Gallbladder dysfunction caused by MYPT1 ablation triggers cholestasis-induced hepatic fibrosis in mice.

BACKGROUND: The incidence of gallbladder diseases is as high as 20%, but whether gallbladder diseases contribute to hepatic disorders remains unknown. METHODS: Here, we established an animal model of gallbladder dysfunction and assessed the role of a diseased gallbladder in cholestasis-induced hepatic fibrosis (CIHF). RESULTS: Mice with smooth muscle-specific deletion of Mypt1, the gene encoding the main regulatory subunit of myosin light chain phosphatase (myosin phosphatase target subunit 1 [MYPT1]), had apparent dysfunction of gallbladder motility. This dysfunction was evidenced by abnormal contractile responses, namely, inhibited cholecystokinin 8-mediated contraction and nitric oxide-resistant relaxation. As a consequence, the gallbladder displayed impaired bile filling and biliary tract dilation comparable to the alterations in CIHF. Interestingly, the mutant animals also displayed CIHF features, including necrotic loci by the age of 1 month and subsequently exhibited progressive fibrosis and hyperplastic/dilated bile ducts. This pathological progression was similar to the phenotypes of the animal model with bile duct ligation and patients with CIHF. The characteristic biomarker of CIHF, serum alkaline phosphatase activity, was also elevated in the mice. Moreover, we observed that the myosin phosphatase target subunit 1 protein level was able to be regulated by several reagents, including lipopolysaccharide, exemplifying the risk factors for gallbladder dysfunction and hence CIHF. CONCLUSIONS: We propose that gallbladder dysfunction caused by myosin phosphatase target subunit 1 ablation is sufficient to induce CIHF in mice, resulting in impairment of the bile transport system.

Crohn's disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data.

Crohn's disease (CD) is caused by immune, environmental, and genetic factors. It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs. To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data. The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction. More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

SAGESDA: Multi-GraphSAGE networks for predicting SnoRNA-disease associations.

Over the years, extensive research has highlighted the functional roles of small nucleolar RNAs in various biological processes associated with the development of complex human diseases. Therefore, understanding the existing relationships between different snoRNAs and diseases is crucial for advancing disease diagnosis and treatment. However, classical biological experiments for identifying snoRNA-disease associations are expensive and time-consuming. Therefore, there is an urgent need for cost-effective computational techniques that can enhance the efficiency and accuracy of prediction. While several computational models have already been proposed, many suffer from limitations and suboptimal performance. In this study, we introduced a novel Graph Neural Network-based (GNN) classification model, called SAGESDA, which is implemented through the GraphSAGE architecture with attention for the prediction of snoRNA-disease associations. The classifier leverages local neighbouring nodes in a heterogeneous network to generate new node embeddings through message passing. The mini-batch gradient descent technique was applied to divide the graph into smaller sub-graphs, which enhances the model's accuracy, speed and scalability. With these advancements, SAGESDA attained an area under the receiver operating characteristic (ROC) curve (AUC) of 0.92 using the standard dot product classifier, surpassing previous related studies. This notable performance demonstrates that SAGESDA is a promising model for predicting unknown snoRNA-disease associations with high accuracy. The SAGESDA implementation details can be obtained from https://github.com/momanyibiffon/SAGESDA.git.

Antagonizing adipose tissue-derived exosome miR-103-hepatocyte phosphatase and tensin homolog pathway alleviates autophagy in non-alcoholic steatohepatitis: A trans-cellular crosstalk.

BACKGROUND: Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis (NASH). However, the underlining mechanism is still unclear, where adipose tissue (AT) derived exosomes may actively participate. MicroRNAs (miRNAs) are commonly secreted from exosomes for cell communication. Though the regulation of miR-103 on insulin sensitivity has been reported, the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices. AIM: To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods. METHODS: The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control. The effect of miR-103 on NASH progression was also explored by antagonizing miR-103, including steatosis and inflammation degree changes. The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog (PTEN) was confirmed by dual-luciferase reporter assay. The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells. Finally, the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments. RESULTS: The expression of miR-103 was increased in NASH mice, compared to the control, and inhibition of miR-103 could alleviate NASH. The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN. MiR-103-anta decreased p-AMPKa, p-mammalian target of rapamycin (mTOR), and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice. Similar results were also observed in NASH-like cells, and further experiments showed PTEN silencing inhibited the effect of miR-103-anta. AT derived-exosome miR-103 aggravated NASH and increased the expressions of p-AMPKa, p-mTOR, and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice. CONCLUSION: AT derived-exosome increased the levels of miR-103 in the liver, and miR-103 aggravated NASH. Mechanically, miR-103 could interact with PTEN and inhibit autophagy.

MYPT1 reduction is a pathogenic factor of erectile dysfunction.

Erectile dysfunction (ED) is closely associated with smooth muscle dysfunction, but its underlying mechanisms remains incompletely understood. We here reported that the reduced expression of myosin phosphatase target subunit 1 (MYPT1), the main regulatory unit of myosin light chain phosphatase, was critical for the development of vasculogenic ED. Male MYPT1 knockout mice had reduced fertility and the penises displayed impaired erections as evidenced by reduced intracavernous pressure (ICP). The penile smooth muscles of the knockout mice displayed enhanced response to G-Protein Couple Receptor agonism and depolarization contractility and resistant relaxation. We further identified a natural compound lotusine that increased the MYPT1 expression by inhibiting SIAH1/2 E3 ligases-mediated protein degradation. This compound sufficiently restored the ICP and improved histological characters of the penile artery of Mypt1 haploinsufficiency mice. In diabetic ED mice (db/db), the decreased expression of MYPT1 was measured, and ICP was improved by lotusine treatment. We conclude that the reduction of MYPT1 is the major pathogenic factor of vasculogenic ED. The restoration of MYPT1 by lotusine improved the function of injured penile smooth muscles, and could be a novel strategy for ED therapy.

Tas2R activation relaxes airway smooth muscle by release of Gαt targeting on AChR signaling.

Both chronic obstructive pulmonary disease (COPD) and asthma are severe respiratory diseases. Bitter receptor-mediated bronchodilation is a potential therapy for asthma, but the mechanism underlying the agonistic relaxation of airway smooth muscle (ASM) is not well defined. By exploring the ASM relaxation mechanism of bitter substances, we observed that pretreatment with the bitter substances nearly abolished the methacholine (MCh)-induced increase in the ASM cell (ASMC) calcium concentration, thereby suppressing the calcium-induced contraction release. The ASM relaxation was significantly inhibited by simultaneous deletion of three Gαt proteins, suggesting an interaction between Tas2R and AChR signaling cascades in the relaxation process. Biochemically, the Gαt released by Tas2R activation complexes with AChR and blocks the Gαq cycling of AChR signal transduction. More importantly, a bitter substance, kudinoside A, not only attenuates airway constriction but also significantly inhibits pulmonary inflammation and tissue remodeling in COPD rats, indicating its modulation of additional Gαq-associated pathological processes. Thus, our results suggest that Tas2R activation may be an ideal strategy for halting multiple pathological processes of COPD.

A Shigella species variant is causally linked to intractable functional constipation.

Intractable functional constipation (IFC) is the most severe form of constipation, but its etiology has long been unknown. We hypothesized that IFC is caused by refractory infection by a pathogenic bacterium. Here, we isolated from patients with IFC a Shigella species - peristaltic contraction-inhibiting bacterium (PIB) - that significantly inhibited peristaltic contraction of the colon by production of docosapentenoic acid (DPA). PIB colonized mice for at least 6 months. Oral administration of PIB was sufficient to induce constipation, which was reversed by PIB-specific phages. A mutated PIB with reduced DPA was incapable of inhibiting colonic function and inducing constipation, suggesting that DPA produced by PIB was the key mediator of the genesis of constipation. PIBs were detected in stools of 56% (38 of 68) of the IFC patients, but not in those of non-IFC or healthy individuals (0 of 180). DPA levels in stools were elevated in 44.12% (30 of 68) of the IFC patients but none of the healthy volunteers (0 of 97). Our results suggest that Shigella sp. PIB may be the critical causative pathogen for IFC, and detection of fecal PIB plus DPA may be a reliable method for IFC diagnosis and classification.

Substrate Viscoelasticity Amplifies Distinctions between Transient and Persistent LPS-Induced Signals.

Macrophages settle in heterogeneous microenvironments rendered by other cells and extracellular matrices. It is well known that chemical stimuli direct macrophage behavior; however, the contributions of viscosity, which increases in inflammatory tissues but not in tumors, are ignored in immune responses including effective activation and timely attenuation. This paper demonstrates that transient lipopolysaccharide (LPS)-treated macrophages benefit from elastic substrates, whereas viscoelastic substrates with similar storage moduli support the inflammatory responses of macrophages under persistent stimulations and consequently amplify the distinctions between the transient and persistent LPS-induced transcriptional programs. Actin filaments (F-actin) fluctuate in line with transcriptional profiles and can be mathematically predicted by a clutch-like model. Moreover, viscosity modifies immune responses through transcription factors NF-κB and C/EBPδ, which act as switches discriminating transient and persistent infections. Interestingly, enhanced immune responses, consistent with the lower activated states, are attenuated promptly by the actin nucleation-related translocation of ATF3 to nuclei. These findings suggest that the substrate viscoelasticity induces more intense inflammation only in the case of persistent infection and promotes more sensitively perceiving the duration of infection through the F-actin correlated transcription factors. In addition, it may facilitate the cognition of immune response in inflammatory and cancerous microenvironments and have a wide range of applications in inflammatory regulations.

The thymus regulates skeletal muscle regeneration by directly promoting satellite cell expansion.

The thymus is the central immune organ, but it is known to progressively degenerate with age. As thymus degeneration is paralleled by the wasting of aging skeletal muscle, we speculated that the thymus may play a role in muscle wasting. Here, using thymectomized mice, we show that the thymus is necessary for skeletal muscle regeneration, a process tightly associated with muscle aging. Compared to control mice, the thymectomized mice displayed comparable growth of muscle mass, but decreased muscle regeneration in response to injury, as evidenced by small and sparse regenerative myofibers along with inhibited expression of regeneration-associated genes myh3, myod, and myogenin. Using paired box 7 (Pax7)-immunofluorescence staining and 5-Bromo-2'-deoxyuridine-incorporation assay, we determined that the decreased regeneration capacity was caused by a limited satellite cell pool. Interestingly, the conditioned culture medium of isolated thymocytes had a potent capacity to directly stimulate satellite cell expansion in vitro. These expanded cells were enriched in subpopulations of quiescent satellite cells (Pax7highMyoDlowEdUpos) and activated satellite cells (Pax7highMyoDhighEdUpos), which were efficiently incorporated into the regenerative myofibers. We thus propose that the thymus plays an essential role in muscle regeneration by directly promoting satellite cell expansion and may function profoundly in the muscle aging process.

Engineering MoxC nanoparticles confined in N,P-codoped porous carbon hollow spheres for enhanced hydrogen evolution reaction.

N,P-codoped porous carbon hollow nanosphere confining ultrafine molybdenum carbide nanoparticles are designed and prepared through a facile method. By virtue of the distinct composite and structure advantages, the resulting composite shows significantly enhanced electrocatalytic performance toward the hydrogen evolution reaction.

Synergistically enhanced hydrogen evolution reaction by ruthenium nanoparticles dispersed on N-doped carbon hollow nanospheres.

Ultrafine Ru nanoparticles dispersed on 3D N-doped carbon hollow nanospheres were firstly prepared by a feasible templating strategy. Due to the synergistic effect of the unique composite and structure, the resulting nanocomposite as a HER catalyst shows extraordinary electrocatalytic performance, superior to that of commercial Pt-C and most previously reported electrocatalysts.

Organic-inorganic Hybrid ([BrCH2 CH2 N(CH3 )3 ]+ 2 [CdBr4 ]2- ) with Unusual Ferroelectric and Switchable Dielectric Bifunctional Properties over Different Temperature Range.

Both ferroelectric and switchable dielectric behaviors are of great academic value and practical significance, but they usually exist alone. If combine the two properties into one compound, it will be more valuable in practical application. In this paper, quasi-spherical (2-bromoethyl) trimethylammonium cation was used to match with [CdBr4 ]2- anion, and a new organic-inorganic hybrid compound ([BrCH2 CH2 N(CH3 )3 ]+ 2 [CdBr4 ]2- , BETABCdBr) was obtained and carefully characterized. The results indicate that this compound undergoes two continuous reversible phase transition around 342 K and 390 K. It could respectively exhibit ferroelectric and switchable dielectric properties over different temperature range. This work may provide a new clue to explore new types of bifunctional phase transition smart materials to meet various application requirements.

Distinct Roles of Smooth Muscle and Non-muscle Myosin Light Chain-Mediated Smooth Muscle Contraction.

Both smooth muscle (SM) and non-muscle (NM) myosin II are expressed in hollow organs such as the bladder and uterus, but their respective roles in contraction and corresponding physiological functions remain to be determined. In this report, we assessed their roles by analyzing mice deficient of Myl9, a gene encoding the SM myosin regulatory light chain (SM RLC). We find that global Myl9-deficient bladders contracted with an apparent sustained phase, despite no initial phase. This sustained contraction was mediated by NM myosin RLC (NM RLC) phosphorylation by myosin light chain kinase (MLCK). NM myosin II was expressed abundantly in the uterus and young mice bladders, of which the force was accordingly sensitive to NM myosin inhibition. Our findings reveal distinct roles of SM RLC and NM RLC in SM contraction.

Ruthenium Nanoparticles Anchored on Graphene Hollow Nanospheres Superior to Platinum for the Hydrogen Evolution Reaction in Alkaline Media.

The design and construction of highly efficient and stable Pt-free catalysts for the electrocatalytic hydrogen evolution reaction (HER) in alkaline media is extremely desirable. Herein, a novel hybrid of ruthenium (Ru) nanoparticles anchored on graphene hollow nanospheres (GHSs) is synthesized by a template-assisted strategy. The combination of ultrafine Ru nanoparticles and hollow spherical support endows the resultant Ru/GHSs an extraordinary catalytic performance with a low overpotential of 24.4 mV at a current density of 10 mA cm-2, a small Tafel slope of 34.8 mV dec-1, as well as long-term stability in 1.0 M KOH solution, which is, to our knowledge, superior to commercial 20% Pt-C catalyst and most of the state-of-the-art HER electrocatalysts reported. Remarkably, this work provides a new route for the development of other metal-based HER electrocatalysts for energy-related applications.

A Novel Synthetic Steroid of 2ß,3α,5α-Trihydroxy-androst-6-one Alleviates the Loss of Rat Retinal Ganglion Cells Caused by Acute Intraocular Hypertension via Inhibiting the Inflammatory Activation of Microglia.

Neuroinflammation has been well recognized as a key pathological event in acute glaucoma. The medical therapy of acute glaucoma mainly focuses on lowering intraocular pressure (IOP), while there are still scarce anti-inflammatory agents in the clinical treatment of acute glaucoma. Here we reported that ß,3α,5α-trihydroxy-androst-6-one (sterone), a novel synthetic polyhydric steroid, blocked neuroinflammation mediated by microglia/macrophages and alleviated the loss of retinal ganglion cells (RGCs) caused by acute intraocular hypertension (AIH). The results showed that sterone significantly inhibited the morphological changes, the up-regulation of inflammatory biomarker ionized calcium-binding adapter molecule 1 (Iba-1), and the mRNA increase of proinflammatory tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) induced by lipopolysaccharide (LPS) in BV2 microglia and RAW264.7 macrophages. Moreover, immunofluorescence and western blotting analysis revealed that sterone markedly abrogated the nuclear translocation and phosphorylation of nuclear factor-κB (NF-κB) p65 subunit. Furthermore, sterone significantly suppressed the inflammatory microglial activation and RGCs' reduction caused by retinal ischemia/reperfusion (I/R) injury in a rat AIH model. These results suggest sterone may be a potential candidate in the treatment of acute glaucoma caused by microglial activation-mediated neuroinflammatory injury.

High extinction ratio super pixel for long wavelength infrared polarization imaging detection based on plasmonic microcavity quantum well infrared photodetectors.

Polarization imaging detection has its unique advantage in discriminating the man-made objects from natural objects. Grating integrated super pixel for polarization imaging detection can simultaneously obtain the first three elements of the Stokes vector, which is the trend of infrared polarization imaging detection in recent years. Here, we demonstrate the first super pixel for long wavelength infrared polarization imaging detection with the extinction ratio of its four polarization directions more than 100. The measured highest polarization extinction ratio is as high as 136, which is the highest reported value of long wavelength infrared polarization imaging detection super pixel. The mechanism is attributed to the excellent mode selectivity of plasmonic microcavity according to the results of three-dimensional theoretical simulation. The experimental responses of the super pixel with four polarization directions are in good agreement with the Malus' Law. In addition, the super pixel can accurately resolve the Stokes parameters at the same time. It is expected to develop the super pixel into a new generation of practical high-polarization-discriminating long wavelength infrared focal plane array.