Dihydroquercetin alleviates dopamine neuron loss via regulating TREM2 activation.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative disorder, marked by the degeneration of dopamine (DA) neurons in the substantia nigra (SN). Current evidence strongly suggests that neuroinflammation, primarily mediated by microglia, contributes to PD pathogenesis. Triggering receptor expressed on myeloid cells 2 (TREM2) might serve as a promising therapeutic target for PD due to its ability to suppress neuroinflammation. Dihydroquercetin (DHQ) is an important natural dihydroflavone and confers apparent anti-inflammatory, antioxidant and anti-fibrotic effects. Recently, DHQ-mediated neuroprotection was exhibited. However, the specific mechanisms of its neuroprotective effects remain incompletely elucidated. METHODS: In this study, rat models were utilized to induce damage to DA neurons using lipopolysaccharide (LPS) and 6-hydroxydopamine (6-OHDA) to assess the impacts of DHQ on the loss of DA neurons. Furthermore, DA neuronal MN9D cells and microglial BV2 cells were employed to investigate the function of TREM2 in DHQ-mediated DA neuroprotection. Finally, TREM2 knockout mice were used to investigate whether the neuroprotective effects mediated by DHQ through a mechanism dependent on TREM2. RESULTS: The main findings demonstrated that DHQ effectively protected DA neurons against neurotoxicity induced by LPS and 6-OHDA and inhibited microglia-elicited neuroinflammation. Meanwhile, DHQ promoted microglial TREM2 signaling activation. Notably, DHQ failed to reduce inflammatory cytokines release and further present neuroprotection from DA neurotoxicity upon TREM2 silencing. Similarly, DHQ didn't exert DA neuroprotection in TREM2 knockout mice. CONCLUSIONS: These findings suggest that DHQ exerted DA neuroprotection by regulating microglia TREM2 activation.

Effect of Chinese quince proanthocyanidins on the inhibition of heterocyclic amines and quality of fried chicken meatballs and tofu.

Heterocyclic amines (HCAs) have potential carcinogenic and mutagenic activity and are generated in cooked protein-rich foods. Adding proanthocyanidins (PAs) to these foods before frying is an effective way to reduce HCAs. In this study, polymeric PAs (PPA) and ultrasound-assisted acid-catalyzed/catechin nucleophilic depolymerized PAs (UAPA, a type of oligomeric PA) were prepared from Chinese quince fruits (CQF). Different levels of PPA and UAPA (0.05%, 0.1%, and 0.15%) were added to chicken meatballs and tofu; then these foods were fried, and the content of HCAs in them after frying was investigated. The results showed that PPA and, particularly, UAPA significantly inhibited the formation of HCAs in fried meatballs and tofu, and this inhibition was dose-dependent. The inhibition of HCAs by both PPA and UAPA was stronger in the chicken meatballs than in fried tofu. The level of total HCAs was significantly reduced by 57.84% (from 11.93 to 5.03 ng/g) after treatment of meatballs with 0.15% UAPA, with inhibition rates of 78.94%, 50.37%, and 17.81% for norharman, harman, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), respectively. Of note, there was a negative correlation between water, lipid, protein, creatine, and glucose content and HCA content in the crust, interior, and whole (crust-plus-interior) measurements of all fried samples. Interestingly, PPA and UAPA were found more effective in inhibiting HCAs in the exterior crust than in the interior of the fried chicken meatballs. These results provide evidence that further studies on the reduction of the formation of harmful HCAs in fried foods by adding CQF PAs could be valuable to the fried food industry. PRACTICAL APPLICATION: Chinese quince proanthocyanidins treatments significantly inhibited the generation of heterocyclic amines (HCAs) in chicken meatballs and tofu when deep-fried. These results suggest that Chinese quince proanthocyanidins can be used as natural food additive for reducing HCAs in fried foods, laying the foundation for using Chinese quince fruit proanthocyanidins for HCA inhibition in the food industry.

A de novo Mutation (p.Gln277X) of Cyclin D2 is Responsible for a Child with Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome.

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH), a type of overgrowth syndrome, is characterized by progressive megalencephaly, cortical brain malformations, and distal limb anomalies. Previous studies have revealed that the overactivity of the phosphatidylinositol 3-kinase-Protein kinase B pathway and the increased cyclin D2 (CCND2) expression were the main factors contributing to this disease. Here, we present the case of a patient who exhibited megalencephaly, polymicrogyria, abnormal neuronal migration, and developmental delay. Serum tandem mass spectrometry and chromosome examination did not detect any metabolic abnormalities or copy number variants. However, whole-exome sequencing and Sanger sequencing revealed a de novo nonsense mutation (NM_001759.3: c.829C>T; p.Gln277X) in the CCND2 gene of the patient. Bioinformatics analysis predicted that this mutation may disrupt the structure and surface charge of the CCND2 protein. This disruption could potentially prevent polyubiquitination of CCND2, leading to its resistance against degradation. Consequently, this could drive cell division and growth by altering the activity of key cell cycle regulatory nodes, ultimately contributing to the development of MPPH. This study not only presents a new case of MPPH and expands the mutation spectrum of CCND2 but also enhances our understanding of the mechanisms connecting CCND2 with overgrowth syndromes.

Superhydrophobic Non-Metallic Surfaces with Multiscale Nano/Micro-Structure: Fabrication and Application.

Multiscale nano/micro-structured surfaces with superhydrophobicity are abundantly observed in nature such as lotus leaves, rose petals and butterfly wings, where microstructures typically reinforce mechanical stability, while nanostructures predominantly govern wettability. To emulate such hierarchical structures in nature, various methods have been widely applied in the past few decades to the manufacture of multiscale structures which can be applied to functionalities ranging from anti-icing and water-oil separation to self-cleaning. In this review, we highlight recent advances in nano/micro-structured superhydrophobic surfaces, with particular focus on non-metallic materials as they are widely used in daily life due to their lightweight, abrasion resistance and ease of processing properties. This review is organized into three sections. First, fabrication methods of multiscale hierarchical structures are introduced with their strengths and weaknesses. Second, four main application areas of anti-icing, water-oil separation, anti-fog and self-cleaning are overviewed by assessing how and why multiscale structures need to be incorporated to carry out their performances. Finally, future directions and challenges for nano/micro-structured surfaces are presented.

Palladium-catalyzed asymmetric carbene coupling en route to inherently chiral heptagon-containing polyarenes.

Developing facile and direct synthesis routes for enantioselective construction of cyclic π-conjugated molecules is crucial. However, originate chirality from the distorted structure around heptagon-containing polyarenes is largely overlooked, the enantioselective construction of all-carbon heptagon-containing polyarenes remains a challenge. Herein, we present a highly enantioselective synthesis route for fabricating all carbon heptagon-containing polyarenes via palladium-catalyzed carbene-based cross-coupling of benzyl bromides and N-arylsulfonylhydrazones. A wide range of nonplanar, saddle-shaped tribenzocycloheptene derivatives are efficiently prepared in high yields with excellent enantioselectivities using this approach. In addition, stereochemical stability experiments show that these saddle-shaped tribenzocycloheptene derivatives have high inversion barriers.

Abnormal performance of peroral endoscopic myotomy (POEM): a case misdiagnosed as achalasia of cardia.

BACKGROUND: Pseudoachalasia is a rare disease that behaves similarly to achalasia (AC), making it sometimes difficult to differentiate. CASE PRESENTATION: We report a case of 49-year-old male with adenocarcinoma of the gastroesophageal junction misdiagnosed as achalasia. No obvious abnormalities were found in his initial examinations including upper digestive endoscopy, upper gastrointestinal imaging and chest computed tomography (CT). During the subsequent introduced-peroral endoscopic myotomy (POEM), it was found that the mucosal layer and the muscular layer had severe adhesion, which did not receive much attention, delayed the clear diagnosis and effect treatment, and ultimately led to a poor prognosis for the patient. CONCLUSIONS: This case suggests that when patients with AC found mucosal and muscular adhesions during POEM surgery, the possibility should be considered that the lesion may be caused by a malignant lesion.

Enhancement of the Tumor Suppression Effect of High-dose Radiation by Low-dose Pre-radiation Through Inhibition of DNA Damage Repair and Increased Pyroptosis.

Radiation therapy has been a critical and effective treatment for cancer. However, not all cells are destroyed by radiation due to the presence of tumor cell radioresistance. In the current study, we investigated the effect of low-dose radiation (LDR) on the tumor suppressive effect of high-dose radiation (HDR) and its mechanism from the perspective of tumor cell death mode and DNA damage repair, aiming to provide a foundation for improving the efficacy of clinical tumor radiotherapy. We found that LDR pre-irradiation strengthened the HDR-inhibited A549 cell proliferation, HDR-induced apoptosis, and G2 phase cell cycle arrest under co-culture conditions. RNA-sequencing showed that differentially expressed genes after irradiation contained pyroptosis-related genes and DNA damage repair related genes. By detecting pyroptosis-related proteins, we found that LDR could enhance HDR-induced pyroptosis. Furthermore, under co-culture conditions, LDR pre-irradiation enhances the HDR-induced DNA damage and further suppresses the DNA damage-repairing process, which eventually leads to cell death. Lastly, we established a tumor-bearing mouse model and further demonstrated that LDR local pre-irradiation could enhance the cancer suppressive effect of HDR. To summarize, our study proved that LDR pre-irradiation enhances the tumor-killing function of HDR when cancer cells and immune cells were coexisting.

New azole derivatives linked to indole/indoline moieties combined with FLC against drug-resistant Candida albicans.

Candida albicans is the most common fungal pathogen associated with human opportunistic infections. Invasive infections caused by C. albicans are becoming increasingly serious. However, with the rising incidence of fungal infection, many fungi are resistant to commonly used drugs. Therefore, there is an urgent need for exploring new anti-fungal drugs that fungi are not resistant to. A series of novel azole derivatives linked to indole/indoline moieties were prepared, and in vitro antifungal activity evaluated. All compounds combined with FLC showed excellent activity against drug-resistant C. albicans with low toxicity. A preliminary mechanistic study indicated that S1 combined with FLC could inhibit the formation of C. albicans biofilms as well as destroy the integrity of cell-membrane structure and mitochondrial function. S1 could be considered a new fungal agent for further study.

A Photosensitivity-Enhanced Plant Growth Algorithm for UAV Path Planning.

With the rise and development of autonomy and intelligence technologies, UAVs will have increasingly significant applications in the future. It is very important to solve the problem of low-altitude penetration of UAVs to protect national territorial security. Based on an S-57 electronic chart file, the land, island, and threat information for an actual combat environment is parsed, extracted, and rasterized to construct a marine combat environment for UAV flight simulation. To address the problem of path planning for low-altitude penetration in complex environments, a photosensitivity-enhanced plant growth algorithm (PEPG) is proposed. Based on the plant growth path planning algorithm (PGPP), the proposed algorithm improves upon the light intensity preprocessing and light intensity calculation methods. Moreover, the kinematic constraints of the UAV, such as the turning angle, are also considered. The planned path that meets the safety flight requirements of the UAV is smoother than that of the original algorithm, and the length is reduced by at least 8.2%. Finally, simulation tests are carried out with three common path planning algorithms, namely, A*, RRT, and GA. The results show that the PEPG algorithm is superior to the other three algorithms in terms of the path length and path quality, and the feasibility and safety of the path are verified via the autonomous tracking flight of a UAV.

Recent advances in neural mechanism of general anesthesia induced unconsciousness: insights from optogenetics and chemogenetics.

For over 170 years, general anesthesia has played a crucial role in clinical practice, yet a comprehensive understanding of the neural mechanisms underlying the induction of unconsciousness by general anesthetics remains elusive. Ongoing research into these mechanisms primarily centers around the brain nuclei and neural circuits associated with sleep-wake. In this context, two sophisticated methodologies, optogenetics and chemogenetics, have emerged as vital tools for recording and modulating the activity of specific neuronal populations or circuits within distinct brain regions. Recent advancements have successfully employed these techniques to investigate the impact of general anesthesia on various brain nuclei and neural pathways. This paper provides an in-depth examination of the use of optogenetic and chemogenetic methodologies in studying the effects of general anesthesia on specific brain nuclei and pathways. Additionally, it discusses in depth the advantages and limitations of these two methodologies, as well as the issues that must be considered for scientific research applications. By shedding light on these facets, this paper serves as a valuable reference for furthering the accurate exploration of the neural mechanisms underlying general anesthesia. It aids researchers and clinicians in effectively evaluating the applicability of these techniques in advancing scientific research and clinical practice.

Long noncoding RNAs HAND2-AS1 ultrasound microbubbles suppress hepatocellular carcinoma progression by regulating the miR-873-5p/tissue inhibitor of matrix metalloproteinase-2 axis.

BACKGROUND: Increasing data indicated that long noncoding RNAs (lncRNAs) were directly or indirectly involved in the occurrence and development of tumors, including hepatocellular carcinoma (HCC). Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues, but its role in HCC progression is unclear. Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes. AIM: To study the role of ultrasound microbubbles (UTMBs) mediated HAND2-AS1 in the progression of HCC, in order to provide a new reference for the treatment of HCC. METHODS: In vitro, we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs, and detected cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) by cell counting kit-8 assay, flow cytometry, Transwell invasion assay and Western blotting, respectively. In addition, we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior. Next, the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2 (TIMP2) overexpression vector, and we detected cell proliferation, apoptosis, invasion and EMT. In vivo, we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability. RESULTS: We found that UTMBs carrying HAND2-AS1 restricted cell proliferation, invasion, and EMT, encouraged apoptosis, and HAND2-AS1 silencing eliminated the effect of UTMBs. Additionally, miR-873-5p targets the gene HAND2-AS1, which also targets the 3'UTR of TIMP2. And miR-873-5p mimic counteracted the impact of HAND2-AS1. Further, miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs. We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase (MMP) 2/MMP9. In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice. CONCLUSION: LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.

Family History of Type 2 Diabetes and Its Association with Beta Cell Function and Lipid Profile in Newly Diagnosed Pediatric Patients with Type 1 Diabetes.

OBJECTIVE: The objective of this study was to explore the associations between a family history of type 2 diabetes (T2D) and beta-cell function, as well as lipid profile, in pediatric patients newly diagnosed with type 1 diabetes (T1D). METHODS: A retrospective analysis was conducted on children under 14 years of age who were newly diagnosed with T1D at the Children's Hospital of Zhejiang University between August 2018 and August 2022. Clinical features, metabolic profiles, beta-cell function, and lipid profile were evaluated. RESULTS: A total of 316 children were diagnosed with new-onset T1D. Among them, 28.2% had a family history of T2D. Patients with T1D who had a family history of T2D experienced a later onset of the disease (p = 0.016), improved HOMA2-%B levels (p = 0.003), and increased concentrations of HDL-C (p = 0.005). In addition, no statistically significant differences in age at onset, HOMA2-%B levels, or HDL-C were found when assessing the interaction between family history of T2D and type of diabetes mellitus (autoimmune T1D/idiopathic T1D). CONCLUSION: A family history of T2D may contribute to the heterogeneity of T1D patients in terms of HOMA2-%B levels and lipid profile. This highlights the significance of taking into account T2D-related factors in the diagnosis and treatment of T1D.

Two new sesterterpenoids from Atractylodes japonica Koidz. ex Kitam.

Two new sesterterpenoids, atractylodes japonica terpenoid acid I (1) and atractylodes japonica terpenoid aldehyde I (2), were isolated from the rhizomes of Atractylodes japonica Koidz. ex Kitam together with ten known compounds (3-12). Their structures were elucidated on the basis of comprehensive spectroscopic analysis (1D/2D NMR, HRESIMS and IR). In addition, all of these isolated compounds were evaluated for their cytotoxic activities against human gastric cancer cell MGC-803 and human hepatocellular cancer cell HepG-2. Most of them exhibited moderate to weak inhibitory effects with IC50 values in the range of 25.15-88.85 µM except for 9-12.

Gender associations between phthalate exposure and biomarkers of oxidative stress: A prospective cohort study.

Previous epidemiologic research has shown that phthalate exposure in pregnant women is related to adverse birth outcomes in a sex-specific manner. However, the biological mechanism of phthalate exposure that causes these birth outcomes remains poorly defined. In this research, we investigated the association between phthalate exposure and placental oxidative stress in a large population-based cohort study, aiming to initially explore the relationship between phthalate exposure and gene expression in placental oxidative stress in a sex-specific manner. Quantitative PCR was performed to measure the expression of placental inflammatory mRNAs (HO-1, HIF1α, and GRP78) in 2469 placentae. The multiple linear regression models were used to investigate the associations between mRNA and urinary phthalate monoesters. Phthalate metabolites monomethyl phthalate (MMP) and mono-n-butyl phthalate (MBP) were positively correlated with higher HIF1α expression in placentae of male fetuses (p < .05). Mono-benzyl phthalate (MBzP) increased the expression of HO-1, HIF1α, and GRP78 in placentae of male fetuses, and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) up-regulated the expression of HIF1α and GRP78. Additionally, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) was negatively correlated with HO-1, HIF1α, and GRP78 in placentae of female fetuses. Maternal phthalate exposure was associated with oxidative stress variations in placental tissues. The associations were closer in the placentas of male fetuses than in that of female ones. The placenta oxidative stress is worth further investigation as a potential mediator of maternal exposure-induced disease risk in children.

Occurrence and distribution of antibiotics and antibiotic resistance genes from the land to ocean in Daliao River-Liaodong Bay, China.

In this study, the pollution status of antibiotics and ARGs in sediments from the land-sea intersection of Liaodong Bay was analyzed. The results showed that the level of antibiotic pollution ranged from ND to 433.27 ng/kg, with quinolones and tetracycline as the dominant antibiotics. The relative abundance of ARGs ranged from 3.62 × 10-3 to 1.32 × 10-1 copies/16SrRNA copies, with aminoglycoside and MLSB resistance genes being dominant. Regarding spatial distribution, the land and estuary areas showed higher antibiotic pollution levels than the offshore areas. Similarly, the land and estuary areas exhibited higher antibiotic diversity than the offshore areas. The ARGs were widely distributed on land, and their abundance gradually decreased to the downstream estuary area. Land and coastal areas exhibited higher ARG diversity than estuary areas. Analysis of environmental factors revealed a significant correlation between ARGs and non-corresponding antibiotics, and some ARGs were affected by heavy metals Cu and Pb.

Transcriptional and post-transcriptional regulation of chloroplast development by nuclear-localized XAP5 CIRCADIAN TIMEKEEPER.

Chlorophyll biosynthesis and breakdown, important cellular processes for photosynthesis, occur in the chloroplast. As a semi-autonomous organelle, chloroplast development is mainly regulated by nuclear-encoded chloroplast proteins and proteins encoded by itself. However, the knowledge of chloroplast development regulated by other organelles is limited. Here, we report that the nuclear-localized XAP5 CIRCADIAN TIMEKEEPER (XCT) is essential for chloroplast development in Arabidopsis. In this study, significantly decreased chlorophyll content phenotypes of cotyledons and subsequently emerging organs from shoot apical meristem were observed in xct-2. XCT is constitutively expressed in various tissues and localized in the nuclear with speckle patterns. RNA-seq analysis identified 207 differently spliced genes and 1511 differently expressed genes, in which chloroplast development-, chlorophyll metabolism- and photosynthesis-related genes were enriched. Further biochemical assays suggested that XCT was co-purified with the well-known splicing factors and transcription machinery, suggesting dual functions of XCT in gene transcription and splicing. Interestingly, we also found that the chlorophyll contents in xct-2 significantly decreased under high temperature and high light condition, indicating XCT integrates temperature and light signals to fine-tune the chlorophyll metabolism in Arabidopsis. Therefore, our results provide new insights into chloroplast development regulation by XCT, a nuclear-localized protein, at the transcriptional and post-transcriptional level.

Maintenance pembrolizumab therapy in patients with metastatic HER2-negative breast cancer with prior response to chemotherapy.

PURPOSE: Accumulating toxicities hinder indefinite chemotherapy for many patients with metastatic/recurrent HER2-negative breast cancer. We conducted a phase II trial of pembrolizumab monotherapy following induction chemotherapy to determine the efficacy of maintenance immunotherapy in patients with metastatic HER2-negative inflammatory breast cancer (IBC) and non-IBC triple-negative breast cancer (TNBC) and a biomarker study. PATIENTS AND METHODS: Patients with a complete response (CR), partial response (PR), or stable disease (SD) after at least 3 cycles of chemotherapy for HER2-negative breast cancer received pembrolizumab, regardless of programmed death-ligand 1 expression. Pembrolizumab (200 mg) was administered every 3 weeks until disease progression, intolerable toxicity, or 2 years of pembrolizumab exposure. The endpoints included the 4-month disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and response biomarkers in the blood. RESULTS: Of 43 treated patients, 11 had metastatic IBC and 32 non-IBC TNBC. The 4-month DCR was 58.1% (95% CI, 43.4%-72.9%). For all patients, the median PFS was 4.8 months (95% CI, 3.0-7.1 months). The toxicity profile was similar to the previous pembrolizumab monotherapy study. Patients with high T-cell clonality at baseline had a longer PFS with pembrolizumab treatment than did those with low T-cell clonality (10.4 vs. 3.6 months, p = 0.04). Patients who achieved SD also demonstrated a significant increase in T-cell clonality during therapy compared to those who didn't achieve SD (20% vs. 5.9% mean increase, respectively; p = 0.04). CONCLUSIONS: Pembrolizumab monotherapy achieved durable treatment responses. Patients with a high baseline T-cell clonality had prolonged disease control with pembrolizumab.

Effects of low protein diets on acid-base balance, electrolyte balance, intestinal structure, and amino acid transport in piglets.

Reducing the dietary crude protein (CP) could effectively reduce pressure on protein ingredient supplies. However, few data have been reported about the extent to which CP can be reduced and whether limiting the use of soybean meal leads to electrolyte imbalance. In this experiment, using the low protein (LP) diet [2% lower than NRC (2012)], seventy-two piglets (35 days old) were randomly divided into 2 groups with 6 replicates of 6 piglets each: CON group (CP = 18.5%) and LP group (CP = 16.5%), to investigate the effect of the LP diet on electrolyte balance, acid-base balance, intestinal structure and amino acid transport in piglets. The results revealed that the LP diet decreased the average daily gain and dietary CP digestibility, and damaged the villi structure of the small intestine. Compared with the CON diet, the potassium content decreased and the chlorine content increased in the LP diet, and similar trends were shown in piglet serum. The arterial pH, pCO2, HCO3 -, and base excess of piglets in the LP group were lower than those in the CON group, while pO2 was higher than those in the CON group. Interestingly, the LP diet significantly increased the lysine content in piglet serum and significantly decreased the levels of arginine, leucine, and glutamic acid. Furthermore, the LP diet significantly affected the expression of some amino acid transport vectors (B0AT1, EAAC1, and y+LAT1). In summary, these findings suggested that the LP diet leads to acid-base imbalance, amino acid transport disorder and amino acids imbalance in piglets, and the dietary electrolyte may be a key factor in the impact of the LP diet on piglet growth performance and intestinal health.

Augmented Mitochondrial Transfer Involved in Astrocytic PSPH Attenuates Cognitive Dysfunction in db/db Mice.

Diabetes-associated cognitive dysfunction (DACD) has ascended to become the second leading cause of mortality among diabetic patients. Phosphoserine phosphatase (PSPH), a pivotal rate-limiting enzyme in L-serine biosynthesis, has been documented to instigate the insulin signaling pathway through dephosphorylation. Concomitantly, CD38, acting as a mediator in mitochondrial transfer, is activated by the insulin pathway. Given that we have demonstrated the beneficial effects of exogenous mitochondrial supplementation on DACD, we further hypothesized whether astrocytic PSPH could contribute to improving DACD by promoting astrocytic mitochondrial transfer into neurons. In the Morris Water Maze (MWM) test, our results demonstrated that overexpression of PSPH in astrocytes alleviated DACD in db/db mice. Astrocyte specific-stimulated by PSPH lentivirus/ adenovirus promoted the spine density both in vivo and in vitro. Mechanistically, astrocytic PSPH amplified the expression of CD38 via initiation of the insulin signaling pathway, thereby promoting astrocytic mitochondria transfer into neurons. In summation, this comprehensive study delineated the pivotal role of astrocytic PSPH in alleviating DACD and expounded upon its intricate cellular mechanism involving mitochondrial transfer. These findings propose that the specific up-regulation of astrocytic PSPH holds promise as a discerning therapeutic modality for DACD.

Comparison of diagnostic criteria for sepsis-associated acute kidney injury in the pediatric intensive care unit: a retrospective cohort study.

Background: pRIFLE (Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease), KDIGO (Kidney Disease Improving Global Outcomes) and pROCK (Pediatric Reference Change Value Optimized for AKI) are diagnostic criteria used for acute kidney injury (AKI) incidence evaluation. The aim of this study was to explore the diagnostic consistency, incidence and mortality rate, clinical signs, and influencing factors of renal injury related to sepsis in children diagnosed by three different AKI diagnostic criteria, and then evaluate which one was more valuable. Methods: A retrospective analysis was performed on the clinical data of children with severe sepsis. The patients were diagnosed and staged according to the 2007 pRIFLE standard, the 2012 KDIGO standard, and the 2018 pROCK standard. The clinical characteristics and prognosis of children with different stages of sepsis were compared between the three diagnostic standards. Results: A total of 62 patients with sepsis were included. Blood stream infection is common (11 cases, 17.74%). According to pRIFLE, KDIGO, and pROCK standards, the incidence of sepsis-associated AKI (SA-AKI) was 74.2%, 67.7%, and 56.5%, respectively. The pRIFLE had the highest diagnostic rate of early detection of SA-AKI. There was no statistical difference in SA-AKI incidence or staging consistency between the pRIFLE and KDIGO groups (κ=0.0671; κ>0.60); the consistency of SA-AKI diagnoses across the three standards was good (all P values <0.05), and pROCK demonstrated a higher specificity. A high Pediatric Risk of Mortality (PRISM) score and high procalcitonin level were independent risk factors. Shock and renal replacement therapy were independent risk factors for SA-AKI death. Death from admission to 28 days after admission was used as an endpoint to draw a survival graph, which revealed that the AKI group had a significantly higher risk of death than did the non-AKI group. Conclusions: The consistency of diagnosing SA-AKI across the three classification criteria was similar, and mortality rate increased with increased SA-AKI staging. The pRIFLE criteria were more sensitive in the early detection of SA-AKI, while the pROCK had higher specificity. There was no significant difference between the pRIFLE and KDIGO in terms of incidence, diagnosis, or staging of SA-AKI.