Search Results (261)

Hemolytic uremic syndrome (HUS), a thrombotic microangiopathy primarily affecting the kidneys, can also involve the central nervous system (CNS), often leading to significant morbidity and mortality. Neurologic manifestations are among the most severe extra-renal complications, particularly in children and during outbreaks of Shiga toxin-producing Escherichia coli (STEC)-associated HUS (typical (tHUS)). This review explores the clinical spectrum, pathophysiology, diagnostic workup, and age-specific outcomes of neurologic involvement in both typical (tHUS) and atypical (aHUS). Neurologic complications occur in up to 11% of pediatric and over 40% of adult STEC-HUS cases in outbreak settings. Presentations include seizures, encephalopathy, focal deficits, movement disorders, and posterior reversible encephalopathy syndrome (PRES). Magnetic resonance imaging (MRI) commonly reveals basal ganglia or parieto-occipital lesions, though subtle or delayed findings may occur. Laboratory workup typically confirms microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and kidney damage, with additional markers of inflammation or metabolic dysregulation. Eculizumab is the first-line treatment for aHUS with CNS involvement, while its utility in STEC-HUS remains uncertain. Although many children recover fully, those with early CNS involvement are at greater risk of developing epilepsy, cognitive delays, or fine motor deficits. Adults may experience lingering neurocognitive symptoms despite apparent clinical recovery. Differences in presentation and imaging findings between age groups emphasize the need for tailored diagnostic and therapeutic strategies. Comprehensive neurorehabilitation and long-term follow-up are crucial for identifying residual deficits. Continued research into predictive biomarkers, neuroprotective interventions, and standardized treatment protocols is needed for improving outcomes in HUS patients with neurological complications. Full article

Built heritage serves as a vital repository of human history and culture, and an examination of its spatial distribution and influencing factors holds significant value for the preservation and advancement of our historical and cultural narratives. This thesis brings together various forms of built heritage, employing methodologies such as kernel density estimation, average nearest neighbor analysis, and standard deviation ellipses to elucidate the characteristics of spatial distribution. Additionally, it investigates the influencing factors through geographical detectors and Multiscale Geographically Weighted Regression (MGWR). The findings reveal several key insights: (1) In terms of geographical patterns, built heritage is predominantly located southeast of the “Hu-Huanyong” line, with notable concentrations at the confluence of Shanxi and Henan provinces, the southeastern region of Guizhou, as well as in southern Anhui, Fujian, and Zhejiang. Moreover, distinct types of built heritage exhibit marked spatial variations. (2) The reliability and significance of the analytical results derived from prefecture and city-level units surpass those obtained from grid and provincial-level analyses. Among the influencing factors, the explanatory power associated with the number of counties emerges as the strongest, while that relating to population density was the weakest; furthermore, interactions among factors that meet significance thresholds reveal enhanced explanatory capabilities. (3) Both road density and population density demonstrate positive correlations; conversely, the positive influence of topographic relief and river density accounts for 90% of their variance. GDP exhibits a negative correlation, with the number of counties contributing to 70% of this negative impact; thus, the distribution of positive and negative influences from various factors varies significantly. Drawing upon these spatial distribution characteristics and the disparities observed in regression coefficients, this thesis delves into potential influence factors and proposes recommendations for the development and safeguarding of built heritage. Full article

Background/Objectives: Iterative reconstruction (IR) techniques were developed to address the shortcomings of filtered back projection (FBP), yet research comparing different types of IR is still missing. This work investigates how reducing radiation dose influences both image quality and noise profiles when using two iterative reconstruction techniques—Sinogram-Affirmed Iterative Reconstruction (SAFIRE) and Advanced Modeled Iterative Reconstruction (ADMIRE)—in comparison to filtered back projection (FBP) in non-enhanced head CT (NECT). Methods: In this retrospective single-center study, 21 consecutive patients underwent standard NECT on a 128-slice CT scanner. Raw data simulated dose reductions to 90% and 70% of the original dose via ReconCT software. For each dose level, images were reconstructed with FBP, SAFIRE 3, and ADMIRE 3. Image noise power spectra quantified objective image noise. Two blinded neuroradiologists scored overall image quality, image noise, image contrast, detail, and artifacts on a 10-point Likert scale in a consensus reading. Quantitative Hounsfield unit (HU) measurements were obtained in white and gray matter regions. Statistical analyses included the Wilcoxon signed-rank test, mixed-effects modeling, ANOVA, and post hoc pairwise comparisons with Bonferroni correction. Results: Both iterative reconstructions significantly reduced image noise compared to FBP across all dose levels (p < 0.001). ADMIRE exhibited superior image noise suppression at low (<0.51 1/mm) and high (>1.31 1/mm) spatial frequencies, whereas SAFIRE performed better in the mid-frequency range (0.51–1.31 1/mm). Subjective scores for overall quality, image noise, image contrast, and detail were higher for ADMIRE and SAFIRE versus FBP at the original dose and simulated doses of 90% and 70% (all p < 0.001). ADMIRE outperformed SAFIRE in artifact reduction (p < 0.001), while SAFIRE achieved slightly higher image contrast scores (p < 0.001). Objective HU values remained stable across reconstruction methods, although SAFIRE yielded marginally higher gray and white matter (WM) attenuations (p < 0.01). Conclusions: Both IR techniques—ADMIRE and SAFIRE—achieved substantial noise reduction and improved image quality relative to FBP in non-enhanced head CT at standard and reduced dose levels on the specific CT system and reconstruction strength tested. ADMIRE showed enhanced suppression of low- and high-frequency image noise and fewer artifacts, while SAFIRE preserved image contrast and reduced mid-frequency noise. These findings support the potential of iterative reconstruction to optimize radiation dose in NECT protocols in line with the ALARA principle, although broader validation in multi-vendor, multi-center settings is warranted. Full article

The presence of pesticides in surface waters has been widely reported worldwide and represents a significant problem that raises concerns on local, regional, national, and international scales. Among these, metolachlor is one of the most widely used herbicides to control annual grasses and broadleaf weeds in various crops. Despite the existing research, data on the effects of metolachlor on the nervous system of fishes, remain limited. The present study aims to investigate the impact of metolachlor during embryonic development on the formation of the nervous system and the subsequent inflammatory response in zebrafish (Danio rerio), focusing specifically on larvae at 24 h post-fertilization (hpf). To achieve this, transgenic zebrafish lines marking neuronal populations Tg(Hu:GFP), glial cells Tg(gfap:GFP), and circulating macrophages Tg(mpeg:GFP) were employed. Following exposure to sub-lethal doses of metolachlor, we observed a significant decrease in GPF-positive cells marking the neuronal population, accompanied by an increase in apoptotic cells within the brain region. Additionally, treated embryos exhibited a marked neuroinflammatory response, characterized by astrogliosis and the specific accumulation of microglia/macrophage-positive cells in the head region. In situ hybridization and real-time PCR analyses revealed a significant downregulation of the neurogenin-1 (ngn1) transcript and a noticeable upregulation of the pro-inflammatory cytokine interleukin-1 beta (il1b). Our findings contribute to the growing body of evidence suggesting that metolachlor, even at early developmental stages, can have detrimental effects on both the formation of the nervous system and the regulation of immune responses. Full article

A pivotal role of metabolic reprogramming in urothelial carcinoma is hallmarked by the dependence of two-fold faster proliferation of urothelial carcinoma cell line T24 than benign cell line TRT-HU1 on five-fold higher glucose (basal) 16 mM vs. 3 mM in McCoy’s 5A media and Keratinocyte Serum Free media, respectively. Here, we report that an additional 10% increase to 17.6 mM and 3.3 mM glucose significantly shortens the doubling time by 3 h and 1 h for T24 and TRT-HUI, respectively. T24 grown at 17.6 mM glucose lowers the confocal localization of the fatty acid mimetic, Betulinic Acid (BA) conjugated to FITC (BA-FITC) with Mito Tracker Red (mitochondrial marker), which doubles the IC50 of BA and BA-FITC by lowering cell cycle arrest in the G0/G1 phase from 54.2% to 43.8% and caspase-3/7 mediated apoptosis and by reversing caspase-3, p53, PTEN, GAPDH, and XIAP gene expression induced by BA in T24 grown at basal glucose (16 mM). Besides slowing the glycogen and pH decline of T24 at basal glucose, BA exhibited an eight-fold higher IC50 than Mitomycin C (MC) on TRT-HU1 by not mimicking the glucose-insensitive cycle arrest and apoptosis of MC. Overall, the glucose sensitivity of the lower IC50 of BA-FITC and BA on T24 vs. TRT-HU1 supports the safety of BA conjugates for theragnostic purposes. Full article

Background/Objectives: Polycystic liver disease (PLD) is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). PLD is more prevalent in women, and women have larger liver cysts, possibly due to estrogen-related mechanisms. Maternal estrogen levels normally increase during pregnancy. Thus, we investigated the pregnancy-associated increase in liver volume, liver cyst volume, total kidney volume (TKV), and kidney cyst growth rates in ADPKD patients. Methods: Kidney, liver, and cyst volumes were measured in 16 ADPKD patients by magnetic resonance imaging (MRI) at multiple timepoints before and after pregnancy. The log-transformed TKV, liver volume, and cyst volume growth rates during a period with pregnancy were compared to a period without pregnancy. Results: In ADPKD patients, a higher annualized liver cyst growth rate was observed during a period with pregnancy compared to a period without pregnancy (34 ± 16%/yr vs. 23 ± 17%/yr; p-value = 0.005). Liver volume growth was also higher during a period with pregnancy, 6 [2, 7]%/yr vs. 0.3 [−0.4, 2]%/yr (p-value = 0.04). In addition, the mean kidney cyst growth rate was higher (12 ± 11%/yr vs. 4 ± 9%/yr; p-value = 0.05), and there was a trend toward a pregnancy-associated increase in the TKV growth rate (6 [4, 8]%/yr vs. 3 [0.8, 5]%/yr, (p-value = 0.14) during a period with pregnancy. Conclusions: In patients with ADPKD, the liver volume and cyst volume growth rates increased during pregnancy. This supports the hypothesis that the estrogen-mediated stimulation of liver cyst growth may contribute to the severe polycystic liver disease that is more prevalent in women than men with ADPKD. Further studies with larger populations are needed to explore the mechanisms and long-term implications of these findings. Full article

Molecular mechanisms responsible for the poor prognosis in patients with intrahepatic cholangiocarcinoma (CCA) are still unknown, but stem cell marker Cluster Differentiation 90 (CD90) has been reported to be associated with a more aggressive cancer phenotype. In this scenario, the TGF-β1 signaling pathway likely has a role as master gene regulator. Aim of the study is to investigate the role of CD90 in iCCA aggressiveness. The molecular profile of HuCCT1/CD90+ and HuCCT1/CD90− cells was obtained through transcriptomic analysis (NGS). Bioinformatic data were confirmed in both cell lines by qRT-PCR and Western blot. Cells were treated with Gemcitabine in monotherapy or in combination with Galunisertib, a selective inhibitor of TGF-βRI, in 2D and 3D models. HuCCT1/CD90+ cells are more proliferative, less migratory, and resistant to Gemcitabine treatment. HuCCT1/CD90+ cells also express lower levels of TGF-β1 compared to /CD90− cell lines. Finally, HuCCT1/CD90+ cells are resistant to Gemcitabine, while the combination of Gemcitabine and Galunisertib displays a synergistic effect on HuCCT1/CD90+ cell proliferation. These results underline that CD90-induced Gemcitabine resistance can be overcome by adding a TGFβ1 inhibitor such as Galunisertib, thereby moving further toward a precision medicine approach in patients with iCCA. Full article

The carnivorous plant Sarracenia purpurea has been traditionally used in various ethnobotanical applications, including treatments for type 2 diabetes and tuberculosis-like symptoms. This study investigates the cytotoxic effects of S. purpurea root extract (Sp-R) on human non-small-cell lung cancer (NSCLC) cell lines, including H1975, H838, and A549, focusing on its impact on cell survival, apoptosis, proliferation, and migration. Additionally, its ability to inhibit the single-stranded DNA-binding activity of human RPA32 (huRPA32), a key protein in DNA replication, was evaluated. Extracts from different plant parts (leaf, stem, and root) were prepared using various solvents (water, methanol, ethanol, and acetone) and screened for apoptosis-inducing potential using the chromatin condensation assay. Among these, the acetone-extracted root fraction (Sp-R-A) exhibited the most potent pro-apoptotic effects. The MTT assay demonstrated a dose-dependent cytotoxic effect on NSCLC cells, with IC₅₀ values of 33.74 μg/mL for H1975, 60.79 μg/mL for H838, and 66.52 μg/mL for A549. Migration and clonogenic assays further revealed that Sp-R-A significantly inhibited cancer cell migration and colony formation in a dose-dependent manner. Moreover, Sp-R-A enhanced apoptosis when combined with the EGFR inhibitor afatinib, suggesting a potential synergistic effect. The electrophoretic mobility shift assay confirmed that Sp-R-A significantly inhibited the DNA-binding activity of huRPA32, with an IC₅₀ of 13.6 μg/mL. AlphaFold structural prediction and molecular docking studies indicated that major bioactive compounds in S. purpurea, including α-amyrin, ursolic acid, and betulinaldehyde, strongly interact with the DNA-binding domain of huRPA32, potentially contributing to its inhibitory effect. Overall, these findings suggest that huRPA32 is a potential molecular target of Sp-R-A and the anticancer potential of S. purpurea root extract against NSCLC is highlighted, supporting further investigation into its therapeutic applications. Full article

Background/Objectives: Upregulation of phosphoglycerate mutase 5 (PGAM5) is correlated with reduced survival outcomes in hepatocellular carcinoma (HCC). PGAM5 knockdown or knockout attenuates HCC growth in in vitro and in vivo models. A novel small molecule inhibitor of PGAM5, LFHP-1c, has recently been characterized. The objective of this study was to determine if LFHP-1c effectively reduces HCC viability in cell models. Methods: The hepatoma and HCC cell lines, HepG2 and HuH7, respectively, were treated with LFHP-1c. Label-free imaging was used to quantify growth. Cellular viability and reactive oxygen species (ROS) production were measured using luminescent or fluorescent assays. Expression of antioxidant and metabolic proteins was measured by immunoblot. HepG2 and HuH7 PGAM5 knockout cell lines were used as negative controls. Results: Treatment with LFHP-1c reduced cell growth and viability in HepG2 and HuH7 cell lines. Reactive oxygen species production was upregulated in both wild-type and PGAM5 knockout cell lines following LFHP-1c exposure. Cell viability was reduced following LFHP-1c treatment in PGAM5 knockout cell lines. Conclusions: LFHP-1c reduces hepatoma and HCC viability and enhances ROS production, but these effects are independent of PGAM5. Full article

This study investigates how the digital economy empowers urban network intensity to address the dilemma of “low-efficiency lock-in” and to promote high-quality and balanced innovation development. Based on panel data from 264 prefecture-level and above cities in China from 2011 to 2022, the study adopts a multi-network perspective—covering innovation, information, and economic networks—and employs fixed effects and two-stage models to examine the impact and underlying mechanisms of the digital economy on disparities in urban innovation efficiency. The results reveal that the digital economy significantly reduces the gap in innovation efficiency across cities, primarily through the optimization of innovation networks and the strengthening of information networks. Moreover, the economic network positively moderates this relationship, amplifying the digital economy’s narrowing effect on innovation disparities. Threshold model tests indicate a nonlinear influence of the digital economy, showing an initial widening followed by a reduction in innovation efficiency gaps as innovation, information, and economic networks evolve. Heterogeneity analysis suggests that among the various dimensions of the digital economy, only digital industrialization plays a significant role in reducing efficiency disparities, while digital governance, digital infrastructure, industrial digitalization, and data valorization do not yet show statistically significant effects. Furthermore, the digital economy significantly reduces innovation efficiency gaps in southern cities, in regions southeast of the Hu Line, and in large cities, whereas in cities northwest of the Hu Line, digital economy development tends to exacerbate these disparities. This study provides both theoretical support for the coordinated improvement of innovation efficiency driven by the digital economy and practical implications for lagging cities aiming to leverage network effects to catch up in innovation performance. Full article

Background/Objectives: Immunocytokines (ICKs) are antibody–cytokine fusion proteins that deliver cytokines directly to tumors to increase immune responses, which are otherwise absent or limited by the delivery of antibodies alone. Tumor-associated glycoprotein-72 (TAG72) is overexpressed in numerous solid tumors. Methods: An anti-TAG72-IL-2 fusion protein was expressed in mammalian cells and tested in vitro for binding and bioactivity, and in vivo in two models. Results: In vitro studies showed high antigen specificity against TAG-72-positive tumor cell lines and IL-2 activity in CD25 (IL-2R)-positive reporter cells. To study the anti-tumor activity of huCC49-IL-2 in an immunocompetent model, the TAG-72 expression was established in murine mammary and colorectal cells by transfection with murine st6galnac-I gene (mSTn). Four daily doses of anti-TAG72-IL-2 monotherapy for TAG-72-expressing orthotopic murine mammary tumors in immunocompetent mice resulted in minimal whole-body toxicity and significant tumor growth reduction mediated by tumor infiltration of IFNγ⁺ CD8⁺ T cells. When mammary tumors were pretreated with image-guided fractionated radiation therapy (IGRT) followed by anti-TAG72-IL-2 therapy, an improved tumor growth inhibition was observed along with an increased tumor infiltration of IFNγ⁺ CD8⁺ T cells and a significant reduction in Foxp3⁺ CD4⁺ cells. Anti-TAG72-IL-2 monotherapy in TAG-72⁺ colorectal tumors led to a significant tumor reduction but also cures (4/7), with a rejection of rechallenges with both TAG-72-positive and -negative MC38 cells, thus demonstrating evidence of immune memory and antigen spreading. Conclusions: antiTAG-72-IL-2 therapy showed strong anti-tumor effects driven by activated CD8⁺ T cells making it a promising approach to the treatment of TAG-72⁺ tumors. Full article

SARS-CoV-2 is classified as a containment level 3 (CL3) pathogen, limiting research access and antiviral testing. To address this, we developed a non-infectious viral surrogate system using reverse genetics to generate sub-genomic replicons. These replicons contained the nsp1 mutations K164A and H165A and had the spike, membrane, ORF6, and ORF7a coding sequences replaced with various reporter and selectable marker genes. Replicons based on the ancestral Wuhan Hu-1 strain and the Delta variant of concern were replication-competent in multiple cell lines, as assessed by Renilla luciferase activity, fluorescence, immunofluorescence staining, and single-molecule fluorescent in situ hybridization. Antiviral assays using transient replicon expression showed that remdesivir effectively inhibited both replicon and viral replication. Ritonavir and cobicistat inhibited Delta variant replicons similarly to wild-type virus but did not inhibit Wuhan Hu-1 replicon replication. To further investigate the impact of nsp1 mutations, we generated a recombinant SARS-CoV-2 virus carrying the K164A and H165A mutations. The virus exhibited attenuated replication across a range of mammalian cell lines, was restricted by the type I interferon response, and showed reduced cytopathic effects. These findings highlight the utility of sub-genomic replicons as reliable CL2-compatible surrogates for studying SARS-CoV-2 replication and drug activity mechanisms. Full article

Land urbanization (LU) is a defining feature of China’s urbanization process and has led to significant carbon emission challenges. To clarify the interaction mechanism between LU and carbon emissions (CEs), this study examines the temporal and spatial characteristics of LU and CEs as well as the direct and spatial spillover effects in the east of the Hu Line. Specifically, three representative regions are selected for heterogeneity analysis: the Three Northeast Provinces region (TNP), the Beijing–Tianjin–Hebei region (BTH), and the Southeast Coastal region (SC). The findings are as follows: (1) Both LU and CEs exhibited consistent upward trends, with average annual growth rates of 4.3% and 3.5%, respectively. (2) Empirical results demonstrate that the direct and indirect effect coefficients of LU on CEs are 0.129 and −0.224, respectively. (3) The direct effect of LU on CEs is significantly positive in both the TNP and the SC, with respective coefficients of 0.336 and 0.177. Notably, a positive spatial spillover effect is observed exclusively in the TNP, with a coefficient of 0.174. In contrast, LU exerts no significant influence on CEs in the BTH. The research findings offer valuable insights into the formulation of differentiated urbanization policies and effective carbon emission reduction policies. Full article

Amid the urgent need to align agricultural practices with the United Nations Sustainable Development Goals (SDGs), this study examines the role of agricultural digitalization in promoting sustainable and green development in China. Specifically, it explores demand-side factors that drive improvements in agricultural green development and categorizes development models into three types: market-oriented, policy-driven, and innovation-driven. Utilizing provincial-level data from 2011 to 2021, this study employs semiparametric and spatial Durbin models to empirically assess the effects, underlying mechanisms, and regional disparities of agricultural digitalization in advancing green development. The main findings are as follows: (1) Overall, both agricultural digitalization and the level of green agricultural development have gradually increased during the study period, with agricultural digitalization significantly contributing to sustainable agricultural development. (2) The impact of agricultural digitalization on green agricultural development shows an upward trend in eastern, coastal, and non-grain-producing regions, as well as in the southeastern areas of the “Hu Huanyong Line”. In contrast, inland regions and the northwestern areas of the “Hu Huanyong Line” exhibit a U-shaped relationship, and grain-producing regions experience a clear inhibitory effect. Additionally, the promoting effect of agricultural digitalization is more pronounced in regions with higher levels of green agricultural development. (3) Agricultural digitalization generates positive spillover effects, benefiting not only the local region but also surrounding areas, with a stronger radiative effect on neighboring regions. (4) Mechanism analysis suggests that under all three development models, agricultural digitalization can effectively enhance green agricultural development by improving the alignment of supply and demand for green agricultural products, accelerating the establishment and promotion of green agricultural brands, strengthening environmental regulation, fostering new agricultural business entities, advancing agricultural mechanization, and improving the efficiency of facility agriculture. Full article

Hepatocellular carcinoma (HCC) is a lethal malignancy associated with drug resistance, resulting in a poor prognosis. High mobility group box 1 (HMGB1) is a chromatin-binding protein that regulates HCC progression. The overexpression of HMGB1 has been found to promote tumorigenesis and drug resistance. In this study, we aimed to investigate the role of HMGB1 expression in tumorigenesis and metastasis and its impact on sorafenib and oxaliplatin resistance. Tissue samples from patients with HCC (n = 48) were subjected to immunohistochemistry. The expression of HMGB1 was correlated with clinical pathology parameters. Moreover, the HCC cell line HuH-7 was used to study the regulatory effect of HMGB1 on cell proliferation, cell adhesion, migration, and invasion by using the siRNA (small interfering RNA) silencing method. Furthermore, drug challenges were performed to determine the effect of HMGB1 on the sensitivity to chemotherapeutic drugs (sorafenib and oxaliplatin). HMGB1 was significantly overexpressed in tumor tissues, highlighted by the expression increment in patients with M1 advanced metastasis tumors with immunoreactivity scores 2.61 and 6.50 for adjacent and tumor tissues, respectively (p-values = 0.0035). The involved mechanisms were then described through the suppression of HCC cell adhesion, migration, and invasion by HMGB1 silencing. Notably, the inhibition of HMGB1 expression promoted sorafenib/oxaliplatin sensitivity in the HCC cell line by increasing the cell toxicity by about 13–18%. Our study demonstrated that HMGB1 shows potential as a promising biomarker and a target for HCC treatment that is involved in tumorigenesis, metastasis, and chemo-drug resistance. Full article