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BACKGROUND Tissue dynamics of von Willebrand factor (VWF) that are vital to its biological function have not been fully characterized. OBJECTIVE To develop a new fluorescent protein--VWF chimera (FP-VWF) that has similar hematologic function to wild-type VWF and use it to monitor the tissue dynamics of VWF distribution. METHODS Genotyping, platelet counting, tail bleeding time assay, agarose gels, western blot, platelet aggregation, proteolytic analysis, and ELISA were applied in characterizing the function of FP-VWF; fluorescence spectrometer and confocal fluorescence microscope were used to monitor the plasma and tissue distribution of FP-VWF. RESULTS The transgenic mice that carry the FP-VWF retain hematologic activity of VWF with plasma levels of FP-VWF reduced by 50% and there are reduced high molecular weight FP-VWF multimers compared to the wild-type mice. The GPIb-binding and ADAMTS-13 (A Disintegrin and Metalloprotease with ThrombSpondin type 1 motif, member 13) proteolytic efficiency of FP-VWF are similar to wild-type VWF. The tissue distribution of FP-VWF was probed directly through its intrinsic fluorescence at normal or stimulated status, which indicated that the medicine-stimulated endogenous FP-VWF seems primarily released from the aorta and cleared in the spleen. Similar results were observed in non-fluorescent mice through a standard immunofluorescence approach. The fluorescence signals of FP-VWF were also similar to the standard dye-based approach in detecting the FeCl3 -induced blood clotting in vivo. CONCLUSIONS Together, these results suggest that this novel FP-VWF chimera is valuable in probing the tissue dynamics of VWF in quite a few biological and pharmaceutical applications.

The aim of this research is to assess the effectiveness and safety of acupuncture combined with rehabilitation therapy for post-stroke fatigue. The methods used in this research are as follows: systematically retrieving China National Knowledge Infrastructure, Chinese Scientific Journal Database, Chinese Biological Medicine Database, Cochrane Library, Medline and Embase were electronically searched from inception to Dec 2020. The dataset included randomized controlled trials (RCTs) with Chinese and English only that compared acupuncture as an adjunct to rehabilitation in stroke patients with fatigue. The methodological quality of the included trials was assessed using the Cochrane risk of bias assessment tool. Statistical analyses were performed by RevMan V.5.4.A total of 6 RCTs were included in this study, including 426 cases (213 cases in the treatment group and 213 cases in the control group). The results of meta-analysis showed that compared with conventional treatment, acupuncture as an adjuvant therapy can significantly reduce the incidence of post-stroke fatigue [MD = -5.45, 95% CI = (-6.75, -4.14), Z = 8.19 (P < 0.001)]. In terms of energy, acupuncture also has an obvious effect [MD = 1.69, 95% CI = (0.27, 3.12), Z = 2.33 (P < 0.02)]. Our systematic review and meta-analysis suggests that acupuncture combined with conventional rehabilitation therapy is an effective therapy for patients suffering from post-stroke fatigue, which is suitable for clinical promotion and use. However, due to methodological weakness and limited number of RCTs, the results should be interpreted cautiously. Further clinical trials with large sample sizes and a rigorous design are needed.

The clinical significance and regulators of IL-13Rα2 in itch and atopic dermatitis (AD) remain unclear. To identify disease-driven regulatory circuits of IL-13Rα2, transcriptomic/pathological analysis was performed in skin from patients with AD, psoriasis, healthy subjects, and murine AD model. Functionality was investigated in sensory neurons, keratinocytes and animal model, by using knockdown (KD), calcium imaging, RNA-seq, cytokine arrays, pharmacological assays, and behavioural investigations. In our study, an upregulated IL-13Rα2 expression was revealed in skin of AD patients, but not psoriasis, in a disease activity-dependent manner. In cultured human keratinocytes, IL-13 increased IL-13Rα2 transcription levels, and this were downregulated by IL-13Rα1KD. IL-13Rα2KD reduced transcription levels of EDNRA, CCL20, CCL26. In contrast, sensory neuron-derived IL-13Rα2 was upregulated by TLR2 heterodimer agonists, Pam3CSK4 and FSL-1. In a mouse cheek model, pre-administration of Pam3CSK4 and FSL-1 enhanced IL-13-elicited scratching behaviour. Consistently, in cultured sensory neurons Pam3CSK4 enhanced IL-13-elicted calcium transients, increased number of responders, and orchestrated chemerin, CCL17 and CCL22 release. These release was inhibited by IL-13Rα2KD. Collectively, IL-13 regulates keratinocyte-derived IL-13Rα2 and TLR2 to modulate neuronal IL-13Rα2, thereby promoting neurogenic inflammation and exacerbating AD and itch. Thus, the cutaneous IL-13-IL-13Rα2 and neuronal TLR2-IL-13Rα2 pathway represent important targets to treat AD and itch.

Aβ42 is one of the most extensively studied blood and Cerebrospinal fluid (CSF) biomarkers for the diagnosis of symptomatic and prodromal Alzheimer’s disease (AD). Because of the heterogeneity and transient nature of Aβ42 oligomers (Aβ42Os), the development of technologies for dynamically detecting changes in the blood or CSF levels of Aβ42 monomers (Aβ42Ms) and Aβ42Os is essential for the accurate diagnosis of AD. The currently commonly used Aβ42 ELISA test kits usually mis-detected the elevated Aβ42Os, leading to incomplete analysis and underestimation of soluble Aβ42, resulting in a comprised performance in AD diagnosis. Herein, we developed a dual-target lateral flow immunoassay (dLFI) using anti-Aβ42 monoclonal antibodies 1F12 and 2C6 for the rapid and point-of-care detection of Aβ42Ms and Aβ42Os in blood samples within 30 min for AD diagnosis. By naked eye observation, the visual detection limit of Aβ42Ms or/and Aβ42Os in dLFI was 154 pg/mL. The test results for dLFI were similar to those observed in the enzyme-linked immunosorbent assay (ELISA). Therefore, this paper-based dLFI provides a practical and rapid method for the on-site detection of two biomarkers in blood or CSF samples without the need for additional expertise or equipment. Graphical Abstract

Aims Apelin is the endogenous ligand of G protein-coupled receptor APJ and play an important role in the regulation of cardiovascular homeostasis. We aimed to investigate whether apelin ameliorates vascular calcification (VC) by inhibition of endoplasmic reticulum stress (ERS). Methods and results VC model in rats was induced by nicotine plus vitamin D, while calcification of vascular smooth muscle cell (VSMC) was induced by beta-glycerophosphate. Alizarin Red S staining showed dramatic calcium deposition in the aorta of rats with VC, while calcium contents and ALP activity also increased in calcified aorta. Protein levels of apelin and APJ were decreased in the calcified aorta. In rats with VC, apelin treatment significantly ameliorated aortic calcification, compliance and stimulation of ERS. The ameliorative effect of apelin on VC and ERS was also observed in calcified VSMCs. ERS stimulator (tunicamycin or DTT) blocked the beneficial effect of apelin. Apelin treatment activated the PI3K/Akt signaling, blockage of which by wortmannin or inhibitor IV prevented the ameliorative effect of apelin, while ERS inhibitor 4-PBA rescued the blockade effect of wortmannin. Akt-induced GSK inhibition prevented the phosphorylation of PERK and IRE1, and the activation of these two major ERS branches. F13A blocked the ameliorative effect of apelin on VC and ERS, which was reversed by treatment with 4-PBA or Akt activator SC79 Conclusions Apelin ameliorated VC by binding to APJ and then prevented ERS activation by stimulating Akt signaling. These results might provide new target for therapy and prevention of VC.

This study aimed to investigate whether inhibition of endoplasmic reticulum stress (ERS) mediated the ameliorative effect of apelin on acute heart failure (AHF). Rabbit model of AHF was induced by sodium pentobarbital. Cardiac dysfunction and injury were detected in the rabbit models of AHF, including impaired hemodynamic parameters and increased levels of CK-MB and cTnI. Apelin treatment dramatically improved cardiac impairment caused by AHF. ERS, indexed by increased GRP78, CHOP, and cleaved-caspase12 protein levels, was simultaneously attenuated by apelin. Apelin also could ameliorate increased protein levels of cleaved-caspase3 and Bax, and improved decreased protein levels of Bcl-2. Two common ERS stimulators, tunicamycin (Tm) and dithiothreitol (DTT) blocked the ameliorative effect of apelin on AHF. Phosphorylated Akt levels increased after apelin treatment in the rabbit models of AHF. The Akt signaling inhibitors wortmannin and LY294002 could block the cardioprotective effect of apelin, which could be relieved by ERS inhibitor 4-phenyl butyric acid (4-PBA). The aforementioned beneficial effects of apelin could all be blocked by APJ receptor antagonist F13A. 4-PBA and SC79, an Akt activator, can restore the ameliorative effect of apelin on AHF blocked by F13A. Apelin treatment dramatically ameliorated cardiac impairment caused by AHF, which might be mediated by APJ/Akt/ERS signaling pathway. These results will shed new light on AHF therapy.

Social anhedonia, or the loss of motivation in and pleasure from social engagement, is an important feature in understanding the etiology and outcome of various psychopathologies. While the Revised Social Anhedonia Scale (RSAS) represents one of the most commonly used self-report measures of social anhedonia, little is known regarding the construct comparability across populations. We examined measurement invariance of the full and brief RSAS in a diverse, international sample of 14,064 participants across nine epidemiological dimensions, including gender, age, ethnicity, education, community income, continent, migrant status, ethnic density, and urbanicity. Both the full and brief RSAS, as represented by a three-factor structure, achieved metric invariance for all dimensions. The full version showed considerable scalar noninvariance for ethnicity and continent, which was significantly reduced in the brief version. These findings suggest that while the scales measure the same construct across diverse groups, mean comparisons are only appropriate for the brief, and not the full, version. Future research may consider using the brief RSAS to ensure cross-national comparability. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The recovery of blood supply after a period of myocardial ischaemia does not restore the heart function and instead results in a serious dysfunction called myocardial ischaemia-reperfusion injury (IRI), which involves several complex pathophysiological processes. Mitochondria have a wide range of functions in maintaining the cellular energy supply, cell signalling and programmed cell death. When mitochondrial function is insufficient or disordered, it may have adverse effects on myocardial ischaemia-reperfusion and therefore mitochondrial dysfunction caused by oxidative stress a core molecular mechanism of IRI. Peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) is an important antioxidant molecule found in mitochondria. However, its role in IRI has not yet been systematically summarized. In this review, we speculate the role of PGC-1α as a key regulator of mitonuclear communication, which may interacts with nuclear factor, erythroid 2 like -1 and -2 (NRF-1/2) to inhibit mitochondrial oxidative stress, promote the clearance of damaged mitochondria, enhance mitochondrial biogenesis, and reduce the burden of IRI.

A 2-pyridone modified zinc phthalocyanine (denoted ZnPc-PYR) achieves a one stone for three birds outcome in the photodynamic therapy (PDT) treatment of cancer. ZnPc-PYR can be excited by both 665 and 808 nm light to treat superficial and deep tumors, store and slowly release singlet oxygen (1O2) to improve its utilization and downregulate the HIF-1 (hypoxia-inducible factor 1) expression level to enhance the tumor cell's sensitivity to PDT treatment under hypoxic conditions.

Coronavirus disease 2019 (COVID-19) is a newly emerged infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The number of COVID-19 cases is continuously increasing and no effective drugs or vaccines are currently available. Accurate and efficient diagnostic testing methods are desperately needed for the detection of SARS-CoV-2 and antiviral antibodies in infected individuals. Various assay techniques, including nucleic acid tests [eg, polymerase chain reaction (PCR), reverse transcription-PCR, real-time loop-mediated isothermal amplification, and CRISPR-Cas-based detection], serological tests [eg, immunoglobulin (Ig)A, IgM/G], imaging tests (eg, computed tomography and positron-emission tomography), and nanoparticle-based detections have been reported for COVID-19 diagnosis. This review aims to present the current diagnostic tools for SARS-CoV-2 and their performance characteristics to inform the appropriate selection of diagnostic and surveillance technologies at optimal testing times. We also describe the advantages of detection using combined nucleic acid and imaging tests, or serological testing and point-of-care diagnostics. Developing reliable protein biomarkers targeting the conserved proteins of SARS-CoV-2 rather than IgA, IgM, or IgG would be useful to manage SARS-CoV-2.

Purpose Ovarian cancer (OC) has the highest mortality among gynecological malignancies. Therefore, it is urgent to explore prognostic biomarkers to improve the survival of OC patients. One of the most prominent metabolic characteristics of cancer is effective glycolysis. Hexokinase 1 (HK1), as the first rate-limiting enzyme in glycolysis, is closely related to cancer progression. However, the role of HK1 in OC remains unclear. Materials and Methods The Cancer Genome Atlas (TCGA) database was used to detect the expression of HK1 in OC patients. The chi-squared test was performed to examine the correlations between HK1 and patients’ clinical characteristics. Survival analyses were undertaken to determine the relationship between HK1 and patient survival, while the univariate/multivariate Cox model was used to evaluate the role of HK1 in patient prognosis. Gene Set Enrichment Analysis (GSEA) was performed to ascertain the related signaling pathways of HK1. RT-qPCR was implemented to validate the mRNA expression of HK1 in OC cells. MTT was used to detect cell viability after adding 2DG and knocking down HK1 in OC cells. HK1 protein expression was examined by Western blotting. Glucose uptake, lactate production, and ATP assays were undertaken following knockdown of HK1 in OC cells. Colony formation assays were performed to determine OC cell proliferation after HK1 knockdown. Transwell and wound healing assays were carried out to detect the invasion and migration of OC cells after HK1 knockdown. Results We found that HK1 expression was increased in OC tissues and cells, and HK1 was related to the clinical characteristics of OC patients. Survival analysis revealed that OC patients in the HK1 overexpression group had poor survival. Moreover, univariant/multivariate analyses showed that HK1 may be an independent biomarker for the poor prognosis of OC patients. OC cell viability and proliferation decreased after knockdown of HK1. Consistently, glucose uptake, lactic acid production, ATP production, invasion, and migration were also decreased. Finally, GSEA enrichment analysis and Western blotting showed that HK1 was involved in MAPK/ERK signaling. Conclusion HK1 may be a biomarker for the poor prognosis of OC patients and a potential therapeutic target.

Stimulator of interferon genes (STING) has been shown to play a critical role in orchestrating immune responses to various pathogens through sensing cyclic dinucleotides. However, how STING regulates intestinal homeostasis is still not completely understood. In this study, we found that STING(−/−) mice were more susceptible to enteric infection with Citrobacter rodentium compared to WT mice evidenced by more severe intestinal inflammation and impaired bacterial clearance. STING(−/−) mice demonstrated lower expression of REG3γ, but not β-defensins and Cramp, in IECs. Consistently, STING(−/−) IECs showed reduced capacity to inhibit bacterial growth. STING agonists, both 10-carboxymethyl-9-acridanone (CMA) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), promoted REG3γ expression IECs. Furthermore, STING agonists promoted WT but not REG3γ-deficient IEC bacterial killing. Mechanistically, STING agonists activated STAT3 and promoted glycolysis in IECs. Inhibition of STAT3 pathway and glycolysis suppressed STING induced REG3γ production in IECs, and abrogated STING-mediated IEC killing of Citrobactor rodentium. Additionally, treatment with the STING ligand, 2,3-cGAMP, inhibited Citrobactor rodentium-induced colitis in vivo. Overall, STING promotes IEC REG3γ expression to inhibit enteric infection and intestinal inflammation, thus, maintaining the intestinal homeostasis.

STUDY QUESTION Whether the testis-specific extracellular vesicle (EV) long noncoding RNAs (lncRNAs) in seminal plasma could be utilized to predict the presence of testicular spermatozoa in nonobstructive azoospermia (NOA) patients? SUMMARY ANSWER Our findings indicate that the panel based on seminal plasma EV lncRNAs was a sensitive and specific method in predicting the presence of testicular spermatozoa and may improve clinical decision-making of NOA. WHAT IS KNOWN ALREADY The adoption of sperm retrieval techniques, especially microdissection testicular sperm extraction (mTESE), in combination with ICSI has revolutionized treatment for NOA. However, there are no precise and noninvasive methods for predicting whether there are testicular spermatozoa in NOA patients before mTESE. STUDY DESIGN, SIZE, DURATION RNA sequencing was performed on seminal plasma EVs from 6 normozoospermic men who underwent IVF due to female factor and 5 idiopathic NOA patients who failed to obtain testicular spermatozoa by mTESE and were diagnosed as having Sertoli cell-only syndrome by postoperative pathology. A biomarker panel of lncRNAs was constructed and verified in 96 NOA patients who underwent mTESE. Decision-making process was established based on the panel in seminal plasma EVs from 45 normozoospermia samples, 43 oligozoospermia samples, 62 cryptozoospermia samples, 96 NOA samples. PARTICIPANTS/MATERIALS, SETTING, METHODS RNA sequencing was done to examine altered profiles of EV lncRNAs in seminal plasma. Furthermore, a panel consisting of EV lncRNAs was established and evaluated in training set and validation sets. MAIN RESULTS AND THE ROLE OF CHANCE A panel consisting of nine differentially expressed testis-specific lncRNAs, including LOC100505685, SPATA42, CCDC37-DT, GABRG3-AS1, LOC440934, LOC101929088 (XR_927561.2), LOC101929088 (XR_001745218.1), LINC00343 and LINC00301, was established in the training set and the AUC was 0.986. Furthermore, the AUC in the validation set was 0.960. Importantly, the panel had a unique advantage when compared with models based on serum hormones from the same group of NOA cases (AUC, 0.970 vs 0.723; 0.959 vs 0.687, respectively). According to the panel of lncRNAs, a decision-making process was established, that is when the score of an NOA case exceeds 0.532, sperm retrieval surgery may be recommended. LIMITATIONS, REASONS FOR CAUTION In the future, the sample size needs to be further expanded. Meanwhile, the regulatory functions and mechanism of lncRNAs in spermatogenesis also need to be elucidated. WIDER IMPLICATIONS OF THE FINDINGS When the score of our panel is below 0.532, subjecting the NOA patients to ineffective surgical interventions may not be recommended due to poor sperm retrieval rate. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Natural Science Foundation of China (81871110, 81971314 and 81971759); the Guangdong Special Support Plan-Science and Technology Innovation Youth Top Talents Project (2016TQ03R444); the Science and Technology Planning Project of Guangdong Province (2016B030230001 and 201707010394); the Key Scientific and Technological Program of Guangzhou City (201604020189); the Pearl River S&T Nova Program of Guangzhou (201806010089); the Transformation of Scientific and Technological Achievements Project of Sun Yat-sen University (80000-18843235) and the Youth Teacher Training Project of Sun Yat-sen University (17ykpy68 and 18ykpy09). There are no competing interests related to this study. TRIAL REGISTRATION NUMBER N/A.

Biochemical and structural characterizations of a protein are the prerequisite for the further understanding of its biological role and potential applications. The expression of recombinant protein is almost unavoidable to produce the amount of the protein required for these studies, especially at the industrial level. Escherichia coli is the single most used system for recombinant protein expression and the first choice for a trial expression. Besides the inherited defects of its prokaryotic origin, the E. coli system has problems like low protein solubility and formation of inclusion bodies. To improve the solubility while assisting correct folding of the target protein, fusing a tag protein prior to its N-terminus is one of the common approaches. GST, MBP, Trx and SUMO proteins are among the most used tags by providing different advantages during recombinant protein expression. Msyb, a small and acidic protein native to E. coli, is another example that could improve the solubility of the target protein. While the biophysical and biochemical properties of these common tag proteins have been studied to a great extent, Msyb protein remains largely uncharacterized. Here, using solution-state NMR, our near-complete resonance assignment of Msyb provides a basis for future structure determination which would help to expand its usage as a common tag protein.

Erastin was initially discovered as a small molecule compound that selectively kills tumor cells expressing ST and RASV12 and was later widely investigated as an inducer of ferroptosis. Ferroptosis is a recently discovered form of cell death caused by peroxidation induced by the accumulation of intracellular lipid reactive oxygen species (L-ROS) in an iron-dependent manner. Erastin can mediate ferroptosis through a variety of molecules including the cystine-glutamate transport receptor (system XC -), the voltage-dependent anion channel (VDAC), and p53. Erastin is able to enhance the sensitivity of chemotherapy and radiotherapy, suggesting a promising future in cancer therapy. We hope that this review will help to better understand the role of erastin in ferroptosis and lay the foundation for further research and the development of erastin-based cancer therapies in the future.

Individuals at risk for schizophrenia-spectrum disorders display abnormalities related to motivational salience, or the ability of stimuli to elicit attention due to associations with rewards or punishments. However, the nature of these abnormalities is unclear because most focus on responses to stimuli from broad “pleasant” and “unpleasant” categories and ignore the variation of motivational salience within these categories. In two groups at risk for schizophrenia-spectrum disorders—a Social Anhedonia group and a Psychotic-like Experiences group—and a control group, the current study examined event-related potential components sensitive to motivational salience—the Early Posterior Negativity (EPN), reflecting earlier selective attention, and the Late Positive Potential (LPP), reflecting sustained attention. Compared to controls, the Social Anhedonia group showed smaller increases in the EPN in response to erotica and smaller increases in the LPP as the motivational salience of pleasant images increased (excitinglarger increases in LPP amplitudes as the motivational salience of pleasant images increased. Also, both at-risk groups showed larger increases in the LPP to threatening images but smaller increases to mutilation images. These findings suggest that examining abnormalities beyond those associated with broad categories may be a way to identify mechanisms of dysfunction.

Male late-onset hypogonadism is an age-related disease, the core mechanism of which is dysfunction of senescent Leydig cells. Recent studies have shown that elimination of senescent cells can restore proper homeostasis to aging tissue. In the present study, we found that the fork head box O (FOXO) transcription factor FOXO4 was specially expressed in human Leydig cells and that its translocation to the nucleus in the elderly was related to decreased testosterone synthesis. Using hydrogen peroxide-induced senescent TM3 Leydig cells as an in vitro model, we observed that FOXO4 maintains the viability of senescent Leydig cells and suppresses their apoptosis. By disrupting the FOXO4-p53 interaction, FOXO4-DRI, a specific FOXO4 blocker, selectively induced p53 nuclear exclusion and apoptosis in senescent Leydig cells. In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.

Purpose Lung cancer is the leading cause of cancer-related mortality. STEAP1 and STEAP2 are overexpressed in various cancers. The purpose of this study was to evaluate the expression and prognostic value of STEAP1 and STEAP2 in patients with lung cancer. Methods The mRNA expression and protein expression of STEAP1 and STEAP2 and their prognostic characteristics were examined using Oncomine, GEPIA, and Kaplan-Meier (KM) plotters. The correlation analysis of STEAP1 and STEAP2 gene and protein levels was conducted using GeneMANIA and STRING. KEGG pathway analysis was used to explore the related signal pathways of STEAP 1 and STEAP2. Immunohistochemical methods were used to compare the expression of STEAP2 in normal lung and non-small cell lung cancer (NSCLC) tissues. Real-time quantitative polymerase chain reaction, western blotting, and immunocytochemistry were used to evaluate the expression of STEAP1 and STEAP2 in three lung cancer cell lines and normal lung epithelial cell lines. Results Analysis of the Oncomine database and GEPIA showed that STEAP1 was upregulated and STEAP2 was downregulated in lung cancer tissue, and both expressions were related to the clinical stage of lung cancer. Immunohistochemical analysis showed that STEAP1 protein expression was significantly upregulated in lung cancer compared to that in adjacent tissues. The expression of STEAP1 was positively correlated with the migration and invasion abilities of lung cancer cells. Compared with paracancer tissues, the expression of STEAP2 protein in lung cancer was significantly downregulated and was correlated with the histological grade of squamous cell carcinoma, pathological classification of adenocarcinoma, tumor, lymph node, and metastasis clinical stage, and lymph node metastasis. The expression of STEAP2 was negatively correlated with the migration and invasion abilities of lung cancer cells. The KM curve showed that the downregulation of STEAP1 expression and upregulation of STEAP2 expression were related to a good lung cancer prognosis. Conclusion STEAP1 and STEAP2 are expected to be potential diagnostic and prognostic markers for lung cancer, which may provide more accurate prognostic indicators for lung cancer.

Although amyloid-β42 (Aβ42) has been used as one of the core biomarkers for Alzheimer’s disease (AD) diagnosis, the dynamic changes of its different forms in the brain, blood, and even intestines and its correlation with the progression of AD disease remain obscure. Herein, we screened Aβ42-specific preferred antibody pairs 1F12/1F12 and 1F12/2C6 to accurately detect Aβ42 types using sandwich ELISA, including total Aβ42, Aβ42 oligomers (Aβ42Os), and Aβ42 monomers (Aβ42Ms). The levels of Aβ42 species in the brain, blood, and intestines of different aged APP/PS1 mice were quantified to study their correlation with AD progression. Total Aβ42 levels in the blood were not correlated with AD progression, but Aβ42Ms level in the blood of 9-month-old APP/PS1 mice was significantly reduced, and Aβ42Os level in the brain was significantly elevated compared to 3-month-old APP/PS1, demonstrating that the levels of Aβ42Ms and Aβ42Os in the blood and brain were correlated with AD progression. Interestingly, in 9-month-old APP/PS1 mice, the level of Aβ42 in the intestine was higher than that in 3-month-old APP/PS1 mice, indicating that the increased level of Aβ42 in the gastrointestinal organs may also be related to the progression of AD. Meanwhile, changes in the gut microbiota composition of APP/PS1 mice with age were also observed. Therefore, the increase in Aβ derived from intestinal tissues and changes in microbiome composition can be used as a potential early diagnosis tool for AD, and further used as an indicator of drug intervention to reduce brain amyloid.

Utilizing catalase-mimicking nanozymes to produce O2 is an effective method to overcome tumor hypoxia. However, it is challenging to fabricate nanozymes with ultrahigh catalytic activity. Palladium nanosheet (Pd NS), a photothermal agent for photothermal therapy (PTT), has superior catalase-mimicking activity. Here, titanium dioxide (TiO2 ) is used to modify Pd NS (denoted Pd@TiO2 ) by a simple one-step method to improve its catalytic activity about 8 times. The enhancement mechanism's fundamental insights are discussed through experiments and density functional theory calculations. Next, zinc phthalocyanine is loaded on Pd@TiO2 to form a nanomotor (denoted PTZCs) with the synergistic activities of photodynamic therapy and PTT. PTZCs inherit the catalase activity of Pd@TiO2 to facilitate the decomposition of endogenous H2 O2 to O2 , which can relieve tumor hypoxia and propel PTZC migration to expand the reach of PTZCs, further enhancing its synergistic treatment outcome both in vitro and in vivo. It is proposed that this work can provide a simple and effective strategy for catalytic activity enhancement and bring a critical new perspective to studying and guiding the nanozyme design.

Study question To investigate the pregnancy outcomes of progestin primed ovarian stimulation protocol, GnRH antagonist protocol and GnRH agonist protocol for young patients undergoing preimplantation genetic testing for monogenic gene diseases. Summary answer PPOS protocol could reduce the normal chromosome formation and further development potential of embryos, suggesting that the PPOS protocol should be used cautiously. What is known already GnRH antagonist protocol (GnRHant) and GnRH agonist protocol (GnRHa) have been used in clinic for many years as routine regimens, and their ovarian stimulation effects and pregnancy outcomes have been confirmed by a large number of literatures. As a new protocol in recent years, the reports of pregnancy outcomes of progestin primed ovarian stimulation protocol (PPOS) are inconsistent. Study design, size, duration This retrospective cohort study was performed in a reproduction center from a tertiary hospital between September 2018 and November 2020 which included 147 young patients ( Participants/materials, setting, methods This study included 147 young patients ( Main results and the role of chance Basic characteristics such as infertility duration, age, and body mass index (BMI) were comparable in study groups. No significant difference was found in the number oocytes retrieved or viable embryos between the groups. Normal karyotype embryo rate of PPOS protocol was significantly lower than GnRHant and GnRHa protocol (57.6% for PPOS vs 76.0% for GnRHant vs 67.3% for GnRHa). No significant difference were found in chemical pregnancy rate (77.3% for PPOS vs 73.3% for GnRHant vs 74.4% for GnRHa) or clinical pregnancy rate (69.8% for PPOS vs 71.7% for GnRHant vs 72.5% for GnRHa). While live birth rate of PPOS protocol was significantly lower than GnRHant and GnRHa protocol ( 45.5% for PPOS vs 58.3% for GnRHant vs 72.2% for GnRHa). Limitations, reasons for caution This is a preliminary study which needs to be further confirmed by large-scale clinical studies. Wider implications of the findings: Although this is a preliminary study which needs to be further confirmed by large-scale clinical studies, the current results suggest that the application of PPOS should be cautious. Trial registration number

Background and Aims: Emerging studies indicate that long noncoding RNAs (lncRNAs) play a role as prognostic markers in many cancers, including liver cancer. Here, we focused on the lncRNA lung cancer-associated transcript 1 (LUCAT1) for liver cancer prognosis. Methods: RNA-seq and phenotype data were downloaded from the Cancer Genome Atlas (TCGA). Chisquare tests were used to evaluate the correlations between LUCAT1 expression and clinical features. Survival analysis and Cox regression analysis were used to compare different LUCAT1 expression groups (optimal cutoff value determined by ROC). The log-rank test was used to calculate the p-value of the Kaplan-Meier curves. A ROC curve was used to evaluate the diagnostic value. Gene Set Enrichment Analysis (GSEA) was performed, and competing endogenous RNA (ceRNA) networks were constructed to explore the potential mechanism. Results: Data mining of the TCGA -Liver Hepatocellular Carcinoma (LIHC) RNA-seq data of 371 patients showed the overexpression of LUCAT1 in cancerous tissue. High LUCAT1 expression was associated with age (p=0.007), histologic grade (p=0.009), T classification (p=0.022), and survival status (p=0.002). High LUCAT1 patients had a poorer overall survival and relapse-free survival than low LUCAT1 patients. Multivariate analysis identified LUCAT1 as an independent risk factor for poor survival. The ROC curve indicated modest diagnostic performance. GSEA revealed the related signaling pathways, and the ceRNA network uncovered the underlying mechanism. Conclusion: High LUCAT1 expression is an independent prognostic factor for liver cancer.

Nitric oxide (NO) can play both prosurvival and prodeath roles in photodynamic therapy (PDT). The generation efficiency of peroxynitrite anions (ONOO-), by NO and superoxide anions (O2•-), significantly influenced the outcome. Reports indicated that such efficiency is closely related to the distance between NO and O2•-. Thus, in this manuscript, l-arginine (Arg) ethyl ester-modified zinc phthalocyanine (Arg-ZnPc) was designed and synthesized as a photosensitizer (PS) and NO donor. Post light irradiation, the guanido of Arg-ZnPc can be effectively oxidized by the generated reactive oxygen species (ROS) in the PDT process to release NO. Such a strategy could ensure O2•- and NO generation in the same place at the same time to guarantee effective ONOO- formation. In addition, NO has other multiple synergistic cancer treatment functions, including tumor tissue vasodilatation for drug extravasation promotion, P-glycoprotein (P-gp) downregulation for drug efflux inhibition, and glutathione depletion for cancer cell endogenous antioxidant defense destruction. In vitro and in vivo results indicated that the effective ONOO- formation and multiple functions of Arg-ZnPc could synergistically enhance its PDT activity and ensure satisfactory cancer treatment outcome.

Liver cancer is a high morbidity and low survival disease all over the world. Chromosomal instability is hallmark of liver cancer. Microtubule-associated serine and threonine kinase 2 (MAST2), as a microtubule associated protein, may involve in tumorous chromosomal instability and plays important roles in cell proliferation and survival. The role of MAST2 in liver cancer has not been well elucidated, which is the aim of our study. In this study, The Cancer Genome Atlas database was used to study the MAST2 mRNA expression in liver cancer, and Chi-squared tests were performed to test the correlation between clinical features and MAST2 expression. ROC curve was performed to examined the diagnostic capacity. The prognostic value of MAST2 in liver cancer was assessed through Kaplan–Meier curves as well as Cox analysis. Our results showed MAST2 was upregulated in liver cancer, and the area under the curve (AUC) was 0.925 and indicated powerful diagnostic capability. High MAST2 expression was associated with advanced clinical status such as histological type (p = 0.0059), histologic grade (p = 0.0142), stage (p = 0.0008), T classification (p = 0.0028), N classification (p = 0.0107), survival status (p = 0.0062), and poor prognosis of patients. Importantly, MAST2 was an independent risk factor for patients’ prognosis after adjusting for other risk factors including stage, T classification, and residual tumor. In total, MAST2 is a potential diagnostic and prognostic biomarker of liver cancer.

Purpose Liver cancer has a high incidence of mortality. DNA replication and posttranscriptional modifications play important roles in the development of liver cancer. Pescadillo (PES1) is a nuclear protein that is involved in embryonic development, ribosome synthesis, DNA replication, and cell cycle progression. Recently, abnormal PES1 expression was reported in several tumors, including neuroblastoma, colon cancer, gastric cancer, and breast cancer. Based on bio-informatic analysis, cell experiments and animal models, the aim of this study is to investigate the expression patterns and specific roles of PES1 in liver cancer. Patients and methods PES1 expression was represented by boxplots. The correlation between PES1 expression and clinical features was assessed by the chi-squared test and Fisher's exact tests. Kaplan-Meier curves compared overall survival between different levels of PES1 expression, and Cox analysis selected potential variables associated with overall survival. The MTT assay investigated the proliferation rate, the scratch assay assessed the migratory ability, and the Transwell assay evaluated the invasion capacity of tumor cells in vitro. Animal models were used to confirm the tumorigenic roles of PES1 in vivo. GSEA illustrated the molecular mechanisms that PES1 participated in. Results We found that PES1 was highly expressed in liver cancer tissues, served as a diagnostic marker, and correlated with poor overall survival (OS) and relapse-free survival (RFS) in patients. In vitro studies indicated that PES1 promoted tumor cell proliferation (P=0.0034), migration (P=0.0026), and invasion (P=0.0008), and this tumorigenic role was confirmed in animal models. GSEA further illuminated molecular mechanisms that PES1 participated in liver cancer occurrence and progression. Conclusion This study suggested that PES1 was upregulated in liver cancer and correlated with poor prognosis, by promoting tumor cell proliferation, migration, and invasion, and PES1 may be a novel diagnostic and prognostic bio-marker and a promising therapeutic target in liver cancer.

Background and Objective. Liver cancer is a common malignant tumor with few poor diagnostic and prognostic markers, which greatly shortens the potential life span of patients. The RNA-binding protein la ribonucleoprotein 4B (LARP4B) has a la motif (lam) that is important in the process of cancer. We aimed to explore the role of LARP4B in the diagnosis and prognosis of liver cancer. Methods. The Cancer Genome Atlas (TCGA) database was searched to detect LARP4B gene expression in liver cancer. The clinical relevance and diagnostic ability of LARP4B were evaluated by a chi-squared test and a receiver operating characteristic (ROC) curve, respectively. Survival and risk factors of patients with liver cancer were assessed by survival analysis and univariate/multivariate Cox regression model. Additionally, we carried out gene set enrichment analysis (GSEA) to identify LARP4B-related signaling pathways in liver cancer. Results. LARP4B mRNA was highly expressed in liver cancer tissues and was correlated with survival status. The chi-squared test showed that LARP4B had clinical relevance, while ROC curves showed that LARP4B had good diagnostic ability. Survival analysis showed that liver cancer patients with high LARP4B expression had shorter overall/relapse-free survival. The univariate/multivariate Cox regression model indicated that high LARP4B expression may be an independent risk factor for the prognosis of liver cancer patients. Finally, we found that genes involved in the G2M checkpoint, E2F targets, and mitotic spindle were differentially enriched in the high LARP4B-expression phenotype. Conclusions. LARP4B is a potential independent biomarker for diagnosis and prognosis in liver cancer patients.

Background and objective: ITGA3 is a cell surface adhesion protein that interacts with extracellular matrix proteins which function in cancer metastasis. We examined the relationship of pancreatic ITGA3 expression with the clinical and pathological characteristics of patients with pancreatic cancer. Methods: Data mining was used to analyze pancreatic cancer data from The Cancer Genome Atlas database. A Chi squared test was used to evaluate correlations of ITGA3 expression with clinical and pathological parameters. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of ITGA3 expression. Survival analysis and Cox regression analysis were used to examine the prognostic value of ITGA3 expression. Gene Set Enrichment Analysis (GSEA) was used to identify signaling pathways related to ITGA3 expression. Results: Pancreatic expression of ITGA3 was greater in patients with pancreatic cancer than those without cancer, and was also associated with histological type, histological grade, stage, T classification, vital status, and relapse. ROC analysis indicated that ITGA3 had significant diagnostic value, in that high expression correlated with poor overall survival and relapse-free survival, especially in patients with early-stage cancer. Cox analysis indicated that high ITGA3 expression was an independent prognostic factor for pancreatic cancer. GSEA analysis identified 9 signaling pathways that were enriched in the presence of high ITGA3 expression. Conclusion: Expression of ITGA3 can be used as a diagnostic and prognostic biomarker in pancreatic cancer.

Progranulin (PGRN) plays critical roles in inflammation, tumorigenesis, and neurodegeneration. PGRN levels in blood and cerebrospinal fluid (CSF) are being increasingly investigated as potential biomarkers for these disorders. However, the value of CSF PGRN as a biomarker has been limited because currently available commercial enzyme-linked immunosorbent assay (ELISA) kits have suboptimal sensitivity for detecting CSF PGRN. In this study, pairs of monoclonal antibodies (MAbs) were first screened from eleven monoclonal antiPGRN antibodies using indirect ELISA, then a sandwich ELISA was established using the 2 optimized MAbs. This system displayed high sensitivity, with a lower limit of detection of 60.0 pg/mL and a lower limit of quantification of 150 pg/mL. By using this ELISA system, we showed varied CSF PGRN levels in different brain disorders. For example, as compared with the normal controls, patients with Alzheimer disease or multiple sclerosis showed mildly increased CSF PGRN; those with aseptic encephalitis or neuropsychiatric systemic lupus erythematosus showed moderately increased CSF PGRN; those with bacterial leptomeningitis showed severely increased CSF PGRN. Additionally, determining CSF PGRN levels could monitor CNS metastasis and CSF seeding of carcinomas. These results indicate that this system can be valuable in studying the diagnostic and prognostic value of CSF PGRN in brain disorders.

Purpose: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the clinic all over the world, which has become a public health challenge. The T/N/M staging system plays a core role in HCC prognosis. However, it cannot precisely stratify the risk of HCC prognosis. MiR-454-3p plays an important role in the progression of tumors. Therefore, we need to develop more reliable prognostic markers for HCC patients which can focus on miR-454-3p. Methods: We used Chi-square and Fisher exact tests to assess correlations between miR-454-3p expression and clinical parameters in liver cancer patients from The Cancer Genome Atlas database (TCGA). Then, Cox regression analysis, Kaplan-Meier curve, and log-rank test were used to compare the difference of survival between the high-expression group and low-expression group, and P value was included. Finally, we used TCGA data set to carry out gene enrichment analysis. Results: In this research, the expression of miR-454-3p increased in HCC and was associated with patient survival, G3/G4 staging, III/IV staging and T staging. Higher miR-454-3p expressed patients had shorter survival time. Besides, mitotic spindle, G2M checkpoint, and E2F targets were differentially enriched in miR-454-3p high-expression phenotype by Gene set enrichment analysis. Conclusion: Overexpression of miR-454-3p may be a significant and independent predictor of poor prognosis in HCC patients.

There is an emerging subjective-objective deficit paradox in schizotypy. Individuals with schizotypy report severe subjective complaints in several key functional domains commensurate with that of individuals with schizophrenia. However, objective assessments of the same domains show relatively intact performance. We examined whether this subjective-objective deficit paradox extends to two closely linked affective processes: emotion regulation and awareness. Individuals with elevated social anhedonia (SocAnh; n = 61) and elevated perceptual aberration/magical ideation (PerMag; n = 73) were compared to control participants (n = 81) on subjective and objective measures of emotion regulation and awareness. Subjective measures included self-report questionnaires assessing regulatory ability, attention to emotion, and emotional clarity. Implicit emotion regulation was assessed by the Emotion Regulation-Implicit Association Test (ER-IAT) while objective emotional awareness was assessed by the Levels of Emotional Awareness Scale (LEAS), a performance-based test. Results showed that both SocAnh and PerMag groups reported notable deficits in almost all subjective measures relative to controls (composite ds 0.55). In contrast, performance on ER-IAT and LEAS was very similar to controls (composite ds 0.11). The current study suggests that the subjective-objective deficit paradox extends to emotion regulation and awareness, highlighting the importance of higher-order cognitive bias in understanding emotional abnormalities in schizotypy.

Blueberry anthocyanin (BA) have strong health benefits as an active natural antioxidant and perfluorooctanoic acid (PFOA) can result in oxidative stress in animals. In our study, the protective effects of BA against stress induced by PFOA was investigated in the planarian Dugesia japonica using oxidative stress biomarkers, ATP contents, ATPase activity, DNA methylation and mRNA expression. PFOA exposure could resulted in malondialdehyde production. At the same time, treatment with BA decreased the production of malondialdehyde in BA-exposed and co-treatment planarians. PFOA caused activities increase in glutathione peroxidase (GPx), glutathione S-transferase (GST) and activities decrease in glutathione reductase (GR). PFOA exposure decreased the GSH and ATP contents. Additionally, it increased the GSSG contents and ATPase activity. BA administration increased the activities of GPx, GST and GR in BA and co-treatment planarians. Meanwhile BA maintained the contents of ATP, ATPase activity, GSH and GSSG by alleviating PFOA toxicity. Moreover, PFOA and BA increased the contents of 5-methylcytosine and decreased 5-hydroxymethylcytosine in all group. In addition, PFOA and BA treated planarians significantly altered the expression of genes associated with above biochemical parameters. The results showed that the mRNA expression of gpx, Djgst, gr, Djnak and dnmt1 were significantly elevated in all groups. Alterations in the mRNA expression levels indicated a stress response to PFOA exposure and anthocyanin protection. These alterations regulated biomarkers of oxidative stress, energy metabolism and DNA methylation levels in planarians. These results indicate that BA attenuated PFOA-induced oxidative stress, energy metabolism, DNA methylation and gene expression disorders.