Metagenomic analysis reveals ecological and functional signatures of oral phageome associated with severe early childhood caries.

OBJECTIVES: Severe early childhood caries (S-ECC) is highly prevalent, affecting children's oral health. S-ECC development is closely associated with the complex oral microbial microbiome and its microorganism interactions, such as the imbalance of bacteriophages and bacteria. Till now, little is known about oral phageome on S-ECC. Therefore, this study aimed to investigate the potential role of the oral phageome in the pathogenesis of S-ECC. METHODS: Unstimulated saliva (2 mL) was collected from 20 children with and without S-ECC for metagenomics analysis. Metagenomics sequencing and bioinformatic analysis were performed to determine the two groups' phageome diversity, taxonomic and functional annotations. Statistical analysis and visualization were performed with R and SPSS Statistics software. RESULTS: 85.7 % of the extracted viral sequences were predicted from phages, in which most phages were classified into Myoviridae, Siphoviridae, and Podoviridae. Alpha diversity decreased, and Beta diversity increased in the S-ECC phageome compared to the healthy group. The abundance of Podoviridae phages increased, and the abundance of Inoviridae, Herelleviridae, and Streptococcus phages decreased in the S-ECC group. Functional annotation revealed increased annotation on glycoside hydrolases and nucleotide metabolism, decreased glycosyl transferases, carbohydrate-binding modules, and biogenic metabolism in the S-ECC phageome. CONCLUSIONS: Metagenomic analysis revealed reduced Streptococcus phages and significant changes in functional annotations within the S-ECC phageome. These findings suggest a potential weakening of the regulatory influence of oral bacteria, which may indicate the development of innovative prevention and treatment strategies for S-ECC. These implications deserve further investigation and hold promise for advancing our understanding and management of S-ECC. CLINICAL SIGNIFICANCE: The findings of this study indicate that oral phageomes are associated with bacterial genomes and metabolic processes, affecting the development of S-ECC. The reduced modulatory effect of the oral phageome in counteracting S-ECC's cariogenic activity suggests a new avenue for the prevention and treatment of S-ECC.

Identification and validation of immune and cuproptosis - related genes for diabetic nephropathy by WGCNA and machine learning.

Background: As the leading cause of chronic kidney disease, diabetic kidney disease (DKD) is an enormous burden for all healthcare systems around the world. However, its early diagnosis has no effective methods. Methods: First, gene expression data in GEO database were extracted, and the differential genes of diabetic tubulopathy were obtained. Immune-related genesets were generated by WGCNA and immune cell infiltration analyses. Then, differentially expressed immune-related cuproptosis genes (DEICGs) were derived by the intersection of differential genes and genes related to cuproptosis and immune. To investigate the functions of DEICGs, volcano plots and GO term enrichment analysis was performed. Machine learning and protein-protein interaction (PPI) network analysis helped to finally screen out hub genes. The diagnostic efficacy of them was evaluated by GSEA analysis, receiver operating characteristic (ROC) curve, single-cell RNA sequencing and the Nephroseq website. The expression of hub genes at the animal level by STZ -induced and db/db DKD mouse models was further verified. Results: Finally, three hub genes, including FSTL1, CX3CR1 and AGR2 that were up-regulated in both the test set GSE30122 and the validation set GSE30529, were screened. The areas under the curve (AUCs) of ROC curves of hub genes were 0.911, 0.935 and 0.922, respectively, and 0.946 when taking as a whole. Correlation analysis showed that the expression level of three hub genes demonstrated their negative relationship with GFR, while those of FSTL1 displayed a positive correlation with the level of serum creatinine. GSEA was enriched in inflammatory and immune-related pathways. Single-nucleus RNA sequencing indicated the main distribution of FSTL1 in podocyte and mesangial cells, the high expression of CX3CR1 in leukocytes and the main localization of AGR2 in the loop of Henle. In mouse models, all three hub genes were increased in both STZ-induced and db/db DKD models. Conclusion: Machine learning was combined with WGCNA, immune cell infiltration and PPI analyses to identify three hub genes associated with cuproptosis, immunity and diabetic nephropathy, which all have great potential as diagnostic markers for DKD and even predict disease progression.

Dietary protein, lipid and insect meal on growth, plasma biochemistry and hepatic immune expression of lake whitefish (Coregonus clupeaformis).

Studies are lacking that investigate the dietary nutrient requirements of lake whitefish (Coregonus clupeaformis), a newly farmed fish species in Ontario, Canada. Dietary levels of protein and lipid must be optimized to ensure high growth performance for the commercial success of this species. Additionally, the inclusion of insect meal in the diet may improve growth and immune response. The objective of this study was to evaluate the effects of dietary protein:lipid ratios and insect meal as a feed additive on the growth performance and hepatic immune function of juvenile lake whitefish (301 ± 10 g). A 16-week (112 day) trial was performed with five diets including a commercial control diet (BCC), and four experimental diets with high or low levels of protein (54 and 48%, respectively) and lipid (18 and 12%, respectively). The high protein dietary groups contained 5% of full-fat black soldier fly larvae (Hermetia illucens). Fish weights, viscera, liver, and blood were collected for further analysis. Specific growth rate, thermal growth coefficient and weight gain were significantly higher in fish fed with the BCC and high protein high lipid (HPHL) diets. However, viscerosomatic index was found to be significantly higher in fish fed the BCC diet, thus HPHL is more optimal for non-visceral weight gain. Higher levels of plasma phosphorus, aspartate aminotransferase and potassium indicated poor growth and stress in fish fed low lipid diets. Relative expression of HSP70, involved in cellular repair, was significantly downregulated in fish fed high lipid diets, and no effects were found on the expression of innate immune and oxidative stress genes. Also, IL8 (CXCL8) and catalase were upregulated (non-significant) in fish fed the HPHL diet with the largest weight gain. No effects of insects were found on growth, plasma biochemistry or gene expression, which suggests 5% dietary inclusion was too low. Overall, we recommend a HPHL diet for the cultivation of lake whitefish based on improved growth performance, low viscera weight, improved plasma biochemistry and downregulation of cellular repair genes.

How does social media use influence the mental health of pancreatic cancer patients: a chain mediating effect of online social support and psychological resilience.

Background: Pancreatic cancer is an extremely malignant disease that poses a serious threat to the mental health of patients. Many cancer patients now use social media for online social support. However, the impact of social media on mental health is currently inconsistent in the academic community. Therefore, this study aimed to examine the mediating effects of online social support and psychological resilience in the relationship between social media use and mental health of pancreatic cancer patients. Methods: Four hundred and twenty-five valid questionnaires were collected through convenience sampling. All data were processed using SPSS 26.0 and AMOS 26.0. We examine the influence relationships among latent variables by constructing a structural equation model. Then SPSS Process Macro was used to test the chain mediating effect of the model. Results: The results showed that (1) anxiety situations occurred in 22.2% of participants (N = 94), while the incidence of depression was 20.2% (N = 86). (2) Social media use positively influenced online social support (ß = 0.990, p < 0.001), psychological resilience (ß = 0.504, p < 0.001), and mental health (ß = 0.330, p < 0.001); online social support positively influenced psychological resilience (ß = 0.535, p < 0.001) and mental health (ß = 0.354, p < 0.001); psychological resilience significantly and positively influenced mental health (ß = 0.243, p < 0.001). (3) The chain mediating effect of online social support and psychological resilience was significant at 0.253 with a confidence interval of [0.178, 0.340]. Conclusion: Pancreatic cancer patients in China are exposed to a high burden of anxiety and depression, which requires urgent attention. Meanwhile, online social support and psychological resilience played a chain mediating role between social media use and mental health (anxiety and depression), and our results provide new insights and ways to support the mental health improvement of pancreatic cancer patients.

Structural and functional differences of the thalamus between drug-naïve Parkinson's disease motor subtypes.

Objective: The thalamus is an integrative hub of motor circuits in Parkinson's disease (PD). This study aimed to investigate the alterations of structure and functional connectivity (FC) of the thalamic subregions in the tremor-dominant (TD) subtype and the postural instability and gait difficulty (PIGD) subtype in PD. Methods: A total of 59 drug-naïve patients (24 TD and 35 PIGD) and 37 healthy controls were recruited. The volumes of the thalamus and the thalamic subregions were calculated using FreeSurfer. Functional connectivity (FC) analysis of the resting-state functional MRI (rsfMRI) was conducted on the thalamic subregions. Finally, the altered structure and FC were used for correlation analysis with clinical motor scores and for further motor subtypes differentiation. Results: The volumes of the left posterior parietal thalamus (PPtha) in TD patients were significantly lower than those of PIGD patients. Compared with PIGD patients, TD patients exhibited higher FC between the thalamic subregions, the left middle temporal gyrus (MTG), the right dorsolateral superior frontal gyrus (SFGdl), the left middle occipital gyrus (MOG), and the right superior temporal gyrus (STG). Compared with HCs, TD patients showed higher FC between the thalamic subregions and the right SFGdl, as well as the left MOG. Compared with HCs, PIGD patients showed lower FC between the thalamic subregions and the left MTG. In addition, the altered FC was closely related to clinical symptoms and performed high-discriminative power in differentiating the motor subtypes. Conclusion: Increased FC between the thalamic subregions and the sensory cortices in TD patients may indicate a better compensatory capacity for impairment of sensory information integration than that in PIGD patients. The altered FC between the thalamus and the MTG was a potential biomarker for the distinction of the PD motor subtypes.

Isolation and characterization of a novel phage belonging to a new genus against Vibrio parahaemolyticus.

BACKGROUND: Vibrio parahaemolyticus is a major foodborne pathogen that contaminates aquatic products and causes great economic losses to aquaculture. Because of the emergence of multidrug-resistant V. parahaemolyticus strains, bacteriophages are considered promising agents for their biocontrol as an alternative or supplement to antibiotics. In this study, a lytic vibriophage, vB_VpaM_R16F (R16F), infecting V. parahaemolyticus 1.1997T was isolated, characterized and evaluated for its biocontrol potential. METHODS: A vibriophage R16F was isolated from sewage from a seafood market with the double-layer agar method. R16F was studied by transmission electron microscopy, host range, sensitivity of phage particles to chloroform, one-step growth curve and lytic activity. The phage genome was sequenced and in-depth characterized, including phylogenetic and taxonomic analysis. RESULTS: R16F belongs to the myovirus morphotype and infects V. parahaemolyticus, but not nine other Vibrio spp. As characterized by determining its host range, one-step growth curve, and lytic activity, phage R16F was found to highly effective in lysing host cells with a short latent period (< 10 min) and a small burst size (13 plaque-forming units). R16F has a linear double-stranded DNA with genome size 139,011 bp and a G + C content of 35.21%. Phylogenetic and intergenomic nucleotide sequence similarity analysis revealed that R16F is distinct from currently known vibriophages and belongs to a novel genus. Several genes (e.g., encoding ultraviolet damage endonuclease and endolysin) that may enhance environmental competitiveness were found in the genome of R16F, while no antibiotic resistance- or virulence factor-related gene was detected. CONCLUSIONS: In consideration of its biological and genetic properties, this newly discovered phage R16F belongs to a novel genus and may be a potential alternate biocontrol agent.

Actinobacillus pleuropneumoniae FliY and YdjN are involved in cysteine/cystine utilization, oxidative resistance, and biofilm formation but are not determinants of virulence.

Introduction: Actinobacillus pleuropneumoniae (A. pleuropneumoniae) is a member of Actinobacillus in family Pasteurellaceae. It is the causative agent of porcine pleuropneumonia, which has caused huge economic losses to pig industry over the world. Cysteine is a precursor of many important biomolecules and defense compounds in the cell. However, molecular mechanisms of cysteine transport in A. pleuropneumoniae are unclear. Methods: In this study, gene-deleted mutants were generated and investigated, to reveal the roles of potential cysteine/cystine transport proteins FliY and YdjN of A. pleuropneumoniae. Results: Our results indicated that the growth of A. pleuropneumoniae was not affected after fliY or ydjN single gene deletion, but absence of both FliY and YdjN decreased the growth ability significantly, when cultured in the chemically defined medium (CDM) supplemented with cysteine or cystine as the only sulfur source. A. pleuropneumoniae double deletion mutant ΔfliYΔydjN showed increased sensitivity to oxidative stress. Besides, trans-complementation of YdjN into ΔfliYΔydjN and wild type leads to increased biofilm formation in CDM. However, the virulence of ΔfliYΔydjN was not attenuated in mice or pigs. Discussion: These findings suggest that A. pleuropneumoniae FliY and YdjN are involved in the cysteine/cystine acquisition, oxidative tolerance, and biofilm formation, but not contribute to the pathogenicity of A. pleuropneumoniae.

Activation of ROS-PERK-TFEB by filbertone ameliorates neurodegenerative diseases via enhancing the autophagy-lysosomal pathway.

The molecular mechanisms underlying the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease remain enigmatic, resulting in an unmet need for therapeutics development. Here, we suggest that filbertone, a key flavor compound found in the fruits of hazel trees of the genus Corylus, can ameliorate PD via lowering the abundance of aggregated α-synuclein. We previously reported that inhibition of hypothalamic inflammation by filbertone is mediated by suppression of nuclear factor kappa-B. Here, we report that filbertone activates PERK through mitochondrial reactive oxygen species production, resulting in the increased nuclear translocation of transcription factor-EB in SH-SY5Y human neuroblastoma cells. TFEB activation by filbertone promotes the autophagy-lysosomal pathway, which in turn alleviates the accumulation of α-synuclein. We also demonstrate that filbertone prevented the loss of dopaminergic neurons in the substantia nigra and striatum of mice on high-fat diet. Filbertone treatment also reduced high-fat diet-induced α-synuclein accumulation through upregulation of the autophagy-lysosomal pathway. In addition, filbertone improved behavioral abnormalities (i.e., latency time to fall and decrease of running distance) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD murine model. In conclusion, filbertone may show promise as a potential therapeutic for neurodegenerative disease.

Sintering, Microstructure, and Mechanical Properties of TiTaNbZrHf High-Entropy Alloys Prepared by Cold Isostatic Pressing and Pressure-Less Sintering of Hydrides.

A TiTaNbZrHf refractory high-entropy alloy (RHEA) was synthesized through a cold isostatic pressing and a pressure-less sintering process in a hydrogen atmosphere using a powder mixture of metal hydride prepared either by mechanical alloying (MA) or by rotating mixing. This study investigates how differences in powder particle sizes impact the RHEA's microstructure and mechanical properties. HCP (a = b = 3.198 Å, c = 5.061 Å) and BCC2 (a = b = c = 3.40 Å) phases were observed in the microstructure of coarse powder TiTaNbZrHf RHEAs at 1400 °C. In contrast, fine powder RHEAs were found to possess two-phase structures of HCP and BCC1 (a = b = c = 3.36 Å) with a higher hardness of 431 HV, compression strength of 1620 MPa, and a plasticity of >20%.

Dual-response fluorescent probe based on nitrogen-doped carbon dots and europium ions hybrid for ratiometric and on-site visual determination of oxytetracycline and tetracycline.

Tetracyclines residues, particularly oxytetracycline (OTC) and tetracycline (TC), have raised extensive concern because of their serious adverse effects on human health. Herein, a dual-response fluorescent probe based on nitrogen-doped carbon dots (N-CDs) and Eu3+ hybrid (N-CDs-Eu3+) was developed to selectively determine OTC and TC. The N-CDs act as ancillary ligands of Eu3+ and recognition units of OTC/TC, while the Eu3+ ions chelated with N-CDs can also specifically recognize OTC/TC. Upon inclusion of OTC/TC, an enhancement in Eu3+ emission occurs due to the energy transfer from OTC/TC to Eu3+ and the efficient elimination of quenching effect caused by H2O molecule, which is attributed to the incorporation of N-CDs; while the blue fluorescence emitted by the N-CDs decreases under the inner filter effect and static quenching effect caused by OTC/TC. Based on the double and reverse response signals, the ratiometric detection of OTC and TC in the range of 0.1-45 µΜ and 0.1-30 µΜ is achieved with a detection limit of 0.017 and 0.041 µM, respectively. In addition, the noticeable variation in fluorescence color of the probe is integrated with a smartphone-assisted analysis device for the rapid on-site quantitative assay of OTC, where the detection limit is 0.15 µΜ. The results show that this probe performs with excellent specificity and anti-interference for both OTC and TC, and satisfactory detection results are obtained in lake water, milk, and honey samples, thereby confirming that the probe exhibits promising application in food safety and environmental monitoring.

A Highly Sensitive and Selective Nano-Fluorescent Probe for Ratiometric and Visual Detection of Oxytetracycline Benefiting from Dual Roles of Nitrogen-Doped Carbon Dots.

The specific detection of oxytetracycline (OTC) residues is significant for food safety and environmental monitoring. However, rapid specific determination of OTC from various tetracyclines is still challenging due to their similar chemical structures. Here, nitrogen-doped carbon dots (NCDs) with excitation and pH-dependent optical properties and a high-fluorescence quantum yield were successfully synthesized, which were directly employed to fabricate a dual-response fluorescence probe by self-assembly with Eu3+ (NCDs/Eu3+) for the ratiometric determination of OTC. The addition of OTC into the probe greatly enhances the characteristic emission of Eu3+ due to the "antenna effect", and the incorporation of NCDs into the probe further improves the Eu3+ fluorescence by remarkably weakening the quenching effect caused by H2O molecules and efficiently shortening the distance of energy transfer from OTC to Eu3+. Meanwhile, the fluorescence of NCDs apparently decreases due to aggregation-caused quenching. The results demonstrate that a ratiometric detection of OTC (0.1-25 µM) with a detection limit of 29 nM based on the double response signals is achieved. Additionally, visual semi-quantitative assay of OTC can be realized with the naked eye under a 365 nm UV lamp according to the fluorescence color change of the as-fabricated probe. This probe exhibits acceptable specificity and anti-interference for OTC assay, holding promise for the fast detection of OTC in real water and milk samples.

Integrated Clinical Features with Plasma and Multi-modal Neuroimaging Biomarkers to Diagnose Mild Cognitive Impairment in Early Drug-Naive Parkinson's Disease.

The pathogenesis of cognitive impairment in Parkinson's disease (PD) patients remains unclear, and there is no ideal diagnostic tool available at present. We assessed integrated clinical features with plasma and multi-modal neuroimaging biomarkers to identify mild cognitive impairment (MCI) in early drug-naive PD patients. 49 early drug-naive PD patients, including 26 with MCI (PD-MCI) and 23 with normal cognition (PD-NC), and 20 controls were recruited. Plasma markers [α-synuclein, beta-amyloid 1-40 (Aß40), beta-amyloid 1-42 (Aß42), and phosphorylated Tau 181 (p-Tau181) levels], functional connectivity (FC) of the default mode network, and cortical thickness (CTh) were evaluated to identify PD-MCI. The PD-MCI group had significantly higher plasma p-Tau181 levels and p-Tau181/Aß42 ratio and lower Aß42/Aß40 ratio compared to the PD-NC group. Compared to PD-NC, the PD-MCI group showed increased FC between left posterior cingulate cortex (pCC) and the left parahippocampal gyrus (PHG), and between the right hippocampal formation and the left anterior cingulate and paracingulate gyri, and the right middle temporal gyrus. Additionally, the PD-MCI group had thinner cortex thickness in the right lateral occipital and frontal pole compared to the PD-NC group. The final model combining clinical characteristics and several variables (age, sex, plasma p-Tau181 level, Aß42/Aß40 ratio, the right lateral occipital CTh, and the FC value between the left pCC and left PHG) had the highest diagnostic accuracy for PD-MCI (AUC = 0.987, 95% CI 0.903-1.000; p = 0.001 compared to age and sex alone). The combination of clinical features, plasma biomarkers, and multi-modal neuroimaging biomarkers can identify early cognitive decline in PD patients.

The Illness Experience of Long COVID Patients: A Qualitative Study Based on the Online Q&A Community Zhihu.

Long COVID is a public health problem that cannot be ignored, and it is critical to understand the long COVID patients' living situations and support this group through their illness narratives. This study is based on grounded theory, and coded the self-produced texts of long COVID patients on the largest online Q&A community in China, Zhihu APP, in an attempt to explore the illness experiences of long COVID patients in China and to understand how they adapt to their illness and reconstruct their lives. The results show that patients face not only the threat of pain from the illness itself, but also social stigma and discrimination. Patients turn their illness experiences into motivation to move forward and reconstruct self and life by 'pushing forward the biographical flows again', 'impression management' and 'self-compassion'. These findings can help policy-makers and medical institutions to provide timely and appropriate policy support and psychological assistance to patients with long COVID, to create a supportive and inclusive social environment, and to reduce discrimination and stigma against them.

Hypoxia signaling in human health and diseases: implications and prospects for therapeutics.

Molecular oxygen (O2) is essential for most biological reactions in mammalian cells. When the intracellular oxygen content decreases, it is called hypoxia. The process of hypoxia is linked to several biological processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, and other stress responses. The mechanism underlying cells respond to oxygen changes to mediate subsequent signal response is the central question during hypoxia. Hypoxia-inducible factors (HIFs) sense hypoxia to regulate the expressions of a series of downstream genes expression, which participate in multiple processes including cell metabolism, cell growth/death, cell proliferation, glycolysis, immune response, microbe infection, tumorigenesis, and metastasis. Importantly, hypoxia signaling also interacts with other cellular pathways, such as phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) signaling, and endoplasmic reticulum (ER) stress. This paper systematically reviews the mechanisms of hypoxia signaling activation, the control of HIF signaling, and the function of HIF signaling in human health and diseases. In addition, the therapeutic targets involved in HIF signaling to balance health and diseases are summarized and highlighted, which would provide novel strategies for the design and development of therapeutic drugs.

HtrA of Actinobacillus pleuropneumoniae is a virulence factor that confers resistance to heat shock and oxidative stress.

Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia, which is a severe and often fatal disease that results in significant economic loss. The means by which A. pleuropneumoniae survives within the host are not clear. High temperature requirement A (HtrA) proteases have been shown to affect cell viability during stressful conditions and are virulence factors in many bacterial species. In this study, we examined the biological role of HtrA during A. pleuropneumoniae infection by analyzing the impact of htrA mutation on virulence-associated phenotypes. We found that htrA mutation had a dramatic impact on stress tolerance. The htrA mutant (ΔhtrA) displayed a lethal phenotype at elevated temperature (42 °C). Further, ΔhtrA exhibited increased susceptibility to H2O2-induced oxidative stress when compared to the parental strain (SLW01) and a complementation strain (ΔhtrA-Compl). Animal infection assays demonstrated that absence of HtrA led to decreased in vivo colonization ability, and ΔhtrA is less virulent in pigs relative to SLW01. Furthermore, pig competitive infection assays demonstrated fewer blood associated CFUs with ΔhtrA infection than with SLW01. These results demonstrate HtrA plays a significant role in the survival and growth of A. pleuropneumoniae during stressful conditions, and that immune escape and invasiveness are important to the process of A. pleuropneumoniae infection.

A smartphone-integrated light-up lanthanide fluorescent probe for the visual and ratiometric detection of total phosphorus in human urine and environmental water samples.

Phosphate (Pi) plays an essential role in aquatic ecosystems as well as in physiological processes. Here, a dual-emission probe for the sensitive, specific and visual analysis of Pi is fabricated by coordinating Eu3+ with luminol and 2,6-pyridinedicarboxylic acid (DPA). Pi can significantly enhance the characteristic fluorescence of Eu3+ at 615 nm by promoting energy transfer from DPA to Eu3+ and reducing the quenching effect of water molecule, luminol with inherent emission at 423 nm further enhances the Eu3+ fluorescence. Accordingly, ratiometric detection of Pi can be achieved with the fluorescence ratio F615/F423 as a function of Pi concentration. Linearity between F615/F423 and Pi concentration in the range of 0.1-25 µM is shown, and the limit of detection (LOD, 3σ/K) for Pi is 0.027 µM. In addition, a continuous change in the fluorescence color of the probe from blue to red is observed with increasing Pi concentration under a UV lamp, and a smartphone-based visual method is used for the convenient and effective semi-quantitative determination of Pi. The dual-emission probe has been successfully applied to ratiometric and visual analysis of Pi in human urine and environmental water samples, and adequate results are obtained.

Altered Neural Network Connectivity Predicts Depression in de novo Parkinson's Disease.

Background: Depression, one of the most frequent non-motor symptoms in Parkinson's disease (PD), was proposed to be related to neural network dysfunction in advanced PD patients. However, the underlying mechanisms in the early stage remain unclear. The study was aimed to explore the alterations of large-scale neural networks in de novo PD patients with depression. Methods: We performed independent component analysis (ICA) on the data of resting-state functional magnetic resonance imaging from 21 de novo PD patients with depression (dPD), 34 de novo PD patients without depression (ndPD), and 43 healthy controls (HCs) to extract functional networks. Intranetwork and internetwork connectivity was calculated for comparison between groups, correlation analysis, and predicting the occurrence of depression in PD. Results: We observed an ordered decrease of connectivity among groups within the ventral attention network (VAN) (dPD < ndPD < HCs), mainly located in the left middle temporal cortex. Besides, dPD patients exhibited hypoconnectivity between the auditory network (AUD) and default mode network (DMN) or VAN compared to ndPD patients or healthy controls. Correlation analysis revealed that depression severity was negatively correlated with connectivity value within VAN and positively correlated with the connectivity value of AUD-VAN in dPD patients, respectively. Further analysis showed that the area under the curve (AUC) for dPD prediction was 0.863 when combining the intranetwork connectivity in VAN and internetwork connectivity in AUD-DMN and AUD-VAN. Conclusion: Our results demonstrated that early dPD may be associated with abnormality of attention bias and especially auditory attention processing. Altered neural network connectivity is expected to be a potential neuroimaging biomarker to predict depression in PD.

PERK activation by SB202190 ameliorates amyloidogenesis via the TFEB-induced autophagy-lysosomal pathway.

The protein kinase R (PKR)-like endoplasmic reticulum (ER) kinase (PERK), a key ER stress sensor of the unfolded protein response (UPR), can confer beneficial effects by facilitating the removal of cytosolic aggregates through the autophagy-lysosome pathway (ALP). In neurodegenerative diseases, the ALP ameliorates the accumulation of intracellular protein aggregates in the brain. Transcription factor-EB (TFEB), a master regulator of the ALP, positively regulates key genes involved in the cellular degradative pathway. However, in neurons, the role of PERK activation in mitigating amyloidogenesis by ALP remains unclear. In this study, we found that SB202190 selectively activates PERK independently of its inhibition of p38 mitogen-activated protein kinase, but not inositol-requiring transmembrane kinase/endoribonuclease-1α (IRE1α) or activating transcription factor 6 (ATF6), in human neuroblastoma cells. PERK activation by SB202190 was dependent on mitochondrial ROS production and promoted Ca2+-calcineurin activation. The activation of the PERK-Ca2+-calcineurin axis by SB202190 positively affects TFEB activity to increase ALP in neuroblastoma cells. Collectively, our study reveals a novel physiological mechanism underlying ALP activation, dependent on PERK activation, for ameliorating amyloidogenesis in neurodegenerative diseases.

The impact of exposure to HPV related information and injunctive norms on young women's intentions to receive the HPV vaccine in China: A structural equation model based on KAP theory.

Background: The HPV vaccination is a crucial line of defensing against cervical cancer. As a result of government support and positive publicity from the majority of media, a craze for HPV vaccination has occurred in China. Besides, the intentions to get the HPV vaccine among women of appropriate age is also influenced by families' and friends' attitudes and perceptions toward HPV vaccine. Therefore, the purpose of this study was to investigate how HPV related information exposure and injunctive norms affect young Chinese women's intentions to receive the HPV vaccine. Methods: A structural equation model was developed based on KAP theory, and 567 effective questionnaires were collected through an online survey. We used SPSS 26.0 for the reliability and validity analysis and the differential testing of demographic characteristics, and Amos 26.0 for the goodness-of-fit analysis and paths testing of the model. Results: Our findings showed that (1) intention to receive HPV vaccine differed significantly in age (P = 0.046), educational background (P = 0.001), and occupation (P = 0.004). (2) Exposure to HPV related information positively affected knowledge about HPV (ß = 0.316, P < 0.001) and intention to receive HPV vaccine (ß = 0.141, P < 0.001). (3) Knowledge about HPV positively affected attitude toward HPV vaccine (ß=0.341, P < 0.001), but negatively affected intention to receive HPV vaccine (ß = -0.148, P < 0.05), and attitude toward HPV vaccine positively affected intention to receive HPV vaccine (ß = 0.594, P < 0.001). (4) Injunctive norms positively affected attitude toward HPV vaccine (ß = 0.362, P < 0.001) and intention to receive HPV vaccine (ß = 0.420, P < 0.001). Conclusions: Exposure to HPV related information influenced young Chinese women's intentions to receive the HPV vaccine and related knowledge, that is, the more frequently they were exposed to HPV related information, the stronger their intentions to receive the vaccine and the higher their HPV knowledge. Also, the perception and support of HPV vaccination by people around them will further influence their attitudes and intentions to receive the HPV vaccine.

Analysis of the reasons for screening failure in phase I clinical trials in China: a retrospective study of the clinical trials screening process.

BACKGROUND: To analyze the main reasons for screening failure in the screening process of healthy subjects in phase I clinical trials and coping strategies. METHODS: We retrospectively collected data from the screening process of 1,640 healthy subjects in 12 phase I clinical trials conducted between April 2019 and July 2020 at the First Affiliated Hospital of Bengbu Medical College. The reasons for screening failure were statistically analyzed (χ2 test), and correlation studies were conducted to explore the main factors associated with screening failure. RESULTS: Among the 1,640 healthy subjects, 632 (38.5%) successfully passed screening, and 1,008 (61.5%) failed screening. Abnormal laboratory test results (43.25%), abnormal vital sign examination results (11.81%), withdrawal of informed consent (10.02%), abnormal height/weight examination results (8.33%), and abnormal electrocardiogram (ECG) examination results (5.66%) accounted for 79.07% of the screening failures. Subjects aged 46-57 years were more likely to fail screening than those aged 18-30 or 31-45 years (158/220 vs. 541/893 vs. 309/527, respectively, P=0.002), and males were more likely than females to fail screening (721/1, 133 vs. 287/507, respectively, P=0.007). However, the distance between the subject's residence and clinical trial institution (P=0.491) was not significantly correlated with screening failure. CONCLUSIONS: Before trial screening, healthy subjects should be informed of the clinical trial risks and have sufficient time to consider or discuss participation with their family members. In addition, subjects should be informed that they should eat lightly, have adequate rest, and maintain a relaxed state of mind prior to screening. Regarding fluctuations in the normal range of laboratory indicators and ECG examination reports during the screening process, clinicians should determine the medical decision level (MDL) for each indicator. If no clinical significance is identified, then the subject can be included. In terms of sex and age, this study provides reasonable suggestions to further improve project protocols and improve the healthy subject screening success rate.