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PLoS Pathogens Jun 2024Stress granules (SGs), formed by untranslated messenger ribonucleoproteins (mRNPs) during cellular stress in eukaryotes, have been linked to flavivirus interference...
Stress granules (SGs), formed by untranslated messenger ribonucleoproteins (mRNPs) during cellular stress in eukaryotes, have been linked to flavivirus interference without clear understanding. This study reveals the role of Zika virus (ZIKV) NS2B as a scaffold protein mediating interaction between protein phosphatase 1α (PP1α) and eukaryotic initiation factor 2α (eIF2α). This interaction promotes eIF2α dephosphorylation by PP1α, inhibiting SG formation. The NS2B-PP1α complex exhibits remarkable stability, resisting ubiquitin-induced degradation and amplifying eIF2α dephosphorylation, thus promoting ZIKV replication. In contrast, the NS2BV35A mutant, interacting exclusively with eIF2α, fails to inhibit SG formation, resulting in reduced viral replication and diminished impact on brain organoid growth. These findings reveal PP1α's dual role in ZIKV infection, inducing interferon production as an antiviral factor and suppressing SG formation as a viral promoter. Moreover, we found that NS2B also serves as a versatile mechanism employed by flaviviruses to counter host antiviral defenses, primarily by broadly inhibiting SG formation. This research advances our comprehension of the complex interplay in flavivirus-host interactions, offering potential for innovative therapeutic strategies against flavivirus infections.
PubMed: 38935808
DOI: 10.1371/journal.ppat.1012355 -
PloS One 2024Although sloped surfaces are common in daily living, most studies of body balance are carried out on flat surfaces, and few data are available for sloping angles below...
INTRODUCTION
Although sloped surfaces are common in daily living, most studies of body balance are carried out on flat surfaces, and few data are available for sloping angles below 14°.
OBJECTIVES
The purpose of this study was to explore the effect of forward and backward sloping surfaces at 7° and 15° on postural equilibrium and the activity of flexor/extensor ankle muscles.
METHODS
Fifteen healthy subjects (8 males and 7 females) (27.67 ± 3.9 years) underwent a posturographic examination associated with a surface electromyogram (EMG) of tibialis anterior (TA), soleus (Sol) and gastrocnemius medialis (GasM) under five conditions of support inclination: 0° (H0), backward inclination at 7° and 15° (DF7 and DF15), forward inclination at 7° and 15° (PF7 and PF15).
RESULTS
Results showed that the center of pressure (CP) was shifted according to the surface slope, with a forward move in PF7 (p <0.001) and PF15 (p <0.001) and a backward move in DF7 (p <0.01) and in DF15 (p <0.001). The mean displacement of the CP along the anterior-posterior axis (Xm) was increased in DF15 (p <0.01) relative to the H0 condition but reduced in PF7 (p <0.01). The normalized EMG revealed higher values when the muscles were in a shortened position (PF7 for Sol, p <0.05; PF15 for GasM, p <0.01; DF15 for TA, p<0.01) and lower values of GasM and Sol when lengthened (DF15, p <0.05).
CONCLUSION
Our findings indicate that standing on a backward sloped surface impairs body balance, while low-angle forward sloped surfaces might improve postural stability. Muscular activity variations of the ankle flexors/extensors, which are stretched or shortened, also seem to be related to the length-tension relationship of skeletal muscles.
Topics: Humans; Male; Female; Adult; Muscle, Skeletal; Postural Balance; Electromyography; Ankle; Young Adult; Ankle Joint
PubMed: 38935639
DOI: 10.1371/journal.pone.0305840 -
PloS One 2024Chronic liver diseases are caused by hepatic viral infection, chemicals, and metabolic stress. The protein Grb2-associated binder 1 (Gab1) binds to various growth factor...
Chronic liver diseases are caused by hepatic viral infection, chemicals, and metabolic stress. The protein Grb2-associated binder 1 (Gab1) binds to various growth factor receptors, and triggers cell differentiation/survival signaling pathways. To identify signaling molecules involved in the progression of liver diseases, we performed reverse-phase protein microarray (RPMA)-based screening of hepatocytes isolated from humanized mice after acute HCV infection. Acute viral infection in humanized liver mice significantly decreased the level of hepatocyte p-Gab1. Moreover, hepatoma cells upon HCV infection decreased Gab1 mRNA at later times of infection (D3 to D5) and p-Gab1 level was inversely related to the production of TGF-β. In contrast, the level of p-Gab1 was increased in CCL4-induced fibrotic liver. Hepatoma cells showed elevation of p-Gab1, along with an increase in STAT3 and ERK activation, upon treatment with HGF (ligand of HGF receptor/c-Met) and CCL4. In Gab1 knockdown hepatoma cells, cell proliferative signaling activity was reduced but the level of activated caspase-3 was increased. These findings suggest that hepatocyte Gab1 expression may play a role in promoting liver fibrosis progression by triggering ERK activation and inhibiting apoptosis. It implies that the Gab1-mediated signaling pathway would be a promising therapeutic target to treat chronic liver diseases.
Topics: Animals; Hepatocytes; Liver Cirrhosis; Adaptor Proteins, Signal Transducing; Apoptosis; Signal Transduction; Cell Proliferation; Humans; Mice; Proto-Oncogene Proteins c-met; Hepatocyte Growth Factor; Cell Line, Tumor; Hepatitis C
PubMed: 38935609
DOI: 10.1371/journal.pone.0306345 -
Gut Microbes 2024Diet is a key player in gut-liver axis. However, the effect of different dietary patterns on gut microbiota and liver functions remains unclear. Here, we used rodent...
Diet is a key player in gut-liver axis. However, the effect of different dietary patterns on gut microbiota and liver functions remains unclear. Here, we used rodent standard chow and purified diet to mimic two common human dietary patterns: grain and plant-based diet and refined-food-based diet, respectively and explored their impacts on gut microbiota and liver. Gut microbiota experienced a great shift with notable increase in , gut bile acid (BA) levels elevated significantly, and liver inflammation was observed in mice fed with the purified diet. Liver inflammation and elevated gut BA levels also occurred in mice fed with the chow diet after receiving ATCC 29,577 (DSV). Restriction of sulfur-containing amino acids (SAAs) prevented liver injury mainly through higher hepatic antioxidant and detoxifying ability and reversed the elevated BA levels due to excess . fermentation of human fecal microbiota with primary BAs demonstrated that DSV enhanced production of secondary BAs. Higher concentration of both primary and secondary BAs were found in the gut of germ-free mice after receiving DSV. In conclusion, Restriction of SAAs in diet may become an effective dietary intervention to prevent liver injury associated with excess in the gut.
Topics: Animals; Gastrointestinal Microbiome; Mice; Liver; Humans; Desulfovibrio; Male; Mice, Inbred C57BL; Bile Acids and Salts; Amino Acids; Diet; Feces; Sulfur; Amino Acids, Sulfur
PubMed: 38935546
DOI: 10.1080/19490976.2024.2370634 -
Cell Reports Jun 2024ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1...
ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1;Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR) macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1 tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion.
PubMed: 38935501
DOI: 10.1016/j.celrep.2024.114400 -
Cell Reports Jun 2024Kisspeptin signaling through its G protein-coupled receptor, KISS1R, plays an indispensable role in regulating reproduction via the hypothalamic-pituitary-gonadal axis....
Kisspeptin signaling through its G protein-coupled receptor, KISS1R, plays an indispensable role in regulating reproduction via the hypothalamic-pituitary-gonadal axis. Dysregulation of this pathway underlies severe disorders like infertility and precocious puberty. Here, we present cryo-EM structures of KISS1R bound to the endogenous agonist kisspeptin-10 and a synthetic analog TAK-448. These structures reveal pivotal interactions between peptide ligands and KISS1R extracellular loops for receptor activation. Both peptides exhibit a conserved binding mode, unveiling their common activation mechanism. Intriguingly, KISS1R displays a distinct 40° angular deviation in its intracellular TM6 region compared to other G-coupled receptors, enabling distinct interactions with G. This study reveals the molecular intricacies governing ligand binding and activation of KISS1R, while highlighting its exceptional ability to couple with G. Our findings pave the way for structure-guided design of therapeutics targeting this physiologically indispensable receptor.
PubMed: 38935498
DOI: 10.1016/j.celrep.2024.114389 -
Journal of Microbiology and... Apr 2024This study aimed to determine the function of LINC00511 in NLRP3 inflammasome-mediated chondrocyte pyroptosis via the regulation of miR-9-5p and FUT 1. Chondrocyte...
This study aimed to determine the function of LINC00511 in NLRP3 inflammasome-mediated chondrocyte pyroptosis via the regulation of miR-9-5p and FUT 1. Chondrocyte inflammatory injury was induced by treating chondrocytes with LPS. Afterwards, the levels of IL-1β and IL-18, the expression of NLRP3, ASC, Caspase-1, and GSDMD, cell viability, and LDH activity in chondrocytes were assessed. LINC00511 expression in LPS-treated chondrocytes was detected, and LINC00511 was subsequently silenced to analyse its role in chondrocyte pyroptosis. The subcellular localization of LINC00511 was predicted and verified. Furthermore, the binding relationships between LINC00511 and miR-9-5p and between miR-9-5p and FUT1 were validated. LINC00511 regulated NLRP3 inflammasome-mediated chondrocyte pyroptosis through the miR-9-5p/FUT1 axis. LPStreated ATDC5 cells exhibited elevated levels of inflammatory injury; increased levels of NLRP3, ASC, Caspase-1, and GSDMD; reduced cell viability; increased LDH activity; and increased LINC00511 expression, while LINC00511 silencing inhibited the NLRP3 inflammasome to restrict LPS-induced chondrocyte pyroptosis. Next, LINC00511 sponged miR-9-5p, which targeted FUT1. Silencing LINC00511 suppressed FUT1 by upregulating miR-9-5p. Additionally, downregulation of miR-9-5p or overexpression of FUT1 neutralized the suppressive effect of LINC00511 knockdown on LPSinduced chondrocyte pyroptosis. Silencing LINC00511 inhibited the NLRP3 inflammasome to quench Caspase-1-dependent chondrocyte pyroptosis in OA by promoting miR-9-5p and downregulating FUT1.
PubMed: 38934781
DOI: 10.4014/jmb.2312.12014 -
Acta Odontologica Scandinavica Jun 2024The Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) is part of the undergraduate dental curriculum. Online teaching has nowadays become common also in...
INTRODUCTION
The Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) is part of the undergraduate dental curriculum. Online teaching has nowadays become common also in dentistry.
OBJECTIVE
To compare undergraduate students' self-assessed ability and satisfaction with learning DC/TMD Axis I between traditional and online learning and to evaluate the possible gains of online teaching.
MATERIAL AND METHODS
Third-year undergraduate dental students in 2018 (traditional learning, Group 1, n = 43/50) and in 2019 (online learning, Group 2, n = 34/50) at the University of Oulu, Finland evaluated their self-assessed ability and satisfaction with learning DC/TMD clinical examination and diagnostics on a 10-point scale. Additionally, those participating in online courses answered to two open-ended questions; Group 2 (n = 50) and another group from the University of Eastern Finland in 2019 and 2020 (n = 75, Group 3). Total of 105/125 students (84%) responded. Content analysis was used to open-ended responses.
RESULTS
The online course reported significantly higher self-assessed ability in measurements (p = 0.004), identifying referred pain (p = 0.043) and statement for the diagnostics (p = 0.017) and also higher self-assessed satisfaction in measurements (p = 0.046). According to the content analysis, essential gains of online teaching were efficient learning, videos and exercises, and adjustability to own timetable.
CONCLUSION
The online learning course can be considered as a good option for traditional learning of the DC/TMD protocol.
Topics: Humans; Temporomandibular Joint Disorders; Education, Dental; Education, Distance; Finland; Male; Female; Curriculum; Surveys and Questionnaires
PubMed: 38934339
DOI: 10.2340/aos.v83.40984 -
Arteriosclerosis, Thrombosis, and... Jun 2024Despite being in an oxygen-rich environment, endothelial cells (ECs) use anaerobic glycolysis (Warburg effect) as the primary metabolic pathway for cellular energy...
BACKGROUND
Despite being in an oxygen-rich environment, endothelial cells (ECs) use anaerobic glycolysis (Warburg effect) as the primary metabolic pathway for cellular energy needs. PFKFB (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase)-3 regulates a critical enzymatic checkpoint in glycolysis and has been shown to induce angiogenesis. This study builds on our efforts to determine the metabolic regulation of ischemic angiogenesis and perfusion recovery in the ischemic muscle.
METHODS
Hypoxia serum starvation (HSS) was used as an in vitro peripheral artery disease (PAD) model, and hind limb ischemia by femoral artery ligation and resection was used as a preclinical PAD model.
RESULTS
Despite increasing PFKFB3-dependent glycolysis, HSS significantly decreased the angiogenic capacity of ischemic ECs. Interestingly, inhibiting PFKFB3 significantly induced the angiogenic capacity of HSS-ECs. Since ischemia induced a significant in PFKFB3 levels in hind limb ischemia muscle versus nonischemic, we wanted to determine whether glucose bioavailability (rather than PFKFB3 expression) in the ischemic muscle is a limiting factor behind impaired angiogenesis. However, treating the ischemic muscle with intramuscular delivery of D-glucose or L-glucose (osmolar control) showed no significant differences in the perfusion recovery, indicating that glucose bioavailability is not a limiting factor to induce ischemic angiogenesis in experimental PAD. Unexpectedly, we found that shRNA-mediated PFKFB3 inhibition in the ischemic muscle resulted in a numerical increase in perfusion recovery and significantly higher vascular density compared with control shRNA (consistent with the increased angiogenic capacity of PFKFB3 silenced HSS-ECs). Based on these data, we hypothesized that inhibiting HSS-induced PFKFB3 in ischemic ECs activates alternative metabolic pathways that revascularize the ischemic muscle in experimental PAD. A comprehensive glucose metabolic gene qPCR arrays in PFKFB3 silenced HSS-ECs, and PFKFB3-inhibited ischemic muscle versus respective controls identified UGP2 (uridine diphosphate-glucose pyrophosphorylase 2), a regulator of protein glycosylation and glycogen synthesis, is induced upon PFKFB3 inhibition in vitro and in vivo. Antibody-mediated inhibition of UGP2 in the ischemic muscle significantly impaired perfusion recovery versus IgG control. Mechanistically, supplementing uridine diphosphate-glucose, a metabolite of UGP2 activity, significantly induced HSS-EC angiogenic capacity in vitro and enhanced perfusion recovery in vivo by increasing protein glycosylation (but not glycogen synthesis).
CONCLUSIONS
Our data present that inhibition of maladaptive PFKFB3-driven glycolysis in HSS-ECs is necessary to promote the UGP2-uridine diphosphate-glucose axis that enhances ischemic angiogenesis and perfusion recovery in experimental PAD.
PubMed: 38934117
DOI: 10.1161/ATVBAHA.124.320665 -
European Journal of Histochemistry : EJH Jun 2024Artificial light can affect eyeball development and increase myopia rate. Matrix metalloproteinase 2 (MMP-2) degrades the extracellular matrix, and induces its...
Effects of artificial light with different spectral compositions on refractive development and matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2 expression in the sclerae of juvenile guinea pigs.
Artificial light can affect eyeball development and increase myopia rate. Matrix metalloproteinase 2 (MMP-2) degrades the extracellular matrix, and induces its remodeling, while tissue inhibitor of matrix MMP-2 (TIMP-2) inhibits active MMP-2. The present study aimed to look into how refractive development and the expression of MMP-2 and TIMP-2 in the guinea pigs' remodeled sclerae are affected by artificial light with varying spectral compositions. Three weeks old guinea pigs were randomly assigned to groups exposed to five different types of light: natural light, LED light with a low color temperature, three full spectrum artificial lights, i.e. E light (continuous spectrum in the range of ~390-780 nm), G light (a blue peak at 450 nm and a small valley 480 nm) and F light (continuous spectrum and wavelength of 400 nm below filtered). A-scan ultrasonography was used to measure the axial lengths of their eyes, every two weeks throughout the experiment. Following twelve weeks of exposure to light, the sclerae were observed by optical and transmission electron microscopy. Immunohistochemistry, Western blot and RT-qPCR were used to detect the MMP-2 and TIMP-2 protein and mRNA expression levels in the sclerae. After four, six, eight, ten, and twelve weeks of illumination, the guinea pigs in the LED and G light groups had axial lengths that were considerably longer than the animals in the natural light group while the guinea pigs in the E and F light groups had considerably shorter axial lengths than those in the LED group. Following twelve weeks of exposure to light, the expression of the scleral MMP-2 protein and mRNA were, from low to high, N group, E group, F group, G group, LED group; however, the expression of the scleral TIMP-2 protein and mRNA were, from high to low, N group, E group, F group, G group, LED group. The comparison between groups was statistically significant (p<0.01). Continuous, peaks-free or valleys-free artificial light with full-spectrum preserves remodeling of scleral extracellular matrix in guinea pigs by downregulating MMP-2 and upregulating TIMP-2, controlling eye axis elongation, and inhibiting the onset and progression of myopia.
Topics: Animals; Guinea Pigs; Matrix Metalloproteinase 2; Tissue Inhibitor of Metalloproteinase-2; Sclera; Light; Myopia; Refraction, Ocular
PubMed: 38934084
DOI: 10.4081/ejh.2024.3982