Cholesterol is dynamically transported among organelles, which is essential for multiple cellular functions. However, the mechanism underlying intracellular cholesterol transport has remained largely ...unknown. We established an amphotericin B-based assay enabling a genome-wide shRNA screen for delayed LDL-cholesterol transport and identified 341 hits with particular enrichment of peroxisome genes, suggesting a previously unappreciated pathway for cholesterol transport. We show dynamic membrane contacts between peroxisome and lysosome, which are mediated by lysosomal Synaptotagmin VII binding to the lipid PI(4,5)P2 on peroxisomal membrane. LDL-cholesterol enhances such contacts, and cholesterol is transported from lysosome to peroxisome. Disruption of critical peroxisome genes leads to cholesterol accumulation in lysosome. Together, these findings reveal an unexpected role of peroxisome in intracellular cholesterol transport. We further demonstrate massive cholesterol accumulation in human patient cells and mouse model of peroxisomal disorders, suggesting a contribution of abnormal cholesterol accumulation to these diseases.
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•Genome-wide RNAi screen reveals 341 genes important for cholesterol transport•Lysosomal Syt7 binds peroxisomal PI(4,5)P2 to bridge the organelle contact•Organelle contacts mediate cholesterol transport from lysosome to peroxisome•Cholesterol is accumulated in cells and animal models of peroxisomal disorders
Lysosome forms dynamic membrane contacts with peroxisome, and cholesterol is transported from lysosome to peroxisome. Massive cholesterol accumulates in the cells from patients with peroxisomal disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In this work, the kinetics study on the reaction between CO2 and tertiary amine catalyzed by zinc(II)‐1,4,8,11‐tetraazacyclotetradecane complexes (CM) and zinc(II)‐1,4,7,10‐tetraazacyclododecane ...complexes (CN) was carried out in a stopped‐flow device. The effects of the catalyst concentration, type of tertiary amines, and temperature on the reaction rate (ν) and catalytic activity (φ) were studied. It was found that the catalyst concentration, tertiary amine with higher pKa, and temperature had positive effects on ν. ν in N‐methyl diethanolamine solution with 10.0 mol m−3 CM and CN were 16.62 and 26.05 folds than the uncatalyzed ν at 298 K, respectively. φ increased with increasing catalyst concentration, decreasing temperature and tertiary amine's pKa. In addition, the kinetics behavior of tertiary amine‐CM/CN‐CO2 systems conformed to the Michaelis–Menten model. The activation energies in catalytic systems were 4%–15% lower than that in the non‐catalytic systems.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Proteins UL31 and UL34 encoded by alphaherpesvirus are critical for viral primary envelopment and nuclear egress. We report here that pseudorabies virus (PRV), a useful model for research on ...herpesvirus pathogenesis, uses N‐myc downstream regulated 1 (NDRG1) to assist the nuclear import of UL31 and UL34. PRV promoted NDRG1 expression through DNA damage‐induced P53 activation, which was beneficial to viral proliferation. PRV induced the nuclear translocation of NDRG1, and its deficiency resulted in the cytosolic retention of UL31 and UL34. Therefore, NDRG1 assisted the nuclear import of UL31 and UL34. Furthermore, in the absence of the nuclear localization signal (NLS), UL31 could still translocate to the nucleus, and NDRG1 lacked an NLS, thus suggesting the existence of other mediators for the nuclear import of UL31 and UL34. We demonstrated that heat shock cognate protein 70 (HSC70) was the key factor in this process. UL31 and UL34 interacted with the N‐terminal domain of NDRG1 and the C‐terminal domain of NDRG1 bound to HSC70. Replenishment of HSC70ΔNLS in HSC70‐knockdown cells, or interference in importin α expression, abolished the nuclear translocation of UL31, UL34, and NDRG1. These results indicated that NDRG1 employs HSC70 to facilitate viral proliferation in the nuclear import of PRV UL31 and UL34.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Pneumonia caused by the 2019 novel Coronavirus (COVID‐2019) shares overlapping signs and symptoms, laboratory findings, imaging features with influenza A pneumonia. We aimed to identify ...their clinical characteristics to help early diagnosis.
Methods
We retrospectively retrieved data for laboratory‐confirmed patients admitted with COVID‐19–induced or influenza A–induced pneumonia from electronic medical records in Ningbo First Hospital, China. We recorded patients' epidemiological and clinical features, as well as radiologic and laboratory findings.
Results
The median age of influenza A cohort was higher and it exhibited higher temperature and higher proportion of pleural effusion. COVID‐19 cohort exhibited higher proportions of fatigue, diarrhea and ground‐glass opacity and higher levels of lymphocyte percentage, absolute lymphocyte count, red‐cell count, hemoglobin and albumin and presented lower levels of monocytes, c‐reactive protein, aspartate aminotransferase, alkaline phosphatase, serum creatinine. Multivariate logistic regression analyses showed that fatigue, ground‐glass opacity, and higher level of albumin were independent risk factors for COVID‐19 pneumonia, while older age, higher temperature, and higher level of monocyte count were independent risk factors for influenza A pneumonia.
Conclusions
In terms of COVID‐19 pneumonia and influenza A pneumonia, fatigue, ground‐glass opacity, and higher level of albumin tend to be helpful for diagnosis of COVID‐19 pneumonia, while older age, higher temperature, and higher level of monocyte count tend to be helpful for the diagnosis of influenza A pneumonia.
Fatigue, ground‐glass opacity and higher level of albumin tend to be helpful for diagnosis of COVID‐19 pneumonia, while older age, higher temperature, and higher level of monocytes count tend to be helpful for the diagnosis of influenza A pneumonia.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Viral infection is a significant risk factor for fertility issues. Here, we demonstrated that infection by neurotropic alphaherpesviruses, such as pseudorabies virus (PRV), could impair female ...fertility by disrupting the hypothalamus-pituitary-ovary axis (HPOA), reducing progesterone (P4) levels, and consequently lowering pregnancy rates. Our study revealed that PRV exploited the transient receptor potential mucolipin 1 (TRPML1) and its lipid activator, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), to facilitate viral entry through lysosomal cholesterol and Ca2+. P4 antagonized this process by inducing lysosomal storage disorders and promoting the proteasomal degradation of TRPML1 via murine double minute 2 (MDM2)-mediated polyubiquitination. Overall, the study identifies a novel mechanism by which PRV hijacks the lysosomal pathway to evade P4-mediated antiviral defense and impair female fertility. This mechanism may be common among alphaherpesviruses and could contribute significantly to their impact on female reproductive health, providing new insights for the development of antiviral therapies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. ...Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
RAB GTPases (RABs) control intracellular membrane trafficking with high precision. In the present study, we carried out a short hairpin RNA (shRNA) screen focused on a library of 62 RABs during ...infection with porcine reproductive and respiratory syndrome virus 2 (PRRSV-2), a member of the family Arteriviridae. We found that 13 RABs negatively affect the yield of PRRSV-2 progeny virus, whereas 29 RABs have a positive impact on the yield of PRRSV-2 progeny virus. Further analysis revealed that PRRSV-2 infection transcriptionally regulated RAB18 through RIG-I/MAVS-mediated canonical NF-κB activation. Disrupting RAB18 expression led to the accumulation of lipid droplets (LDs), impaired LDs catabolism, and flawed viral replication and assembly. We also discovered that PRRSV-2 co-opts chaperone-mediated autophagy (CMA) for lipolysis via RAB18, as indicated by the enhanced associations between RAB18 and perlipin 2 (PLIN2), CMA-specific lysosomal associated membrane protein 2A (LAMP2A), and heat shock protein family A (Hsp70) member 8 (HSPA8/HSC70) during PRRSV-2 infection. Knockdown of HSPA8 and LAMP2A impacted on the yield of PRRSV-2 progeny virus, implying that the virus utilizes RAB18 to promote CMA-mediated lipolysis. Importantly, we determined that the C-terminal domain (CTD) of HSPA8 could bind to the switch II domain of RAB18, and the CTD of PLIN2 was capable of associating with HSPA8, suggesting that HSPA8 facilitates the interaction between RAB18 and PLIN2 in the CMA process. In summary, our findings elucidate how PRRSV-2 hijacks CMA-mediated lipid metabolism through innate immune activation to enhance the yield of progeny virus, offering novel insights for the development of anti-PRRSV-2 treatments.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Porcine reproductive and respiratory syndrome virus (PRRSV) presents a significant economic concern for the global swine industry due to its connection to serious production losses and increased ...mortality rates. There is currently no specific treatment for PRRSV. Previously, we had uncovered that PRRSV-activated lipophagy to facilitate viral replication. However, the precise mechanism that PRRSV used to trigger autophagy remained unclear. Here, we found that PRRSV GP5 enhanced mitochondrial Ca
uptake from ER by promoting ER-mitochondria contact, resulting in mROS release. Elevated mROS induced autophagy, which alleviated NLRP3 inflammasome activation for optimal viral replication. Our study shed light on a novel mechanism revealing how PRRSV exploits mROS to facilitate viral replication.
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The work investigated the potential application of Mg-laden biochar prepared from Mg-enriched bamboo to remove and recover phosphate from water. The Mg-laden biochar samples were ...synthesized at 400 °C, 500 °C and 600 °C. With the increasing synthesized temperature, the production rate of adsorbent decreased but the Mg content and specific surface area increased. Factors on phosphate adsorption including kinetic, isotherm, pH, dosage were examined through batch experiments. The maximum phosphate adsorption amount was 344, 357 and 370 mg/g for biochar-Mg-400, biochar-Mg-500 and biochar-Mg-600, respectively. The effect of phosphate adsorption on Mg-laden biochar samples was also investigated by fixed-bed column experiments, and the maximum adsorption amount calculated by Thomas model was 60.7, 61.2 and 62.2 mg/g, respectively. The adsorbed phosphate could be successfully desorbed by 3 M NaOH solution and the regenerated Mg-laden biochar samples could be reused at least 5 times for phosphate adsorption. The bioavailability of postsorption biochar was proved very well through the Mehlich 3 method. Phosphate adsorption characteristic and FTIR analysis indicated that the adsorption was mainly controlled by two mechanisms: ligand exchange and electrostatic attraction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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