bluuebunny/crossref_metadata_2025 huggingface dataset:
Adverse Drug Reaction Discovery Using a Tumor-Biomarker Knowledge Graph
Authors: Wang Meng , Ma Xinyu , Si Jingwen , Tang Hongjia , Wang Haofen , Li Tunliang , Ouyang Wen , Gong Liying , Tang Yongzhong , He Xi , Huang Wei , Liu Xing
Published: January 2021

Adverse drug reactions (ADRs) are a major public health concern, and early detection is crucial for drug development and patient safety. Together with the increasing availability of large-scale literature data, machine learning has the potential to predict unknown ADRs from current knowledge. By the machine learning methods, we constructed a Tumor-Biomarker Knowledge Graph (TBKG) which contains four types of node: Tumor, Biomarker, Drug, and ADR using biomedical literatures. Based on this knowledge graph, we not only discovered potential ADRs of antitumor drugs but also provided explanations. Experiments on real-world data show that our model can achieve 0.81 accuracy of three cross-validation and the ADRs discovery of Osimertinib was chosen for the clinical validation. Calculated ADRs of Osimertinib by our model consisted of the known ADRs which were in line with the official manual and some unreported rare ADRs in clinical cases. Results also showed that our model outperformed traditional co-occurrence methods. Moreover, each calculated ADRs were attached with the corresponding paths of “tumor-biomarker-drug” in the knowledge graph which could help to obtain in-depth insights into the underlying mechanisms. In conclusion, the tumor-biomarker knowledge-graph based approach is an explainable method for potential ADRs discovery based on biomarkers and might be valuable to the community working on the emerging field of biomedical literature mining and provide impetus for the mechanism research of ADRs.
Inhibition of iNKT Cells by the HLA-G-ILT2 Checkpoint and Poor Stimulation by HLA-G-Expressing Tolerogenic DC
Authors: Wu Ching-Lien , Caumartin Julien , Amodio Giada , Anna François , Loustau Maria , Gregori Silvia , Langlade-Demoyen Pierre , LeMaoult Joel
Published: January 2021

Invariant Natural Killer T (iNKT) cells are a small and distinct population of T cells crucial in immunomodulation. After activation by alpha-GalactosylCeramide (αGC), an exogenic glycolipid antigen, iNKT cells can rapidly release cytokines to enhance specific anti-tumor activity. Several human clinical trials on iNKT cell-based anti-cancer are ongoing, however results are not as striking as in murine models. Given that iNKT-based immunotherapies are dependent mainly on antigen-presenting cells (APC), a human tolerogenic molecule with no murine homolog, such as Human Leucocyte Antigen G (HLA-G), could contribute to this discrepancy. HLA-G is a well-known immune checkpoint molecule involved in fetal-maternal tolerance and in tumor immune escape. HLA-G exerts its immunomodulatory functions through the interaction with immune inhibitory receptors such as ILT2, differentially expressed on immune cell subsets. We hypothesized that HLA-G might inhibit iNKT function directly or by inducing tolerogenic APC leading to iNKT cell anergy, which could impact the results of current clinical trials. Using an ILT2-transduced murine iNKT cell line and human iNKT cells, we demonstrate that iNKT cells are sensitive to HLA-G, which inhibits their cytokine secretion. Furthermore, human HLA-G+dendritic cells, called DC-10, failed at inducing iNKT cell activation compared to their autologous HLA-G‒DCs counterparts. Our data show for the first time that the HLA-G/ILT2 ICP is involved in iNKT cell function modulation.
Effects of Vessel Distance and Sex on the Behavior of Endangered Killer Whales
Authors: Holt Marla M. , Tennessen Jennifer B. , Ward Eric J. , Hanson M. Bradley , Emmons Candice K. , Giles Deborah A. , Hogan Jeffrey T.
Published: January 2021

Accurate knowledge of behavior is necessary to effectively manage the effects of human activities on wildlife, including vessel-based whale-watching. Yet, the wholly aquatic nature of cetaceans makes understanding their basic behavioral ecology quite challenging. An endangered population of killer whales faces several identified threats including prey availability and disturbance from vessels and sound. We used bio-logging tags that were temporally attached to individuals of the endangered Southern Resident killer whale population to more fully understand their subsurface behavior and to investigate vessel effects on behavior, including foraging behavior involving prey capture. We collected tag data over three field seasons in the waters surrounding the San Juan Islands, WA, United States, corresponding to the core summer area of the critical habitat of the population. Here, we used hidden Markov models to identify latent behavioral states that include characterization of different foraging states from sound and movement variables recorded by the multi-sensor tags. We tested a number of vessel variables (e.g., vessel counts, distance, and speed) on state transition probabilities, state occurrence and time spent within each behavioral state. Whales made fewer dives involving prey capture and spent less time in these dives when vessels had an average distance less than 400 yd (366 m). Additionally, we found both a sex and vessel distance effect on the state transition probabilities, suggesting that females and males respond differently to nearby vessels. Specifically, females were more likely to transition to a non-foraging state when vessels had an average distance less than 400 yd (366 m). A female’s decision to forego foraging states due to the close proximity of vessels could have cascading effects on the ability to meet energetic requirements to support reproductive efforts. This is particularly concerning in an endangered population that is in decline. Our findings, suggesting that female killer whales are at greater risk to close approaches by vessels, highlight the importance of understanding sex-specific responses to disturbance. These findings can inform future management decisions seeking to preserve foraging opportunities and enhance recovery efforts relevant to many cetacean species, including vulnerable and endangered populations.
Atlantic Grey Seal Milk Shows Continuous Changes in Key Metabolites and Indicators of Metabolic Transition in Pups From Birth to Weaning
Authors: Watson David G. , Pomeroy Patrick P. , Kennedy Malcolm W.
Published: January 2021

Mothers of the Atlantic grey seal,Halichoerus grypus, lactate for about 20 days, during which they do not feed and may have no access to water. Following weaning, they depart to sea leaving their pups unattended and unfed for up to another 40 days. We are interested in how this lactation strategy supports the pups’ rapid growth and development while also preparing them for their long fast before independently going to sea. We report a broad spectrum metabolomic analysis of whole milks of these seals that reveals continuous changes in key metabolites from birth to weaning. Certain components exhibit abbreviated appearances at the onset of lactation, followed by continuous rises or falls in others until weaning. Riboflavin/Vitamin B2, hormone-related sterol sulfates, lactose, and complex oligosaccharides all appear in milk briefly after birth then disappear. Lipids associated with cellular signaling and brain development occur at highest levels shortly after birth, then diminish. In contrast, other lipids and Vitamin B6/pyridoxine steadily increase as weaning approaches. Overall, these findings may indicate an early transition from carbohydrate to fat-based energy metabolism and establishment of gut microbiomes in pups, followed by provisioning for post-weaning development and fasting.
Face Mask Use in the Community for Reducing the Spread of COVID-19: A Systematic Review
Authors: Coclite Daniela , Napoletano Antonello , Gianola Silvia , del Monaco Andrea , D'Angelo Daniela , Fauci Alice , Iacorossi Laura , Latina Roberto , Torre Giuseppe La , Mastroianni Claudio M. , Renzi Cristina , Castellini Greta , Iannone Primiano
Published: January 2021

Background: Evidence is needed on the effectiveness of wearing face masks in the community to prevent SARS-CoV-2 transmission.

Methods: Systematic review and meta-analysis to investigate the efficacy and effectiveness of face mask use in a community setting and to predict the effectiveness of wearing a mask. We searched MEDLINE, EMBASE, SCISEARCH, The Cochrane Library, and pre-prints from inception to 22 April 2020 without restriction by language. We rated the certainty of evidence according to Cochrane and GRADE approach.

Findings: Our search identified 35 studies, including three randomized controlled trials (RCTs) (4,017 patients), 10 comparative studies (18,984 patients), 13 predictive models, nine laboratory experimental studies. For reducing infection rates, the estimates of cluster-RCTs were in favor of wearing face masks vs. no mask, but not at statistically significant levels (adjusted OR 0.90, 95% CI 0.78–1.05). Similar findings were reported in observational studies. Mathematical models indicated an important decrease in mortality when the population mask coverage is near-universal, regardless of mask efficacy. In the best-case scenario, when the mask efficacy is at 95%, the R0 can fall to 0.99 from an initial value of 16.90. Levels of mask filtration efficiency were heterogeneous, depending on the materials used (surgical mask: 45–97%). One laboratory study suggested a viral load reduction of 0.25 (95% CI 0.09–0.67) in favor of mask vs. no mask.

Interpretation: The findings of this systematic review and meta-analysis support the use of face masks in a community setting. Robust randomized trials on face mask effectiveness are needed to inform evidence-based policies.

PROSPERO registration: CRD42020184963.
Normalized Protein Catabolic Rate Is a Superior Nutritional Marker Associated With Dialysis Adequacy in Continuous Ambulatory Peritoneal Dialysis Patients
Authors: Qin Aiya , Liu Xiang , Yin Xiaomeng , Zhou Huan , Tang Yi , Qin Wei
Published: January 2021

Introduction:Current knowledge of the relationship between normalized protein catabolic rate (nPCR) and dialysis adequacy is limited. Our study aimed to explore the potential relationship between nPCR and dialysis adequacy.

Methods:In this cross-sectional study, we analyzed the association of nPCR with peritoneal dialysis adequacy in 266 continuous ambulatory peritoneal dialysis (CAPD) patients (mean age 48.6 ± 13.1 years; 50.8% male). The patients were divided into two groups: a dialysis inadequacy group (total weekly Kt/V urea < 1.70) and a dialysis adequacy group (total weekly Kt/V urea≥1.70). We then analyzed the correlation between dialysis adequacy and the patients' primary cause of end-stage renal disease, nutritional and inflammatory markers, and biochemical parameters. Multivariable logistic regression analysis was also used to identify risk factors for inadequate dialysis.

Results:We observed a significantly higher level of nPCR (0.98 ± 0.22 vs. 0.79 ± 0.18 g/kg/day,p< 0.001) in the dialysis adequacy group, whereas we observed no significant differences among other nutritional markers such as albumin, prealbumin, and transferrin. Correlation analyses revealed that dialysis adequacy was positively associated with residual glomerular filtration rate (rGFR), hemoglobin, serum calcium, and body mass index (BMI), while dialysis adequacy was negatively associated with leak-protein, uric acid, high-sensitivity C-reactive protein, interleukin-6, and serum phosphorus. Furthermore, a logistic regression analysis revealed that gender (male), nPCR <0.815 g/kg/day, higher weight, and rGFR <2.43 mL/min/1.73 m2were independent risk factors for inadequate dialysis.

Conclusion:Nutritional status is closely associated with dialysis adequacy. Among common nutritional markers, nPCR may be superior for predicting CAPD dialysis adequacy. Gender (male), nPCR <0.815 g/kg/day, higher weight, and rGFR <2.43 mL/min/1.73 m2are independent risk factors for dialysis inadequacy in CAPD patients.
Association Between Use of Anti-gout Preparations and Dementia: Nested Case–Control Nationwide Population-Based Cohort Study
Authors: Chuang Tsung-Ju , Wang Yu-Hsun , Wei James Cheng-Chung , Yeh Chih-Jung
Published: January 2021

Objectives:Gout is the most common form of inflammatory arthritis and was found to be independently associated with incident dementia in the elderly. However, the associations between anti-gout preparations and dementia were not well-studied.

Methods:Data were collected from Taiwan's National Health Insurance Research Database (NHIRD). A 2005–2013 retrospective cohort study was conducted, and all investigated subjects were identified by International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Clinical Modification. Conditional logistic regression was used to evaluate the odds ratio of dementia in relation to different gout preparations (benzbromarone, allopurinol, sulfinpyrazone, probenecid) and number of days of anti-gout preparation use, after adjustment for potential confounding variables.

Results:A total of 3,242 gout patients with and without dementia were selected from the NHIRD and included in the final analysis after 1:1 matching for age, gender, and diagnosis year of gout. In the anti-gout preparations, only use of Benzbromarone decreased the risk of dementia (adjusted OR, 0.81; 95% CI, 0.68–0.97). The result of the subgroup analysis revealed a trend toward a lower risk of dementia with longer use of benzbromarone. Use of benzbromarone for ≥180 days showed a significantly lower risk of dementia (adjusted OR, 0.72; 95% CI, 0.58–0.89). Moreover, the protective effect was more pronounced in males compared with females.

Conclusion:This cohort study reveals that gout patients taking benzbromarone are at a decreased risk of developing incident dementia, especially with longer use and in male. Further prospective trials are warranted to confirm our findings.
Effect of Collagen Tripeptide and Adjusting for Climate Change on Skin Hydration in Middle-Aged Women: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Tak Young Jin , Shin Dae Keun , Kim Ae Hyang , Kim Jun Il , Lee Ye Li , Ko Hyun-Chang , Kim Yong-Woo , Lee Sang Yeoup
Published: January 2021

Introduction: Although collagen is widely used in various forms as a functional ingredient in skin care products, the effect of oral supplementation of collagen tripeptides (CTPs) on human skin is unclear. Moreover, the majority of the positive outcomes of CTP reported so far have not considered the effect of weather conditions. Therefore, we tested the effect of CTP and adjusting for climate change on skin properties in middle-aged women.

Materials and Methods: A randomized controlled trial was conducted with 84 women between 40 and 60 years of age. Participants were randomized to receive placebo or 1,000 mg CTP daily for 12 weeks. CTP was prepared from the skin of Nile Tilapia by the digestion method using collagenase from non-pathogenic bacteria of the genus Bacillus. Skin hydration, wrinkling, and elasticity were assessed at baseline and after 6 and 12 weeks with adjustments for temperature, humidity, and ultraviolet A exposure during the evaluation time using weather data from the regional meteorological office.

Results: Of the 82 participants, 74 completed the trial without adverse effects. Compared with the control group, trans-epidermal water loss was reduced more in the CTP group after 12 weeks (P < 0.05). At 12 weeks, even after adjustment for humidity, temperature, and UVA in the region, the difference of the two groups in TEWL remained statistically significant (adjusted for humidity and temperature, P = 0.024; adjusted for UVA, P = 0.032; adjusted for temperature, high temperature, and ultraviolet A, P = 0.031). In terms of skin hydration, more improvement was evident in the CTP group than in the control group. In the subgroup analysis, subjects under 50 years of age showed a significant improvement in total score and moisture in the subjective skin improvement questionnaire after taking CTP for 12 weeks. Application of CTP was well-tolerated, and no notable adverse effect was reported from both groups.

Discussion: Our findings suggest that oral ingestion of CTP from the Skin of Nile Tilapia (Oreochromis niloticus) is well-tolerated and helps reduce water loss in in middle-aged women.

Clinical Trial Registration:www.clinicaltrials.gov/, Identifier: NCT03505684.
The Glomeromycota in the Neotropics
Authors: Stürmer Sidney Luiz , Kemmelmeier Karl
Published: January 2021

Arbuscular mycorrhizal fungi (AMF—Glomeromycota) are a group of soil fungi with a widespread occurrence in terrestrial ecosystems where they play important roles that influence plant growth and ecosystem processes. The aim of this paper is to reveal AMF distribution in the Neotropics based on an extensive biogeography database with literature data from the last five decades. All four orders and 11 families were reported in the Neotropics. 221 species (69% of the total number of species for the phylum) were registered in the Neotropics pertaining to 37 genera. Acaulospora, Glomus, Scutellospora, and Funneliformis were the most speciose genera and represented by 47, 29, 15, and 13 species, respectively. Seventy-six species were originally described from Neotropics, which represents 24% of the total diversity of Glomeromycota. The most representative families were Gigasporaceae, Ambisporaceae, and Acaulosporaceae with 89%, 80%, and 79% of species within each family detected in the Neotropics, respectively. AMF were detected in 11 biomes and 52 ecological regions in 19 countries. Biomes with the largest number of species were Tropical and Subtropical Moist Forests (186 species), Tropical and Subtropical Dry Broadleaf forests (127 species), and Tropical and Subtropical Grasslands (124 species), and Jaccard’s similarity among them was 53–57%. Mean annual temperature and precipitation were not correlated with total AMF species richness. The Neotropics biomes shelter a large amount of the total diversity of Glomeromycota and studies of occurrence of these fungi should be encouraged considering their importance in maintaining terrestrial ecosystems.
Recent Advances in a Polydopamine-Mediated Antimicrobial Adhesion System
Authors: Singh Indu , Dhawan Gagan , Gupta Seema , Kumar Pradeep
Published: January 2021

The drug resistance developed by bacteria during antibiotic treatment has been a call to action for researchers and scientists across the globe, as bacteria and fungi develop ever increasing resistance to current drugs. Innovative antimicrobial/antibacterial materials and coatings to combat such infections have become a priority, as many infections are caused by indwelling implants (e.g., catheters) as well as improving postsurgical function and outcomes. Pathogenic microorganisms that can exist either in planktonic form or as biofilms in water-carrying pipelines are one of the sources responsible for causing water-borne infections. To combat this, researchers have developed nanotextured surfaces with bactericidal properties mirroring the topographical features of some natural antibacterial materials. Protein-based adhesives, secreted by marine mussels, contain a catecholic amino acid, 3,4-dihydroxyphenylalanine (DOPA), which, in the presence of lysine amino acid, empowers with the ability to anchor them to various surfaces in both wet and saline habitats. Inspired by these features, a novel coating material derived from a catechol derivative, dopamine, known as polydopamine (PDA), has been designed and developed with the ability to adhere to almost all kinds of substrates. Looking at the immense potential of PDA, this review article offers an overview of the recent growth in the field of PDA and its derivatives, especially focusing the promising applications as antibacterial nanocoatings and discussing various antimicrobial mechanisms including reactive oxygen species-mediated antimicrobial properties.
Mycobacterium tuberculosis and M. bovis BCG Moreau Fumarate Reductase Operons Produce Different Polypeptides That May Be Related to Non-canonical Functions
Authors: Schwarz Marcos Gustavo Araujo , Antunes Deborah , Corrêa Paloma Rezende , Silva-Gonçalves Antônio José da , Malaga Wladimir , Caffarena Ernesto Raul , Guilhot Christophe , Mendonça-Lima Leila
Published: January 2021

Tuberculosis is a world widespread disease, caused by Mycobacterium tuberculosis (M.tb). Although considered an obligate aerobe, this organism can resist life-limiting conditions such as microaerophily mainly due to its set of enzymes responsible for energy production and coenzyme restoration under these conditions. One of these enzymes is fumarate reductase, an heterotetrameric complex composed of a catalytic (FrdA), an iron-sulfur cluster (FrdB) and two transmembrane (FrdC and FrdD) subunits involved in anaerobic respiration and important for the maintenance of membrane potential. In this work, aiming to further characterize this enzyme function in mycobacteria, we analyzed the expression of FrdB-containing proteins in M.tb and Mycobacterium bovis Bacillus Calmette–Guérin (BCG) Moreau, the Brazilian vaccine strain against tuberculosis. We identified three isoforms in both mycobacteria, two of them corresponding to the predicted encoded polypeptides of M.tb (27 kDa) and BCG Moreau (40 kDa) frd sequences, as due to an insertion on the latter’s operon a fused FrdBC protein is expected. The third 52 kDa band can be explained by a transcriptional slippage event, typically occurring when mutation arises in a repetitive region within a coding sequence, thought to reduce its impact allowing the production of both native and variant forms. Comparative modeling of the M.tb and BCG Moreau predicted protein complexes allowed the detection of subtle overall differences, showing a high degree of structure and maybe functional resemblance among them. Axenic growth and macrophage infection assays show that the frd locus is important for proper bacterial development in both scenarios, and that both M.tb’s and BCG Moreau’s alleles can partially revert the hampered phenotype of the knockout strain. Altogether, our results show that the frdABCD operon of Mycobacteria may have evolved to possess other yet non-described functions, such as those necessary during aerobic logarithmic growth and early stage steps of infection.
Antisense Transcripts and Antisense Protein: A New Perspective on Human Immunodeficiency Virus Type 1
Authors: Savoret Juliette , Mesnard Jean-Michel , Gross Antoine , Chazal Nathalie
Published: January 2021

It was first predicted in 1988 that there may be an Open Reading Frame (ORF) on the negative strand of the Human Immunodeficiency Virus type 1 (HIV-1) genome that could encode a protein named AntiSense Protein (ASP). In spite of some controversy, reports began to emerge some years later describing the detection of HIV-1 antisense transcripts, the presence of ASP in transfected and infected cells, and the existence of an immune response targeting ASP. Recently, it was established that theaspgene is exclusively conserved within the pandemic group M of HIV-1. In this review, we summarize the latest findings on HIV-1 antisense transcripts and ASP, and we discuss their potential functions in HIV-1 infection together with the role played by antisense transcripts and ASPs in some other viruses. Finally, we suggest pathways raised by the study of antisense transcripts and ASPs that may warrant exploration in the future.
The Influence of Some Axial Ligands on Ruthenium–Phthalocyanine Complexes: Chemical, Photochemical, and Photobiological Properties
Authors: Martins Tássia Joi , Negri Laisa Bonafim , Pernomian Laena , Faial Kelson do Carmo Freitas , Xue Congcong , Akhimie Regina N. , Hamblin Michael R. , Turro Claudia , da Silva Roberto S.
Published: January 2021

This work presents a new procedure to synthesize ruthenium–phthalocyanine complexes and uses diverse spectroscopic techniques to characterize trans-[RuCl(Pc)DMSO] (I) (Pc = phthalocyanine) and trans-[Ru(Pc)(4-ampy)2] (II) (4-ampy = 4-aminopyridine). The triplet excited-state lifetimes of (I) measured by nanosecond transient absorption showed that two processes occurred, one around 15 ns and the other around 3.8 μs. Axial ligands seemed to affect the singlet oxygen quantum yield. Yields of 0.62 and 0.14 were achieved for (I) and (II), respectively. The lower value obtained for (II) probably resulted from secondary reactions of singlet oxygen in the presence of the ruthenium complex. We also investigate how axial ligands in the ruthenium–phthalocyanine complexes affect their photo-bioactivity in B16F10 murine melanoma cells. In the case of (I) at 1 μmol/L, photosensitization with 5.95 J/cm2 provided B16F10 cell viability of 6%, showing that (I) was more active than (II) at the same concentration. Furthermore, (II) was detected intracellularly in B16F10 cell extracts. The behavior of the evaluated ruthenium–phthalocyanine complexes point to the potential use of (I) as a metal-based drug in clinical therapy. Changes in axial ligands can modulate the photosensitizer activity of the ruthenium phthalocyanine complexes.
pH-Induced Local Unfolding of the Phl p 6 Pollen Allergen From cpH-MD
Authors: Hofer Florian , Kamenik Anna S. , Fernández-Quintero Monica L. , Kraml Johannes , Liedl Klaus R.
Published: January 2021

Susceptibility to endosomal degradation is a decisive contribution to a protein's immunogenicity. It is assumed that the processing kinetics of structured proteins are inherently linked to their probability of local unfolding. In this study, we quantify the impact of endosomal acidification on the conformational stability of the major timothy grass pollen allergen Phl p 6. We use state of the art sampling approaches in combination with constant pH MD techniques to profile pH-dependent local unfolding events in atomistic detail. Integrating our findings into the current view on type 1 allergic sensitization, we characterize local protein dynamics in the context of proteolytic degradation at neutral and acidic pH for the wild type protein and point mutants with varying proteolytic stability. We analyze extensive simulation data using Markov state models and retrieve highly reliable thermodynamic and kinetic information at varying pH levels. Thereby we capture the impact of endolysosomal acidification on the structure and dynamics of the Phl p 6 mutants. We find that upon protonation at lower pH values, the conformational flexibilities in key areas of the wild type protein, i.e., T-cell epitopes and early proteolytic cleavage sites, increase significantly. A decrease of the pH even leads to local unfolding in otherwise stable secondary structure elements, which is a prerequisite for proteolytic cleavage. This effect is even more pronounced in the destabilized mutant, while no unfolding was observed for the stabilized mutant. In summary, we report detailed structural models which rationalize the experimentally observed cleavage pattern during endosomal acidification.
Kinetic, Structural, and Mutational Analysis of Acyl-CoA Carboxylase From Thermobifida fusca YX
Authors: Shivaiah Kiran-Kumar , Upton Bryon , Nikolau Basil J.
Published: January 2021

Acyl-CoA carboxylases (AcCCase) are biotin-dependent enzymes that are capable of carboxylating more than one short chain acyl-CoA substrate. We have conducted structural and kinetic analyses of such an AcCCase from Thermobifida fusca YX, which exhibits promiscuity in carboxylating acetyl-CoA, propionyl-CoA, and butyryl-CoA. The enzyme consists of two catalytic subunits (TfAcCCA and TfAcCCB) and a non-catalytic subunit, TfAcCCE, and is organized in quaternary structure with a A6B6E6 stoichiometry. Moreover, this holoenzyme structure appears to be primarily assembled from two A3 and a B6E6 subcomplexes. The role of the TfAcCCE subunit is to facilitate the assembly of the holoenzyme complex, and thereby activate catalysis. Based on prior studies of an AcCCase from Streptomyces coelicolor, we explored whether a conserved Asp residue in the TfAcCCB subunit may have a role in determining the substrate selectivity of these types of enzymes. Mutating this D427 residue resulted in alterations in the substrate specificity of the TfAcCCase, increasing proficiency for carboxylating acetyl-CoA, while decreasing carboxylation proficiency with propionyl-CoA and butyryl-CoA. Collectively these results suggest that residue D427 of AcCCB subunits is an important, but not sole determinant of the substrate specificity of AcCCase enzymes.
StructureMan: A Structure Manipulation Tool to Study Large Scale Biomolecular Interactions
Authors: Xian Yuejiao , Xie Yixin , Silva Sebastian Miki , Karki Chitra B. , Qiu Weihong , Li Lin
Published: January 2021

Studying biomolecular interactions is a crucial but challenging task. Due to their large scales, many biomolecular interactions are difficult to be simulated via all atom models. An effective approach to investigate the biomolecular interactions is highly demanded in many areas. Here we introduce a Structure Manipulation (StructureMan) program to operate the structures when studying the large-scale biomolecular interactions. This novel StructureMan tool provides comprehensive operations which can be utilized to study the interactions in various large biological systems. Combining with electrostatic calculation programs such as DelPhi and DelPhiForce, StructureMan was implemented to reveal the detailed electrostatic features in two large biological examples, the viral capsid and molecular motor-microtubule complexes. Applications on these two examples revealed interesting binding mechanisms in the viral capsid and molecular motor. Such applications demonstrated that the StructureMan can be widely used when studying the biomolecular interactions in large scale biological problems. This novel tool provides an alternative approach to efficiently study the biomolecular interactions, especially for large scale biology systems. The StructureMan tool is available at our website:http://compbio.utep.edu/static/downloads/script-for-munipulation2.zip.
Comparison of Therapies in MS Patients After the First Demyelinating Event in Real Clinical Practice in the Czech Republic: Data From the National Registry ReMuS
Authors: Pavelek Zbyšek , Sobíšek Lukáš , Šarláková Jana , Potužník Pavel , Peterka Marek , Štětkárová Ivana , Štourač Pavel , Mareš Jan , Hradílek Pavel , Ampapa Radek , Grünermelová Markéta , Vachová Marta , Recmanová Eva , Angelucci Francesco , Halúsková Simona , Vališ Martin
Published: January 2021

Background: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system. Well-established drugs used for MS patients after the first demyelinating event in the Czech Republic include glatiramer acetate (GA), interferon beta-1a (IFNβ-1a), IFN beta-1b (IFNβ-1b), peginterferon beta-1a (peg-IFNβ-1a), and teriflunomide.

Objective: The objective of this observational study was to compare the effectiveness of the abovementioned drugs in patients with MS who initiated their therapy after the first demyelinating event. Patients were followed for up to 2 years in real clinical practice in the Czech Republic.

Methods: A total of 1,654 MS patients treated after the first demyelinating event and followed up for 2 years were enrolled. Evaluation parameters (endpoints) included the annualized relapse rate (ARR), time to next relapse, change in the Expanded Disability Status Scale (EDSS) score, and time of confirmed disease progression (CDP). When patients ended the therapy before the observational period, the reason for ending the therapy among different treatments was compared.

Results: No significant difference was found among the groups of patients treated with IFNβ-1a/1b, GA, or teriflunomide for the following parameters: time to the first relapse, change in the EDSS score, and the proportion of patients with CDP. Compared to IFNβ-1a (44 mcg), a significant increase in the percentage of relapse-free patients was found for GA, but this treatment effect was not confirmed by the validation analysis. Compared to the other drugs, there was a significant difference in the reasons for terminating GA therapy.

Conclusion: Small differences were found among GA, IFNβ and teriflunomide therapies, with no significant impact on the final outcome after 2 years. Therefore, in clinical practice, we recommend choosing the drug based on individual potential risk from long-term therapy and on patient preferences and clinical characteristics.
The Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score Is Associated With Poor Outcome of Acute Ischemic Stroke
Authors: Tian Mengke , Li Youfeng , Wang Xiao , Tian Xuan , Pei Lu-lu , Wang Xin , Zhang Luyang , Sun Wenxian , Wu Jun , Sun Shilei , Ning Mingming , Buonanno Ferdinando , Xu Yuming , Song Bo
Published: January 2021

Background: The combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP) is considered a novel score to reflect systemic inflammation and nutritional status. This study aimed to investigate the association between HALP score and poor outcome in patients with acute ischemic stroke (AIS).

Methods: Consecutive AIS patients within 24 h after onset were prospectively enrolled. Poor outcome was a combination of a new stroke event (ischemic and hemorrhagic) and all-cause death within 90 days and 1 year. The association between HALP score and poor outcome was analyzed using Cox proportional hazards.

Results: A total of 1,337 patients were included. Overall, 60 (4.5%) and 118 (8.8%) patients experienced poor outcome within 90 days and 1 year, respectively. Patients in the highest tertile of HALP score had a lower risk of poor outcome within 90 days and 1 year (hazard ratio: 0.25 and 0.42; 95% confidence intervals: 0.11–0.57 and 0.25–0.69, P for trend <0.01 for all) compared with those in the lowest tertile after adjusting relevant confounding factors. Adding HALP score to the conventional risk factors improved prediction of poor outcome in patients with AIS within 90 days and 1 year (net reclassification index, 48.38 and 28.95%; integrated discrimination improvement, 1.51 and 1.51%; P < 0.05 for all).

Conclusions: Increased HALP score was associated with a decreased risk of recurrent stroke and death within 90 days and 1 year after stroke onset, suggesting that HALP score may serve as a powerful indicator for AIS.
Brain Magnetic Resonance Imaging Characteristics of Anti-Leucine-Rich Glioma-Inactivated 1 Encephalitis and Their Clinical Relevance: A Single-Center Study in China
Authors: Shao Xiali , Fan Siyuan , Luo Huan , Wong Ting Yat , Zhang Weihong , Guan Hongzhi , Qiu Anqi
Published: January 2021

Objective: To characterize the magnetic resonance imaging (MRI) features of anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis and explore their clinical relevance.

Methods: Patients with anti-LGI1 encephalitis who underwent MRI at our center were included in this study. Baseline and follow-up MRI characteristics were evaluated, and relationships between lesion location and clinical symptoms were analyzed. The extent of signal abnormalities within the lesion overlap region was measured and correlated with modified Rankin Scale scores and serum antibody titer.

Results: Seventy-six patients were enrolled, of which 57 (75%) were classified as MR positive. Brain lesions were located in medial temporal lobe (MTL) (89%) and basal ganglia (BG) (28%). Hippocampus and amygdala were lesion hubs with more than 50% lesion overlap. BG lesions were found in 30% of patients with faciobrachial dystonic seizure (FBDS) and only 7% of patients without FBDS (p = 0.013). Meanwhile, MTL lesions were more commonly observed in patients with memory impairment (70 vs. 0%, p = 0.017). MRI features included hyperintensity and edema at baseline, as well as hypointensity and atrophy at follow-up. Correlations between signal intensity of lesion hubs (including hippocampus and amygdala) and modified Rankin Scale scores were found on T2 (r = 0.414, p < 0.001) and diffusion-weighted imaging (r = 0.456, p < 0.001).

Conclusion: MTL and BG are two important structures affected by anti-LGI1 encephalitis, and they are associated with distinctive symptoms. Our study provided evidence from Chinese patients that BG lesions are more commonly observed in patients with FBDS, potentially suggesting BG localization. Furthermore, in addition to supporting diagnosis, MRI has the potential to quantify disease severity.
Nutritional Implications of Trade-Offs Between Fresh and Processed Potato Products in the United Kingdom (UK)
Authors: Dogbe Wisdom , Revoredo-Giha Cesar
Published: January 2021

The UK ranks eleven among world potato producing countries with annual per capita production of about 102 kg. Since 2007, the price of potatoes has increased by 44 per cent and UK households have shown a decreasing trend on their purchases of potatoes. At the same time, retailers and manufacturers have been introducing processed potato products, which also has affected the demand for fresh potatoes. This has shifted demand from fresh potatoes to processed potatoes suggesting that consumers substitute fresh potatoes for processed ones. However, the extent to which this affect individual weekly nutritional composition is unknown. The objective of this study is to estimate the nutritional trade-offs between fresh and processed potatoes consumed in the UK using home scanner panel dataset for Great Britain in 2018. Price and expenditure elasticities were estimated using the linearized version of the Exact Affine Stone Index (EASI) Demand System. Using estimated elasticities, we analyzed the implications of substituting fresh potatoes for processed potatoes on nutrient intake. The results, in terms of the degree of substitution between fresh potatoes and processed potato products, suggest that consumers consider new potatoes baby and baking potatoes as substitutes for mashed potatoes. Maris piper potatoes and new potatoes baby are substitutes for frozen chips and other potatoes whilst white old potatoes and other vegetables and salads are complements to frozen chips and other potatoes. Finally, price reductions in the processed potatoes will increase average weekly caloric intake as well as the intakes of saturated fat and sodium. The latter has implications for public health as they are the major causes of cardiovascular diseases and certain cancers.
Predicting the Local Response of Metastatic Brain Tumor to Gamma Knife Radiosurgery by Radiomics With a Machine Learning Method
Authors: Kawahara Daisuke , Tang Xueyan , Lee Chung K. , Nagata Yasushi , Watanabe Yoichi
Published: January 2021

Purpose

The current study proposed a model to predict the response of brain metastases (BMs) treated by Gamma knife radiosurgery (GKRS) using a machine learning (ML) method with radiomics features. The model can be used as a decision tool by clinicians for the most desirable treatment outcome.

Methods and Material

Using MR image data taken by a FLASH (3D fast, low-angle shot) scanning protocol with gadolinium (Gd) contrast-enhanced T1-weighting, the local response (LR) of 157 metastatic brain tumors was categorized into two groups (Group I: responder and Group II: non-responder). We performed a radiomics analysis of those tumors, resulting in more than 700 features. To build a machine learning model, first, we used the least absolute shrinkage and selection operator (LASSO) regression to reduce the number of radiomics features to the minimum number of features useful for the prediction. Then, a prediction model was constructed by using a neural network (NN) classifier with 10 hidden layers and rectified linear unit activation. The training model was evaluated with five-fold cross-validation. For the final evaluation, the NN model was applied to a set of data not used for model creation. The accuracy and sensitivity and the area under the receiver operating characteristic curve (AUC) of the prediction model of LR were analyzed. The performance of the ML model was compared with a visual evaluation method, for which the LR of tumors was predicted by examining the image enhancement pattern of the tumor on MR images.

Results

By the LASSO analysis of the training data, we found seven radiomics features useful for the classification. The accuracy and sensitivity of the visual evaluation method were 44 and 54%. On the other hand, the accuracy and sensitivity of the proposed NN model were 78 and 87%, and the AUC was 0.87.

Conclusions

The proposed NN model using the radiomics features can help physicians to gain a more realistic expectation of the treatment outcome than the traditional method.
VISTA Expression on Immune Cells Correlates With Favorable Prognosis in Patients With Triple-Negative Breast Cancer
Authors: Cao Xi , Ren Xinyu , Zhou Yidong , Mao Feng , Lin Yan , Wu Huanwen , Sun Qiang
Published: January 2021

V-domain Ig suppressor of T-cell activation (VISTA), a newly discovered negative immune checkpoint, is thought to be related to immunotherapy resistance and may become a new immune therapeutic target. Here, we evaluated the expression of VISTA in a cohort containing 254 patients with untreated triple-negative breast cancer. The relevance of VISTA expression, clinicopathologic parameters, expression of other immune markers, and prognosis were investigated in the whole cohort. Genomic analysis of 139 triple-negative breast cancer (TNBC) patients from the cancer genome atlas (TCGA) was also performed. VISTA was expressed in the immune cells (ICs) and in the tumor cells (TCs) in 87.8% (223/254) and 18.5% (47/254) of the cohort, respectively. VISTA-positive ICs were associated with no lymph node metastasis (p < 0.001), American Joint Committee on Cancer (AJCC) stage I and II (p = 0.001) and basal-like subtype (p < 0.001). VISTA expression in ICs positively correlated with some tumor-infiltrating lymphocytes (TILs) types, particularly with the CD4+TILs, which was consistent with mRNA level analysis from the TCGA database. Survival analysis showed that patients with VISTA-positive ICs had prolonged relapse-free and overall survival compared with the negative ones, especially among T1-2N0 stage patients. Multivariate analysis showed that it independently predicted the prognosis. These data confirmed the regulatory role of VISTA in anti-tumor immunity, changed our perception of VISTA as a negative immune checkpoint, and suggested VISTA as a potential therapeutic target for TNBC.
Dose–Response Between Serum Prealbumin and All-Cause Mortality After Hepatectomy in Patients With Hepatocellular Carcinoma
Authors: Huo Rong-Rui , Liu Hao-Tian , Deng Zhu-Jian , Liang Xiu-Mei , Gong Wen-Feng , Qi Lu-Nan , You Xue-Mei , Xiang Bang-De , Li Le-Qun , Ma Liang , Zhong Jian-Hong
Published: January 2021

Background

The relationship between serum prealbumin and the risk of all-cause mortality after hepatectomy in patients with hepatocellular carcinoma (HCC) needs to be evaluated.

Methods

We conducted a retrospective study. A Cox proportional hazards regression model was used to adjust for potential confounders. Prealbumin level was transformed by Z-scores and categorized into quartiles (Q1: <147 mg/L, Q2: 147–194 mg/L, Q3: 194–239 mg/L, Q4: >239 mg/L). We assessed the dose-response relationship between serum prealbumin and the risk of all-cause mortality using a restricted cubic spline model.

Results

Data were included from 2,022 HCC patients who underwent hepatectomy at Guangxi Medical University Cancer Hospital in China between January 2006 and January 2016. The adjusted hazard ratios (HRs) for increasing quartiles of serum prealbumin were 0.78 [95% confidence interval (CI): 0.64–0.95] for Q2, 0.66 (0.53–0.81) for Q3, and 0.51 (0.41–0.64) for Q4 in the Cox model (all P < 0.001). Serum prealbumin showed an L-shaped, non-linear dose-response relationship with the risk of all-cause mortality (P < 0.001). Among patients whose serum prealbumin was below 250 mg/L, risk of all-cause mortality decreased by 27% (95% CI: 18–36%) per increase of one standard deviation (69.8 mg/L) in serum prealbumin.

Conclusions

Levels of serum prealbumin under 250 mg/L may be considered dangerous with respect to all-cause mortality after hepatectomy in HCC patients. Serum prealbumin may be useful as a prognostic marker in HCC patients undergoing hepatectomy.
Next-Generation Immunotherapies to Improve Anticancer Immunity
Authors: Shi Yaoyao , Tomczak Katarzyna , Li June , Ochieng Joshua K. , Lee Younghee , Haymaker Cara
Published: January 2021

Checkpoint inhibitors are widely used immunotherapies for advanced cancer. Nonetheless, checkpoint inhibitors have a relatively low response rate, work in a limited range of cancers, and have some unignorable side effects. Checkpoint inhibitors aim to reinvigorate exhausted or suppressed T cells in the tumor microenvironment (TME). However, the TME contains various other immune cell subsets that interact to determine the fate of cytotoxic T cells. Activation of cytotoxic T cells is initiated by antigen cross-presentation of dendritic cells. Dendritic cells could also release chemokines and cytokines to recruit and foster T cells. B cells, another type of antigen-presenting cell, also foster T cells and can produce tumor-specific antibodies. Neutrophils, a granulocyte cell subset in the TME, impede the proliferation and activation of T cells. The TME also consists of cytotoxic innate natural killer cells, which kill tumor cells efficiently. Natural killer cells can eradicate major histocompatibility complex I-negative tumor cells, which escape cytotoxic T cell–mediated destruction. A thorough understanding of the immune mechanism of the TME, as reviewed here, will lead to further development of more powerful therapeutic strategies. We have also reviewed the clinical outcomes of patients treated with drugs targeting these immune cells to identify strategies for improvement and possible immunotherapy combinations.
Amino Acid Degrading Enzymes and Autophagy in Cancer Therapy
Authors: Wang Ziyu , Xie Qinghong , Zhou Haifeng , Zhang Min , Shen Jie , Ju Dianwen
Published: January 2021

Recently, there has been renewed interest in metabolic therapy for cancer, particularly in amino acid deprivation by enzymes. L-asparaginase was approved for the treatment of acute lymphoblastic leukemia by the U.S. Food and Drug Administration. Arginine deiminase and recombinant human arginase have been developed into clinical trials as potential cancer therapeutic agents for the treatment of arginine-auxotrophic tumors. Moreover, other novel amino acid degrading enzymes, such as glutaminase, methionase, lysine oxidase, phenylalanine ammonia lyase, have been developed for the treatment of malignant cancers. One of the greatest obstacles faced by anticancer drugs is the development of drug resistance, which is reported to be associated with autophagy. Autophagy is an evolutionarily conserved catabolic process that is responsible for the degradation of dysfunctional proteins and organelles. There is a growing body of literature revealing that, in response to metabolism stress, autophagy could be induced by amino acid deprivation. The manipulation of autophagy in combination with amino acid degrading enzymes is actively being investigated as a potential therapeutic approach in preclinical studies. Importantly, shedding light on how autophagy fuels tumor metabolism during amino acid deprivation will enable more potential combinational therapeutic strategies. This study summarizes recent advances, discussing several potential anticancer enzymes, and highlighting the promising combined therapeutic strategy of amino acid degrading enzymes and autophagy modulators in tumors