bluuebunny/crossref_metadata_2025 huggingface dataset:
The ORF8 Protein of SARS-CoV-2 Modulates the Spike Protein and Its Implications in Viral Transmission
Authors: Chou Jen-Mei , Tsai Jo-Ling , Hung Jo-Ning , Chen I-Hua , Chen Szu-Ting , Tsai Ming-Han
Published: May 2022

COVID-19 is currently global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Accompanying the rapid spread of the error-prone RNA-based genome, several dominant SARS-CoV-2 variants have been genetically identified. The mutations in the spike protein, which are essential for receptor binding and fusion, have been intensively investigated for their contributions to viral transmission. Nevertheless, the importance of other viral proteins and their mutations in SARS-CoV-2 lifecycle and transmission remains fairly understood. Here, we report the strong potency of an accessory protein ORF8 in modulating the level and processing of the spike protein. The expression of ORF8 protein does not affect propagation but expression of spike protein, which may lead to pseudovirions with less spike protein on the surface, therefore less infection potential. At the protein level, ORF8 expression led to downregulation and insufficient S1/S2 cleavage of the spike protein in a dose-dependent manner. ORF8 exhibits a strong interaction with the spike protein mainly at S1 domains and mediates its degradation through multiple pathways. The dominant clinical isolated ORF8 variants with the reduced protein stability exhibited the increased capacity of viral transmission without compromising their inhibitory effects on HLA-A2. Although the increase in spike protein level and Spike pseudovirus production observed by using highly transmissible clinical spike variants, there was no significant compromise in ORF8-mediated downregulation. Because ORF8 is important for immune surveillance and might be required for viral fitness in vivo, the alteration of the spike protein might be an optional strategy used by SARS-CoV-2 to promote viral transmission by escaping the inhibitory effects of ORF8. Therefore, our report emphasized the importance of ORF8 in SARS-CoV-2 spike protein production, maturation, and possible evolution.
Validation of an Accurate Automated Multiplex Immunofluorescence Method for Immuno-Profiling Melanoma
Authors: Yaseen Zarwa , Gide Tuba N. , Conway Jordan W. , Potter Alison J. , Quek Camelia , Hong Angela M. , Long Georgina V. , Scolyer Richard A. , Wilmott James S.
Published: May 2022

Multiplex immunofluorescence staining enables the simultaneous detection of multiple immune markers in a single tissue section, and is a useful tool for the identification of specific cell populations within the tumour microenvironment. However, this technology has rarely been validated against standard clinical immunohistology, which is a barrier for its integration into clinical practice. This study sought to validate and investigate the accuracy, precision and reproducibility of a multiplex immunofluorescence compared with immunohistochemistry (IHC), including tissue staining, imaging and analysis, in characterising the expression of immune and melanoma markers in both the tumour and its microenvironment. Traditional chromogenic IHC, single-plex immunofluorescence and multiplex immunofluorescence were each performed on serial tissue sections of a formalin-fixed paraffin-embedded (FFPE) tissue microarray containing metastatic melanoma specimens from 67 patients. The panel included the immune cell markers CD8, CD68, CD16, the immune checkpoint PD-L1, and melanoma tumour marker SOX10. Slides were stained with the Opal™ 7 colour Kit (Akoya Biosciences) on the intelliPATH autostainer (Biocare Medical) and imaged using the Vectra 3.0.5 microscope. Marker expression was quantified using Halo v.3.2.181 (Indica Labs). Comparison of the IHC and single-plex immunofluorescence revealed highly significant positive correlations between the cell densities of CD8, CD68, CD16, PD-L1 and SOX10 marker positive cells (Spearman’s rho = 0.927 to 0.750, p < 0.0001). Highly significant correlations were also observed for all markers between single-plex immunofluorescence and multiplex immunofluorescence staining (Spearman’s rho >0.9, p < 0.0001). Finally, correlation analysis of the three multiplex replicates revealed a high degree of reproducibility between slides (Spearman’s rho >0.940, p < 0.0001). Together, these data highlight the reliability and validity of multiplex immunofluorescence in accurately profiling the tumour and its associated microenvironment using FFPE metastatic melanoma specimens. This validated multiplex panel can be utilised for research evaluating melanoma and its microenvironment, such as studies performed to predict patient response or resistance to immunotherapies.
A Drug Combination Rescues Frataxin-Dependent Neural and Cardiac Pathophysiology in FA Models
Authors: Abeti Rosella , Jasoliya Mittal , Al-Mahdawi Sahar , Pook Mark , Gonzalez-Robles Cristina , Hui Chun Kiu , Cortopassi Gino , Giunti Paola
Published: May 2022

Friedreich’s ataxia (FA) is an inherited multisystemic neuro- and cardio-degenerative disorder. Seventy-four clinical trials are listed for FA (including past and present), but none are considered FDA/EMA-approved therapy. To date, FA therapeutic strategies have focused along two main lines using a single-drug approach: a) increasing frataxin and b) enhancing downstream pathways, including antioxidant levels and mitochondrial function. Our novel strategy employed a combinatorial approach to screen approved compounds to determine if a combination of molecules provided an additive or synergistic benefit to FA cells and/or animal models. Eight single drug molecules were administered to FA fibroblast patient cells: nicotinamide riboside, hemin, betamethasone, resveratrol, epicatechin, histone deacetylase inhibitor 109, methylene blue, and dimethyl fumarate. We measured their individual ability to induce FXN transcription and mitochondrial biogenesis in patient cells. Single-drug testing highlighted that dimethyl fumarate and resveratrol increased these two parameters. In addition, the simultaneous administration of these two drugs was the most effective in terms of FXN mRNA and mitobiogenesis increase. Interestingly, this combination also improved mitochondrial functions and reduced reactive oxygen species in neurons and cardiomyocytes. Behavioral tests in an FA mouse model treated with dimethyl fumarate and resveratrol demonstrated improved rotarod performance. Our data suggest that dimethyl fumarate is effective as a single agent, and the addition of resveratrol provides further benefit in some assays without showing toxicity. Therefore, they could be a valuable combination to counteract FA pathophysiology. Further studies will help fully understand the potential of a combined therapeutic strategy in FA pathophysiology.
Learning the Quantum Centroid Force Correction in Molecular Systems: A Localized Approach
Authors: Wu Chuixiong , Li Ruye , Yu Kuang
Published: May 2022

Molecular mechanics (MM) is a powerful tool to study the properties of molecular systems in the fields of biology and materials science. With the development of ab initio force field and the application of ab initio potential energy surface, the nuclear quantum effect (NQE) is becoming increasingly important for the robustness of the simulation. However, the state-of-the-art path-integral molecular dynamics simulation, which incorporates NQE in MM, is still too expensive to conduct for most biological and material systems. In this work, we analyze the locality of NQE, using both analytical and numerical approaches, and conclude that NQE is an extremely localized phenomenon in nonreactive molecular systems. Therefore, we can use localized machine learning (ML) models to predict quantum force corrections both accurately and efficiently. Using liquid water as example, we show that the ML facilitated centroid MD can reproduce the NQEs in both the thermodynamical and the dynamical properties, with a minimal increase in computational time compared to classical molecular dynamics. This simple approach thus largely decreases the computational cost of quantum simulations, making it really accessible to the studies of large-scale molecular systems.
Neuroinflammation: A Possible Link Between Chronic Vascular Disorders and Neurodegenerative Diseases
Authors: Moyse Emmanuel , Krantic Slavica , Djellouli Nesrine , Roger Sébastien , Angoulvant Denis , Debacq Camille , Leroy Victoire , Fougere Bertrand , Aidoud Amal
Published: May 2022

Various age-related diseases involve systemic inflammation, i.e. a stereotyped series of acute immune system responses, and aging itself is commonly associated with low-grade inflammation or inflamm’aging. Neuroinflammation is defined as inflammation-like processes inside the central nervous system, which this review discusses as a possible link between cardiovascular disease-related chronic inflammation and neurodegenerative diseases. To this aim, neuroinflammation mechanisms are first summarized, encompassing the cellular effectors and the molecular mediators. A comparative survey of the best-known physiological contexts of neuroinflammation (neurodegenerative diseases and transient ischemia) reveals some common features such as microglia activation. The recently published transcriptomic characterizations of microglia have pointed a marker core signature among neurodegenerative diseases, but also unraveled the discrepancies with neuroinflammations related with acute diseases of vascular origin. We next review the links between systemic inflammation and neuroinflammation, beginning with molecular features of respective pro-inflammatory cells, i.e. macrophages and microglia. Finally, we point out a gap of knowledge concerning the atherosclerosis-related neuroinflammation, which is for the most surprising given that atherosclerosis is established as a major risk factor for neurodegenerative diseases.
Autophagy Impairment in App Knock-in Alzheimer’s Model Mice
Authors: Jiang Richeng , Shimozawa Makoto , Mayer Johanna , Tambaro Simone , Kumar Rakesh , Abelein Axel , Winblad Bengt , Bogdanovic Nenad , Nilsson Per
Published: May 2022

Alzheimer’s disease (AD) is characterized by impaired protein homeostasis leading to amyloid-β peptide (Aβ) amyloidosis. Amyloid precursor protein (APP) knock-in mice exhibit robust Aβ pathology, providing possibilities to determine its effect on protein homeostasis including autophagy. Here we compared human AD postmortem brain tissue with brains from two different types of App knock-in mice, AppNL–F and AppNL–G–F mice, exhibiting AD-like pathology. In AD postmortem brains, p62 levels are increased and p62-positive staining is detected in neurons, including potential axonal beadings, as well as in the vasculature and in corpora amylacea. Interestingly, p62 is also increased in the neurons in 12-month-old AppNL–G–F mice. In brain homogenates from 12-month-old AppNL–G–F mice, both p62 and light chain 3 (LC3)-II levels are increased as compared to wildtype (WT) mice, indicating inhibited autophagy. Double immunostaining for LC3 and Aβ revealed LC3-positive puncta in hippocampus of 24-month-old AppNL–F mice around the Aβ plaques which was subsequently identified by electron microscopy imaging as an accumulation of autophagic vacuoles in dystrophic neurites around the Aβ plaques. Taken together, autophagy is impaired in App knock-in mice upon increased Aβ pathology, indicating that App knock-in mouse models provide a platform for understanding the correlation between Aβ and autophagy.
Mouse Model of Weak Depression Exhibiting Suppressed cAMP Signaling in the Amygdala, Lower Lipid Catabolism in Liver, and Correlated Gut Microbiota
Authors: Shimada Kousuke , Nohara Masakatsu , Yasuoka Akihito , Kamei Asuka , Shinozaki Fumika , Kondo Kaori , Inoue Ryo , Kondo Takashi , Abe Keiko
Published: May 2022

To establish a mouse model of weak depression, we raised 6-week-old C57BL/6N mice in single (SH) or group housing (GH) conditions for 2 weeks. The SH group showed less social interaction with stranger mice, learning disability in behavioral tests, and lower plasma corticosterone levels. The cecal microbiota of the SH group showed significant segregation from the GH group in the principal coordinate analysis (PCoA). Transcriptome analysis of the amygdala and liver detected multiple differentially expressed genes (DEGs). In the amygdala of SH mice, suppression of the cyclic adenine monophosphate (cAMP) signal was predicted and confirmed by the reduced immunoreactivity of phosphorylated cAMP-responsive element-binding protein. In the liver of SH mice, downregulation of beta-oxidation was predicted. Interestingly, the expression levels of over 100 DEGs showed a significant correlation with the occupancy of two bacterial genera, Lactobacillus (Lactobacillaceae) and Anaerostipes (Lachnospiraceae). These bacteria-correlated DEGs included JunB, the downstream component of cAMP signaling in the amygdala, and carnitine palmitoyltransferase 1A (Cpt1a), a key enzyme of beta-oxidation in the liver. This trans-omical analysis also suggested that nicotinamide adenine dinucleotide (NAD) synthesis in the liver may be linked to the occupancy of Lactobacillus through the regulation of nicotinamide phosphoribosyltransferase (NAMPT) and kynureninase (KYNU) genes. Our results suggested that SH condition along with the presence of correlated bacteria species causes weak depression phenotype in young mice and provides a suitable model to study food ingredient that is able to cure weak depression.
Predicting the Effects of Repetitive Transcranial Magnetic Stimulation on Cognitive Functions in Patients With Alzheimer's Disease by Automated EEG Analysis
Authors: Kayasandik Cihan Bilge , Velioglu Halil Aziz , Hanoglu Lutfu
Published: May 2022

Alzheimer's disease (AD) is a progressive, neurodegenerative brain disorder that generally affects the elderly. Today, after the limited benefit of the pharmacological treatment strategies, numerous noninvasive brain stimulation techniques have been developed. Transcranial magnetic stimulation (TMS), based on electromagnetic stimulation, is one of the most widely used methods. The main problem in the use of TMS is the existence of large individual variability in the results. This causes a waste of money, time, and more importantly, a burden for delicate patients. Hence, it is a necessity to form an efficient and personalized TMS application protocol. In this paper, we performed a machine-learning analysis to see whether it is possible to predict the responses of patients with AD to TMS by analyzing their electroencephalography (EEG) signals. For that purpose, we analyzed both the EEG signals collected before and after the TMS application (EEG1 and EEG2, respectively). Through correlating EEG1 and repetitive transcranial magnetic stimulation (rTMS) outcomes, we tried to see whether it is possible to predict patients' responses before the treatment application. On the other hand, by EEG2 analysis, we investigated TMS impacts on EEG, more importantly if this impact is correlated with patients' response to the treatment. We used the support vector machine (SVM) classifier due to its multiple advantages for the current task with feature selection processes by stepwise linear discriminant analysis (SWLDA) and SVM. However, to justify our numerical analysis framework, we examined and compared the performances of different feature selection and classification techniques. Since we have a limited sample number, we used the leave-one-out method for the validation with the Monte Carlo technique to eliminate bias by a small sample size. In the conclusion, we observed that the correlation between rTMS outcomes and EEG2 is stronger than EEG1, since we observed, respectively, 93 and 79% of accuracies during our data analysis. Besides the informative features of EEG2 are focused on theta band, it indicates that TMS is characterizing the theta band signals in patients with AD in direct relation to patients' response to rTMS. This shows that it is more possible to determine patients' benefit from the TMS at the early stages of the treatment, which would increase the efficiency of rTMS applications in patients with Alzheimer's disease.
The Connection Between Selected Caspases Levels in Bronchoalveolar Lavage Fluid and Severity After Brain Injury
Authors: Siwicka-Gieroba Dorota , Terpilowska Sylwia , Robba Chiara , Barud Małgorzata , Kubik-Komar Agnieszka , Dabrowski Wojciech
Published: May 2022

Objective

The interaction between the brain and lungs has been the subject of many clinical reports, while the exact impact of brain injury on the physiology of the respiratory system is still subject to numerous experimental studies. The purpose of this study was to investigate the activation of selected caspases levels in bronchoalveolar lavage fluid (mini BALF) of patients after isolated brain injury and their correlation with the severity of the injury.

Methods

The analysis was performed on patients who were admitted to the intensive care unit (ICU) for severe isolated brain injury from March 2018 to April 2020. All patients were intubated and mechanically ventilated. Mini BALF was collected within the first 6–8 h after trauma and on days 3 and 7 after admission. The concentrations of selected caspases were determined and correlated with the severity of brain injury evaluated by the Rotterdam CT Score, Glasgow Coma Score, and 28-day mortality.

Results

Our results showed significantly elevated levels of selected caspases on days 3 and 7 after brain injury, and revealed apoptosis activation during the first 7 days after brain trauma. We found a significant different correlation between the elevation of selected caspases 3, 6, 8, and 9, and the Glasgow Coma Score, Rotterdam CT scale, and 28-day mortality.

Conclusions

The increased levels of selected caspases in the mini BALF in our patients indicate an intensified activation of apoptosis in the lungs, which is related to brain injury itself via various apoptotic pathways and correlates with the severity of brain injury.
Sex Differences in Collateral Circulation and Outcome After Mechanical Thrombectomy in Acute Ischemic Stroke
Authors: Lagebrant Christian , Ramgren Birgitta , Hassani Espili Ashkan , Marañon Antonio , Kremer Christine
Published: May 2022

Background

Collateral circulation is known to lead to smaller infarct volume and better functional outcome after mechanical thrombectomy (MT), but studies examining sex differences in collateral circulation are scarce. The aim of this study was to investigate if collateral circulation has a different impact on outcome in women and men.

Methods

A single-center retrospective study of 487 patients (230 men and 257 women) treated with MT for acute ischemic stroke in the anterior cerebral circulation. Collateral circulation was assessed on computed tomography angiography images. The outcome was evaluated at 90 days according to the modified Rankin Scale (mRS).

Results

Women were older, median age 76 years (IQR 68-83) vs. 71 years (IQR 63–78). Stroke severity and time to recanalization were comparable. More women had moderate or good collaterals in 58.4 vs. 47.0% for men (p = 0.01). Among patients with moderate and good collaterals significantly more men (61%) were functionally independent (mRS 0–2) than women (41.5%) (p = < 0.01). This difference remained significant after correcting for age by linear weighting, 60.4 vs. 46.8% (p = 0.03).

Conclusion

Women had better collateral flow but showed worse functional outcomes, while good collateral flow led to better outcomes in men, even after correcting for age. Further clinical studies on peri- and post-interventional care, factors affecting recovery after hospital discharge as well as basic research on the neurovascular unit are needed to find modifiable targets to improve clinical outcomes for women.
The “Black Straight-Line Sign” in the Putamen in Diffusion-Weighted Imaging: A Potential Diagnostic MRI Marker for Multiple System Atrophy
Authors: Zheng Yiming , Wang Xiwen , Zhao Huajian , Jiang Yanyan , Zhu Ying , Chen Jing , Sun Wei , Wang Zhaoxia , Sun Yunchuang
Published: May 2022

Background and Purpose

The diagnosis of multiple system atrophy (MSA) remains challenging in clinical practice. This study investigated the value of hypointense signals in the putamen (“black straight-line sign”) in diffusion-weighted imaging (DWI) of brain MRI for distinguishing (MSA) from Parkinson's disease (PD).

Methods

We retrospectively enrolled 30 MSA patients, 30 PD patients, and 30 healthy controls who had undergone brain MRI between 2016 and 2020. Two readers independently assessed the signal intensity of the bilateral putamen on DWI. The putaminal hypointensity was scored using 4-point visual scales. Putaminal hypointensity and the presence of a “black straight-line sign” were statistically compared between MSA and PD or healthy controls.

Results

The mean scores of putaminal hypointensity in DWI in the MSA group were significantly higher than in both the PD (U = 315.5, P = 0.034) and healthy control groups (U = 304.0, P = 0.022). Uni- or bilateral putaminal hypointensity in DWI with a score ≥2 was identified in 53.3% (16/30), 16.7% (5/30), and 13.3% (4/30) of MSA, PD, and healthy controls, respectively, with significant differences between MSA and PD (X2 = 8.864, P = 0.003) or healthy controls (X2 = 10.800, P = 0.001). Notably, the “black straight-line sign” of the putamen was observed in 16/30 (sensitivity 53.3%) patients with MSA, while it was absent in PD and healthy controls (specificity 100%). There were no significant differences for the presence of “black straight-line sign” in the MSA-P and MSA-C groups (X2 = 0.433, P = 0.510).

Conclusion

The “black straight-line sign” of the putamen in DWI of head MRIs has the potential to serve as a diagnostic marker for distinguishing MSA from PD.
Measurement Accuracy of Freezing of Gait Scoring Based on Videos
Authors: Kondo Yuki , Mizuno Katsuhiro , Bando Kyota , Suzuki Ippei , Nakamura Takuya , Hashide Shusei , Kadone Hideki , Suzuki Kenji
Published: May 2022

Freezing of gait (FOG) is a common symptom in the late stages of Parkinson’s disease and related disorders. Videos are the gold standard method to conduct FOG scoring; however, the measurement accuracy of FOG scoring based on videos has not been formally assessed, despite its use in previous studies. This study aimed to calculate the measurement accuracy of video-based FOG scoring. Three evaluators scored the FOG based on 157 video data points collected from 21 patients using an annotation tool. One evaluator measured the intra-rater reliability of the retest. The total duration of observed FOG, percentage of the time spent with FOG during the walking task (%FOG), and FOG phenotypes (shuffling, trembling, and complete akinesia) were evaluated. Intraclass correlation coefficients were used to determine the intra- and inter-rater reliabilities. The duration of FOG and %FOG showed good measurement accuracy for both intra-rater and inter-rater reliabilities. However, the FOG phenotypes showed poor measurement accuracy in inter-rater reliability. These results indicate that the temporal characteristics of FOG can be scored with a high degree of measurement accuracy, even with different evaluators; conversely, the FOG phenotypes need to be scored by several evaluators.
Soft Tribology and Its Relationship With the Sensory Perception in Dairy Products: A Review
Authors: Corvera-Paredes Beatriz , Sánchez-Reséndiz Aidee I. , Medina Dora I. , Espiricueta-Candelaria Rosa S. , Serna-Saldívar Sergio , Chuck-Hernández Cristina
Published: May 2022

Nowadays, dairy products, especially fermented products such as yogurt, fromage frais, sour cream and custard, are among the most studied foods through tribological analysis due to their semi-solid appearance and close relationship with attributes like smoothness, creaminess and astringency. In tribology, dairy products are used to provide information about the friction coefficient (CoF) generated between tongue, palate, and teeth through the construction of a Stribeck curve. This provides important information about the relationship between friction, food composition, and sensory attributes and can be influenced by many factors, such as the type of surface, tribometer, and whether saliva interaction is contemplated. This work will review the most recent and relevant information on tribological studies, challenges, opportunity areas, saliva interactions with dairy proteins, and their relation to dairy product sensory.
The Ile191Val Variant of the TAS1R2 Subunit of Sweet Taste Receptors Is Associated With Reduced HbA1c in a Human Cohort With Variable Levels of Glucose Homeostasis
Authors: Serrano Joan , Yi Fanchao , Smith Joshua , Pratley Richard E. , Kyriazis George A.
Published: May 2022

The Ile191Val variant of the TAS1R2 gene of sweet taste receptors causes a partial loss-of-function and is associated with reduced glucose excursions in a healthy lean cohort. However, it is unclear whether this polymorphism contributes to the regulation of glucose homeostasis in metabolically unhealthy individuals. Thus, we used participants with variable glycemic profiles and obesity to assess the effects of the TAS1R2-Ile191Val variant. We found that the Val minor allele carriers had lower HbA1c at all levels of fasting glucose and glucose tolerance. These effects were not due to differences in beta-cell function or insulin sensitivity assessed with a frequently sampled intravenous glucose tolerance test. This study extends our previous findings and provides further evidence that sweet taste receptor function may contribute to glucose regulation in humans.
Immune-Enhancing Effects of Co-treatment With Kalopanax pictus Nakai Bark and Nelumbo nucifera Gaertner Leaf Extract in a Cyclophosphamide-Induced Immunosuppressed Rat Model
Authors: Park Young Mi , Lee Hak Yong , Shin Dong Yeop , Kim Dae Sung , Yoo Jin Joo , Yang Hye Jeong , Kim Min Jung , Bae Jun Sang
Published: May 2022

Objective

Immune system disorders can result in various pathological conditions, such as infections and cancer. Identifying therapies that enhance the immune response might be crucial for immunocompromised individuals. Therefore, we assessed the immune-enhancing effect of co-treatment with Kalopanax pictus Nakai Bark and Nelumbo nucifera Gaertner leaf extract (KPNN) in a cyclophosphamide (Cy)-induced immunosuppressed rat model.

Materials and Methods

For in vitro studies, macrophages and splenocytes were treated with various KPNN doses in the presence or absence of Cy. Macrophage viability, nitric oxide production, splenocyte viability, cytokine production and natural killer (NK) cell activity were analyzed. For in vivo studies, analysis of weekly body weight, dietary intake, tissue weight, immune-related blood cell count, cytokine levels, and spleen biopsy was performed in a Cy-induced immunocompromised animal model.

Results

KPNN significantly increased phospho-NF-κB and phospho-ERK protein levels and cell viability in macrophages. KPNN significantly increased the NK cell activity in splenocytes compared to that in the control. Cy treatment decreased tumor necrosis factor (TNF)-α, interleukin (IL)-6, and interferon-γ production. In the Cy-induced immunosuppression rat model, KPNN-treated rats had significantly higher body weights and tissue weights than the Cy-treated rats. Additionally, KPNN treatment restored the immune-related factors, such as total leukocyte, lymphocyte, and intermediate cell contents, to their normal levels in the blood. The blood cytokines (TNF-α and IL-6) were increased, and spleen tissue damage was significantly alleviated.

Conclusions

Collectively, KPNN exerts an immune-enhancing effect suggesting their potential as an immunostimulatory agent or functional food.
Real-World Efficacy of Bevacizumab in Patients With Recurrent Epithelial Ovarian Cancer
Authors: Hung Jo-Ni , Hsu Shih-Tien , Sun Lou , Hwang Sheau-Feng , Liu Chih-Ku , Shih Yu-Hsiang , Chen Ming-Jer , Wang Jun-Sing , Lu Chien-Hsing
Published: May 2022

Background

Bevacizumab in combination with chemotherapy prolonged the progression-free survival (PFS) of patients with recurrent epithelial ovarian cancer (EOC) in large-scale randomized controlled trials. However, real-world data for the use of bevacizumab in Asian patients with EOC is lacking. This study investigated the efficacy of adding bevacizumab to chemotherapy and compared it with that of chemotherapy alone in patients with recurrent EOC using real-world data from an Asian population.

Method

We conducted a retrospective cohort study using data from a tertiary medical center in central Taiwan. Patients who had EOC with first relapse between 2011 and 2019 were enrolled. Patients’ medical histories, medication treatment, and relevant information were collected. The outcomes were PFS and overall survival (OS). The Kaplan-Meier plot was used to generate a survival curve for OS and PFS. Cox proportional hazard analysis was used to determine the associations of Bevacizumab treatment with OS and PFS with adjustment of relevant variables. Subgroup analyses were conducted to determine if there was a significant variation in the aforementioned associations.

Results

After a median follow-up of 23 months, 67% of patients in the Bevacizumab group and 81% of patients in the non-Bevacizumab group had disease progression or death. There was no significant between-group difference in OS (p = 0.475). The median duration of PFS was 18.9 and 9.6 months, respectively, favoring those who were treated with Bevacizumab. After multivariate adjustment, treatment with Bevacizumab was associated with a lower risk of disease progression (hazard ratio 0.33, 95% CI 0.13-0.85, p = 0.021). The improvement in PFS was consistent in the subgroups of different histological types, different disease stages at diagnosis, different treatment-free intervals, those undergoing or not undergoing secondary cytoreductive surgery, diverse chemotherapy regimens.

Conclusion

Our findings provided crucial insights into the efficacy of bevacizumab for the treatment of recurrent EOC in the real-world setting.
Concurrent Germline and Somatic Mutations in FLCN and Preliminary Exploration of Its Function: A Case Report
Authors: Wang Tao , Yang Yang , Feng Huayi , Cui Bo , Lv Zheng , Zhao Wenlei , Zhang Xiangyi , Ma Xin
Published: May 2022

Birt–Hogg–Dube syndrome is an autosomal dominant condition that arises from germline folliculin (FLCN) mutations. It is characterized by skin fibrofolliculomas, lung cysts, pneumothorax, and renal cancer. Here, we present the case of a 36-year-old woman with asymptomatic, multiple renal tumors and a history of spontaneous pneumothorax. Genetic analysis revealed a hotspot FLCN germline mutation, c.1285dupC (p.H429fs), and a novel somatic mutation, c.470delT (p.F157fs). This information and the results of immunohistochemical analysis of the renal tumors indicated features compatible with a tumor suppressor role of FLCN. Two transcription factors, oncogenic TFEB and TFE3, were shown to be regulated by FLCN inactivation, which results in their nuclear localization. We showed that a deficiency in the tumor suppressor FLCN leads to deregulation of the mammalian target of rapamycin signaling (mTOR) pathway. A potential link between FLCN mutation and ciliary length was also examined. Thus, the mutation identified in our patient provides novel insights into the relationship among FLCN mutations, TFEB/TFE3, mTOR, and cilia. However, an in-depth understanding of the role of folliculin in the molecular pathogenesis of renal cancer requires further study.
Case Report: Lung Ultrasound in Critically Ill Neonates With Lung Diseases: Experience From Several Typical Cases
Authors: Deng Biying , Xu Fengdan , Li Jinfeng , Mai Minling , Chen Qin , Liao Jinfeng , He Xiaoguang , Li Ning
Published: May 2022

Lung ultrasound (LUS) can be used to diagnose various neonatal lung diseases. It more sensitively diagnoses pulmonary edema, pneumothorax, pulmonary consolidation, and atelectasis than traditional X-ray and quickly determines the cause of dyspnea. As a component of severe ultrasound, LUS enables rapid bedside visualization of lung diseases and plays a major role in guiding the differential diagnosis of disease, ventilator treatment, and lung recruitment. This study introduced the application of LUS in the diagnosis and treatment of critically ill neonates with lung diseases.
Application of the Artificial Intelligence Algorithm Model for Screening of Inborn Errors of Metabolism
Authors: Zhou Muping , Deng Liyuan , Huang Yan , Xiao Ying , Wen Jun , Liu Na , Zeng Yingchao , Zhang Hua
Published: May 2022

Inborn errors of metabolism (IEMs) are strongly related to abnormal growth and development in newborns and can even result in death. In total, 94,648 newborns were enrolled for expanded newborn screening using tandem mass spectrometry (MS/MS) from 2016 to 2020 at the Neonatal Disease Screening Center of the Maternal and Child Health Hospital in Shaoyang City, China. A total of 23 confirmed cases were detected in our study with an incidence rate of 1:4,115. A total of 10 types of IEM were identified, and the most common IEMs were phenylalanine hydroxylase deficiency (PAHD; 1:15,775) and primary carnitine deficiency (PCD; 1:18,930). Mutations in phenylalanine hydroxylase (PAH) and SLC22A5 were the leading causes of IEMs. To evaluate the application effect of artificial intelligence (AI) in newborn screening, we used AI to retrospectively analyze the screening results and found that the false-positive rate could be decreased by more than 24.9% after using AI. Meanwhile, a missed case with neonatal intrahepatic cholestasis citrin deficiency (NICCD) was found, the infant had a normal citrulline level (31 μmol/L; cutoff value of 6–32 μmol/L), indicating that citrulline may not be the best biomarker of intrahepatic cholestasis citrin deficiency. Our results indicated that the use of AI in newborn screening could improve efficiency significantly. Hence, we propose a novel strategy that combines expanded neonatal IEM screening with AI to reduce the occurrence of false positives and false negatives.
Management of Gartland Type 1 Supracondylar Fractures: A Systematic Review
Authors: Coupal Stephanie , Lukas Kenneth , Plint Amy , Bhatt Maala , Cheung Kevin , Smit Kevin , Carsen Sasha
Published: May 2022

Purpose

Gartland Type 1 supracondylar humerus fractures are stable, non-displaced injuries treated with non-operative management. This systematic review was performed to gather evidence on the optimal form of immobilization to treat these fractures.

Methods

The review process was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search was performed in November 2020. Articles were eligible if they included children less than 18 years old, with non-displaced supracondylar fractures, treated non-operatively. Randomized trials, quasi-experimental trials, and prospective cohort studies were included. Outcomes of interest included fracture displacement, pain control, time to return to normal activities, return of range of motion (ROM), child/parent satisfaction, adverse events, and cost. Risk of bias was assessed using the Newcastle-Ottawa scale, Rob-2, and the ROBINS tools.

Results

After duplicate records were removed, 525 records were evaluated with 9 studies meeting the inclusion criteria and 5 reporting clinical outcomes. The studies were heterogenous, in intervention and outcomes, and all at moderate risk of bias. Within the available evidence there were no cases of fracture displacement. Two small studies suggested that cuff and collar treatment provided inadequate pain control and delay in return to normal activities, compared to posterior splints. Two randomized control trials (RCTs) suggested that soft fiberglass casts reduced appointment time and increased parent satisfaction, compared to traditional casts. No studies directly compared posterior splints to circumferential casts.

Conclusion

There is insufficient high-quality evidence to determine the optimal conservative treatment for patients with Gartland type 1 supracondylar fractures. Level of Evidence Level II systematic review of Level II studies.

Systematic Review Registration

[PROSPERO], identifier [CRD42020144616].
The Pyroptosis-Related Signature Predicts Diagnosis and Indicates Immune Characteristic in Major Depressive Disorder
Authors: Deng Zhifang , Liu Jue , He Shen , Gao Wenqi
Published: May 2022

Pyroptosis is recently identified as an inflammatory form of programmed cell death. However, the roles of pyroptosis-related genes (PS genes) in major depressive disorder (MDD) remain unclear. This study developed a novel diagnostic model for MDD based on PS genes and explored the pathological mechanisms associated with pyroptosis. First, we obtained 23 PS genes that were differentially expressed between healthy controls and MDD cases from GSE98793 dataset. There were obvious variation in immune cell infiltration profiles and immune-related pathway enrichment between healthy controls and MDD cases. Then, a novel diagnostic model consisting of eight PS genes (GPER1, GZMA, HMGB1, IL1RN, NLRC4, NLRP3, UTS2, and CAPN1) for MDD was constructed by random forest (RF) and least absolute shrinkage and selection operator (LASSO) analyses. ROC analysis revealed that our model has good diagnostic performance, AUC = 0.795 (95% CI 0.721–0.868). Subsequently, the consensus clustering method based on 23 differentially expressed PS genes was constructed to divide all MDD cases into two distinct pyroptosis subtypes (cluster A and B) with different immune and biological characteristics. Principal component analysis (PCA) algorithm was performed to calculate the pyroptosis scores (“PS-scores”) for each sample to quantify the pyroptosis regulation subtypes. The MDD patients in cluster B had higher “PS-scores” than those in cluster A. Furthermore, we also found that MDD patients in cluster B showed lower expression levels of 11 interferon (IFN)-α isoforms. In conclusion, pyroptosis may play an important role in MDD and can provide new insights into the diagnosis and underlying mechanisms of MDD.
Effects of Noninvasive Brain Stimulation Combined With Antidepressants in Patients With Poststroke Depression: A Systematic Review and Meta-Analysis
Authors: Liang Jiabin , Feng Jie , He Jinhua , Jiang Yong , Zhang Haoyu , Chen Hanwei
Published: May 2022

Objective: To evaluated the efficacy and safety of noninvasive brain stimulation (NIBS) combined with antidepressants in patients with poststroke depression (PSD).

Methods: Seven databases were searched to identify randomized controlled trials of NIBS combined with antidepressants in the treatment of PSD based on the international classification of diseases (ICD-10) criteria and exclusion criteria. The retrieval time was from the database establishment to 31 October 2021. Two researchers independently screened the identified studies through the search strategy, extracted their characteristics, and evaluated the quality of the included literature. Cochrane Collaboration’s tool was used to assess risk of bias. RevMan 5.3 software was applied for meta-analysis.

Results: A total of 34 randomized controlled trials were included, involving 2,711 patients with PSD. Meta-analysis showed that the total effective rate was higher in the combined therapy than the antidepressant alone [odds ratio (OR): 4.33; 95% confidence interval (CI): 3.07 to 6.11; p < 0.00001]. The Hamilton depressive scale (HAMD) score was significantly lower in repeated transcranial magnetic stimulation (rTMS) (≤10 Hz) combined with antidepressant than in antidepressant alone [standard mean difference (SMD): −1.44; 95% CI: −1.86 to −1.03; p < 0.00001]. No significant difference was seen in rTMS (>10 Hz) combined with antidepressant versus antidepressant alone (SMD: −4.02; 95% CI: −10.43 to 2.39; p = 0.22). In addition, combination therapy more strongly improved the modified Barthel index (MBI) scale than antidepressants [mean difference (MD): 8.29; 95% CI: 5.23–11.35; p < 0.00001]. Adverse effects were not significantly different between two therapies (OR: 1.33; 95% CI: 0.87 to 2.04; p = 0.18).

Conclusion: Low-frequency rTMS (≤10 Hz) combined with antidepressants tends to be more effective than antidepressants alone in patients with PSD, and there are no significant adverse effects. In addition, combined therapy may enhance quality of life after stroke. Combination therapy with high-frequency rTMS (>10 Hz) showed no advantage in treating PSD. The transcranial electrical stimulation (TES) combined with antidepressants might be more effective than antidepressants alone, which are needed to confirm by more clinical trials since the.
Formononetin Improves the Survival of Random Skin Flaps Through PI3K/Akt-Mediated Nrf2 Antioxidant Defense System
Authors: Li Haoliang , Jiang Renhao , Lou Lejing , Jia Chao , Zou Linfang , Chen Mochuan
Published: May 2022

Random-pattern skin flap is widely used in plastic and reconstructive surgery. However, its clinical effect is limited by ischemia necrosis occurs at the distal part of flap. Previous studies have proved that the protective effect of formononetin was associated with its antioxidant, anti-inflammatory ability. However, further research is still needed on the effect of formononetin on flap viability. The purpose of our study was to investigate the effect of formononetin on flap survival and the underlying mechanisms. Two doses (25 mg/kg, 50 mg/kg)of formononetin were administered for seven consecutive days on flap model. Flap tissues were collected on postoperative day 7. Our results revealed that formononetin promoted skin flap viability in a dose-dependent manner. Using immunohistochemical staining and western blot, we found that formononetin significantly reduced oxidative stress and inflammation. Hematoxylin and eosin (H and E) staining, laser Doppler images and immunofluorescence staining showed the enhancement of angiogenesis after formononetin treatment. Mechanistically, we demonstrated that the antioxidation of formononetin was mediated by activation and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2), while down-regulating cytoplasmic Kelch-like ECH-associated protein 1 (Keap1) expression. Co-treatment with formononetin and LY294002 (15 mg/kg), a potent Phosphatidylinositol-3-kinase (PI3K) inhibitor, which aborted nuclear Nrf2 expression and phosphorylated Akt, indicating that formononetin-mediated Nrf2 activation was related to PI3K/Akt pathway. Overall, our findings revealed that formononetin increased angiogenesis, reduced oxidative stress and inflammation, thus promoting flap survival. We highlighted the antioxidant effects of formononetin since the Nrf2 system was activated. Therefore, formononetin might be a promising candidate drug that can enhance survival of skin flaps.
Holographic Imaging Using an Imperfect Plane Wave Illumination With a Background Phase
Authors: Li Rujia , Yang Feng , Cao Liangcai
Published: May 2022

Aberrations in the optical components and misalignments in the optical system cause a background phase in the coherent illumination. To reconstruct the object phase, the background phase illuminating the object must be measured and subtracted. For diffraction imaging and in-line holography, the traditional phase retrieval method reconstructs the phase diffracting from clear edges. However, it falls into stagnation when solving a background phase slowly varying in the spatial domain. In this study, we propose to solve the background phase using a modulation-based phase retrieval method. Alternative structured phase modulation (ASPM) can be the phase constraint to avoid stagnation when solving the background phase without clear edges. With ASPM, the background phase in the experiment can be efficiently retrieved when 16 phase patterns are employed. The ASPM acts as a phase grating to concentrate the intensities and provides robustness to noise. Compared to the conventional random phase modulations, the ASPM method had a smaller error value in the reconstruction iterations, which leads to a better reconstruction quality. After measuring and subtracting the background phase, the object phase was retrieved using a coherent diffraction imaging system. A phase plate can be accurately reconstructed under three different background phases.
Inhibitory Spike-Timing-Dependent Plasticity Can Account for Pathological Strengthening of Pallido-Subthalamic Synapses in Parkinson’s Disease
Authors: Madadi Asl Mojtaba , Asadi Atefeh , Enayati Jamil , Valizadeh Alireza
Published: May 2022

Parkinson’s disease (PD) is a neurodegenerative brain disorder associated with dysfunction of the basal ganglia (BG) circuitry. Dopamine (DA) depletion in experimental PD models leads to the pathological strengthening of pallido-subthalamic synaptic connections, contributing to the emergence of abnormally synchronized neuronal activity in the external segment of the globus pallidus (GPe) and subthalamic nucleus (STN). Augmented GPe-STN transmission following loss of DA was attributed to heterosynaptic plasticity mechanisms induced by cortico-subthalamic inputs. However, synaptic plasticity may play a role in this process. Here, by employing computational modeling we show that assuming inhibitory spike-timing-dependent plasticity (iSTDP) at pallido-subthalamic synapses can account for pathological strengthening of pallido-subthalamic synapses in PD by further promoting correlated neuronal activity in the GPe-STN network. In addition, we show that GPe-STN transmission delays can shape bistable activity-connectivity states due to iSTDP, characterized by strong connectivity and strong synchronized activity (pathological states) as opposed to weak connectivity and desynchronized activity (physiological states). Our results may shed light on how abnormal reshaping of GPe-STN connectivity by synaptic plasticity during parkinsonism is related to the PD pathophysiology and contribute to the development of therapeutic brain stimulation techniques targeting plasticity-induced rewiring of network connectivity.
Transcriptome Analyses of Near Isogenic Lines Reveal Putative Drought Tolerance Controlling Genes in Wheat
Authors: Nouraei Sina , Mia Md Sultan , Liu Hui , Turner Neil C. , Yan Guijun
Published: May 2022

Graphical Abstract

The workflow of this study. (1) Near isogenic lines for qDSI.4B.1 QTL responsible for drought tolerance were grown in control and drought stress conditions, (2) grain samples were collected at 7 and 14 days after stress initiation at anthesis, (3) RNA was extracted, (4) sequenced and (5) data were analysed and organized with focus on 4BS, (6) six candidate genes were found for drought tolerance in qDSI.4B.1 interval and sequencing results were confirmed by qRT-PCR, (7) the protein products and (8) molecular function of the candidate genes were future studied.