order parameters. They link the neural substrate to the generalization capabilities and provide a unified methodology bridging gaps between neuroscience, machine learning, and cognitive science. We overview recent progress in studying the geometry of neural manifolds, particularly in visual object recognition, and discuss theories connecting manifold dimension and radius to generalization capacity. Second, we suggest that the theory of learning in wide DNNs, especially in the thermodynamic limit, provides mechanistic insights into the learning processes generating desired neural representational geometries and generalization. This includes the role of weight norm regularization, network architecture, and hyper-parameters. We will explore recent advances in this theory and ongoing challenges. We also discuss the dynamics of learning and its relevance to the issue of representational drift in the brain.

Metal-Organic Framework Based on Ratiometric dual-Fluorescent Sensor Using for Accurate Quantification and on-Site Visual Detection of Ascorbic Acid.

Ascorbic acid is very important to the metabolic process of the body, but excessive intake can lead to diarrhea, kidney calculi and stomach cramps. However, complicated production procedures and harsh experimental settings limit many detection methods, and a simpler and more accurate measurement method is needed. In this study, a smartphone-assisted ratiometric fluorescence sensor was developed for the portable analysis of ascorbic acid. Leveraging the catalytic properties of MIL-53(Fe) to expedite the conversion of H2O2 into hydroxyl radicals, thereby facilitating the oxidation of o-phenylenediamine and terephthalic acid bridging ligand. The sensor showcased exceptional sensitivity in detecting ascorbic acid within a linear range of 0.3-100 µM, boasting an impressive limit of detection at 0.15 µM. Furthermore, through the utilization of color extraction RGB values captured by smartphones, accurate detection of ascorbic acid was achieved with a detection limit of 0.4 µM. Real fruit samples exhibited robust spiked recovery rates ranging from 91 to 119%, accompanied by relative standard deviations ≤ 4.7%. The MIL-53(Fe) nanozyme-based smartphone-assisted ratiometric fluorescence sensor offers an ascorbic acid fluorescence detection device that is visible, accurate, sensitive, and reasonably priced.

Reliable biological and multi-omics research through biometrology.

Metrology is the science of measurement and its applications, whereas biometrology is the science of biological measurement and its applications. Biometrology aims to achieve accuracy and consistency of biological measurements by focusing on the development of metrological traceability, biological reference measurement procedures, and reference materials. Irreproducibility of biological and multi-omics research results from different laboratories, platforms, and analysis methods is hampering the translation of research into clinical uses and can often be attributed to the lack of biologists' attention to the general principles of metrology. In this paper, the progresses of biometrology including metrology on nucleic acid, protein, and cell measurements and its impacts on the improvement of reliability and comparability in biological research are reviewed. Challenges in obtaining more reliable biological and multi-omics measurements due to the lack of primary reference measurement procedures and new standards for biological reference materials faced by biometrology are discussed. In the future, in addition to establishing reliable reference measurement procedures, developing reference materials from single or multiple parameters to multi-omics scale should be emphasized. Thinking in way of biometrology is warranted for facilitating the translation of high-throughput omics research into clinical practices.

Practice efficiency and total cost of care with bispecifics and CAR-T in relapsed/refractory diffuse large B-cell lymphoma: an institutional perspective.

Aim: Novel treatment options for relapsed/refractory diffuse large B-cell lymphoma include T-cell targeting therapies. Practice efficiency and cost are important for informed treatment decisions.Materials/methods: An institutional decision-maker cost model was developed for 6-month, 1-year and median cycles of treatment time horizons comparing practice efficiency and costs of epcoritamab vs glofitamab and axicabtagene ciloleucel (axi-cel).Results: Overall, epcoritamab required the shortest personnel and chair time, except over 1 year (second shortest chair time). Across all time horizons, epcoritamab was cost-saving vs axi-cel and had similar costs to glofitamab on a per-month basis.Conclusion: Epcoritamab reduced personnel and chair time. Additionally, epcoritamab was cost-saving vs axi-cel and had similar costs to glofitamab on a per-month basis.

There are new ways to treat diffuse large B-cell lymphoma, which is a type of cancer called lymphoma. When new treatments are available it is important to see if they take more or less time to give to patients and how much they cost versus other treatments. This study looked at three drugs used to treat diffuse large B-cell lymphoma, including epcoritamab, axi-cel and glofitamab. It estimated the time and cost with those treatments in patients who get them for 6 months, 1 year or for the most common length of time in the clinical trials. In most of the scenarios, epcoritamab had the least time needed for nurses or doctors and the least time needed for a patient to be in a chair in a clinic. When thinking about the cost per month, epcoritamab saved money versus axi-cel and was similar to glofitamab.

Precut Over a Pancreatic Duct Stent Versus Transpancreatic Precut Sphincterotomy for Difficult Biliary Cannulation in Endoscopic Retrograde Cholangiopancreatography: A Retrospective Cohort Study.

BACKGROUND: Precut over a pancreatic duct stent (PPDS) and transpancreatic precut sphincterotomy (TPS) with immediate pancreatic duct stent placement are techniques employed to promote biliary access during endoscopic retrograde cholangiopancreatography (ERCP) in cases of challenging biliary cannulation. However, limited data are available to compare the efficacy of these two pancreatic stent-assisted precut sphincterotomy techniques. AIMS: The aim of this study was to compare the efficacy of PPDS versus TPS. METHODS: A retrospective analysis was performed on the clinical data of consecutive patients who underwent ERCP between April 1, 2019 and May 31, 2023. According to the selected cannulation approaches, patients were assigned to two groups. In the PPDS group, a pancreatic duct stent was initially placed, followed by needle-knife precut over the stent. In the TPS group, transpancreatic precut sphincterotomy was initially performed, followed by immediate pancreatic stent placement. The success rate of biliary cannulation and the incidence of post-ERCP pancreatitis (PEP) between the two groups were analysed. RESULTS: Among 864 patients who underwent ERCP, 46 patients were equally enrolled in the two groups. Selective bile duct cannulation was successfully achieved in 42 out of 46 (91.3%) cases using the PPDS and in 32 out of 46 (69.6%) cases using TPS technique alone, indicating significantly higher success rate of bile duct cannulation with PPDS compared to TPS (91.3% vs. 69.6%, P = 0.009). The overall success rates for bile duct cannulation were 93.5% and 97.8% in the PPDS and TPS groups, respectively, with no significant difference identified (P = 0.307). PEP occurred in 0 and 4 (8.7%) cases in the PPDS and TPS groups, respectively, with no significant difference between the two groups (8.7% vs. 0%, P = 0.117). There were no cases of bleeding or perforation in either group. CONCLUSIONS: Both PPDS and TPS followed by immediate pancreatic duct stent placement are viable options. TPS stands out for its simplicity and cost-effectiveness, while PPDS is more appropriate for patients who are at a high-risk of developing PEP.

Optimal compressed sensing strategies for an array of nonlinear olfactory receptor neurons with and without spontaneous activity.

There are numerous different odorant molecules in nature but only a relatively small number of olfactory receptor neurons (ORNs) in brains. This "compressed sensing" challenge is compounded by the constraint that ORNs are nonlinear sensors with a finite dynamic range. Here, we investigate possible optimal olfactory coding strategies by maximizing mutual information between odor mixtures and ORNs' responses with respect to the bipartite odor-receptor interaction network (ORIN) characterized by sensitivities between all odorant-ORN pairs. For ORNs without spontaneous (basal) activity, we find that the optimal ORIN is sparse-a finite fraction of sensitives are zero, and the nonzero sensitivities follow a broad distribution that depends on the odor statistics. We show analytically that sparsity in the optimal ORIN originates from a trade-off between the broad tuning of ORNs and possible interference. Furthermore, we show that the optimal ORIN enhances performances of downstream learning tasks (reconstruction and classification). For ORNs with a finite basal activity, we find that having inhibitory odor-receptor interactions increases the coding capacity and the fraction of inhibitory interactions increases with the ORN basal activity. We argue that basal activities in sensory receptors in different organisms are due to the trade-off between the increase in coding capacity and the cost of maintaining the spontaneous basal activity. Our theoretical findings are consistent with existing experiments and predictions are made to further test our theory. The optimal coding model provides a unifying framework to understand the peripheral olfactory systems across different organisms.

Mechanism study of improving anaerobic co-digestion performance of waste activated sludge and food waste by Fe3O4.

A large amount of waste activated sludge (WAS) and food waste (FW) are produced every year in China. Anaerobic co-digestion is considered to be an effective way to solve this problem. This study applied FW/WAS mixture as co-substrate to create different digestive environment, aiming to understand the mechanism of Fe3O4 particles in promoting AD performance. The results showed that the addition of Fe3O4 presented various performances when facing different digestive acidification stress brought by different mixing ratios of WAS and FW. Methanogenic pathways and microbial communities varied with substrates' properties. For group A (WAS mono-digestion), the acetoclastic methanogens dominated, 20 mg/g VS (according to the iron element) Fe3O4 could promote methane production, while 200 mg/g VS Fe3O4 would inhibit microbial activity. The promoted methane production by Fe3O4 was attributable to the promotion of sludge hydrolysis. For group B (WAS: FW = 1:0.5, based on VS addition, similarly hereinafter), Fe3O4 triggered direct interspecific electron transfer (DIET) between bacteria and methanogens. For group C (WAS: FW = 1:1), the hydrogenotrophic methanogens dominated, bacteria excreted more non-conductive polysaccharides in EPS to resist unfavorable environment, thereby it prevented their contact with Fe3O4 particles. So, it was difficult for Fe3O4 to trigger DIET and promote the digestive performance of batch experiments in such condition.

Functional implications of sexual dimorphism of transporter patterns along the rat proximal tubule: modeling and analysis.

The goal of this study is to investigate the functional implications of the sexual dimorphism in transporter patterns along the proximal tubule. To do so, we have developed sex-specific computational models of solute and water transport in the proximal convoluted tubule of the rat kidney. The models account for the sex differences in expression levels of the apical and basolateral transporters, in single-nephron glomerular filtration rate, and in tubular dimensions. Model simulations predict that 70.6 and 38.7% of the filtered volume is reabsorbed by the proximal tubule of the male and female rat kidneys, respectively. The lower fractional volume reabsorption in females can be attributed to their smaller transport area and lower aquaporin-1 expression level. The latter also results in a larger contribution of the paracellular pathway to water transport. Correspondingly similar fractions (70.9 and 39.2%) of the filtered Na+ are reabsorbed by the male and female proximal tubule models, respectively. The lower fractional Na+ reabsorption in females is due primarily to their smaller transport area and lower Na+/H+ exchanger isoform 3 and claudin-2 expression levels. Notably, unlike most Na+ transporters, whose expression levels are lower in females, Na+-glucose cotransporter 2 (SGLT2) expression levels are 2.5-fold higher in females. Model simulations suggest that the higher SGLT2 expression in females may compensate for their lower tubular transport area to achieve a hyperglycemic tolerance similar to that of males.

Knockdown of autophagy-related protein 6, Beclin-1, decreases cell growth, invasion, and metastasis and has a positive effect on chemotherapy-induced cytotoxicity in osteosarcoma cells.

Beclin-1, a well-known key regulator of autophagy, has been implicated in many disorders, including cancer, aging, and degenerative diseases. Previous studies demonstrated that Beclin-1 participated in tumorgenesis and was highly expressed in colorectal cancer cells, primary duodenal adenocarcinoma, and hepatocellular carcinoma cells, and overexpression of Beclin-1 could induce autophagic cell death in leukemia cells. However, the exact effects and molecular mechanisms of Beclin-1-mediated autophagy in osteosarcoma are still unknown up to now. Here, we evaluated the role of Beclin-1 in human osteosarcoma cell lines in vivo and in vitro. In order to characterize the endogenous expression of Beclin-1 in osteosarcoma cell lines, we performed real-time PCR and Western blot analysis. We further analyzed the level of Beclin-1 in osteosarcoma cells after chemotherapy and investigated the impact of autophagy inhibition on chemotherapy-induced cytotoxicity. We used the small interfering RNA (siRNA) directed against Beclin-1 to infect the osteosarcoma cell line with relatively high Belcin-1 expression. Furthermore, we determine the functional relevance of Beclin-1 knockdown to osteosarcoma cell growth, migration, and invasion, and investigate the expression levels of matrix metallopeptidase-2 (MMP-2), MMP-9, phosphoinositide 3-kinase p85α (PI3Kp85α), and phosphorylated AKT (p-AKT). As a result, HOS osteosarcoma cells exhibited higher Beclin-1 expression. Anticancer agents including doxorubicin, cisplatin, and methotrexate each induced Beclin-1 up-regulation in human osteosarcoma cells, and siRNA-mediated knockdown of Beclin-1 suppressed cell proliferation, migration, and invasion indicated by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenylthetrazolium bromide, would healing, and transwell assays. Cell apoptosis induced by anticancer agents was markedly increased. Knockdown of Beclin-1 or inhibition of autophagy by 3-methyladenine (an inhibitor of autophagy and PI3K) rendered them significantly more sensitive to chemotherapy. Addition of the pan-caspase inhibitor ZVAD-FMK partly reversed the cisplatin-induced cell death. When Beclin-1 expression was inhibited, the expression of PI3Kp85α, p-AKT, and MMP-9 was downregulated in HOS cells. In addition, the tumor volumes in subcutaneous nude mouse models in Beclin-1-deleted HOS cells were significantly smaller than those of control group. These results suggested that knockdown of Beclin-1 by siRNA exerts inhibitory effects on growth and migration of osteosarcoma cells possibly via blockade of the PI3K/AKT signaling. Beclin-1 knockdown rendered them significantly more sensitive to chemotherapy through activating apoptosis pathway. The results of this study suggest that Beclin-1 plays an important role in proliferation and tumor progression in osteosarcoma and inhibition autophagy can increase the efficacy of anticancer agent therapy.

Liraglutide does not increase heart rate of diabetic patients during acute myocardial infarction.

BACKGROUND: Glucagon-like peptide 1 receptor agonists have been shown to reduce all-cause and cardiovascular mortality in patients with Type 2 diabetes mellitus (T2DM). The probable increase in heart rate hinders its early usage in acute myocardial infarction patients. In our study, we aimed to find out whether the use of liraglutide in patients with acute myocardial infarction as early as at the time of hospitalization would increase the heart rate. METHODS: This was an observational retrospective study. From December 2020 to August 2021, 200 patients with acute myocardial infarction were included in our study and divided into three groups: T2DM + liraglutide group (n = 46), T2DM + non-liraglutide group (n = 42), and non-T2DM group (n = 112). The primary outcomes were the differences in heart rate. Secondary outcomes were differences in systolic and diastolic blood pressure. RESULTS: There were no significant differences in heart rate among the three groups at admission, the day before the first shot of liraglutide, and before discharge. There was also no significant difference in heart rate between diabetic patients with acute myocardial infarction and those on liraglutide during the hospital stay. And there were no differences of beta-blocker dosages among the three groups. Liraglutide did not affect the blood pressure during acute myocardial infarction. CONCLUSIONS: Liraglutide did not increase the heart rate in diabetic patients during acute myocardial infarction and did not lead to an increase in the dose of beta-blockers in the patients. It also had no effect on blood pressure and showed better efficacy in lowering glucose levels without additional hypoglycemic events.

Thrombus aspiration is associated with improved platelet inhibition rate following dual antiplatelet therapy in acute myocardial infarction patients.

BACKGROUND: It is well-established that thrombus aspiration during primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) indicates a higher thrombus burden and necessitates more intensive antithrombotic therapy. The bidirectional association between adverse events in AMI patients and platelet reactivity is typically observed during dual antiplatelet therapy (DAPT). OBJECTIVE: To investigate platelet reactivity after DAPT in AMI patients with thrombus aspiration performed during PCI. METHODS: In this retrospective study, we examined 269 consecutive AMI patients who underwent PCI and recorded their demographic, clinical and laboratory data. The platelet reactivity was measured with thromboelastogram (TEM). RESULTS: Ultimately, 208 patients were included in this study and divided into a Thrombus Aspiration group (N = 97) and a PCI Alone group (N = 111) based on whether thrombus aspiration was performed or not. The adenosine diphosphate (ADP)-induced platelet inhibition rate in the Thrombus Aspiration group was higher than that in the PCI Alone group (P < 0.001). Furthermore, multivariate linear regression analysis revealed that the ADP-induced platelet inhibition rate was independently associated with leukocyte count, thrombus aspiration and the combination of aspirin and ticagrelor as DAPT after adjusting for potential covariates in all AMI patients. CONCLUSION: In conclusion, clinicians should exercise heightened attention towards the bleeding risk among patients undergoing PCI concomitant with Thrombus Aspiration postoperatively.

Olea europaea leaf exosome-like nanovesicles encapsulated in a hyaluronic acid / tannic acid hydrogel dressing with dual "defense-repair" effects for treating skin photoaging.

Photoaging, primarily caused by ultraviolet (UV) light, is the major factor in extrinsic skin aging. Existing anti-photoaging strategies mainly focus on early sun protection or repairing damaged skin, lacking a comprehensive treatment strategy. Therefore, this study developed a dressing that actively shields against UV radiation and repairs photoaged skin, offering double protection. This study utilized exosome-like nanovesicles derived from Olea europaea leaves (OLELNVs), enhancing them into a potent core biomaterial with high-dose effects and skin-friendly, non-cytotoxic inhibition of cell aging. These nanovesicles were incorporated into a cross-linked hyaluronic acid (HA) and tannic acid (TA) hydrogel with strong UV-absorbing properties, creating the OLELNVs@HA/TA hydrogel system. In vitro and in vivo experiments demonstrated that OLELNVs@HA/TA hydrogel can effectively reduce UV-induced skin damage and promote skin repair and regeneration. Additionally, RNA-seq and clustering analysis of miR168a-5p predicted targets revealed significant down-regulation of the NF-κB signaling pathway, mediating inflammatory aging responses. Overall, the OLELNVs@HA/TA hydrogel represents a novel dual-strategy approach for clinical application in combating photoaging.

Full-term pregnancy with retroperitoneal giant mucinous cyst: A case report and literature review.

RATIONALE: Retroperitoneal benign cysts during pregnancy are extremely rare and often remain asymptomatic until they attain a very large size. Diagnosis typically relies on a pathological tissue biopsy. The decision to pursue 1-step or 2-step surgical treatment should be tailored to each individual case rather than generalized. PATIENT CONCERNS: This case report presents the unique scenario of a pregnant woman with a confirmed pregnancy complicated by a large retroperitoneal cyst. The patient had a retroperitoneal cyst during her initial pregnancy, which went undetected during the first cesarean section. However, it was identified during her second pregnancy by which time it had grown to 13.0 cm × 15.0 cm × 25.0 cm, and extended from the liver margin to right ovarian pelvic infundibulopelvic ligament. Consequently, it was removed smoothly during her second cesarean section. DIAGNOSES: Postoperative pathology results indicated a massive retroperitoneal mucinous cystadenoma. INTERVENTIONS: The giant retroperitoneal cyst was smoothly excised during the second cesarean delivery for 1-step surgical treatment. OUTCOMES: Under the combined spinal and epidural anesthesia, a live female infant was delivered at 38 3/7 gestational weeks and the neonatal weight was 3200g. Under general anesthesia with endotracheal intubation, the giant retroperitoneal cyst was excised smoothly without complications. LESSONS: The findings of this case report contribute to the understanding of the diagnostic modalities, surgical approaches and postoperative considerations of giant retroperitoneal cysts associated with pregnancy.

Investigation of the correlation between the change in the projected lung area and forced vital capacity using biphasic chest dynamic digital radiography: a cross-sectional study.

Background: Chest dynamic digital radiography (DDR) is used as a supplementary tool for the routine pulmonary function test (PFT); however, its potential as a novel standard PFT method has yet to be explored. Therefore, the present study aimed to investigate the correlation between the change in the projected lung area (ΔPLA) and forced vital capacity (FVC) using chest DDR, and to establish a DDR-FVC estimation model and a predictive value model for the ΔPLA. Methods: In total, 139 participants who underwent chest DDR and the PFT in the same period at The First Affiliated Hospital of Guangzhou Medical University from April 2022 to February 2023 were prospectively included in the study. The patients' age, gender, height, and weight measurements were recorded. Additionally, the ΔPLA was measured, and the IWS workstation software was used for automated outlining and calculation. Subsequently, a correlation analysis and regression analysis models were employed to examine the relationship between the ΔPLA, FVC, and individual physiological characteristics. Additionally, an independent sample t-test was used to determine whether there were any significant differences between the normal and abnormal FVC groups. Results: The 139 participants were grouped according to the results of the ratio of measured/predicted FVC values (FVC%pred); those with an FVC%pred ≥80%, were allocated to the normal FVC group, and those with an FVC%pred <80% were allocated to the abnormal FVC group. The correlation coefficient was >0.8 in the full sample; the ΔPLA showed a significant linear correlation with the measured FVC value [r=0.81, 95% confidence interval (CI): 0.75-0.86, P<0.001]. There was a significant difference in the ΔPLA between the normal and abnormal FVC groups. With the ΔPLA, age, gender, height, and weight as predictor variables, the following DDR-FVC estimation model was established: DDR-FVC estimation model = -0.997 + 1.35×10-4 × ΔPLA + 0.017 × height - 0.014 × age + 0.249 × gender (1 for male and 0 for female) [adjusted R2 (adj. R2)=0.731, F=94.615, P<0.001]. The following formula was used to determine the predictive value of the ΔPLA: Predictive value of ΔPLA = -12,504.287 + 173.185 × height + 62.971 × weight - 84.933 × age (adj. R2=0.393, F=20.453, P<0.001). Conclusions: There was a linear correlation between the ΔPLA measured by biphasic chest DDR and the FVC. A model for estimating the FVC was established based on the ΔPLA, which allows the FVC to be assessed by the ΔPLA measured by biphasic chest DDR. A predictive value model for the ΔPLA was also established to provide ΔPLA reference values for assessment and comparison.

Regulating Astrocytes via Short Fibers for Spinal Cord Repair.

Reactive astrogliosis is the main cause of secondary injury to the central nerves. Biomaterials can effectively suppress astrocyte activation, but the mechanism remains unclear. Herein, Differentially Expressed Genes (DEGs) are identified through whole transcriptome sequencing in a mouse model of spinal cord injury, revealing the VIM gene as a pivotal regulator in the reactive astrocytes. Moreover, DEGs are predominantly concentrated in the extracellular matrix (ECM). Based on these, 3D injectable electrospun short fibers are constructed to inhibit reactive astrogliosis. Histological staining and functional analysis indicated that fibers with unique 3D network spatial structures can effectively constrain the reactive astrocytes. RNA sequencing and single-cell sequencing results reveal that short fibers downregulate the expression of the VIM gene in astrocytes by modulating the "ECM receptor interaction" pathway, inhibiting the transcription of downstream Vimentin protein, and thereby effectively suppressing reactive astrogliosis. Additionally, fibers block the binding of Vimentin protein with inflammation-related proteins, downregulate the NF-κB signaling pathway, inhibit neuron apoptosis, and consequently promote the recovery of spinal cord neural function. Through mechanism elucidation-material design-feedback regulation, this study provides a detailed analysis of the mechanism chain by which short fibers constrain the abnormal spatial expansion of astrocytes and promote spinal cord neural function.

Curve fitting and jump detection on nonparametric regression with missing data.

In this paper, by virtual of the inverse probability weighted technique, we considered the jump-preserving estimation on the nonparametric regression models with missing data on response variable. First, we used local piecewise-linear expansion respectively with left and right kernel to approximate the unknown regression function. Second, we obtained the left- and right-limit estimation of regression function at each observed points and then determinated the final estimators by residual sums of squares. Third, we presented the convergence rate of estimators and the residual sums of squares. Finally, we illustrated the performance of our proposed method through some simulation studies and a conjunctivitis example from The Affiliated Hospital of Hangzhou Normal University.

Microstructural Characterization and Prior Particle Boundary (PPB) of PM Nickel-Based Superalloys by Spark Plasma Sintering (SPS).

This research investigates the microstructure and defects of powder metallurgy (PM) nickel-based superalloys prepared by spark plasma sintering (SPS). The densification, microstructural evolution, and precipitate phase evolution processes of FGH96 superalloy after powder heat treatment (PHT) and sintering via SPS are specifically analyzed. Experimental results demonstrate that SPS technology, when applied to sinter at the sub-solidus temperature of the γ' phase, effectively mitigates the formation of a prior particle boundary (PPB). Based on experimental and computational findings, it has been determined that the presence of elemental segregation and Al2O3 oxides on the surface of pre-alloyed powders leads to the preferential precipitation of MC-type carbides and Al2O3 and ZrO2 oxides in the sintering necks during the hot consolidation process, resulting in the formation of PPB. This study contributes to the understanding of microstructural modifications achieved through SPS technology, providing crucial information for optimizing sintering conditions and reducing the widespread occurrence of PPB, ultimately enhancing the material performance of PM nickel-based superalloys.

Application and prospect of the therapeutic strategy of inhibiting cellular senescence combined with pro-regenerative biomaterials in regenerative medicine.

Complete regeneration of damaged tissues/organs has always been the ultimate challenge in regenerative medicine. Aging has long been considered the basis of age-related diseases, as senescent cells gradually accumulate in tissues with increasing age, tissues exhibit aging and normal physiological functions are inhibited. In recent years, in damaged tissues, scholars have found that the number of cells with features of cellular senescence continues to increase over time. The accumulation of senescent cells severely hinders the healing of damaged tissues. Furthermore, by clearing senescent cells or inhibiting the aging microenvironment, damaged tissues regained their original regenerative and repair capabilities. On the other hand, various biomaterials have been proved to have good biocompatibility and can effectively support cell regeneration after injury. Combining the two solutions, inhibiting the cellular senescence in damaged tissues and establishing a pro-regenerative environment through biomaterial technology gradually reveals a new, unexpected treatment strategy applied to the field of regenerative medicine. In this review, we first elucidate the main characteristics of senescent cells from morphological, functional and molecular levels, and discuss in detail the process of accumulation of senescent cells in tissues. Then, we will explore in depth how the accumulation of senescent cells after damage affects tissue repair and regeneration at different stages. Finally, we will turn to how to promote tissue regeneration and repair in the field of regenerative medicine by inhibiting cellular senescence combined with biomaterial technology. Our goal is to understand the relationship between cellular senescence and tissue regeneration through this new perspective, and provide valuable references for the development of new therapeutic strategies in the future.

A single dose of ketamine relieves fentanyl-induced-hyperalgesia by reducing inflammation initiated by the TLR4/NF-κB pathway in rat spinal cord neurons.

A large amount of clinical evidence has revealed that ketamine can relieve fentanyl-induced hyperalgesia. However, the underlying mechanism is still unclear. In the current study, a single dose of ketamine (5 mg/kg or 10 mg/kg), TAK-242 (3 mg/kg), or saline was intraperitoneally injected into rats 15 min before four subcutaneous injections of fentanyl. Results revealed that pre-administration of ketamine alleviated fentanyl-induced hyperalgesia according to hind paw-pressure and paw-withdrawal tests. High-dose ketamine can reverse the expression of toll-like receptor-dimer (d-TLR4), phospho- nuclear factor kappa-B (p-NF-κB, p-p65), cyclooxygenase-2 (COX-2), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) 1 d after fentanyl injection in the spinal cord. Moreover, fentany-linduced-hyperalgesia and changes in the expression of the aforementioned proteins can be attenuated by TAK-242, an inhibitor of TLR4, as well as ketamine. Importantly, TLR4, p-p65, COX-2, and IL-1ß were expressed in neurons but not in glial cells in the spinal cord 1 d after fentanyl injection. In conclusion, results suggested that a single dose of ketamine can relieve fentanyl-induced-hyperalgesia via the TLR4/NF-κB pathway in spinal cord neurons.

Differential regulation of H3K9/H3K14 acetylation by small molecules drives neuron-fate-induction of glioma cell.

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple oncogenes and cell cycle genes, while ones of H3K9ac and histone 3 at lysine 14 (H3K14ac) were increased in the promoter of neuron-specific genes. We then compiled a list of genes controlled by H3K9ac and H3K14ac, and proved that it is a good predictive power for pathologic grading and survival prediction. Moreover, cAMP agonist combined with HDACi also induced glioma stem cells (GSCs) to differentiate into neuron-like cells through the regulation of H3K9ac/K14ac, indicating that combined induction has the potential for recurrence-preventive application. Furthermore, the combination of cAMP activator plus HDACi significantly repressed the tumor growth in a subcutaneous GSC-derived tumor model, and temozolomide cooperated with the differentiation-inducing combination to prolong the survival in an orthotopic GSC-derived tumor model. These findings highlight epigenetic reprogramming through H3K9ac and H3K14ac as a novel approach for driving neuron-fate-induction of GBM cells.