Neurovascular coupling dysfunction associated with cognitive impairment in presbycusis.

The neuropathological mechanism underlying presbycusis remains unclear. This study aimed to illustrate the mechanism of neurovascular coupling associated with cognitive impairment in patients with presbycusis. We assessed the coupling of cerebral blood perfusion with spontaneous neuronal activity by calculating the correlation coefficients between cerebral blood flow and blood oxygen level-dependent-derived quantitative maps (amplitude of low-frequency fluctuation, fractional amplitude of low-frequency fluctuation, regional homogeneity, degree centrality). Four neurovascular coupling metrics (cerebral blood flow-amplitude of low-frequency fluctuation, cerebral blood flow-fractional amplitude of low-frequency fluctuation, cerebral blood flow-regional homogeneity and cerebral blood flow-degree centrality) were compared at the global and regional levels between the presbycusis group and the healthy control group, and the intrinsic association between the altered neurovascular coupling metrics and the neuropsychological scale was further analysed in the presbycusis group. At the global level, neurovascular coupling was significantly lower in the presbycusis group than in the control group and partially related to cognitive level. At the regional level, neurovascular biomarkers were significantly elevated in three brain regions and significantly decreased in one brain region, all of which involved the Papez circuit. Regional neurovascular coupling provides more information than global neurovascular coupling, and neurovascular coupling dysfunction within the Papez circuit has been shown to reveal the causes of poor cognitive and emotional responses in age-related hearing loss patients.

Targeting TGFß receptor-mediated snail and twist: WSG, a polysaccharide from Ganoderma lucidum, and it-based dissolvable microneedle patch suppress melanoma cells.

Cutaneous melanoma is a lethal skin cancer variant with pronounced aggressiveness and metastatic potential. However, few targeted medications inhibit the progression of melanoma. Ganoderma lucidum, which is a type of mushroom, is widely used as a non-toxic alternative adjunct therapy for cancer patients. This study determines the effect of WSG, which is a water-soluble glucan that is derived from G. lucidum, on melanoma cells. The results show that WSG inhibits cell viability and the mobility of melanoma cells. WSG induces changes in the expression of epithelial-to-mesenchymal transition (EMT)-related markers. WSG also downregulates EMT-related transcription factors, Snail and Twist. Signal transduction assays show that WSG reduces the protein levels in transforming growth factor ß receptors (TGFßRs) and consequently inhibits the phosphorylation of intracellular signaling molecules, such as FAK, ERK1/2 and Smad2. An In vivo study shows that WSG suppresses melanoma growth in B16F10-bearing mice. To enhance transdermal drug delivery and prevent oxidation, two highly biocompatible compounds, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), are used to synthesize a dissolvable microneedle patch that is loaded with WSG (MN-WSG). A functional assay shows that MN-WSG has an effect that is comparable to that of WSG alone. These results show that WSG has significant potential as a therapeutic agent for melanoma treatment. MN-WSG may allow groundbreaking therapeutic approaches and offers a novel method for delivering this potent compound effectively.

Risk factors of video urodynamics and bladder management for long-term complications in patients with chronic spinal cord injury.

This study explores 15-year urological complications in chronic spinal cord injury (SCI) patients and investigates the predictive factors from video-urodynamic study (VUDS) and bladder management. Analyzing 864 SCI patients with a mean 15.6-year follow-up, we assessed complications and utilized multivariate logistic regression for risk evaluation. VUDS factors such as autonomic dysreflexia, detrusor sphincter dyssynergia, vesicourethral reflux (VUR), contracted bladder, and high voiding detrusor pressure significantly increased the likelihood of recurrent urinary tract infections (rUTI). Low bladder compliance, VUR, and contracted bladder notably raised the risk of hydronephrosis, while contracted bladder and detrusor overactivity with detrusor underactivity heightened chronic kidney disease risk. Volitional voiding reduced rUTI and VUR risk, whereas Valsalva maneuver-assisted voiding increased hydronephrosis risk. In conclusion, a contracted bladder identified in VUDS is associated with long-term urological complications in SCI, we propose that patients already experiencing a contracted bladder should prioritize volitional voiding as their preferred bladder management strategy to minimize the risk of additional complications such as rUTI and VUR. These findings unveil previously unexplored aspects in research, emphasizing the need for proactive management strategies in this patient population.

Paternal care plasticity: males care more for early- than late-developing embryos in an arboreal breeding treefrog.

BACKGROUND: Parental care benefits offspring but comes with costs. To optimize the trade-off of costs and benefits, parents should adjust care based on intrinsic and/or extrinsic conditions. The harm to offspring hypothesis suggests that parents should invest more in younger offspring than older offspring because younger offspring are more vulnerable. However, this hypothesis has rarely been comprehensively tested, as many studies only reveal an inverse correlation between parental care and offspring age, without directly testing the effects of offspring age on their vulnerability. To test this hypothesis, we studied Kurixalus eiffingeri, an arboreal treefrog with paternal care. We first performed a field survey by monitoring paternal care during embryonic development. Subsequently, we conducted a field experiment to assess the prevalence of egg predators (a semi-slug, Parmarion martensi) and the plasticity of male care. Finally, we conducted a laboratory experiment to assess how embryo age affects predation by P. martensi. RESULTS: Our results showed that (1) male attendance and brooding frequency affected embryo survival, and (2) males attended and brooded eggs more frequently in the early stage than in the late stage. The experimental results showed that (3) males increased attendance frequency when the predators were present, and (4) the embryonic predation by the semi-slug during the early was significantly higher than in the late stage. CONCLUSIONS: Our findings highlight the importance of paternal care to embryo survival, and the care behavior is plastic. Moreover, our results provide evidence consistent with the predictions of the harm to offspring hypothesis, as males tend to care more for younger offspring which are more vulnerable.

Preliminary study on AI-assisted diagnosis of bone remodeling in chronic maxillary sinusitis.

OBJECTIVE: To construct the deep learning convolution neural network (CNN) model and machine learning support vector machine (SVM) model of bone remodeling of chronic maxillary sinusitis (CMS) based on CT image data to improve the accuracy of image diagnosis. METHODS: Maxillary sinus CT data of 1000 samples in 500 patients from January 2018 to December 2021 in our hospital was collected. The first part is the establishment and testing of chronic maxillary sinusitis detection model by 461 images. The second part is the establishment and testing of the detection model of chronic maxillary sinusitis with bone remodeling by 802 images. The sensitivity, specificity and accuracy and area under the curve (AUC) value of the test set were recorded, respectively. RESULTS: Preliminary application results of CT based AI in the diagnosis of chronic maxillary sinusitis and bone remodeling. The sensitivity, specificity and accuracy of the test set of 93 samples of CMS, were 0.9796, 0.8636 and 0.9247, respectively. Simultaneously, the value of AUC was 0.94. And the sensitivity, specificity and accuracy of the test set of 161 samples of CMS with bone remodeling were 0.7353, 0.9685 and 0.9193, respectively. Simultaneously, the value of AUC was 0.89. CONCLUSION: It is feasible to use artificial intelligence research methods such as deep learning and machine learning to automatically identify CMS and bone remodeling in MSCT images of paranasal sinuses, which is helpful to standardize imaging diagnosis and meet the needs of clinical application.

Intravascular Laser Blood Irradiation (ILIB) Enhances Antioxidant Activity and Energy Metabolism in Aging Ovaries.

BACKGROUND: Ovarian aging is characterized by the accumulation of free radicals, leading to tissue damage and affecting reproductive health. Intravascular laser irradiation of blood (ILIB, using a low-energy He-Ne laser) is known for its efficacy in treating vascular-related diseases by reducing free radicals and inflammation. However, its impact on ovarian aging remains unexplored. This study aimed to investigate the effects of ILIB on oxidative stress and energy metabolism in aging ovaries. METHODS: Genetic analysis was conducted on 75 infertile patients with aging ovaries, divided into ILIB-treated and control (CTRL) groups. Patients underwent two courses of laser treatment, and clinical parameters were evaluated. Cumulus cells were collected for the genetic analysis of oxeiptosis, glycolysis, and the tricarboxylic acid (TCA) cycle. RESULTS: The analysis of gene expression patterns revealed intriguing findings in ILIB-treated patients compared to the untreated group. Notably, ILIB treatment resulted in significant upregulation of oxeiptosis-related genes AIFM1 and NRF2, suggesting a potential protective effect against oxidative stress-induced cell death. Furthermore, ILIB treatment led to a downregulation of glycolysis-associated gene hexokinase 2 (HK2), indicating a shift away from anaerobic metabolism, along with an increase in PDHA levels, indicative of enhanced mitochondrial function. Consistent with these changes, ILIB-treated patients exhibited elevated expression of the key TCA cycle genes citrate synthase (CS), succinate dehydrogenase complex subunit A (SDHA), and fumarate hydratase (FH), signifying improved energy metabolism. CONCLUSION: The findings from this study underscore the potential of ILIB as a therapeutic strategy for mitigating ovarian aging. By targeting oxidative stress and enhancing energy metabolism, ILIB holds promise for preserving ovarian function and reproductive health in aging individuals. Further research is warranted to elucidate the underlying mechanisms and optimize the application of ILIB in clinical settings, with the ultimate goal of improving fertility outcomes in women experiencing age-related ovarian decline.

Microstructure and Perfusion Alterations of Globus Pallidus in Neonates with Hyperbilirubinemia.

BACKGROUND: Previous studies have indicated the abnormality of the globus pallidus in neonates with hyperbilirubinemia. OBJECTIVE: This study aims to explore the microstructure and cerebral perfusion of globus pallidus in neonatal hyperbilirubinemia by using Diffusion Tensor Imaging (DTI) and Arterial Spin Labeling (ASL) approaches. METHODS: Thirty-seven neonates were enrolled in this study, which were classified into Bilirubin-Induced Neurologic Dysfunction (BIND) group (hyperbilirubinemia with BIND, n=12), non-BIND group (hyperbilirubinemia without BIND, n=15), and healthy controls (HC) group (n=10). The quantitative values of globus pallidus were calculated from DTI, including the Apparent Diffusion Coefficient (ADC), the Fractional Anisotropy (FA), and Volume Ratio (VR) values. Additionally, the relative Cerebral Blood Flow (rCBF) values were obtained from ASL. RESULTS: It was observed that the mean DTI signal of globus pallidus was significantly different among the three groups (p < 0.05). However, there were no significant differences in the rCBF of globus pallidus among the three groups (p > 0.05). A positive correlation was also observed between the fractional anisotropy (FA) value and serum bilirubin level (r = 0.561, p = 0.002), while the VR value showed a negative correlation with serum bilirubin level (r=-0.484, p=0.011). The area under the curve (AUC) of FA, VR, and FA and VR combined was 0.897, 0.858, and 0.933, respectively. CONCLUSION: The alterations of microstructure in globus pallidus, especially FA and VR value, may be valuable and sensitive at the early stage of hyperbilirubinemia encephalopathy, suggesting that early hyperbilirubinemia may lead to cytotoxic edema and decreased permeability of the cell membrane.

Aberrant Intra- and Inter-Network Connectivity in Idiopathic Sudden Sensorineural Hearing Loss with Tinnitus.

BACKGROUND: Idiopathic Sudden Sensorineural Hearing Loss (ISSNHL) is related to alterations in brain cortical and subcortical structures, and changes in brain functional activities involving multiple networks, which is often accompanied by tinnitus. There have been many in-depth research studies conducted concerning ISSNHL. Despite this, the neurophysiological mechanisms of ISSNHL with tinnitus are still under exploration. OBJECTIVE: The study aimed to investigate the neural mechanism in ISSNHL patients with tinnitus based on the alterations in intra- and inter-network Functional Connectivity (FC) of multiple networks. METHODS: Thirty ISSNHL subjects and 37 healthy subjects underwent resting-state functional Magnetic Resonance Imaging (rs-fMRI). Independent Component Analysis (ICA) was used to identify 8 Resting-state Networks (RSNs). Furthermore, the study used a two-sample t-test to calculate the intra-network FC differences, while calculating Functional Network Connectivity (FNC) to detect the inter-network FC differences. RESULTS: By using the ICA approach, tinnitus patients with ISSNHL were found to have FC changes in the following RSNs: CN, VN, DMN, ECN, SMN, and AUN. In addition, the interconnections of VN-SMN, VN-ECN, and ECN-DAN were weakened. CONCLUSION: The present study has demonstrated changes in FC within and between networks in ISSNHL with tinnitus, providing ideas for further study on the neuropathological mechanism of the disease.

First report of the chromosomal integration of carbapenemase gene blaIMP-19 in Acinetobacter baumannii AB322: the legacy of integron in phage-plasmid?

Integration of carbapenemase gene blaIMP into the chromosome of carbapenem-resistant Acinetobacter baumannii (CRAB) has not been reported. The aim of this study was to explore the genomic characteristics of CRAB AB322 isolated from a Taiwanese patient diagnosed with bacteremia in 2011, whose chromosome harbors blaIMP-19. Disk diffusion and broth microdilution were employed to analyze the antimicrobial susceptibility of AB322 to 14 antimicrobials. Nanopore whole-genome sequencing platform was utilized for AB322 genome sequencing, and conjugation was further performed to investigate the transferability of blaIMP-19 to amikacin-resistant A. baumannii 218 (AB218) and Acinetobacter nosocomialis 254 (AN254). The results showed that AB322 was classified as multidrug-resistant A. baumannii but remained susceptible to ampicillin/sulbactam, colistin, and tigecycline. Whole-genome sequencing revealed the AB322 genome, consisting of a 4,098,985-bp chromosome, a 71,590-bp conjugative plasmid named pAB322-1, and an 8,726-bp plasmid named pAB322-2. Multilocus sequence typing analysis indicated that AB322 belonged to sequence type 1. AB322 chromosome harbored numerous acquired antimicrobial resistance genes, including aph(3')-Ia, aadA1b, aadA1, aac(6')-Ib3, aac (3)-Ia, blaADC-25, blaOXA-69, blaIMP-19, catA1, sul1, and tet(A), conferring resistance to ß-lactams, aminoglycosides, chloramphenicol, sulfamethoxazole, and tetracyclines. Moreover, blaIMP-19 was identified to be situated within class 1 integron In240 and an incomplete PHAGE_Salmon_SJ46_NC_031129 on AB322 chromosome. However, conjugation experiments revealed that blaIMP-19 could not be transferred to AB218 and AN254 in our testing conditions. In conclusion, we first report the presence of chromosomal-integrated blaIMP-19 in CRAB, possibly mediated by integron. The future dissemination of blaIMP-19 among different species, leading to carbapenem resistance dissemination, requires close monitoring. IMPORTANCE: The horizontal transfer of antimicrobial-resistant genes is crucial for the dissemination of resistance, especially as Acinetobacter baumannii has emerged as a clinically significant pathogen. However, in this study, we first report the integration of the blaIMP-19 gene into the chromosome of A. baumannii, and such horizontal transfer may be associated with integron-phage elements. Additionally, it is possible that these DNA fragments carrying antimicrobial-resistant genes could further spread to other pathogens by moving horizontally onto conjugative plasmids.

Aberrant Brain Triple-Network Effective Connectivity Patterns in Type 2 Diabetes Mellitus.

INTRODUCTION: Aberrant brain functional connectivity network is thought to be related to cognitive impairment in patients with type 2 diabetes mellitus (T2DM). This study aims to investigate the triple-network effective connectivity patterns in patients with T2DM within and between the default mode network (DMN), salience network (SN), and executive control network (ECN) and their associations with cognitive declines. METHODS: In total, 92 patients with T2DM and 98 matched healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Spectral dynamic causal modeling (spDCM) was used for effective connectivity analysis within the triple network. The posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), lateral prefrontal cortex (LPFC), supramarginal gyrus (SMG), and anterior insula (AINS) were selected as the regions of interest. Group comparisons were performed for effective connectivity calculated using the fully connected model, and the relationships between effective connectivity alterations and cognitive impairment as well as clinical parameters were detected. RESULTS: Compared to HCs, patients with T2DM exhibited increased or decreased effective connectivity patterns within the triple network. Furthermore, diabetes duration was significantly negatively correlated with increased effective connectivity from the r-LPFC to the mPFC, while body mass index (BMI) was significantly positively correlated with increased effective connectivity from the l-LPFC to the l-AINS (r = - 0.353, p = 0.001; r = 0.377, p = 0.004). CONCLUSION: These results indicate abnormal effective connectivity patterns within the triple network model in patients with T2DM and provide new insight into the neurological mechanisms of T2DM and related cognitive dysfunction.

Neuromodulation techniques in poststroke motor impairment recovery: Efficacy, challenges, and future directions.

Cerebrovascular accidents, also known as strokes, represent a major global public health challenge and contribute to substantial mortality, disability, and socioeconomic burden. Multidisciplinary approaches for poststroke therapies are crucial for recovering lost functions and adapting to new limitations. This review discusses the potential of neuromodulation techniques, repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, spinal cord stimulation (SCS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), as innovative strategies for facilitating poststroke recovery. Neuromodulation is an emerging adjunct to conventional therapies that target neural plasticity to restore lost function and compensate for damaged brain areas. The techniques discussed in this review have different efficacies in enhancing neural plasticity, optimizing motor recovery, and mitigating poststroke impairments. Specifically, rTMS has shown significant promise in enhancing motor function, whereas SCS has shown potential in improving limb movement and reducing disability. Similarly, VNS, typically used to treat epilepsy, has shown promise in enhancing poststroke motor recovery, while DBS may be used to improve poststroke motor recovery and symptom mitigation. Further studies with standardized protocols are warranted to elucidate the efficacy of these methods and integrate them into mainstream clinical practice to optimize poststroke care.

Topological disruption of low- and high-order functional networks in presbycusis.

Prior efforts have manifested that functional connectivity (FC) network disruptions are concerned with cognitive disorder in presbycusis. The present research was designed to investigate the topological reorganization and classification performance of low-order functional connectivity (LOFC) and high-order functional connectivity (HOFC) networks in patients with presbycusis. Resting-state functional magnetic resonance imaging (Rs-fMRI) data were obtained in 60 patients with presbycusis and 50 matched healthy control subjects (HCs). LOFC and HOFC networks were then constructed, and the topological metrics obtained from the constructed networks were compared to evaluate topological differences in global, nodal network metrics, modularity and rich-club organization between patients with presbycusis and HCs. The use of HOFC profiles boosted presbycusis classification accuracy, sensitivity and specificity compared to that using LOFC profiles. The brain networks in both patients with presbycusis and HCs exhibited small-world properties within the given threshold range, and striking differences between groups in topological metrics were discovered in the constructed networks (LOFC and HOFC). NBS analysis identified a subnetwork involving 26 nodes and 23 signally altered internodal connections in patients with presbycusis in comparison to HCs in HOFC networks. This study highlighted the topological differences between LOFC and HOFC networks in patients with presbycusis, suggesting that HOFC profiles may help to further identify brain network abnormalities in presbycusis.

Tinnitus classification based on resting-state functional connectivity using a convolutional neural network architecture.

OBJECTIVES: Many studies have investigated aberrant functional connectivity (FC) using resting-state functional MRI (rs-fMRI) in subjective tinnitus patients. However, no studies have verified the efficacy of resting-state FC as a diagnostic imaging marker. We established a convolutional neural network (CNN) model based on rs-fMRI FC to distinguish tinnitus patients from healthy controls, providing guidance and fast diagnostic tools for the clinical diagnosis of subjective tinnitus. METHODS: A CNN architecture was trained on rs-fMRI data from 100 tinnitus patients and 100 healthy controls using an asymmetric convolutional layer. Additionally, a traditional machine learning model and a transfer learning model were included for comparison with the CNN, and each of the three models was tested on three different brain atlases. RESULTS: Of the three models, the CNN model outperformed the other two models with the highest area under the curve, especially on the Dos_160 atlas (AUC = 0.944). Meanwhile, the model with the best classification performance highlights the crucial role of the default mode network, salience network, and sensorimotor network in distinguishing between normal controls and patients with subjective tinnitus. CONCLUSION: Our CNN model could appropriately tackle the diagnosis of tinnitus patients using rs-fMRI and confirmed the diagnostic value of FC as measured by rs-fMRI.

Machine learning models for screening clinically significant nephrolithiasis in overweight and obese populations.

PURPOSES: Our aim is to build and evaluate models to screen for clinically significant nephrolithiasis in overweight and obesity populations using machine learning (ML) methodologies and simple health checkup clinical and urine parameters easily obtained in clinics. METHODS: We developed ML models to screen for clinically significant nephrolithiasis (kidney stone > 2 mm) in overweight and obese populations (body mass index, BMI ≥ 25 kg/m2) using gender, age, BMI, gout, diabetes mellitus, estimated glomerular filtration rate, bacteriuria, urine pH, urine red blood cell counts, and urine specific gravity. The data were collected from hospitals in Kaohsiung, Taiwan between 2012 and 2021. RESULTS: Of the 2928 subjects we enrolled, 1148 (39.21%) had clinically significant nephrolithiasis and 1780 (60.79%) did not. The testing dataset consisted of data collected from 574 subjects, 235 (40.94%) with clinically significant nephrolithiasis and 339 (59.06%) without. One model had a testing area under curve of 0.965 (95% CI, 0.9506-0.9794), a sensitivity of 0.860 (95% CI, 0.8152-0.9040), a specificity of 0.947 (95% CI, 0.9230-0.9708), a positive predictive value of 0.918 (95% CI, 0.8820-0.9544), and negative predictive value of 0.907 (95% CI, 0.8756-0.9371). CONCLUSION: This ML-based model was found able to effectively distinguish the overweight and obese subjects with clinically significant nephrolithiasis from those without. We believe that such a model can serve as an easily accessible and reliable screening tool for nephrolithiasis in overweight and obesity populations and make possible early intervention such as lifestyle modifications and medication for prevention stone complications.

Diffusion-/perfusion-weighted imaging fusion to automatically identify stroke within 4.5 h.

OBJECTIVES: We aimed to develop machine learning (ML) models based on diffusion- and perfusion-weighted imaging fusion (DP fusion) for identifying stroke within 4.5 h, to compare them with DWI- and/or PWI-based ML models, and to construct an automatic segmentation-classification model and compare with manual labeling methods. METHODS: ML models were developed from multimodal MRI datasets of acute stroke patients within 24 h of clear symptom onset from two centers. The processes included manual segmentation, registration, DP fusion, feature extraction, and model establishment (logistic regression (LR) and support vector machine (SVM)). A segmentation-classification model (X-Net) was proposed for automatically identifying stroke within 4.5 h. The area under the receiver operating characteristic curve (AUC), sensitivity, Dice coefficients, decision curve analysis, and calibration curves were used to evaluate model performance. RESULTS: A total of 418 patients (≤ 4.5 h: 214; > 4.5 h: 204) were evaluated. The DP fusion model achieved the highest AUC in identifying the onset time in the training (LR: 0.95; SVM: 0.92) and test sets (LR: 0.91; SVM: 0.90). The DP fusion-LR model displayed consistent positive and greater net benefits than other models across a broad range of risk thresholds. The calibration curve demonstrated the good calibration of the DP fusion-LR model (average absolute error: 0.049). The X-Net model obtained the highest Dice coefficients (DWI: 0.81; Tmax: 0.83) and achieved similar performance to manual labeling (AUC: 0.84). CONCLUSIONS: The automatic segmentation-classification models based on DWI and PWI fusion images had high performance in identifying stroke within 4.5 h. CLINICAL RELEVANCE STATEMENT: Perfusion-weighted imaging (PWI) fusion images had high performance in identifying stroke within 4.5 h. The automatic segmentation-classification models based on DWI and PWI fusion images could provide clinicians with decision-making guidance for acute stroke patients with unknown onset time. KEY POINTS: • The diffusion/perfusion-weighted imaging fusion model had the best performance in identifying stroke within 4.5 h. • The X-Net model had the highest Dice and achieved performance close to manual labeling in segmenting lesions of acute stroke. • The automatic segmentation-classification model based on DP fusion images performed well in identifying stroke within 4.5 h.

Multipathway regulation induced by 4-(phenylsulfonyl)morpholine derivatives against triple-negative breast cancer.

Phenotypic drug discovery (PDD) is an effective drug discovery approach by observation of therapeutic effects on disease phenotypes, especially in complex disease systems. Triple-negative breast cancer (TNBC) is composed of several complex disease features, including high tumor heterogeneity, high invasive and metastatic potential, and a lack of effective therapeutic targets. Therefore, identifying effective and novel agents through PDD is a current trend in TNBC drug development. In this study, 23 novel small molecules were synthesized using 4-(phenylsulfonyl)morpholine as a pharmacophore. Among these derivatives, GL24 (4m) exhibited the lowest half-maximal inhibitory concentration value (0.90 µM) in MDA-MB-231 cells. To investigate the tumor-suppressive mechanisms of GL24, transcriptomic analyses were used to detect the perturbation for gene expression upon GL24 treatment. Followed by gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, multiple ER stress-dependent tumor suppressive signals were identified, such as unfolded protein response (UPR), p53 pathway, G2/M checkpoint, and E2F targets. Most of the identified pathways triggered by GL24 eventually led to cell-cycle arrest and then to apoptosis. In summary, we developed a novel 4-(phenylsulfonyl)morpholine derivative GL24 with a strong potential for inhibiting TNBC cell growth through ER stress-dependent tumor suppressive signals.

Modular Edge Analysis Reveals Chemotherapy-induced Brain Network Changes in Lung Cancer Patients.

BACKGROUND: Lung cancer patients with post-chemotherapy may have disconnected or weakened function connections within brain networks. OBJECTIVE: This study aimed to explore the abnormality of brain functional networks in lung cancer patients with post-chemotherapy by modular edge analysis. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed on 40 patients after chemotherapy, 40 patients before chemotherapy and 40 normal controls. Patients in all three groups were age and sex well-matched. Then, modular edge analysis was applied to assess brain functional network alterations. RESULTS: Post-chemotherapy patients had the worst MoCA scores among the three groups (p < 0.001). In intra-modular connections, compared with normal controls, the patients after chemotherapy had decreased connection strengths in the occipital lobe module (p < 0.05). Compared with the nonchemotherapy group, the patients after chemotherapy had decreased connection strengths in the subcortical module (p < 0.05). In inter-modular connections, compared with normal controls, the patients after chemotherapy had decreased connection strength in the frontal-temporal lobe modules (p < 0.05). Compared with the non-chemotherapy group, the patients after chemotherapy had decreased connection strength in the subcortical-temporal lobe modules (p < 0.05). CONCLUSION: The results reveal that chemotherapy can disrupt connections in brain functional networks. As far as we know, the use of modular edge analysis to report changes in brain functional brain networks associated with chemotherapy was rarely reported. Modular edge analysis may play a crucial part in predicting the clinical outcome for the patients after chemotherapy.

A 19-year longitudinal study to characterize carbapenem-nonsusceptible Acinetobacter isolated from patients with bloodstream infections and the contribution of conjugative plasmids to carbapenem resistance and virulence.

BACKGROUND: This study aimed to characterize carbapenem-nonsusceptible Acinetobacter (CNSA) isolated from patients with bacteremia from 1997 to 2015. METHODS: A total of 173 CNSA (12.3%) was recovered from 1403 Acinetobacter isolates. The presence of selected ß-lactamase genes in CNSA was determined by PCR amplification. The conjugation test was used to determine the transferability of metallo-ß-lactamase (MBL)-carrying plasmids. Whole genome sequencing in combination with phenotypic assays was carried out to characterize MBL-plasmids. RESULTS: In general, a trend of increasing numbers of CNSA was observed. Among the 173 CNSA, A. baumannii (54.9%) was the most common species, followed by A. nosocomialis (23.1%) and A. soli (12.1%). A total of 49 (28.3%) CNSA were extensively drug-resistant, and all were A. baumannii. The most common class D carbapenemase gene in 173 CNSA was blaOXA-24-like (32.4%), followed by ISAba1-blaOXA-51-like (20.8%), ISAba1-blaOXA-23 (20.2%), and IS1006/IS1008-blaOXA-58 (11.6%). MBL genes, blaVIM-11,blaIMP-1, and blaIMP-19 were detected in 9 (5.2%), 20 (11.6%), and 1 (0.6%) CNSA isolates, respectively. Transfer of MBL genes to AB218 and AN254 recipient cells was successful for 7 and 6 of the 30 MBL-plasmids, respectively. The seven AB218-derived transconjugants carrying MBL-plasmids produced less biofilm but showed higher virulence to larvae than recipient AB218. CONCLUSIONS: Our 19-year longitudinal study revealed a stable increase in CNSA during 2005-2015. blaOXA-24-like, ISAba1-blaOXA-51-like, and ISAba1-blaOXA-23 were the major determinants of Acinetobacter carbapenem resistance. MBL-carrying plasmids contribute not only to the carbapenem resistance but also to A. baumannii virulence.

Evaluation of glymphatic system activity by diffusion tensor image analysis along the perivascular space in presbycusis.

PURPOSE: Previous studies have suggested that presbycusis (age-related hearing loss) is accompanied with cognitive decline and dementia. However, the neural mechanism underlying the cognitive decline in presbycusis remains unclear. This study aimed to evaluate the glymphatic system function in presbycusis patients compared to healthy controls using diffusion tensor imaging (DTI) with the perivascular space (DTI-ALPS) method. METHODS: DTI scans were obtained from 30 presbycusis patients with cognitive decline (PCD), 30 presbycusis patients with no cognitive decline (PNCD) and 40 age-, gender-, and education-matched healthy controls (HCs). The DTI-ALPS index was calculated for each group. We evaluated the differences in the DTI-ALPS index among PCD, PNCD and HCs. In addition, we conducted a correlation analysis between the DTI-ALPS index and cognitive performance. RESULTS: There were significant differences of the DTI-ALPS index among three groups. Post-hoc analysis suggested that the DTI-ALPS index in PCD was significantly lower patients in relative to PNCD and HCs (1.49147 vs. 1.57441 vs. 1.62020, p < 0.001). After correcting for age, gender, and education, the DTI-ALPS index is positively correlated with the MoCA scores (rho = 0.426, p = 0.026). CONCLUSION: Presbycusis patients with cognitive impairment exhibited decreased glymphatic activity than those without cognitive impairment and HCs. The DTI-ALPS index may provide useful disease progression or treatment biomarkers for patients with presbycusis as an indicator of modulation of glymphatic activity.

FL-circAS: an integrative resource and analysis for full-length sequences and alternative splicing of circular RNAs with nanopore sequencing.

Circular RNAs (circRNAs) are RNA molecules with a continuous loop structure characterized by back-splice junctions (BSJs). While analyses of short-read RNA sequencing have identified millions of BSJ events, it is inherently challenging to determine exact full-length sequences and alternatively spliced (AS) isoforms of circRNAs. Recent advances in nanopore long-read sequencing with circRNA enrichment bring an unprecedented opportunity for investigating the issues. Here, we developed FL-circAS (https://cosbi.ee.ncku.edu.tw/FL-circAS/), which collected such long-read sequencing data of 20 cell lines/tissues and thereby identified 884 636 BSJs with 1 853 692 full-length circRNA isoforms in human and 115 173 BSJs with 135 617 full-length circRNA isoforms in mouse. FL-circAS also provides multiple circRNA features. For circRNA expression, FL-circAS calculates expression levels for each circRNA isoform, cell line/tissue specificity at both the BSJ and isoform levels, and AS entropy for each BSJ across samples. For circRNA biogenesis, FL-circAS identifies reverse complementary sequences and RNA binding protein (RBP) binding sites residing in flanking sequences of BSJs. For functional patterns, FL-circAS identifies potential microRNA/RBP binding sites and several types of evidence for circRNA translation on each full-length circRNA isoform. FL-circAS provides user-friendly interfaces for browsing, searching, analyzing, and downloading data, serving as the first resource for discovering full-length circRNAs at the isoform level.