bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Graph Learning for Circuit Deobfuscation
Authors: Chen Zhiqian , Zhang Lei , Kolhe Gaurav , Kamali Hadi Mardani , Rafatirad Setareh , Pudukotai Dinakarrao Sai Manoj , Homayoun Houman , Lu Chang-Tien , Zhao Liang
Published: May 2021

Circuit obfuscation is a recently proposed defense mechanism to protect the intellectual property (IP) of digital integrated circuits (ICs) from reverse engineering. There have been effective schemes, such as satisfiability (SAT)-checking based attacks that can potentially decrypt obfuscated circuits, which is called deobfuscation. Deobfuscation runtime could be days or years, depending on the layouts of the obfuscated ICs. Hence, accurately pre-estimating the deobfuscation runtime within a reasonable amount of time is crucial for IC designers to optimize their defense. However, it is challenging due to (1) the complexity of graph-structured circuit; (2) the varying-size topology of obfuscated circuits; (3) requirement on efficiency for deobfuscation method. This study proposes a framework that predicts the deobfuscation runtime based on graph deep learning techniques to address the challenges mentioned above. A conjunctive normal form (CNF) bipartite graph is utilized to characterize the complexity of this SAT problem by analyzing the SAT attack method. Multi-order information of the graph matrix is designed to identify the essential features and reduce the computational cost. To overcome the difficulty in capturing the dynamic size of the CNF graph, an energy-based kernel is proposed to aggregate dynamic features into an identical vector space. Then, we designed a framework, Deep Survival Analysis with Graph (DSAG), which integrates energy-based layers and predicts runtime inspired by censored regression in survival analysis. Integrating uncensored data with censored data, the proposed model improves the standard regression significantly. DSAG is an end-to-end framework that can automatically extract the determinant features for deobfuscation runtime. Extensive experiments on benchmarks demonstrate its effectiveness and efficiency.
Hyperglycemia at 1h-OGTT in Pregnancy: A Reliable Predictor of Metabolic Outcomes?
Authors: Succurro Elena , Fraticelli Federica , Franzago Marica , Fiorentino Teresa Vanessa , Andreozzi Francesco , Vitacolonna Ester , Sesti Giorgio
Published: May 2021

Gestational diabetes mellitus (GDM) is associated with a high risk of developing type 2 diabetes (T2DM) and cardiovascular disease (CVD). Identifying among GDM women those who are at high risk may help prevent T2DM and, possibly CVD. Several studies have shown that in women with GDM, hyperglycemia at 1 h during an oral glucose tolerance test (OGTT) (1-h PG) is not only associated with an increase in adverse maternal and perinatal outcomes but is also an independent predictor of T2DM. Interestingly, also in pregnant women who did not meet the criteria for a GDM diagnosis, 1-h PG was an independent predictor of postpartum impaired insulin sensitivity and beta-cell dysfunction. Moreover, maternal 1- and 2-h PG levels have been found to be independently associated with insulin resistance and impaired insulin secretion also during childhood. There is evidence that hyperglycemia at 1h PG during pregnancy may identify women at high risk of future CVD, due to its association with an unfavorable CV risk profile, inflammation, arterial stiffness and endothelial dysfunction. Overall, hyperglycemia at 1h during an OGTT in pregnancy may be a valuable prediction tool for identifying women at a high risk of future T2DM, who may then benefit from therapeutic strategies aimed at preventing cardiovascular outcomes.
New-Onset Atrial Fibrillation in Patients With Primary Aldosteronism Receiving Different Treatment Strategies: Systematic Review and Pooled Analysis of Three Studies
Authors: Tsai Cheng-Hsuan , Chen Ya-Li , Pan Chien-Ting , Lin Yen-Tin , Lee Po-Chin , Chiu Yu-Wei , Liao Che-Wei , Chen Zheng-Wei , Chang Chin-Chen , Chang Yi-Yao , Hung Chi-Sheng , Lin Yen-Hung
Published: May 2021

Background

Primary aldosteronism (PA) is a common cause of secondary hypertension and associated with higher incidence of new-onset atrial fibrillation (NOAF). However, the effects of surgical or medical therapies on preventing NOAF in PA patents remain unclear. The aim of this meta-analysis study was to assess the risk of NOAF among PA patients receiving mineralocorticoid receptor antagonist (MRA) treatment, PA patients receiving adrenalectomy, and patients with essential hypertension.

Methods

We performed the meta-analysis of the randomized or observational studies that investigated the incidence rate of NOAF in PA patients receiving MRA treatment versus PA patients receiving adrenalectomy from database inception until December 01, 2020 which were identified from PubMed, Embase, and Cochrane Library.

Results

A total of 172 related studies were reviewed, of which three fulfilled the inclusion criteria, including a total of 2,705 PA patients. The results of meta-analysis demonstrated a higher incidence of NOAF among the PA patients receiving MRA treatment compared to the PA patients receiving adrenalectomy (pooled odds ratio [OR]: 2.83, 95% confidence interval [CI]: 1.76–4.57 in the random effects model, I2 = 0%). The pooled OR for the PA patients receiving MRA treatment compared to the patients with essential hypertension was 1.91 (95% CI: 1.11–3.28). The pooled OR for the PA patients receiving adrenalectomy compared to the patients with essential hypertension was 0.70 (95% CI: 0.28–1.79).

Conclusion

Compared to the essential hypertension patients and the PA patients receiving adrenalectomy, the patients with PA receiving MRA treatment had a higher risk of NOAF.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/, identifier CRD42021222022.
The Spillover Effect Evaluation of Chinese Emissions Trading Scheme
Authors: Li Xinwu , Wang Chan , Liao Lianggui , Wen Hongxin
Published: May 2021

Carbon emissions trading scheme (ETS) is becoming a crucial policy in mitigating global climate change. This paper purposes to evaluate the spillover effect of Chinese ETS policy with the data of 30 provinces’ carbon emissions in China by China-MRIO model and input-output analysis. The MRIO model provides the change in production value in each region in the intermediate demand and final demand. 2012 and 2015 were selected as case study years to highlight the spillover effects of ETS policy. The results show that some pilot regions such as Beijing, Tianjin, Shanghai and Chongqing reduced their directed CO2 emissions while Guangdong and Hubei increased their directed CO2 compared to 2012. However, there were places like Hebei, Shanxi, Inner Mongolia, Ningxia, and Xinjiang that undertook a mass of embodied CO2 emissions which were majorly caused by providing intermediate products. Similarly, the pilot regions transferred out CO2 emissions by using a good deal of intermediate products. Thus, it is argued that carbon transfer evaluation can provide scientific support for carbon allowance formulating and it is important for policymakers to consider embodied carbon emissions in intermediate product trading when allocating carbon allowance under the market strength of ETS.
Sphaeropsis sapinea and Associated Endophytes in Scots Pine: Interactions and Effect on the Host Under Variable Water Content
Authors: Blumenstein Kathrin , Bußkamp Johanna , Langer Gitta Jutta , Schlößer Rebekka , Parra Rojas Natalia Marion , Terhonen Eeva
Published: May 2021

The ascomycete Sphaeropsis sapinea is the causal agent of the Diplodia Tip Blight disease on pines and other conifer species. This fungus has a symptomless endophytic life stage. Disease symptoms become visible when trees have been weakened by abiotic stress, usually related to warmer temperatures and drought. Currently, this disease is observed regularly in Scots pine (Pinus sylvestris) sites in parts of Europe, such as Germany, increasing dramatically in the last decade. Changes in climatic conditions will gradually increase the damage caused by this fungus, because it is favored by elevated temperature. Thus, host trees with reduced vitality due to climate change-related environmental stress are expected to be more susceptible to an outbreak of Diplodia Tip Blight disease. There is currently no established and effective method to control S. sapinea. This project aims to reveal the nature of the endophyte community of Scots pine. Utilizing the antagonistic core community of endophytes could serve as a novel tool for disease control. Results from this study provide a starting point for new solutions to improve forest health and counter S. sapinea disease outbreaks. We screened potential antagonistic endophytes against S. sapinea and infected Scots pine seedlings with the most common endophytes and S. sapinea alone and combination. The host was stressed by limiting access to water. The antagonism study revealed 13 possible fungi with the ability to inhibit the growth of S. sapinea in vitro, for example Sydowia polyspora. None of the tested co-infected fungi (Desmazierella acicola, Didymellaceae sp., Microsphaeropsis olivacea, Sydowia polyspora, and Truncatella conorum-piceae) showed strong necrosis development in vivo, even when host stress increased due to drought. However, the infection experiment demonstrated that drought conditions enhance the effect of the disease outbreak, triggering S. sapinea to cause more necrosis in the infected twigs.
Novel Non-coding RNA Analysis in Multiple Myeloma Identified Through High-Throughput Sequencing
Authors: Lu Minqiu , Wu Yin , Gao Wen , Tian Ying , Wang Guorong , Liu Aijun , Chen Wenming
Published: May 2021

This study aimed to explore the potential effects of novel non-coding ribose nucleic acids (ncRNAs) in patients with multiple myeloma (MM). The gene expression profile of plasma cells was used for sequence analysis to explore the expression pattern of ncRNAs in MM. The expression patterns of non-coding RNAs in MM were analyzed by RNA sequencing (whole-transcriptome-specific RNA sequencing). Next, the expression of the selected ncRNAs was verified by quantitative real-time polymerase chain reaction. Further, the lncRNA-associated competitive endogenous RNA network in MM was elucidated using deep RNA-seq. Differentially expressed (DE) ncRNAs were significantly regulated in patients with MM. DE target lncRNAs were analyzed by cis and trans targeting prediction. Two new lncRNAs were shown to be related to MM oncogenes. MSTRG.155519 played a carcinogenic role in myeloma by targeting CEACAM1; MSTRG.13132 was related to FAM46C. Finally, the network of lncRNA–mRNA–miRNA in MM was constructed in this study. The expression of non-coding RNAs through sequence and functional analyses might be helpful for further studies on the pathogenesis of MM and the development of new MM-targeted therapy for non-coding RNAs.
Insights From Y-STRs: Forensic Characteristics, Genetic Affinities, and Linguistic Classifications of Guangdong Hakka and She Groups
Authors: Luo Chunfang , Duan Lizhong , Li Yanning , Xie Qiqian , Wang Lingxiang , Ru Kai , Nazir Shahid , Jawad Muhammad , Zhao Yifeng , Wang Fenfen , Du Zhengming , Peng Dehua , Wen Shao-Qing , Qiu Pingming , Fan Haoliang
Published: May 2021

Guangdong province is situated in the south of China with a population size of 113.46 million. Hakka is officially recognized as a branch of Han Chinese, and She is the official minority group in mainland China. There are approximately 25 million Hakka people who mainly live in the East and North regions of China, while there are only 0.7 million She people. The genetic characterization and forensic parameters of these two groups are poorly defined (She) or still need to be explored (Hakka). In this study, we have genotyped 475 unrelated Guangdong males (260 Hakka and 215 She) with Promega PowerPlex® Y23 System. A total of 176 and 155 different alleles were observed across all 23 Y-STRs for Guangdong Hakka (with a range of allele frequencies from 0.0038 to 0.7423) and Guangdong She (0.0047–0.8605), respectively. The gene diversity ranged from 0.4877 to 0.9671 (Guangdong Hakka) and 0.3277–0.9526 (Guangdong She), while the haplotype diversities were 0.9994 and 0.9939 for Guangdong Hakka and Guangdong She, with discrimination capacity values of 0.8885 and 0.5674, respectively. With reference to geographical and linguistic scales, the phylogenetic analyses showed us that Guangdong Hakka has a close relationship with Southern Han, and the genetic pool of Guangdong Hakka was influenced by surrounding Han populations. The predominant haplogroups of the Guangdong She group were O2-M122 and O2a2a1a2-M7, while Guangdong She clustered with other Tibeto-Burman language-speaking populations (Guizhou Tujia and Hunan Tujia), which shows us that the Guangdong She group is one of the branches of Tibeto-Burman populations and the Huonie dialect of She languages may be a branch of Tibeto-Burman language families.
FCGR Genetic Variation in Two Populations From Ecuador Highlands—Extensive Copy-Number Variation, Distinctive Distribution of Functional Polymorphisms, and a Novel, Locally Common, Chimeric FCGR3B/A (CD16B/A) Gene
Authors: Moraru Manuela , Perez-Portilla Adriana , Al-Akioui Sanz Karima , Blazquez-Moreno Alfonso , Arnaiz-Villena Antonio , Reyburn Hugh T. , Vilches Carlos
Published: May 2021

Fcγ receptors (FcγR), cell-surface glycoproteins that bind antigen-IgG complexes, control both humoral and cellular immune responses. TheFCGRlocus on chromosome 1q23.3 comprises five homologous genes encoding low-affinity FcγRII and FcγRIII, and displays functionally relevant polymorphism that impacts on human health. Recurrent events of non-allelic homologous recombination across theFCGRlocus result in copy-number variation of ~82.5 kbp-long fragments known as copy-number regions (CNR). Here, we characterize a recently described deletion that we name CNR5, which results in loss ofFCGR3A,FCGR3B, andFCGR2C, and generation of a recombinantFCGR3B/Agene. We show that the CNR5 recombination spot lies at the beginning of the thirdFCGR3intron. Although theFCGR3B/A-encoded hybrid protein CD16B/A reaches the plasma membrane in transfected cells, its possible natural expression, predictably restricted to neutrophils, could not be demonstrated in resting or interferon γ-stimulated cells. As the CNR5-deletion was originally described in an Ecuadorian family from Llano Grande (an indigenous community in North-Eastern Quito), we characterized theFCGRgenetic variation in two populations from the highlands of Ecuador. Our results reveal that CNR5-deletion is relatively frequent in Llano Grande (5 carriers out of 36 donors). Furthermore, we found a high frequency of two strong-phagocytosis variants: theFCGR3B-NA1 haplotype and the CNR1 duplication, which translates into an increasedFCGR3BandFCGR2Ccopy-number. CNR1 duplication was particularly increased in Llano Grande, 77.8% of the studied sample carrying at least one such duplication. In contrast, an extended haplotype CD16A-176V – CD32C-ORF+2B.2 – CD32B-2B.4 including strong activating and inhibitory FcγR variants was absent in Llano Grande and found at a low frequency (8.6%) in Ecuador highlands. This particular distribution ofFCGRpolymorphism, possibly a result of selective pressures, further confirms the importance of a comprehensive, joint analysis of all genetic variations in the locus and warrants additional studies on their putative clinical impact. In conclusion, our study confirms important ethnic variation at theFCGRlocus; it shows a distinctiveFCGRpolymorphism distribution in Ecuador highlands; provides a molecular characterization of a novel CNR5-deletion associated with CD16A and CD16B deficiency; and confirms its presence in that population.
Comparative Immunomodulatory Evaluation of the Receptor Binding Domain of the SARS-CoV-2 Spike Protein; a Potential Vaccine Candidate Which Imparts Potent Humoral and Th1 Type Immune Response in a Mouse Model
Authors: Shrivastava Tripti , Singh Balwant , Rizvi Zaigham Abbas , Verma Rohit , Goswami Sandeep , Vishwakarma Preeti , Jakhar Kamini , Sonar Sudipta , Mani Shailendra , Bhattacharyya Sankar , Awasthi Amit , Surjit Milan
Published: May 2021

The newly emerged novel coronavirus, SARS-CoV-2, the causative agent of COVID-19 has proven to be a threat to the human race globally, thus, vaccine development against SARS-CoV-2 is an unmet need driving mass vaccination efforts. The receptor binding domain of the spike protein of this coronavirus has multiple neutralizing epitopes and is associated with viral entry. Here we have designed and characterized the SARS-CoV-2 spike protein fragment 330-526 as receptor binding domain 330-526 (RBD330-526) with two native glycosylation sites (N331 and N343); as a potential subunit vaccine candidate. We initially characterized RBD330-526 biochemically and investigated its thermal stability, humoral and T cell immune response of various RBD protein formulations (with or without adjuvant) to evaluate the inherent immunogenicity and immunomodulatory effect. Our result showed that the purified RBD immunogen is stable up to 72 h, without any apparent loss in affinity or specificity of interaction with the ACE2 receptor. Upon immunization in mice, RBD generates a high titer humoral response, elevated IFN-γ producing CD4+ cells, cytotoxic T cells, and robust neutralizing antibodies against live SARS-CoV-2 virus. Our results collectively support the potential of RBD330-526 as a promising vaccine candidate against SARS-CoV-2.
Adipose Extracellular Vesicles: Messengers From and to Macrophages in Regulating Immunometabolic Homeostasis or Disorders
Authors: Zhou Zixin , Tao Yan , Zhao Hui , Wang Qun
Published: May 2021

Adipose tissue is comprised of heterogenous cell populations that regulate both energy metabolism and immune reactions. Macrophages play critical roles in regulating immunometabolic homeostasis or disorders through cooperation with adipocytes, adipose tissue-derived stem cells (ADSCs) or other cells in adipose tissue. Extracellular vesicles (EVs) are recently recognized as efficient messengers for intercellular communication. Emerging evidences have demonstrated that adipose EVs are actively involved in the mutual interactions of macrophages, adipocytes and ADSCs, which produce considerable influences on immunometabolism under healthy or obese conditions. Here, we will elaborate the production and the characteristics of adipose EVs that are related to macrophages under different metabolic demands or stresses, whilst discuss the roles of these EVs in regulating local or systemic immunometabolic homeostasis or disorders in the context of adipocyte-macrophage dialogue and ADSC-macrophage interaction. Particularly, we provide a profile of dynamic adipose microenvironments based on macrophages. Adipose EVs act as the messengers between ADSCs and macrophages to maintain the balance of metabolism and immunity, while drive a vicious cycle between hypertrophic adipocytes and inflammatory macrophages to cause immunometabolic imbalance. This review may provide valuable information about the physio- or pathological roles of adipose EVs and the application of adipose EVs in the diagnosis and treatment of metabolic diseases.
SARS-CoV-2-Specific Antibody Prevalence and Symptoms in a Local Austrian Population
Authors: Ladage Dennis , Höglinger Yana , Ladage Dorothee , Adler Christoph , Yalcin Israfil , Harzer Oliver , Braun Ralf J.
Published: May 2021

Background: Since December 2019 the novel coronavirus (SARS-CoV-2) is the center of global attention due to its rapid transmission and toll on health care systems and global economy. Population-based serosurveys measuring antibodies for SARS-CoV-2 provide one method for estimating previous infection rates including the symptom-free courses of the disease and monitoring the progression of the epidemic.

Methods: In June 2020 we succeeded in testing almost half of the population of an Austrian township (1,359 inhabitants) with a reported higher incidence for COVID-19 infections (17 PCR positive cases have been officially reported until the date of sample collection, i.e., 1.2% of the total population). We determined the prevalence of SARS-CoV-2-specific antibodies in this population, factors affecting, and symptoms correlated with prior infection. Antibodies were determined using a CE-certified quality-controlled ELISA test for SARS-CoV-2-specific IgG and IgA antibodies.

Results: We found a high prevalence of 9% positive antibodies among the town population in comparison to 6% of the neighboring villages. This was considerably higher than the officially known RT-PCR-approved COVID-19 cases (1.2%) in the town population. Twenty percent of SARS-CoV-2-antibody positive cases declared being asymptomatic in a questionnaire. On the other hand, we identified six single major symptoms, including anosmia/ageusia, weight loss, anorexia, general debility, dyspnea, and fever, and especially their combination to be of high prognostic value for predicting SARS-CoV-2 infection in a patient.

Conclusions: This population study demonstrated a high prevalence of antibodies to SARS-CoV-2 as a marker of past infections in an Austrian township. Several symptoms revealed a diagnostic value especially in combination.
Very-Short-Term Sleep Deprivation Slows Early Recovery of Lymphocytes in Septic Patients
Authors: Zhang Yujing , Wu Yuming , Xu Dan , Xiao Ping , Xie Bing , Huang Haiyan , Shang You , Yuan Shiying , Zhang Jiancheng
Published: May 2021

Sleep plays an important role in immune function. However, the effects of very-short-term sleep deprivation on the early recovery of immune function after sepsis remain unclear. This study was conducted in the intensive care unit to investigate the effects of 2 consecutive days of sleep deprivation (SD) on lymphocyte recovery over the following few days in septic patients who were recovering from a critical illness. The patients' self-reports of sleep quality was assessed using the Richards–Campbell Sleep Questionnaire at 0 and 24 h after inclusion. The demographic, clinical, laboratory, treatment, and outcome data were collected and compared between the good sleep group and poor sleep group. We found that 2 consecutive days of SD decreased the absolute lymphocyte count (ALC) and ALC recovery at 3 days after SD. Furthermore, post-septic poor sleep decreased the plasma levels of atrial natriuretic peptide (ANP) immediately after 2 consecutive days of SD. The ANP levels at 24 h after inclusion were positively correlated with ALC recovery, the number of CD3+ T cells, or the number of CD3+ CD4+ cells in the peripheral blood on day 5 after inclusion. Our data suggested that very-short-term poor sleep quality could slow down lymphocyte recovery over the following few days in septic patients who were recovering from a critical illness. Our results underscore the significance of very-short-term SD on serious negative effects on the immune function. Therefore, it is suggested that continuous SD or several short-term SD with short intervals should be avoided in septic patients.
Case Report: A Severe and Multi-Site Nocardia farcinica Infection Rapidly and Precisely Identified by Metagenomic Next-Generation Sequencing
Authors: Jiao Mengfan , Deng Xiang , Yang Hongfu , Dong Junqiang , Lv Jun , Li Fang
Published: May 2021

Nocardia genus is an aerobic, gram-positive, and opportunistic pathogen, which mainly affects cell-mediated immunosuppressed patients. Early diagnosis and treatment greatly improve prognosis. However, the limitation of golden standard-bacterial culture exists. Here, we report a 61-year-old male with pneumonia, sepsis and intermuscular abscesses induced by Nocardia farcinica. Venous blood culture reported negative results. Former improper diagnosis and treatment did not improve his condition. With the assistant of metagenomic next-generation sequencing, the pathogen was identified as Nocardia farcinica. He was then applied with accurate treatment and had a remarkable clinical and radiological improvement.
Candida albicans Biofilm Inhibition by Ethnobotanicals and Ethnobotanically-Synthesized Gold Nanoparticles
Authors: Judan Cruz Khristina G. , Alfonso Eleonor D. , Fernando Somar Israel D. , Watanabe Kozo
Published: May 2021

The virulence and drug resistance of globally prevalent Candida albicans has presented complications toward its control while advances in effective antivirulence drugs remain critical. Emerging methods are now being evaluated to facilitate development of novel therapeutic approaches against this pathogen. This study focuses on the biofilm formation inhibition of ethnobotanical crude extracts and the use of nanotechnology through the ethnobotanically-synthesized gold nanoparticles to control C. albicans. Control on biofilm formation was compared using crude extracts (CEs) and biologically synthesized gold nanoparticles (CEs + AuNPs). Significantly lower biofilm formation was exhibited in thirteen (13) CEs and fourteen (14) CEs + AuNPs. Biofilm-linked genes Bcr1 and HSP90 expression were consequently downregulated. Higher biofilm inhibition activity was noted in some CEs + AuNPs compared to its counterpart CEs. This study emphasizes the biofilm inhibition activity of ethnobotanicals and the use of nanoparticles to enhance delivery of compounds, and points to its prospects for developing anti-pathogenic drugs without evolving resistance.
Cross Modal Few-Shot Contextual Transfer for Heterogenous Image Classification
Authors: Chen Zhikui , Zhang Xu , Huang Wei , Gao Jing , Zhang Suhua
Published: May 2021

Deep transfer learning aims at dealing with challenges in new tasks with insufficient samples. However, when it comes to few-shot learning scenarios, due to the low diversity of several known training samples, they are prone to be dominated by specificity, thus leading to one-sidedness local features instead of the reliable global feature of the actual categories they belong to. To alleviate the difficulty, we propose a cross-modal few-shot contextual transfer method that leverages the contextual information as a supplement and learns context awareness transfer in few-shot image classification scenes, which fully utilizes the information in heterogeneous data. The similarity measure in the image classification task is reformulated via fusing textual semantic modal information and visual semantic modal information extracted from images. This performs as a supplement and helps to inhibit the sample specificity. Besides, to better extract local visual features and reorganize the recognition pattern, the deep transfer scheme is also used for reusing a powerful extractor from the pre-trained model. Simulation experiments show that the introduction of cross-modal and intra-modal contextual information can effectively suppress the deviation of defining category features with few samples and improve the accuracy of few-shot image classification tasks.
Attenuated SIRT1 Activity Leads to PER2 Cytoplasmic Localization and Dampens the Amplitude of Bmal1 Promoter-Driven Circadian Oscillation
Authors: Ashimori Atsushige , Nakahata Yasukazu , Sato Toshiya , Fukamizu Yuichiro , Matsui Takaaki , Yoshitane Hikari , Fukada Yoshitaka , Shinohara Kazuyuki , Bessho Yasumasa
Published: May 2021

The circadian clock possesses robust systems to maintain the rhythm approximately 24 h, from cellular to organismal levels, whereas aging is known to be one of the risk factors linked to the alternation of circadian physiology and behavior. The amount of many metabolites in the cells/body is altered with the aging process, and the most prominent metabolite among them is the oxidized form of nicotinamide adenine dinucleotide (NAD+), which is associated with posttranslational modifications of acetylation and poly-ADP-ribosylation status of circadian clock proteins and decreases with aging. However, how low NAD+ condition in cells, which mimics aged or pathophysiological conditions, affects the circadian clock is largely unknown. Here, we show that low NAD+ in cultured cells promotes PER2 to be retained in the cytoplasm through the NAD+/SIRT1 axis, which leads to the attenuated amplitude of Bmal1 promoter-driven luciferase oscillation. We found that, among the core clock proteins, PER2 is mainly affected in its subcellular localization by NAD+ amount, and a higher cytoplasmic PER2 localization was observed under low NAD+ condition. We further found that NAD+-dependent deacetylase SIRT1 is the regulator of PER2 subcellular localization. Thus, we anticipate that the altered PER2 subcellular localization by low NAD+ is one of the complex changes that occurs in the aged circadian clock.
Selective Neuromodulation of the Vagus Nerve
Authors: Fitchett Adam , Mastitskaya Svetlana , Aristovich Kirill
Published: May 2021

Vagus nerve stimulation (VNS) is an effective technique for the treatment of refractory epilepsy and shows potential for the treatment of a range of other serious conditions. However, until now stimulation has generally been supramaximal and non-selective, resulting in a range of side effects. Selective VNS (sVNS) aims to mitigate this by targeting specific fiber types within the nerve to produce functionally specific effects. In recent years, several key paradigms of sVNS have been developed—spatially selective, fiber-selective, anodal block, neural titration, and kilohertz electrical stimulation block—as well as various stimulation pulse parameters and electrode array geometries. sVNS can significantly reduce the severity of side effects, and in some cases increase efficacy of the treatment. While most studies have focused on fiber-selective sVNS, spatially selective sVNS has demonstrated comparable mitigation of side-effects. It has the potential to achieve greater specificity and provide crucial information about vagal nerve physiology. Anodal block achieves strong side-effect mitigation too, but is much less specific than fiber- and spatially selective paradigms. The major hurdle to achieving better selectivity of VNS is a limited knowledge of functional anatomical organization of vagus nerve. It is also crucial to optimize electrode array geometry and pulse shape, as well as expand the applications of sVNS beyond the current focus on cardiovascular disease.
Cochlin Deficiency Protects Against Noise-Induced Hearing Loss
Authors: Seist Richard , Landegger Lukas D. , Robertson Nahid G. , Vasilijic Sasa , Morton Cynthia C. , Stankovic Konstantina M.
Published: May 2021

Cochlin is the most abundant protein in the inner ear. To study its function in response to noise trauma, we exposed adolescent wild-type (Coch+/+) and cochlin knock-out (Coch–/–) mice to noise (8–16 kHz, 103 dB SPL, 2 h) that causes a permanent threshold shift and hair cell loss. Two weeks after noise exposure, Coch–/– mice had substantially less elevation in noise-induced auditory thresholds and hair cell loss than Coch+/+ mice, consistent with cochlin deficiency providing protection from noise trauma. Comparison of pre-noise exposure thresholds of auditory brain stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) in Coch–/– mice and Coch+/+ littermates revealed a small and significant elevation in thresholds of Coch–/– mice, overall consistent with a small conductive hearing loss in Coch–/– mice. We show quantitatively that the pro-inflammatory component of cochlin, LCCL, is upregulated after noise exposure in perilymph of wild-type mice compared to unexposed mice, as is the enzyme catalyzing LCCL release, aggrecanase1, encoded by Adamts4. We further show that upregulation of pro-inflammatory cytokines in perilymph and cochlear soft-tissue after noise exposure is lower in cochlin knock-out than wild-type mice. Taken together, our data demonstrate for the first time that cochlin deficiency results in conductive hearing loss that protects against physiologic and molecular effects of noise trauma.
Invaginating Structures in Synapses – Perspective
Authors: Petralia Ronald S. , Yao Pamela J. , Kapogiannis Dimitrios , Wang Ya-Xian
Published: May 2021

Invaginating structures are common in the synapses of most animals. However, the details of these invaginating structures remain understudied in part because they are not well resolved in light microscopy and were often misidentified in early electron microscope (EM) studies. Utilizing experimental techniques along with the latest advances in microscopy, such as focused ion beam-scanning EM (FIB-SEM), evidence is gradually building to suggest that the synaptic invaginating structures contribute to synapse development, maintenance, and plasticity. These invaginating structures are most elaborate in synapses mediating rapid integration of signals, such as muscle contraction, mechanoreception, and vision. Here we argue that the synaptic invaginations should be considered in future studies seeking to understand their role in sensory integration and coordination, learning, and memory. We review the various types of invaginating structures in the synapses and discuss their potential functions. We also present several new examples of invaginating structures from a variety of animals including Drosophila and mice, mainly using FIB-SEM, with which we trace the form and arrangement of these structures.
Dietary Intake of Vegetables and Cooking Oil Was Associated With Drug-Induced Liver Injury During Tuberculosis Treatment: A Preliminary Cohort Study
Authors: Wang Jinyu , Xiong Ke , Xu Lei , Zhang Chao , Zhao Shanliang , Liu Yufeng , Ma Aiguo
Published: May 2021

Background and Purpose: Drug-induced liver injury is challenging during tuberculosis treatment. There is no epidemiological data investigating the relation between dietary intake and the risk of drug-induced liver injury during tuberculosis treatment. The aim of this study is to investigate the association of food and nutrient intake with the incidence of tuberculosis-drug-induced liver injury.

Methods: A cohort study was conducted in two city-level tuberculosis-specialized hospitals in Linyi City and Qingdao City, China from January 2011 to December 2013. The dietary intake was assessed by a 3-day 24-h food recall survey and a standard food-frequency questionnaire. The liver functions including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were monitored throughout the 6-month tuberculosis therapy. Liver injury was defined as ALT or AST higher than two times of the upper limit of normal (ULN). Liver dysfunction was defined as ALT or AST higher than the ULN. The ULN for ALT and AST is 40 U/L. Multivariate logistic regression analyses were performed to determine the dietary factors associated with the incidence of liver injury and liver dysfunction.

Results: A total of 605 patients were included in the analysis. During the treatment, 8.1% patients exhibited liver injury and 23.3% patients exhibited liver dysfunction. A lower intake of vegetables was associated with a higher risk of liver injury [OR (95% CI): 3.50 (1.52–8.08), P = 0.003) and liver dysfunction [OR (95% CI): 2.37 (1.31–4.29), P = 0.004], while a lower intake of cooking oil was associated with a lower risk of liver injury [OR (95% CI): 0.44 (0.20–0.96), P = 0.040)] and liver dysfunction [OR (95% CI): 0.51 (0.31–0.85), P = 0.009].

Conclusion: The current study indicated that the higher risks of tuberculosis-drug-induced liver injury and liver dysfunction were statistically associated with decreased vegetable intake and increased cooking oil intake.
Case Report: Anlotinib Combined With Sintilimab as Third-Line Treatment in a Metastatic Urothelial Bladder Carcinoma Patient With FGFR3 Mutation
Authors: Cao Jian-zhou , Wu Wei , Pan Jin-feng , Wang Hong-wei , Jiang Jun-hui , Ma Qi
Published: May 2021

We report on a case of metastatic urothelial bladder carcinoma (mUBC) treated with anlotinib combined with sintilimab. A 69-year-old male was diagnosed with non-muscle invasive bladder cancer (NMIBC). He received transurethral resection of bladder tumor (TURBT) and intravesical gemcitabine chemotherapy. After the patients’ cancer progressed to mUBC, cisplatin-based chemotherapy (gemcitabine combined with cisplatin, GC) was performed to this patient as first line therapy for four cycles. However, the disease progressed again within 6 months. Local radiotherapy was performed on the metastatic lesions, and after radiotherapy, the patient received anti-PD-1 antibody (sintilimab 200 mg, q3w)combined with Albumin-bound (Nab)-paclitaxel (100 mg, qw) as the second-line therapy, but the patient’s cancer was still observed to be progressing. Molecular characterization confirmed the presence of FGFR3 mutations in the patient. Anlotinib was recommended to this patient. After the patient was fully informed and he was aware of off-label use of the drug, then, Nab-paclitaxel was replaced by anlotinib (10 mg D1–14, q3w) and sintilimab infusions were maintained for every 3 weeks. Partial response (PR) was observed through imaging examinations and stable disease (SD) was observed for more than 11 months; the patient’s quality of life also improved. This case suggested that anlotinib combined with sintilimab may be a safe and effective choice in the treatment of mUBC in patients with FGFR3 mutations.
Exploring MRI Characteristics of Brain Diffuse Midline Gliomas With the H3 K27M Mutation Using Radiomics
Authors: Li Qian , Dong Fei , Jiang Biao , Zhang Minming
Published: May 2021

Objectives

To explore the magnetic resonance imaging (MRI) characteristics of brain diffuse midline gliomas with the H3 K27M mutation (DMG-M) using radiomics.

Materials and Methods

Thirty patients with diffuse midline gliomas, including 16 with the H3 K27M mutant and 14 with wild type tumors, were retrospectively included in this study. A total of 272 radiomic features were initially extracted from MR images of each tumor. Principal component analysis, univariate analysis, and three other feature selection methods, including variance thresholding, recursive feature elimination, and the elastic net, were used to analyze the radiomic features. Based on the results, related visually accessible features of the tumors were further evaluated.

Results

Patients with DMG-M were younger than those with diffuse midline gliomas with H3 K27M wild (DMG-W) (median, 25.5 and 48 years old, respectively; p=0.005). Principal component analysis showed that there were obvious overlaps in the first two principal components for both DMG-M and DMG-W tumors. The feature selection results showed that few features from T2-weighted images (T2WI) were useful for differentiating DMG-M and DMG-W tumors. Thereafter, four visually accessible features related to T2WI were further extracted and analyzed. Among these features, only cystic formation showed a significant difference between the two types of tumors (OR=7.800, 95% CI 1.476–41.214, p=0.024).

Conclusions

DMGs with and without the H3 K27M mutation shared similar MRI characteristics. T2W sequences may be valuable, and cystic formation a useful MRI biomarker, for diagnosing brain DMG-M.
Exosomes Promote Pre-Metastatic Niche Formation in Gastric Cancer
Authors: Gao Jing , Li Song , Xu Qian , Zhang Xue , Huang Miao , Dai Xin , Liu Lian
Published: May 2021

Gastric cancer has a high rate of metastasis, during which pre-metastatic niches (PMN) provide a supportive environment for the upcoming tumor cells. Exosomes are bilayer vesicles secreted by cells containing biological information that mediates communication between cells. Using exosomes, gastric cancer cells establish PMN remotely in multifarious perspectives, including immunosuppression, stroma remodeling, angiogenesis, mesothelial mesenchymal transformation, and organotropism. In turn, the cell components in PMN secrete exosomes that interact with each other and provide onco-promoting signals. In this review, we highlight the role of exosomes in PMN formation in gastric cancer and discuss their potential values in gastric cancer metastasis diagnosis, prevention, and treatment.
Targeting Mutated p53 Dependency in Triple-Negative Breast Cancer Cells Through CDK7 Inhibition
Authors: Peng Jingyu , Yang Ming , Bi Ran , Wang Yueyuan , Wang Chunxi , Wei Xue , Zhang Zhihao , Xie Xiao , Wei Wei
Published: May 2021

Background

Cyclin-dependent kinase 7 (CDK7) is crucial for cell cycle progression and gene expression transcriptional regulation, which are often not assessed in cancer developing process. CDK7 inhibitors have emerged as promising drugs for treating diverse cancers, including breast cancer. However, the mechanism behind its anticancer effect has not been well investigated. Here, the possible mechanism of CDK7 inhibitors for treating human triple-negative breast cancer (TNBC) has been studied.

Methods

The effects of CDK7 inhibitors on breast cancer cells have been identified by measuring cell viability (Cell Counting Kit-8) and cell proliferation and calculating colony formation. The short hairpin RNA and short interfering RNA were used for the construction of knockdown cells. To assess the expression of associated proteins, western blot was used.

Results

This study confirmed that, compared to hormone receptor-positive breast cancer cells, TNBC cells were more sensitive to THZ1, a novel CDK7 inhibitor. THZ1 treatment specifically downregulated mutated p53 in a dose- and time-dependent manner in TNBC cells with p53 mutation. Another CDK7 inhibitor, LDC4297, also potently interfered with the expression of mutated p53. Furthermore, endogenous CDK7 expression was positively correlated with the levels of mutated p53 in TNBC cells with p53 mutation. Downregulating mutated p53 expression significantly suppressed the proliferation of TNBC cells with p53 mutation.

Conclusion

Our findings demonstrated that targeting CDK7 was an effective approach for the treatment of TNBC with p53 mutation.
Quantitative T2*-Weighted Imaging and Reduced Field-of-View Diffusion-Weighted Imaging of Rectal Cancer: Correlation of R2* and Apparent Diffusion Coefficient With Histopathological Prognostic Factors
Authors: Peng Yang , Luo Yan , Hu Xuemei , Shen Yaqi , Hu Daoyu , Li Zhen , Kamel Ihab
Published: May 2021

Purpose

To assess T2*-weighted imaging (T2*WI) and reduced field-of-view diffusion-weighted Imaging (rDWI) derived parameters and their relationships with histopathological factors in patients with rectal cancer.

Methods

Fifty-four patients with pathologically-proven rectal cancer underwent preoperative T2*-weighted imaging and rDWI in this retrospective study. R2* values from T2*-weighted imaging and apparent diffusion coefficient (ADC) values from rDWI were compared in terms of different histopathological prognostic factors using student’s t-test or Mann-Whitney U-test. The correlations of R2* and ADC with prognostic factors were assessed by Spearman correlation analysis. The diagnostic performances of R2* and ADC were analyzed by receiver operating characteristic curves (ROC) separately and jointly.

Results

Significant positive correlation was found between R2* values and T stage, lymph node involvement, histological grades, CEA level, the presence of EMVI and tumor deposit (r = 0.374 ~ 0.673, p = 0.000–0.006), with the exception of CA19-9 level, CRM status and tumor involvement in the circumference lumen (TIL). Meanwhile, ADC values negatively correlated with almost all the prognostic factors (r = −0.588 to −0.299, p = 0.000–0.030), except CA19-9 level. The AUC range was 0.724–0.907 for R2* and 0.674–0.887 for ADC in discrimination of different prognostic factors. While showing the highest AUC of 0.913 (0.803–1.000) in differentiation of T stage, combination of R2* and ADC with reference to different prognostic factors did not significantly improve the diagnostic performance in comparison with individual R2*/ADC parameter.

Conclusions

R2* and ADC were associated with important histopathological prognostic factors of rectal cancer. R2* might act as additional quantitative imaging marker for tumor characterization of rectal cancer.
Development and Validation of a Combined Model for Preoperative Prediction of Lymph Node Metastasis in Peripheral Lung Adenocarcinoma
Authors: Li Qi , He Xiao-qun , Fan Xiao , Zhu Chao-nan , Lv Jun-wei , Luo Tian-you
Published: May 2021

Background

Based on the “seed and soil” theory proposed by previous studies, we aimed to develop and validate a combined model of machine learning for predicting lymph node metastasis (LNM) in patients with peripheral lung adenocarcinoma (PLADC).

Methods

Radiomics models were developed in a primary cohort of 390 patients (training cohort) with pathologically confirmed PLADC from January 2016 to August 2018. The patients were divided into the LNM (−) and LNM (+) groups. Thereafter, the patients were subdivided according to TNM stages N0, N1, N2, and N3. Radiomic features from unenhanced computed tomography (CT) were extracted. Radiomic signatures of the primary tumor (R1) and adjacent pleura (R2) were built as predictors of LNM. CT morphological features and clinical characteristics were compared between both groups. A combined model incorporating R1, R2, and CT morphological features, and clinical risk factors was developed by multivariate analysis. The combined model’s performance was assessed by receiver operating characteristic (ROC) curve. An internal validation cohort containing 166 consecutive patients from September 2018 to November 2019 was also assessed.

Results

Thirty-one radiomic features of R1 and R2 were significant predictors of LNM (all P < 0.05). Sex, smoking history, tumor size, density, air bronchogram, spiculation, lobulation, necrosis, pleural effusion, and pleural involvement also differed significantly between the groups (all P < 0.05). R1, R2, tumor size, and spiculation in the combined model were independent risk factors for predicting LNM in patients with PLADC, with area under the ROC curves (AUCs) of 0.897 and 0.883 in the training and validation cohorts, respectively. The combined model identified N0, N1, N2, and N3, with AUCs ranging from 0.691–0.927 in the training cohort and 0.700–0.951 in the validation cohort, respectively, thereby indicating good performance.

Conclusion

CT phenotypes of the primary tumor and adjacent pleura were significantly associated with LNM. A combined model incorporating radiomic signatures, CT morphological features, and clinical risk factors can assess LNM of patients with PLADC accurately and non-invasively.
Development and Validation of Novel Nomograms Using Serum Tumor Markers for the Prediction of Preoperative Histologic Grades in Gastroenteropancreatic Neuroendocrine Tumors
Authors: Li Yan , Wu Zhi-Qi , Xu Qin , Goyal Hemant , Xu Hua-Guo
Published: May 2021

Background

To develop and validate nomogram models for the preoperatively prediction of the histologic grade of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) to provide appropriate treatments.

Methods

A total of 1014 participants, including 211 healthy controls, 293 patients with benign diseases, 299 patients with cancers, and 211 patients with GEP-NETs were included in the final analysis. Their sociodemographic and laboratory information, including serum tumor markers such as AFP, CEA, CA19-9, CA72-4, Cyfra21-1 and NSE were collected. Nomogram models were developed to preoperatively predict histologic grades of GEP-NETs.

Results

Among six serum tumor markers, only NSE was found to have a statistically significant association with the histologic grades in GEP-NETs (G1 vs. G2: p < 0.05; G2 vs. G3: p < 0.001; G1 vs. G3: p < 0.0001), which was combined with sex and age to develop the nomogram models. The first nomogram (to differentiate grade 1(G1) and grade 2/3 tumor (G2/G3)) showed a strong association to differentiate with an AUC of 0.747 (95% CI: 0.663-0.832) and 0.735 (95% CI: 0.624-0.847) in the training and validation datasets, respectively. The second nomogram (to differentiate G1/G2 and G3 tumors) showed a strong association to differentiate with an AUC of 0.827 (95% CI: 0.744-0.911) and 0.847 (95% CI: 0.744-0.950) in the training and validation datasets, respectively. The ROC, area under ROC curve (AUC), calibration curve and decision curve analysis (DCA) demonstrated the clinical usefulness of both models.

Conclusions

We proposed two novel nomogram models based on sex, age and serum NSE levels to preoperatively predict the histologic grades in GEP-NETs to assist the clinical decision-making.