bluuebunny/crossref_metadata_2025 huggingface dataset:
Robust Prediction of Immune Checkpoint Inhibition Therapy for Non-Small Cell Lung Cancer
Authors: Jiang Jiehan , Jin Zheng , Zhang Yiqun , Peng Ling , Zhang Yue , Zhu Zhiruo , Wang Yaohui , Tong De , Yang Yining , Wang Jianfei , Yang Yadong , Xiao Kui
Published: April 2021

Background

The development of immune checkpoint inhibitors (ICIs) is a revolutionary milestone in the field of immune-oncology. However, the low response rate is the major problem of ICI treatment. The recent studies showed that response rate to single-agent programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibition in unselected non-small cell lung cancer (NSCLC) patients is 25% so that researchers defined several biomarkers to predict the response of immunotherapy in ICIs treatment. Common biomarkers like tumor mutational burden (TMB) and PD-L1 expression have several limitations, such as low accuracy and inadequately validated cutoff value.

Methods

Two published and an unpublished ICIs treatment NSCLC cohorts with 129 patients were collected and divided into a training cohort (n = 53), a validation cohort (n = 22), and two independent test cohorts (n = 34 and n = 20). We identified six immune-related pathways whose mutational status was significantly associated with overall survival after ICIs treatment. Then these pathways mutational status combined with TMB, PD-L1 expression and intratumor heterogeneity were incorporated to build a Bayesian-regularization neural networks (BRNN) model to predict the ICIs treatment response.

Results

We firstly proved that TMB, PD-L1, and mutant-allele tumor heterogeneity (MATH) were independent biomarkers. The survival analysis of six immune-related pathways revealed the mutational status could distinguish overall survival after ICIs treatment. When predicting immunotherapy efficacy, the overall accuracy of area under curve (AUC) in validation cohort reaches 0.85, outperforming previous predictors in either sensitivity or specificity. And the AUC in two independent test cohorts reach 0.74 and 0.80.

Conclusion

We developed a pathway-model that could predict the efficacy of ICIs in NSCLC patients. Our study made a significant contribution to solving the low prediction accuracy of immunotherapy of single biomarker. With the accumulation of larger data sets, further studies are warranted to refine the predictive performance of the approach.
Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway
Authors: Gui Zeping , Suo Chuanjian , Wang Zijie , Zheng Ming , Fei Shuang , Chen Hao , Sun Li , Han Zhijian , Tao Jun , Ju Xiaobin , Yang Haiwei , Gu Min , Tan Ruoyun
Published: April 2021

Chronic renal graft dysfunction (CAD) is caused by multiple factors, including glomerular sclerosis, inflammation, interstitial fibrosis and tubular atrophy (IF/TA). However, the most prominent elements of CAD are IF/TA. Our studies have confirmed that endothelial-mesenchymal transition (EndMT) is an important source to allograft IF/TA. The characteristic of EndMT is the loss of endothelial marker and the acquisition of mesenchymal or fibroblastic phenotypes. Autophagy is an intracellular degradation pathway that is regulated by autophagy-related proteins and plays a vital role in many fibrotic conditions. However, whether or not autophagy contributes to fibrosis of renal allograft and how such mechanism occurs still remains unclear. Autophagy related 16 like gene (ATG16L) is a critical autophagy-related gene (ARG) necessary for autophagosome formation. Here, we first analyzed kidney transplant patient tissues from Gene Expression Omnibus (GEO) datasets and 60 transplant patients from our center. Recipients with stable kidney function were defined as non-CAD group and all patients in CAD group were histopathologically diagnosed with CAD. Results showed that ATG16L, as one significant differential ARG, was less expressed in CAD group compared to the non-CAD group. Furthermore, we found there were less autophagosomes and autolysosomes in transplanted kidneys of CAD patients, and downregulation of autophagy is a poor prognostic factor. In vitro, we found out that the knockdown of ATG16L enhanced the process of EndMT in human renal glomerular endothelial cells (HRGECs). In vivo, the changes of EndMT and autophagic flux were then detected in rat renal transplant models of CAD. We demonstrated the occurrence of EndMT, and indicated that abundance of ATG16L was accompanied by the dynamic autophagic flux change along different stages of kidney transplantation. Mechanistically, knockdown of ATG16L, specifically in endothelial cells, reduced of NF-κB degradation and excreted inflammatory cytokines (IL-1β, IL-6 and TNF-α), which could facilitate EndMT. In conclusion, ATG16L-dependent autophagic flux causing by transplant showed progressive loss increase over time. Inflammatory cytokines from this process promoted EndMT, thereby leading to progression of CAD. ATG16L served as a negative regulator of EndMT and development of renal graft fibrosis, and autophagy can be explored as a potential therapeutic target for chronic renal graft dysfunction.
Baricitinib Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating the Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathway
Authors: Dang Chun , Lu Yaoheng , Chen Xingyu , Li Qian
Published: April 2021

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) and a CD4+ T cell-mediated autoimmune disease. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is recognized as the major mechanism that regulates the differentiation and function of T helper (Th) 1 and Th17 cells, which are recognized as pivotal effector cells responsible for the development of EAE. We used baricitinib, a JAK 1/2 inhibitor, to investigate the therapeutic efficacy of inhibiting the JAK/STAT pathway in EAE mice. Our results showed that baricitinib significantly delayed the onset time, decreased the severity of clinical symptoms, shortened the duration of EAE, and alleviated demyelination and immune cell infiltration in the spinal cord. In addition, baricitinib treatment downregulated the proportion of interferon-γ+CD4+ Th1 and interleukin-17+CD4+ Th17 cells, decreased the levels of retinoic acid-related orphan receptor γ t and T-bet mRNA, inhibited lymphocyte proliferation, and decreased the expression of proinflammatory cytokines and chemokines in the spleen of mice with EAE. Furthermore, our results showed the role of baricitinib in suppressing the phosphorylation of STATs 1, 3, and 4 in the spleen of EAE mice. Therefore, our study demonstrates that baricitinib could potentially alleviate inflammation in mice with EAE and may be a promising candidate for treating MS.
Control of T Cell Metabolism by Cytokines and Hormones
Authors: Bishop Emma L. , Gudgeon Nancy , Dimeloe Sarah
Published: April 2021

Dynamic, coordinated changes in metabolic pathway activity underpin the protective and inflammatory activity of T cells, through provision of energy and biosynthetic precursors for effector functions, as well as direct effects of metabolic enzymes, intermediates and end-products on signaling pathways and transcriptional mechanisms. Consequently, it has become increasingly clear that the metabolic status of the tissue microenvironment directly influences T cell activity, with changes in nutrient and/or metabolite abundance leading to dysfunctional T cell metabolism and interlinked immune function. Emerging evidence now indicates that additional signals are integrated by T cells to determine their overall metabolic phenotype, including those arising from interaction with cytokines and hormones in their environment. The impact of these on T cell metabolism, the mechanisms involved and the pathological implications are discussed in this review article.
Coastal Garbage Patches: Fronts Accumulate Plastic Films at Ashmore Reef Marine Park (Pulau Pasir), Australia
Authors: Hajbane Sara , Calmanovici Bruna , Reisser Julia , Jolly Adam , Summers Vyvyan , Ferrari Francesco , Ghadouani Anas , Pattiaratchi Charitha
Published: April 2021

Millions of tons of buoyant plastic materials enter oceans annually, the majority originating from terrestrial sources and transported to oceans where oceanographic processes disperse or accumulate them. Some of these materials beach while others accumulate in convergent zones in coastal seas and the open ocean. Although accumulations associated with subtropical gyres, for example, the “Great Pacific Garbage Patch” (GPGP) are well-known, coastal accumulation zones have received less attention. Here we report quantities and characteristics of plastics accumulated in fronts encountered within the Ashmore Reef marine park (Pulau Pasir), northern Australia. These areas, as well as surrounding waters, were sampled using Manta trawls, drone, and snorkel surveys conducted in October 2018. With mean plastic concentrations of 523,146 pieces km−2 for plastics > 500 micron these hotpots contained plastic concentrations an order of magnitude higher than surrounding waters (16,561 pieces km−2) and comparable to the largest known accumulation zone: the GPGP. Furthermore, the mean mass within hotspots was 5,161 g km–2 vs. 9 g km–2 in surrounding waters. Therefore, we classify the features described in this study as types of “Coastal Garbage Patches” (CGPs). Importantly, the coastal fronts accumulating plastics in CGPs are key habitats for many marine species. Biomass outnumbered plastics by weight, with a ratio of 0.521 in CGPs and 0.016 in surrounding waters vs. 287.7 recorded in the GPGP. Polymer types found between the CGPs and GPGP were similar, but plastic films vastly dominated in the CGPs, whilst they were amongst the rarest types found in the GPGP. This study demonstrates the existence of CGPs coinciding with high priority conservation zones in coastal waters and highlights a need for further research into these environments.
Differential Effects of Substrate Type and Genet on Growth of Microfragments of Acropora palmata
Authors: Papke Erin , Wallace Bailey , Hamlyn Sarah , Nowicki Robert
Published: April 2021

Global decline of coral reefs has led to a widespread adoption of asexual propagation techniques for coral restoration, whereby coral colonies are fragmented and allowed to re-grow before being returned to the reef. While this approach has become increasingly popular and successful, many questions remain regarding best practices to maximize restoration speed, efficiency, and survival. Two variables that may influence growth and survival of asexually fragmented colonies include coral genet and growth substrate. Here, we evaluate the effects of genet and substrate (commercially available ceramic vs. in-house made cement) on the survival and growth of 221 microfragments of elkhorn coral Acropora palmata over 193 days. All corals survived the experimental period, and doubled their initial size in 45 days, with an average growth of 545% over the study duration. Growth was generally linear, though the growth of some corals more closely matched logistic, logarithmic, or exponential curves. Both genet and substrate had significant effects on coral growth, though the two factors did not interact. Genet had a stronger influence on coral growth than substrate, with the fastest genet growing at 216% the rate of the slowest genet. Corals on cement substrate grew at 111.9% the rate of those grown on ceramic. This represents both a significant cost savings and elimination of logistical challenges to restoration practitioners, as the cement substrate ingredients are cheap and globally available. Our work shows that both genet and substrate should be considered when undertaking asexual restoration of Acropora palmata to maximize restoration speed and efficiency.
Optimal Spatiotemporal Scales to Aggregate Satellite Ocean Color Data for Nearshore Reefs and Tropical Coastal Waters: Two Case Studies
Authors: Geiger Erick F. , Heron Scott F. , Hernández William J. , Caldwell Jamie M. , Falinski Kim , Callender Tova , Greene Austin L. , Liu Gang , De La Cour Jacqueline L. , Armstrong Roy A. , Donahue Megan J. , Eakin C. Mark
Published: April 2021

Remotely sensed ocean color data are useful for monitoring water quality in coastal environments. However, moderate resolution (hundreds of meters to a few kilometers) satellite data are underutilized in these environments because of frequent data gaps from cloud cover and algorithm complexities in shallow waters. Aggregating satellite data over larger space and time scales is a common method to reduce data gaps and generate a more complete time series, but potentially smooths out the small-scale, episodic changes in water quality that can have ecological influences. By comparing aggregated satellite estimates of Kd(490) with related in-water measurements, we can understand the extent to which aggregation methods are viable for filling gaps while being able to characterize ecologically relevant water quality conditions. In this study, we tested a combination of six spatial and seven temporal scales for aggregating data from the VIIRS instrument at several coral reef locations in Maui, Hawai‘i and Puerto Rico and compared these with in situ measurements of Kd(490) and turbidity. In Maui, we found that the median value of a 5-pixels, 7-days spatiotemporal cube of satellite data yielded a robust result capable of differentiating observations across small space and time domains and had the best correlation among spatiotemporal cubes when compared with in situ Kd(490) across 11 nearshore sites (R2 = 0.84). We also found long-term averages (i.e., chronic condition) of VIIRS data using this aggregation method follow a similar spatial pattern to onshore turbidity measurements along the Maui coast over a three-year period. In Puerto Rico, we found that the median of a 13-pixels, 13-days spatiotemporal cube of satellite data yielded the best overall result with an R2 = 0.54 when compared with in situ Kd(490) measurements for one nearshore site with measurement dates spanning 2016–2019. As spatiotemporal cubes of different dimensions yielded optimum results in the two locations, we recommend local analysis of spatial and temporal optima when applying this technique elsewhere. The use of satellite data and in situ water quality measurements provide complementary information, each enhancing understanding of the issues affecting coastal ecosystems, including coral reefs, and the success of management efforts.
Assessment of Water Quality Along the Southeast Coast of India During COVID-19 Lockdown
Authors: Vijay Prakash K. , Geetha Vimala Ch. S. , Preethi Latha T. , Jayaram Chiranjivi , Nagamani P. V. , Laxmi Ch. N. V.
Published: April 2021

The COVID-19 pandemic has affected the entire world and has had a devastating impact on both lives and livelihoods in India. The only way to defeat the rapid spread of COVID-19, is to shut down socio-economic activities and to maintain minimal human interaction with the implementation of a lockdown. Such lockdowns have manifested in a pollution curtailment in almost all spheres of the planet, including in marine pollution. Quantifying this decrease in pollution levels enables the scientific community to assess the contribution of anthropogenic (especially non-essential) activities to global/regional pollution levels. This paper aims to study the impact of the stringent lockdown period (phase 1 and 2) on coastal water quality along the Chennai coast of India, by analyzing suspended matter concentration (SPM), a key element of water quality and diffuse attenuation coefficient, Kd(490), using LANDSAT-8 Operational Land Imager (OLI) data. LANDSAT-8/OLI, L1TP scenes were subjected to radiometric calibration and atmospheric correction to derive surface reflectance values from raw digital numbers using ACOLITE software and a brief insight has been given for the Dark Spectrum Fitting algorithm used in ACOLITE. SPM concentration decreased by 15.48 and 37.50% in the Chennai and Ennore ports, respectively, due to minimal vessel movement and cargo handling. The stringent lockdown led to the operation of fewer thermal plant units, thus less fly ash was emanated, resulting in a 28.05% reduction in SPM levels over Ennore creek. As industrial and commercial activities subsided, the city’s water bodies became clearer than they were just a fortnight prior to the lockdown, with a reduction of 22.26% of SPM in Adyar and 33.97% in Cooum riverine estuaries. Decrease in Kd(490) showed a positive relationship with SPM and thus improved coastal water quality because of the reduction of SPM during this period. The variations in PM2.5 and PM10 concentrations were studied using National Air Quality Monitoring Programme (NAMP) data and reduced levels in particulate matter concentration (PM2.5 and PM10) for the Adyar residential area (24.38 and 28.43%) and for the Nungampakkam commercial area (36.09 and 67.18%) were observed. A significant reduction in PM2.5 concentration (45.63%) was observed in the Ennore-Manali Industrial region.
An Anodized Titanium/Sol-Gel Composite Coating with Self-Healable Superhydrophobic and Oleophobic Property
Authors: Li Tinghua , Dong Chongjian , Liu Yupeng , Wu Jun , Zhang Xia , Gong Xiaowei , Zhao Wei , Wang Daoai , Zhu Donglai
Published: April 2021

Superhydrophobic and oleophobic surfaces have attracted increasing attention because of their self-cleaning properties. A composite coating composed of anodized titanium and sol-gel (TiAO/SG) was developed and has good superhydrophobic and oleophobic property. The anodized titanium coating was prepared on the titanium substrate and then a sol-gel layer was coated on the surface of the anodized titanium layer to obtain a composite coating with superhydrophobic and oleophobic properties. The adhesion weight of glycerol on the surface of the superhydrophobic titanium wire decreased to 4.8% of that of untreated titanium wire, which showed that the material had good oleophobic property. This new composite coating could achieve self-healing superhydrophobicity by releasing loaded perfluorodenytriethoxysilane to the surface of the coating. Given its superhydrophobicity, self-healing and wear resistance, the TiAO/SG coating was expected to achieve healable self-cleaning protection in titanium devices.
Field–Frequency-Dependent Non-linear Rheological Behavior of Magnetorheological Grease Under Large Amplitude Oscillatory Shear
Authors: Wang Huixing , Chang Tianxiao , Li Yancheng , Li Shaoqi , Zhang Guang , Wang Jiong
Published: April 2021

This article investigates the influence of frequency on the field-dependent non-linear rheology of magnetorheological (MR) grease under large amplitude oscillatory shear (LAOS). First, the LAOS tests with different driving frequencies were conducted on MR grease at four magnetic fields, and the storage and loss moduli under the frequency of 0.1, 0.5, 1, and 5 Hz were compared to obtain an overall understanding of the frequency-dependent viscoelastic behavior of MR grease. Based on this, the three-dimensional (3D) Lissajous curves and decomposed stress curves under two typical frequencies were depicted to provide the non-linear elastic and viscous behavior. Finally, the elastic and viscous measures containing higher harmonics from Fourier transform (FT)-Chebyshev analysis were used to quantitatively interpret the influence of the frequency on the non-linear rheology of MR grease, namely, strain stiffening (softening) and shear thickening (thinning), under LAOS with different magnetic fields. It was found that, under the application of the magnetic field, the onset of the non-linear behavior of MR grease was frequency-dependent. However, when the shear strain amplitude increased in the post-yield region, the non-linear rheology of MRG-70 was not affected by the oscillatory frequency.
A Ferroptosis-Related Signature Robustly Predicts Clinical Outcomes and Associates With Immune Microenvironment for Thyroid Cancer
Authors: Ge Mingqin , Niu Jie , Hu Ping , Tong Aihua , Dai Yan , Xu Fangjiang , Li Fuyuan
Published: April 2021

Objective: This study aimed to construct a prognostic ferroptosis-related signature for thyroid cancer and probe into the association with tumor immune microenvironment.

Methods: Based on the expression profiles of ferroptosis-related genes, a LASSO cox regression model was established for thyroid cancer. Kaplan-Meier survival analysis was presented between high and low risk groups. The predictive performance was assessed by ROC. The predictive independency was validated via multivariate cox regression analysis and stratified analysis. A nomogram was established and verified by calibration curves. The enriched signaling pathways were predicted via GSEA. The association between the signature and immune cell infiltration was analyzed by CIBERSORT. The ferroptosis-related genes were validated in thyroid cancer tissues by immunohistochemistry and RT-qPCR.

Results: A ferroptosis-related eight gene model was established for predicting the prognosis of thyroid cancer. Patients with high risk score indicated a poorer prognosis than those with low risk score (p = 1.186e-03). The AUCs for 1-, 2-, and 3-year survival were 0.887, 0.890, and 0.840, respectively. Following adjusting other prognostic factors, the model could independently predict the prognosis (p = 0.015, HR: 1.870, 95%CI: 1.132–3.090). A nomogram combining the signature and age was constructed. The nomogram-predicted probability of 1-, 3-, and 5-year survival approached the actual survival time. Several ferroptosis-related pathways were enriched in the high-risk group. The signature was distinctly associated with the immune cell infiltration. After validation, the eight genes were abnormally expressed between thyroid cancer and control tissues.

Conclusion: Our findings established a prognostic ferroptosis-related signature that was associated with the immune microenvironment for thyroid cancer.
A Nephrologist Perspective on Obesity: From Kidney Injury to Clinical Management
Authors: García-Carro Clara , Vergara Ander , Bermejo Sheila , Azancot María A. , Sellarés Joana , Soler Maria José
Published: April 2021

Obesity is one of the epidemics of our era. Its prevalence is higher than 30% in the U.S. and it is estimated to increase by 50% in 2030. Obesity is associated with a higher risk of all-cause mortality and it is known to be a cause of chronic kidney disease (CKD). Typically, obesity-related glomerulopathy (ORG) is ascribed to renal hemodynamic changes that lead to hyperfiltration, albuminuria and, finally, impairment in glomerular filtration rate due to glomerulosclerosis. Though not only hemodynamics are responsible for ORG: adipokines could cause local effects on mesangial and tubular cells and podocytes promoting maladaptive responses to hyperfiltration. Furthermore, hypertension and type 2 diabetes mellitus, two conditions generally associated with obesity, are both amplifiers of obesity injury in the renal parenchyma, as well as complications of overweight. As in the native kidney, obesity is also related to worse outcomes in kidney transplantation. Despite its impact in CKD and cardiovascular morbility and mortality, therapeutic strategies to fight against obesity-related CKD were limited for decades to renin-angiotensin blockade and bariatric surgery for patients who accomplished very restrictive criteria. Last years, different drugs have been approved or are under study for the treatment of obesity. Glucagon-like peptide-1 receptor agonists are promising in obesity-related CKD since they have shown benefits in terms of losing weight in obese patients, as well as preventing the onset of macroalbuminuria and slowing the decline of eGFR in type 2 diabetes. These new families of glucose-lowering drugs are a new frontier to be crossed by nephrologists to stop obesity-related CKD progression.
Stringent Primer Termination by an Archaeo-Eukaryotic DNA Primase
Authors: Bergsch Jan , Devillier Jean-Christophe , Jeschke Gunnar , Lipps Georg
Published: April 2021

Priming of single stranded templates is essential for DNA replication. In recent years, significant progress was made in understanding how DNA primase fulfils this fundamental function, particularly with regard to the initiation. Equally intriguing is the unique property of archeao-eukaryotic primases to terminate primer formation at a well-defined unit length. The apparent ability to “count” the number of bases incorporated prior to primer release is not well understood, different mechanisms having been proposed for different species. We report a mechanistic investigation of primer termination by the pRN1 primase from Sulfolobus islandicus. Using an HPLC-based assay we determined structural features of the primer 5′-end that are required for consistent termination. Mutations within the unstructured linker connecting the catalytic domain to the template binding domain allowed us to assess the effect of altered linker length and flexibility on primer termination.
The Dynamic Ion Motive Force Powering the Bacterial Flagellar Motor
Authors: Biquet-Bisquert Anaïs , Labesse Gilles , Pedaci Francesco , Nord Ashley L.
Published: April 2021

The bacterial flagellar motor (BFM) is a rotary molecular motor embedded in the cell membrane of numerous bacteria. It turns a flagellum which acts as a propeller, enabling bacterial motility and chemotaxis. The BFM is rotated by stator units, inner membrane protein complexes that stochastically associate to and dissociate from individual motors at a rate which depends on the mechanical and electrochemical environment. Stator units consume the ion motive force (IMF), the electrochemical gradient across the inner membrane that results from cellular respiration, converting the electrochemical energy of translocated ions into mechanical energy, imparted to the rotor. Here, we review some of the main results that form the base of our current understanding of the relationship between the IMF and the functioning of the flagellar motor. We examine a series of studies that establish a linear proportionality between IMF and motor speed, and we discuss more recent evidence that the stator units sense the IMF, altering their rates of dynamic assembly. This, in turn, raises the question of to what degree the classical dependence of motor speed on IMF is due to stator dynamics vs. the rate of ion flow through the stators. Finally, while long assumed to be static and homogeneous, there is mounting evidence that the IMF is dynamic, and that its fluctuations control important phenomena such as cell-to-cell signaling and mechanotransduction. Within the growing toolbox of single cell bacterial electrophysiology, one of the best tools to probe IMF fluctuations may, ironically, be the motor that consumes it. Perfecting our incomplete understanding of how the BFM employs the energy of ion flow will help decipher the dynamical behavior of the bacterial IMF.
Systemic Expression, Purification, and Initial Structural Characterization of Bacteriophage T4 Proteins Without Known Structure Homologs
Authors: Zhang Kaining , Li Xiaojiao , Wang Zhihao , Li Guanglin , Ma Biyun , Chen Huan , Li Na , Yang Huaiyu , Wang Yawen , Liu Bing
Published: April 2021

Bacteriophage T4 ofEscherichia coliis one of the most studied phages. Research into it has led to numerous contributions to phage biology and biochemistry. Coding about 300 gene products, this double-stranded DNA virus is the best-understood model in phage study and modern genomics and proteomics. Ranging from viral RNA polymerase, commonly found in phages, to thymidylate synthase, whose mRNA requires eukaryotic-like self-splicing, its gene products provide a pool of fine examples for phage research. However, there are still up to 130 gene products that remain poorly characterized despite being one of the most-studied model phages. With the recent advancement of cryo-electron microscopy, we have a glimpse of the virion and the structural proteins that present in the final assembly. Unfortunately, proteins participating in other stages of phage development are absent. Here, we report our systemic analysis on 22 of these structurally uncharacterized proteins, of which none has a known homologous structure due to the low sequence homology to published structures and does not belong to the category of viral structural protein. Using NMR spectroscopy and cryo-EM, we provided a set of preliminary structural information for some of these proteins including NMR backbone assignment for Cef. Our findings pave the way for structural determination for the phage proteins, whose sequences are mainly conserved among phages. While this work provides the foundation for structural determinations of proteins like Gp57B, Cef, Y04L, and Mrh, otherin vitrostudies would also benefit from the high yield expression of these proteins.
Title: Hypermethylation of miRNA Genes During Nodule Development
Authors: Piya Sarbottam , Lopes-Caitar Valeria S. , Kim Won‐Seok , Pantalone Vince , Krishnan Hari B. , Hewezi Tarek
Published: April 2021

DNA methylation has recently emerged as a powerful regulatory mechanism controlling the expression of key regulators of various developmental processes, including nodulation. However, the functional role of DNA methylation in regulating the expression of microRNA (miRNA) genes during the formation and development of nitrogen-fixing nodules remains largely unknown. In this study, we profiled DNA methylation patterns of miRNA genes during nodule formation, development, and early senescence stages in soybean (Glycine max) through the analysis of methylC—seq data. Absolute DNA methylation levels in the CG, CHH, and CHH sequence contexts over the promoter and primary transcript regions of miRNA genes were significantly higher in the nodules compared with the corresponding root tissues at these three distinct nodule developmental stages. We identified a total of 82 differentially methylated miRNAs in the nodules compared with roots. Differential DNA methylation of these 82 miRNAs was detected only in the promoter (69), primary transcript region (3), and both in the promoter and primary transcript regions (10). The large majority of these differentially methylated miRNAs were hypermethylated in nodules compared with the corresponding root tissues and were found mainly in the CHH context and showed stage-specific methylation patterns. Differentially methylated regions in the promoters of 25 miRNAs overlapped with transposable elements, a finding that may explain the vulnerability of miRNAs to DNA methylation changes during nodule development. Gene expression analysis of a set of promoter-differentially methylated miRNAs pointed to a negative association between DNA methylation and miRNA expression. Gene Ontology and pathways analyses indicate that changes in DNA methylation of miRNA genes are reprogrammed and contribute to nodule development through indirect regulation of genes involved in cellular processes and pathways with well-established roles in nodulation.
Networks in the Field of Tourette Syndrome
Authors: Kleimaker Alexander , Kleimaker Maximilian , Behm Amelie , Weissbach Anne , Bäumer Tobias , Beste Christian , Roessner Veit , Münchau Alexander
Published: April 2021

Gilles de la Tourette syndrome (TS) is a neuropsychiatric neurodevelopmental disorder with the cardinal clinical features of motor and phonic tics. Clinical phenomenology can be complex since, besides tics, there are other features including premonitory urges preceding tics, pali-, echo-, and coprophenomena, hypersensitivity to external stimuli, and symptom dependency on stress, attention, and other less well-defined factors. Also, the rate of comorbidities, particularly attention deficit hyperactivity disorder and obsessive-compulsive disorder, is high. Mirroring the complexities of the clinical course and phenomenology, pathophysiological findings are very diverse, and etiology is disputed. It has become clear, though, that abnormalities in the basal ganglia and their connections with cortical areas are key for the understanding of the pathophysiology and as regards etiology, genetic factors are crucial. Against this background, both adequate clinical management of TS and TS-related research require multidisciplinary preferably international cooperation in larger groups or networks to address the multiple facets of this disorder and yield valid and useful data. In particular, large numbers of patients are needed for brain imaging and genetic studies. To meet these requirements, a number of networks and groups in the field of TS have developed over the years creating an efficient, lively, and supportive international research community. In this review, we will provide an overview of these groups and networks.
Prevalence and Effect of Cerebral Small Vessel Disease in Stroke Patients With Aspirin Treatment Failure–A Hospital-Based Stroke Secondary Prevention Registry
Authors: Chou Ping-Song , Sung Pi-Shan , Liu Chi-Hung , Sung Yueh-Feng , Tzeng Ray-Chang , Yang Chun-Pai , Lien Chi-Hsun , Po Helen L. , Ho Shang-Chang , Tsai Yi-Te , Chen Tsang-Shan , Wu Shey-Lin , Hu Han-Hwa , Chao A-Ching
Published: April 2021

Background: Breakthrough strokes during treatment with aspirin, termed clinical aspirin treatment failure (ATF), is common in clinical practice. The burden of cerebral small vessel disease (SVD) is associated with an increased recurrent ischemic stroke risk. However, the association between SVD and ATF remains unclear. This study investigated the prevalence and clinical characteristics of SVD in stroke patients with ATF.

Methods: Data from a prospective, and multicenter stroke with ATF registry established in 2018 in Taiwan were used, and 300 patients who developed ischemic stroke concurrent with regular use of aspirin were enrolled. White matter lesions (WMLs) and cerebral microbleeds (CMBs) were identified using the Fazekas scale and Microbleed Anatomical Rating Scale, respectively. Demographic data, cardiovascular comorbidities, and index stroke characteristics of patients with different WML and CMB severities were compared. Logistic regression analyses were performed to explore the factors independently associated with outcomes after ATF.

Results: The mean patient age was 69.5 ± 11.8 years, and 70.0% of patients were men. Among all patients, periventricular WML (PVWML), deep WML (DWML), and CMB prevalence was 93.3, 90.0, and 52.5%, respectively. Furthermore, 46.0% of the index strokes were small vessel occlusions. Severe PVWMLs and DWMLs were significantly associated with high CMB burdens. Patients with moderate-to-severe PVWMLs and DWMLs were significantly older and had higher cardiovascular comorbidity prevalence than did patients with no or mild WMLs. Moreover, patients with favorable outcomes exhibited significantly low prevalence of severe PVWMLs (p = 0.001) and DWMLs (p = 0.001). After logistic regression was applied, severe WMLs predicted less favorable outcomes independently, compared with those with no to moderate PVWMLs and DWMLs [odds ratio (OR), 0.47; 95% confidence interval (CI), 0.25–0.87 for severe PVWMLs; OR, 0.40; 95% CI, 0.21–0.79 for severe DWMLs].

Conclusions: SVD is common in stroke patients with ATF. PVWMLs and DWMLs are independently associated with functional outcomes in stroke patients with ATF. The burden of SVD should be considered in future antiplatelet strategies for stroke patients after ATF.
Effects of External Auditory Meatus Occlusion on Ocular Vestibular Evoked Myogenic Potentials Induced by Bone Conducted Sound
Authors: Murofushi Toshihisa , Ohki Masafumi , Tsubota Masahito
Published: April 2021

To facilitate more reliable recordings of the ocular vestibular evoked myogenic potentials (oVEMP) induced by bone-conducted sound using the B81 bone conduction transducer, we preliminarily studied the effects of external auditory meatus occlusion using an earplug on such oVEMP. Eight healthy volunteers (four males and four females, 26–48 years of age, mean age: 34. 5 years) and 14 patients with vestibular disease (2 males and 12 females, 18–59 years of age, mean age: 41.5 years) were enrolled. oVEMP testing was performed using a B81 placed on the temple. Tone bursts (500 Hz, rise/fall time: 2 ms, plateau time: 2 ms, and 70 dB nHL) were presented at a rate of 5.1 Hz. N1-P1 amplitudes were measured and analyzed. Occlusion resulted in significantly larger N1-P1 amplitudes [mean ± SE (SD): 12.3 ± 1.67 (6.71) μV vs. 9.55 ± 1.55 (6.21) μV; p = 0.020, paired t-test]. While four patients did not exhibit any response on either side in the absence of occlusion, all of them showed unilateral or bilateral responses when occlusion was employed. In any patient occlusion did not result in loss of oVEMP responses. External auditory meatus occlusion using an earplug could allow more reliable recordings of bone conduction transducer-induced oVEMP.
Retinal Vessel Responses to Flicker Stimulation Are Impaired in Cav2.3-Deficient Mice—An in-vivo Evaluation Using Retinal Vessel Analysis (RVA)
Authors: Neumaier Felix , Kotliar Konstantin , Haeren Roel Hubert Louis , Temel Yasin , Lüke Jan Niklas , Seyam Osama , Lindauer Ute , Clusmann Hans , Hescheler Jürgen , Schubert Gerrit Alexander , Schneider Toni , Albanna Walid
Published: April 2021

Objective: Metabolic demand increases with neuronal activity and adequate energy supply is ensured by neurovascular coupling (NVC). Impairments of NVC have been reported in the context of several diseases and may correlate with disease severity and outcome. Voltage-gated Ca2+-channels (VGCCs) are involved in the regulation of vasomotor tone. In the present study, we compared arterial and venous responses to flicker stimulation in Cav2.3-competent (Cav2.3[+/+]) and -deficient (Cav2.3[−/−]) mice using retinal vessel analysis.

Methods: The mice were anesthetized and the pupil of one eye was dilated by application of a mydriaticum. An adapted prototype of retinal vessel analyzer was used to perform dynamic retinal vessel analysis. Arterial and venous responses were quantified in terms of the area under the curve (AUCart/AUCven) during flicker application, mean maximum dilation (mMDart/mMDven) and time to maximum dilation (tMDart/tMDven) during the flicker, dilation at flicker cessation (DFCart/DFCven), mean maximum constriction (mMCart/mMCven), time to maximum constriction (tMCart/tMCven) after the flicker and reactive magnitude (RMart/RMven).

Results: A total of 33 retinal scans were conducted in 22 Cav2.3[+/+] and 11 Cav2.3[−/−] mice. Cav2.3[−/−] mice were characterized by attenuated and partially reversed arterial and venous responses, as reflected in significantly lower AUCart (p = 0.031) and AUCven (p = 0.047), a trend toward reduced DFCart (p = 0.100), DFCven (p = 0.100), mMDven (p = 0.075), and RMart (p = 0.090) and a trend toward increased tMDart (p = 0.096).

Conclusion: To our knowledge, this is the first study using a novel, non-invasive analysis technique to document impairment of retinal vessel responses in VGCC-deficient mice. We propose that Cav2.3 channels could be involved in NVC and may contribute to the impairment of vasomotor responses under pathophysiological conditions.
Astroglial Glutamine Synthetase and the Pathogenesis of Mesial Temporal Lobe Epilepsy
Authors: Sandhu Mani Ratnesh S. , Gruenbaum Benjamin F. , Gruenbaum Shaun E. , Dhaher Roni , Deshpande Ketaki , Funaro Melissa C. , Lee Tih-Shih W. , Zaveri Hitten P. , Eid Tore
Published: April 2021

The enzyme glutamine synthetase (GS), also referred to as glutamate ammonia ligase, is abundant in astrocytes and catalyzes the conversion of ammonia and glutamate to glutamine. Deficiency or dysfunction of astrocytic GS in discrete brain regions have been associated with several types of epilepsy, including medically-intractable mesial temporal lobe epilepsy (MTLE), neocortical epilepsies, and glioblastoma-associated epilepsy. Moreover, experimental inhibition or deletion of GS in the entorhinal-hippocampal territory of laboratory animals causes an MTLE-like syndrome characterized by spontaneous, recurrent hippocampal-onset seizures, loss of hippocampal neurons, and in some cases comorbid depressive-like features. The goal of this review is to summarize and discuss the possible roles of astroglial GS in the pathogenesis of epilepsy.
A Real-Time Stability Control Method Through sEMG Interface for Lower Extremity Rehabilitation Exoskeletons
Authors: Wang Can , Guo Ziming , Duan Shengcai , He Bailin , Yuan Ye , Wu Xinyu
Published: April 2021

Herein, we propose a real-time stable control gait switching method for the exoskeleton rehabilitation robot. Exoskeleton rehabilitation robots have been extensively developed during the past decade and are able to offer valuable motor ability to paraplegics. However, achieving stable states of the human-exoskeleton system while conserving wearer strength remains challenging. The constant switching of gaits during walking may affect the center of gravity, resulting in imbalance of human–exoskeleton system. In this study, it was determined that forming an equilateral triangle with two crutch-supporting points and a supporting leg has a positive impact on walking stability and ergonomic interaction. First, the gaits planning and stability analysis based on human kinematics model and zero moment point method for the lower limb exoskeleton are demonstrated. Second, a neural interface based on surface electromyography (sEMG), which realizes the intention recognition and muscle fatigue estimation, is constructed. Third, the stability of human–exoskeleton system and ergonomic effects are tested through different gaits with planned and unplanned gait switching strategy on the SIAT lower limb rehabilitation exoskeleton. The intention recognition based on long short-term memory (LSTM) model can achieve an accuracy of nearly 99%. The experimental results verified the feasibility and efficiency of the proposed gait switching method for enhancing stability and ergonomic effects of lower limb rehabilitation exoskeleton.
Characteristics of Cohesin Mutation in Acute Myeloid Leukemia and Its Clinical Significance
Authors: Han Caixia , Gao Xuefeng , Li Yonghui , Zhang Juan , Yang Erna , Zhang Li , Yu Li
Published: April 2021

The occurrence of gene mutation is a major contributor to the initiation and propagation of acute myeloid leukemia (AML). Accumulating evidence suggests that genes encoding cohesin subunits have a high prevalence of mutations in AML, especially in the t(8;21) subtype. Therefore, it is important to understand how cohesin mutations contribute to leukemogenesis. However, the fundamental understanding of cohesin mutation in clonal expansion and myeloid transformation in hematopoietic cells remains ambiguous. Previous studies briefly introduced the cohesin mutation in AML; however, an in-depth summary of mutations in AML was not provided, and the correlation between cohesin and AML1-ETO in t (8;21) AML was also not analyzed. By summarizing the major findings regarding the cohesin mutation in AML, this review aims to define the characteristics of the cohesin complex mutation, identify its relationships with co-occurring gene mutations, assess its roles in clonal evolution, and discuss its potential for the prognosis of AML. In particular, we focus on the function of cohesin mutations in RUNX1-RUNX1T1 fusion.
The Pharmacological or Genetic Blockade of Endogenous De Novo Fatty Acid Synthesis Does Not Increase the Uptake of Exogenous Lipids in Ovarian Cancer Cells
Authors: Grunt Thomas W. , Lemberger Lisa , Colomer Ramón , López−Rodríguez María Luz , Wagner Renate
Published: April 2021

Ovarian cancer(OC) is a serious threat to women worldwide. Peritoneal dissemination, ascites and omental metastasis are typical features for disease progression, which occurs in a micro-environment that is rich in high-energy lipids. OC cells require high amounts of lipids for survival and growth. Not only do they import lipids from the host, they also produce lipidsde novo. Inhibitors of fatty acid(FA) synthase(FASN) – the rate-limiting enzyme of endogenous FA synthesis that is overexpressed in OC – induce growth-arrest and apoptosis, rendering them promising candidates for cancer drug development. However, cancer researchers have long hypothesized that the lipid deficiency caused by FASN inhibition can be circumvented by increasing the uptake of exogenous lipids from the host, which would confer resistance to FASN inhibitors. In contrast to a very recent report in colorectal cancer, we demonstrate in OC cells (A2780, OVCAR3, SKOV3) that neither FASN inhibitors (G28UCM, Fasnall) nor FASN-specific siRNAs can stimulate a relief pathway leading to enhanced uptake of extrinsic FAs or low density lipoproteins (LDLs). Instead, we observed that the growth-arrest due to FASN inhibition or FASN knock-down was associated with significant dose- and time-dependent reduction in the uptake of fluorescently labeled FAs and LDLs. Western blotting showed that the expression of the FA receptor CD36, the LDL receptor(LDLR) and the lipid transport proteins fatty acid binding proteins 1–9 (FABP1–9) was not affected by the treatment. Next, we compared experimental blockade of endogenous lipid production with physiologic depletion of exogenous lipids. Lipid-free media, similar to FASN inhibitors, caused growth-arrest. Although lipid-depleted cells have diminished amounts of CD36, LDLR and FABPs, they can still activate a restorative pathway that causes enhanced import of fluorophore-labeled FAs and LDLs. Overall, our data show that OC cells are strictly lipid-depend and exquisitely sensitive to FASN inhibitors, providing a strong rationale for developing anti-FASN strategies for clinical use against OC.
Prediction of Target-Drug Therapy by Identifying Gene Mutations in Lung Cancer With Histopathological Stained Image and Deep Learning Techniques
Authors: Huang Kaimei , Mo Zhiyi , Zhu Wen , Liao Bo , Yang Yachao , Wu Fang-Xiang
Published: April 2021

Lung cancer is a kind of cancer with high morbidity and mortality which is associated with various gene mutations. Individualized targeted-drug therapy has become the optimized treatment of lung cancer, especially benefit for patients who are not qualified for lung lobectomy. It is crucial to accurately identify mutant genes within tumor region from stained pathological slice. Therefore, we mainly focus on identifying mutant gene of lung cancer by analyzing the pathological images. In this study, we have proposed a method by identifying gene mutations in lung cancer with histopathological stained image and deep learning to predict target-drug therapy, referred to as DeepIMLH. The DeepIMLH algorithm first downloaded 180 hematoxylin-eosin staining (H&E) images of lung cancer from the Cancer Gene Atlas (TCGA). Then deep convolution Gaussian mixture model (DCGMM) was used to perform color normalization. Convolutional neural network (CNN) and residual network (Res-Net) were used to identifying mutated gene from H&E stained imaging and achieved good accuracy. It demonstrated that our method can be used to choose targeted-drug therapy which might be applied to clinical practice. More studies should be conducted though.