Autophagy plays an important role in the infectious processes of diverse pathogens. For instance, cellular autophagy could be harnessed by viruses to facilitate replication. However, it is still ...uncertain about the interplay of autophagy and swine acute diarrhea syndrome coronavirus (SADS-CoV) in cells. In this study, we reported that SADS-CoV infection could induce a complete autophagy process both in vitro and in vivo, and an inhibition of autophagy significantly decreased SADS-CoV production, thus suggesting that autophagy facilitated the replication of SADS-CoV. We found that ER stress and its downstream IRE1 pathway were indispensable in the processes of SADS-CoV-induced autophagy. We also demonstrated that IRE1-JNK-Beclin 1 signaling pathway, neither PERK-EIF2S1 nor ATF6 pathways, was essential during SADS-CoV-induced autophagy. Importantly, our work provided the first evidence that expression of SADS-CoV PLP2-TM protein induced autophagy through the IRE1-JNK-Beclin 1 signaling pathway. Furthermore, the interaction of viral PLP2-TMF451-L490 domain and substrate-binding domain of GRP78 was identified to activate the IRE1-JNK-Beclin 1 signaling pathway, and thus resulting in autophagy, and in turn, enhancing SADS-CoV replication. Collectively, these results not only showed that autophagy promoted SADS-CoV replication in cultured cells, but also revealed that the molecular mechanism underlying SADS-CoV-induced autophagy in cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Suicide attempts (SA) and non-suicidal self-injury (NSSI) are prevalent in adolescents and important risk factors of suicide death. Both SA and NSSI are associated with multiple psychosocial, ...behavioral, biological and genetic factors. This study examined similarities and differences in psychological vulnerability and internalizing and externalizing problems between adolescents with SA and NSSI.
Participants consisted of 11,831 students and had a mean age of 14.97 (SD = 1.46) years. Students completed a structured questionnaire to report their demographic information, psychological characteristics, internalizing and externalizing problems, SA and NSSI. Based on the history of NSSI and SA in the last year, the sample was divided into four groups: non-self-harm (NSH), NSSI only, SA only, and NSSI+SA. Multivariate analyses of covariance and post-hoc pairwise comparisons were performed for multiple comparisons.
Compared with NSH group, adolescents with either NSSI or SA scored significantly higher on trait anger, impulsiveness, hopelessness, internalizing and externalizing problems. NSSI+SA group and SA only group scored significantly higher than NSSI only group but both did not score significantly different on most psychological and behavioral variables.
Limitations include reliance on self-reported measures and cross-sectional survey.
Psychological and behavioral profiles between adolescents with SA and NSSI are similar but are more severe in suicide attempters. The findings highlight the necessity of assessing psychological and behavioral problems for prevention and early intervention of adolescent self-harm.
•Adolescents who had engaged in self-harm had more behavioral and emotional problems than those without self-harm.•Psychological and behavioral profiles were more similar than different between adolescents with SA and NSSI.•Psychological and behavioral problems were more severe in adolescents with SA than with NSSI.
Abstract
Drugs produce their therapeutic effects by modulating specific targets, and there are 89 innovative targets of first-in-class drugs approved in 2004–17, each with information about drug ...clinical trial dated back to 1984. Analysis of the clinical trial timelines of these targets may reveal the trial-speed differentiating features for facilitating target assessment. Here we present a comprehensive analysis of all these 89 targets, following the earlier studies for prospective prediction of clinical success of the targets of clinical trial drugs. Our analysis confirmed the literature-reported common druggability characteristics for clinical success of these innovative targets, exposed trial-speed differentiating features associated to the on-target and off-target collateral effects in humans and further revealed a simple rule for identifying the speedy human targets through clinical trials (from the earliest phase I to the 1st drug approval within 8 years). This simple rule correctly identified 75.0% of the 28 speedy human targets and only unexpectedly misclassified 13.2% of 53 non-speedy human targets. Certain extraordinary circumstances were also discovered to likely contribute to the misclassification of some human targets by this simple rule. Investigation and knowledge of trial-speed differentiating features enable prioritized drug discovery and development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ObjectiveLupus nephritis (LN) is a major complication and cause of death among patients with SLE. This research used in vivo and in vitro experiments to explore the therapeutic potential of metformin ...in kidney injury from LN-induced inflammation.MethodsIn vivo study, 8-week-old MRL/MpJ-Faslpr/J (MRL/lpr) mice were randomly divided into two groups (n=12 each): daily administration of 0.3 mg/mL metformin in drinking water and control (water only). Body weight and urinary samples were measured biweekly. Mice were sacrificed after 8-week treatment to harvest serum, lymph nodes, spleen and kidneys. In vitro study, human kidney-2 (HK-2) cells were pretreated with 1 mM metformin for 1 hour and then stimulated with 20 µg/mL lipopolysaccharides (LPS) or 10 ng/mL tumour necrosis factor-α (TNF-α) for another 48 hours. Protein was collected for subsequent analysis.ResultsWe found that metformin administration improved renal function in MRL/lpr lupus-prone mice, measured by decreased urea nitrogen and urinary proteins. Metformin reduced immunoglobulin G and complement C3 deposition in glomeruli. The treatment also downregulated systemic and renal inflammation, as seen in decreased renal infiltration of F4/80-positive macrophages and reduced splenic and renal MCP-1 (monocyte chemoattractant protein-1) and TNF-α, and renal IL-1β (interleukin 1β) expression. Metformin administration decreased renal expression of necroptosis markers p-RIPK1 (phosphorylated receptor-interacting protein kinase 1) and p-MLKL, along with tubular injury marker KIM-1 (kidney injury molecule-1) in lupus mice. In addition, metformin alleviated the necroptosis of HK-2 cells stimulated by LPS and TNF-α, evidencing by a decrease in the expression of necroptosis markers p-RIPK1, p-RIPK3 and p-MLKL, and the inflammasome-related markers NLRP3 (NLR family pyrin domain containing 3), ASC (apoptosis-associated speck-like protein containing a CARD), caspase-1. Mechanistically, metformin treatment upregulated p-AMPK (phosphorylated AMP-activated protein kinase) and downregulated p-STAT3 (phosphorylated signal transducer and activator of transcription 3) expression in the kidneys. Moreover, AMPKα2 knockdown abolished the protective effects of metformin in vitro.ConclusionsMetformin alleviated kidney injury in LN though suppressing renal necroptosis and inflammation via the AMPK/STAT3 pathway.
•Propose a novel Halbach array permanent magnet flowmeter (HA-PMFM) for liquid metal flow measurement by applying the Halbach ring to a Faraday-type permanent magnet flowmeter (PMFM).•Carry out ...multi-physics simulation and analysis on PMFM, considering the coupling of electric field, magnetic field, fluid dynamics, and heat transfer.•HA-PMFM demonstrates a sensitivity improvement of over 68 % compared to traditional permanent magnet flowmeter (Trad-PMFM) with the same volume. Furthermore, under the same sensitivity, HA-PMFM achieves a volume reduction of more than 50 % compared to Trad-PMFM.•Designed an HA-PMFM with a measurement sensitivity of 0.67 mV/LPM and a maximum operating temperature of 1100 K.
A novel Halbach array permanent magnet flowmeter (HA-PMFM) for liquid metal flow measurement is designed in this paper, where Halbach ring magnet array (HR) is applied to the PMFM. The performance variations of HA-PMFM are numerically investigated by adjusting parameters such as the HR size, pipe dimension, fluid temperature, and flow rate and comparisons are made against the traditional structure PMFM (Trad-PMFM). High-fidelity multi-physics coupled numerical simulation is used as the research approach. It is found that enhancing the magnetic field intensity in the measured fluid region of PMFM not only improves measurement sensitivity but also leads to an increase in pressure drop. At the same volume, HA-PMFM exhibits an enhancement in measurement sensitivity of over 68 % and an increase in pressure drop of more than 16.4 % compared to Trad-PMFM. Under the same sensitivity, HA-PMFM has the advantage of size reduction by more than 50 % compared to Trad-PMFM. A HA-PMFM with a measurement sensitivity of 0.67 mV/LPM is designed in this work, where the pressure drop levels are comparable to traditional vortex flowmeters and the maximum operating temperature is up to 1100 K. It holds promise for further development and application in view of the advantages of high measurement sensitivity, small size, wide operating range and rapid dynamic response.
The establishment of a heterojunction is a crucial strategy to design highly effective nonnoble metal nanocatalysts for the photocatalytic nitrogen reduction reaction (PNRR). Heteropoly blues ...(r-POMs) can act as electron-transfer mediators in PNRR, but its agglomeration limits the further promotion of PNRR productivity. In this work, we construct a protonation-modified surface of N-vacancy g-C3N4 (HV-C3N4), achieving the high dispersion of r-POMs via the surface modification strategy. Enlightened by the synergy effect of the nitrogenase, r-POMs were anchored onto HV-C3N4 nanosheets through an electrostatic self-assembly method for preparing r-POMs-based protonation-defective graphitic carbonitride (HV-C3N4/r-POMs). As an electron donor, r-PW12 can match with the energy level of HV-C3N4 to build a heterojunction. The electron redistribution of the heterojunction facilitates the optimization of the electronic structure for enhancing the performance of PNRR. HV-C3N4/r-PW12 exhibits the best PNRR efficiency of 171.4 μmol L–1 h–1, which is boosted by 94.39% (HV-C3N4) and 86.98% (r-PW12). The isotope 15NH4 + experiment proves that ammonia is derived from N2, not carbon nitride. This study opens up a crucial view to achieve the high dispersion of r-POMs nanoparticles and develop high-efficiency nonnoble metal photocatalysts for the PNRR.
Group B Streptococcus (GBS) infection is the leading cause of septicemia, meningitis, and pneumonia in neonates. Aberrant gut colonization in early life may predispose children to various diseases in ...adulthood. However, the associations between gut microbial changes and GBS colonization is still unclear.
The composition and diversity of meconium microbiota in GBS group were similar to that of healthy controls. However, we identified several specific taxa that were differentially abundant between the two groups (linear discriminant analysis (LDA) effect size (LEfSe): p < 0.05, LDA > 2.0). Particularly, the relative abundance of Lactobacillus paracasei was significantly reduced, indicating a role in GBS colonization.
Our study presented a series of bacterial species colonized by GBS, thus providing novel evidence in support of initial intestinal microbiota dysbiosis in the neonates with mother's GBS colonization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recognition of viral invasion by innate antiviral immune system triggers activation of the type I interferon (IFN-I) and proinflammatory signaling pathways. Subsequently, IFN-I induction regulates ...expression of a group of genes known as IFN-I-stimulated genes (ISGs) to block viral infection. The tripartite motif containing 22 (TRIM22) is an ISG with strong antiviral functions. Here we have shown that the TRIM22 has been strongly upregulated both transcriptionally and translationally upon Zika virus (ZIKV) infection. ZIKV infection is associated with a wide range of clinical manifestations in human from mild to severe symptoms including abnormal fetal brain development. We found that the antiviral function of TRIM22 plays a crucial role in counterattacking ZIKV infection. Overexpression of TRIM22 protein inhibited ZIKV growth whereas deletion of TRIM22 in host cells increased ZIKV infectivity. Mechanistically, TRIM22, as a functional E3 ubiquitin ligase, promoted the ubiquitination and degradation of ZIKV nonstructural protein 1 (NS1) and nonstructural protein 3 (NS3). Further studies showed that the SPRY domain and Ring domain of TRIM22 played important roles in protein interaction and degradation, respectively. In addition, we found that TRIM22 also inhibited other flaviviruses infection including dengue virus (DENV) and yellow fever virus (YFV). Thus, TRIM22 is an ISG with important role in host defense against flaviviruses through binding and degradation of the NS1 and NS3 proteins.
Irreversible neurological dysfunction (IND) is an adverse event after cervical spinal cord injury (CSCI). However, there is still a shortage of objective criteria for the early prediction of ...neurological function. We aimed to screen independent predictors of IND and use these findings to construct a nomogram that could predict the development of neurological function in CSCI patients.
Patients with CSCI attending the Affiliated Hospital of Southwest Medical University between January 2014 and March 2021 were included in this study. We divided the patients into two groups: reversible neurological dysfunction (RND) and IND. The independent predictors of IND in CSCI patients were screened using the regularization technique to construct a nomogram, which was finally converted into an online calculator. Concordance index (C-index), calibration curves analysis and decision curve analysis (DCA) evaluated the model's discrimination, calibration, and clinical applicability. We tested the nomogram in an external validation cohort and performed internal validation using the bootstrap method.
We enrolled 193 individuals with CSCI in this study, including IND (n = 75) and RND (n = 118). Six features, including age, American spinal injury association Impairment Scale (AIS) grade, signal of spinal cord (SC), maximum canal compromise (MCC), intramedullary lesion length (IMLL), and specialized institution-based rehabilitation (SIBR), were included in the model. The C-index of 0.882 from the training set and its externally validated value of 0.827 demonstrated the model's prediction accuracy. Meanwhile, the model has satisfactory actual consistency and clinical applicability, verified in the calibration curve and DCA.
We constructed a prediction model based on six clinical and MRI features that can be used to assess the probability of developing IND in patients with CSCI.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
To find the potential relation between changes in retinal large vessels and terminal vessels using colour Doppler flow imaging (CDFI) and optical coherence tomography angiography (OCTA) and ...to compare the respective advantages of CDFI and OCTA in evaluating vascular changes in retinitis pigmentosa (RP) patients.
Methods
A prospective series of case study was conducted to enrol RP patients and age‐matched controls, who were, respectively, imaged by CDFI and OCTA. Repeatability and reproducibility of both CDFI and OCTA were performed among healthy volunteers. The central retinal artery (CRA) was detected by CDFI analysis to provide parameters of peak systolic velocity (PSV), end‐diastolic velocity (EDV) and time‐averaged maximum velocity (TAMV). Retinal parameters were evaluated from OCTA images, including vascular area density (VAD) of the superficial vascular layer, the fovea avascular zone (FAZ) area and retinal thickness. RP patients were separated into a high‐vision group and a low‐vision group, according to median vision (0.3, LogMAR 0.5). Multiple comparisons were used to analyse the data between groups. A correlation analysis was used to determine the correlation between CDFI and OCTA parameters.
Results
Twenty RP patients (40 eyes) and thirteen normal volunteers (26 eyes) were enrolled in this study. Repeatability and reproducibility of the measurements by CDFI had higher CVs, from 4.5% to 15.4%, than those measurements by OCTA (<5%). All the CDFI and OCTA parameters examined had significant reductions in RP patients compared to those in the controls (p < 0.01). Compared to the high‐vision group, the low‐vision group exhibited a statistically significant decrease in vascular parameters of the FAZ area, fovea VAD and parafovea nasal side VAD (p < 0.05); as well as in the parameters of the fovea thickness, and the parafovea nasal, superior and inferior side thickness (p < 0.05). From the correlation analysis, a significant association was found between the vision and CDFI parameters (PSV and time‐averaged maximum velocity (TAMX), p < 0.05), and the vision and OCTA parameters (FAZ area, fovea and nasal side VAD, retinal thickness in all sides, p < 0.05). PSV and TAMX of the CRA were closely related to the OCTA superficial VAD in all sides, whereas the CDFI parameters showed poor correlation with retinal thickness.
Conclusions
Colour Doppler flow imaging (CDFI) and OCTA parameters revealed a significant reduction in RP patients when compared to the controls. OCTA can detect vision‐related microvascular and thickness changes around the macula between high‐ and low‐vision groups, which happen earlier than the changes in large vessels. In addition to good repeatability and reproducibility, OCTA may have significant utility in the diagnosis and monitoring of disease progression in RP patients.
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