Truncated tau interferes with the autophagy and endolysosomal pathway and results in lipid accumulation.

The autophagy-lysosomal pathway plays a critical role in the clearance of tau protein aggregates that deposit in the brain in tauopathies, and defects in this system are associated with disease pathogenesis. Here, we report that expression of Tau35, a tauopathy-associated carboxy-terminal fragment of tau, leads to lipid accumulation in cell lines and primary cortical neurons. Our findings suggest that this is likely due to a deleterious block of autophagic clearance and lysosomal degradative capacity by Tau35. Notably, upon induction of autophagy by Torin 1, Tau35 inhibited nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosomal biogenesis. Both cell lines and primary cortical neurons expressing Tau35 also exhibited changes in endosomal protein expression. These findings implicate autophagic and endolysosomal dysfunction as key pathological mechanisms through which disease-associated tau fragments could lead to the development and progression of tauopathy.

GMFB/AKT/TGF-ß3 in Müller cells mediated early retinal degeneration in a streptozotocin-induced rat diabetes model.

Retinal degeneration, characterized by Müller cell gliosis and photoreceptor apoptosis, is considered an early event in diabetic retinopathy (DR). Our previous study proposed that GMFB may mediate diabetic retinal degeneration. This study identified GMFB as a sensitive and functional gliosis marker for DR. Compared to the wild type (WT) group, Gmfb knockout (KO) significantly improved visual function, attenuated gliosis, reduced the apoptosis of neurons, and decreased the mRNA levels of tumor necrosis factor α (Tnf-α) and interleukin-1ß (Il-1ß) in diabetic retinas. Tgf-ß3 was enriched by hub genes using RNA sequencing in primary WT and KO Müller cells. Gmfb KO significantly upregulated the transforming growth factor (TGF)-ß3 protein level via the AKT pathway. The protective effect of TGF-ß3 in the vitreous resulted in significantly improved visual function and decreased the number of apoptotic cells in the diabetic retina. The protection of Gmfb KO in primary Müller cells against high glucose (HG)-induced photoreceptor apoptosis was partially counteracted by TGF-ß3 antibody and administration of TGFBR1/2 inhibitors. Nuclear receptor subfamily 3 group C member 1 (NR3C1) binds to the promoter region of Gmfb and regulates Gmfb mRNA at the transcriptional level. NR3C1 was increased in the retinas of early diabetic rats but decreased in the retinas of late diabetic rats. N'-[(1E)-(3-Methoxyphenyl)Methylene]-3-Methyl-1H-Pyrazole-5-Carbohydrazide (DS-5) was identified as an inhibitor of GMFB, having a protective role in DR. We demonstrated that GMFB/AKT/TGF-ß3 mediated early diabetic retinal degeneration in diabetic rats. This study provides a novel therapeutic strategy for treating retinal degeneration in patients with DR.

Potential causal links of long-term exposure to PM2.5 and its chemical components with the risk of nasopharyngeal carcinoma recurrence: A 10-year cohort study in South China.

There is a lack of evidence from cohort studies on the causal association of long-term exposure to ambient fine particulate matter (PM2.5) and its chemical components with the risk of nasopharyngeal carcinoma (NPC) recurrence. Based on a 10-year prospective cohort of 1184 newly diagnosed NPC patients, we comprehensively evaluated the potential causal links of ambient PM2.5 and its chemical components including black carbon (BC), organic matter (OM), sulfate (SO4 2-), nitrate (NO3 -), and ammonium (NH4 +) with the recurrence risk of NPC using a marginal structural Cox model adjusted with inverse probability weighting. We observed 291 NPC patients experiencing recurrence during the 10-year follow-up and estimated a 33% increased risk of NPC recurrence (hazard ratio [HR]: 1.33, 95% confidence interval [CI]: 1.02-1.74) following each interquartile range (IQR) increase in PM2.5 exposure. Each IQR increment in BC, NH4 +, OM, NO3 -, and SO4 2- was associated with HRs of 1.36 (95%CI: 1.13-1.65), 1.35 (95%CI: 1.07-1.70), 1.33 (95%CI: 1.11-1.59), 1.32 (95%CI: 1.06-1.64), 1.31 (95%CI: 1.08-1.57). The elderly, patients with no family history of cancer, no smoking history, no drinking history, and those with severe conditions may exhibit a greater likelihood of NPC recurrence following exposure to PM2.5 and its chemical components. Additionally, the effect estimates of the five components are greater among patients who were exposed to high concentration than in the full cohort of patients. Our study provides solid evidence for a potential relationship between long-term exposure to PM2.5 and its components and the risk of NPC recurrence.

Wnt5a/ß-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration.

BACKGROUND: Neovascular age-related macular degeneration (nAMD), accounts for up to 90% of AMD-associated vision loss, ultimately resulting in the formation of fibrotic scar in the macular region. The pathogenesis of subretinal fibrosis in nAMD involves the process of epithelial-mesenchymal transition (EMT) occurring in retinal pigment epithelium (RPE). Here, we aim to investigate the underlying mechanisms involved in the Wnt signaling during the EMT of RPE cells and in the pathological process of subretinal fibrosis secondary to nAMD. METHODS: In vivo, the induction of subretinal fibrosis was performed in male C57BL/6J mice through laser photocoagulation. Either FH535 (a ß-catenin inhibitor) or Box5 (a Wnt5a inhibitor) was intravitreally administered on the same day or 14 days following laser induction. The RPE-Bruch's membrane-choriocapillaris complex (RBCC) tissues were collected and subjected to Western blot analysis and immunofluorescence to examine fibrovascular and Wnt-related markers. In vitro, transforming growth factor beta 1 (TGFß1)-treated ARPE-19 cells were co-incubated with or without FH535, Foxy-5 (a Wnt5a-mimicking peptide), Box5, or Wnt5a shRNA, respectively. The changes in EMT- and Wnt-related signaling molecules, as well as cell functions were assessed using qRT-PCR, nuclear-cytoplasmic fractionation assay, Western blot, immunofluorescence, scratch assay or transwell migration assay. The cell viability of ARPE-19 cells was determined using Cell Counting Kit (CCK)-8. RESULTS: The in vivo analysis demonstrated Wnt5a/ROR1, but not Wnt3a, was upregulated in the RBCCs of the laser-induced CNV mice compared to the normal control group. Intravitreal injection of FH535 effectively reduced Wnt5a protein expression. Both FH535 and Box5 effectively attenuated subretinal fibrosis and EMT, as well as the activation of ß-catenin in laser-induced CNV mice, as evidenced by the significant reduction in areas positive for fibronectin, alpha-smooth muscle actin (α-SMA), collagen I, and active ß-catenin labeling. In vitro, Wnt5a/ROR1, active ß-catenin, and some other Wnt signaling molecules were upregulated in the TGFß1-induced EMT cell model using ARPE-19 cells. Co-treatment with FH535, Box5, or Wnt5a shRNA markedly suppressed the activation of Wnt5a, nuclear translocation of active ß-catenin, as well as the EMT in TGFß1-treated ARPE-19 cells. Conversely, treatment with Foxy-5 independently resulted in the activation of abovementioned molecules and subsequent induction of EMT in ARPE-19 cells. CONCLUSIONS: Our study reveals a reciprocal activation between Wnt5a and ß-catenin to mediate EMT as a pivotal driver of subretinal fibrosis in nAMD. This positive feedback loop provides valuable insights into potential therapeutic strategies to treat subretinal fibrosis in nAMD patients.

LncRNA S100PBP promotes proliferation and steroid hormone synthesis of granulosa cells by sponging MiR-2285bc-BMPR2 in bovine†.

In bovine follicular development, the proliferation of bovine granulosa cells affects follicular selection, atresia, and cystic follicle formation. When cystic follicles appear on the ovaries, granulosa cells stop proliferating, resulting in the reduction of granulosa cells layer. In our previous study, the whole transcriptome sequencing revealed that Bone morphogenetic protein receptor 2 (BMPR2) was differentially expressed between cystic and normal follicular granulosa cells. We speculated that long noncoding RNA may act as competing endogenous RNA targeting microRNAs and then regulating the expression of BMPR2 and the function of granulosa cells, thereby affecting follicular development and cyst formation. In this study, the results elucidated that long noncoding RNA S100PBP (NONBTAT011846.2) directly bound miR-2285bc, which targeted in the BMPR2 3'-UTR. miR-2285bc suppresses granulosa cells proliferation by downregulating BMPR2 expression. Furthermore, long noncoding RNA S100PBP was silenced by small interfering RNA, and long noncoding RNA S100PBP regulated BMPR2 expression by sponging miR-2285bc investigated through cross-verification. When small interfering RNA of long noncoding RNA S100PBP was transfected into granulosa cells, the results revealed similar molecular changes as those transfected with miR-2285bc mimics. Silencing long noncoding RNA S100PBP or overexpressing miR-2285bc altered the expressions of some follicular development-related genes, which could be related to follicular cyst occurrence. In conclusion, our findings support that long noncoding RNA S100PBP regulates the expression of BMPR2 through sponge miR-2285bc, promotes the proliferation of granulosa cells, inhibits their apoptosis, and increases the synthesis and secretion of follicular steroid hormones, thus promoting the development of bovine follicles.

Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

A Propeller-Like Ligand-Directed Construction of a Tetranuclear Cerium-Organic Framework for Single-Step Ethylene Purification from Ternary C2 Mixtures.

The efficient single-step purification of ethylene from ternary C2 mixtures containing ethane and acetylene is challenging and demanding. Herein, we introduce a novel cerium-based metal-organic framework (MOF) of Ce-NTB-rtk synthesized via a ligand-conformer strategy. The Ce-NTB-rtk features a rare tetranuclear cerium cluster and 2D kgd layers pillared by a 3D rtl framework concomitant with an extraordinary (3,3,12)-c network. The compound encompasses microporous cavities replete with a nonpolar microenvironment. Gas sorption and breakthrough experiments demonstrate its superior affinity for C2H6 and C2H2 over C2H4, enabling effective single-step ethylene purification. Computational simulations reveal that preferential adsorptions are facilitated by different interaction strengths of C-H···O hydrogen bonds. The performance of Ce-NTB-rtk in separation selectivity and regeneration capacity makes it a promising candidate for sustainable and cost-effective ethylene purification, showcasing the potential of MOFs in advanced gas separation applications.

Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials.

The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer's disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression.

Single amino acid variation in MAB21L1 is dominantly associated with congenital eye defects.

BACKGROUND: Diagnosis of a genetic disease and determination of the causative molecular lesion rely on the availability of the disease-associated pedigrees. Microphthalmia is a congenital eye defect due to an insufficiently developed visual system; its prevalence is 1-3 in 10 000 live births. OBJECTIVE: We analysed a pedigree exhibiting autosomal dominant inheritance of microphthalmia to determine the genetic lesion; used AlphaFold2 to predict the changes in the protein's 3-Dimensional structure; and compared wild-type and variant proteins in cultured cells or Drosophila model was used to explore the cellular or developmental function of the encoded product. RESULTS: We identified a novel missense variation, F52L, in MAB21L1 that is absent in population databases and present exclusively in the individuals diagnosed with microphthalmia in this pedigree. Common structural changes were predicted for the disease-associated variants clustered at amino acids 49-52, and these variant products were also predominantly trapped in the cytoplasm of cultured human lens epithelia. To recapitulate its dominant effect in development, we expressed the Drosophila homologue corresponding to MAB21L1F52L and caused malformation of sensory organs. CONCLUSION: Mutations at the residues 49-52 of MAB21L1 compromise eye development. We recommend including MAB21L1 in the genetic testing panel for congenital eye disorders.

RNA-seq analysis of small intestine transcriptional changes induced by starvation stress in piglets.

Piglets may experience a variety of stress injuries, but the molecular regulatory mechanisms underlying these injuries are not well understood. In this study, we analysed the ileum of Large White (LW) and Mashen (MS) piglets at different times of starvation using chemical staining and transcriptome analysis. The intestinal barrier of piglets was damaged after starvation stress, but the intestinal antistress ability of MS piglets was stronger than LW piglets. A total of 8021 differentially expressed genes (DEGs) were identified in two breeds. Interestingly, the immune capacity (CHUK, TLR3) of MS piglets increased significantly after short-term starvation stress, while energy metabolism (NAGS, PLA2G12B, AGCG8) was predominant in LW piglets. After long-term starvation stress, the level of energy metabolism (PLIN5, PLA2G12B) was significantly increased in MS piglets. The expression of immune (HLA-DQB1, IGHG4, COL3A1, CD28, LAT) and disease (HSPA1B, MINPPI, ADH1C, GAL3ST1) related genes were significantly increased in two breeds of piglets. These results suggest that short-term stress mainly enhances immunity and energy metabolism in piglets, while long-term starvation produces greater stress on piglets, making it difficult for them to compensate for the damage to their bodies through self-regulation. This information can help improve the stress resistance of piglets through molecular breeding.

Risk of stroke admission after long-term exposure to PM1: Evidence from a large cohort in South China.

BACKGROUND: Limited attention has been paid to the health effects of long-term PM1 exposure on stroke admission. Current investigations exploring the long-term PM exposure effect are largely based on observational studies, and PM generally is not allocated randomly to participants. Using traditional regression models might confuse messaging and hinder policy recommendations for pollution control and disease prevention policies. METHODS: We conducted a cohort study among 36,271 adults from one of the largest cities in China in 2015 and followed up through 2020. Hazard ratios of stroke admissions following long-term PM1 exposure were estimated via a causal inference approach, marginal structural time-varying Cox proportional hazard model, accounting for multiple confounders. Additionally, several sensitivity analyses and impact modification analyses were carried out. RESULTS AND DISCUSSION: Associations with 1 µg/m3 increase in long-term PM1 were identified for total (HR, 1.079; 95 %CI, 1.012-1.151) and ischemic stroke admissions (HR, 1.092; 95 %CI, 1.018-1.171). The harmful associations varied with exposure duration, initially increasing and then decreasing. The 2-3 years cumulative exposure was associated with a 3.3-5.4 % raised risk for total stroke. For every 1 µg/m³ increase in long-term PM1 exposure, females exhibited a higher risk of both total and ischemic stroke (13 % and 16 %) than men (4 % and 5 %). Low-exposure individuals (whose annual PM1 concentrations were under the third quartile among the annual concentrations for all the participants) exhibited greater sensitivity to PM1 effects (total stroke: 1.079 vs. 1.107; ischemic stroke: 1.092 vs. 1.116). The results underline the importance of safeguarding low-exposed people in highly polluted areas and suggest that long-term PM1 exposure may increase stroke admission risk, warranting attention to vulnerable groups.

How long-term PM exposure may affect all-site cancer mortality: Evidence from a large cohort in southern China.

BACKGROUND: Evidence of a potential causal link between long-term exposure to particulate matter (PM) and all-site cancer mortality from large population cohorts remained limited and suffered from residual confounding issues with traditional statistical methods. AIMS: We aimed to examine the potential causal relationship between long-term PM exposure and all-site cancer mortality in South China using causal inference methods. METHODS: We used a cohort in southern China that recruited 580,757 participants from 2009 through 2015 and tracked until 2020. Annual averages of PM1, PM2.5, and PM10 concentrations were generated with validated spatiotemporal models. We employed a causal inference approach, the Marginal Structural Cox model, based on observational data to evaluate the association between long-term exposure to PM and all-site cancer mortality. RESULTS: With an increase of 1 µg/m³ in PM1, PM2.5, and PM10, the hazard ratios (HRs) and 95% confidence interval (CI) for all-site cancer were 1.033 (95% CI: 1.025-1.041), 1.032 (95% CI: 1.027-1.038), and 1.020 (95% CI: 1.016-1.025), respectively. The HRs (95% CI) for digestive system and respiratory system cancer mortality associated with each 1 µg/m³ increase in PM1 were 1.022 (1.009-1.035) and 1.053 (1.038-1.068), respectively. In addition, inactive participants, who never smoked, or who lived in areas of low surrounding greenness were more susceptible to the effects of PM exposure, the HRs (95% CI) for all-site cancer mortality were 1.042 (1.031-1.053), 1.041 (1.032-1.050), and 1.0473 (1.025-1.070) for every 1 µg/m³ increase in PM1, respectively. The effect of PM1 tended to be more pronounced in the low-exposure group than in the general population, and multiple sensitivity analyses confirmed the robustness of the results. CONCLUSION: This study provided evidence that long-term exposure to PM may elevate the risk of all-site cancer mortality, emphasizing the potential health benefits of improving air quality for cancer prevention.

Unveiling causal connections: Long-term particulate matter exposure and type 2 diabetes mellitus mortality in Southern China.

Evidence of the potential causal links between long-term exposure to particulate matters (PM, i.e., PM1, PM2.5, and PM1-2.5) and T2DM mortality based on large cohorts is limited. In contrast, the existing evidence usually suffers from inherent bias with the traditional association assessment. A prospective cohort of 580,757 participants in the southern region of China were recruited during 2009 and 2015 and followed up through December 2020. PM exposure at each residential address was estimated by linking to the well-established high-resolution simulation dataset. Hazard ratios (HRs) were calculated using time-varying marginal structural Cox models, an established causal inference approach, after adjusting for potential confounders. During follow-up, a total of 717 subjects died from T2DM. For every 1 µg/m3 increase in PM2.5, the adjusted HRs and 95% confidence interval (CI) for T2DM mortality was 1.036 (1.019-1.053). Similarly, for every 1 µg/m3 increase in PM1 and PM1-2.5, the adjusted HRs and 95% CIs were 1.032 (1.003-1.062) and 1.085 (1.054-1.116), respectively. Additionally, we observed a generally more pronounced impact among individuals with lower levels of education or lower residential greenness which as measured by the Normalized Difference Vegetation Index (NDVI). We identified substantial interactions between NDVI and PM1 (P-interaction = 0.003), NDVI and PM2.5 (P-interaction = 0.019), as well as education levels and PM1 (P-interaction = 0.049). The study emphasizes the need to consider environmental and socio-economic factors in strategies to reduce T2DM mortality. We found that PM1, PM2.5, and PM1-2.5 heighten the peril of T2DM mortality, with education and green space exposure roles in modifying it.

Response of phosphorus fractions transformation and microbial community to carbon-to-phosphorus ratios during sludge composting.

Phosphorus (P) is one of the essential nutrient elements for plant growth and development. Sludge compost products can be used as an important source of soil P to solve the shortage of soil P. The difference in the initial carbon-to-phosphorus ratio (C/P) will lead to difference in the bacterial community, which would affect the biological pathway of P conversion in composting. However, few studies have been reported on adjusting the initial C/P of composting to explore P conversion. Therefore, this study investigated the response of P component transformations, bacterial community and P availability to C/P during sludge composting by adjusting initial C/P. The results showed that increasing C/P promoted the mineralization of organic P and significantly increased the content of the labile P. High C/P also increased the relative content of available P, especially when the C/P was at 45 and 60, it reached 60.51% and 60.47%. High C/P caused differences in the community structure, and improved the binding ability of microbial network modules and the competitiveness of microbial communities. Additionally, high C/P strengthened the effect of microbial communities on the transformation of P components. Finally, the study showed that C/P was the main contributor to P content variation (64.7%) and indirectly affected P component conversion by affecting the microbial community. Therefore, adjusting the C/P is crucial to improve the P utilization rate of composting products.

Molecular pathogenesis of subretinal fibrosis in neovascular AMD focusing on epithelial-mesenchymal transformation of retinal pigment epithelium.

Age-related macular degeneration (AMD) is a leading cause of vision loss among elderly people in developed countries. Neovascular AMD (nAMD) accounts for more than 90% of AMD-related vision loss. At present, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is widely used as the first-line therapy to decrease the choroidal and retinal neovascularizations, and thus to improve or maintain the visual acuity of the patients with nAMD. However, about 1/3 patients still progress to irreversible visual impairment due to subretinal fibrosis even with adequate anti-VEGF treatment. Extensive literatures support the critical role of epithelial-mesenchymal transformation (EMT) of retinal pigment epithelium (RPE) in the pathogenesis of subretinal fibrosis in nAMD, but the underlying mechanisms still remain largely unknown. This review summarized the molecular pathogenesis of subretinal fibrosis in nAMD, especially focusing on the transforming growth factor-ß (TGF-ß)-induced EMT pathways. It was also discussed how these pathways crosstalk and respond to signals from the microenvironment to mediate EMT and contribute to the progression of nAMD-related subretinal fibrosis. Targeting EMT signaling pathways might provide a promising and effective therapeutic strategy to treat subretinal fibrosis secondary to nAMD.

Deep learning for precise axial localization of trapped microspheres in reflective optical systems.

High-precision axial localization measurement is an important part of micro-nanometer optical measurement, but there have been issues such as low calibration efficiency, poor accuracy, and cumbersome measurement, especially in reflected light illumination systems, where the lack of clarity of imaging details leads to the low accuracy of commonly used methods. Herein, we develop a trained residual neural network coupled with a convenient data acquisition strategy to address this challenge. Our method improves the axial localization precision of microspheres in both reflective illumination systems and transmission illumination systems. Using this new localization method, the reference position of the trapped microsphere can be extracted from the identification results, namely the "positioning point" among the experimental groups. This point relies on the unique signal characteristics of each sample measurement, eliminates systematic repeatability errors when performing identification across samples, and improves the localization precision of different samples. This method has been verified on both transmission and reflected illumination optical tweezers platforms. We will bring greater convenience to measurements in solution environments and will provide higher-order guarantees for force spectroscopy measurements in scenarios such as microsphere-based super-resolution microscopy and the surface mechanical properties of adherent flexible materials and cells.

Effects of BAMBI on luteinized follicular granulosa cell proliferation and steroid hormone production in sheep.

Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) regulates mammalian ovarian follicle growth and maturation; however, its effect on luteinized granulosa cells (LGCs) in sheep ovarian follicles remains unknown. Here we explored the regulatory role of LGC functions and steroid hormone synthesis by BAMBI. Multiple sequence alignment revealed that the sheep BAMBI gene sequence was relatively conserved. Sheep LGCs were strongly positive for BAMBI. LGC proliferation increased when BAMBI was silenced and decreased when BAMBI was overexpressed. After BAMBI overexpression, the expression of CASP3, CASP8, CASP9, and BAX significantly increased, whereas that of BCL2 and the ratio of BCL2/BAX expression decreased. The opposite was observed after BAMBI silencing. CDKN1A, CCND1, and CCND2 were downregulated with BAMBI overexpression and upregulated with BAMBI silencing. Expression of steroid hormone-related genes (CYP11A1, STAR, and 3BHSD), except CYP19A1, significantly increased after BAMBI overexpression. Moreover, estrogen and progesterone secretion increased after BAMBI overexpression and decreased after BAMBI interference. The effect of the exogenous addition of bone morphogenetic protein 2 (BMP2) on GCs was similar to that of BAMBI overexpression. In conclusion, BAMBI can regulate the proliferation and steroid hormone synthesis of sheep LGCs, and BMP2 can affect LGCs as an activator of BAMBI. These findings provide a basis for further research on the physiological role of BAMBI.

Modifying the Fiber Structure and Filtration Performance of Polyester Materials Based on Two Different Preparation Methods.

How to build a satisfactory indoor environment has become increasingly important. In this paper, the synthesis and improvement of the most widely used polyester materials in China were carried out based on two different preparation methods, and the structures and filtration performances were tested and analyzed. The results showed that a carbon black coating was wrapped on the surfaces of the new synthetic polyester filter fibers. Compared with the original materials, the filtration efficiencies of PM10, PM2.5, and PM1 were increased by 0.88-6.26, 1.68-8.78, and 0.42-4.84%, respectively. The best filtration velocity was 1.1 m/s, and the new synthetic polyester materials with direct impregnation demonstrated superior filtration performance. The filtration efficiency of the new synthetic polyester materials was improved on the particulates with sizes of 1.0-5.0 µm. The filtration performance of G4 was better than that of G3. The filtration efficiencies of PM10, PM2.5, and PM1 were improved by 4.89, 4.20, and 11.69%, respectively. The quality factor value can be used to assess the comprehensive filtration performance of air filters in practical applications. It could provide reference values for the selection of synthetic methods of new filter materials.

Aquaporin 11 alleviates retinal Müller intracellular edema through water efflux in diabetic retinopathy.

Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear functions. This study aims to explore the role of AQP11 in the pathogenesis of intracellular edema of Müller glia in diabetic retinopathy (DR). Here, we found that AQP11 expression, primarily located at the endfeet of Müller glia, was down-regulated with diabetes progression, accompanied by intracellular edema, which was alleviated by intravitreal injection of lentivirus-mediated AQP11 overexpression. Similarly, intracellular edema of hypoxia-treated rat Müller cell line (rMC-1) was aggravated by AQP11 inhibition, while attenuated by AQP11 overexpression, accompanied by enhanced function in glutamate metabolism and reduced cell death. The down-regulation of AQP11 was also verified in the Müller glia from the epiretinal membranes (ERMs) of proliferative DR (PDR) patients. Mechanistically, down-regulation of AQP11 in DR was mediated by the HIF-1α-dependent and independent miRNA-AQP11 axis. Overall, we deciphered the AQP11 down-regulation, mediated by miRNA-AQP11 axis, resulted in Müller drainage dysfunction and subsequent intracellular edema in DR, which was partially reversed by AQP11 overexpression. Our findings propose a novel mechanism for the pathogenesis of DME, thus targeting AQP11 regulation provides a new therapeutic strategy for DME.

Comprehensive Bibliometric Analysis of Stem Cell Research in Alzheimer's Disease from 2004 to 2022.

INTRODUCTION: Stem cell-based regenerative medicine has provided an excellent opportunity to investigate therapeutic strategies and innovative treatments for Alzheimer's disease (AD). However, there is an absence of visual overviews to assess the published literature systematically. METHODS: In this review, the bibliometric approach was used to estimate the searched data on stem cell research in AD from 2004 to 2022, and we also utilized CiteSpace and VOSviewer software to evaluate the contributions and co-occurrence relationships of different countries/regions, institutes, journals, and authors as well as to discover research hot spots and encouraging future trends in this field. RESULTS: From 2004 to 2022, a total of 3,428 publications were retrieved. The number of publications and citations on stem cell research in AD has increased dramatically in the last nearly 20 years, especially since 2016. North America and Asia were the top 2 highest output regions. The leading country in terms of publications and access to collaborative networks was the USA. Centrality analysis revealed that the UCL (0.05) was at the core of the network. The Journal of Alzheimer's Disease (n = 102, 2.98%) was the most productive academic journal. The analyses of keyword burst detection indicated that exosomes, risk factors, and drug delivery only had burst recently. Citations and co-citation achievements clarified that cluster #0 induced pluripotent stem cells, #2 mesenchymal stem cells, #3 microglia, and #6 adult hippocampal neurogenesis persisted to recent time. CONCLUSION: This bibliometric analysis provides a comprehensive guide for clinicians and scholars working in this field. These analysis and results hope to provide useful information and references for future understanding of the challenges behind translating underlying stem cell biology into novel clinical therapeutic potential in AD.