bluuebunny/crossref_metadata_2025 huggingface dataset:
Sodium Valproate Combined With Topiramate vs. Sodium Valproate Alone for Refractory Epilepsy: A Systematic Review and Meta-Analysis
Authors: Ji Zhen-Ye , Huang Yi-Qian , He Wen-Zhen
Published: January 2022

Background: Among antiepileptic drugs (AEDs), sodium valproate alone or in the combination of topiramate (TPM) for treating refractory epilepsy was controversial. This meta-analysis aimed to systematically evaluate the clinical effects of these two regimens in this population.

Methods: Relevant studies up to August 2021 were identified through systematic searches of CNKI, Wanfang, PubMed, and Embase databases. We assessed the effectiveness and the frequency of absence seizures, atonic seizures, and tonic–clonic seizures. The included literature's risk of bias was evaluated using the Cochrane Collaboration's Risk of Bias tool. Sensitivity analysis was conducted to confirm the results' stability. STATA 15.0 was utilized for all pooled analyses in the included studies.

Results: Totally 10 articles were determined for our meta-analysis, involving 976 patients with epilepsy in total (combined group, n = 488; monotherapy group, n = 488). The results of this meta-analysis indicated that the total effective rate of sodium valproate combined with TPM was higher than that of sodium valproate alone (random-effect model: OR = 3.52; 95% CI 1.47 to 8.47; p < 0.001; I2 = 73.8%). The frequency of absence seizures in the combined group was lower (fixed-effect model: WMD = −6.02; 95% CI −6.50 to −5.54; I2 = 0.0%) than that in the monotherapy group, with a statistical difference (p < 0.05). The combined group had lower frequency of atonic seizures (WMD = −4.56, 95% CI −6.02 to −3.10; I2 = 82.6%) and lower frequency of tonic–clonic seizures (WMD = −3.32; 95% CI −4.75 to −1.89; I2 = 96.4%). In addition, the distinct difference of adverse events was non-existent between two groups.

Conclusions: Sodium valproate combined with TPM was more effective than sodium valproate alone for epilepsy therapy. This meta-analysis provides feasibility data for a larger-scale study on AED therapy of refractory epilepsy and may contribute to better therapy strategies for epilepsy clinically.
The NMT Scalp EEG Dataset: An Open-Source Annotated Dataset of Healthy and Pathological EEG Recordings for Predictive Modeling
Authors: Khan Hassan Aqeel , Ul Ain Rahat , Kamboh Awais Mehmood , Butt Hammad Tanveer , Shafait Saima , Alamgir Wasim , Stricker Didier , Shafait Faisal
Published: January 2022

Electroencephalogram (EEG) is widely used for the diagnosis of neurological conditions like epilepsy, neurodegenerative illnesses and sleep related disorders. Proper interpretation of EEG recordings requires the expertise of trained neurologists, a resource which is scarce in the developing world. Neurologists spend a significant portion of their time sifting through EEG recordings looking for abnormalities. Most recordings turn out to be completely normal, owing to the low yield of EEG tests. To minimize such wastage of time and effort, automatic algorithms could be used to provide pre-diagnostic screening to separate normal from abnormal EEG. Data driven machine learning offers a way forward however, design and verification of modern machine learning algorithms require properly curated labeled datasets. To avoid bias, deep learning based methods must be trained on large datasets from diverse sources. This work presents a new open-source dataset, named the NMT Scalp EEG Dataset, consisting of 2,417 recordings from unique participants spanning almost 625 h. Each recording is labeled as normal or abnormal by a team of qualified neurologists. Demographic information such as gender and age of the patient are also included. Our dataset focuses on the South Asian population. Several existing state-of-the-art deep learning architectures developed for pre-diagnostic screening of EEG are implemented and evaluated on the NMT, and referenced against baseline performance on the well-known Temple University Hospital EEG Abnormal Corpus. Generalization of deep learning based architectures across the NMT and the reference datasets is also investigated. The NMT dataset is being released to increase the diversity of EEG datasets and to overcome the scarcity of accurately annotated publicly available datasets for EEG research.
Roots of the Malformations of Cortical Development in the Cell Biology of Neural Progenitor Cells
Authors: Ossola Chiara , Kalebic Nereo
Published: January 2022

The cerebral cortex is a structure that underlies various brain functions, including cognition and language. Mammalian cerebral cortex starts developing during the embryonic period with the neural progenitor cells generating neurons. Newborn neurons migrate along progenitors’ radial processes from the site of their origin in the germinal zones to the cortical plate, where they mature and integrate in the forming circuitry. Cell biological features of neural progenitors, such as the location and timing of their mitoses, together with their characteristic morphologies, can directly or indirectly regulate the abundance and the identity of their neuronal progeny. Alterations in the complex and delicate process of cerebral cortex development can lead to malformations of cortical development (MCDs). They include various structural abnormalities that affect the size, thickness and/or folding pattern of the developing cortex. Their clinical manifestations can entail a neurodevelopmental disorder, such as epilepsy, developmental delay, intellectual disability, or autism spectrum disorder. The recent advancements of molecular and neuroimaging techniques, along with the development of appropriate in vitro and in vivo model systems, have enabled the assessment of the genetic and environmental causes of MCDs. Here we broadly review the cell biological characteristics of neural progenitor cells and focus on those features whose perturbations have been linked to MCDs.
Hypothesis Relating the Structure, Biochemistry and Function of Active Zone Material Macromolecules at a Neuromuscular Junction
Authors: Szule Joseph A.
Published: January 2022

This report integrates knowledge of in situ macromolecular structures and synaptic protein biochemistry to propose a unified hypothesis for the regulation of certain vesicle trafficking events (i.e., docking, priming, Ca2+-triggering, and membrane fusion) that lead to neurotransmitter secretion from specialized “active zones” of presynaptic axon terminals. Advancements in electron tomography, to image tissue sections in 3D at nanometer scale resolution, have led to structural characterizations of a network of different classes of macromolecules at the active zone, called “Active Zone Material’. At frog neuromuscular junctions, the classes of Active Zone Material macromolecules “top-masts”, “booms”, “spars”, “ribs” and “pins” direct synaptic vesicle docking while “pins”, “ribs” and “pegs” regulate priming to influence Ca2+-triggering and membrane fusion. Other classes, “beams”, “steps”, “masts”, and “synaptic vesicle luminal filaments’ likely help organize and maintain the structural integrity of active zones. Extensive studies on the biochemistry that regulates secretion have led to comprehensive characterizations of the many conserved proteins universally involved in these trafficking events. Here, a hypothesis including a partial proteomic atlas of Active Zone Material is presented which considers the common roles, binding partners, physical features/structure, and relative positioning in the axon terminal of both the proteins and classes of macromolecules involved in the vesicle trafficking events. The hypothesis designates voltage-gated Ca2+ channels and Ca2+-gated K+ channels to ribs and pegs that are connected to macromolecules that span the presynaptic membrane at the active zone. SNARE proteins (Syntaxin, SNAP25, and Synaptobrevin), SNARE-interacting proteins Synaptotagmin, Munc13, Munc18, Complexin, and NSF are designated to ribs and/or pins. Rab3A and Rabphillin-3A are designated to top-masts and/or booms and/or spars. RIM, Bassoon, and Piccolo are designated to beams, steps, masts, ribs, spars, booms, and top-masts. Spectrin is designated to beams. Lastly, the luminal portions of SV2 are thought to form the bulk of the observed synaptic vesicle luminal filaments. The goal here is to help direct future studies that aim to bridge Active Zone Material structure, biochemistry, and function to ultimately determine how it regulates the trafficking events in vivo that lead to neurotransmitter secretion.
Pyroptosis Regulators and Tumor Microenvironment Infiltration Characterization in Clear Cell Renal Cell Carcinoma
Authors: Zhang Xi , Wei Xiyi , Wang Yichun , Wang Shuai , Ji Chengjian , Yao Liangyu , Song Ninghong
Published: January 2022

Background

It is well known that chronic inflammation can promote the occurrence and progression of cancer. As a type of proinflammatory death, pyroptosis can recast a suitable microenvironment to promote tumor growth. However, the potential role of pyroptosis in clear cell renal cell carcinoma (ccRCC) remains unclear.

Methods

The transcriptome expression profile and mutation profile data of ccRCC with clinical characteristics included in this study were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Consensus clustering was used for clustering. Gene set enrichment analysis (GSEA) analysis were applied to evaluate the biological mechanisms. Single sample gene set enrichment analysis (ssGSEA) was applied for evaluating the proportion of various immune infiltrating cells. The ESTIMATE algorithm was involved to compute the immune microenvironment scores.

Results

Among the 17 pyroptosis regulators, a total of 15 pyroptosis regulators were differential expressed between tumor and normal tissues, in which 12 of them emerged strong correlations with prognoses. According to the pyroptosis components, the ccRCC patients were divided into four pyroptosis subtypes with different clinical, molecular, and pathway characteristics. Compared with other clusters, cluster B showed the pyroptosis heat phenotype, while cluster D represented the pyroptosis cold phenotype with poor overall survival. In addition, we performed principal component analysis (PCA) on the differential genes between clusters to construct the pyroptosis index. Furthermore, the pyroptosis index was significantly correlated with survival in different tumor mutation statuses and different grades and stages. Besides, the expression of pyroptosis-related regulators was related to the infiltration of immune cells and the expression of immune checkpoints, among which AIM2 was considered as the most significant immune-related pyroptosis regulator. Ultimately, we found that AIM2 was related to the immune activation pathway and was significantly overexpressed in tumor tissues.

Conclusion

This study revealed that pyroptosis regulators and pyroptosis index played an important role in the development and prognoses of ccRCC. Moreover, AIM2 can be used as a predictor of the response of immunotherapy. Assessing the pyroptosis patterns may help evaluate the tumor status and guide immunotherapy strategies.
Case Report: Large Granular Lymphocyte Leukemia (LGLL)—A Case Series of Challenging Presentations
Authors: Pflug Natali , Littauer Annika , Beverungen David , Sretenovic Aleksandra , Wahnschaffe Linus , Braun Till , Dechow Annika , Jungherz Dennis , Otte Moritz , Monecke Astrid , Bach Enrica , Franke Georg-Nikolaus , Schwind Sebastian , Jentzsch Madlen , Platzbecker Uwe , Herling Marco , Vucinic Vladan
Published: January 2022

Large granular lymphocyte leukemia (LGLL) represents a rare group of diseases with considerable difficulties in their correct diagnostic workup and therapy. The major challenges lie in their distinction from reactive (including autoimmune) lymphoproliferations. Moreover, monoclonal LGL proliferative diseases are in fact a heterogeneous group of disorders, as recognized by the three subtypes in the current WHO classification. It distinguishes two chronic forms (the focus of this case series), namely T-LGLL and chronic lymphoproliferative disorders of Natural Killer cells (CLPD-NK) as well as aggressive NK-cell leukemia. In the clinical routine, the variable presentations and phenotypes of T-LGLL and CLPD-NK are underappreciated. The relevant differential diagnoses range from benign reactive T-cell expansions to other mature T-cell leukemias to highly aggressive γδ-lymphomas. T-LGLL or CLPD-NK patients suffer from a wide variety of symptoms often including, but not limited to, cytopenias or classical autoimmune phenomena. They receive treatments ranging from mere supportive measures (e.g. antibiotics, growth factors, transfusions) over strategies of immunosuppression up to anti-leukemic therapies. The diagnostic pitfalls range from recognition of the subtle T-cell proliferation, repeated establishment of monoclonality, assignment to a descript immunophenotypic pattern, and interpretations of molecular aberrancies. Here, we report a series of selected cases to represent the spectrum of LGLL. The purpose is to raise awareness among the scientifically or practically interested readers of the wide variety of clinical, immunological, and phenotypic features of the various forms of LGLL, e.g. of T-cell type, including its γδ forms or those of NK-lineage. We highlight the characteristics and courses of four unique cases from two academic centers, including those from a prospective nationwide LGLL registry. Each case of this instructive catalogue serves to transport a key message from the areas of (chronic inflammatory) contexts in which LGLL can arise as well as from the fields of differential diagnostics and of various treatment options. Implications for optimization in these areas are discussed.
Ex Vivo Chemosensitivity Profiling of Acute Myeloid Leukemia and Its Correlation With Clinical Response and Outcome to Chemotherapy
Authors: Zhang Yi , Ji Min , Zhao Jin-Yan , Wang Hua-Feng , Wang Chong-Wu , Li Wei , Ye Jing-Jing , Lu Fei , Lin Li-Hui , Gao Yan-Ting , Jin Jie , Li Li , Ji Chun-Yan , Ballesteros Joan , Zhu Hong-Hu
Published: January 2022

We evaluated the predictive value of the ex-vivo PharmaFlow PM platform in measuring the pharmacological activity of drug combinations consisting of 20 different chemotherapy regimens (20 Tx) administered in 104 acute myeloid leukemia (AML) patients. The predicted sensitivities of alternative treatments for each patient were ranked in five 20% categories, from resistant to sensitive (Groups 1–5). The complete remission (CR) rates of the five groups were 0%, 12.5%, 38.5%, 50.0%, and 81.3%, respectively. The heat map showed a good relationship between drug sensitivity with CR (Group 4 + 5 vs. Group 1 + 2+3: 77.5% vs. 27.3%, p = 0.002) and the European Leukemia Net risk group (22.6% vs. 63.6%, p = 0.015). The predicted coincidence rate was 90.9% in Group 1 + 2 and 81.3% in Group 5. According to the recommendations of the PharmaFlow PM platform, the CR rate would have increased by about 16.3% in one cycle. The overall survival (OS) was shorter in patients predicted to be resistant (Group 1 + 2 vs. Group 3 + 4+5, p = 0.086). In multivariable analysis, CR after one cycle was an independent prognostic factor for OS [p = 0.001; 95% CI 0.202 (0.080–0.511)], and ex-vivo chemosensitivity was a potential predictive factor for OS [p = 0.078; 95% CI 0.696 (0.465–1.041)]. To conclude, the PharmaFlow PM platform is a rapid and valuable tool for predicting clinical response and outcomes in AML patients.
Clinical Characteristics of Pediatric Respiratory Tract Infection and Respiratory Pathogen Isolation During the Coronavirus Disease 2019 Pandemic
Authors: Tang Xifeng , Dai Ge , Jiang Xiaohui , Wang Ting , Sun Huiming , Chen Zhengrong , Huang Li , Wang Meijuan , Zhu Canhong , Yan Yongdong , Jiang Wujun
Published: January 2022

Objective: We sought to compare the clinical characteristics of pediatric respiratory tract infection and respiratory pathogen isolations during the coronavirus disease (COVID-19) pandemic to those of cases in 2018 and 2019.

Methods: Our study included all children from 28 days to 15 years old with respiratory tract infections who were admitted to the Department of Respiration, in the Children's Hospital of Soochow University, between January 2018 and December 2020. Human rhinovirus (HRV) and human metapneumovirus (hMPV) were detected by reverse transcription polymerase chain reaction (RT-PCR). Mycoplasma pneumoniae (MP) and human bocavirus (HBoV) were detected by real-time fluorescence quantitative polymerase chain reaction (qPCR); In parallel, Mycoplasma pneumoniae was detected by enzyme-linked immunosorbent assays, and bacteria were detected by culture in blood, bronchoalveolar lavage specimen, and pleural fluid.

Results: Compared to 2018 and 2019, the pathogen detection rate was significantly lower in 2020. With regard to infections caused by single pathogens, in 2020, the detection rates of MP were the lowest and those of HRV were the highest when compared to those in 2018 and 2019. Meanwhile, the positive rates of respiratory syncytial virus (RSV) and hMPV reported in 2020 were less than those recorded in 2018 but similar to those recorded in 2019. Also, the 2020 rate of adenovirus (ADV) was lower than that recorded in 2019, but similar to that recorded in 2018. There were no statistical differences in the positive rates of HBoV and PIV III over the 3 years surveyed. Infections in infants were significantly less common in 2020, but no significant difference was found among children aged 1 to 3 years. The detection rate of pathogens in children old than 5 years in 2020 was significantly lower than those recorded in the previous 2 years. Notably, the pathogen detection rates in the first and second quarters of 2020 were similar to those recorded in the previous 2 years; however, the rates were reduced in the third and fourth quarters of 2020. As for co-infections, the positive rate was at its lowest in 2020. In the previous 2 years, viral–MP was the most common type of mixed infection. By contrast, in 2020, viral–viral infections were the most common combination.

Conclusion: The pathogen detection rate was significantly reduced in Suzhou City during the COVID-19 pandemic. Public interventions may help to prevent respiratory pathogen infections in children.
Serum N-Terminal Pro-B-Type Natriuretic Peptide as a Biomarker of Critical Pulmonary Stenosis in Neonates
Authors: Lin Zhiwei , Chen Yanru , Zhou Lin , Chen Sun , Xia Hongping
Published: January 2022

Objectives: To determine the efficacy of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in predicting critical pulmonary stenosis (CPS) in neonates.

Methods: All neonates with pulmonary stenosis (PS) admitted to the neonatal intensive care unit of Xinhua Hospital from October 2014 to December 2020 were retrospectively reviewed. Infants with serum NT-proBNP levels measured within 48 h after birth were enrolled and divided into CPS and non-CPS groups. Serum NT-proBNP levels and cardiac Doppler indices were compared between the two groups. Correlations were determined using the Spearman's rank correlation coefficient. Receiver operator characteristic curve analysis was used to explore the predictive value of NT-proBNP for identifying neonatal CPS.

Results: Among 96 infants diagnosed with PS by echocardiography, 46 were enrolled (21 and 25 in the non-CPS and CPS groups, respectively). Serum NT-proBNP levels were significantly higher in the CPS group than in the non-CPS group [3,600 (2,040–8,251) vs. 1,280 (953–2,386) pg/ml, P = 0.003]. Spearman's analysis suggested a positive correlation between Ln(NT-proBNP) levels and the transvalvular pulmonary gradient (r = 0.311, P = 0.038), as well as between Ln(NT-proBNP) levels and pulmonary artery velocity (r = 0.308, P = 0.040). Receiver operating characteristic curve analysis showed that a cutoff serum NT-proBNP level of 2,395 pg/ml yielded a 66.7 and 78.9% sensitivity and specificity for identifying CPS, respectively. The area under the curve was 0.784 (95% CI, 0.637–0.931). A positive correlation was found between Ln(NT-proBNP) and length of hospital stay (r = 0.312, P < 0.05).

Conclusion: Serum NT-proBNP level was positively correlated with PS severity and could be used as a biomarker to identify CPS in neonates.
Case Report: Sustained Efficacy of Lumasiran at 18 Months in Primary Hyperoxaluria Type 1
Authors: Chiodini Benedetta , Tram Nathalie , Adams Brigitte , Hennaut Elise , Lolin Ksenija , Ismaili Khalid
Published: January 2022

Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, ultimately responsible for kidney stones, kidney failure and systemic oxalosis. Lumasiran, is a liver-directed RNA interference therapeutic agent. It has been shown to reduce hepatic oxalate production by targeting glycolate oxidase, and to dramatically reduce oxalate excretion.

Care Report: We present the case of a teenager patient affected by PH1, who entered in the lumasiran compassionate use program. The patient had a rapid and sustained decrease in urinary oxalate/creatinine ratio, with a mean reduction after lumasiran administration of about 70%. During the 18 months long follow-up, urinary oxalate remained low, reaching nearly normal values. Plasma oxalate also decreased dramatically. Normal levels were reached immediately after the first dose and remained consistently low thereafter. During the same follow-up period, eGFR remained stable at about 60 ml/min/1.73 m2, but no new kidney stones were observed. Existing kidney stones did not increase in size. The patient did not suffer renal colic events and did not require further urological interventions.

Conclusion: In our severely affected PH1 patient, lumasiran proved to be very effective in rapidly and consistently reducing plasma oxalate and urinary excretion to normal and near-normal levels, respectively. In the 18 months long follow-up post-lumasiran, the eGFR remained stable and the patient showed clinical improvements. As far as we know, this report covers the longest observation period after initiation of this novel RNAi therapy.
B. infantis EVC001 Is Well-Tolerated and Improves Human Milk Oligosaccharide Utilization in Preterm Infants in the Neonatal Intensive Care Unit
Authors: Bajorek Sarah , Duar Rebbeca M. , Corrigan Maxwell , Matrone Christa , Winn Kathryn A. , Norman Susan , Mitchell Ryan D. , Cagney Orla , Aksenov Alexander A. , Melnik Alexey V. , Kopylova Evguenia , Perez Jose
Published: January 2022

Not all infants carry specialized gut microbes, meaning they cannot digest human milk oligosaccharides and therefore do not receive complete benefits from human milk. B. infantis EVC001 is equipped to convert the full array of complex oligosaccharides into compounds usable by the infant, making it an ideal candidate to stabilize gut function and improve nutrition in preterm infants. A prospective, open-label study design was used to evaluate the tolerability of B. infantis EVC001 and its effects on the fecal microbiota in preterm infants in a Neonatal Intensive Care Unit. Thirty preterm infants <1,500 g and/or <33 weeks gestation at birth were divided into two matched groups, and control infants were enrolled and discharged prior to enrolling EVC001 infants to prevent cross-colonization of B. infantis: (1) fifteen control infants received no EVC001, and (2) fifteen infants received once-daily feedings of B. infantis EVC001 (8.0 x 109 CFU) in MCT oil. Clinical information regarding medications, growth, nutrition, gastrointestinal events, diagnoses, and procedures was collected throughout admission. Infant stool samples were collected at baseline, Study Days 14 and 28, and 34-, 36-, and 38-weeks of gestation. Taxonomic composition of the fecal microbiota, functional microbiota analysis, B. infantis, and human milk oligosaccharides (HMOs) in the stool were determined or quantified using 16S rRNA gene sequencing, metagenomic sequencing, qPCR, and mass spectrometry, respectively. No adverse events or tolerability issues related to EVC001 were reported. Control infants had no detectable levels of B. infantis. EVC001 infants achieved high levels of B. infantis (mean = 9.7 Log10 CFU/μg fecal DNA) by Study Day 14, correlating with less fecal HMOs (ρ = −0.83, P < 0.0001), indicating better HMO utilization in the gut. In this study, B. infantis EVC001 was shown to be safe, well-tolerated, and efficient in colonizing the preterm infant gut and able to increase the abundance of bifidobacteria capable of metabolizing HMOs, resulting in significantly improved utilization of human milk.

Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT03939546, identifier: NCT03939546.
A Review of Pharmacology, Toxicity and Pharmacokinetics of 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside
Authors: Wang Cheng , Dai Shu , Gong Lihong , Fu Ke , Ma Cheng , Liu Yanfang , Zhou Honglin , Li Yunxia
Published: January 2022

Polygonum multiflorum Thunb. (He-shou-wu in Chinese), a Chinese botanical drug with a long history, is widely used to treat a variety of chronic diseases in clinic, and has been given the reputation of “rejuvenating and prolonging life” in many places. 2,3,4′,5-tetrahydroxystilbene-2-O-β-D-glucoside (TSG, C20H22O9) is the main and unique active ingredient isolated from Polygonum multiflorum Thunb., which has extensive pharmacological activities. Modern pharmacological studies have confirmed that TSG exhibits significant activities in treating various diseases, including inflammatory diseases, neurodegenerative diseases, cardiovascular diseases, hepatic steatosis, osteoporosis, depression and diabetic nephropathy. Therefore, this review comprehensively summarizes the pharmacological and pharmacokinetic properties of TSG up to 2021 by searching the databases of Web of Science, PubMed, ScienceDirect and CNKI. According to the data, TSG shows remarkable anti-inflammation, antioxidation, neuroprotection, cardiovascular protection, hepatoprotection, anti-osteoporosis, enhancement of memory and anti-aging activities through regulating multiple molecular mechanisms, such as NF-κB, AMPK, PI3K-AKT, JNK, ROS-NO, Bcl-2/Bax/Caspase-3, ERK1/2, TGF-β/Smad, Nrf2, eNOS/NO and SIRT1. In addition, the toxicity and pharmacokinetics of TSG are also discussed in this review, which provided direction and basis for the further development and clinical application of TSG.
Discovery of Small Molecule NSC290956 as a Therapeutic Agent for KRas Mutant Non-Small-Cell Lung Cancer
Authors: Zhang Jiaxin , Liu Zuojia , Zhao Wenjing , Yin Xunzhe , Zheng Xiliang , Liu Chuanbo , Wang Jin , Wang Erkang
Published: January 2022

HRas-GTP has a transient intermediate state with a “non-signaling open conformation” in GTP hydrolysis and nucleotide exchange. Due to the same hydrolysis process and the structural homology, it can be speculated that the active KRas adopts the same characteristics with the “open conformation.” This implies that agents locking this “open conformation” may theoretically block KRas-dependent signaling. Applying our specificity-affinity drug screening approach, NSC290956 was chosen by high affinity and specificity interaction with the “open conformation” structure HRasG60A-GppNp. In mutant KRas-driven non-small-cell lung cancer (NSCLC) model system, NSC290956 effectively suppresses the KRas-GTP state and gives pharmacological KRas inhibition with concomitant blockages of both the MAPK-ERK and AKT-mTOR pathways. The dual inhibitory effects lead to the metabolic phenotype switching from glycolysis to mitochondrial metabolism, which promotes the cancer cell death. In the xenograft model, NSC290956 significantly reduces H358 tumor growth in nude mice by mechanisms similar to those observed in the cells. Our work indicates that NSC290956 can be a promising agent for the mutant KRas-driven NSCLC therapy.
The Interaction Between Pulmonary Fibrosis and COVID-19 and the Application of Related Anti-Fibrotic Drugs
Authors: Shen Hao , Zhang Nu , Liu Yuqing , Yang Xuerong , He Yuanyuan , Li Qi , Shen Xiaoyan , Zhu Yulian , Yang Yong
Published: January 2022

COVID-19 is a highly contagious respiratory disease, which mainly affects the lungs. Critically ill patients are easily complicated by cytokine storms, acute respiratory distress syndrome (ARDS), and respiratory failure, which seriously threaten their lives. Pulmonary fibrosis (PF) is a common interstitial lung disease, and its pathogenesis may involve the participation of a variety of immune cells and inflammatory factors. Current studies have shown that patients with COVID-19 may be complicated by pulmonary fibrosis, and patients with pulmonary fibrosis may also be at higher risk of contracting COVID-19 than healthy people. Pulmonary fibrosis is an important risk factor leading to the aggravation of COVID-19 disease. COVID-19 complicated by cytokine storm and ARDS mechanism pathways are similar to the pathogenesis of pulmonary fibrosis. The potential interaction between pulmonary fibrosis and COVID-19 can cause acute exacerbation of the patient’s condition, but the potential mechanism between the two has not been fully elucidated. Most of the drug treatment programs for COVID-19-related pulmonary fibrosis are currently formulated about the relevant guidelines for idiopathic pulmonary fibrosis (IPF), and there is no clear drug treatment program recommendation. This article aims to summarize the relevant mechanism pathways of COVID-19 and pulmonary fibrosis, explore the interrelationships and possible mechanisms, and discuss the value and risks of existing and potential COVID-19-related pulmonary fibrosis treatment drugs, to provide reference for anti-fibrosis treatment for patients.
Research Progress on Leucine-Rich Alpha-2 Glycoprotein 1: A Review
Authors: Zou Yonghui , Xu Yi , Chen Xiaofeng , Wu Yaoqi , Fu Longsheng , Lv Yanni
Published: January 2022

Leucine-rich alpha⁃2 glycoprotein 1 (LRG1) is an important member of the leucine-rich repetitive sequence protein family. LRG1 was mainly involved in normal physiological activities of the nervous system, such as synapse formation, synapse growth, the development of nerve processes, neurotransmitter transfer and release, and cell adhesion molecules or ligand-binding proteins. Also, LRG1 affected the development of respiratory diseases, hematological diseases, endocrine diseases, tumor diseases, eye diseases, cardiovascular diseases, rheumatic immune diseases, infectious diseases, etc. LRG1 was a newly discovered important upstream signaling molecule of transforming growth factor⁃β (TGF⁃β) that affected various pathological processes through the TGF⁃β signaling pathway. However, research on LRG1 and its involvement in the occurrence and development of diseases was still in its infancy and the current studies were mainly focused on proteomic detection and basic animal experimental reports. We could reasonably predict that LRG1 might act as a new direction and strategy for the treatment of many diseases.
Effects of Measurement Configurations on the Sensitivity of Morpho Butterfly Scales Based Chemical Biosensor
Authors: Dong Zhengqiong , Zhao Hang , Nie Lei , Tang Shaokang , Li Chenyang , Wang Xuanze
Published: January 2022

The Morpho butterfly wing with tree-shaped alternating multilayer is an effective chemical biosensor to distinguish between ambient medium, and its detection sensitivity is inextricably linked to the measurement configuration including incident angle, azimuthal angle, and so on. In order to reveal the effects and the selection of measurement configuration. In this work, the model of the Morpho butterfly wing is built using the rigorous coupled-wave analysis method by considering its profile is a rectangular-groove grating. On basis of the above model, the reflectivity of different diffraction orders at a different incident angle and azimuthal angle is calculated, and the influence of incident angle and azimuthal angle on performance of Morpho butterfly scales-based biosensor is analyzed. The optimal incident angle at each azimuthal angle is given according to the proposed choice rule, then the azimuthal angle and the corresponding incident angle can be selected further.
Ultrasonic Elastography of the Rectus Femoris, a Potential Tool to Predict Sarcopenia in Patients With Chronic Obstructive Pulmonary Disease
Authors: Deng Mingming , Zhou Xiaoming , Li Yanxia , Yin Yan , Liang Chaonan , Zhang Qin , Lu Jingwen , Wang Mengchan , Wang Yu , Sun Yue , Li Ruixia , Yan Liming , Wang Qiuyue , Hou Gang
Published: January 2022

Purpose: Skeletal muscle dysfunction is common in patients with chronic obstructive pulmonary disease (COPD) and is associated with a poor prognosis. Abnormal muscle quantity of the lower limbs is a manifestation of skeletal muscle dysfunction in patients with COPD. Shear wave ultrasound elastography (SWE) is a novel and possible tool to evaluate qualitative muscle parameters. This study explores the feasibility of SWE to measure the stiffness of the rectus femoris and evaluates its value in predicting sarcopenia in patients with COPD.

Methods: Ultrasound examination of the rectus femoris was performed to determine the mean elasticity index (SWEmean), cross-sectional area (RFcsa), and thickness (RFthick) using grayscale ultrasonography (US) and SWE in 53 patients with COPD and 23 age-matched non-COPD healthy controls. The serum levels of circulating biomarkers (GDF15, resistin, and TNF-α) were measured using ELISA. The definition of sarcopenia followed the guidelines from the Asian Working Group for Sarcopenia. Receiver operating characteristic (ROC) curve analysis of the SWEmean, RFthick, and RFcsa was used to evaluate their predictive ability for sarcopenia.

Results: The intraobserver and interobserver repeatability of SWE performance was excellent (all correlation coefficients > 0.95; p < 0.05). The SWEmean of the rectus femoris in patients with COPD (8.98 ± 3.12 kPa) was decreased compared with that in healthy controls (17.00 ± 5.14 kPa) and decreased with advanced global initiative for chronic obstructive lung disease (GOLD) stage. Furthermore, SWEmean was found to be independent of sex, height, and body mass, and a lower SWEmean in patients with COPD was positively associated with reduced pulmonary function, worse physical function, poor exercise tolerance, decreased muscle strength, and worse dyspnea index score. The correlation between physical function [five-repetition sit-to-stand test (5STST)], muscle function, and SWEmean was higher than those of RFthick and RFcsa. In addition, SWEmean was negatively correlated with serum GDF15 levels (r = −0.472, p < 0.001), serum resistin levels (r = −0.291, p = 0.035), and serum TNF-α levels (r = −0.433, p = 0.001). Finally, the predictive power of SWEmean [area under the curve (AUC): 0.863] in the diagnosis of sarcopenia was higher than that of RFthick (AUC: 0.802) and RFcsa (AUC: 0.816).

Conclusion: Compared with grayscale US, SWE was not affected by the patient’s height, weight, or BMI and better represented skeletal muscle function and physical function. Furthermore, SWE is a promising potential tool to predict sarcopenia in patients with COPD.
Equal-Volume Strength Training With Different Training Frequencies Induces Similar Muscle Hypertrophy and Strength Improvement in Trained Participants
Authors: Hamarsland Håvard , Moen Hermann , Skaar Ole Johannes , Jorang Preben Wahlstrøm , Rødahl Håvard Saeterøy , Rønnestad Bent R.
Published: January 2022

The main goal of the current study was to compare the effects of volume-equated training frequency on gains in muscle mass and strength. In addition, we aimed to investigate whether the effect of training frequency was affected by the complexity, concerning the degrees of freedom, of an exercise. Participants were randomized to a moderate training frequency group (two weekly sessions) or high training frequency group (four weekly sessions). Twenty-one participants (male: 11, female: 10, age: 25.9 ± 4.0) completed the 9-week whole-body progressive heavy resistance training intervention with moderate (n = 13) or high (n = 8) training frequency. Whole-body and regional changes in lean mass were measured using dual-energy x-ray absorptiometry, while the vastus lateralis thickness was measured by ultrasound. Changes in muscle strength were measured as one repetition maximum for squat, hack squat, bench press, and chest press. No differences between groups were observed for any of the measures of muscle growth or muscle strength. Muscle strength increased to a greater extent in hack squat and chest press than squat and bench press for both moderate (50 and 21% vs. 19 and 14%, respectively) and high-frequency groups (63 and 31% vs. 19 and 16%, respectively), with no differences between groups. These results suggest that training frequency is less decisive when weekly training volume is equated. Further, familiarity with an exercise seems to be of greater importance for strength adaptations than the complexity of the exercise.
Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels
Authors: Dixon Rose E.
Published: January 2022

The architectural specializations and targeted delivery pathways of cardiomyocytes ensure that L-type Ca2+ channels (CaV1.2) are concentrated on the t-tubule sarcolemma within nanometers of their intracellular partners the type 2 ryanodine receptors (RyR2) which cluster on the junctional sarcoplasmic reticulum (jSR). The organization and distribution of these two groups of cardiac calcium channel clusters critically underlies the uniform contraction of the myocardium. Ca2+ signaling between these two sets of adjacent clusters produces Ca2+ sparks that in health, cannot escalate into Ca2+ waves because there is sufficient separation of adjacent clusters so that the release of Ca2+ from one RyR2 cluster or supercluster, cannot activate and sustain the release of Ca2+ from neighboring clusters. Instead, thousands of these Ca2+ release units (CRUs) generate near simultaneous Ca2+ sparks across every cardiomyocyte during the action potential when calcium induced calcium release from RyR2 is stimulated by depolarization induced Ca2+ influx through voltage dependent CaV1.2 channel clusters. These sparks summate to generate a global Ca2+ transient that activates the myofilaments and thus the electrical signal of the action potential is transduced into a functional output, myocardial contraction. To generate more, or less contractile force to match the hemodynamic and metabolic demands of the body, the heart responds to β-adrenergic signaling by altering activity of calcium channels to tune excitation-contraction coupling accordingly. Recent accumulating evidence suggests that this tuning process also involves altered expression, and dynamic reorganization of CaV1.2 and RyR2 channels on their respective membranes to control the amplitude of Ca2+ entry, SR Ca2+ release and myocardial function. In heart failure and aging, altered distribution and reorganization of these key Ca2+ signaling proteins occurs alongside architectural remodeling and is thought to contribute to impaired contractile function. In the present review we discuss these latest developments, their implications, and future questions to be addressed.
The Roles of Floral Organ Genes in Regulating Rosaceae Fruit Development
Authors: Yao Jia-Long , Kang Chunying , Gu Chao , Gleave Andrew Peter
Published: January 2022

The function of floral organ identity genes, APETALA1/2/3, PISTILLATA, AGAMOUS, and SEPALLATA1/2/3, in flower development is highly conserved across angiosperms. Emerging evidence shows that these genes also play important roles in the development of the fruit that originates from floral organs following pollination and fertilization. However, their roles in fruit development may vary significantly between species depending on the floral organ types contributing to the fruit tissues. Fruits of the Rosaceae family develop from different floral organ types depending on the species, for example, peach fruit flesh develops from carpellary tissues, whereas apple and strawberry fruit flesh develop from extra-carpellary tissues, the hypanthium and receptacle, respectively. In this review, we summarize recent advances in understanding floral organ gene function in Rosaceae fruit development and analyze the similarities and diversities within this family as well as between Rosaceae and the model plant species Arabidopsis and tomato. We conclude by suggesting future research opportunities using genomics resources to rapidly dissect gene function in this family of perennial plants.
Screening of Onion (Allium cepa L.) Genotypes for Waterlogging Tolerance
Authors: Gedam Pranjali A. , Shirsat Dhananjay V. , Arunachalam Thangasamy , Ghosh Sourav , Gawande Suresh J. , Mahajan Vijay , Gupta Amar Jeet , Singh Major
Published: January 2022

Onion production is severely affected by waterlogging conditions, which are created due to heavy rainfall. Hence, the identification of waterlogging-tolerant onion genotypes is crucial for increasing onion production. In the present study, 100 distinct onion genotypes were screened for waterlogging tolerance under artificial conditions by using the phenotypic approach in the monsoon season of 2017. Based on plant survival and recovery and changes in bulb weight, we identified 19 tolerant, 27 intermediate tolerant, and 54 highly sensitive onion genotypes. The tolerant genotypes exhibited higher plant survival and better recovery and bulb size, whereas sensitive genotypes exhibited higher plant mortality, poor recovery, and small bulb size under waterlogging conditions. Furthermore, a subset of 12 contrasting genotypes was selected for field trials during monsoon seasons 2018 and 2019. Results revealed that considerable variation in the morphological, physiological, and yield characteristics were observed across the genotypes under stress conditions. Waterlogging-tolerant genotypes, namely, Acc. 1666, Acc. 1622, W-355, W-208, KH-M-2, and RGP-5, exhibited higher plant height, leaf number, leaf area, leaf length, chlorophyll content, membrane stability index (MSI), pyruvic acid, antioxidant content, and bulb yield than sensitive genotypes under stress conditions. Furthermore, the principal component analysis biplot revealed a strong association of leaf number, leaf area, chlorophyll content, MSI, and bulb yield with tolerant genotypes under stress conditions. The study indicates that the waterlogging-tolerant onion genotypes with promising stress-adaptive traits can be used in plant breeding programs for developing waterlogging-tolerant onion varieties.
Exploiting High-Throughput Indoor Phenotyping to Characterize the Founders of a Structured B. napus Breeding Population
Authors: Ebersbach Jana , Khan Nazifa Azam , McQuillan Ian , Higgins Erin E. , Horner Kyla , Bandi Venkat , Gutwin Carl , Vail Sally Lynne , Robinson Steve J. , Parkin Isobel A. P.
Published: January 2022

Phenotyping is considered a significant bottleneck impeding fast and efficient crop improvement. Similar to many crops, Brassica napus, an internationally important oilseed crop, suffers from low genetic diversity, and will require exploitation of diverse genetic resources to develop locally adapted, high yielding and stress resistant cultivars. A pilot study was completed to assess the feasibility of using indoor high-throughput phenotyping (HTP), semi-automated image processing, and machine learning to capture the phenotypic diversity of agronomically important traits in a diverse B. napus breeding population, SKBnNAM, introduced here for the first time. The experiment comprised 50 spring-type B. napus lines, grown and phenotyped in six replicates under two treatment conditions (control and drought) over 38 days in a LemnaTec Scanalyzer 3D facility. Growth traits including plant height, width, projected leaf area, and estimated biovolume were extracted and derived through processing of RGB and NIR images. Anthesis was automatically and accurately scored (97% accuracy) and the number of flowers per plant and day was approximated alongside relevant canopy traits (width, angle). Further, supervised machine learning was used to predict the total number of raceme branches from flower attributes with 91% accuracy (linear regression and Huber regression algorithms) and to identify mild drought stress, a complex trait which typically has to be empirically scored (0.85 area under the receiver operating characteristic curve, random forest classifier algorithm). The study demonstrates the potential of HTP, image processing and computer vision for effective characterization of agronomic trait diversity in B. napus, although limitations of the platform did create significant variation that limited the utility of the data. However, the results underscore the value of machine learning for phenotyping studies, particularly for complex traits such as drought stress resistance.
Quantitative Trait Loci Mapping and Development of KASP Marker Smut Screening Assay Using High-Density Genetic Map and Bulked Segregant RNA Sequencing in Sugarcane (Saccharum spp.)
Authors: Gao Yijing , Zhou Shan , Huang Yuxin , Zhang Baoqing , Xu Yuhui , Zhang Gemin , Lakshmanan Prakash , Yang Rongzhong , Zhou Hui , Huang Dongliang , Liu Junxian , Tan Hongwei , He Weizhong , Yang Cuifang , Duan Weixing
Published: January 2022

Sugarcane is one of the most important industrial crops globally. It is the second largest source of bioethanol, and a major crop for biomass-derived electricity and sugar worldwide. Smut, caused bySporisorium scitamineum, is a major sugarcane disease in many countries, and is managed by smut-resistant varieties. In China, smut remains the single largest constraint for sugarcane production, and consequently it impacts the value of sugarcane as an energy feedstock. Quantitative trait loci (QTLs) associated with smut resistance and linked diagnostic markers are valuable tools for smut resistance breeding. Here, we developed an F1population (192 progeny) by crossing two sugarcane varieties with contrasting smut resistance and used for genome-wide single nucleotide polymorphism (SNP) discovery and mapping, using a high-throughput genotyping method called “specific locus amplified fragment sequencing (SLAF-seq) and bulked-segregant RNA sequencing (BSR-seq). SLAF-seq generated 148,500 polymorphic SNP markers. Using SNP and previously identified SSR markers, an integrated genetic map with an average 1.96 cM marker interval was produced. With this genetic map and smut resistance scores of the F1individuals from four crop years, 21 major QTLs were mapped, with a phenotypic variance explanation (PVE) > 8.0%. Among them, 10 QTLs were stable (repeatable) with PVEs ranging from 8.0 to 81.7%. Further, four QTLs were detected based on BSR-seq analysis. aligning major QTLs with the genome of a sugarcane progenitorSaccharum spontaneum, six markers were found co-localized. Markers located in QTLs and functional annotation of BSR-seq-derived unigenes helped identify four disease resistance candidate genes located in major QTLs. 77 SNPs from major QTLs were then converted to Kompetitive Allele-Specific PCR (KASP) markers, of which five were highly significantly linked to smut resistance. The co-localized QTLs, candidate resistance genes, and KASP markers identified in this study provide practically useful tools for marker-assisted sugarcane smut resistance breeding.