bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Characterization and Expression Analysis of CAMTA Gene Family Under Salt Stress in Cucurbita moschata and Cucurbita maxima
Authors: Yuan Jingping , Shen Changwei , Chen Bihua , Shen Aimin , Li Xinzheng
Published: June 2021

Cucurbita Linn. vegetables have a long history of cultivation and have been cultivated all over the world. With the increasing area of saline–alkali soil, Cucurbita Linn. is affected by salt stress, and calmodulin-binding transcription activator (CAMTA) is known for its important biological functions. Although the CAMTA gene family has been identified in several species, there is no comprehensive analysis on Cucurbita species. In this study, we analyzed the genome of Cucurbita maxima and Cucurbita moschata. Five C. moschata calmodulin-binding transcription activators (CmoCAMTAs) and six C. maxima calmodulin-binding transcription activators (CmaCAMTAs) were identified, and they were divided into three subfamilies (Subfamilies I, II, and III) based on the sequence identity of amino acids. CAMTAs from the same subfamily usually have similar exon–intron distribution and conserved domains (CG-1, TIG, IQ, and Ank_2). Chromosome localization analysis showed that CmoCAMTAs and CmaCAMTAs were unevenly distributed across four and five out of 21 chromosomes, respectively. There were a total of three duplicate gene pairs, and all of which had experienced segmental duplication events. The transcriptional profiles of CmoCAMTAs and CmaCAMTAs in roots, stems, leaves, and fruits showed that these CAMTAs have tissue specificity. Cis-acting elements analysis showed that most of CmoCAMTAs and CmaCAMTAs responded to salt stress. By analyzing the transcriptional profiles of CmoCAMTAs and CmaCAMTAs under salt stress, it was shown that both C. moschata and C. maxima shared similarities against salt tolerance and that it is likely to contribute to the development of these species. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) further demonstrated the key role of CmoCAMTAs and CmaCAMTAs under salt stress. This study provided a theoretical basis for studying the function and mechanism of CAMTAs in Cucurbita Linn.
Identification of Main-Effect and Environmental Interaction QTL and Their Candidate Genes for Drought Tolerance in a Wheat RIL Population Between Two Elite Spring Cultivars
Authors: Rabbi S. M. Hisam Al , Kumar Ajay , Mohajeri Naraghi Sepehr , Sapkota Suraj , Alamri Mohammed S. , Elias Elias M. , Kianian Shahryar , Seetan Raed , Missaoui Ali , Solanki Shyam , Mergoum Mohamed
Published: June 2021

Understanding the genetics of drought tolerance can expedite the development of drought-tolerant cultivars in wheat. In this study, we dissected the genetics of drought tolerance in spring wheat using a recombinant inbred line (RIL) population derived from a cross between a drought-tolerant cultivar, ‘Reeder’ (PI613586), and a high-yielding but drought-susceptible cultivar, ‘Albany.’ The RIL population was evaluated for grain yield (YLD), grain volume weight (GVW), thousand kernel weight (TKW), plant height (PH), and days to heading (DH) at nine different environments. The Infinium 90 k-based high-density genetic map was generated using 10,657 polymorphic SNP markers representing 2,057 unique loci. Quantitative trait loci (QTL) analysis detected a total of 11 consistent QTL for drought tolerance-related traits. Of these, six QTL were exclusively identified in drought-prone environments, and five were constitutive QTL (identified under both drought and normal conditions). One major QTL on chromosome 7B was identified exclusively under drought environments and explained 13.6% of the phenotypic variation (PV) for YLD. Two other major QTL were detected, one each on chromosomes 7B and 2B under drought-prone environments, and explained 14.86 and 13.94% of phenotypic variation for GVW and YLD, respectively. One novel QTL for drought tolerance was identified on chromosome 2D. In silico expression analysis of candidate genes underlaying the exclusive QTLs associated with drought stress identified the enrichment of ribosomal and chloroplast photosynthesis-associated proteins showing the most expression variability, thus possibly contributing to stress response by modulating the glycosyltransferase (TraesCS6A01G116400) and hexosyltransferase (TraesCS7B01G013300) unique genes present in QTL 21 and 24, respectively. While both parents contributed favorable alleles to these QTL, unexpectedly, the high-yielding and less drought-tolerant parent contributed desirable alleles for drought tolerance at four out of six loci. Regardless of the origin, all QTL with significant drought tolerance could assist significantly in the development of drought-tolerant wheat cultivars, using genomics-assisted breeding approaches.
Strategies to Uplift Novel Mendelian Gene Discovery for Improved Clinical Outcomes
Authors: Seaby Eleanor G. , Rehm Heidi L. , O’Donnell-Luria Anne
Published: June 2021

Rare genetic disorders, while individually rare, are collectively common. They represent some of the most severe disorders affecting patients worldwide with significant morbidity and mortality. Over the last decade, advances in genomic methods have significantly uplifted diagnostic rates for patients and facilitated novel and targeted therapies. However, many patients with rare genetic disorders still remain undiagnosed as the genetic etiology of only a proportion of Mendelian conditions has been discovered to date. This article explores existing strategies to identify novel Mendelian genes and how these discoveries impact clinical care and therapeutics. We discuss the importance of data sharing, phenotype-driven approaches, patient-led approaches, utilization of large-scale genomic sequencing projects, constraint-based methods, integration of multi-omics data, and gene-to-patient methods. We further consider the health economic advantages of novel gene discovery and speculate on potential future methods for improved clinical outcomes.
RETRACTED: Oncological Effects and Prognostic Value of AMAP1 in Gastric Cancer
Authors: Li Jiao , Tian Shan , Guo Yingyun , Dong Weiguo
Published: June 2021

Purpose

We examined the diagnostic significance, prognostic value, and potential function of AMAP1 in gastric cancer (GC).

Methods

Comprehensive bioinformatic analysis was conducted to investigate differential expression of AMAP1 mRNA and protein in GC. Meta-analyses were utilized to determine the overall prognostic correlation of AMAP1 mRNA in patients with GC. A panel of vitro assays was applied to assess target microRNA and AMAP1 protein in GC cell lines and tissues, respectively.

Results

AMAP1 mRNA and protein levels were upregulated in GC specimens, compared to matched normal tissues. AMAP1 mRNA exhibited promising results regarding differential diagnosis of GC and normal tissue. Meta-analysis based on the TCGA and GEO databases revealed that high AMAP1 mRNA abundance was associated with poor overall survival (HR = 1.42; 95% CI: 1.06–1.89) and was correlated with reduced progression-free survival (HR = 1.89; 95% CI: 1.51–2.36) in GC patients. Moreover, AMAP1 was negatively correlated with miR-192-3p (r = −0.3843; P < 0.0001). A dual-luciferase assay revealed that miR-192-3p targeted AMAP1. Levels of miR-192-3p were significantly higher in GC tissues and GC cells than in normal tissues and cells. Moreover, AMAP1 silencing resulted in reduced GC proliferation, migration, and invasion.

Conclusion

AMAP1 is a novel oncogene in GC and is negatively correlated with by miR-192-3p. AMAP1 may act as a diagnostic and prognostic marker of GC.
Type 1 Diabetes and the HLA Region: Genetic Association Besides Classical HLA Class II Genes
Authors: Sticht Jana , Álvaro-Benito Miguel , Konigorski Stefan
Published: June 2021

Type 1 diabetes is an autoimmune disease with rising incidence in high-income countries. Genetic and environmental predisposing factors contribute to the etiology of the disease, although their interaction is not sufficiently understood to allow for preventive action. Strongest known associations with genetic variation map to classical HLA class II genes. Because of its genetic complexity, the HLA region has been under-represented in genome-wide association studies, having potentially hindered the identification of relevant associations underlying the etiology of the disease. Here, we performed a comprehensive HLA-wide genetic association analysis of type 1 diabetes including multi-allelic and rare variants. We used high-density whole-exome sequencing data of the HLA region in the large UK Biobank dataset to apply gene-based association tests with a carefully defined type 1 diabetes phenotype (97 cases and 48,700 controls). Exon-based and single-variant association tests were used to complement the analysis. We replicated the known association of type 1 diabetes with the classical HLA-DQ gene. Tailoring the analysis toward rare variants, we additionally identified the lysine methyl transferase EHMT2 as associated. Deeper insight into genetic variation associated with disease as presented and discussed in detail here can help unraveling mechanistic details of the etiology of type 1 diabetes. More specifically, we hypothesize that genetic variation in EHMT2 could impact autoimmunity in type 1 diabetes development.
Short- and Long-Lived Autoantibody-Secreting Cells in Autoimmune Neurological Disorders
Authors: Zografou C. , Vakrakou A. G. , Stathopoulos P.
Published: June 2021

As B cells differentiate into antibody-secreting cells (ASCs), short-lived plasmablasts (SLPBs) are produced by a primary extrafollicular response, followed by the generation of memory B cells and long-lived plasma cells (LLPCs) in germinal centers (GCs). Generation of IgG4 antibodies is T helper type 2 (Th2) and IL-4, -13, and -10-driven and can occur parallel to IgE, in response to chronic stimulation by allergens and helminths. Although IgG4 antibodies are non-crosslinking and have limited ability to mobilize complement and cellular cytotoxicity, when self-tolerance is lost, they can disrupt ligand-receptor binding and cause a wide range of autoimmune disorders including neurological autoimmunity. In myasthenia gravis with predominantly IgG4 autoantibodies against muscle-specific kinase (MuSK), it has been observed that one-time CD20+B cell depletion with rituximab commonly leads to long-term remission and a marked reduction in autoantibody titer, pointing to a short-lived nature of autoantibody-secreting cells. This is also observed in other predominantly IgG4 autoantibody-mediated neurological disorders, such as chronic inflammatory demyelinating polyneuropathy and autoimmune encephalitis with autoantibodies against the Ranvier paranode and juxtaparanode, respectively, and extends beyond neurological autoimmunity as well. Although IgG1 autoantibody-mediated neurological disorders can also respond well to rituximab induction therapy in combination with an autoantibody titer drop, remission tends to be less long-lasting and cases where titers are refractory tend to occur more often than in IgG4 autoimmunity. Moreover, presence of GC-like structures in the thymus of myasthenic patients with predominantly IgG1 autoantibodies against the acetylcholine receptor and in ovarian teratomas of autoimmune encephalitis patients with predominantly IgG1 autoantibodies against the N‐methyl‐d‐aspartate receptor (NMDAR) confers increased the ability to generate LLPCs. Here, we review available information on the short-and long-lived nature of ASCs in IgG1 and IgG4 autoantibody-mediated neurological disorders and highlight common mechanisms as well as differences, all of which can inform therapeutic strategies and personalized medical approaches.
Climate Change Increases Susceptibility to Grazers in a Foundation Seaweed
Authors: Kinnby Alexandra , Toth Gunilla B. , Pavia Henrik
Published: June 2021

Climate change leads to multiple effects caused by simultaneous shifts in several physical factors which will interact with species and ecosystems in complex ways. In marine systems the effects of climate change include altered salinity, increased temperature, and elevated pCO2 which are currently affecting and will continue to affect marine species and ecosystems. Seaweeds are primary producers and foundation species in coastal ecosystems, which are particularly vulnerable to climate change. The brown seaweed Fucus vesiculosus (bladderwrack) is an important foundation species in nearshore ecosystems throughout its natural range in the North Atlantic Ocean and the Baltic Sea. This study investigates how individual and interactive effects of temperature, salinity, and pCO2 affect F. vesiculosus, using a fully crossed experimental design. We assessed the effects on F. vesiculosus in terms of growth, biochemical composition (phlorotannin content, C:N ratio, and ∂13C), and susceptibility to the specialized grazer Littorina obtusata. We observed that elevated pCO2 had a positive effect on seaweed growth in ambient temperature, but not in elevated temperature, while growth increased in low salinity at ambient but not high temperature, regardless of pCO2-level. In parallel to the statistically significant, but relatively small, positive effects on F. vesiculosus growth, we found that the seaweeds became much more susceptible to grazing in elevated pCO2 and reduced salinity, regardless of temperature. Furthermore, the ability of the seaweeds to induce chemical defenses (phlorotannins) was strongly reduced by all the climate stressors. Seaweeds exposed to ambient conditions more than doubled their phlorotannin content in the presence of grazers, while seaweeds exposed to any single or combined stress conditions showed only minor increases in phlorotannin content, or none at all. Despite the minor positive effects on seaweed growth, the results of this study imply that climate change can strongly affect the ability of fucoid seaweeds to induce chemical defenses and increase their susceptibility to grazers. This will likely lead to widespread consequences under future climate conditions, considering the important role of F. vesiculosus and other fucoids in many coastal ecosystems.
Prevalence of Celiac Disease in Patients With Turner Syndrome: Systematic Review and Meta-Analysis
Authors: Al-Bluwi Ghada S. M. , AlNababteh Asma H. , Östlundh Linda , Al-Shamsi Saif , Al-Rifai Rami H.
Published: June 2021

Introduction: Celiac disease (CD) is a multifactorial autoimmune disorder, and studies have reported that patients with Turner syndrome (TS) are at risk for CD. This systematic review and meta-analysis aimed to quantify the weighted prevalence of CD among patients with TS and determine the weighted strength of association between TS and CD.

Methods: Studies published between January 1991 and December 2019 were retrieved from four electronic databases: PubMed, Scopus, Web of Science, and Embase. Eligible studies were identified and relevant data were extracted by two independent reviewers following specific eligibility criteria and a data extraction plan. Using the random-effects model, the pooled, overall and subgroup CD prevalence rates were determined, and sources of heterogeneity were investigated using meta-regression.

Results: Among a total of 1,116 screened citations, 36 eligible studies were included in the quantitative synthesis. Nearly two-thirds of the studies (61.1%) were from European countries. Of the 6,291 patients with TS who were tested for CD, 241 were diagnosed with CD, with a crude CD prevalence of 3.8%. The highest and lowest CD prevalence rates of 20.0 and 0.0% were reported in Sweden and Germany, respectively. The estimated overall weighted CD prevalence was 4.5% (95% confidence interval [CI], 3.3–5.9, I2, 67.4%). The weighted serology-based CD prevalence in patients with TS (3.4%, 95% CI, 1.0–6.6) was similar to the weighted biopsy-based CD prevalence (4.8%; 95% CI, 3.4–6.5). The strength of association between TS and CD was estimated in only four studies (odds ratio 18.1, 95% CI, 1.82–180; odds ratio 4.34, 95% CI, 1.48–12.75; rate ratio 14, 95% CI, 1.48–12.75; rate ratio 42.5, 95% CI, 12.4–144.8). Given the lack of uniformity in the type of reported measures of association and study design, producing a weighted effect measure to evaluate the strength of association between TS and CD was unfeasible.

Conclusion: Nearly 1 in every 22 patients with TS had CD. Regular screening for CD in patients with TS might facilitate early diagnosis and therapeutic management to prevent adverse effects of CD such as being underweight and osteoporosis.
CT Quantification of COVID-19 Pneumonia at Admission Can Predict Progression to Critical Illness: A Retrospective Multicenter Cohort Study
Authors: Pang Baoguo , Li Haijun , Liu Qin , Wu Penghui , Xia Tingting , Zhang Xiaoxian , Le Wenjun , Li Jianyu , Lai Lihua , Ou Changxing , Ma Jianjuan , Liu Shuai , Zhou Fuling , Wang Xinlu , Xie Jiaxing , Zhang Qingling , Jiang Min , Liu Yumei , Zeng Qingsi
Published: June 2021

Objective: Early identification of coronavirus disease 2019 (COVID-19) patients with worse outcomes may benefit clinical management of patients. We aimed to quantify pneumonia findings on CT at admission to predict progression to critical illness in COVID-19 patients.

Methods: This retrospective study included laboratory-confirmed adult patients with COVID-19. All patients underwent a thin-section chest computed tomography (CT) scans showing evidence of pneumonia. CT images with severe moving artifacts were excluded from analysis. Patients' clinical and laboratory data were collected from medical records. Three quantitative CT features of pneumonia lesions were automatically calculated using a care.ai Intelligent Multi-disciplinary Imaging Diagnosis Platform Intelligent Evaluation System of Chest CT for COVID-19, denoting the percentage of pneumonia volume (PPV), ground-glass opacity volume (PGV), and consolidation volume (PCV). According to Chinese COVID-19 guidelines (trial version 7), patients were divided into noncritical and critical groups. Critical illness was defined as a composite of admission to the intensive care unit, respiratory failure requiring mechanical ventilation, shock, or death. The performance of PPV, PGV, and PCV in discrimination of critical illness was assessed. The correlations between PPV and laboratory variables were assessed by Pearson correlation analysis.

Results: A total of 140 patients were included, with mean age of 58.6 years, and 85 (60.7%) were male. Thirty-two (22.9%) patients were critical. Using a cutoff value of 22.6%, the PPV had the highest performance in predicting critical illness, with an area under the curve of 0.868, sensitivity of 81.3%, and specificity of 80.6%. The PPV had moderately positive correlation with neutrophil (%) (r = 0.535, p < 0.001), erythrocyte sedimentation rate (r = 0.567, p < 0.001), d-Dimer (r = 0.444, p < 0.001), high-sensitivity C-reactive protein (r = 0.495, p < 0.001), aspartate aminotransferase (r = 0.410, p < 0.001), lactate dehydrogenase (r = 0.644, p < 0.001), and urea nitrogen (r = 0.439, p < 0.001), whereas the PPV had moderately negative correlation with lymphocyte (%) (r = −0.535, p < 0.001).

Conclusions: Pneumonia volume quantified on initial CT can non-invasively predict the progression to critical illness in advance, which serve as a prognostic marker of COVID-19.
Pandemic Worry and Preventive Health Behaviors During the COVID-19 Outbreak
Authors: Li Minghui , Lv Gang , Hsieh Stephanie , Shao Rongjie , Yuan Jing
Published: June 2021

Objective: As schools are preparing for onsite learning, it is urgently needed to characterize the extent of pandemic worry and to examine predictors of adopting preventive health behaviors of hand washing, face mask wearing, and maintaining social distance among student pharmacists.

Methods: An online survey was sent to 326 student pharmacists in the United States. Pandemic worry was measured using a seven-point Likert scale ranging from extremely not afraid of, to extremely afraid of getting COVID-19. The health belief model (HBM) was the theoretical framework of this study. Preventive health behaviors and components of the HBM were also measured using seven-point Likert scales (one indicated extremely unlikely; seven indicated extremely likely). Multivariable linear regression models were used to identify predictors of each behavior.

Results: A medium level of pandemic worry (M = 4.2, SD = 1.92) was identified and females reported a higher pandemic worry. Respondents reported that they were extremely likely to wash their hands (M = 6.8, SD = 0.48) and maintain social distance (M = 6.6, SD = 0.92), but were moderately unlikely to wear face masks (M = 2.2, SD = 1.51). Determinants of face mask wearing included pandemic worry, perceived benefits, cue to action, self-efficacy, and being of an Asian American. Perceived barriers were negatively associated with face mask wearing.

Conclusion: Strategies should be implemented to reduce the psychological impact of COVID-19 pandemic among student pharmacists. Predictors identified in this study should be incorporated in efforts to improve face mask wearing. Continued monitoring of pandemic worry and preventive health behaviors is of great significance when universities and colleges are for onsite learning.
Liquor Flavour Is Associated With the Physicochemical Property and Microbial Diversity of Fermented Grains in Waxy and Non-waxy Sorghum (Sorghum bicolor) During Fermentation
Authors: Liu Chunjuan , Gong Xiangwei , Zhao Guan , Soe Htet Maw Ni , Jia Zhiyong , Yan Zongke , Liu Lili , Zhai Qinghua , Huang Ting , Deng Xiping , Feng Baili
Published: June 2021

The fermentation process of Chinese Xifeng liquor involves numerous microbes. However, the sources of microbes in fermented grain and the link between liquor flavour and physicochemical properties and microbial diversity during fermentation still remain unknown. Herein, two waxy (JiNiang 2 [JN-2] and JinNuo 3 [JN-3]) and four non-waxy (JiZa 127 [JZ-127], JinZa 34 [JZ-34], LiaoZa 19 [LZ-19], and JiaXian [JX]) sorghum varieties were selected for the comprehensive analysis of the relationship between liquor flavour and the physicochemical properties and microbial diversity of fermented grains. Results showed that ethyl acetate was the main flavour component of JZ-127, JZ-34, and JX, whereas ethyl lactate was mainly detected in JN-2, JN-3, and LZ-19. Ethyl lactate accounted for half of the ethyl acetate content, and JX exhibited a higher liquor yield than the other sorghum varieties. The fermented grains of waxy sorghum presented higher temperature and reducing sugar contents but lower moisture and starch contents than their non-waxy counterparts during fermentation. We selected JN-3 and JX sorghum varieties to further investigate the microbial changes in the fermented grains. The bacterial diversity gradually reduced, whereas the fungal diversity showed nearly no change in either JN-3 or JX.Lactobacilluswas the most abundant bacterial genus, and its level rapidly increased during fermentation. The abundance ofLactobacillusaccounted for the total proportion of bacteria in JX, and it was higher than that in JN-3.Saccharomyceswas the most abundant fungal genus in JX, but its abundance accounted for a small proportion of fungi in JN-3. Four esters and five alcohols were significantly positively related to Proteobacteria, Bacteroidetes, and Actinobacteria; Alphaproteobacteria, Actinobacteria, and Bacteroidia; Bacillales, Bacteroidales, and Rhodospirillales; andAcetobacter,Pediococcus, andPrevotella_7. This positive relation is in contrast with that observed for Firmicutes, Bacilli, Lactobacillales, andLactobacillus. Meanwhile,Aspergilluswas the only fungal microorganism that showed a significantly negative relation with such compounds (except for butanol and isopentanol). These findings will help in understanding the fermentation mechanism and flavour formation of fermented Xifeng liquor.
Evolution of Bacterial Cross-Resistance to Lytic Phages and Albicidin Antibiotic
Authors: Kortright Kaitlyn E. , Doss-Gollin Simon , Chan Benjamin K. , Turner Paul E.
Published: June 2021

Due to concerns over the global increase of antibiotic-resistant bacteria, alternative antibacterial strategies, such as phage therapy, are increasingly being considered. However, evolution of bacterial resistance to new therapeutics is almost a certainty; indeed, it is possible that resistance to alternative treatments might result in an evolved trade-up such as enhanced antibiotic resistance. Here, we hypothesize that selection for Escherichia coli bacteria to resist phage T6, phage U115, or albicidin, a DNA gyrase inhibitor, should often result in a pleiotropic trade-up in the form of cross-resistance, because all three antibacterial agents interact with the Tsx porin. Selection imposed by any one of the antibacterials resulted in cross-resistance to all three of them, in each of the 29 spontaneous bacterial mutants examined in this study. Furthermore, cross-resistance did not cause measurable fitness (growth) deficiencies for any of the bacterial mutants, when competed against wild-type E. coli in both low-resource and high-resource environments. A combination of whole-genome and targeted sequencing confirmed that mutants differed from wild-type E. coli via change(s) in the tsx gene. Our results indicate that evolution of cross-resistance occurs frequently in E. coli subjected to independent selection by phage T6, phage U115 or albicidin. This study cautions that deployment of new antibacterial therapies such as phage therapy, should be preceded by a thorough investigation of evolutionary consequences of the treatment, to avoid the potential for evolved trade-ups.
Review of Machine Learning Methods for the Prediction and Reconstruction of Metabolic Pathways
Authors: Shah Hayat Ali , Liu Juan , Yang Zhihui , Feng Jing
Published: June 2021

Prediction and reconstruction of metabolic pathways play significant roles in many fields such as genetic engineering, metabolic engineering, drug discovery, and are becoming the most active research topics in synthetic biology. With the increase of related data and with the development of machine learning techniques, there have many machine leaning based methods been proposed for prediction or reconstruction of metabolic pathways. Machine learning techniques are showing state-of-the-art performance to handle the rapidly increasing volume of data in synthetic biology. To support researchers in this field, we briefly review the research progress of metabolic pathway reconstruction and prediction based on machine learning. Some challenging issues in the reconstruction of metabolic pathways are also discussed in this paper.
BowSaw: Inferring Higher-Order Trait Interactions Associated With Complex Biological Phenotypes
Authors: DiMucci Demetrius , Kon Mark , Segrè Daniel
Published: June 2021

Machine learning is helping the interpretation of biological complexity by enabling the inference and classification of cellular, organismal and ecological phenotypes based on large datasets, e.g., from genomic, transcriptomic and metagenomic analyses. A number of available algorithms can help search these datasets to uncover patterns associated with specific traits, including disease-related attributes. While, in many instances, treating an algorithm as a black box is sufficient, it is interesting to pursue an enhanced understanding of how system variables end up contributing to a specific output, as an avenue toward new mechanistic insight. Here we address this challenge through a suite of algorithms, named BowSaw, which takes advantage of the structure of a trained random forest algorithm to identify combinations of variables (“rules”) frequently used for classification. We first apply BowSaw to a simulated dataset and show that the algorithm can accurately recover the sets of variables used to generate the phenotypes through complex Boolean rules, even under challenging noise levels. We next apply our method to data from the integrative Human Microbiome Project and find previously unreported high-order combinations of microbial taxa putatively associated with Crohn’s disease. By leveraging the structure of trees within a random forest, BowSaw provides a new way of using decision trees to generate testable biological hypotheses.
A Primer on the oxDNA Model of DNA: When to Use it, How to Simulate it and How to Interpret the Results
Authors: Sengar A. , Ouldridge T. E. , Henrich O. , Rovigatti L. , Šulc P.
Published: June 2021

The oxDNA model of Deoxyribonucleic acid has been applied widely to systems in biology, biophysics and nanotechnology. It is currently available via two independent open source packages. Here we present a set of clearly documented exemplar simulations that simultaneously provide both an introduction to simulating the model, and a review of the model’s fundamental properties. We outline how simulation results can be interpreted in terms of—and feed into our understanding of—less detailed models that operate at larger length scales, and provide guidance on whether simulating a system with oxDNA is worthwhile.
Perspectives of Manipulative and High-Performance Nanosystems to Manage Consequences of Emerging New Severe Acute Respiratory Syndrome Coronavirus 2 Variants
Authors: Gage Alexander , Brunson Kaitlyn , Morris Kevin , Wallen Scott L. , Dhau Jaspreet , Gohel Hardik , Kaushik Ajeet
Published: June 2021

The emergence of new SARS-CoV-2 variants made the COVID-19 infection pandemic and/or endemic more severe and life-threatening due to ease of transmission, rapid infection, high mortality, and capacity to neutralize the therapeutic ability of developed vaccines. These consequences raise questions on established COVID-19 infection management strategies based on nano-assisted approaches, including rapid diagnostics, therapeutics, and efficient trapping and virus eradication through stimuli-assisted masks and filters composed of nanosystems. Considering these concerns as motivation, this perspective article highlights the role and aspects of nano-enabled approaches to manage the consequences of the COVID-19 infection pandemic associated with newer SARS-CoV-2 variants of concern and significance generated due to mutations. The controlled high-performance of a nanosystem seems capable of effectively detecting new variables for rapid diagnostics, performing site-specific delivery of a therapeutic agent needed for effective treatment, and developing technologies to purify the air and sanitizing premises. The outcomes of this report project manipulative, multifunctional nanosystems for developing high-performance technologies needed to manage consequences of newer SARS-CoV-2 variants efficiently and effectively through an overall targeted, smart approach.
All Central Nervous System Neuro- and Vascular-Communication Channels Are Surrounded With Cerebrospinal Fluid
Authors: Fahmy Lara M. , Chen Yongsheng , Xuan Stephanie , Haacke E. Mark , Hu Jiani , Jiang Quan
Published: June 2021

Background:Recent emerging evidence has highlighted the potential critical role of cerebrospinal fluid (CSF) in cerebral waste clearance and immunomodulation. It is already very well-established that the central nervous system (CNS) is completely submerged in CSF on a macro-level; but to what extent is this true on a micro-level? Specifically, within the peri-neural and peri-vascular spaces within the CNS parenchyma. Therefore, the objective of this study was to use magnetic resonance imaging (MRI) to simultaneously map the presence of CSF within all peri-neural (cranial and spinal nerves) and peri-vascular spacesin vivoin humans. Four MRI protocols each with five participants were used to image the CSF in the brain and spinal cord. Our findings indicated that all CNS neuro- and vascular-communication channels are surrounded with CSF. In other words, all peri-neural spaces surrounding the cranial and spinal nerves as well as all peri-vascular spaces surrounding MRI-visible vasculature were filled with CSF. These findings suggest that anatomically, substance exchange between the brain parenchyma and outside tissues including lymphatic ones can only occur through CSF pathways and/or vascular pathways, warranting further investigation into its implications in cerebral waste clearance and immunity.
Characterization of HIV-Associated Neurocognitive Impairment in Middle-Aged and Older Persons With HIV in Lima, Peru
Authors: Diaz Monica M. , Zacarías Marcela Gil , Sotolongo Patricia , Sanes María F. , Franklin Donald J. , Marquine María J. , Cherner Mariana , Cárcamo Cesar , Ellis Ronald J. , Lanata Serggio , García Patricia J.
Published: June 2021

Background: With widespread use of antiretroviral medications, people living with HIV (PWH) are living longer worldwide, increasing their risk of developing neurocognitive impairment (NCI). The proportion of Peruvians over age 60 is expected to increase to 25% of the population by 2050, including PWH. Therefore, the problem of aging and NCI, especially in the setting of HIV infection, is uniquely pressing. We sought to study the rates of and risk factors associated with NCI among middle-aged and older PWH in Lima, Peru.

Materials and Methods: Sociodemographic, medical (infectious and non-infectious), and psychiatric comorbidity and laboratory data were collected. We administered a brief neuropsychological battery evaluating seven cognitive domains affected in HIV-associated NCI and a depression screening. Cognitive test raw scores were converted to T-scores that were demographically adjusted. Descriptive statistics were performed together with regression (unadjusted and adjusted) analyses to determine potential risk factors for NCI among PWH.

Results: This was a cross-sectional study in which 144 PWH aged ≥40 years attending a large HIV clinic in Lima, Peru, were recruited from September 2019 to March 2020. Mean age was 51.6 ± 7.7 years, and mean years of education were 14.0 ± 3.1 with 15% females. Median [interquartile range (IQR)] current CD4 and nadir CD4 were 554 (371, 723) and 179 (83, 291), respectively, and 10% currently had AIDS. The prevalence of NCI was 28.5%, and many demonstrated difficulty with attention and working memory (70%). One-quarter of PWH had mild depression or worse on Patient Health Questionnaire 9 (PHQ-9 ≥ 5). In bivariate analyses, neither a depression history nor a higher PHQ-9 score correlated with NCI. No other non-communicable medical or psychiatric comorbidity nor HIV characteristic was predictive of NCI. Having a positive lifetime history of hepatitis B infection, pulmonary tuberculosis, or syphilis increased risk of NCI (PR 1.72; 95% CI 1.04–2.86) in unadjusted analyses, but not in adjusted analyses.

Conclusions: NCI among older Peruvians with HIV was found to be highly prevalent with levels consistent with prior reports of HIV-associated NCI worldwide. Common latent HIV-associated co-infections, including latent syphilis, hepatitis B infection, or pulmonary tuberculosis, may increase the risk of NCI among middle-aged and older PWH in Peru.
Quality of Life Following Cochlear Implantation in Patients With Menière's Disease
Authors: Sanchez-Cuadrado Isabel , Calvino Miryam , Morales-Puebla Jose Manuel , Gavilán Javier , Mato Teresa , Peñarrocha Julio , Prim Maria Pilar , Lassaletta Luis
Published: June 2021

Background: Menière's disease (MD) is a disorder characterized by auditory and vestibular dysfunction that significantly deteriorates patients' quality of life (QoL). In addition to the management of vestibular symptoms, some patients with bilateral hearing loss meet criteria for cochlear implantation (CI).

Objectives: (1) To assess hearing results and QoL outcomes following CI in patients with MD. (2) To compare these results to a matched control group of patients who had undergone CI. (3) To analyse differences in MD patients who have undergone simultaneous or sequential labyrinthectomy or previous neurectomy.

Methods: A retrospective analysis of a study group of 18 implanted patients with MD and a matched control group of 18 implanted patients without MD, who had CI at a tertiary referral center. Hearing and speech understanding were assessed via pure-tone audiometry (PTA) and disyllabic perception tests in quiet. QoL was assessed via the Nijmegen Cochlear Implant Questionnaire (NCIQ), the Glasgow Benefit Inventory (GBI), the Speech, Spatial and Qualities of Hearing Scale (SSQ12), and the Hearing Implant Sound Quality Index (HISQUI19). The impact of MD ablative surgeries was analyzed in the study group (MD group).

Results: Mean pre-operative PTA thresholds were significantly lower in the MD group (103 vs. 121 dB). A significant improvement in hearing outcomes was observed following CI in both groups (p < 0.001), with a maximum Speech Discrimination Score of 64 and 65% disyllables at 65 dB for the MD and control group, respectively. Subjective outcomes, as measured by the NCIQ, GBI, SSQ12, and HISQUI19 did not significantly differ between groups. In the MD group, despite achieving similar hearing results, QoL outcomes were worse in patients who underwent simultaneous CI and labyrinthectomy compared to the rest of the MD group. Post-operative NCIQ results were significantly better in patients who had undergone a previous retrosigmoid neurectomy when compared to those who had undergone only CI surgery in the subdomains “basic sound perception” (p = 0.038), “speech” (p = 0.005), “activity” (p = 0.038), and “social interactions” (p = 0.038).

Conclusion: Patients with MD and severe hearing loss obtain hearing results and QoL benefits similar to other CI candidates. Delayed CI after labyrinthectomy or vestibular neurectomy can be performed with similar or better results, respectively, to those of other cochlear implanted patients. Patients who undergo simultaneous CI and labyrinthectomy may achieve similar hearing results but careful pre-operative counseling is needed.
Long-Term Outcome of Enterprise Stenting for Symptomatic ICAS in a High-Volume Stroke Center
Authors: Cui Rongrong , Yan Long , Kang Kaijiang , Yang Ming , Yu Ying , Mo Dapeng , Gao Feng , Wang Yongjun , Lou Xin , Miao Zhongrong , Ma Ning
Published: June 2021

Background and Purpose: The Enterprise stent has been used for treating intracranial atherosclerotic stenosis (ICAS), but its long-term outcome remains unclear. The purpose of this study was to evaluate the long-term clinical efficacy of the Enterprise stent used for patients with symptomatic ICAS due to hypoperfusion.

Method: Patients with symptomatic ICAS due to hypoperfusion treated with the Enterprise stents from a high-volume stroke center were evaluated. The successful recanalization was defined as the Modified Thrombolysis In Cerebral Infarction (mTICI) ≥ 2b. The stroke and neurological death that occurred within 72 h after the procedure as well as long-term clinical and imaging outcomes were analyzed.

Results: Overall, 130 patients with 130 ICAS treated with the Enterprise stent were included in our study. The successful recanalization rate was 100%. The mean pre- and postprocedural stenosis was 82.9 ± 8.9% vs. 15.1 ± 8.4%. Periprocedural complications occurred in 5 (3.8%) patients within 72 h after the procedure. Clinical follow-up data were available in 125 (96.2%) patients (median, 24 months) and any stroke or neurological death was encountered in 6 (4.8%) patients. Angiographic follow-up data was obtained from 118 (90.8%) patients (median, 13.5 months). In addition, 1-year in-stent restenosis (>70%) was found in 17 (14.4%) patients, and among them, 4 (23.5%) patients were symptomatic.

Conclusion: Deployment of Enterprise stent is safe for ICAS. The short-term and long-term outcomes were acceptable, but the efficacy of the Enterprise stent needs to be further evaluated in future studies.
Effect of Sitting Position vs. Supine Position With the Head Turned to the Affected Side on Benign Paroxysmal Positional Vertigo Fatigue
Authors: Imai Takao , Nishiike Suetaka , Okumura Tomoko , Takeda Noriaki , Sato Takashi , Ohta Yumi , Kamakura Takefumi , Inohara Hidenori
Published: June 2021

Objective: In benign paroxysmal positional vertigo (BPPV), positional nystagmus becomes generally weaker when the Dix–Hallpike test is repeated. This phenomenon is termed BPPV fatigue. We previously reported that the effect of BPPV fatigue deteriorates over time (i.e., the positional nystagmus is observed again after maintaining a sitting head position). The aim of this study was to investigate whether the effect of BPPV fatigue attenuates after maintaining a supine position with the head turned to the affected side.

Methods: Twenty patients with posterior-canal-type BPPV were assigned to two groups. Group A received Dix–Hallpike test, were returned to the sitting position (reverse Dix–Hallpike test) with a sitting head position for 10 min, and then received a second Dix–Hallpike test. Group B received Dix–Hallpike test, were kept in the supine position with the head turned to the affected side for 10 min, and then received reverse Dix–Hallpike test followed by the second Dix–Hallpike test. The maximum slow phase eye velocity (MSPEV) of positional nystagmus induced by the first, reverse, and second Dix–Hallpike test were analyzed.

Results: The ratio of MSPEV of the positional nystagmus induced by the second Dix–Hallpike test relative to the first Dix–Hallpike test was significantly smaller in group B than that in group A. There was no difference in the MSPEV of the positional nystagmus induced by the reverse Dix–Hallpike test between group A and B.

Conclusions: The effect of BPPV fatigue is continued by maintaining a supine position with the head turned to the affected side, while the effect is weakened by maintaining a sitting head position. On the basis of the most widely accepted theory of the pathophysiology of BPPV fatigue, in which the particles become dispersed along the canal during head movement in the Dix–Hallpike test, we found an inconsistency whereby the dispersed otoconial debris return to a mass during the sitting position but do not return to a mass in the supine position with the head turned to the affected side. Future studies are required to determine the exact pathophysiology of BPPV fatigue.

Classification of Evidence: 2b.
Sources of Added Sugars Intake Among the U.S. Population: Analysis by Selected Sociodemographic Factors Using the National Health and Nutrition Examination Survey 2011–18
Authors: Ricciuto Laurie , Fulgoni Victor L. , Gaine P. Courtney , Scott Maria O. , DiFrancesco Loretta
Published: June 2021

Recent estimates of added sugars intake among the U.S. population show intakes are above recommended levels. Knowledge about the sources of added sugars contributing to intakes is required to inform dietary guidance, and understanding how those sources vary across sociodemographic subgroups could also help to target guidance. The purpose of this study was to provide a comprehensive update on sources of added sugars among the U.S. population, and to examine variations in sources according to sociodemographic factors. Regression analyses on intake data from NHANES 2011–18 were used to examine sources of added sugars intake among the full sample (N = 30,678) and among subsamples stratified by age, gender, ethnicity, and income. Results showed the majority of added sugars in the diet (61–66%) came from a few sources, and the top two sources were sweetened beverages and sweet bakery products, regardless of age, ethnicity, or income. Sweetened beverages, including soft drinks and fruit drinks, as well as tea, were the largest contributors to added sugars intake. There were some age-, ethnic-, and income-related differences in the relative contributions of added sugars sources, highlighting the need to consider sociodemographic contexts when developing dietary guidance or other supports for healthy eating.
Case Report: Exceptional Response to Avelumab After Failure of Electrochemotherapy in a Patient With Rapidly Progressive, PD-L1-Negative Merkel Cell Carcinoma
Authors: Torchio Martina , Cattaneo Laura , Milione Massimo , Prinzi Natalie , Corti Francesca , Ungari Marco , Anichini Andrea , Mortarini Roberta , Occhini Antonio , Bertino Giulia , Maurichi Andrea , Coppa Jorgelina , Di Bartolomeo Maria , de Braud Filippo Guglielmo , Pusceddu Sara
Published: June 2021

This case report shows, for the first time, a patient experiencing a complete response after one dose of avelumab following extensive disease progression with prior electrochemotherapy (ECT) treatment. We suggest that ECT may help to establish a tumor microenvironment favorable to immunotherapy. Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with seldom durable chemotherapy responses. ECT has recently emerged as a potential treatment option for several malignancies, including MCC. Avelumab, an anti-programmed cell death-ligand 1 (PD-L1) monoclonal antibody, became the first approved treatment for patients with metastatic MCC. ECT has been shown to activate the immune response, but it is still unknown how ECT may affect patient’s response to subsequent immunotherapy. We report a case of a patient with MCC who presented with a rapidly growing skin nodule of the right cheek and experienced extensive disease progression following surgical debulking and ECT treatment. The patient received a flat dose of 800 mg avelumab intravenously every 2 weeks showing complete tumor regression after only one dose. Immunohistochemical analysis of surgical and post-ECT biopsies collected from the primary lesion revealed tumor expression of programmed cell death protein-1 (PD-1), but not PD-L1. Analysis of the tumor samples also revealed no expression of Merkel cell polyomavirus (MCPyV). Comparison of the biopsies showed a decrease in myeloid and T-cell markers after ECT but an increase in major histocompatibility complex (MHC) class I expression on tumor cells. Additionally, the patient experienced an increase in neutrophil-to-lymphocyte ratio and lactate dehydrogenase values post-ECT, which subsequently decreased with avelumab treatment. As of 30 October 2019, the patient was still receiving avelumab treatment and had an ongoing complete response. In this case report, a patient with PD-L1-negative and MCPyV-negative MCC who had disease progression following ECT experienced complete tumor regression with avelumab treatment, suggesting, for the first time to our knowledge, that ECT may help to establish a tumor microenvironment favorable to immunotherapy via a potential abscopal effect. Tumor-intrinsic PD-1 expression and modulation of MHC class I antigens after ECT may contribute to the clinical efficacy of avelumab in this context.