bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex-Specific Behavioral Response to Early Adolescent Stress in the Genetically More Stress-Reactive Wistar Kyoto More Immobile, and Its Nearly Isogenic Wistar Kyoto Less Immobile Control Strain
Authors: Kim Sarah , Gacek Stephanie A. , Mocchi Madaline M. , Redei Eva E.
Published: December 2021

Genetic predisposition and environmental stress are known etiologies of stress-related psychiatric disorders. Environmental stress during adolescence is assumed to be particularly detrimental for adult affective behaviors. To investigate how genetic stress-reactivity differences modify the effects of stress during adolescence on adult affective behaviors we employed two inbred strains with differing stress reactivity. The Wistar Kyoto More Immobile (WMI) rat strain show increased stress-reactivity and despair-like behaviors as well as passive coping compared to the nearly isogenic control strain, the Wistar Kyoto Less Immobile (WLI). Males and females of these strains were exposed to contextual fear conditioning (CFC) during early adolescence (EA), between 32 and 34 postnatal days (PND), and were tested for the consequences of this mild EA stress in adulthood. Early adolescent stress significantly decreased anxiety-like behavior, measured in the open field test (OFT) and increased social interaction and recognition in adult males of both strains compared to controls. In contrast, no significant effects of EA stress were observed in adult females in these behaviors. Both males and females of the genetically less stress-reactive WLI strain showed significantly increased immobility in the forced swim test (FST) after EA stress compared to controls. In contrast, immobility was significantly attenuated by EA stress in adult WMI females compared to controls. Transcriptomic changes of the glucocorticoid receptor (Nr3c1, GR) and the brain-derived neurotrophic factor (Bdnf) illuminate primarily strain and stress-dependent changes, respectively, in the prefrontal cortex and hippocampus of adults. These results suggest that contrary to expectations, limited adolescent stress is beneficial to males thru decreasing anxiety and enhancing social behaviors, and to the stress more-reactive WMI females by way of decreasing passive coping.
Tunable Neural Encoding of a Symbolic Robotic Manipulation Algorithm
Authors: Katz Garrett E. , Akshay  , Davis Gregory P. , Gentili Rodolphe J. , Reggia James A.
Published: December 2021

We present a neurocomputational controller for robotic manipulation based on the recently developed “neural virtual machine” (NVM). The NVM is a purely neural recurrent architecture that emulates a Turing-complete, purely symbolic virtual machine. We program the NVM with a symbolic algorithm that solves blocks-world restacking problems, and execute it in a robotic simulation environment. Our results show that the NVM-based controller can faithfully replicate the execution traces and performance levels of a traditional non-neural program executing the same restacking procedure. Moreover, after programming the NVM, the neurocomputational encodings of symbolic block stacking knowledge can be fine-tuned to further improve performance, by applying reinforcement learning to the underlying neural architecture.
Dietary Choline Protects Against Cognitive Decline After Surgery in Mice
Authors: Maurer Sara V. , Kong Cuicui , Terrando Niccolò , Williams Christina L.
Published: December 2021

Perioperative neurocognitive disorders (PNDs) are a common complication following procedures such as orthopedic surgery. Using a mouse model of tibial fracture and repair surgery, we have previously shown an increase in neuroinflammation and hippocampal-dependent cognitive deficits. These changes were ameliorated with the addition of a cholinergic agonist. Here, we sought to examine the effects of a high-choline diet for 3 weeks prior to tibial fracture surgery. We evaluated memory using novel object recognition (NOR) as well as young neurons and glial cell morphology at 1 day and 2 weeks post-surgery. At both time points, tibial fracture impaired NOR performance, and dietary choline rescued these impairments. Astrocytic density and hilar granule cells increased 1 day after tibial fracture, and these increases were partially blunted by dietary choline. An increase in young neurons in the subgranular zone of the dentate gyrus was found 2 weeks after tibial fracture. This increase was partially blunted by choline supplementation. This suggests that shortly after tibial fracture, hippocampal reorganization is a possible mechanism for acute impaired memory. These findings together suggest that non-pharmaceutical approaches, such as pre-surgical dietary intervention with choline, may be able to prevent PNDs.
Why Has Deep Brain Stimulation Had So Little Impact in Psychiatry?
Authors: Mocking Roel J. T. , Graat Ilse , Denys Damiaan
Published: December 2021

Over two decades ago, the first scientific publication on deep brain stimulation (DBS) in psychiatry was published. The evidence for effectiveness of DBS for several psychiatric disorders has been steadily accumulating since the first report of DBS for Obsessive Compulsive Disorder (OCD) in 1999. However, the number of psychiatric patients treated with DBS is lagging behind, particularly in comparison with neurology. The number of patients treated with DBS for psychiatric indications worldwide probably does not exceed 500, compared to almost 300,000 patients with neurological disorders that have been treated with DBS within the same period of 20 years. It is not the lack of patients, knowledge, technology, or efficacy of DBS that hinders its development and application in psychiatry. Here, we discuss the reasons for the gap between DBS in neurology and in psychiatry, which seemed to involve the scientific and social signature of psychiatry.
Extracranial Carotid Plaque Hemorrhage Is Independently Associated With Poor 3-month Functional Outcome After Acute Ischemic Stroke—A Prospective Cohort Study
Authors: Che Fengli , Liu Yanfang , Gong Xiping , Wang Anxin , Bai Xiaoyan , Ju Yi , Sui Binbin , Jing Jing , Geng Xiaokun , Zhao Xingquan
Published: December 2021

Background and Purpose: Carotid plaque hemorrhage (IPH) is a critical plaque vulnerable feature. We aim to elucidate the association between symptomatic extracranial carotid atherosclerotic IPH and poor 3-month functional outcome after acute ischemic stroke by high-resolution vessel wall MRI (HRVMRI).

Methods: We prospectively studied consecutive patients with a recent stroke or transient ischemic attack (TIA) of carotid atherosclerotic origin. All patients underwent a High-Resolution (HR) VWMRI scan of ipsilateral extracranial carotid within 1 week after admission. The patients recruited were interviewed by telephone after 3 months after stroke onset. The primary outcome was a 3-month functional prognosis of stroke, expressed as a modified Rankin Scale (mRS) score. A poor prognosis was defined as a 3-month modified Rankin Scale (mRS) score ≥ of 3. Univariate analysis was used to analyze the correlation between risk factors and IPH. The relation between IPH and 3-month functional outcome was analyzed by Logistic regression analysis.

Results: A total of 156 patients (mean age, 61.18 ± 10.12 years; 108 males) were included in the final analysis. There were significant differences in the age, gender, smoking history, national institutes of health stroke scale (NIHSS) on admission, and diastolic blood pressure (DBP) on admission between the IPH group and the non-IPH group (all p < 0.05). During the follow-up, 32 patients (20.5%) had a poor functional outcome. According to the prognosis analysis of poor functional recovery, there was a significant difference between the two groups [36.7 vs. 16.7%; unadjusted odds ratio (OR), 2.32, 95% confidence interval (CI), 1.12–4.81, p = 0.024). Even after adjusting for confounding factors [such as age, gender, smoking history, National Institutes of Health Stroke Scale (NIHSS) on admission, DBP on admission, stenosis rate of carotid artery (CA), calcification, loose matrix, lipo-rich necrotic core (LRNC), and statins accepted at 3 months], IPH was still a strong predictor of poor 3-month outcome, and the adjusted OR was 3.66 (95% CI 1.68–7.94, p = 0.001).

Conclusions: Extracranial carotid IPH is significantly associated with poor 3-month outcome after acute ischemic stroke and can predict the poor 3-month functional prognosis.
Association Between the Number of Intratympanic Steroid Injections and Hearing Recovery in Sudden Sensorineural Hearing Loss
Authors: Wang Yixu , Gao Ge , Wang Le , Ma Xin , Yu Lisheng , Ye Fanglei
Published: December 2021

The frequency of intratympanic (IT) steroid injection varies from once daily to once weekly or less among studies and does not reach a uniform standard. This study investigated the potential association between the number of IT steroid injections and hearing recovery to determine the optimal number in sudden sensorineural hearing loss (SSNHL) patients. A retrospective study involving 233 SSNHL patients receiving IT steroids plus batroxobin within 7 days of onset was performed. Patients were followed up for 3 months. More than 15 dB of HL improvement in the pretreatment pure tone average (PTA) was defined as effective. The effective group had a higher IT injection numbers than the ineffective group (≥ 6 times: 84.6 vs. 61.1, p < 0.001). Regardless of the unadjusted model or adjusted model, patients who received more frequent IT steroid injections seemed more likely to recover hearing (unadjusted model, OR, 95% CI: 1.25, 1.06–1.48; p = 0.007; adjusted model, OR, 95% CI: 1.21, 1.01–1.45; p = 0.044). Six IT injections had the highest rate of hearing recovery (79.1%). In conclusion, IT injection number was an independent factor that was positively associated with hearing recovery, and the optimal number of IT steroid injections was 6. Batroxobin plus higher number of IT steroid injections showed more effective for treating SSNHL.
Correlation Between Retinal Microvascular Abnormalities and Total Magnetic Resonance Imaging Burden of Cerebral Small Vessel Disease in Patients With Type 2 Diabetes
Authors: Zhang Ying , Zhang Zhixiang , Zhang Min , Cao Yin , Yun Wenwei
Published: December 2021

Background and Purpose: Diabetic retinopathy (DR) is one of the common microvascular complications in diabetes. The total magnetic resonance imaging (MRI) burden of cerebral small vessel disease (CSVD) tends to be increased in diabetic patients and is a marker of microvascular disease; however, the relationship between DR and CSVD is unclear. This study aimed to explore the relationship between retinal microvascular abnormalities and the total MRI burden of CSVD in patients with type 2 diabetes.

Methods: Data were collected from patients with type 2 diabetes who were hospitalized between December 2019 and November 2020 in Changzhou Second People’s Hospital affiliated to Nanjing Medical University. All patients underwent retinal photography and cerebral MRI. The central retinal artery equivalent (CRAE), the central retinal venous equivalent (CRVE), and arteriole-to-venule ratio (AVR) were calculated using Image J software to determine the retinal vascular calibers for each patient. The total MRI burden score for CSVD was determined, and the relationship between retinal microvascular abnormalities and the total MRI burden of CSVD was analyzed.

Results: Of the 151 diabetic patients included in the study, 84 (55.6%) had no diabetic retinopathy (NDR), 27 (17.9%) had mild DR, and 40 (26.5%) had moderate, or severe non-proliferative DR (grouped together for this study as “more than mild DR”). In patients with more than mild DR, the proportion of moderate to severe burden of CSVD was 75%, which was higher than in patients with mild DR (48.1%) or NDR (26.2%). Patients with moderate to severe burden of CSVD were more likely than those with mild burden of CSVD to have narrowed retinal arterioles (105.24 ± 8.42 μm vs. 109.45 ± 7.93 μm), widened retinal venules (201.67 ± 16.25 μm vs. 193.95 ± 13.54 μm), and lower arteriole-to-venule ratio (0.52 ± 0.05 vs. 0.57 ± 0.04) (P < 0.05 for all). The degree of DR (r = 0.465, P < 0.001) and CRVE (r = 0.366, P < 0.001) were positively correlated with the total MRI burden of CSVD. Multivariate logistic regression analysis indicated that, after adjustments were made for age, smoking, alcohol consumption, hypertension, and other factors, more than mild DR (OR, 4.383; P = 0.028), CRAE (OR, 0.490; P = 0.031), and CRVE (OR, 1.475; P = 0.041) were independently associated with moderate to severe burden of CSVD.

Conclusion: Retinal microvascular abnormalities in patients with type 2 diabetes are associated with the presence of cerebral small vessel lesions. The degree of DR and retinal vessel changes can be used as predictors of intracranial microcirculation lesions.
Biorealistic Control of Hand Prosthesis Augments Functional Performance of Individuals With Amputation
Authors: Luo Qi , Niu Chuanxin M. , Chou Chih-Hong , Liang Wenyuan , Deng Xiaoqian , Hao Manzhao , Lan Ning
Published: December 2021

The human hand has compliant properties arising from muscle biomechanics and neural reflexes, which are absent in conventional prosthetic hands. We recently proved the feasibility to restore neuromuscular reflex control (NRC) to prosthetic hands using real-time computing neuromorphic chips. Here we show that restored NRC augments the ability of individuals with forearm amputation to complete grasping tasks, including standard Box and Blocks Test (BBT), Golf Balls Test (GBT), and Potato Chips Test (PCT). The latter two were more challenging, but novel to prosthesis tests. Performance of a biorealistic controller (BC) with restored NRC was compared to that of a proportional linear feedback (PLF) controller. Eleven individuals with forearm amputation were divided into two groups: one with experience of myocontrol of a prosthetic hand and another without any. Controller performances were evaluated by success rate, failure (drop/break) rate in each grasping task. In controller property tests, biorealistic control achieved a better compliant property with a 23.2% wider range of stiffness adjustment than that of PLF control. In functional grasping tests, participants could control prosthetic hands more rapidly and steadily with neuromuscular reflex. For participants with myocontrol experience, biorealistic control yielded 20.4, 39.4, and 195.2% improvements in BBT, GBT, and PCT, respectively, compared to PLF control. Interestingly, greater improvements were achieved by participants without any myocontrol experience for BBT, GBT, and PCT at 27.4, 48.9, and 344.3%, respectively. The functional gain of biorealistic control over conventional control was more dramatic in more difficult grasp tasks of GBT and PCT, demonstrating the advantage of NRC. Results support the hypothesis that restoring neuromuscular reflex in hand prosthesis can improve neural motor compatibility to human sensorimotor system, hence enabling individuals with amputation to perform delicate grasps that are not tested with conventional prosthetic hands.
Asymmetry in the Central Nervous System: A Clinical Neuroscience Perspective
Authors: Mundorf Annakarina , Peterburs Jutta , Ocklenburg Sebastian
Published: December 2021

Recent large-scale neuroimaging studies suggest that most parts of the human brain show structural differences between the left and the right hemisphere. Such structural hemispheric asymmetries have been reported for both cortical and subcortical structures. Interestingly, many neurodevelopmental and psychiatric disorders have been associated with altered functional hemispheric asymmetries. However, findings concerning the relation between structural hemispheric asymmetries and disorders have largely been inconsistent, both within specific disorders as well as between disorders. In the present review, we compare structural asymmetries from a clinical neuroscience perspective across different disorders. We focus especially on recent large-scale neuroimaging studies, to concentrate on replicable effects. With the notable exception of major depressive disorder, all reviewed disorders were associated with distinct patterns of alterations in structural hemispheric asymmetries. While autism spectrum disorder was associated with altered structural hemispheric asymmetries in a broader range of brain areas, most other disorders were linked to more specific alterations in brain areas related to cognitive functions that have been associated with the symptomology of these disorders. The implications of these findings are highlighted in the context of transdiagnostic approaches to psychopathology.
Effects of Syringic Acid on Apoptosis, Inflammation, and AKT/mTOR Signaling Pathway in Gastric Cancer Cells
Authors: Pei Jinjin , Velu Periyannan , Zareian Mohsen , Feng Zili , Vijayalakshmi Annamalai
Published: December 2021

Gastric cancer is one of the most common cancer and deadly disease worldwide. Despite substantial advances made in the treatment of gastric cancer, existing therapies still encounter bottlenecks. Chemotherapy, for instance, could lead to serious side effects, high drug resistance and treatment failure. Phytochemical-derived compounds from plants offer novel strategies as potent drug molecules in cancer therapy. Given the low toxicity and higher tolerance rate of naturally occurring compounds, the present study evaluated the effects of syringic acid on cytotoxicity, oxidative stress, mitochondrial membrane potential, apoptosis, and inflammatory responses in gastric cancer cell line (AGS). AGS cells were treated with various concentrations (5–40 μg/mL) of syringic acid for 24 h, after which cytotoxicity was analyzed. Reactive Oxygen Species (ROS), antioxidant enzyme activities, mitochondrial membrane potential (MMP, Δψm), cell morphologies, the expression of apoptotic markers and protein expression patterns were also investigated. Results indicated that syringic acid-treated cells developed anti-cancer activities by losing MMP, cell viability, and enhancing intracellular ROS. Syringic acid selectively developed apoptosis in a dose-dependent manner via enhanced regulation of caspase-3, caspase-9 and Poly ADP-ribose Polymerase (PARP) whereas decreasing the expression levels of p53 and BCL-2. Syringic acid also lowered activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) whereas Thio Barbituric Acid Reactive Substances (TBARS) increased. Syringic acid suppressed gastric cancer cell proliferation, inflammation, and induced apoptosis by upregulating mTOR via AKT signaling pathway. The study suggests syringic acid may constitute a promising chemotherapeutic candidate for gastric cancer treatment. Our study is the first report on the anti-cancer effects of syringic acid against gastric cancer cells via apoptosis, inhibition of inflammation, and the suppression of the mTOR/AKT signaling pathway.
Bifidobacterium animalis subsp. lactis HN019 Effects on Gut Health: A Review
Authors: Cheng Jing , Laitila Arja , Ouwehand Arthur C.
Published: December 2021

Optimal gut motility is central to bowel function and gut health. The link between the gut dysmotility related disorders and dysfunctional-intestinal barriers has led to a hypothesis that certain probiotics could help in normalizing gut motility and maintain gut health. This review investigates the roles of Bifidobacterium animalis subsp. lactis HN019 (B. lactis HN019™) on gut health, and its mechanisms of action in various pre-clinical and clinical studies. Research supports the hypothesis that B. lactis HN019™ has a beneficial role in maintaining intestinal barrier function during gastrointestinal infections by competing and excluding potential pathogens via different mechanisms; maintaining normal tight junction function in vitro; and regulating host immune defense toward pathogens in both in vitro and human studies. This has been observed to lead to reduced incidence of diarrhea. Interestingly, B. lactis HN019™ also supports normal physiological function in immunosenescent elderly and competes and excludes potential pathogens. Furthermore, B. lactis HN019™ reduced intestinal transit time and increased bowel movement frequency in functional constipation, potentially by modulating gut–brain–microbiota axis, mainly via serotonin signaling pathway, through short chain fatty acids derived from microbial fermentation. B. lactis HN019™ is thus a probiotic that can contribute to relieving gut dysmotility related disorders.
Modelled Economic Analysis for Dacomitinib–A Cost Effectiveness Analysis in Treating Patients With EGFR-Mutation-Positive Non-Small Cell Lung Cancer in China
Authors: Yu Yong-feng , Luan Luan , Zhu Fan-fan , Dong Peng , Ma Li-Heng , Li Lan-ting , Gao Lan , Lu Shun
Published: December 2021

Objectives

To establish the cost-effectiveness of dacomitinib compared to gefitinib from the Chinese healthcare system perspective.

Patients

Advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations.

Methods

Partitioned survival analysis was undertaken to examine the cost-effectiveness of dacomitinib utilising individual patient data (IPD) from the pivotal randomised controlled trial (RCT) (ARCHER 1050). The three health states modelled were progression-free, post-progression, and death. Parametric survival distributions were fitted to IPD against the Kaplan-Meier survival curves corresponding to progression-free survival (PFS) and overall survival (OS) outcomes by randomised groups. Costs included drug acquisition and administration, outpatient management (outpatient consultation and examinations), and best supportive care costs. Utility weights were sourced from the pivotal trial and other published literature. The incremental cost-effectiveness ratio (ICER) was calculated with costs and quality-adjusted life years (QALYs) discounted at an annual rate of 5%. Both deterministic and probabilistic sensitivity analyses were undertaken.

Results

In the base case, dacomitinib (CNY 265,512 and 1.95 QALY) was associated with higher costs and QALY gains compared to gefitinib (CNY 247,048 and 1.61 QALYs), resulting in an ICER of CNY 58,947/QALY. Using the empirical WTP/QALY threshold, dacomitinib is a cost-effective treatment strategy for patients with EGFR-mutation-positive advanced NSCLC. The probabilistic sensitivity analysis suggested that dacomitinib had a 97% probability of being cost-effective.

Conclusions

Dacomitinib is a cost-effective treatment strategy in treating patients with EGFR-mutation-positive NSCLC from the Chinese healthcare system perspective. The uncertainty around the cost-effectiveness of dacomitinib could be reduced if long-term survival data become available.

Clinical Trial Registration

NCT01024413
ADD3 Deletion in Glioblastoma Predicts Disease Status and Survival
Authors: Kiang Karrie Mei-Yee , Sun Stella , Leung Gilberto Ka-Kit
Published: December 2021

Loss of heterozygosity (LOH) on chromosome 10 frequently occurs in gliomas. Whereas genetic loci with allelic deletion often implicate tumor suppressor genes, a putative tumor suppressor Adducin3 (ADD3) mapped to chromosome 10q25.2 was found to be preferentially downregulated in high-grade gliomas compared with low-grade lesions. In this study, we unveil how the assessment of ADD3 deletion provides clinical significance in glioblastoma (GBM). By deletion mapping, we assessed the frequency of LOH in forty-three glioma specimens using five microsatellite markers spanning chromosome 10q23-10qter. Data were validated in The Cancer Genome Atlas (TCGA) cohort with 203 GBM patients. We found that allelic loss in both D10S173 (ADD3/MXI1 locus) and D10S1137 (MGMT locus) were positively associated with tumor grading and proliferative index (MIB-1). However, LOH events at only the ADD3/MXI1 locus provided prognostic significance with a marked reduction in patient survival and appeared to have diagnostic potential in differentiating high-grade gliomas from low-grade ones. Furthermore, we showed progressive loss of ADD3 in six out of seven patient-paired gliomas with malignant progression, as well as in recurrent GBMs. These findings suggest the significance of ADD3/MXI1 locus as a promising marker that can be used to refine the LOH10q assessment. Data further suggest the role of ADD3 as a novel tumor suppressor, whereby the loss of ADD3 is indicative of a progressive disease that may at least partially account for rapid disease progression in GBM. This study revealed for the first time the downregulation of ADD3 on the genetic level resulting from copy number deletion.
Clinical Values and Markers of Radiation-Induced Liver Disease for Hepatocellular Carcinoma With Portal Vein Tumor Thrombus Treated With Stereotactic Body Radiotherapy
Authors: Jia Jun , Sun Jing , Duan Xuezhang , Li Wengang
Published: December 2021

Background

Information about radiation-induced liver disease (RILD) in hepatocellular carcinoma (HCC) patients preexisting hepatitis B cirrhosis with portal vein tumor thrombus (PVTT) extended to the main portal vein treated with stereotactic body radiotherapy (SBRT) is still inadequate and the predictive markers for RILD have not been cleared in these patients. The aim of the study is to identify factors that can be used to predict RILD and to evaluate the influence of RILD in these patients.

Methods

In our study, 59 patients were analyzed and evaluated from December 2015 to June 2019, according to the entry criteria. After treatment, 59 patients were followed up within the first month and then every 3 months. Hematology test, tumor markers, three-phasic CT scan of the lungs, and CT or MRI scan of the liver were performed at each follow up.

Results

Median overall survival time was 10.7 months (range, 5.8 to 14.9). RILD appeared in 17 of the 59 patients (28.8%) at the 3rd month after SBRT. In the univariate analysis, not only the CP score class (A or B) but also each different pretreatment CP score (p < 0.05) was a significant predictive factor of RILD. More RILD cases were detected with the increase of CP score. The recovery rate decreased as the baseline CP score increased (p < 0.05). It was found that the overall survival time was affected by only baseline CP score and RILD (p < 0.05).

Conclusions

The development of RILD has a dependency on the CP score in these patients. CP scores before treatment and RILD are significantly associated with overall survival. SBRT is an effective and safe method for patients with CP ≤ B7. For patients with CP-B8, liver function should be monitored more frequently. It is not safe enough for the SBRT treatment in CP-B9 patients.
CD248+ Cancer-Associated Fibroblasts: A Novel Prognostic and Therapeutic Target for Renal Cell Carcinoma
Authors: Xu Chao , Zhang Keying , Yang Fa , Zhou Xiang , Liu Shaojie , Li Yu , Ma Shanjin , Zhao Xiaolong , Lu Tong , Lu Shiqi , Zhang JiaYu , Li Hongji , Han Donghui , Wen Weihong , Qin Weijun
Published: December 2021

Background

The tumor microenvironment (TME) plays an important role in the progression of renal cell carcinoma (RCC). Cancer-associated fibroblasts (CAFs) are considered to constitute a major component of the TME and participate in various tumor-promoting molecular events. We have previously confirmed that CD248 represents a promising biomarker of CAFs, which may provide insight into CAF-based tumor-promoting effects. However, CAF-mediated tumor progression and the potential mechanism of CD248 remain largely unknown in RCC patients.

Methods

Expression profiling and clinical data of RCC patients were obtained from The Cancer Genome Atlas (TCGA) database. An MCP-counter algorithm and Kaplan–Meier survival analysis were performed to explore the prognostic value of CAFs and CD248, respectively. A Pearson correlation coefficient test and Student’s t-test were employed to evaluate the relationship between immunosuppressive TME and CD248 or CAFs. Immunohistochemistry and immunofluorescence staining were performed to confirm CD248 expression within CAFs. CD248-specific siRNA was used to investigate the potential function of CD248 in CAF tumor promotion. Differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and enrichment analysis were conducted to clarify the function of CD248+ CAFs in RCC progression and the associated regulatory mechanism.

Results

CD248 overexpression and CAF infiltration could predict poor RCC prognosis, which may involve the immunosuppressive TME. CD248 may serve as a promising CAFs biomarker and be involved with the tumor-promoting effect of CAFs. Moreover, CD248+ CAF infiltration may contribute to RCC progression and an immunosuppressive TME through cell-extracellular matrix (ECM) interactions and metabolism regulation.

Conclusion

CD248+ CAFs participate in the regulation of RCC progression and immunosuppressive TME, which may represent a novel prognostic and therapeutic target for RCC.
Results From the WAGR Syndrome Patient Registry: Characterization of WAGR Spectrum and Recommendations for Care Management
Authors: Duffy Kelly A. , Trout Kelly L. , Gunckle Jennifer M. , Krantz Shari McCullen , Morris John , Kalish Jennifer M.
Published: December 2021

WAGR syndrome is a rare genetic disorder characterized by Wilms tumor, Aniridia, Genitourinary anomalies, and Range of developmental delays. In addition to the classic features, patients affected by WAGR syndrome can develop obesity and kidney failure, and a wide variety of non-classical manifestations have also been described. This suggests that a broader phenotypic spectrum beyond the classic syndrome exists and here we demonstrate that spectrum using data from the WAGR Syndrome Patient Registry. In the present study, we collected information from 91 individuals enrolled in the registry to explore self-reported health issues in this patient population. A wide variety of common clinical issues not classically associated with the disorder were found, prompting the redefinition from WAGR syndrome to WAGR spectrum disorder to incorporate the phenotypic variations that occur. A comprehensive care management approach is needed to address the wide range of clinical issues and we propose a care model for patients affected by WAGR spectrum disorder. Further research is needed to solidify the breath of the phenotype and confirm the observations in this study to advance individualized patient care in this population.
Antibacterial Activity and Optimal Treatment of Ceftazidime-Avibactam and Aztreonam-Avibactam Against Bloodstream Infections Caused by Carbapenem-Resistant Klebsiella pneumoniae
Authors: Yu Wei , Chen Yunbo , Shen Ping , Ji Jinru , Ying Chaoqun , Liu Zhiying , Xiong Luying , Qiu Yunqing , Xiao Yonghong
Published: December 2021

Objectives: This work was to investigate the activity and optimal treatments of ceftazidime-avibactam (CZA) and aztreonam-avibactam (AZA) against bloodstream infections caused by carbapenem resistant Klebsiella pneumoniae (BSIs-CRKP).

Methods: A total of 318 nonduplicate BSIs-CRKP isolates were collected from Blood Bacterial Resistant Investigation Collaborative System (BRICS) program. The minimum inhibitory concentration (MIC) of CZA and AZA were determined by agar dilution method. Carbapenemase genes and multilocus sequence typing were amplified by PCR. Monte Carlo simulation (MCS) was conducted to calculate cumulative fraction of response (CFR) of different CZA or AZA administrations.

Results: The MIC90 of CZA and AZA were 128/4 and 1/4 mg/L, respectively. There are 87.4 and 3.5% isolates carried blaKPC-2 and blaNDM-1. A total of 68 ST types were identified and 29 novel ST types. ST11 accounted for 66.6%. Further MCS showed CFR of CZA using two-step infusion therapy (rapid first-step 0.5 h infusion and slow second-step 3 h infusion, TSIT) (2.5 g 0.5 h, 3.75 g every 8 h with 3 h infusion and 3.75 g 0.5 h, 2.5 g every 8 h with 3 h infusion) was above 89%. The CFR of AZA with TSIT was above 96%.

Conclusion: TSIT with sufficient pharmacokinetic conditions could be useful for enhancing the therapeutic efficacy of CZA and AZA against BSIs-CRKP.
Crowd Funding for Orphan Drugs: The Case of Baby Pia
Authors: Pinxten Wim
Published: December 2021

Medical crowdfunding is a relatively new strategy to obtain access to orphan drugs. The case of Baby Pia, a Belgian girl with SMA type 1 for whom in 2018 more than $ 2.1 million was raised to get her treated with Zolgensma®, illustrates well the potential power of medical crowdfunding. But apart from the success in raising money, the case is also of particular importance for the ethical issues it brings to the surface as related to justice, equity, power imbalances, responsibility, accountability, indebtedness and privacy.
Machine Learning Prediction of Cardiac Resynchronisation Therapy Response From Combination of Clinical and Model-Driven Data
Authors: Khamzin Svyatoslav , Dokuchaev Arsenii , Bazhutina Anastasia , Chumarnaya Tatiana , Zubarev Stepan , Lyubimtseva Tamara , Lebedeva Viktoria , Lebedev Dmitry , Gurev Viatcheslav , Solovyova Olga
Published: December 2021

Background: Up to 30–50% of chronic heart failure patients who underwent cardiac resynchronization therapy (CRT) do not respond to the treatment. Therefore, patient stratification for CRT and optimization of CRT device settings remain a challenge.

Objective: The main goal of our study is to develop a predictive model of CRT outcome using a combination of clinical data recorded in patients before CRT and simulations of the response to biventricular (BiV) pacing in personalized computational models of the cardiac electrophysiology.

Materials and Methods: Retrospective data from 57 patients who underwent CRT device implantation was utilized. Positive response to CRT was defined by a 10% increase in the left ventricular ejection fraction in a year after implantation. For each patient, an anatomical model of the heart and torso was reconstructed from MRI and CT images and tailored to ECG recorded in the participant. The models were used to compute ventricular activation time, ECG duration and electrical dyssynchrony indices during intrinsic rhythm and BiV pacing from the sites of implanted leads. For building a predictive model of CRT response, we used clinical data recorded before CRT device implantation together with model-derived biomarkers of ventricular excitation in the left bundle branch block mode of activation and under BiV stimulation. Several Machine Learning (ML) classifiers and feature selection algorithms were tested on the hybrid dataset, and the quality of predictors was assessed using the area under receiver operating curve (ROC AUC). The classifiers on the hybrid data were compared with ML models built on clinical data only.

Results: The best ML classifier utilizing a hybrid set of clinical and model-driven data demonstrated ROC AUC of 0.82, an accuracy of 0.82, sensitivity of 0.85, and specificity of 0.78, improving quality over that of ML predictors built on clinical data from much larger datasets by more than 0.1. Distance from the LV pacing site to the post-infarction zone and ventricular activation characteristics under BiV pacing were shown as the most relevant model-driven features for CRT response classification.

Conclusion: Our results suggest that combination of clinical and model-driven data increases the accuracy of classification models for CRT outcomes.
Pathophysiology of Circulating Biomarkers and Relationship With Vascular Aging: A Review of the Literature From VascAgeNet Group on Circulating Biomarkers, European Cooperation in Science and Technology Action 18216
Authors: Gopcevic Kristina R. , Gkaliagkousi Eugenia , Nemcsik János , Acet Ömür , Bernal-Lopez M. Rosa , Bruno Rosa M. , Climie Rachel E. , Fountoulakis Nikolaos , Fraenkel Emil , Lazaridis Antonios , Navickas Petras , Rochfort Keith D. , Šatrauskienė Agnė , Zupkauskienė Jūratė , Terentes-Printzios Dimitrios
Published: December 2021

Impairment of the arteries is a product of sustained exposure to various deleterious factors and progresses with time; a phenomenon inherent to vascular aging. Oxidative stress, inflammation, the accumulation of harmful agents in high cardiovascular risk conditions, changes to the extracellular matrix, and/or alterations of the epigenetic modification of molecules, are all vital pathophysiological processes proven to contribute to vascular aging, and also lead to changes in levels of associated circulating molecules. Many of these molecules are consequently recognized as markers of vascular impairment and accelerated vascular aging in clinical and research settings, however, for these molecules to be classified as biomarkers of vascular aging, further criteria must be met. In this paper, we conducted a scoping literature review identifying thirty of the most important, and eight less important, biomarkers of vascular aging. Herein, we overview a selection of the most important molecules connected with the above-mentioned pathological conditions and study their usefulness as circulating biomarkers of vascular aging.
Are Young Swimmers Short and Middle Distances Energy Cost Sex-Specific?
Authors: Massini Danilo A. , Almeida Tiago A. F. , Vasconcelos Camila M. T. , Macedo Anderson G. , Espada Mário A. C. , Reis Joana F. , Alves Francisco J. B. , Fernandes Ricardo J. P. , Pessôa Filho Dalton M.
Published: December 2021

This study assessed the energy cost in swimming (C) during short and middle distances to analyze the sex-specific responses of C during supramaximal velocity and whether body composition account to the expected differences. Twenty-six swimmers (13 men and 13 women: 16.7 ± 1.9 vs. 15.5 ± 2.8 years old and 70.8 ± 10.6 vs. 55.9 ± 7.0 kg of weight) performed maximal front crawl swimming trials in 50, 100, and 200 m. The oxygen uptake (V˙O2) was analyzed along with the tests (and post-exercise) through a portable gas analyser connected to a respiratory snorkel. Blood samples were collected before and after exercise (at the 1st, 3rd, 5th, and 7th min) to determine blood lactate concentration [La–]. The lean mass of the trunk (LMTrunk), upper limb (LMUL), and lower limb (LMLL) was assessed using dual X-ray energy absorptiometry. Anaerobic energy demand was calculated from the phosphagen and glycolytic components, with the first corresponding to the fast component of the V˙O2 bi-exponential recovery phase and the second from the 2.72 ml × kg–1 equivalent for each 1.0 mmol × L–1 [La–] variation above the baseline value. The aerobic demand was obtained from the integral value of the V˙O2 vs. swimming time curve. The C was estimated by the rate between total energy releasing (in Joules) and swimming velocity. The sex effect on C for each swimming trial was verified by the two-way ANOVA (Bonferroni post hoc test) and the relationships between LMTrunk, LMUL, and LMLL to C were tested by Pearson coefficient. The C was higher for men than women in 50 (1.8 ± 0.3 vs. 1.3 ± 0.3 kJ × m–1), 100 (1.4 ± 0.1 vs. 1.0 ± 0.2 kJ × m–1), and 200 m (1.0 ± 0.2 vs. 0.8 ± 0.1 kJ × m–1) with p < 0.01 for all comparisons. In addition, C differed between distances for each sex (p < 0.01). The regional LMTrunk (26.5 ± 3.6 vs. 20.1 ± 2.6 kg), LMUL (6.8 ± 1.0 vs. 4.3 ± 0.8 kg), and LMLL (20.4 ± 2.6 vs. 13.6 ± 2.5 kg) for men vs. women were significantly correlated to C in 50 (R2adj = 0.73), 100 (R2adj = 0.61), and 200 m (R2adj = 0.60, p < 0.01). Therefore, the increase in C with distance is higher for men than women and is determined by the lean mass in trunk and upper and lower limbs independent of the differences in body composition between sexes.
A Comparative Metabolomic Analysis Reveals Difference Manufacture Suitability in “Yinghong 9” and “Huangyu” Teas (Camellia sinensis)
Authors: Mei Xin , Lin Chuyuan , Wan Shihua , Chen Baoyi , Wu Hualing , Zhang Lingyun
Published: December 2021

“Yinghong 9” is a widely cultivated large-leaf variety in South China, and the black tea made from it has a high aroma and strong sweet flavor. “Huangyu” is a light-sensitive tea variety with yellow leaves. It was cultivated from the bud-mutation of “Yinghong 9” and has a very low level of chlorophyll during young shoot development. Due to chlorophyll being involved in carbon fixation and assimilation, the changes in photosynthesis might potentially affect the accumulation of flavor metabolites, as well as the quality of “Huangyu” tea. Although “Huangyu” has a golden yellow color and high amino acid content, the mechanism underlying the formation of leaf color and drinking value remains unclear. The widely targeted metabolomics and GC-MS analysis were performed to reveal the differences of key metabolites in fresh and fermented leaves between “Yinghong 9” and “Huangyu.” The results showed that tea polyphenols, total chlorophyll, and carotenoids were more abundant in “Yinghong 9.” Targeted metabolomics analysis indicated that kaempferol-3-glycoside was more abundant in “Yinghong 9,” while “Huangyu” had a higher ratio of kaempferol-3-glucoside to kaempferol-3-galactoside. Compared with “Yinghong 9” fresh leaves, the contents of zeaxanthin and zeaxanthin palmitate were significantly higher in “Huangyu.” The contents of α-farnesene, β-cyclocitral, nerolidol, and trans-geranylacetone, which were from carotenoid degradation and involved in flowery-fruity-like flavor in “Huangyu” fermented leaves, were higher than those of “Yinghong 9.” Our results indicated that “Huangyu” was suitable for manufacturing non-fermented tea because of its yellow leaf and flowery-fruity-like compounds from carotenoid degradation.
Comparative Transcriptome Profiling Reveals Defense-Related Genes Against Ralstonia solanacearum Infection in Tobacco
Authors: Pan Xiaoying , Chen Junbiao , Yang Aiguo , Yuan Qinghua , Zhao Weicai , Xu Tingyu , Chen Bowen , Ren Min , Geng Ruimei , Zong Zhaohui , Ma Zhuwen , Huang Zhenrui , Zhang Zhenchen
Published: December 2021

Bacterial wilt (BW) caused by Ralstonia solanacearum (R. solanacearum), is a vascular disease affecting diverse solanaceous crops and causing tremendous damage to crop production. However, our knowledge of the mechanism underlying its resistance or susceptibility is very limited. In this study, we characterized the physiological differences and compared the defense-related transcriptomes of two tobacco varieties, 4411-3 (highly resistant, HR) and K326 (moderately resistant, MR), after R. solanacearum infection at 0, 10, and 17 days after inoculation (dpi). A total of 3967 differentially expressed genes (DEGs) were identified between the HR and MR genotypes under mock condition at three time points, including1395 up-regulated genes in the HR genotype and 2640 up-regulated genes in the MR genotype. Also, 6,233 and 21,541 DEGs were induced in the HR and MR genotypes after R. solanacearum infection, respectively. Furthermore, GO and KEGG analyses revealed that DEGs in the HR genotype were related to the cell wall, starch and sucrose metabolism, glutathione metabolism, ABC transporters, endocytosis, glycerolipid metabolism, and glycerophospholipid metabolism. The defense-related genes generally showed genotype-specific regulation and expression differences after R. solanacearum infection. In addition, genes related to auxin and ABA were dramatically up-regulated in the HR genotype. The contents of auxin and ABA in the MR genotype were significantly higher than those in the HR genotype after R. solanacearum infection, providing insight into the defense mechanisms of tobacco. Altogether, these results clarify the physiological and transcriptional regulation of R. solanacearum resistance infection in tobacco, and improve our understanding of the molecular mechanism underlying the plant-pathogen interaction.
Exogenous Putrescine Alleviates Drought Stress by Altering Reactive Oxygen Species Scavenging and Biosynthesis of Polyamines in the Seedlings of Cabernet Sauvignon
Authors: Zhao Jiaqi , Wang Xuefei , Pan Xingbo , Jiang Qianqian , Xi Zhumei
Published: December 2021

Climate change imposes intensive dry conditions in most grape-growing regions. Drought stress is one of the most devastating abiotic factors threatening grape growth, yield, and fruit quality. In this study, the alleviation effect of exogenous putrescine (Put) was evaluated using the seedlings of Cabernet Sauvignon (Vitis vinifera L.) subjected to drought stress. The phenotype, photosynthesis index, membrane injury index (MII), and antioxidant system, as well as the dynamic changes of endogenous polyamines (PAs) of grape seedlings, were monitored. Results showed that drought stress increased the MII, lipid peroxidation, and the contents of reactive oxygen species (ROS) (H2O2 and O2–), while it decreased the antioxidant enzyme activity and the net photosynthesis rate (Pn). However, the application of Put alleviated the effects of drought stress by altering ROS scavenging, enhancing the antioxidant system, and increasing the net Pn. Put distinctly increased the activity of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), as well as the contents of ascorbic acid (AsA) and glutathione (GSH). Meanwhile, exogenous Put also promoted the metabolism of endogenous PAs by upregulating their synthetic genes. Our results confirmed that the exogenous application of Put can enhance the antioxidant capacity as well as alter the PA pool, which provides better drought tolerance for Cabernet Sauvignon seedlings.
Automatic and Accurate Calculation of Rice Seed Setting Rate Based on Image Segmentation and Deep Learning
Authors: Guo Yixin , Li Shuai , Zhang Zhanguo , Li Yang , Hu Zhenbang , Xin Dawei , Chen Qingshan , Wang Jingguo , Zhu Rongsheng
Published: December 2021

The rice seed setting rate (RSSR) is an important component in calculating rice yields and a key phenotype for its genetic analysis. Automatic calculations of RSSR through computer vision technology have great significance for rice yield predictions. The basic premise for calculating RSSR is having an accurate and high throughput identification of rice grains. In this study, we propose a method based on image segmentation and deep learning to automatically identify rice grains and calculate RSSR. By collecting information on the rice panicle, our proposed image automatic segmentation method can detect the full grain and empty grain, after which the RSSR can be calculated by our proposed rice seed setting rate optimization algorithm (RSSROA). Finally, the proposed method was used to predict the RSSR during which process, the average identification accuracy reached 99.43%. This method has therefore been proven as an effective, non-invasive method for high throughput identification and calculation of RSSR. It is also applicable to soybean yields, as well as wheat and other crops with similar characteristics.
On the Impact of Information Technologies Secondary-School Capacity in Business Development: Evidence From Smart Cities Around the World
Authors: Barba-Sánchez Virginia , Orozco-Barbosa Luis , Arias-Antúnez Enrique
Published: December 2021

Smart City initiatives across the globe have spurred increasing demand for high-skilled workers. The digital transformation, one of the main building blocks of the Smart City movement, is calling for a workforce prepared to develop novel business processes. Problem-solving, critical and analytical thinking are now the essential skills being looked at by employees. The development of the so-called STEM curriculum, Science, Technology, Engineering, and Mathematics is being given a lot of attention by educational boards in response to preparing young generations for the Smart City work market. Based on the IMD Smart City Index, PISA, and World Bank reports, we develop a model for assessing the impact of the IT secondary school capacities on Smart-City business developments. The model reveals the relationship between the technological capacity of the secondary-school, and the business activity of a Smart City. Moreover, the study shows the existence of a positive relationship between the IT capacity of secondary schools and the resulting entrepreneurial activity of the city. Our results are of interest to decision-makers and stakeholders responsible for designing educational policies and agents involved in the digital transformation and development of Smart Cities initiatives.