Estimating the volume of penumbra in rodents using DTI and stack-based ensemble machine learning framework.

BACKGROUND: This study investigates the potential of diffusion tensor imaging (DTI) in identifying penumbral volume (PV) compared to the standard gadolinium-required perfusion-diffusion mismatch (PDM), utilizing a stack-based ensemble machine learning (ML) approach with enhanced explainability. METHODS: Sixteen male rats were subjected to middle cerebral artery occlusion. The penumbra was identified using PDM at 30 and 90 min after occlusion. We used 11 DTI-derived metrics and 14 distance-based features to train five voxel-wise ML models. The model predictions were integrated using stack-based ensemble techniques. ML-estimated and PDM-defined PVs were compared to evaluate model performance through volume similarity assessment, the Pearson correlation analysis, and Bland-Altman analysis. Feature importance was determined for explainability. RESULTS: In the test rats, the ML-estimated median PV was 106.4 mL (interquartile range 44.6-157.3 mL), whereas the PDM-defined median PV was 102.0 mL (52.1-144.9 mL). These PVs had a volume similarity of 0.88 (0.79-0.96), a Pearson correlation coefficient of 0.93 (p < 0.001), and a Bland-Altman bias of 2.5 mL (2.4% of the mean PDM-defined PV), with 95% limits of agreement ranging from -44.9 to 49.9 mL. Among the features used for PV prediction, the mean diffusivity was the most important feature. CONCLUSIONS: Our study confirmed that PV can be estimated using DTI metrics with a stack-based ensemble ML approach, yielding results comparable to the volume defined by the standard PDM. The model explainability enhanced its clinical relevance. Human studies are warranted to validate our findings. RELEVANCE STATEMENT: The proposed DTI-based ML model can estimate PV without the need for contrast agent administration, offering a valuable option for patients with kidney dysfunction. It also can serve as an alternative if perfusion map interpretation fails in the clinical setting. KEY POINTS: • Penumbral volume can be estimated by DTI combined with stack-based ensemble ML. • Mean diffusivity was the most important feature used for predicting penumbral volume. • The proposed approach can be beneficial for patients with kidney dysfunction.

Boswellianols A-I, Structurally Diverse Diterpenoids from the Oleo-Gum Resin of Boswellia carterii and Their TGF-ß Inhibition Activity.

Olibanum, a golden oleo-gum resin from species in the Boswellia genus (Burseraceae family), is a famous traditional herbal medicine widely used around the world. Previous phytochemical studies mainly focused on the non-polar fractions of olibanum. In this study, nine novel diterpenoids, boswellianols A-I (1-9), and three known compounds were isolated from the polar methanolic fraction of the oleo-gum resin of Boswellia carterii. Their structures were determined through comprehensive spectroscopic analysis as well as experimental and calculated electronic circular dichroism (ECD) data comparison. Compound 1 is a novel diterpenoid possessing an undescribed prenylmaaliane-type skeleton with a 6/6/3 tricyclic system. Compounds 2-4 were unusual prenylaromadendrane-type diterpenoids, and compounds 5-9 were new highly oxidized cembrane-type diterpenoids. Compounds 1 and 5 showed significant transforming growth factor ß (TGF-ß) inhibitory activity via inhibiting the TGF-ß-induced phosphorylation of Smad3 and the expression of fibronectin and N-cadherin (the biomarker of the epithelial-mesenchymal transition) in a dose-dependent manner in LX-2 human hepatic stellate cells, indicating that compounds 1 and 5 should be potential anti-fibrosis agents. These findings give a new insight into the chemical constituents of the polar fraction of olibanum and their inhibitory activities on the TGF-ß/Smad signaling pathway.

Different wavelengths of LED irradiation promote secondary metabolite production in Pycnoporus sanguineus for antioxidant and immunomodulatory applications.

Pycnoporus sanguineus is a fungus of the phylum Basidiomycota that has many applications in traditional medicine, modern pharmaceuticals, and agricultural industries. Light plays an essential role in the metabolism, growth, and development of fungi. This study evaluated the mycelial growth and antioxidant and anti-inflammatory activities in P. sanguineus fermentation broth (PFB) cultured under different wavelengths of LED irradiation or in the dark. Compared to the dark cultures, the dry weight of mycelia in red- and yellow-light cultures decreased by 37 and 35% and the yields of pigments increased by 30.92 ± 2.18 mg and 31.75 ± 3.06 mg, respectively. Compared with the dark culture, the DPPH free radical scavenging ability, ABTS+ free radical scavenging capacity, and reducing power of yellow-light cultures increased significantly, and their total phenolic content peaked at 180.0 ± 8.34 µg/mL. However, the reducing power in blue-light cultures was significantly reduced, though the total phenol content did not vary with that of dark cultures. In LPS- and IFN-γ-stimulated RAW 264.7 cells, nitrite release was significantly reduced in the red and yellow light-irradiated PFB compared with the dark culture. In the dark, yellow-, and green-light cultures, TNF-α production in the inflamed RAW 264.7 cells was inhibited by 62, 46, and 14%, respectively. With red-, blue-, and white-light irradiation, TNF-α production was significantly enhanced. Based on these results, we propose that by adjusting the wavelength of the light source during culture, one can effectively modulate the growth, development, and metabolism of P. sanguineus.

Biofabricated poly (γ-glutamic acid) bio-ink reinforced with calcium silicate exhibiting superior mechanical properties and biocompatibility for bone regeneration.

Background/purpose: The modification in 3D hydrogels, tissue engineering, and biomaterials science has enabled us to fabricate novel substitutes for bone regeneration. This study aimed to combine different biomaterials by 3D technique to fabricate a promising all-rounded hydrogel for bone regeneration. Materials and methods: In this study, glycidyl methacrylate (GMA)-modified poly γ-glutamic acid (γ-PGA-GMA) hydrogels with calcium silicate (CS) hydrogel of different concentrations were fabricated by a 3D printing technique, and their biocompatibility and capability in bone regeneration were also evaluated. Results: The results showed that CS γ-PGA-GMA could be successfully fabricated, and the presence of CS enhanced the rheological and mechanical properties of γ-PGA-GMA hydrogels, thus making them more adept at 3D printing and implantations. SEM images of the surface structure showed that higher CS concentrations (5% and 10%) contributed to denser surface architectures, thus achieving improved cellular adhesion and stem cell proliferation. Furthermore, higher concentrations of CS resulted in elevated expressions of osteogenic-related markers such as alkaline phosphatase (ALP) and osteocalcin (OC), as well as enhanced calcium deposition represented by the increased Alizarin Red S staining. In vivo studies referring to critical defects of rabbit femur further showed that the existence of hydrogels alone was able to induce partial bone regeneration, demonstrated by the results from quantitative and qualitative analysis of micro-CT scans. However, CS alterations caused significant increases in bone regeneration, as indicated by micro-CT and histological staining. Conclusion: These results robustly suggest combining different biomaterials is crucial to producing a well-rounded hydrogel for tissue regeneration. We hope this study could be applied as a platform for others to brainstorm potential out-of-the-box solutions, contributing to developing high-potential biomaterials for bone regeneration.

Atrophy of the cholinergic regions advances from early to late mild cognitive impairment.

PURPOSE: We investigated the volumetric changes in the components of the cholinergic pathway for patients with early mild cognitive impairment (EMCI) and those with late mild cognitive impairment (LMCI). The effect of patients' apolipoprotein 4 (APOE-ε4) allele status on the structural changes were analyzed. METHODS: Structural magnetic resonance imaging data were collected. Patients' demographic information, plasma data, and validated global cognitive composite scores were included. Relevant features were extracted for constructing machine learning models to differentiate between EMCI (n = 312) and LMCI (n = 541) and predict patients' neurocognitive function. The data were analyzed primarily through one-way analysis of variance and two-way analysis of covariance. RESULTS: Considerable differences were observed in cholinergic structural changes between patients with EMCI and LMCI. Cholinergic atrophy was more prominent in the LMCI cohort than in the EMCI cohort (P < 0.05 family-wise error corrected). APOE-ε4 differentially affected cholinergic atrophy in the LMCI and EMCI cohorts. For LMCI cohort, APOE-ε4 carriers exhibited increased brain atrophy (left amygdala: P = 0.001; right amygdala: P = 0.006, and right Ch123, P = 0.032). EMCI and LCMI patients showed distinctive associations of gray matter volumes in cholinergic regions with executive (R2 = 0.063 and 0.030 for EMCI and LMCI, respectively) and language (R2 = 0.095 and 0.042 for EMCI and LMCI, respectively) function. CONCLUSIONS: Our data confirmed significant cholinergic atrophy differences between early and late stages of mild cognitive impairment. The impact of the APOE-ε4 allele on cholinergic atrophy varied between the LMCI and EMCI groups.

A prospective reappraisal of motor outcome prediction in patients with acute stroke by using atlas-based diffusion tensor imaging biomarkers.

BACKGROUND: Diffusion tensor imaging (DTI) biomarkers can be used to quantify microstructural changes in the cerebral white matter (WM) following injury. OBJECTIVES: This prospective single-center study aimed to evaluate whether atlas-based DTI-derived metrics obtained within 1 week after stroke can predict the motor outcome at 3 months. METHODS: Forty patients with small acute stroke (2-7 days after onset) involving the corticospinal tract were included. Each patient underwent magnetic resonance imaging (MRI) within 1 week and at 3 months after stroke, and the changes based on DTI-derived metrics were compared by performing WM tract atlas-based quantitative analysis. RESULTS: A total of 40 patients were included, with median age 63.5 years and a majority of males (72.5%). Patients were classified into good-prognosis group (mRS 0-2, n = 27) and poor-prognosis group (mRS 3-5, n = 13) by outcome. The median (25th-75th percentile) of MD (0.7 (0.6-0.7) vs. 0.7 (0.7-0.8); p = 0.049) and AD (0.6 (0.5, 0.7) vs. 0.7 (0.6, 0.8); p = 0.023) ratios within 1 week were significantly lower in the poor-prognosis group compared to the good-prognosis group. The ROC curve of the combined DTI-derived metrics model showed comparable Youden index (65.5% vs. 58.4%-65.4%) and higher specificity (96.3% vs. 69.2%-88.5%) compared to clinical indexes. The area under the ROC curve of the combined DTI-derived metrics model is comparable to those of the clinical indexes (all p > 0.1) and higher than those of the individual DTI-derived metrics parameters. CONCLUSIONS: Atlas-based DTI-derived metrics at acute stage provide objective information for prognosis prediction of patients with ischemic or lacunar stroke.

Mechanical Versus Bioprosthetic Aortic Valve Replacement in Patients Undergoing Bentall Procedure.

BACKGROUND: The widely used Bentall procedure is the criterion standard treatment for aortic root pathology. Studies comparing the long-term outcomes of bioprosthetic and mechanical valves in patients undergoing the Bentall procedure are limited. METHODS AND RESULTS: Patients who underwent the Bentall procedure with a bioprosthetic or mechanical valve between 2001 and 2018 were identified from Taiwan's National Health Insurance Research Database. The primary outcome of interest was all-cause mortality. Inverse probability of treatment weighting was performed to compare the 2 prosthetic types. In total, 1052 patients who underwent the Bentall procedure were identified. Among these patients, 351 (33.4%) and 701 (66.6%) chose bioprosthetic and mechanical valves, respectively. After inverse probability of treatment weighting, no significant differences in the in-hospital mortality (odds ratio, 0.96 [95% CI, 0.77-1.19]; P=0.716) and all-cause mortality (34.1% vs. 38.1%; hazard ratio, 0.90 [95% CI, 0.78-1.04]; P=0.154) were observed between the groups. The benefits of relative mortality associated with mechanical valves were apparent in younger patients and persisted until ≈50 years of age. CONCLUSIONS: No differences in survival benefits were observed between the valves in patients who underwent the Bentall procedure. Additionally, bioprosthetic valves may be a reasonable choice for patients aged >50 years when receiving the Bentall procedure in this valve-in-valve era.

[Distribution Characteristics and Risk Assessment of Tetracycline Antibiotics (TCs) in Soil-Vegetable System with Soil Fertilized with Animal Manure].

The effects of antibiotic contamination on vegetable safety and the ecological risks of soil after returning livestock and poultry manure to the land require sufficient future attention. Tetracycline antibiotics (TCs) are often detected at high concentrations in livestock manure and vegetable production soils. Recently, pot experiments and field investigation methods have often been used to understand the effects of TCs contamination on the vegetable safety and ecological risks of soil, whereas field experiments are employed less frequently. This study investigated the distribution characteristics of TCs in the soil-vegetable system following manure application using a combination of pot and field experiments. The human health risks of the edible parts of Chinese flowing cabbage were assessed using the health risk quotient method based on the acceptable daily intake (ADI-HQ), and the ecological risks of TCs-contaminated soils were evaluated using the risk quotient method associated with the species sensitivity distribution model (SSD-RQ). The results showed that oxytetracycline (OTC) was the major type of TCs in Chinese flowering cabbage based on both the pot and field experiments. The maximum contents (dry weight) of OTC in the aboveground parts of the Chinese flowering cabbage for the pot and field experiments were 29.25 µg·kg-1 and 45.03 µg·kg-1, respectively, whereas those of their underground parts were 87.32 µg·kg-1 and 135.44 µg·kg-1, respectively. Meanwhile, higher contents of TCs were detected in Chinese flowering cabbage collected from the field experiment than those from the pot experiment. OTC was also the major type of TCs in soil from both the pot and field experiments, with their contents up to 604.30 µg·kg-1 and 1013.68 µg·kg-1, respectively. Higher residual contents of three TCs were detected in soils collected from the field experiment than those from the pot experiment. Under the experimental conditions, with the except that OTC in Chinese flowering cabbage from the field experiment would pose medium health risks (HQ>0.1) to children, the contents of three TCs in other treated Chinese flowering cabbage would pose low health risks (HQ ≤ 0.1) to adults and children. In the pot experiments, three TCs present in Chinese flowering cabbage would pose low health risks (HQ ≤ 0.1) to adults and children. Additionally, the TCs in soils with manure application from the pot and field experiments may have posed both moderate or high levels of ecological risks (HQ>0.1 or HQ>1). Therefore, the effects of antibiotic contamination on vegetable safety and their potential ecological risks on soil following manure fertilization need to be given special attention.

The exosomal secretomes of mesenchymal stem cells extracted via 3D-printed lithium-doped calcium silicate scaffolds promote osteochondral regeneration.

The development of surface modification techniques has brought about a major paradigm shift in the clinical applications of bone tissue regeneration. Biofabrication strategies enable the creation of scaffolds with specific microstructural environments and biological components. Lithium (Li) has been reported to exhibit anti-inflammatory, osteogenic, and chondrogenic properties by promoting several intracellular signaling pathways. Currently, research focuses on fabricating scaffolds with simultaneous dual bioactivities to enhance osteochondral regeneration. In this study, we modified the surface of calcium silicate (CS) scaffolds with Li using a simple immersion technique and evaluated their capabilities for bone regeneration. The results showed that Li ions could be easily coated onto the surfaces of CS scaffolds without affecting the microstructural properties of CS itself. Furthermore, the modifications did not affect the printing capabilities of the CS, and porous scaffolds could be fabricated via extrusion. Moreover, the presence of Li improved the surface roughness and hydrophilicity, thus leading to enhanced secretion of osteochondral-related regeneration factors, such as alkaline phosphatase (ALP), bone sialoprotein (BSP), and collagen II (Col II) proteins. Subsequent in vivo studies, including histological and micro-CT analyses, confirmed that the Li-modified CS scaffolds promoted osteochondral regeneration. The transcriptome analysis suggested that the enhanced osteochondrogenic capabilities of our scaffolds were influenced by paracrine exosomes. We hope this study will inspire further research on osteochondral regeneration.

Thalamocortical coherence predicts persistent postconcussive symptoms.

The pathogenetic mechanism of persistent post-concussive symptoms (PCS) following concussion remains unclear. Thalamic damage is known to play a role in PCS prolongation while the evidence and biomarkers that trigger persistent PCS have never been elucidated. We collected longitudinal neuroimaging and behavior data from patients and rodents after concussion, complemented with rodents' histological staining data, to unravel the early biomarkers of persistent PCS. Diffusion tensor imaging (DTI) were acquired to investigated the thalamic damage, while quantitative thalamocortical coherence was derived through resting-state functional MRI for evaluating thalamocortical functioning and predicting long-term behavioral outcome. Patients with prolonged symptoms showed abnormal DTI-derived indices at the boundaries of bilateral thalami (peri-thalamic regions). Both patients and rats with persistent symptoms demonstrated enhanced thalamocortical coherence between different thalamocortical circuits, which disrupted thalamocortical multifunctionality. In rodents, the persistent DTI abnormalities were validated in thalamic reticular nucleus (TRN) through immunohistochemistry, and correlated with enhanced thalamocortical coherence. Strong predictive power of these coherence biomarkers for long-term PCS was also validated using another patient cohort. Postconcussive events may begin with persistent TRN injury, followed by disrupted thalamocortical coherence and prolonged PCS. Functional MRI-based coherence measures can be surrogate biomarkers for early prediction of long-term PCS.

The prognosis of citrin deficiency differs between early-identified newborn and later-onset symptomatic infants.

BACKGROUND: The prognosis for patients with citrin deficiency is not always benign. This study examined the differences between patients identified early by newborn screening and patients identified later with cholestasis/hepatitis. MATERIALS AND METHODS: This retrospective study included 42 patients with genetically confirmed SLC25A13 mutations who were born between May 1996 and August 2019. Fifteen patients were identified during newborn screening (NBS group) and 27 patients were identified through the onset of cholestasis/hepatitis in infancy (clinical group). RESULTS: Overall, 90% of the patients presented with cholestasis, among whom 86% (31/36) recovered at a median age of 174 days. Compared with patients in the clinical group, patients in the NBS group were significantly younger at diagnosis and at cholestasis-free achievement; they also had significantly lower levels of peak direct bilirubin and liver enzymes. At the median follow-up age of 11.8 years, 21% of the patients had dyslipidemia, whereas 36% of the patients had failure to thrive. The overall mortality rate was 2.4%. Variant c.851_854del was the most frequent, constituting 44% of the mutant alleles. CONCLUSION: Patients identified early by NBS had a better prognosis, demonstrating the importance of a timely diagnosis of NICCD and the need for careful follow-up. IMPACT: Some cases of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) are not benign. Compared with patients identified later based on the presence of cholestasis/hepatitis, patients identified early by newborn screening have less severe cholestasis and are cholestasis-free at a significantly younger age. A timely diagnosis is needed, along with follow-up examinations that assess metabolic profile and body weight, to improve the long-term prognosis of NICCD patients.

Highly Thermally Stable, Reversible, and Flexible Main Chain Type Benzoxazine Hybrid Incorporating Both Polydimethylsiloxane and Double-Decker Shaped Polyhedral Silsesquioxane Units through Diels-Alder Reaction.

This work synthesizes a new bifunctional furan derivative (PDMS-FBZ) through a sequence of hydrosilylation of nadic anhydride (ND) with polydimethylsiloxane (PDMS), reaction of the product with p-aminophenol to form PDMS-ND-OH, and its subsequent Mannich reaction with furfurylamine and CH2 O. Then, the main chain-type copolymer PDMS-DABZ-DDSQ is prepared through a Diels-Alder (DA) cycloaddition of PDMS-FBZ with the bismaleimide-functionalized double-decker silsesquioxane derivative DDSQ-BMI. Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy confirm the structure of this PDMS-DABZ-DDSQ copolymer; differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic mechanical analysis (DMA) reveal it to have high flexibility and high thermal stability (Tg = 177 °C; Td10 = 441 °C; char yield = 60.1 wt%); contact angle measurements reveal a low surface free energy (18.18 mJ m-2 ) after thermal ring-opening polymerization, because the inorganic PDMS and DDSQ units are dispersed well, as revealed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). This PDMS-DABZ-DDSQ copolymer possesses reversible properties arising from the DA and retro-DA reactions, suggesting its possible application as a functional high-performance material.

Additive manufacturing of Schwann cell-laden collagen/alginate nerve guidance conduits by freeform reversible embedding regulate neurogenesis via exosomes secretion towards peripheral nerve regeneration.

Peripheral nerve injury is a common clinical problem that could be debilitating to one's quality of life. The complex nerve guidance conduits (NGCs) with cells in order to improve nerve regeneration. Therefore, we used freeform reversible embedding of suspended hydrogels to fabricate Schwann cells (SCs)-laden collagen/alginate (Col/Alg) NGCs. First, we evaluated Col influence on the characteristics of NGCs. After which, Wharton's jelly mesenchymal stem cells (WJMSC) are seeded onto the inner channel of NGCs and evaluated neural regeneration behaviors. Results indicated the SCs-laden NGCs with 2.5 % Col found the highest proliferation and secretion of neurotrophic protein. Furthermore, co-culture of SCs promoted differentiation of WJMSC as seen from the increased neurogenic-related protein in NGCs. To determine the molecular mechanism between SCs and WJMSC, we demonstrated the neurotrophic factors secreted by SCs act on tropomyosin receptor kinase A (TrkA) receptors of WJMSC to promote nerve regeneration. In addition, our study demonstrated SCs-derived exosomes had a critical role in regulating neural differentiation of WJMSC. Taken together, this study demonstrates the fabrication of SCs-laden Col/Alg NGCs for nerve regeneration and understanding regarding the synergistic regenerative mechanisms of different cells could bring us a step closer for clinical treatment of large nerve defects.

Automatic segmentation and radiomic texture analysis for osteoporosis screening using chest low-dose computed tomography.

OBJECTIVE: This study developed a diagnostic tool combining machine learning (ML) segmentation and radiomic texture analysis (RTA) for bone density screening using chest low-dose computed tomography (LDCT). METHODS: A total of 197 patients who underwent LDCT followed by dual-energy X-ray absorptiometry were analyzed. First, an autosegmentation model was trained using LDCT to delineate the thoracic vertebral body (VB). Second, a two-level classifier was developed using radiomic features extracted from VBs for the hierarchical pairwise classification of each patient's bone status. All the patients were initially classified as either normal or abnormal, and all patients with abnormal bone density were then subdivided into an osteopenia group and an osteoporosis group. The performance of the classifier was evaluated through fivefold cross-validation. RESULTS: The model for automated VB segmentation achieved a Sorenson-Dice coefficient of 0.87 ± 0.01. Furthermore, the area under the receiver operating characteristic curve scores for the two-level classifier were 0.96 ± 0.01 for detecting abnormal bone density (accuracy = 0.91 ± 0.02; sensitivity = 0.93 ± 0.03; specificity = 0.89 ± 0.03) and 0.98 ± 0.01 for distinguishing osteoporosis (accuracy = 0.94 ± 0.02; sensitivity = 0.95 ± 0.03; specificity = 0.93 ± 0.03). The testing prediction accuracy levels for the first- and second-level classifiers were 0.92 ± 0.04 and 0.94 ± 0.05, respectively. The overall testing prediction accuracy of our method was 0.90 ± 0.05. CONCLUSION: The combination of ML segmentation and RTA for automated bone density prediction based on LDCT scans is a feasible approach that could be valuable for osteoporosis screening during lung cancer screening. KEY POINTS: • This study developed an automatic diagnostic tool combining machine learning-based segmentation and radiomic texture analysis for bone density screening using chest low-dose computed tomography. • The developed method enables opportunistic screening without quantitative computed tomography or a dedicated phantom. • The developed method could be integrated into the current clinical workflow and used as an adjunct for opportunistic screening or for patients who are ineligible for screening with dual-energy X-ray absorptiometry.

Sorting nexin-dependent therapeutic targeting of oncogenic epidermal growth factor receptor.

Overexpression and/or overactivation of the Epidermal Growth Factor Receptor (EGFR) is oncogenic in several tumor types yet targeting the kinase domain of wildtype EGFR has had limited success. EGFR has numerous kinase-independent roles, one of which is accomplished through the Sorting Nexin-dependent retrotranslocation of EGFR to the nucleus, which is observed in some metastatic cancers and therapeutically resistant disease. Here, we have utilized the BAR domain of Sorting Nexin 1 to create a peptide-based therapeutic (cSNX1.3) that promotes cell death in EGFR-expressing cancer. We evaluated the efficacy of cSNX1.3 in tumor-bearing WAP-TGFα transgenic mice (an EGFR-dependent model of breast cancer), where cSNX1.3 treatment resulted in significant tumor regression without observable toxicity. Evaluation of remaining tumor tissues found evidence of increased PARP cleavage, suggesting apoptotic tumor cell death. To evaluate the mechanism of action for cSNX1.3, we found that cSNX1.3 binds the C-terminus of the EGFR kinase domain at an interface site opposite the ATP binding domain with a Kd of ~4.0 µM. In vitro analysis found that cSNX1.3 inhibits the nuclear localization of EGFR. To determine specificity, we evaluated cancer cell lines expressing wildtype EGFR (MDA-MB-468, BT20 and A549), mutant EGFR (H1975) and non-transformed lines (CHO and MCF10A). Only transformed lines expressing wildtype EGFR responded to cSNX1.3, while mutant EGFR and normal cells responded better to an EGFR kinase inhibitor. Phenotypically, cSNX1.3 inhibits EGF-, NRG-, and HGF-dependent migration, but not HA-dependent migration. Together, these data indicate that targeting retrotranslocation of EGFR may be a potent therapeutic for RTK-active cancer.

Altered diffusivity of the subarachnoid cisterns in the rat brain following neurological disorders.

BACKGROUND: Although changes in diffusion characteristics of the brain parenchyma in neurological disorders are widely studied and used in clinical practice, the change in diffusivity in the cerebrospinal fluid (CSF) system is rarely reported. In this study, free water diffusion in the subarachnoid cisterns and ventricles of the rat brain was examined using diffusion magnetic resonance imaging (MRI), and the effects of neurological disorders on diffusivity in CSF system were investigated. METHODS: Diffusion MRI and T2-weighted images were obtained in the intact rats, 24 h after ischemic stroke, and 50 days after mild traumatic brain injury (mTBI). We conducted the assessment of diffusivity in the rat brain in the subarachnoid cisterns around the midbrain, as well as the lateral ventricles. One-way ANOVA and Kruskal-Wallis test were used to evaluate the change in mean diffusivity (MD) and MD histogram, respectively, in CSF system following different neurological disease. RESULTS: A significant decrease in the mean MD value of the subarachnoid cisterns was observed in the stroke rats compared with the intact and mTBI rats (p < 0.005). In addition, the skewness (p < 0.002), maximum MD (p < 0.002), and MD percentiles (p < 0.002) in the stroke rats differed significantly from those in the intact and mTBI rats. By contrast, no difference was observed in the mean MD value of the lateral ventricles among three groups of rats. We proposed that the assessment of the subarachnoid cisterns, rather than the lateral ventricles, in the rat brain would be useful in providing diffusion information in the CSF system. CONCLUSIONS: Alterations in MD parameters of the subarachnoid cisterns after stroke provide evidence that brain injury may alter the characteristics of free water diffusion not only in the brain parenchyma but also in the CSF system.

Bioprosthetic versus mechanical mitral valve replacements in patients with rheumatic heart disease.

BACKGROUND: Rheumatic heart disease (RHD) remains a critical problem in developed countries. Few studies have compared the long-term outcomes of bioprosthetic valves and mechanical valves in patients with RHD who have received mitral valve (MV) replacement. METHODS: Patients with RHD who received MV replacement with bioprosthetic or mechanical valves were identified between 2000 and 2013 from Taiwan's National Health Insurance Research Database. The primary late outcomes of interest were all-cause mortality and redo MV surgery. Propensity score matching at a 1:1 ratio was performed. RESULTS: We identified 3638 patients with RHD who underwent MV replacement. Among those patients, 1075 (29.5%) and 2563 (70.5%) chose a bioprosthetic valve and mechanical valve, respectively. After matching, 788 patients were assigned to each group. No significant difference in the risk of in-hospital mortality was observed between groups (P = .920). Higher risks of all-cause mortality (10-year actuarial estimates: 50.6% vs 45.5%; hazard ratio, 1.19; 95% confidence interval, 1.01-1.41; P = .040) and MV reoperation (10-year actuarial estimates: 8.9% vs 0.93%; subdistribution hazard ratio, 4.56; 95% confidence interval, 1.71-12.17; P <.01) were observed in the bioprosthetic valve group. Furthermore, the relative mortality benefit associated with mechanical valves was more apparent in younger patients and the beneficial effect persisted until approximately 65 years of age. CONCLUSIONS: In the patients with RHD who underwent MV replacement, mechanical valves were associated with more favorable long-term outcomes in patients younger than the age of 65 years.

Minor Copper-Doped Aluminum Alloy Enabling Long-Lifetime Organic Light-Emitting Diodes.

Aluminum has been extensively used as a conductor material in numerous electronic devices, including solar cells, light-emitting diodes (LEDs), organic LEDs (OLEDs), and thin-film transistors. However, its spiking surface and easy electromigration have limited its performance. To overcome this, a trace amount of nonprecious copper dopant has been proven effective in enhancing device reliability. Nevertheless, a comprehensive investigation regarding the effect of copper doping on the morphology at the aluminum conductor-organic interface is yet to be done. We had hence fabricated a series of green OLED devices to probe how copper doping affected the aluminum conductor, morphologically and electrically, and the corresponding device's efficiency and lifetime performance. We found 4 wt % copper doping to be highly effective in enabling a spike-less and smoother aluminum interface, which in turn enabled the fabrication of devices with much higher efficiency and lifetime. Specifically, the corresponding power efficacy at 1000 cd/m2 was increased from 32 to 42 lm/W and the lifetime increased from 75 to 263 h, an increment of 250%. Atomic force microscopy confirmed that the copper doping did help smooth out the conductor interface as deposited and reduce electromigration upon operation.

Development and Validation of Novel Deep-Learning Models Using Multiple Data Types for Lung Cancer Survival.

A well-established lung-cancer-survival-prediction model that relies on multiple data types, multiple novel machine-learning algorithms, and external testing is absent in the literature. This study aims to address this gap and determine the critical factors of lung cancer survival. We selected non-small-cell lung cancer patients from a retrospective dataset of the Taipei Medical University Clinical Research Database and Taiwan Cancer Registry between January 2008 and December 2018. All patients were monitored from the index date of cancer diagnosis until the event of death. Variables, including demographics, comorbidities, medications, laboratories, and patient gene tests, were used. Nine machine-learning algorithms with various modes were used. The performance of the algorithms was measured by the area under the receiver operating characteristic curve (AUC). In total, 3714 patients were included. The best performance of the artificial neural network (ANN) model was achieved when integrating all variables with the AUC, accuracy, precision, recall, and F1-score of 0.89, 0.82, 0.91, 0.75, and 0.65, respectively. The most important features were cancer stage, cancer size, age of diagnosis, smoking, drinking status, EGFR gene, and body mass index. Overall, the ANN model improved predictive performance when integrating different data types.

Early Dysbiosis and Dampened Gut Microbe Oscillation Precede Motor Dysfunction and Neuropathology in Animal Models of Parkinson's Disease.

BACKGROUND: Studies have shown different gut microbiomes in patients with Parkinson's disease (PD) compared to unaffected controls. However, when the gut microbiota shift toward dysbiosis in the PD process remains unclear. OBJECTIVE: We aim to investigate the changes in gut microbiota, locomotor function, and neuropathology longitudinally in PD rodent models. METHODS: Fecal microbiota were longitudinally assessed by sequencing the V4-V5 region of the 16S ribosomal RNA gene in a human mutant α-synuclein over-expressing mouse model of PD, SNCA p.A53T mice, and the non-transgenic littermate controls. The locomotor function, neuronal integrity, and α-synuclein expression in the different brain regions were compared between groups. Human fecal microbiota communities from 58 patients with PD and 46 unaffected controls were also analyzed using metagenomic sequencing for comparison. RESULTS: Compared to non-transgenic littermate controls, the altered gut microbiota of the SNCA p.A53T mice can be detected as early as 2 months old, and the diurnal oscillation of the gut microbiome was dampened throughout PD progression starting from 4 months old. However, neuropathology changes and motor deficits were observed starting at 6 months old. Similar changes in altered gut microbiota were also observed in another PD genetic mouse model carrying the LRRK2 p.G2019S mutation at 2 months old. Among the commonly enriched gut microbiota in both PD genetic mouse models, the abundance of Parabateroides Merdae and Ruminococcus torques were also increased in human PD patients compared to controls. CONCLUSION: These findings revealed the altered gut microbiota communities and oscillations preceding the occurrence of neuropathy and motor dysfunction in the PD process.