Silencing of cysteine and serine rich nuclear protein 1 inhibits apoptosis, senescence and collagen degradation in human-derived vaginal fibroblasts in response to oxidative stress or DNA damage.

Pelvic organ prolapse (POP) is a group of diseases caused by extracellular matrix (ECM) degradation in pelvic supportive tissues. Cysteine and serine rich nuclear protein 1 (CSRNP1) is involved in cell proliferation and survival regulation, and reportedly facilitates collagen breakdown in human chondrocytes. The present study aimed to probe the effect of CSRNP1 on collagen metabolism in human-derived vaginal fibroblasts. High expression of CSRNP1 was found in POP patient-derived vaginal fibroblasts in comparison to normal-derived vaginal fibroblasts. Following functional experiments revealed that CSRNP1 overexpression led to proliferation inhibition, apoptosis and collagen degradation in normal vaginal fibroblasts. In line with this, silencing of CSRNP1 inhibited hydrogen peroxide (H2O2)-triggered apoptosis, ROS generation and collagen loss in normal vaginal fibroblasts. Silencing of CSRNP1 also reduced the expression of cell senescence markers p21 and γ-H2Ax (the histone H2Ax phosphorylated at Ser139), as well as curbed collagen breakdown in normal vaginal fibroblasts caused by a DNA damage agent etoposide. Transcriptomic analysis of vaginal fibroblasts showed that differentially expressed genes affected by CSRNP1 overexpression were mainly enriched in the Wnt signaling pathway. Treatment with a Wnt pathway inhibitor DKK1 blocked CSRNP1 knockdown-caused collagen deposition. Mechanistically, CSRNP1 was identified to be a target of Snail family transcriptional repressor 2 (SNAI2). Forced expression of CSRNP1 reversed the anti-apoptotic, anti-senescent and anti-collagen loss effects of SNAI2 in normal vaginal fibroblasts exposed to H2O2 or etoposide. Our study indicates that the SNAI2/CSRNP1 axis may be a key driver in POP progression, which provides a potential therapeutic strategy for POP.

Endovascular Management of Post-Irradiated Carotid Blowout Syndrome in Patients with Lower Neck Cancers.

OBJECTIVE: Lower neck cancers (LNCs) include specific tumour types and have some different vascular supply or collaterals from other head and neck cancers. This prospective study evaluated the outcome of endovascular management of post-irradiated carotid blowout syndrome (PCBS) in patients with LNC by comparing reconstructive management (RE) and deconstructive management (DE). METHODS: This was a single centre, prospective cohort study. Patients with LNC complicated by PCBS between 2015 and 2021 were enrolled for RE or DE. RE was performed by stent graft placement covering the pathological lesion and preventive external carotid artery (ECA) embolisation without balloon test occlusion (BTO). DE was performed after successful BTO by permanent coil or adhesive agent embolisation of the internal carotid artery (ICA) and ECA to common carotid artery, or ICA occlusion alone if the pathological lesion was ICA only. Cross occlusion included the proximal and distal ends of the pathological lesion in all patients. Re-bleeding events, haemostatic period, and neurological complications were evaluated. RESULTS: Fifty-nine patients (mean age 58.5 years; 56 male) were enrolled, including 28 patients undergoing RE and 31 patients undergoing DE. Three patients originally grouped to DE were transferred to RE owing to failed BTO. The results of RE vs. DE were as follows: rebleeding events, 13/28 (46%) vs. 10/31 (32%) (p = .27); haemostatic period, 9.4 ± 14.0 months vs. 14.2 ± 27.8 months (p = .59); neurological complication, 4/28 (14%) vs. 5/31 (16%) (p = .84); and survival time, 11.8 ± 14.6 months vs. 15.1 ± 27.5 months (p = .61). CONCLUSION: No difference in rebleeding risk or neurological complications was observed between the DE and RE groups. RE could be used as a potential routine treatment for PCBS in patients with LNC.

SARS-CoV-2 nucleocapsid protein, rather than spike protein, triggers a cytokine storm originating from lung epithelial cells in patients with COVID-19.

PURPOSE: The aim of this study was to elucidate the factors associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may initiate cytokine cascades and correlate the clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with their serum cytokine profiles. METHODS: Recombinant baculoviruses displaying SARS-CoV-2 spike or nucleocapsid protein were constructed and transfected into A549 cells and THP-1-derived macrophages, to determine which protein initiate cytokine release. SARS-CoV-2-specific antibody titers and cytokine profiles of patients with COVID-19 were determined, and the results were associated with their clinical characteristics, such as development of pneumonia or length of hospital stay. RESULTS: The SARS-CoV-2 nucleocapsid protein, rather than the spike protein, triggers lung epithelial A549 cells to express IP-10, RANTES, IL-16, MIP-1α, basic FGF, eotaxin, IL-15, PDGF-BB, TRAIL, VEGF-A, and IL-5. Additionally, serum CTACK, basic FGF, GRO-α, IL-1α, IL-1RA, IL-2Rα, IL-9, IL-15, IL-16, IL-18, IP-10, M-CSF, MIF, MIG, RANTES, SCGF-ß, SDF-1α, TNF-α, TNF-ß, VEGF, PDGF-BB, TRAIL, ß-NGF, eotaxin, GM-CSF, IFN-α2, INF-γ, and MCP-1 levels were considerably increased in patients with COVID-19. Among them, patients with pneumonia had higher serum IP-10 and M-CSF levels than patients without. Patients requiring less than 3 weeks to show negative COVID-19 tests after contracting COVID-19 had higher serum IP-10 levels than the remaining patients. CONCLUSION: Our study revealed that nucleocapsid protein, lung epithelial cells, and IP-10 may be potential targets for the development of new strategies to prevent, or control, severe COVID-19.

Distinguishing methicillin-resistant Staphylococcus aureus from methicillin-sensitive strains by combining Fe3O4 magnetic nanoparticle-based affinity mass spectrometry with a machine learning strategy.

Pathogenic bacteria, including drug-resistant variants such as methicillin-resistant Staphylococcus aureus (MRSA), can cause severe infections in the human body. Early detection of MRSA is essential for clinical diagnosis and proper treatment, considering the distinct therapeutic strategies for methicillin-sensitive S. aureus (MSSA) and MRSA infections. However, the similarities between MRSA and MSSA properties present a challenge in promptly and accurately distinguishing between them. This work introduces an approach to differentiate MRSA from MSSA utilizing matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) in conjunction with a neural network-based classification model. Four distinct strains of S. aureus were utilized, comprising three MSSA strains and one MRSA strain. The classification accuracy of our model ranges from ~ 92 to ~ 97% for each strain. We used deep SHapley Additive exPlanations to reveal the unique feature peaks for each bacterial strain. Furthermore, Fe3O4 MNPs were used as affinity probes for sample enrichment to eliminate the overnight culture and reduce the time in sample preparation. The limit of detection of the MNP-based affinity approach toward S. aureus combined with our machine learning strategy was as low as ~ 8 × 103 CFU mL-1. The feasibility of using the current approach for the identification of S. aureus in juice samples was also demonstrated.

Percutaneous transluminal angioplasty and stenting of post-irradiated stenosis of subclavian artery: A matched case-control study.

BACKGROUND: Although radiotherapy is common for head/neck and chest cancers (HNCC), it can result in post-irradiation stenosis of the subclavian artery (PISSA). The efficacy of percutaneous transluminal angioplasty and stenting (PTAS) to treat severe PISSA is not well-clarified. AIMS: To compare the technical safety and outcomes of PTAS between patients with severe PISSA (RT group) and radiation-naïve counterparts (non-RT group). METHODS: During 2000 and 2021, we retrospectively enrolled patients with severe symptomatic stenosis (>60%) of the subclavian artery who underwent PTAS. The rate of new recent vertebrobasilar ischaemic lesions (NRVBIL), diagnosed on diffusion-weight imaging (DWI) within 24 h of postprocedural brain MRI; symptom relief; and long-term stent patency were compared between the two groups. RESULTS: Technical success was achieved in all 61 patients in the two groups. Compared with the non-RT group (44 cases, 44 lesions), the RT group (17 cases, 18 lesions) had longer stenoses (22.1 vs 11.1 mm, P = 0.003), more ulcerative plaques (38.9% vs 9.1%, P = 0.010), and more medial- or distal-segment stenoses (44.4% vs 9.1%, P<0.001). The technical safety and outcome between the non-RT group and the RT group were NRVBIL on DWI of periprocedural brain MRI 30.0% vs 23.1%, P = 0.727; symptom recurrence rate (mean follow-up 67.1 ± 50.0 months) 2.3% vs 11.8%, P = 0.185; and significant in-stent restenosis rate (>50%) 2.3% vs 11.1%, P = 0.200. CONCLUSION: The technical safety and outcome of PTAS for PISSA were not inferior to those of radiation-naïve counterparts. PTAS for PISSA is an effective treatment for medically refractory ischaemic symptoms of HNCC patients with PISSA.

Motility and swimming: universal description and generic trajectories.

Autonomous locomotion is a ubiquitous phenomenon in biology and in physics of active systems at microscopic scale. This includes prokaryotic, eukaryotic cells (crawling and swimming) and artificial swimmers. An outstanding feature is the ability of these entities to follow complex trajectories, ranging from straight, curved (circular, helical...), to random-like ones. The non-straight nature of these trajectories is often explained as a consequence of the asymmetry of the particle or the medium in which it moves, or due to the presence of bounding walls, etc... Here, we show that for a particle driven by a concentration field of an active species, straight, circular and helical trajectories emerge naturally in the absence of asymmetry of the particle or that of suspending medium. Our proof is based on general considerations, without referring to an explicit form of a model. We show that these three trajectories correspond to self-congruent solutions. Self-congruency means that the states of the system at different moments of time can be made identical by an appropriate combination of rotation and translation of the coordinate space. We show that these solutions are exhibited by spherically symmetric particles as a result of a series of pitchfork bifurcations, leading to spontaneous symmetry breaking in the concentration field driving the particle motility. Self-congruent dynamics in one and two dimensions are analyzed as well. Finally, we present a simple explicit nonlinear exactly solvable model of fully isotropic phoretic particle that shows the transitions from a non-motile state to straight motion to circular motion to helical motion as a series of spontaneous symmetry-breaking bifurcations. Whether a system exhibits or not a given trajectory only depends on the numerical values of parameters entering the model, while asymmetry of swimmer shape, or anisotropy of the suspending medium, or influence of bounding walls are not necessary.

Clinical and imaging findings for the evaluation of large Rathke's cleft cysts and cystic craniopharyngiomas.

PURPOSE: Large Rathke's cleft cysts (LRCCs) and cystic craniopharyngiomas (CCPs) arise from the same embryological origin and may have similar MR presentations. However, the two tumors have different management strategies and outcomes. This study was designed to evaluate the clinical and imaging findings of LRCCs and CCPs, aiming to evaluate their pretreatment diagnosis and outcomes. METHODS: We retrospectively enrolled 20 patients with LRCCs and 25 patients with CCPs. Both tumors had a maximal diameter of more than 20 mm. We evaluated the patients' clinical and MR imaging findings, including symptoms, management strategies, outcomes, anatomic growth patterns and signal changes. RESULTS: The age of onset for LRCCs versus CCPs was 49.0 ± 16.8 versus 34.2 ± 22.2 years (p = .022); the following outcomes were observed for LRCCs versus CCPs: (1) postoperative diabetes insipidus: 6/20 (30%) versus 17/25 (68%) (p = .006); and (2) posttreatment recurrence: 2/20 (10%) versus 10/25 (40%) (p = .025). The following MR findings were observed for LRCCs versus CCPs: (1) solid component: 7/20 (35%) versus 21/25 (84%) (p = .001); (2) thick cyst wall: 2/20 (10%) versus 12/25 (48%) (p = .009); (3) intracystic septation: 1/20 (5%) versus 8/25 (32%) (p = .030); (4) snowman shape: 18/20 (90%) versus 1/25 (4%) (p < .001); (5) off-midline extension: 0/0 (0%) versus 10/25 (40%) (p = .001); and (6) oblique angle of the sagittal long axis of the tumor: 89.9° versus 107.1° (p = .001). CONCLUSIONS: LRCCs can be differentiated from CCPs based on their clinical and imaging findings, especially their specific anatomical growth patterns. We suggest using the pretreatment diagnosis to select the appropriate surgical approach and thus improve the clinical outcome.

Investigation of the Relationship between Body Parameters and mAs Using Non-Contact Two-Dimensional Thickness Measurement in Chest Digital Radiography.

The current study aimed to investigate the relationship between body parameters and the current-time product (mAs) in chest digital radiography using a non-contact infrared thickness-measurement sensor. An anthropomorphic chest phantom was first used to understand variations in mAs over multiple positionings during chest radiography when using the automatic exposure control (AEC) technique. In a human study, 929 consecutive male subjects who underwent regular chest examinations were enrolled, and their height (H), weight (W), and body mass index (BMI) were recorded. In addition, their chest thickness (T) was measured at exhalation using a non-contact infrared sensor, and chest radiography was then performed using the AEC technique. Finally, the relationship between four body parameters (T, BMI, T*BMI, and W/H) and mAs was investigated by fitting the body parameters to mAs using three curve models. The phantom study showed that the maximum mAs was 1.76 times higher than the lowest mAs during multiple positionings in chest radiography. In the human study, all chest radiographs passed the routine quality control procedure and had an exposure index between 100 and 212. In curve fitting, the comparisons showed that W/H had a closer relationship with mAs than the other body parameters, while the first-order power model with W/H fitted to mAs performed the best and had an R-square of 0.9971. We concluded that the relationship between W/H and mAs in the first-order power model may be helpful in predicting the optimal mAs and reducing the radiation dose for chest radiography when using the AEC technique.

Percutaneous transluminal angioplasty and stenting of post-irradiation stenosis of the vertebral artery.

BACKGROUND: The outcomes of percutaneous transluminal angioplasty and stenting (PTAS) in patients with medically refractory post-irradiation stenosis of the vertebral artery (PISVA) have not been clarified. AIM: This retrospective study evaluated the safety and outcomes of PTAS in patients with severe PISVA compared with their radiation-naïve counterparts (non-RT group). METHODS: Patients with medically refractory severe symptomatic vertebral artery stenosis and undergoing PTAS between 2000 and 2021 were classified as the PISVA group or the non-RT group. The periprocedural neurological complications, periprocedural brain magnetic resonance imaging, the extent of symptom relief, and long-term stent patency were compared. RESULTS: As compared with the non-RT group (22 cases, 24 lesions), the PISVA group (10 cases, 10 lesions) was younger (62.0 ± 8.6 vs 72.4 ± 9.7 years, P = 0.006) and less frequently had hypertension (40.0% vs 86.4%, P = 0.013) and diabetes mellitus (10.0% vs 54.6%, P = 0.024). Periprocedural embolic infarction was not significantly different between the non-RT group and the PISVA group (37.5% vs 35.7%, P = 1.000). At a mean follow-up of 72.1 ± 58.7 (3-244) months, there was no significant between-group differences in the symptom recurrence rate (0.00% vs 4.55%, P = 1.000) and in-stent restenosis rate (10.0% vs 12.5%, P = 1.000). CONCLUSION: PTAS of severe medically refractory PISVA is effective in the management of vertebrobasilar ischemic symptoms in head and neck cancer patients. Technical safety and outcome of the procedure were like those features in radiation-naïve patients.

Perineural Invasion is a Powerful Prognostic Factor for Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy.

BACKGROUND: Taiwan has the highest incidence of upper tract urothelial carcinoma (UTUC) worldwide. Although many pathological factors can predict the prognosis of UTUC, previous studies have rarely discussed perineural invasion (PNI). Therefore, we aimed to investigate the effect of PNI on a well-established cohort of patients with UTUC. METHODS: This retrospective study included 803 patients with non-metastatic UTUC who underwent radical nephroureterectomy between June 2000 and August 2019. Demographic and clinicopathological parameters, including PNI, were collected for analysis. Using the Kaplan-Meier method and Cox proportional hazards model, we evaluated the significance of PNI with respect to progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The median follow-up was 30.9 months, and there were 83 cases of PNI (10.3%). PNI-positive patients had unfavorable pathological features, including high pT stage, positive lymph node involvement, high tumor grade, and more lymphovascular invasion (all p < 0.001). Kaplan-Meier analysis showed that PNI was significantly associated with PFS, CSS, and OS (all p < 0.00001), and when combined with lymphovascular invasion, patients could be divided into groups with distinct survival rates (all p < 0.00001). In multivariate analysis, PNI was an independent factor leading to worse PFS (hazard ratio [HR] 1.72, 95% confidence interval [CI] 1.19-2.50; p = 0.004), CSS (HR 2.54, 95% CI 1.58-4.10; p = 0.0001), and OS (HR 1.78, 95% CI 1.19-2.65; p = 0.005). CONCLUSIONS: We demonstrated an association between PNI and the prognosis of UTUC. Routine assessment of PNI in UTUC with standardized protocols may help achieve better risk stratification and subject selection for perioperative treatment.

Influence of angioplasty and stenting on intracranial artery stenosis: preliminary results of high-resolution vessel wall imaging evaluation.

OBJECTIVES: To investigate whether the imaging changes on high-resolution vessel wall imaging (HR-VWI) in patients before and after percutaneous transluminal angioplasty and stenting (PTAS) contribute to predicting the clinical outcome. METHODS: The study included 24 severe intracranial artery stenosis (SICAS) patients undergoing PTAS with Wingspan Stent between 2018 and 2020 and had a 1-year follow-up. Three HR-VWI sessions (preprocedural, early [within 24 h], and delayed postprocedural [134.7 ± 27.1 days)]) in each subject were performed with 3-Tesla MRI. We evaluated periprocedural HR-VWI changes in patients with and without recurrent cerebral ischemic symptoms (RCIS) within 1-year follow-up. RESULTS: On CE-T1WI of the patients without RCIS, a significant decrease in enhanced area was observed on early postprocedural (0.04 ± 0.02 cm2, p = 0.001) and delayed postprocedural (0.04 ± 0.02 cm2; p = 0.001) HR-VWI compared to preprocedural (0.07 ± 0.02 cm2) HR-VWI. Patients with RCIS demonstrated no significant loss of enhanced area on CE-T1WI of early postprocedural HR-VWI (p = 0.180). Significant decreases in calibrated T1 signals were observed in both presence (1.77 ± 0.70 vs. 0.79 ± 0.52; p = 0.018) and absence (1.42 ± 0.62 vs. 0.83 ± 0.40; p = 0.001) of RCIS in early postprocedural HR-VWI. CONCLUSION: The preliminary results showed the presence of reduced contrast enhancement immediately after PTAS may indicate less recurrent stroke events within 1 year. Further studies are necessary to confirm the phenomena in a longer observation period. KEY POINTS: • Early postprocedural high-resolution vessel imaging (HR-VWI) within 24 h can effectively predict a 1-year outcome following intracranial stenting. • For stenotic lesions after stenting without reduced contrast enhancement on HR-VWI within 24 h may need closer clinical surveillance for potentially higher risk of stroke events within 1 year.

Shortened cerebral circulation time correlates with seizures in brain arteriovenous malformation: a cross-sectional quantitative digital subtraction angiography study.

OBJECTIVE: Seizure is the most common clinical presentation in patients with nonhemorrhagic brain arteriovenous malformations (BAVMs) and it influences their quality of life. Angioarchitectural analysis of the seizure risk for BAVMs is subjective and does not consider hemodynamics. This study aimed to investigate the angioarchitectural and hemodynamic factors that may be associated with seizure in patients with BAVMs. METHODS: From 2011 to 2019, 104 patients with supratentorial BAVMs without previous hemorrhage or treatment were included and grouped according to the initial presentation of seizure. Their angiograms and MRI results were analyzed for morphological characteristics and quantitative digital subtraction angiography (QDSA) parameters. Modified cerebral circulation time (mCCT) was defined as the difference between the bolus arrival time of the ipsilateral cavernous internal carotid artery and the parietal vein on lateral DSA. Logistic regression analysis was performed to estimate the odds ratio (OR) for BAVMs presenting with seizure. RESULTS: The seizure group had shorter mCCT (1.98 s vs. 2.44 s, p = 0.005) and more BAVMs with temporal location (45% vs. 30.8%, p = 0.013), neoangiogenesis (55% vs. 33%, p = 0.03), and long draining veins (95% vs. 72%, p = 0.004) than did the nonseizure group. Shorter mCCT (OR: 3.4, p = 0.02), temporal location (OR: 13.4, p < 0.001), and neoangiogenesis (OR: 4.7, p = 0.013) were independently associated with higher risks of seizure, after adjustments for age, gender, BAVM volume, and long draining vein. CONCLUSIONS: Shorter mCCT, temporal location, and neoangiogenesis were associated with epileptic BAVMs. QDSA can objectively evaluate hemodynamic changes in epileptic BAVMs. KEY POINTS: • Quantitative digital subtraction angiography may be used to evaluate the hemodynamic differences between brain arteriovenous malformations presenting with and without seizure. • BAVMs with temporal location, neoangiogenesis, and shortened cerebral circulation time were more likely to present with seizure.

Neuroprotective Action of Coumarin Derivatives through Activation of TRKB-CREB-BDNF Pathway and Reduction of Caspase Activity in Neuronal Cells Expressing Pro-Aggregated Tau Protein.

Hyperphosphorylation and aggregation of the microtubule binding protein tau is a neuropathological hallmark of Alzheimer's disease/tauopathies. Tau neurotoxicity provokes alterations in brain-derived neurotrophic factor (BDNF)/tropomycin receptor kinase B (TRKB)/cAMP-response-element binding protein (CREB) signaling to contribute to neurodegeneration. Compounds activating TRKB may therefore provide beneficial effects in tauopathies. LM-031, a coumarin derivative, has demonstrated the potential to improve BDNF signaling in neuronal cells expressing pro-aggregated ΔK280 tau mutant. In this study, we investigated if LM-031 analogous compounds provide neuroprotection effects through interaction with TRKB in SH-SY5Y cells expressing ΔK280 tauRD-DsRed folding reporter. All four LMDS compounds reduced tau aggregation and reactive oxygen species. Among them, LMDS-1 and -2 reduced caspase-1, caspase-6 and caspase-3 activities and promoted neurite outgrowth, and the effect was significantly reversed by knockdown of TRKB. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in these cells, implying that the neuroprotective effects of LMDS-1/2 are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. Furthermore, LMDS-1/2 demonstrated their ability to quench the intrinsic fluorescence of tryptophan residues within the extracellular domain of TRKB, thereby consolidating their interaction with TRKB. Our results suggest that LMDS-1/2 exert neuroprotection through activating TRKB signaling, and shed light on their potential application in therapeutics of Alzheimer's disease/tauopathies.

Immune Reconstitution Inflammatory Syndrome Induced by Mycobacterium avium Complex Infection Presenting as Chronic Inflammatory Demyelinating Polyneuropathy in a Young AIDS Patient.

Antiretroviral therapy (ART) can restore protective immune responses against opportunistic infections (OIs) and reduce mortality in patients with human immunodeficiency virus (HIV) infections. Some patients treated with ART may develop immune reconstitution inflammatory syndrome (IRIS). Mycobacterium avium complex (MAC)-related IRIS most commonly presents as lymphadenitis, soft-tissue abscesses, and deteriorating lung infiltrates. However, neurological presentations of IRIS induced by MAC have been rarely described. We report the case of a 31-year-old man with an HIV infection. He developed productive cough and chronic inflammatory demyelinating polyneuropathy (CIDP) three months after the initiation of ART. He experienced an excellent virological and immunological response. Sputum culture grew MAC. The patient was diagnosed with MAC-related IRIS presenting as CIDP, based on his history and laboratory, radiologic, and electrophysiological findings. Results: Neurological symptoms improved after plasmapheresis and intravenous immunoglobulin (IVIG) treatment. To our knowledge, this is the first reported case of CIDP due to MAC-related IRIS. Clinicians should consider MAC-related IRIS in the differential diagnosis of CIDP in patients with HIV infections following the initiation of ART.

Transforming Growth Factor Beta 1 and p44/42 Expression in Cardinal Ligament Tissues of Patients with Pelvic Organ Prolapse.

BACKGROUND Pelvic organ prolapse (POP) is a disease associated with collagen loss and decreased fibroblast proliferation. Transforming growth factor beta 1 (TGF-ß1) controls collagen synthesis and degradation in pelvic connective tissue. Although the p44/42 MAPK pathway has been implicated in collagen production and extracellular matrix disorders, its expression in POP remains unknown. This study aimed to investigate TGF-ß1 and p44/42 expression in cardinal ligament tissues in patients with POP. MATERIAL AND METHODS Cardinal ligament tissues were obtained from 30 patients with POP (POP group) and 30 patients with benign gynecological disorders who had undergone total hysterectomy (control group). The clinical characteristics of the 2 groups were summarized. Immunohistochemical staining and western blotting analysis were performed to measure the expression of TGF-ß1, p44/42, phospho-p44/42, MMP9, TIMP1, caspase 3, collagen I, and collagen III in the cardinal ligament tissues. RESULTS Patients with POP had significantly lower TGF-ß1 and phospho-p44/42 levels than did control patients (P<0.05). The expression of TIMP1, collagen I, and collagen III was significantly lower, and the expression of MMP9 and caspase 3 was significantly higher in the POP group than in the control group (P<0.05). Moreover, the expression of phospho-p44/42 was positively correlated with the expression of TGF-ß1, collagen I, and collagen III. CONCLUSIONS The expression levels of phospho-p44/42 and TGF-ß1 were decreased in patients with POP and were positively correlated with collagen expression. Low levels of TGF-ß1 and phospho-p44/42 expression in patients with POP may be associated with the occurrence of POP.

Expression of COX-2 and Nrf2/GPx3 in the anterior vaginal wall tissues of women with pelvic organ prolapse.

PURPOSE: To evaluate COX-2 and Nrf2/GPx3 expressions in the lamina propria of the anterior vaginal wall tissues of women with and without pelvic organ prolapse (POP). METHODS: Tissue samples of anterior vaginal wall were examined using HE staining, immuohistochemical staining and Western blot for the expressions of COX-2/PGE2, Nrf2/GPx3, MMP2, TIMP1, collagen I and collagen III (n = 35, per group). RESULTS: Compared with control group, collagen fibers of the anterior vaginal wall were disorganized and discontinuous. Expressions of Nrf2, GPx3, TIMP1, collagen I and collagen III were found significantly lower in POP group (P < 0.05); while, expressions of COX-2, PGE2, and MMP2 were found significantly higher in POP group (P < 0.05). Statistically significant correlations of COX-2 and Nrf2/GPx3 were showed (P < 0.01). CONCLUSION: We found that the interaction between inflammation and oxidative stress was closely related to the development of POP. This study demonstrates that COX-2 and Nrf2 pathways may be involved in pathogenesis of POP, as promising potential therapeutic targets and agents.

Landscape forest impacts the potential activity time of an invasive lizard and its possibilities for range expansion in Taiwan under climate warming.

Climate warming may have an impact on invasive species and their ecological consequences. Invasive reptiles, which have temperature-dependent physiology, are expected to be greatly impacted by climate warming, though data supporting this is limited. We investigated the potential impact of a warmer climate on an invasive lizard, Eutropis multifasciata, in Taiwan. A mechanistic model, NicheMapR, was used to simulate the maximum activity time available at three elevations, with varying forest densities, under the current climate and a warmer scenario. The results show that climate warming will provide this species more time for activity in the currently occupied lowland region but not in the mountain areas, which are covered with dense forests. However, if the landscape becomes more open in mountain areas, it will become more suitable for this species and may enable an expansion upslope. Our results show that climate warming has a positive impact on this species, and that landscape's characteristics profoundly modulate its impact and the possibilities for elevational expansion in the future.

Epoxidation Catalyzed by the Nonheme Iron(II)- and 2-Oxoglutarate-Dependent Oxygenase, AsqJ: Mechanistic Elucidation of Oxygen Atom Transfer by a Ferryl Intermediate.

Mechanisms of enzymatic epoxidation via oxygen atom transfer (OAT) to an olefin moiety is mainly derived from the studies on thiolate-heme containing epoxidases, such as cytochrome P450 epoxidases. The molecular basis of epoxidation catalyzed by nonheme-iron enzymes is much less explored. Herein, we present a detailed study on epoxidation catalyzed by the nonheme iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase, AsqJ. The native substrate and analogues with different para substituents ranging from electron-donating groups (e.g., methoxy) to electron-withdrawing groups (e.g., trifluoromethyl) were used to probe the mechanism. The results derived from transient-state enzyme kinetics, Mössbauer spectroscopy, reaction product analysis, X-ray crystallography, density functional theory calculations, and molecular dynamic simulations collectively revealed the following mechanistic insights: (1) The rapid O2 addition to the AsqJ Fe(II) center occurs with the iron-bound 2OG adopting an online-binding mode in which the C1 carboxylate group of 2OG is trans to the proximal histidine (His134) of the 2-His-1-carboxylate facial triad, instead of assuming the offline-binding mode with the C1 carboxylate group trans to the distal histidine (His211); (2) The decay rate constant of the ferryl intermediate is not strongly affected by the nature of the para substituents of the substrate during the OAT step, a reactivity behavior that is drastically different from nonheme Fe(IV)-oxo synthetic model complexes; (3) The OAT step most likely proceeds through a stepwise process with the initial formation of a C(benzylic)-O bond to generate an Fe-alkoxide species, which is observed in the AsqJ crystal structure. The subsequent C3-O bond formation completes the epoxide installation.

Pentraxin 3 deficiency exacerbates lipopolysaccharide-induced inflammation in adipose tissue.

BACKGROUND/OBJECTIVES: Pentraxin 3 (PTX3) has been characterized as a soluble and multifunctional pattern recognition protein in the regulation of innate immune response. However, little is known about its role in adipose tissue inflammation and obesity. Herein, we investigated the role of PTX3 in the regulation of lipopolysaccharide (LPS)-induced inflammation in adipocytes and adipose tissue, as well as high-fat diet (HFD)-induced metabolic inflammation in obesity. METHODS: Ptx3 knockdown 3T3-L1 Cells were generated using shRNA for Ptx3 gene and treated with different inflammatory stimuli. For the in vivo studies, Ptx3 knockout mice were treated with 0.3 mg/kg of LPS for 6 h. Adipose tissues were collected for gene and protein expression by qPCR and western blotting, respectively. Ptx3 knockout mice were fed with HFD for 12 week since 6 week of age. RESULTS: We observed that the expression of PTX3 in adipose tissue and serum PTX3 were markedly increased in response to LPS administration. Knocking down Ptx3 in 3T3-L1 cells reduced adipogenesis and caused a more profound and sustained upregulation of proinflammatory gene expression and signaling pathway activation during LPS-stimulated inflammation in 3T3-L1 adipocytes. In vivo studies showed that PTX3 deficiency significantly exacerbated the LPS-induced upregulation of inflammatory genes and downregulation of adipogeneic genes in visceral and subcutaneous adipose tissue of mice. Accordingly, LPS stimulation elicited increased activation of nuclear factor-κB (NF-κB) and p44/42 MAPK (Erk1/2) signaling pathways in visceral and subcutaneous adipose tissue. The expression of PTX3 in adipose tissue was also induced by HFD, and PTX3 deficiency led to the upregulation of proinflammatory genes in visceral adipose tissue of HFD-induced obese mice. CONCLUSIONS: Our results suggest a protective role of PTX3 in LPS- and HFD-induced sustained inflammation in adipose tissue.

Early Seroreversion After 2 Doses of Hepatitis A Vaccination in Human Immunodeficiency Virus-Positive Patients: Incidence and Associated Factors.

Serological responses (Seroresponse) and durability of hepatitis A virus (HAV) vaccination are reduced among human immunodeficiency virus (HIV)-positive patients. Incidence of and associated factors with early seroreversion (loss of seroresponse) among HIV-positive patients who have achieved seroresponses after two doses of HAV vaccination remain unclear. In this multicenter study, we followed HIV-positive adults who had mounted seroresponses after completing two doses of HAV vaccination during a recent outbreak of acute hepatitis A between 2015 and 2017, a 1:4 case-control study was conducted to identify factors associated with seroreversion. Case patients were those with seroreversion, and controls were those with similar follow-up durations who were able to maintain seroresponses. During the study period, 49 of the 1,256 patients (3.9%) seroreverted after a median follow-up of 611 days. In a case-control study, seroreversion was more likely to occur in patients with a higher weight (adjusted odds ratio [aOR], 1.703; 95% confidence interval [CI], 1.292-2.323, per 10-kg increment) and HIV viremia at the time of vaccination (aOR, 2.922; 95% CI, 1.067-7.924), whereas positive seroresponse at 6 months of HAV vaccination and higher CD4 lymphocyte counts at vaccination were inversely associated with early seroreversion with an aOR of 0.059 (95% CI, 0.020-0.154) and 0.837 (95% CI, 0.704-0.979, per 100-cell/mm3 increment), respectively, in multivariable analyses. Conclusion: During an outbreak setting, early seroreversion following two-dose HAV vaccination occurred in 3.9% of HIV-positive patients. Lower and delayed seroresponses to HAV vaccination, a higher weight, and HIV viremia and lower CD4 lymphocyte counts at the time of HAV vaccination were associated with early seroreversion. Regular monitoring of seroresponse and booster vaccination might be warranted, especially in HIV-positive adults with predictors of early seroreversion.