EGFR-ERK1/2 signaling and mitochondrial dynamics in seasonal ovarian steroidogenesis of the muskrats (Ondatra zibethicus).

The dynamic systems of mitochondria, including mitochondrial fusion and fission, are essential for ovarian endocrine and follicular development. Meanwhile, ERK1/2 signaling is an important mechanism mediating altered mitochondrial dynamics and steroidogenesis. The purpose of this study was to investigate the seasonal changes in ovarian steroidogenesis concerning EGFR-ERK1/2 signaling and mitochondrial dynamics of the muskrats (Ondatra zibethicus). The results showed that follicular development in the muskrats remained in the tertiary follicular stage during the non-breeding season, accompanied by a significant decrease in serum and ovarian concentrations of 17ß-estradiol and progesterone from the breeding season to the non-breeding season. EGF, EGFR, ERK1/2, p-ERK1/2, and mitochondrial dynamics regulators were mainly localized in granulosa cells and theca cells of muskrats during the breeding and non-breeding seasons. The mRNA levels of Egfr, Erk1/2, Mfn1/2, Opa1, Drp1, and steroidogenic enzymes in the ovaries were remarkably higher during the breeding season. The 17ß-estradiol concentrations in the serum and ovaries as well as the relative levels of Mfn1/2, Opa1, and Drp1 were positively associated with each other. Furthermore, transcriptomic analysis of the ovaries revealed that differentially expressed genes might be linked to steroid biosynthesis, estrogen signaling pathway, and mitochondrial membrane-related pathways. In conclusion, these results suggest that the up-regulation of mitochondrial dynamics regulators during the breeding season is closely associated with enhanced ovarian steroidogenesis in the muskrats, which may be regulated by upstream EGFR-ERK1/2 signaling.

Regulation and Role of Adiponectin Secretion in Rat Ovarian Granulosa Cells.

Adiponectin is an important adipokine involved in glucose and lipid metabolism, but its secretion and potential role in regulating glucose utilization during ovarian development remains unclear. This study aims to investigate the mechanism and effects of follicle-stimulating hormones (FSHs) on adiponectin secretion and its following impact on glucose transport in the granulosa cells of rat ovaries. A range of experimental techniques were utilized to test our research, including immunoblotting, immunohistochemistry, immunofluorescence, ELISA, histological staining, real-time quantitative PCR, and transcriptome analysis. The immunohistochemistry results indicated that adiponectin was primarily located in the granulosa cells of rat ovaries. In primary granulosa cells cultured in vitro, both Western blot and immunofluorescence assays demonstrated that FSH significantly induced adiponectin secretion within 2 h of incubation, primarily via the PKA signaling pathway rather than the PI3K/AKT pathway. Concurrently, the addition of the AdipoR1/AdipoR2 dual agonist AdipoRon to the culture medium significantly stimulated the protein expression of GLUT1 in rat granulosa cells, resulting in enhanced glucose absorption. Consistent with these in vitro findings, rats injected with eCG (which shares structural and functional similarities with FSH) exhibited significantly increased adiponectin levels in both the ovaries and blood. Moreover, there was a notable elevation in mRNA and protein levels of AdipoRs and GLUTs following eCG administration. Transcriptomic analysis further revealed a positive correlation between the expression of the intraovarian adiponectin system and glucose transporter. The present study represents a novel investigation, demonstrating that FSH stimulates adiponectin secretion in ovarian granulosa cells through the PKA signaling pathway. This mechanism potentially influences glucose transport (GLUT1) and utilization within the ovaries.

[Application of metagenomic next-generation sequencing technology in preterm infants with sepsis following antibiotic use]. / å®åŸºå› ç»„äºŒä»£æµ‹åºæŠ€æœ¯åœ¨æŠ—ç”Ÿç´ ä½¿ç”¨åŽçš„æ—©äº§å„¿è´¥è¡€ç—‡ä¸­çš„åº”ç”¨.

OBJECTIVES: To explore the value of metagenomic next-generation sequencing (mNGS) technology in the etiological diagnosis of sepsis in preterm infants following antibiotic use. METHODS: A retrospective analysis of medical records for 45 preterm infants with sepsis who were treated at Henan Provincial People's Hospital. All patients received antibiotic treatment for ≥3 days and underwent both blood culture and mNGS testing. The detection rates of pathogens by blood culture and mNGS testing were compared. RESULTS: The positive detection rate of pathogens by blood mNGS was higher than that by blood culture (44% vs 4%; P<0.001). Blood mNGS detected 28 strains of pathogens, including 23 bacteria, 4 fungi, and 1 Ureaplasma parvum. Blood culture identified one case each of Rhodotorula mucilaginosa and Klebsiella pneumoniae. In the group treated with antibiotics for >10 days, the positive rate of blood mNGS testing was higher than that of blood culture (40% vs 3%; P<0.001); similarly, in the group treated with antibiotics for ≤10 days, the positive rate of blood mNGS testing was also higher than that of blood culture (53% vs 7%; P=0.020). Treatment plans were adjusted based on blood mNGS results for 13 patients, with an effectiveness rate of 85% (11/13). CONCLUSIONS: In preterm infants with sepsis following antibiotic use, the positive rate of pathogen detection by blood mNGS is higher than that by blood culture and is unaffected by the duration of antibiotic use. Therefore, mNGS testing can be considered for confirming pathogens when clinical suspicion of infection is high but blood culture fails to detect the pathogen.

Reliable detection of malachite green by self-assembled SERS substrates based on gold-silicon heterogeneous nano pineapple structures.

Morphology regulation of heterodimer nanoparticles and the use of their asymmetric features for further practical applications are crucial because of the rich optical properties and various combinations of heterodimers. This work used silicon to asymmetrically wrap half of a gold sphere and grew gold branches on the bare gold surface to form heterogeneous nano pineapples (NPPs) which can effectively improve Surface-enhanced Raman scattering (SERS) properties through chemical enhancement and lightning-rod effect respectively. The asymmetric structures of NPPs enabled them to self-assemble into the monolayer membrane with consistent branch orientation. The prepared substrate had high homogeneity and better SERS ability than disorganized substrates, and achieved reliable detection of malachite green (MG) in clams with a detection limit of 7.8 × 10-11 M. This work provided a guide to further revise the morphology of heterodimers and a new idea for the use of asymmetric dimers for practically photochemical and biomedical sensing.

Inhibition of METTL3 in macrophages provides protection against intestinal inflammation.

Inflammatory bowel disease (IBD) is prevalent, and no satisfactory therapeutic options are available because the mechanisms underlying its development are poorly understood. In this study, we discovered that increased expression of methyltransferase-like 3 (METTL3) in macrophages was correlated with the development of colitis and that depletion of METTL3 in macrophages protected mice against dextran sodium sulfate (DSS)-induced colitis. Mechanistic characterization indicated that METTL3 depletion increased the YTHDF3-mediated expression of phosphoglycolate phosphatase (PGP), which resulted in glucose metabolism reprogramming and the suppression of CD4+ T helper 1 (Th1) cell differentiation. Further analysis revealed that glucose metabolism contributed to the ability of METTL3 depletion to ameliorate colitis symptoms. In addition, we developed two potent small molecule METTL3 inhibitors, namely, F039-0002 and 7460-0250, that strongly ameliorated DSS-induced colitis. Overall, our study suggests that METTL3 plays crucial roles in the progression of colitis and highlights the potential of targeting METTL3 to attenuate intestinal inflammation for the treatment of colitis.

"Influencing the influencers:" a field experimental approach to promoting effective mental health communication on TikTok.

A substantial body of social scientific research considers the negative mental health consequences of social media use on TikTok. Fewer, however, consider the potentially positive impact that mental health content creators ("influencers") on TikTok can have to improve health outcomes; including the degree to which the platform exposes users to evidence-based mental health communication. Our novel, influencer-led approach remedies this shortcoming by attempting to change TikTok creator content-producing behavior via a large, within-subject field experiment (N = 105 creators with a reach of over 16.9 million viewers; N = 3465 unique videos). Our randomly-assigned field intervention exposed influencers on the platform to either (a) asynchronous digital (.pdf) toolkits, or (b) both toolkits and synchronous virtual training sessions that aimed to promote effective evidence-based mental health communication (relative to a control condition, exposed to neither intervention). We find that creators treated with our asynchronous toolkits-and, in some cases, those also attending synchronous training sessions-were significantly more likely to (i) feature evidence-based mental health content in their videos and (ii) generate video content related to mental health issues. Moderation analyses further reveal that these effects are not limited to only those creators with followings under 2 million users. Importantly, we also document large system-level effects of exposure to our interventions; such that TikTok videos featuring evidence-based content received over half a million additional views in the post-intervention period in the study's treatment groups, while treatment group mental health content (in general) received over three million additional views. We conclude by discussing how simple, cost-effective, and influencer-led interventions like ours can be deployed at scale to influence mental health content on TikTok.

Distinct regulation of ASCL1 by the cell cycle and chemotherapy in small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive and lethal malignancy. Achaete-scute homolog 1 (ASCL1) is essential for the initiation of SCLC in mice and the development of pulmonary neuroendocrine cells (PNECs) which are the major cells of origin for SCLC. However, the regulatory mechanism of ASCL1 in SCLC remains elusive. Here, we found that ASCL1 expression gradually increases as the tumors grow in a mouse SCLC model and is regulated by the cell cycle. Mechanistically CDK2-CyclinA2 complex phosphorylates ASCL1, which results in increased proteasome-mediated ASCL1 protein degradation by E3 ubiquitin ligase HUWE1 during mitosis. TCF3 promotes the multi-site phosphorylation of ASCL1 through the CDK2-CyclinA2 complex and the interaction between ASCL1 and TCF3 protects ASCL1 from degradation. The dissociation of TCF3 from ASCL1 during mitosis accelerates the degradation of ASCL1. In addition, chemotherapy drugs greatly reduce the transcription of ASCL1 in SCLC cells. Depletion of ASCL1 sensitizes SCLC cells to chemotherapy drugs. Together, our study demonstrates that ASCL1 is a cell-cycle regulated protein and provides a theoretical basis for applying cell-cycle related antitumor drugs in SCLC treatment. Implications: Our study revealed a novel regulatory mechanism of ASCL1 by cell cycle and chemotherapy drugs in SCLC. Treating SCLC patients with a combination of ASCL1-targeting therapy and chemotherapy drugs could potentially be beneficial.

Vitamin D status alters genes involved in ovarian steroidogenesis in muskrat granulosa cells.

This study aims to explore the relationship between altered vitamin D (VitD3) status and ovarian steroidogenesis in muskrats during the breeding and non-breeding seasons. During the breeding season, the ovaries of muskrats were observably enlarged and increased in weight, accompanied by elevated serum and ovarian VitD3 status. Vitamin D receptor (VDR), VitD3 metabolic molecules (CYP2R1, CYP27B1, and CYP24A1), and steroidogenic enzymes were immunolocalized in the ovarian cells of muskrats. The mRNA levels of VDR, CYP2R1, CYP27B1, and steroidogenic enzymes were considerably higher during the breeding season compared to the non-breeding season. RNA-seq analysis revealed a prominent enrichment of vitamin-related and ovarian steroidogenesis pathways. Furthermore, the addition of 1,25(OH)2D3 to the muskrat granulosa cells in vitro increased VDR and steroidogenic enzymes mRNA levels and enhanced the 17ß-estradiol level. Overall, these findings supported that VitD3 promotes the secretion of steroid hormones, thereby affecting seasonal changes in ovarian function in the muskrats.

Relationship between increased serum neurofilament light chain and glial fibrillary acidic protein levels with non-motor symptoms in patients with Parkinson's disease.

BACKGROUND: This study set out to investigate the relationship between serum neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and various non-motor symptoms (NMSs) in patients with Parkinson's disease (PD). METHODS: The study included 37 healthy controls (HCs) and 51 PD patients. Clinical assessments of PD symptoms were conducted for all PD patients. The NMSS was utilised to evaluate the NMS burden (NMSB) in individuals. Based on the severity of NMSB, we further categorised the PD group into two subgroups: mild-moderate NMSB group and severe-very severe NMSB group. The amounts of NFL and GFAP in the serum were measured using an extremely sensitive single molecule array (Simoa) method. Statistical analyses were performed on the collected data using SPSS 26.0 and R (version 3.6.3). RESULTS: Serum GFAP and NFL levels in the PD group with severe-very severe NMSB were significantly higher than those in the mild-moderate NMSB group (GFAP: P < 0.007; NFL: P < 0.009). Serum NFL and GFAP levels had positive correlations with NMSS total scores (GFAP: r = 0.326, P = 0.020; NFL: r = 0.318, P = 0.023) and multiple subdomains. The relationship between the attention/memory domains of NMSS and NFL levels is significantly positive (r = 0.283, P = 0.044). Similarly, the mood/apathy domains of NMSS are also significantly positively correlated with GFAP levels (r = 0.441, P = 0.001). Patients with emotional problems or cognitive impairment had higher GFAP or NFL levels, respectively. Furthermore, it has been demonstrated that NMSs play a mediating role in the quality of life of patients with PD. Moreover, the combination of NFL and GFAP has proven to be more effective than using a single component in identifying PD patients with severe-very severe NMSB. CONCLUSIONS: The severity of NMSs in PD patients, particularly cognitive and emotional symptoms, was found to be associated with the levels of serum NFL and GFAP. This study marks the first attempt to examine the connection between NMSs of PD and the simultaneous identification of NFL and GFAP levels.

Targeted Liposomes Sensitize Plastic Melanoma to Ferroptosis via Senescence Induction and Coenzyme Depletion.

Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G0/G1 phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.

Utility of serum neurofilament light chain and glial fibrillary acidic protein as diagnostic biomarkers of freezing of gait in Parkinson's disease.

Freezing of gait (FOG) is one of the most distressing features of Parkinson's disease (PD), increasing the risks of fractures and seriously affecting patients' quality of life. We aimed to examine the potential diagnostic roles of serum neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP) in PD patients with FOG (PD-FOG). We included 99 patients, comprising 54 PD patients without FOG (PD-NoFOG), 45 PD-FOG and 37 healthy controls (HCs). Our results indicated serum markers were significantly higher in PD-FOG and postural instability and gait difficulty (PIGD) motor subtype patients than in PD-NoFOG and non-PIGD subtype patients (P < 0.05), respectively. Patients with high concentrations of the markers NFL and GFAP had higher PIGD scores and greater FOG severity than those with low concentrations. Moreover, serum levels of both NFL and GFAP were significantly positively associated with age, FOG severity, PD-FOG status, and negatively associated with Mini-Mental State Examination (MMSE) scores. Logistic regression analysis identified serum levels of NFL and GFAP as independent risk factors for PD-FOG. Mediation analysis revealed that MMSE scores fully mediated the relationship between serum GFAP levels and FOG-Q scores, accounting for 33.33% of the total effects (indirect effect = 0.01, 95% CI 0.01-0.02). NFL levels differentiated PD-FOG from PD-NoFOG with reliable diagnostic accuracy (AUC 0.75, 95% CI 0.66-0.84), and the combination of NFL, GFAP, duration and MMSE scores demonstrated high accuracy (AUC 0.84, 95% CI 0.76-0.91). Our findings support the notion that NFL and GFAP may be potential biomarkers for the diagnosis of PD-FOG.

Investigation of seasonal changes in lipid synthesis and metabolism-related genes in the oviduct of Chinese brown frog (Rana dybowskii).

A peculiar physiological characteristic of the Chinese brown frog (Rana dybowskii) is that its oviduct dilates during pre-brumation rather than during the breeding season. This research aimed to examine the expression of genes connected with lipid synthesis and metabolism in the oviduct of R. dybowskii during both the breeding season and pre-brumation. We observed significant changes in the weight and size of the oviduct between the breeding season and pre-brumation. Furthermore, compared to the breeding season, pre-brumation exhibited significantly lower triglyceride content and a marked increase in free fatty acid content. Immunohistochemical results revealed the spatial distribution of triglyceride synthase (Dgat1), triglyceride hydrolase (Lpl and Hsl), fatty acid synthase (Fasn), and fatty acid oxidases (Cpt1a, Acadl, and Hadh) in oviductal glandular cells and epithelial cells during both the breeding season and pre-brumation. While the mRNA levels of triglycerides and free fatty acid synthesis genes (dgat1 and fasn) did not show a significant difference between the breeding season and pre-brumation, the mRNA levels of genes involved in triglycerides and free fatty acid metabolism (lpl, cpt1a, acadl, acox and hadh) were considerably higher during pre-brumation. Furthermore, the R. dybowskii oviduct's transcriptomic and metabolomic data confirmed differential expression of genes and metabolites enriched in lipid metabolism signaling pathways during both the breeding season and pre-brumation. Overall, these results suggest that alterations in lipid synthesis and metabolism during pre-brumation may potentially influence the expanding size of the oviduct, contributing to the successful overwintering of R. dybowskii.

Corrigendum: Transcriptome analyses reveal photosynthesis-related genes involved in photosynthetic regulation under low temperature stress in Lavandula angustifolia Mill.

[This corrects the article DOI: 10.3389/fpls.2023.1268666.].

Transcriptome analyses reveal photosynthesis-related genes involved in photosynthetic regulation under low temperature stress in Lavandula angustifolia Mill.

In order to reveal the mechanisms of photosynthetic regulation of Lavandula angustifolia Mill. under low temperature stress, photosynthesis-related genes were screened and the molecular mechanism were analyzed for this species growing in Harbin, northeast of China. RNA-seq technique and photosynthetic physiology measurement were performed under 20°C, 10°C, and 0°C in this study. The results showed that the observing modified rectangular hyperbola mode could accurately reflect the light-response processes under low temperature stress and the low temperature reduced the light energy utilization of L. angustifolia. The stomatal conductance decreased with the temperature dropping, which was associated with the up-regulation of LaBAM1s, LaMPK4-1 and LaMMK2. The up-regulation of LaMPK4-1 and LaMMK2 was beneficial for ROS scavenging. The improvement of cold resistance in L. angustifolia was related to the up-regulated expression of LaFBA and LaOMTs and down-regulated expression of LaGAPAs, LaGOX, and LaTKL1s with the temperature decreasing. The up-expression of LaPSY at 10°C than it at 20°C could protect the photosynthetic organs from oxidative damage. Moreover, the photosynthetic rates at 10°C and 0°C were close to the measured values, which was related to the interactions of RCA with SBPase and Rubisco with SBPase. These findings could provide a theoretical reference for further exploring the cold tolerance mechanism of L. angustifolia, as an important aromatic plant resource, and promoting its cultivation and distribution in the northeast of China.

Expression of cholesterol synthesis and steroidogenic markers in females of the Chinese brown frog (Rana dybowskii) during prespawning and prehibernation.

The oviduct of the Chinese brown frog (Rana dybowskii) expands in prehibernation rather than in prespawning, which is one of the physiological phenomena that occur in the preparation for hibernation. Steroid hormones are known to regulate oviductal development. Cholesterol synthesis and steroidogenesis may play an important role in the expansion of the oviduct before hibernation. In this study, we investigated the expression patterns of the markers that are involved in the de novo steroid synthesis pathway in the oviduct of R. dybowskii during prespawning and prehibernation. According to histological analysis, the oviduct of R. dybowskii contains epithelial cells, glandular cells, and tubule lumens. During prehibernation, oviductal pipe diameter and weight were significantly larger than during prespawning. 3-Hydroxy-3-methylglutaryl CoA reductase (HMGCR), low-density lipoprotein receptor (LDLR), steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), and steroidogenic factor 1 (SF-1) were detected in epithelial cells in prehibernation and glandular cells during prespawning. HMGCR, LDLR, StAR, and P450scc protein expression levels were higher in prehibernation than during prespawning, but the SF-1 protein expression level did not significantly differ. HMGCR, LDLR, StAR, P450scc (CYP11A1), and SF-1 (NR5A1) mRNA expression levels were significantly higher in prehibernation compared with prespawning. The transcriptome results showed that the steroid synthesis pathway was highly expressed during prehibernation. Existing results indicate that the oviduct is able to synthesize steroid hormones using cholesterol, and that steroid hormones may affect the oviductal functions of R. dybowskii.

Seasonal patterns of prolactin, prolactin receptor, and STAT5 expression in the ovaries of wild ground squirrels (Citellus dauricus Brandt).

Prolactin (PRL) is a hormone crucial for normal reproduction, functioning as an autocrine, paracrine, and endocrine factor. This study aimed to examine the immunolocalization and expression patterns of PRL, prolactin receptor (PRLR), and signal transducer and activator of transcription 5 (STAT5) in the ovaries of wild ground squirrels during both breeding and non-breeding periods. Significant seasonal variations were observed in ovarian weights, with higher values during the breeding season and relatively lower values during the nonbreeding season. PRL, PRLR, STAT5, and p-STAT5 were immunolocalized in granulosa cells and luteal cells during the breeding season, whereas they were exclusively found in granulosa cells during the non-breeding season. The mRNA expression levels of Prl, Prlr, and Stat5 were increased in ovarian tissues during the breeding season compared to the non-breeding season. Moreover, the mean mRNA levels of Prl, Prlr, and Stat5 exhibited a positive correlation with ovarian weights. Both circulating PRL and ovarian PRL concentrations were significantly elevated during the breeding season. Additionally, transcriptomic analysis of ovarian tissues revealed differentially expressed genes possibly associated with ovarian function and mammary gland development, including ovarian follicle development, steroid synthesis, and regulation of reproductive process. These findings suggest that PRL might play an essential endocrine, autocrine, or paracrine role in the regulation of seasonal changes in the ovarian functions in wild ground squirrels.

The habitual characteristic of smart phone use under relevant cues among Chinese college students.

Excessive smartphone use may be habitual behavior induced by cues associated with the phone. Habitual behavior occurs outside of awareness and is characterized by lack of control. It is not like problematic smartphone use (PSU) (Brand et al., 2016), which is used to either limit behavior or produce pleasure and relieve feelings of pain, stress, and failure despite significant harmful consequences. 62 college students participated in experiments to test the effects of visual cues and self-control, which are the important characteristic of habitual behavior in smartphone-related behavior. The results showed that a significantly larger amount of cue-related phone use behavior occurred in the setting where participants (a) had their smartphones in sight and (b) were given no instructions to exert self-control, compared to when neither of the two conditions was imposed. The habitual model is a useful framework for understanding PSU and can help people avoid it with less stress. The results provide substantial implications for reducing the frequency and duration of smartphone use among college populations.

Barriers and Facilitators of Surgical Prehabilitation Adherence from the Patient Perspective: a Mixed Method Study.

BACKGROUND: Adherence to prehabilitation is crucial for optimal benefit, but reasons for low adherence to home-based programs remain unexplored. Our aim was to identify and explore barriers and facilitators to prehabilitation adherence among patients undergoing abdominal surgery. METHODS: Nested in a single-center randomized controlled trial on prehabilitation (Perioperative Optimization With Enhanced Recovery (POWER)), this study had an explanatory sequential design with a connect integration. Patients randomized to the intervention arm were included in the quantitative analysis, and a subset of them was invited for a semi-structured interview. The exposure was the frequency of barriers to physical activity and healthy eating, and the outcome was adherence to those components of prehabilitation. Logistic or linear regression was used as appropriate. RESULTS: Among 133 participants in the intervention arm, 116 (87.2%) completed the initial survey ((56.9% women, median age 61 years old (IQR 49.0; 69.4)). The most frequent barriers to exercise and healthy eating were medical issues (59%) and lack of motivation (31%), respectively. There was no significant association between the barriers to physical activity score and adherence to this component of the program (OR 0.89, 95% CI 0.78-1.02, p=0.09). Higher barriers to healthy eating scores were associated with lower Mediterranean diet scores pre- and post-intervention (coef.: -0.32, 95% CI: -0.49; -0.15, p<0.001; and coef.: -0.27, 95% CI: -0.47; -0.07, p=0.01, respectively). Interviews with 15 participants revealed that participating in prehabilitation was a motivator for healthy eating and exercising through goal setting, time-efficient workouts, and promoting self-efficacy. CONCLUSIONS: We identified key barriers to be addressed and facilitators to be leveraged in future prehabilitation programs. TRIAL REGISTRATION: NCT04504266.

Podophyllotoxin-loaded PEGylated E-selectin peptide conjugate targeted cancer site to enhance tumor inhibition and reduce side effect.

E-selectin, which is highly expressed in vascular endothelial cells near tumor and get involved in the all tumor growth steps: occurrence, proliferation and metastasis, is considered as a promise targeted protein for antitumor drug discovery. Herein, we would like to report the design, preparation and the anticancer evaluation of the peptide-PEG-podophyllotoxin conjugate(PEG-Pep-PODO), in which the short peptide (CIELLQAR) was used as the E-selectin ligand for the targeting purpose and the PEG portion the molecule got the conjugate self-assembled to form a water soluble nanoparticle. In vitro release study showed that the conjugated and entrapped PODO could be released simultaneously in the presence of GSH (highly expressed in tumor environmental conditions) and the GSH would catalyze the break of the disufur bond which linked of the PODO and the peptide-PEG portion of the conjugate. Cell adhesion test of the PEG-Pep-PODO indicated that E-selectin ligand peptide CIELLQAR could get specifically and efficiently binding to the E-selectin expressing human umbilical vein endothelial cells (HUVEC). In vitro cytotoxicity assay further revealed that PEG-Pep-PODO significantly improved the selectivity of PEG-Pep-PODO for killing the tumor cells and normal cells compared with PODO solution formulation. More importantly, the in vivo experiment demonstrated that the conjugate would accumulate of the PODO payload in tumor through targeting endothelial cells in the tumor microenvironment, which resulted in the much improved in vivo inhibition of tumor growth, intratumoral microvessel density, and decreased systemic toxicity of this nanoparticle over the free PODO. Furthermore, this water soluble conjugate greatly improved the pharmacokinetic properties of the mother molecule.

Seasonal expressions of the translocator protein (18 kDa), voltage-dependent anion channel, and steroidogenic acute regulatory protein in the scent glands of muskrats (Ondatra zibethicus).

Steroidogenesis machinery involves the steroidogenic acute regulatory protein (StAR), which regulates cholesterol transfer within the mitochondria, and the transport of cholesterol via a channel composed of 18-kDa translocator protein (TSPO), the voltage-dependent anion channel (VDAC) plus some accessory proteins. In this study, we investigated the immunolocalizations and expressions of StAR, TSPO, VDAC and cytochrome P450 side chain cleavage enzyme (P450scc, CYP11A1) in the scent glands of muskrats (Ondatra zibethicus) during the breeding and non-breeding periods. StAR, TSPO, VDAC and CYP11A1 were immunolocalized in the scent glandular, interstitial and epithelial cells in both breeding and non-breeding seasons with stronger immunostaining in the breeding season. The mRNA expression levels of StAR, TSPO, VDAC and CYP11A1 were higher in the scent glands of the breeding season than those of the non-breeding season. The circulating follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) as well as scent glandular T and dihydrotestosterone (DHT) concentrations were also significantly higher in the breeding season. Additionally, the transcriptomic study in the scent glands identified that differentially expressed genes might be related to the lipid metabolic process, integral component of membrane, and steroid hormone receptor activity and hormone activity using GO analysis. Further in vitro study verified that StAR, TSPO, VDAC and CYP11A1 expression levels increased significantly after human chorionic gonadotropin, hCG/FSH treatment compared with the control group. The KEGG pathway enriched by differentially expressed genes detected to be involved in endocrine system or amino acid metabolism. These findings suggested that the scent glands of the muskrats have ability to synthesize steroids de novo, and that the steroid hormones may have an important regulatory role in the scent glandular function via an autocrine/paracrine pathway.