bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune Profile and Clinical Outcome of Breakthrough Cases After Vaccination With an Inactivated SARS-CoV-2 Vaccine
Authors: Duarte Luisa F. , Gálvez Nicolás M. S. , Iturriaga Carolina , Melo-González Felipe , Soto Jorge A. , Schultz Bárbara M. , Urzúa Marcela , González Liliana A. , Vázquez Yaneisi , Ríos Mariana , Berríos-Rojas Roslye V. , Rivera-Pérez Daniela , Moreno-Tapia Daniela , Pacheco Gaspar A. , Vallejos Omar P. , Hoppe-Elsholz Guillermo , Navarrete María S. , Rojas Álvaro , Fasce Rodrigo A. , Fernández Jorge , Mora Judith , Ramírez Eugenio , Zeng Gang , Meng Weining , González-Aramundiz José V. , González Pablo A. , Abarca Katia , Bueno Susan M. , Kalergis Alexis M.
Published: September 2021

Constant efforts to prevent infections by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are actively carried out around the world. Several vaccines are currently approved for emergency use in the population, while ongoing studies continue to provide information on their safety and effectiveness. CoronaVac is an inactivated SARS-CoV-2 vaccine with a good safety and immunogenicity profile as seen in phase 1, 2, and 3 clinical trials around the world, with an effectiveness of 65.9% for symptomatic cases. Although vaccination reduces the risk of disease, infections can still occur during or after completion of the vaccination schedule (breakthrough cases). This report describes the clinical and immunological profile of vaccine breakthrough cases reported in a clinical trial in progress in Chile that is evaluating the safety, immunogenicity, and efficacy of two vaccination schedules of CoronaVac (clinicaltrials.gov NCT04651790). Out of the 2,263 fully vaccinated subjects, at end of June 2021, 45 have reported symptomatic SARS-CoV-2 infection 14 or more days after the second dose (1.99% of fully vaccinated subjects). Of the 45 breakthrough cases, 96% developed mild disease; one case developed a moderate disease; and one developed a severe disease and required mechanical ventilation. Both cases that developed moderate and severe disease were adults over 60 years old and presented comorbidities. The immune response before and after SARS-CoV-2 infection was analyzed in nine vaccine breakthrough cases, revealing that six of them exhibited circulating anti-S1-RBD IgG antibodies with neutralizing capacities after immunization, which showed a significant increase 2 and 4 weeks after symptoms onset. Two cases exhibited low circulating anti-S1-RBD IgG and almost non-existing neutralizing capacity after either vaccination or infection, although they developed a mild disease. An increase in the number of interferon-γ-secreting T cells specific for SARS-CoV-2 was detected 2 weeks after the second dose in seven cases and after symptoms onset. In conclusion, breakthrough cases were mostly mild and did not necessarily correlate with a lack of vaccine-induced immunity, suggesting that other factors, to be defined in future studies, could lead to symptomatic infection after vaccination with CoronaVac.
Neutrophils Facilitate Prolonged Inflammasome Response in the DAMP-Rich Inflammatory Milieu
Authors: Son Seunghwan , Yoon Sung-Hyun , Chae Byeong Jun , Hwang Inhwa , Shim Do-Wan , Choe Young Ho , Hyun Young-Min , Yu Je-Wook
Published: September 2021

Aberrant inflammasome activation contributes to various chronic inflammatory diseases; however, pyroptosis of inflammasome-active cells promptly terminates local inflammasome response. Molecular mechanisms underlying prolonged inflammasome signaling thus require further elucidation. Here, we report that neutrophil-specific resistance to pyroptosis and NLRP3 desensitization can facilitate sustained inflammasome response and interleukin-1β secretion. Unlike macrophages, inflammasome-activated neutrophils did not undergo pyroptosis, indicated by using in vitro cell-based assay and in vivo mouse model. Intriguingly, danger-associated molecular patterns (DAMP)-rich milieu in the inflammatory region significantly abrogated NLRP3-activating potential of macrophages, but not of neutrophils. This macrophage-specific NLRP3 desensitization was associated with DAMP-induced mitochondrial depolarization that was not observed in neutrophils due to a lack of SARM1 expression. Indeed, valinomycin-induced compulsory mitochondrial depolarization in neutrophils restored inflammasome-dependent cell death and ATP-induced NLRP3 desensitization in neutrophils. Alongside prolonged inflammasome-activating potential, neutrophils predominantly secreted interleukin-1β rather than other proinflammatory cytokines upon NLRP3 stimulation. Furthermore, inflammasome-activated neutrophils did not trigger efferocytosis-mediated M2 macrophage polarization essential for the initiation of inflammation resolution. Taken together, our results indicate that neutrophils can prolong inflammasome response via mitochondria-dependent resistance to NLRP3 desensitization and function as major interleukin-1β-secreting cells in DAMP-rich inflammatory region.
Case Report: Immune and Genomic Characteristics Associated With Hyperprogression in a Patient With Metastatic Deficient Mismatch Repair Gastrointestinal Cancer Treated With Anti-PD-1 Antibody
Authors: Zhou Wenyue , Zhou Yuwen , Yi Cheng , Shu Xinyao , Wei Guixia , Chen Xiaorong , Shen Xudong , Qiu Meng
Published: September 2021

Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status of tumors is a distinct predictive biomarker of immune checkpoint inhibitors (ICIs) for colorectal and non-colorectal cancer populations. The overall response rate (ORR) varies from approximately 40% to 60%, indicating that nearly half of MSI-H tumors do not respond to ICIs. The mechanism of response heterogeneity in MSI-H/dMMR cancers is unclear. Some patients who have been treated with ICIs have developed a novel pattern of progression called hyperprogression, which is defined as unexpected accelerated tumor growth. No case of MSI-H/dMMR immunotherapy-associated hyperprogression has been reported in the literature. Here, we present the case of a patient with dMMR gastrointestinal cancer who suffered hyperprogressive disease (HPD) after treatment with nivolumab. We explored the potential mechanisms of HPD by clinical, immune, and genomic characteristics. Extremely high levels of serum LDH, low TMB and TILs, and the disruption of TGFβ signaling, may be related to hyperprogression.
Mechanisms of Pond Expansion in a Rapidly Submerging Marsh
Authors: Himmelstein Joshua , Vinent Orencio Duran , Temmerman Stijn , Kirwan Matthew L.
Published: September 2021

The development and expansion of ponds within otherwise vegetated coastal marshes is a primary driver of marsh loss throughout the world. Previous studies propose that large ponds expand through a wind wave-driven positive feedback, where pond edge erosion rates increase with pond size, whereas biochemical processes control the formation and expansion of smaller ponds. However, it remains unclear which mechanisms dominate at a given scale, and thus how, and how fast, ponds increase their size. Here, we use historical photographs and field measurements in a rapidly submerging microtidal marsh to quantify pond development and identify the processes involved. We find that as small ponds emerge on the marsh platform, they quickly coalesce and merge, increasing the number of larger ponds. Pond expansion rates are maximized for intermediate size ponds and decrease for larger ponds, where the contribution of wave-driven erosion is negligible. Vegetation biomass, soil shear strength, and porewater biogeochemical indices of marsh health are higher in marshes adjacent to stable ponds than in those adjacent to unstable ponds, suggesting that pond growth rates are negatively related to the health of the surrounding marsh. We find that the model of Vinent et al. (2021) correctly predicts measured pond growth rates and size distribution, which suggest the different mechanisms driving pond growth are a result of marsh drowning due to sea level rise (SLR) and can be estimated by simplified physical models. Finally, we show that all relevant processes increasing pond size can be summarized by an empirical power-law equation for pond growth which predicts the temporal change of the maximum pond size as a lower bound for the total pond area in the system. This gives a timescale for the growth of ponds by merging and thus the critical time window for interventions to prevent the irreversible pond expansion associated with large scale pond merging.
Elucidation of the Algicidal Mechanism of the Marine Bacterium Pseudoruegeria sp. M32A2M Against the Harmful Alga Alexandrium catenella Based on Time-Course Transcriptome Analysis
Authors: Cho Suhyung , Cho Sang-Hyeok , Ko So-Ra , Jeong Yujin , Lee Eunju , Jin Sangrak , Jeong Bo-Seong , Oh Byung-Ha , Oh Hee-Mock , Ahn Chi-Yong , Cho Byung-Kwan
Published: September 2021

The marine dinoflagellate Alexandrium is associated with harmful algal blooms (HABs) worldwide, causing paralytic shellfish poisoning (PSP) in humans. We found that the marine bacterium Pseudoruegeria sp. M32A2M exhibits algicidal activity against Alexandrium catenella (Group I), inhibiting its motility and consequently inducing cell disruption after 24 h of co-culture. To understand the communication between the two organisms, we investigated the time-course cellular responses through genome-wide transcriptome analysis. Functional analysis of differentially expressed genes revealed that the core reactions of the photosystem in A. catenella were inhibited within 2 h, eventually downregulating the entire pathways of oxidative phosphorylation and carbon fixation, as well as associated metabolic pathways. Conversely, Pseudoruegeria upregulated its glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation pathways. Also, the transporters for nutrients such as C3/C4 carbohydrates and peptides were highly upregulated, leading to the speculation that nutrients released by disrupted A. catenella cells affect the central metabolism of Pseudoruegeria. In addition, we analyzed the secondary metabolite-synthesizing clusters of Pseudoruegeria that were upregulated by co-culture, suggesting their potential roles in algicidal activity. Our time-course transcriptome analysis elucidates how A. catenella is affected by algicidal bacteria and how these bacteria obtain functional benefits through metabolic pathways.
Limited Progress in Improving Gender and Geographic Representation in Coral Reef Science
Authors: Ahmadia Gabby N. , Cheng Samantha H. , Andradi-Brown Dominic A. , Baez Stacy K. , Barnes Megan D. , Bennett Nathan J. , Campbell Stuart J. , Darling Emily S. , Estradivari  , Gill David , Gress Erika , Gurney Georgina G. , Horigue Vera , Jakub Raymond , Kennedy Emma V. , Mahajan Shauna L. , Mangubhai Sangeeta , Matsuda Shayle B. , Muthiga Nyawira A. , Navarro Michael O. , Santodomingo Nadia , Vallès Henri , Veverka Laura , Villagomez Angelo , Wenger Amelia S. , Wosu Adaoma
Published: September 2021

Despite increasing recognition of the need for more diverse and equitable representation in the sciences, it is unclear whether measurable progress has been made. Here, we examine trends in authorship in coral reef science from 1,677 articles published over the past 16 years (2003–2018) and find that while representation of authors that are women (from 18 to 33%) and from non-OECD nations (from 4 to 13%) have increased over time, progress is slow in achieving more equitable representation. For example, at the current rate, it would take over two decades for female representation to reach 50%. Given that there are more coral reef non-OECD countries, at the current rate, truly equitable representation of non-OECD countries would take even longer. OECD nations also continue to dominate authorship contributions in coral reef science (89%), in research conducted in both OECD (63%) and non-OECD nations (68%). We identify systemic issues that remain prevalent in coral reef science (i.e., parachute science, gender bias) that likely contribute to observed trends. We provide recommendations to address systemic biases in research to foster a more inclusive global science community. Adoption of these recommendations will lead to more creative, innovative, and impactful scientific approaches urgently needed for coral reefs and contribute to environmental justice efforts.
Transcriptome Profiling Based on Different Time Points After Hatching Provides a Core Set of Gene Resource for Understanding Larval Immune Response Mechanisms Against Vibrio anguillarum Infection in Amphioctopus fangsiao
Authors: Bao Xiaokai , Li Yan , Zhang Jianbai , Chen Xipan , Xu Xiaohui , Feng Yanwei , Sun Guohua , Liu Xiumei , Li Bin , Wang Weijun , Li Zan , Yang Jianmin
Published: September 2021

Immune defense systems are indispensable for living organisms. Within an immune network, problems with any given link can impact the normal life activities of an organism.Amphioctopus fangsiaois a cephalopod that exists widely throughout the world’s oceans. Because of its nervous system and locomotive organs, it has become increasingly studied in recent years.Vibrio anguillarumis one of the most common pathogenic bacteria in aquaculture organisms. It is highly infectious and can infect almost all aquaculture organisms.V. anguillaruminfection can cause many adverse biological phenomena, including tissue bleeding. Study the immune response afterV. anguillaruminfection would help us to understand the molecular mechanisms of immune response in aquaculture organisms. In this research, we infected the primary incubationA. fangsiaowithV. anguillarumfor 24 h. We analyzed gene expression inA. fangsiaolarvae via transcriptome profiles at 0, 4, 12, and 24 h after hatching, and 1,385, 734, and 6,109 differentially expressed genes (DEGs) were identified at these three time points. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to identify immune-related DEGs. Protein–protein interaction networks were constructed to examine interactions between immune-related genes. Twenty hub genes involved in multiple KEGG signaling pathways or with multiple protein–protein interaction relationships were identified, and their differential expression verified by quantitative RT-PCR. We first studiedV. anguillaruminfection ofA. fangsiaolarvae by means of protein–protein interaction networks. The results provide valuable genetic resources for understanding immunity in molluscan larvae. These data serve as a theoretical basis for the artificial breeding ofA. fangsiao.
Gene Expression Analysis in Four Dogs With Canine Pemphigus Clinical Subtypes Reveals B Cell Signatures and Immune Activation Pathways Similar to Human Disease
Authors: Raef Haya S. , Piedra-Mora Cesar , Wong Neil B. , Ma Diana Junyue , David Clement N. , Robinson Nicholas A. , Almela Ramón M. , Richmond Jillian M.
Published: September 2021

Pemphigus is a group of autoimmune-mediated mucocutaneous blistering diseases characterized by acantholysis. Pemphigus has also been recognized in dogs and shares similar clinical characteristics and variants with human pemphigus. While relationships between human and canine pemphigus have been reported, gene expression patterns across species have not been described in the literature. We sought to perform gene expression analysis of lesional skin tissue from four dogs with various forms of pemphigus to examine gene expression during spontaneous disease in dogs. We found increased T and B cell signatures in canine pemphigus lesions compared to controls, as well as significant upregulation ofCCL3, CCL4, CXCL10, andCXCL8 (IL8), among other genes. Similar chemokine/cytokine expression patterns and immune infiltrates have been reported in humans, suggesting that these genes play a role in spontaneous disease. Direct comparison of our dataset to previously published human pemphigus datasets revealed five conserved differentially expressed genes:CD19, WIF1, CXCL10, CD86, andS100A12. Our data expands our understanding of pemphigus and facilitates identification of biomarkers for prediction of disease prognosis and treatment response, which may be useful for future veterinary and human clinical trials.
Diel-Regulated Transcriptional Cascades of Microbial Eukaryotes in the North Pacific Subtropical Gyre
Authors: Groussman Ryan D. , Coesel Sacha N. , Durham Bryndan P. , Armbrust E. Virginia
Published: September 2021

Open-ocean surface waters host a diverse community of single-celled eukaryotic plankton (protists) consisting of phototrophs, heterotrophs, and mixotrophs. The productivity and biomass of these organisms oscillate over diel cycles, and yet the underlying transcriptional processes are known for few members of the community. Here, we examined a 4-day diel time series of transcriptional abundance profiles for the protist community (0.2–100 μm in cell size) in the North Pacific Subtropical Gyre near Station ALOHA. De novo assembly of poly-A+ selected metatranscriptomes yielded over 30 million contigs with taxonomic and functional annotations assigned to 54 and 25% of translated contigs, respectively. The completeness of the resulting environmental eukaryotic taxonomic bins was assessed, and 48 genera were further evaluated for diel patterns in transcript abundances. These environmental transcriptome bins maintained reproducible temporal partitioning of total gene family abundances, with haptophyte and ochrophyte genera generally showing the greatest diel partitioning of their transcriptomes. The haptophyte Phaeocystis demonstrated the highest proportion of transcript diel periodicity, while most other protists had intermediate levels of periodicity regardless of their trophic status. Dinoflagellates, except for the parasitoid genus Amoebophrya, exhibit the fewest diel oscillations of transcript abundances. Diel-regulated gene families were enriched in key metabolic pathways; photosynthesis, carbon fixation, and fatty acid biosynthesis gene families had peak times concentrated around dawn, while gene families involved in protein turnover (proteasome and protein processing) are most active during the high intensity daylight hours. TCA cycle, oxidative phosphorylation and fatty acid degradation predominantly peaked near dusk. We identified temporal pathway enrichments unique to certain taxa, including assimilatory sulfate reduction at dawn in dictyophytes and signaling pathways at early evening in haptophytes, pointing to possible taxon-specific channels of carbon and nutrients through the microbial community. These results illustrate the synchrony of transcriptional regulation to the diel cycle and how the protist community of the North Pacific Subtropical Gyre structures their transcriptomes to guide the daily flux of matter and energy through the gyre ecosystem.
Influence of Microplastics on the Growth and the Intestinal Microbiota Composition of Brine Shrimp
Authors: Li Hongyu , Chen Hongwei , Wang Jiao , Li Jiayao , Liu Sitong , Tu Jianbo , Chen Yanzhen , Zong Yanping , Zhang Pingping , Wang Zhiyun , Liu Xianhua
Published: September 2021

Microplastics (MPs) are ubiquitous in the aquatic environment and can be frequently ingested by zooplankton, leading to various effects. Brine shrimp (Artemia parthenogenetica) has an important role in the energy flow through trophic levels in different seawater systems. In this work, the influence of polyethylene (PE) and polystyrene (PS) MPs on the growth of brine shrimp and corresponding changes of gut microbiota were investigated. Our results showed that the MPs remarkably reduced the growth rate of brine shrimp, and the two types of MPs have different impacts. The average body length of brine shrimps was reduced by 17.92 and 14.95% in the PE group and PS group, respectively. MPs are mainly found in the intestine, and their exposure evidently affects the gut microbiota. By using 16S rRNA gene high-throughput sequencing, 32 phyla of bacteria were detected in the intestine, and the microbiome consisted mainly of Proteobacteria, Firmicutes, and Actinobacteria. MPs’ exposure significantly increased the gut microbial diversity. For the PE group, the proportion of Actinobacteria and Bacteroidetes increased by 45.26 and 2.73%, respectively. For the PS group, it was 54.95 and 1.27%, respectively. According to the analysis on genus level, the proportions of Ponticoccus, Seohaeicola, Polycyclovorans, and Methylophaga decreased by 46.38, 1.24, 1.07, and 2.66%, respectively, for the PE group and 57.87, 1.43, 0.88, and 2.24%, respectively, for the PS group. In contrast, the proportions of Stappia, Microbacterium, and Dietzia increased by 1.12, 23.27, and 11.59%, respectively, for the PE group, and 1.09, 3.79, and 42.96%, respectively, for the PS group. These experimental results demonstrated that the ingestion of MPs by brine shrimp can alter the composition of the gut microbiota and lead to a slow growth rate. This study provides preliminary data support for understanding the biotoxicity of MPs to invertebrate zooplankton and is conducive to the further risk assessment of MP exposure.
Fatty Acids Derivatives From Eukaryotic Microalgae, Pathways and Potential Applications
Authors: Blasio Martina , Balzano Sergio
Published: September 2021

The exploitation of petrochemical hydrocarbons is compromising ecosystem and human health and biotechnological research is increasingly focusing on sustainable materials from plants and, to a lesser extent, microalgae. Fatty acid derivatives include, among others, oxylipins, hydroxy fatty acids, diols, alkenones, and wax esters. They can occur as storage lipids or cell wall components and possess, in some cases, striking cosmeceutical, pharmaceutical, and nutraceutical properties. In addition, long chain (>20) fatty acid derivatives mostly contain highly reduced methylenic carbons and exhibit a combustion enthalpy higher than that of C14–20fatty acids, being potentially suitable as biofuel candidates. Finally, being the building blocks of cell wall components, some fatty acid derivatives might also be used as starters for the industrial synthesis of different polymers. Within this context, microalgae can be a promising source of fatty acid derivatives and, in contrast with terrestrial plants, do not require arable land neither clean water for their growth. Microalgal mass culturing for the extraction and the exploitation of fatty acid derivatives, along with products that are relevant in nutraceutics (e.g., polyunsaturated fatty acids), might contribute in increasing the viability of microalgal biotechnologies. This review explores fatty acids derivatives from microalgae with applications in the field of renewable energies, biomaterials and pharmaceuticals.Nannochloropsisspp. (Eustigmatophyceae, Heterokontophyta) are particularly interesting for biotechnological applications since they grow at faster rates than many other species and possess hydroxy fatty acids and aliphatic cell wall polymers.
Basalt-Hosted Microbial Communities in the Subsurface of the Young Volcanic Island of Surtsey, Iceland
Authors: Bergsten Pauline , Vannier Pauline , Klonowski Alexandra María , Knobloch Stephen , Gudmundsson Magnús Tumi , Jackson Marie Dolores , Marteinsson Viggó Thor
Published: September 2021

The island of Surtsey was formed in 1963–1967 on the offshore Icelandic volcanic rift zone. It offers a unique opportunity to study the subsurface biosphere in newly formed oceanic crust and an associated hydrothermal-seawater system, whose maximum temperature is currently above 120°C at about 100m below surface. Here, we present new insights into the diversity, distribution, and abundance of microorganisms in the subsurface of the island, 50years after its creation. Samples, including basaltic tuff drill cores and associated fluids acquired at successive depths as well as surface fumes from fumaroles, were collected during expedition 5059 of the International Continental Scientific Drilling Program specifically designed to collect microbiological samples. Results of this microbial survey are investigated with 16S rRNA gene amplicon sequencing and scanning electron microscopy. To distinguish endemic microbial taxa of subsurface rocks from potential contaminants present in the drilling fluid, we use both methodological and computational strategies. Our 16S rRNA gene analysis results expose diverse and distinct microbial communities in the drill cores and the borehole fluid samples, which harbor thermophiles in high abundance. Whereas some taxonomic lineages detected across these habitats remain uncharacterized (e.g., Acetothermiia, Ammonifexales), our results highlight potential residents of the subsurface that could be identified at lower taxonomic rank such asThermaerobacter, BRH-c8a (Desulfallas-Sporotomaculum),Thioalkalimicrobium,andSulfurospirillum. Microscopy images reveal possible biotic structures attached to the basaltic substrate. Finally, microbial colonization of the newly formed basaltic crust and the metabolic potential are discussed on the basis of the data.
Congenital Transmission of Apicomplexan Parasites: A Review
Authors: Rojas-Pirela Maura , Medina Lisvaneth , Rojas Maria Verónica , Liempi Ana Isabel , Castillo Christian , Pérez-Pérez Elizabeth , Guerrero-Muñoz Jesús , Araneda Sebastian , Kemmerling Ulrike
Published: September 2021

Apicomplexans are a group of pathogenic protists that cause various diseases in humans and animals that cause economic losses worldwide. These unicellular eukaryotes are characterized by having a complex life cycle and the ability to evade the immune system of their host organism. Infections caused by some of these parasites affect millions of pregnant women worldwide, leading to various adverse maternal and fetal/placental effects. Unfortunately, the exact pathogenesis of congenital apicomplexan diseases is far from being understood, including the mechanisms of how they cross the placental barrier. In this review, we highlight important aspects of the diseases caused by species ofPlasmodium, Babesia, Toxoplasma, andNeospora, their infection during pregnancy, emphasizing the possible role played by the placenta in the host-pathogen interaction.
Clinical Application Value of Circulating Cell-free DNA in Hepatocellular Carcinoma
Authors: Zhang Yuyuan , Liu Zaoqu , Ji Kun , Li Xin , Wang Caihong , Ren Zhigang , Liu Yang , Chen Xinju , Han Xinwei , Meng Lingfang , Li Lifeng , Li Zhen
Published: September 2021

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and a leading cause of cancer-related deaths. Due to late diagnosis, early intrahepatic metastasis and nonresponse to systemic treatments, surgical resection and/or biopsy specimens remain the gold standard for disease staging, grading and clinical decision-making. Since only a small amount of tissue was obtained in a needle biopsy, the conventional tissue biopsy is unable to represent tumor heterogeneity in HCC. For this reason, it is imperative to find a new non-invasive and easily available diagnostic tool to detect HCC at an early stage and to monitor HCC recurrence. The past decade has witnessed considerable evolution in the development of liquid biopsy technologies with the emergence of next-generation sequencing. As a liquid biopsy approach, molecular analysis of cell-free DNA (cfDNA), characterized by noninvasiveness and real-time analysis, may accurately represent the tumor burden and comprehensively reflect genetic profile of HCC. Therefore, cfDNA may be used clinically as a predictive biomarker in early diagnosis, outcome assessment, and even molecular typing. In this review, we provide an update on the recent advances made in clinical applications of cfDNA in HCC.
Mislocalization of Nucleocytoplasmic Transport Proteins in Human Huntington’s Disease PSC-Derived Striatal Neurons
Authors: Lange Jenny , Wood-Kaczmar Alison , Ali Aneesa , Farag Sahar , Ghosh Rhia , Parker Jennifer , Casey Caroline , Uno Yumiko , Kunugi Akiyoshi , Ferretti Patrizia , Andre Ralph , Tabrizi Sarah J.
Published: September 2021

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). Disease progression is characterized by the loss of vulnerable neuronal populations within the striatum. A consistent phenotype across HD models is disruption of nucleocytoplasmic transport and nuclear pore complex (NPC) function. Here we demonstrate that high content imaging is a suitable method for detecting mislocalization of lamin-B1, RAN and RANGAP1 in striatal neuronal cultures thus allowing a robust, unbiased, highly powered approach to assay nuclear pore deficits. Furthermore, nuclear pore deficits extended to the selectively vulnerable DARPP32 + subpopulation neurons, but not to astrocytes. Striatal neuron cultures are further affected by changes in gene and protein expression of RAN, RANGAP1 and lamin-B1. Lowering total HTT using HTT-targeted anti-sense oligonucleotides partially restored gene expression, as well as subtly reducing mislocalization of proteins involved in nucleocytoplasmic transport. This suggests that mislocalization of RAN, RANGAP1 and lamin-B1 cannot be normalized by simply reducing expression of CAG-expanded HTT in the absence of healthy HTT protein.
Age of First Exposure to Contact and Collision Sports and Later in Life Brain Health: A Narrative Review
Authors: Iverson Grant L. , Büttner Fionn , Caccese Jaclyn B.
Published: September 2021

A controversial theory proposes that playing tackle football before the age of 12 causes later in life brain health problems. This theory arose from a small study of 42 retired National Football League (NFL) players, which reported that those who started playing tackle football at a younger age performed worse on selected neuropsychological tests and a word reading test. The authors concluded that these differences were likely due to greater exposure to repetitive neurotrauma during a developmentally sensitive maturational period in their lives. Several subsequent studies of current high school and collegiate contact/collision sports athletes, and former high school, collegiate, and professional tackle football players have not replicated these findings. This narrative review aims to (i) discuss the fundamental concepts, issues, and controversies surrounding existing research on age of first exposure (AFE) to contact/collision sport, and (ii) provide a balanced interpretation, including risk of bias assessment findings, of this body of evidence. Among 21 studies, 11 studies examined former athletes, 8 studies examined current athletes, and 2 studies examined both former and current athletes. Although the literature on whether younger AFE to tackle football is associated with later in life cognitive, neurobehavioral, or mental health problems in former NFL players is mixed, the largest study of retired NFL players (N = 3,506) suggested there was not a significant association between earlier AFE to organized tackle football and worse subjectively experienced cognitive functioning, depression, or anxiety. Furthermore, no published studies of current athletes show a significant association between playing tackle football (or other contact/collision sports) before the age of 12 and cognitive, neurobehavioral, or mental health problems. It is important to note that all studies were judged to be at high overall risk of bias, indicating that more methodologically rigorous research is needed to understand whether there is an association between AFE to contact/collision sports and later in life brain health. The accumulated research to date suggests that earlier AFE to contact/collision sports is not associated with worse cognitive functioning or mental health in (i) current high school athletes, (ii) current collegiate athletes, or (iii) middle-aged men who played high school football. The literature on former NFL players is mixed and does not, at present, clearly support the theory that exposure to tackle football before age 12 is associated with later in life cognitive impairment or mental health problems.
Auditory Tests for Characterizing Hearing Deficits in Listeners With Various Hearing Abilities: The BEAR Test Battery
Authors: Sanchez-Lopez Raul , Nielsen Silje Grini , El-Haj-Ali Mouhamad , Bianchi Federica , Fereczkowski Michal , Cañete Oscar M. , Wu Mengfan , Neher Tobias , Dau Torsten , Santurette Sébastien
Published: September 2021

The Better hEAring Rehabilitation (BEAR) project aims to provide a new clinical profiling tool—a test battery—for hearing loss characterization. Although the loss of sensitivity can be efficiently measured using pure-tone audiometry, the assessment of supra-threshold hearing deficits remains a challenge. In contrast to the classical “attenuation-distortion” model, the proposed BEAR approach is based on the hypothesis that the hearing abilities of a given listener can be characterized along two dimensions, reflecting independent types of perceptual deficits (distortions). A data-driven approach provided evidence for the existence of different auditory profiles with different degrees of distortions. Ten tests were included in a test battery, based on their clinical feasibility, time efficiency, and related evidence from the literature. The tests were divided into six categories: audibility, speech perception, binaural processing abilities, loudness perception, spectro-temporal modulation sensitivity, and spectro-temporal resolution. Seventy-five listeners with symmetric, mild-to-severe sensorineural hearing loss were selected from a clinical population. The analysis of the results showed interrelations among outcomes related to high-frequency processing and outcome measures related to low-frequency processing abilities. The results showed the ability of the tests to reveal differences among individuals and their potential use in clinical settings.
Honeybee Brain Oscillations Are Generated by Microtubules. The Concept of a Brain Central Oscillator
Authors: Gutierrez Brenda C. , Pita Almenar Marcelo R. , Martínez Luciano J. , Siñeriz Louis Manuel , Albarracín Virginia H. , Cantero María del Rocío , Cantiello Horacio F.
Published: September 2021

Microtubules (MTs) are important structures of the cytoskeleton in neurons. Mammalian brain MTs act as biomolecular transistors that generate highly synchronous electrical oscillations. However, their role in brain function is largely unknown. To gain insight into the MT electrical oscillatory activity of the brain, we turned to the honeybee (Apis mellifera) as a useful model to isolate brains and MTs. The patch clamp technique was applied to MT sheets of purified honeybee brain MTs. High resistance seal patches showed electrical oscillations that linearly depended on the holding potential between ± 200 mV and had an average conductance in the order of ~9 nS. To place these oscillations in the context of the brain, we also explored local field potential (LFP) recordings from the Triton X-permeabilized whole honeybee brain unmasking spontaneous oscillations after but not before tissue permeabilization. Frequency domain spectral analysis of time records indicated at least two major peaks at approximately ~38 Hz and ~93 Hz in both preparations. The present data provide evidence that MT electrical oscillations are a novel signaling mechanism implicated in brain wave activity observed in the insect brain.
Noise Exposure Potentiates Exocytosis From Cochlear Inner Hair Cells
Authors: Boero Luis E. , Payne Shelby , Gómez-Casati Maria Eugenia , Rutherford Mark A. , Goutman Juan D.
Published: September 2021

Noise-induced hearing loss has gained relevance as one of the most common forms of hearing impairment. The anatomical correlates of hearing loss, principally cell damage and/or death, are relatively well-understood histologically. However, much less is known about the physiological aspects of damaged, surviving cells. Here we addressed the functional consequences of noise exposure on the capacity of inner hair cells (IHCs) to release synaptic vesicles at synapses with spiral ganglion neurons (SGNs). Mice of either sex at postnatal day (P) 15–16 were exposed to 1–12 kHz noise at 120 dB sound pressure level (SPL), for 1 h. Exocytosis was measured by tracking changes in membrane capacitance (ΔCm) from IHCs of the apical cochlea. Upon IHC depolarization to different membrane potentials, ΔCm showed the typical bell-shaped curve that mirrors the voltage dependence of Ca2+ influx, in both exposed and unexposed cells. Surprisingly, from IHCs at 1-day after exposure (d.a.e.), we found potentiation of exocytosis at the peak of the bell-shaped curve. The increase in exocytosis was not accompanied by changes in whole-cell Ca2+ influx, suggesting a modification in coupling between Ca2+ channels and synaptic vesicles. Consistent with this notion, noise exposure also changed the Ca2+-dependence of exocytosis from linear to supralinear. Noise exposure did not cause loss of IHCs, but did result in a small reduction in the number of IHC-SGN synapses at 1-d.a.e. which recovered by 14-d.a.e. In contrast, a strong reduction in auditory brainstem response wave-I amplitude (representing synchronous firing of SGNs) and distortion product otoacoustic emissions (reflecting outer hair cell function) indicated a profound hearing loss at 1- and 14-d.a.e. To determine the role of glutamate release in the noise-induced potentiation of exocytosis, we evaluated vesicular glutamate transporter-3 (Vglut3) knock-out (KO) mice. Unlike WT, IHCs from Vglut3KO mice showed a noise-induced reduction in ΔCm and Ca2+ influx with no change in the Ca2+-dependence of exocytosis. Together, these results indicate that traumatic noise exposure triggers changes of IHC synaptic function including a Vglut3-dependent potentiation of exocytosis.
Predictive Value of Geriatric Nutritional Risk Index in Patients With Coronary Artery Disease: A Meta-Analysis
Authors: Fan Yu , He Lian , Zhou Yongjing , Man Changfeng
Published: September 2021

Background:Low Geriatric Nutritional Risk Index has been identified as an index of impaired nutritional state. The objective of the meta-analysis was to assess the association of the Geriatric Nutritional Risk Index (GNRI) with adverse outcomes in patients with coronary artery disease (CAD).

Methods:Relevant studies were identified by comprehensively searching PubMed and Embase databases in May 2021. Studies assessing the association of GNRI with all-cause mortality or major adverse cardiovascular events (MACEs) in patients with CAD were included. The predictive value of GNRI was summarized by pooling multivariable adjusted risk ratios (RR) with 95% confidence intervals (CI) per GNRI point decrease or the lowest vs. the highest GNRI group.

Results:A total of eight studies involving 9277 patients with CAD were analyzed. Meta-analysis showed that the lowest GNRI was associated with a higher risk of all-cause mortality (RR 2.10; 95% CI 1.68–2.63) and MACEs (RR 2.84; 95% CI 1.56–5.16), respectively. Furthermore, per point decrease in GNRI was associated with 8 and 10% additional risk of all-cause mortality and MACEs. Subgroup analysis indicated that the value of low GNRI in predicting all-cause mortality was not affected by subtype of patients or follow-up duration.

Conclusion:Low GNRI score at baseline was associated with a higher risk of all-cause mortality and cardiovascular events in patients with CAD. The nutritional state estimated by the GNRI score could provide important predictive information in patients with CAD.
Pioneering BRCA1/2 Point-Of-Care Testing for Integration of Germline and Tumor Genetics in Breast Cancer Risk Management: A Vision for the Future of Translational Pharmacogenomics
Authors: Mampunye Lwando , van der Merwe Nerina C. , Grant Kathleen A. , Peeters Armand V. , Torrorey-Sawe Rispah , French David J. , Moremi Kelebogile E. , Kidd Martin , van Eeden Petrus C. , Pienaar Fredrieka M. , Kotze Maritha J.
Published: September 2021

Research performed in South African (SA) breast, ovarian and prostate cancer patients resulted in the development of a rapid BRCA point-of-care (POC) assay designed as a time- and cost-effective alternative to laboratory-based technologies currently used for first-tier germline DNA testing. In this study the performance of the new assay was evaluated for use on a portable screening device (ParaDNA), with the long-term goal to enable rollout at POC as an inventive step to meet the World Health Organization’s sustainable development goals for Africa. DNA samples for germline testing were obtained retrospectively from 50 patients with early-stage hormone receptor-positive breast cancer referred for genomic tumor profiling (MammaPrint). Currently, SA patients with the luminal-type breast cancer are not routinely selected for BRCA1/2 testing as is the case for triple-negative disease. An initial evaluation involved the use of multiple control samples representing each of the pathogenic founder/recurrent variants included in the BRCA 1.0 POC Research Assay. Comparison with a validated laboratory-based first-tier real-time polymerase chain reaction (PCR) assay demonstrated 100% concordance. Clinical utility was evident in five patients with the founder BRCA2 c.7934delG variant, identified at the 10% (5/50) threshold considered cost-effective for BRCA1/2 testing. BRCA2 c.7934delG carrier status was associated with a significantly younger age (p=0.03) at diagnosis of breast cancer compared to non-carriers. In three of the BRCA2 c.7934delG carriers a high-risk MammaPrint 70-gene profile was noted, indicating a significantly increased risk for both secondary cancers and breast cancer recurrence. Initiating germline DNA testing at the POC for clinical interpretation early in the treatment planning process, will increase access to the most common pathogenic BRCA1/2 variants identified in SA and reduce loss to follow-up for timely gene-targeted risk reduction intervention. The ease of using cheek swabs/saliva in future for result generation within approximately one hour assay time, coupled with low cost and a high BRCA1/2 founder variant detection rate, will improve access to genomic medicine in Africa. Application of translational pharmacogenomics across ethnic groups, irrespective of age, family history, tumor subtype or recurrence risk profile, is imperative to sustainably implement preventative healthcare and improve clinical outcome in resource-constrained clinical settings.
CircNRIP1 Encapsulated by Bone Marrow Mesenchymal Stem Cell–Derived Extracellular Vesicles Aggravates Osteosarcoma by Modulating the miR-532-3p/AKT3/PI3K/AKT Axis
Authors: Shi Zuowei , Wang Kaifu , Xing Yufei , Yang Xuefeng
Published: September 2021

Emerging evidence indicates that extracellular vesicle (EV)-encapsulated circRNAs have the potential diagnostic and prognostic values for malignancies. However, the role of circNRIP1 in osteosarcoma remains unclear. We herein investigated the therapeutic potential of circNRIP1 delivered by bone marrow mesenchymal stem cell–derived EVs (BMSC-EVs) in osteosarcoma. The expression of circNRIP1 was examined in the clinical tissue samples of osteosarcoma patients, after which the downstream genes of circNRIP1 were bioinformatically predicted. Gain- and loss-of function assays were then performed in osteosarcoma cells with manipulation of circNRIP1 and miR-532-3p expression. EVs isolated from BMSCs were characterized and co-cultured with osteosarcoma cells to examine their effects on cell phenotypes, as reflected by CCK-8 and Transwell assays. Further, a mouse model of tumor xenografts was established for in vivo substantiation. circNRIP1 was upregulated in osteosarcoma tissues and cells. Overexpression of circNRIP1 promoted the proliferative, migratory, and invasive potential of osteosarcoma cells. Co-culture data showed that BMSC-EVs could transfer circNRIP1 into osteosarcoma cells where it competitively bound to miR-532-3p and weakened miR-532-3p’s binding ability to AKT3. By this mechanism, the PI3K/AKT signaling pathway was activated and the malignant characteristics of osteosarcoma cells were stimulated. In vivo experimental results unveiled that circNRIP1-overexpressing BMSC-EVs in nude mice resulted in enhanced tumor growth. In conclusion, the BMSC-EV-enclosed circNRIP1 revealed a new molecular mechanism in the pathogenesis of osteosarcoma, which might provide a novel therapeutic target for osteosarcoma.
Machine Learning-Based CT Radiomics Analysis for Prognostic Prediction in Metastatic Non-Small Cell Lung Cancer Patients With EGFR-T790M Mutation Receiving Third-Generation EGFR-TKI Osimertinib Treatment
Authors: Tang Xin , Li Yuan , Yan Wei-feng , Qian Wen-lei , Pang Tong , Gong You-ling , Yang Zhi-gang
Published: September 2021

Background and Purpose

As a third-generation EGFR tyrosine kinase inhibitor (TKI), osimertinib is approved for treating advanced non-small cell lung cancer (NSCLC) patients with EGFR-T790M mutation after progression on first- or second-generation EGFR-TKIs such as gefitinib, erlotinib and afatinib. We aim at exploring the feasibility and effectiveness of using radiomic features from chest CT scan to predict the prognosis of metastatic non-small cell lung cancer (NSCLC) patients with EGFR-T790M mutation receiving second-line osimertinib therapy.

Methods

Contrast-enhanced and unenhanced chest CT images before osimertinib treatment were collected from 201 and 273 metastatic NSCLC patients with EGFR-T790M mutation, respectively. Radiomic features were extracted from the volume of interest. LASSO regression was used to preliminarily evaluate the prognostic values of different radiomic features. We then performed machine learning-based analyses including random forest (RF), support vector machine (SVM), stepwise regression (SR) and LASSO regression with 5-fold cross-validation (CV) to establish the optimal radiomic model for predicting the progression-free survival (PFS) of osimertinib treatment. Finally, a combined clinical-radiomic model was developed and validated using the concordance index (C-index), decision-curve analysis (DCA) and calibration curve analysis.

Results

Disease progression occurred in 174/273 (63.7%) cases. CT morphological features had no ability in predicting patients’ prognosis in osimertinib treatment. Univariate COX regression followed by LASSO regression analyses identified 23 and 6 radiomic features from the contrast-enhanced and unenhanced CT with prognostic value, respectively. The 23 contrast-enhanced radiomic features were further used to construct radiomic models using different machine learning strategies. Radiomic model built by SR exhibited superior predictive accuracy than RF, SVR or LASSO model (mean C-index of the 5-fold CV: 0.660 vs. 0.560 vs. 0.598 vs. 0.590). Adding the SR radiomic model to the clinical model could remarkably strengthen the C-index of the latter from 0.672 to 0.755. DCA and calibration curve analyses also demonstrated good performance of the combined clinical-radiomic model.

Conclusions

Radiomic features extracted from the contrast-enhanced chest CT could be used to evaluate metastatic NSCLC patients’ prognosis in osimertinib treatment. Prognostic models combing both radiomic features and clinical factors had a great performance in predicting patients’ outcomes.