Heat shock protein 90 chaperone activity is required for hepatitis A virus replication.

UNC Libraries · 2025-10-16

HSP90 heat shock chaperones are essential for maintaining cellular proteostasis, as well as the ATP-dependent folding and functional maturation of many viral proteins. As a result, inhibitors of HSP90 have broad antiviral activity, disrupting replication of many viruses at concentrations below those causing cytotoxicity. Among the <em>Picornaviridae</em>, HSP90 inhibitors block replication of multiple <em>Enterovirus</em>, <em>Aphthovirus,</em> and <em>Cardiovirus</em> species, in some cases, by preventing post-translational processing and assembly of P1 capsid proteins. Hepatitis A virus (HAV), classified within the genus <em>Hepatovirus</em>, has been suggested to be an exception among picornaviruses and to replicate independently of HSP90, possibly because its slow translational kinetics could facilitate co-translational folding and assembly of its capsid proteins. However, we show here that HAV replication is highly dependent upon HSP90, both in human hepatocyte-derived cell lines, in which the 50% inhibitory concentration of geldanamycin was 8.7-11.8 nM, and <em>in vivo</em> in <em>Ifnar1^-/-</em> mice. Label-free proteomics experiments suggested that HSP90 interacts with capsid proteins or their precursors and may thus facilitate the folding and assembly of capsid proteins, as it does for enteroviruses and aphthoviruses. By contrast, there was no evidence for HSP90 interacting with any nonstructural protein, and HSP90 inhibitors did not impair 3C^pro proteolytic activity. Despite this, and in contrast to previous studies of enteroviruses and aphthoviruses, geldanamycin potently inhibited replication of a subgenomic HAV replicon. We conclude that HAV is no exception from the HSP90-dependent nature of other picornaviruses and indeed is more dependent on HSP90 than other picornaviruses for amplification of its genome.IMPORTANCEHepatitis A virus (HAV), a common cause of acute infectious hepatitis, has been reported to differ from other picornaviruses in not requiring heat shock protein HSP90 for efficient replication. However, we show here that productive HAV infection is highly dependent on HSP90 and that HAV replication is potently blocked both in cell culture and <em>in vivo</em> in the murine liver by chemical inhibitors of HSP90. Such inhibitors also disrupt the replication of a subgenomic HAV RNA replicon, indicating that HSP90 is required for the assembly of functional replication organelles. This highlights a key difference from other picornaviruses for which HSP90 is required primarily, if not exclusively, for the maturation of the P1 capsid proteins.

Design, synthesis and anti-gastric cancer activity of stable Bisamide curcumin analogues

Bioorganic Chemistry · 2025-07-23

Long‐Term Follow‐Up of Patients With Positive Antiphospholipid Antibodies After Fetal Death: Five Typical Cases From a Prospective Cohort Study

Immunity Inflammation and Disease · 2025-02-01

BACKGROUND: Testing of antiphospholipid antibodies (aPLs) has attracted increasing attention for its association with thrombosis and pregnancy loss. However, few studies reported long-term monitoring outcomes of patients who experienced pregnancy loss and exhibited positivity for aPLs. OBJECTIVE: We investigated the causes of fetal death in five cases with positive aPLs and traced the patients for changes in aPLs, subsequent pregnancy outcomes, and thrombotic events. METHODS: This is a report of five typical cases from a prospective cohort study on the diagnosis of antiphospholipid syndrome (APS) in patients who were hospitalized for fetal death in Xining, China. Long-term follow-up was conducted and repeat aPL testing was recommended when the patients were confirmed or suspect APS. RESULTS: All five patients had subsequent pregnancies that resulted in term livebirths. None of the patients experienced thrombotic events. One showed progression of aPL serostatus from alone IgM of aβ2GP-1 to both IgM and IgG of aβ2GP-1, two exhibited fluctuation of aPL serostatus, and one had negative conversion, and the other one had not retested aPLs and did not receive any intervention with uneventful subsequent pregnancy. CONCLUSIONS: The aPLs of a patient with APS may develop or may disappear, so long-term monitoring cannot be discounted. Also, a woman who has experienced fetal death and exhibits positivity for aPLs may not necessarily be a patient with APS, as there are a variety of conditions in which aPLs appear.

Ectopic Eruption And Canine Path

International Dental Journal · 2025-10-01

To investigate the correlation between ectopic eruption of the first permanent maxillary molars and the eruption path of the permanent canines in children aged 6 to 9 years. Panoramic radiographs of children with ectopic eruption of the first permanent maxillary molars were analyzed. Measurements included the inclination angle of the permanent canines, eruption height, and position relative to adjacent teeth (S1: distal to the deciduous canine; S2: mesial to the deciduous canine; S3: mesial to the permanent lateral incisor; S4: mesial to the permanent central incisor). Correlations were assessed. At Nolla stage 6, the severity of ectopic eruption was positively correlated with the inclination angle of the ipsilateral permanent canines (rs = 0.146, P < 0.05) but not with eruption height or position relative to adjacent teeth (P > 0.05). At Nolla stages 7 and 8, severity was positively correlated with eruption height and position relative to adjacent teeth (0 < rs < 0.7, P < 0.05) but not with inclination angle (P > 0.05). Ectopic eruption of maxillary molars may affect canine eruption due to space deficiency and genetic factors. The severity of ectopic eruption correlates with the tendency of canine impaction. Early intervention, such as deciduous canine extraction and arch expansion, may help guide proper eruption.

The Position and Momentum of Particles Belonging to the Same Physical Modulus Value

SSRN Electronic Journal · 2025-01-01

Antiphospholipid syndrome in patients with fetal death: a prospective longitudinal cohort study

Clinical and Experimental Medicine · 2025-03-10 · 1 citations

To investigate the causes of fetal death, focusing on maternal antiphospholipid syndrome diagnosis, and to follow the patients for changes in antiphospholipid antibodies, subsequent pregnancy outcomes, and thrombotic events. This is a prospective longitudinal cohort study that recruited patients who were hospitalized for fetal death at ≥ 10 weeks of gestation from three tertiary hospitals in China. Antiphospholipid syndrome was diagnosed according to the 2006 Sydney classification criteria. In total, 159 patients were recruited to the study; 3 were excluded and 144 of whom tested for aPLs. Among these, 126 (87.5%) were available for diagnostic analysis of antiphospholipid syndrome, 13 (10.3%) of which carried a diagnosis of antiphospholipid syndrome. Meanwhile, 136 of 156 patients had fetal samples for which copy number variation sequencing was completed, and 12 (8.8%) of which carried a diagnosis of fetal chromosomal abnormalities. During later follow-up, among the 13 patients with antiphospholipid syndrome, seven were persistently positive serostatus of antiphospholipid antibodies, four exhibited fluctuation, and one had negative conversion; four patients with subsequent pregnancies received guideline-based therapy and had term livebirths. None of the participants experienced thrombotic events. Maternal antiphospholipid syndrome was found to be one of the important causes of fetal death, contributing 10.3% of cases of fetal death at ≥ 10 weeks of gestation, slight ahead of fetal chromosomal abnormalities. Follow-up indicated that the serostatus of antiphospholipid antibodies may fluctuate significantly in some patients with antiphospholipid syndrome.Clinical trial registration:As this study was an observational study, we did not register it as a clinical trial.

Advanced gastric small cell carcinoma with immunotherapy-based treatment: A case report

World Journal of Gastrointestinal Oncology · 2025-12-10

BACKGROUND The clinical and pathological characteristics of primary gastric small cell carcinoma (GSCC) resemble those of small cell lung cancer, which is less sensitive to chemotherapy and has a poor prognosis. Currently, platinum-etoposide chemotherapy is a primary chemotherapy regimen for small cell carcinoma, but it is still imperfect. Programmed cell death ligand 1 (PD-L1) inhibitors are recommended for the treatment of small cell lung cancer. However, to determine whether PD-L1 inhibitors are optimal for metastatic GSCC requires more clinical data. CASE SUMMARY A 67-year-old male experienced upper abdominal pain without any obvious cause for 1 week. Gastroscopy examination revealed a mass in the gastric body. Pathological examination of the biopsy specimen combined with immunohistochemistry showed a high-grade neuroendocrine carcinoma (small cell carcinoma). Genetic tests showed TP53 , CREBBP , RB1 , ABCB1 , DNMT3A , and HGF gene mutations. Computed tomography (neck + chest + abdomen) showed multiple enlarged lymph nodes, occupying space in the greater curvature of the stomach and intrahepatic metastases. A regimen consisting of cisplatin and etoposide combined with durvalumab was administered every three weeks as palliative chemotherapy, for seven cycles. Durvalumab was then maintained every three weeks. However, the tumor recurred two months after the completion of chemotherapy. A regimen consisting of carboplatin and irinotecan combined with durvalumab was then given every three weeks. The tumor in the gastric body and liver shrank significantly, and the patient did not report any specific discomfort. CONCLUSION GSCC is a highly malignant tumor with a poor prognosis. Whether immune-related drugs are optimal for metastatic GSCC requires further exploration.

Trauma Evaluation During Pregnancy Is Independently Associated With Adverse Perinatal Outcomes Regardless of Injury Presence and Severity [ID 1256]

Obstetrics and Gynecology · 2025-05-15

Introduction: Trauma complicates approximately 8% of pregnancies. It is the leading nonobstetrical cause of maternal death and poses significant fetal risk. We hypothesize that a need for trauma evaluation during pregnancy, regardless of injury, is a potential marker for adverse perinatal outcomes. Methods: A single-institution retrospective cohort review was performed of pregnant patients from 2010 to 2020 who sustained traumatic mechanisms. Perinatal outcomes were compared with National Inpatient Sample (NIS) averages. Subset analysis of trauma patients without injury was performed. Multivariate regression highlighted independent predictors of adverse perinatal outcomes after trauma. Results: A total of 537 mother–fetus pairs were collected. Patients who sustained a traumatic mechanism at any gestational age during pregnancy had poorer perinatal outcomes, including preterm labor (odds ratio [OR] 1.40), placental abruption (OR 3.55), neonatal intensive care unit admission (OR 2.75), and neonatal demise (OR 1.71) compared to national averages ( P &lt;.001). This held true regardless of whether injury was sustained. Logistic regression demonstrated an independent association between adverse perinatal outcomes and maternal injury severity score (ISS) (OR 1.13 per ISS unit, P =.016), earlier gestational age of pregnancy at the time of trauma (OR 1.03 per day before term, P =.010), and lower maternal age (OR 0.96 per year). CONCLUSIONS/IMPLICATIONS: In this retrospective analysis, adverse perinatal outcomes correlate with injury severity and with earlier gestational age. However, even in the absence of acute injuries, patients who underwent trauma evaluation during pregnancy had significantly poorer perinatal outcomes compared to national averages. Trauma evaluation may independently represent a marker for high-risk pregnancy, warranting closer monitoring.

NLRX1 orchestrates neuronal mitophagy in Alzheimer’s Disease: a mechanistic exploration

Neurological Research · 2025-09-26 · 3 citations

BACKGROUND: Mitophagy dysfunction in Alzheimer's Disease (AD) accelerates disease progression, highlighting the need for novel therapeutic targets. Although Nucleotide oligomerization domain - like receptor X1 (NLRX1) regulates mitophagy, its role in AD remains unclear. This study aimed to elucidate NLRX1's function in AD - associated mitophagy and its therapeutic potential. METHODS: APP/PS1 transgenic mice and N2A - SW cells were used to establish AD models. Behavioral assays evaluated cognitive function in APP/PS1 mice, while transmission electron microscopy examined mitochondrial morphology. ELISA measured β - amyloid (Aβ)1-42 levels, and RT - qPCR and Western blot analyzed NLRX1 and mitophagy - related proteins after manipulating NLRX1 expression. RESULTS: APP/PS1 mice had cognitive impairment, elevated Aβ1-42, and abnormal mitochondrial morphology, with reduced NLRX1 expression. NLRX1 - RNAi worsened mitochondrial function, increased Aβ1-42 and mitochondrial ROS, decreased the LC3B - II/I ratio, and upregulated Cyt - C, HSP60, and TIM23, while NLRX1 overexpression alleviated these effects. Co-immunoprecipitation confirmed NLRX1's interaction with key mitophagy protein. CONCLUSION: NLRX1 is a key regulator of neuronal mitophagy in AD, and its downregulation impairs mitophagy, suggesting it as a potential therapeutic target.

DB‐YOLO: An Enhanced YOLO11 Approach for Vehicle and Pedestrian Detection in Foggy Scenarios

IET Image Processing · 2025-01-01

ABSTRACT During autonomous driving, accurate detection of vehicles and pedestrians is important. Under foggy conditions, vehicle and pedestrian targets in visual sensor images often appear blurred, occluded, or with reduced contrast, which significantly hinders feature extraction. To address these challenges, in this paper, based on YOLO11, namely, DB‐YOLO, a vehicle and pedestrian detection algorithm for foggy scenes, is proposed. First, in accordance with the atmospheric scattering theory of imaging under foggy conditions, a dual‐backbone feature extraction structure is designed to implicitly model the degradation mechanism of foggy images, fuse high‐level and low‐level features, and gradually increase the receptive field, improving the representation ability of the model for foggy images. Second, a C3K2_iAFF module is introduced. This module employs an attention‐based data fusion approach to achieve more efficient feature fusion by suppressing irrelevant features that are polluted by haze while improving useful features that are related to the target. Additionally, an efficient upconvolution block (EUCB) upsampling method is used in the neck network to further suppress haze noise and improve key features. The experimental results reveal that DB‐YOLO achieved mAP50 values of 56.6% and 40% on two public foggy datasets, representing improvements of 8.1% and 2.5%, respectively, over the baseline model. The proposed approach has better detection performance than multiple state‐of‐the‐art (SOTA) models do. This study provides effective technical support for increasing the perceptual robustness of autonomous driving systems under adverse weather conditions.