The tight junction protein Claudin-5 limits endothelial cell motility.

Steinberg's differential adhesion hypothesis suggests that adhesive mechanisms are important for sorting of cells and tissues during morphogenesis (Steinberg, 2007). During zebrafish vasculogenesis, endothelial cells sort into arterial and venous vessel beds but it is unknown whether this involves adhesive mechanisms. Claudins are tight junction proteins regulating the permeability of epithelial and endothelial tissue barriers. Previously, the roles of claudins during organ development have exclusively been related to their canonical functions in determining paracellular permeability. Here, we use atomic force microscopy to quantify claudin-5-dependent adhesion and find that this strongly contributes to the adhesive forces between arterial endothelial cells. Based on genetic manipulations, we reveal a non-canonical role of Claudin-5a during zebrafish vasculogenesis, which involves the regulation of adhesive forces between adjacent dorsal aortic endothelial cells. In vitro and in vivo studies demonstrate that loss of claudin-5 results in increased motility of dorsal aorta endothelial cells and in a failure of the dorsal aorta to lumenize. Our findings uncover a novel role of claudin-5 in limiting arterial endothelial cell motility, which goes beyond its traditional sealing function during embryonic development.

Circular RNA circ-FoxO3 attenuates blood-brain barrier damage by inducing autophagy during ischemia/reperfusion.

Blood-brain barrier (BBB) damage can be a result of central nervous system (CNS) diseases and may be a cause of CNS deterioration. However, there are still many unknowns regarding effective and targeted therapies for maintaining BBB integrity during ischemia/reperfusion (I/R) injury. In this study, we demonstrate that the circular RNA of FoxO3 (circ-FoxO3) promotes autophagy via mTORC1 inhibition to attenuate BBB collapse under I/R. Upregulation of circ-FoxO3 and autophagic flux were detected in brain microvessel endothelial cells in patients with hemorrhagic transformation and in mice models with middle cerebral artery occlusion/reperfusion. In vivo and in vitro studies indicated that circ-FoxO3 alleviated BBB damage principally by autophagy activation. Mechanistically, we found that circ-FoxO3 inhibited mTORC1 activity mainly by sequestering mTOR and E2F1, thus promoting autophagy to clear cytotoxic aggregates for improving BBB integrity. These results demonstrate that circ-FoxO3 plays a novel role in protecting against BBB damage, and that circ-FoxO3 may be a promising therapeutic target for neurological disorders associated with BBB damage.

Correlations of Omentin-1 and Leptin with Bone Metabolism and Plasma Glucose Upon Type 2 Diabetes Mellitus and Osteoporosis.

BACKGROUND: The goal was to investigate the correlations of peripheral blood Omentin-1 and leptin (LEP) levels with bone metabolism and plasma glucose in patients with type 2 diabetes mellitus (T2DM) complicated with oste-oporosis (OP). METHODS: One hundred patients with T2DM admitted from September 2019 to September 2021 were divided into group A (n = 36, OP with T-score ≤ -2.5), group B (n = 50, osteopenia with T-score between -1 and -2.5), and group C (n = 14, non-OP with T-score > -1) according to the values of bone mineral density (BMD). Thirty healthy adults physically examined in the same period were selected as group D. The levels of peripheral blood Omentin-1 and LEP, bone metabolism, and plasma glucose were compared among the four groups. The correlations of peripheral blood Omentin-1 and LEP levels with bone metabolism and plasma glucose were explored by Pearson's analysis. RESULTS: In group A, the levels of Omentin-1 and LEP in peripheral blood were lowest, the serum levels of beta C-terminal cross-linked telopeptides of type I collagen (ß-CTX) and osteocalcin (OCN) were highest, the serum level of total N-terminal propeptide of type I procollagen (tPINP) was lowest, and the levels of fasting plasma glucose (FPG), 2-hours postprandial plasma glucose (2hPG) and glycosylated hemoglobin A1c (HbA1c) were highest, se-quentially followed by those of group B, group C, and group D (p < 0.05). Omentin-1 and LEP in peripheral blood were negatively correlated with ß-CTX, OCN, 2hPG, and HbA1c and positively correlated with tPINP and FPG (p < 0.05). CONCLUSIONS: The expressions of Omentin-1 and LEP in peripheral blood have correlations with bone metabolism and plasma glucose in patients with T2DM complicated with OP.

A Bi-level representation learning model for medical visual question answering.

Medical Visual Question Answering (VQA) targets at answering questions related to given medical images and it contains tremendous potential in healthcare services. However, researches on medical VQA are still facing challenges, particularly on how to learn a fine-grained multimodal semantic representation from relatively small volume of data resources for answer prediction. Moreover, the long-tailed distribution labels of medical VQA data frequently result in poor performance of models. To this end, we propose a novel bi-level representation learning model with two reasoning modules to learn bi-level representations for the medical VQA task. One is sentence-level reasoning to learn sentence-level semantic representations from multimodal input. The other is token-level reasoning that employs an attention mechanism to generate a multimodal contextual vector by fusing image features and word embeddings. The contextual vector is used to filter irrelevant semantic representations from sentence-level reasoning to generate a fine-grained multimodal representation. Furthermore, a label-distribution-smooth margin loss is proposed to minimize generalization error bound of long-tailed distribution datasets by modifying margin bound of different labels in training set. Based on standard VQA-Rad dataset and PathVQA dataset, the proposed model achieves 0.7605 and 0.5434 on accuracy, 0.7741 and 0.5288 on F1-score, respectively, outperforming a set of state-of-the-art baseline models.

The Circular RNA circSKA3 Binds Integrin ß1 to Induce Invadopodium Formation Enhancing Breast Cancer Invasion.

Metastatic cancer cells invade surrounding tissues by forming dynamic actin-based invadopodia, which degrade the surrounding extracellular matrix and allow cancer cell invasion. Regulatory RNAs, including circular RNA, have been implicated in this process. By microarray, we found that the circular RNA circSKA3 was highly expressed in breast cancer cells and human breast cancer tissues. We further found that the invasive capacity of breast cancer cells was positively correlated with circSKA3 expression, through the formation of invadopodia. Mechanistically, we identified Tks5 and integrin ß1 as circSKA3 binding partners in these tumor-derived invadopodia. Ectopic circSKA3 expression conferred increased tumor invasiveness in vitro and in vivo. We further identified the RNA-protein binding sites between circSKA3, Tks5 and integrin ß1. In tumor formation assays, we found that circSKA3 expression promoted tumor progression and invadopodium formation. Mutation of the circSKA3 binding sites or transfection with blocking oligos abrogated the observed effects. Thus, we provide evidence that the circular RNA circSKA3 promotes tumor progression by complexing with Tks5 and integrin ß1, inducing invadopodium formation.

Effect of photoperiods on development and acaricide susceptibility in the two-spotted spider mite, Tetranychus urticae.

Demographic analysis of Tetranychus urticae under photoperiods of 12L:12D, 14L:10D and 18L:6D at 75% relative humidity and 25 °C showed that the developmental time and oviposition per female declined with increasing light period. The nymph, oviposition and adult stages were significantly shortened, resulting in shorter generation duration and faster population decline, but there was no effect on egg and larval stages of T. urticae. Kaplan-Meier survival analysis followed by a log-rank test indicated that the mean and median survival times were 40.4 (12:12), 39.1 (14:10), and 38.1 (18:6) days, and 42.0, 40.0, 39.0 days, respectively-this difference among photoperiods was significant. The total number of eggs per female under the three photoperiods was 69.63 (12:12), 77.44 (14:10) and 42.17 (18:6), respectively, and the sex ratios were 70.0, 81.6 and 71.6% female offspring. Under 14 h light, T. urticae experienced its highest net reproductive rate (R0 = 83.0577), intrinsic rate of increase (rm = 0.2740), finite rate of increase (λ = 1.3153), lowest mean generation time (T = 16.1277 days) and population doubling time (Dt = 2.5294 days). All demographic parameters displayed a decreasing relationship with the light phase under the three photoperiods. No significant difference in susceptibilities to the acaricides diafenthiuron and propargite was shown among the three photoperiods. The results of this study indicated that the 14L:10D photoperiod was optimal for the development and reproduction of T. urticae, and the 18L:6D period was disadvantageous for spider mite development.

Niacin nutrition and rumen-protected niacin supplementation in dairy cows: an updated review.

As the precursor to NAD+ and NADP+, niacin is important for catabolic and anabolic redox reactions. In addition, niacin is known for its anti-lipolytic action via a hydroxycarboxylic acid-2-receptor-dependent mechanism. The anti-lipolytic effects of traditional free niacin supplementation during transition periods had been studied extensively, but the reported effects are ambiguous. In the past decade, a series of studies were conducted to evaluate the effects of rumen-protected niacin (RPN) on production performance and metabolic status in early lactation and on heat stress in dairy cows. Feeding RPN seems more effective than free niacin regarding increasing circulating niacin concentration. The rebound of plasma NEFA was found after termination of niacin abomasal infusion. Feeding RPN or infusion of niacin via the abomasum could suppress lipolysis and reduce insulin resistance in early lactation. Additionally, RPN supplementation could possibly relieve heat stress through vasodilation during moderate to severe heat stress condition. However, these beneficial effects of niacin supplementation have not always been observed. The inconsistent results across studies may be related to dosages of niacin supplementation, rebound of plasma NEFA concentration, stage of lactation or severity of heat stress. Overall, the current review is to present updated information on niacin nutrition in dairy cows and the recommendations are given for future research.

Activatable Small-Molecule Photoacoustic Probes that Cross the Blood-Brain Barrier for Visualization of Copper(II) in Mice with Alzheimer's Disease.

Copper enrichment in the brain is highly related to Alzheimer's disease (AD) pathogenesis, but in vivo tracing of Cu2+ in the brain by imaging techniques is still a great challenge. In this work, we developed a series of activatable photoacoustic (PA) probes with low molecular weights (less than 438 Da), RPS1-RPS4, which can specifically chelate with Cu2+ to form radicals with turn-on PA signals in the near-infrared (NIR) region. Introducing the electron-donating group N,N-dimethylaniline into the probe was found to significantly enhance the radical stability and PA intensity. The best probe in the series, RPS1, showed a fast response (within seconds) to Cu2+ with high selectivity and a low PA detection limit of 90.9 nm. Owing to the low molecular weight and amphiphilic structure, RPS1 could effectively cross the blood-brain barrier (BBB) and thus allowed us, for the first time, to visualize Cu2+ in vivo via PA imaging in the brains of AD mice.

The Circular RNA Interacts with STAT3, Increasing Its Nuclear Translocation and Wound Repair by Modulating Dnmt3a and miR-17 Function.

Delayed or impaired wound healing is a major health issue worldwide, especially in patients with diabetes and atherosclerosis. Here we show that expression of the circular RNA circ-Amotl1 accelerated healing process in a mouse excisional wound model. Further studies showed that ectopic circ-Amotl1 increased protein levels of Stat3 and Dnmt3a. The increased Dnmt3a then methylated the promoter of microRNA miR-17, decreasing miR-17-5p levels but increasing fibronectin expression. We found that Stat3, similar to Dnmt3a and fibronectin, was a target of miR-17-5p. Decreased miR-17-5p levels would increase expression of fibronectin, Dnmt3a, and Stat3. All of these led to increased cell adhesion, migration, proliferation, survival, and wound repair. Furthermore, we found that circ-Amotl1 not only increased Stat3 expression but also facilitated Stat3 nuclear translocation. Thus, the ectopic expressed circ-Amotl1 and Stat3 were mainly translocated to nucleus. In the presence of circ-Amotl1, Stat3 interacted with Dnmt3a promoter with increased affinity, facilitating Dnmt3a transcription. Ectopic application of circ-Amotl1 accelerating wound repair may shed light on skin wound healing clinically.

Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2.

Most RNAs generated by the human genome have no protein-coding ability and are termed non-coding RNAs. Among these include circular RNAs, which include exonic circular RNAs (circRNA), mainly found in the cytoplasm, and intronic RNAs (ciRNA), predominantly detected in the nucleus. The biological functions of circular RNAs remain largely unknown, although ciRNAs have been reported to promote gene transcription, while circRNAs may function as microRNA sponges. We demonstrate that the circular RNA circ-Foxo3 was highly expressed in non-cancer cells and were associated with cell cycle progression. Silencing endogenous circ-Foxo3 promoted cell proliferation. Ectopic expression of circ-Foxo3 repressed cell cycle progression by binding to the cell cycle proteins cyclin-dependent kinase 2 (also known as cell division protein kinase 2 or CDK2) and cyclin-dependent kinase inhibitor 1 (or p21), resulting in the formation of a ternary complex. Normally, CDK2 interacts with cyclin A and cyclin E to facilitate cell cycle entry, while p21works to inhibit these interactions and arrest cell cycle progression. The formation of this circ-Foxo3-p21-CDK2 ternary complex arrested the function of CDK2 and blocked cell cycle progression.

Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses.

AIMS: Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo approaches. METHODS AND RESULTS: Using the approaches of molecular and cellular biology, we show that a circular RNA generated from a member of the forkhead family of transcription factors, Foxo3, namely circ-Foxo3, was highly expressed in heart samples of aged patients and mice, which was correlated with markers of cellular senescence. Doxorubicin-induced cardiomyopathy was aggravated by ectopic expression of circ-Foxo3 but was relieved by silencing endogenous circ-Foxo3. We also found that silencing circ-Foxo3 inhibited senescence of mouse embryonic fibroblasts and that ectopic expression of circ-Foxo3 induced senescence. We found that circ-Foxo3 was mainly distributed in the cytoplasm, where it interacted with the anti-senescent protein ID-1 and the transcription factor E2F1, as well as the anti-stress proteins FAK and HIF1α. CONCLUSION: We conclude that ID-1, E2F1, FAK, and HIF1α interact with circ-Foxo3 and are retained in the cytoplasm and could no longer exert their anti-senescent and anti-stress roles, resulting in increased cellular senescence.

Maternal nutrition modulates fetal development by inducing placental efficiency changes in gilts.

BACKGROUND: Intra-uterine growth restriction (IUGR) and fetal overgrowth increase risks to postnatal health. Maternal nutrition is the major intrauterine environmental factor that alters fetal weight. However, the mechanisms underlying the effects of maternal nutrition on fetal development are not entirely clear. We developed a pig model, and using isobaric tags for relative and absolute quantification (iTRAQ), we investigated alterations in the placental proteome of gilts on a normal-energy-intake (Con) and high-energy-intake (HE) diet. RESULTS: In the Con group, heavy and light fetuses were found at the tubal and cervical ends of the uterus respectively at 90 d of gestation. Moreover, the heavy fetuses had a higher glucose concentration than the light fetuses. However, a higher uniformity was noted in the HE group. Placental promoters between these two positions indicated that 78 and 50 differentially expressed proteins were detected in the Con and HE groups respectively. In the Con group, these proteins were involved in lipid metabolism (HADHA, AACS, CAD), nutrient transport (GLUT, SLC27A1), and energy metabolism (NDUFV1, NDUFV2, ATP5C1). However, in the HE group they mainly participated in transcriptional and translational regulation, and intracellular vesicular transport. CONCLUSIONS: Our findings revealed that maternal nutrition may alter birth weight mainly through the modulation of placental lipid and energy metabolism, which also provides a possible mechanism to explain the higher uniformity of fetal weight in gilts fed a HE diet.

The combination of osthole with baicalin protects mice from Staphylococcus aureus pneumonia.

We reported the inhibition of α-Hemolysin (Hla) production in methicillin-resistant Staphylococcus aureus USA300 by osthole and further investigated the combination of osthole and baicalin in the treatment of staphylococcal pneumonia. Using cytotoxicity assays and a mouse model of intranasal lung infection, we evaluated the effect of combined therapy. Our results suggest that the combination of osthole and baicalin alleviated S. aureus-mediated A549 cell injury and protected mice from S. aureus pneumonia.

Synergistic inhibitory effect of scopoletin and bisdemethoxycurcumin on Tetranychus cinnabarinus (Boisduval) (Acari: Tetranychidae).

The study aimed to investigate the synergistic activity of scopoletin and bisdemethoxycurcumin (BDMC) against the carmine spider mite Tetranychus cinnabarinus. The acaricidal activities of mixtures of scopoletin and BDMC against T. cinnabarinus female adults were measured via slide dipping and leaf disc dipping. A mathematical model was established by SPSS software. Bioassays for multiple effects including contact, ovicidal, cowpea root intake, repellency and oviposition inhibitory activity were carried out. The optimal mass ratio of the mixture of scopoletin and BDMC (at their respective LC(50)), the median lethal concentration (LC(50)) and the co-toxicity coefficient were 7:6, 0.19 mg/mL and 129, respectively. LC(50) values of contact activities of the mixture at optimal ratio against adults, nymphs, larvae, and eggs were 0.19, 0.18, 0.06, and 1.52 mg/mL, respectively. LC(50) values of cowpea root intake activity against adults and nymphs were 5.62 and 6.52 mg/mL, respectively. The highest repellent rates against adults and nymphs were 69.5% and 72.5%, respectively. The mixture of scopoletin and BDMC at the optimal mass ratio possessed strong acaricidal activity against T. cinnabarinus at various developmental stages.

Actively Q-switched ytterbium-doped fiber laser by an all-optical Q-switcher based on graphene saturable absorber.

We demonstrate an all-optical Q-switcher based on graphene saturable absorber (GSA). Due to the cross absorption modulation (XAM) effect in graphene, we can change the transmittance of signal light periodically by introducing a train of laser pulses into graphene. This allows controlling the Q-factor of the cavity. This Q-switcher has many advantages such as all-fiber structure, all-optical modulation, broadband applications. With this Q-switcher, we have successfully fabricated an actively Q-switched ytterbium-doped fiber laser. The pulse repetition rate can be tuned from 30.32 kHz to 101.29 kHz. What's more, synchronization of the Q-switched laser pulses and modulation laser pulses can be realized, which has many potential applications such as nonlinear frequency conversion, multi-color pump probe spectroscopy and Raman scattering spectroscopy.

Specific binding of Clostridium perfringens enterotoxin fragment to Claudin-b and modulation of zebrafish epidermal barrier.

Claudins (Cldn) are the major components of tight junctions (TJs) sealing the paracellular cleft in tissue barriers of various organs. Zebrafish Cldnb, the homolog of mammalian Cldn4, is expressed at epithelial cell-cell contacts and is important for regulating epidermal permeability. The bacterial toxin Clostridium perfringens enterotoxin (CPE) has been shown to bind to a subset of mammalian Cldns. In this study, we used the Cldn-binding C-terminal domain of CPE (194-319 amino acids, cCPE 194-319 ) to investigate its functional role in modulating zebrafish larval epidermal barriers. In vitro analyses show that cCPE 194-319 removed Cldn4 from epithelial cells and disrupted the monolayer tightness, which could be rescued by the removal of cCPE 194-319. Incubation of zebrafish larvae with cCPE 194-319 removed Cldnb specifically from the epidermal cell membrane. Dye diffusion analysis with 4-kDa fluorescent dextran indicated that the permeability of the epidermal barrier increased due to cCPE 194-319 incubation. Electron microscopic investigation revealed reversible loss of TJ integrity by Cldnb removal. Collectively, these results suggest that cCPE 194-319 could be used as a Cldnb modulator to transiently open the epidermal barrier in zebrafish. In addition, zebrafish might be used as an in vivo system to investigate the capability of cCPE to enhance drug delivery across tissue barriers.

Flexible, Transparent, Thickness-Controllable SWCNT/PEDOT:PSS Hybrid Films Based on Coffee-Ring Lithography for Functional Noncontact Sensing Device.

Flexible transparent conductive films (FTCFs) as the essential components of the next generation of functional circuits and devices are presently attracting more attention. Here, a new strategy has been demonstrated to fabricate thickness-controllable FTCFs through coffee ring lithography (CRL) of single-wall carbon nanotube (SWCNT)/poly(3,4-ethylenedioxythiophene)-polystyrenesulfonate ( PEDOT: PSS) hybrid ink. The influence of ink concentration and volume on the thickness and size of hybrid film has been investigated systematically. Results show that the final FTCFs present a high performance, including a homogeneous thickness of 60-65 nm, a sheet resistance of 1.8 kohm/sq, a visible/infrared-range transmittance (79%, PET = 90%), and a dynamic mechanical property (>1000 cycle, much better than ITO film), respectively, when SWCNT concentration is 0.2 mg/mL, ink volume is 0.4 µL, drying at room temperature. Moreover, the benefits of these kinds of FTCFs have been verified through a full transparent, flexible noncontact sensing panel (3 × 4 sensing pixels) and a flexible battery-free wireless sensor based on a humidity sensing mechanism, showing excellent human/machine interaction with high sensitivity, good stability, and fast response/recovery ability.

Molecular cloning and expression of glutathione S-transferases involved in propargite resistance of the carmine spider mite, Tetranychus cinnabarinus (Boisduval).

The carmine spider mite (CSM) Tetranychus cinnabarinus has become a serious pest in China and has developed resistance to acaricide propargite as it is used to control mites worldwide including T. cinnabarinus. In this study, a resistant colony of T. cinnabarinus, PRR34 (37.78-fold resistant ratio), was established after 34 generations of propargite selection, and cross-resistance patterns of 7 other acaricides were determined in comparison with a susceptible strain (SS). The contribution of detoxification enzymes to propargite tolerance were investigated using biological, biochemical and molecular approaches. Enzyme inhibitor synergist tests suggested glutathione S-transferases (GST) involvement in propargite-resistance of PRR34, and GST activity against 1-chloro-2,4-dinitrobenzene (CDNB) was correlated with the development of resistance. Eight novel GST genes (TcGSTd1, TcGSTd2, TcGSTm1, TcGSTm2, TcGSTm3, TcGSTm4 and TcGSTm5) were cloned, and phylogenetic analysis showed that the eight GST genes were most closely related to GST family delta and mu from Tetranychusurticae. Quantitative RT-PCR revealed that the expression level of GSTs in PPR34 strain increased in larvae, nymphs and adults, while decreased in eggs compared with that of SS. Collectively, these results support a role of GSTs in mediating resistance to propargite in the PRR34 strain. TcGSTd1,TcGSTd2 and TcGSTm2 genes might play significant roles in propargite resistance of CSM, especially at adult stage. This is the first attempt to define specific genes involved in GST mediated propargite resistance of T. cinnabarinus at the transcriptional level.

Exploration beyond osteoarthritis: the association and mechanism of its related comorbidities.

Osteoarthritis is the most prevalent age-related degenerative joint disease and a leading cause of pain and disability in aged people. Its etiology is multifaceted, involving factors such as biomechanics, pro-inflammatory mediators, genetics, and metabolism. Beyond its evident impact on joint functionality and the erosion of patients' quality of life, OA exhibits symbiotic relationships with various systemic diseases, giving rise to various complications. This review reveals OA's extensive impact, encompassing osteoporosis, sarcopenia, cardiovascular diseases, diabetes mellitus, neurological disorders, mental health, and even cancer. Shared inflammatory processes, genetic factors, and lifestyle elements link OA to these systemic conditions. Consequently, recognizing these connections and addressing them offers opportunities to enhance patient care and reduce the burden of associated diseases, emphasizing the need for a holistic approach to managing OA and its complications.

Tryptophan metabolism and piglet diarrhea: Where we stand and the challenges ahead.

The intestinal architecture of piglets is vulnerable to disruption during weaning transition and leads to diarrhea, frequently accompanied by inflammation and metabolic disturbances (including amino acid metabolism). Tryptophan (Trp) plays an essential role in orchestrating intestinal immune tolerance through its metabolism via the kynurenine, 5-hydroxytryptamine, or indole pathways, which could be dictated by the gut microbiota either directly or indirectly. Emerging evidence suggests a strong association between piglet diarrhea and Trp metabolism. Here we aim to summarize the intricate balance of microbiota-host crosstalk by analyzing alterations in both the host and microbial pathways of Trp and discuss how Trp metabolism may affect piglet diarrhea. Overall, this review could provide valuable insights to explore effective strategies for managing piglet diarrhea and the related challenges.