bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase Change Material of Copper–Germanium Alloy as Solar Latent Heat Storage at High Temperatures
Authors: Gokon Nobuyuki , Jie Chew Shun , Nakano Yuya , Okazaki Shogo , Kodama Tatsuya , Hatamachi Tsuyoshi , Bellan Selvan
Published: June 2021

A copper–germanium alloy (Cu–Ge alloy) was examined as a phase change material, at temperatures exceeding 600°C, for latent heat storage in solar thermal applications. First, the thermo-physical properties of the Cu–Ge alloy were examined using differential scanning calorimetry, thermomechanical analysis, and laser flash analysis. Second, to evaluate the thermal response and reliability of the Cu–Ge alloy, the cyclic properties of thermal charge/discharge were examined under various thermal conditions. The alloys obtained after the tests were examined for their chemical compatibility with the stainless steel container using an electron probe micro analyzer. The elemental distribution of each Cu–Ge alloy was evaluated using cyclic performance tests. Finally, the chemical compatibility of the Cu–Ge alloy was evaluated using a high-temperature test with candidate materials of a phase change material container vessel [stainless steel (SUS310S), Inconel625, silicon carbide (SiC), and alumina (Al2O3)]. The Cu–Ge alloy exhibited significant potential as a latent heat storage material in next-generation solar thermal power plants because it demonstrates various advantages, including a superior storage capacity at a temperature of 644°C, temperature coherence to the phase diagram, a quick thermal response, satisfactory cyclic behavior of charge/discharge modes, a thermodynamically stable metallographic structure, and non-reactivity with container ceramic materials (SiC and Al2O3).
“The Forest Has Become Our New Living Room” – The Critical Importance of Urban Forests During the COVID-19 Pandemic
Authors: Weinbrenner Hannes , Breithut Jasmin , Hebermehl Wiebke , Kaufmann Anna , Klinger Tabea , Palm Therese , Wirth Kristina
Published: June 2021

Out of nowhere the COVID-19 pandemic has turned people’s everyday lives upside down. Public places in urban areas were closed. However, leaving the house for recreational and leisure purposes in nature was still allowed in Germany – even during lockdown in March and April of 2020. As a result, urban forests have gained unprecedented importance – not only for recreational activities, but also for maintaining social contacts and coping with psychological stress. With these diverse requirements, many people have appropriated urban forests in new and changed ways. Using the example of the forests around the southern German city of Freiburg, a team of researchers from the Department of Societal Change at the Forest Research Institute Baden-Württemberg (FVA) carried out a mixed-method study to investigate how these appropriation practices are working and to shed some light on the relevance of forests for city residents in these circumstances. In addition to the statistical analysis of an online questionnaire, ethnographic observation data and Instagram posts were analyzed. This methodological triangulation was carried out in order to purposefully combine the strengths of each method while at the same time reducing the intrinsic biases and blind spots. This resulted in a better understanding of the importance of urban forest during this extraordinary period of time. Our results show that urban forests became critically important during the lockdown. Many visitors appropriated the forest with very different motives and for different purposes. For many visitors, the forest provided the same functions during this extraordinary period that public spaces otherwise do. The forest was not only consumed as a natural space, but also constructed by visitors as a social space. We can illustrate how this social meaning was both negotiated and reproduced. To provide an abstraction of our results, we refer to the theory of spatial appropriation as well as to new approaches in sociology of space that conceptualize space as a network of social relations. These results give rise to broader questions for future research projects, recreational forest research, forest and health, and forest planning.
The ‘Shellome’ of the Crocus Clam Tridacna crocea Emphasizes Essential Components of Mollusk Shell Biomineralization
Authors: Takeuchi Takeshi , Fujie Manabu , Koyanagi Ryo , Plasseraud Laurent , Ziegler-Devin Isabelle , Brosse Nicolas , Broussard Cédric , Satoh Noriyuki , Marin Frédéric
Published: June 2021

Molluscan shells are among the most fascinating research objects because of their diverse morphologies and textures. The formation of these delicate biomineralized structures is a matrix-mediated process. A question that arises is what are the essential components required to build these exoskeletons. In order to understand the molecular mechanisms of molluscan shell formation, it is crucial to identify organic macromolecules in different shells from diverse taxa. In the case of bivalves, however, taxon sampling in previous shell proteomics studies are focused predominantly on representatives of the class Pteriomorphia such as pearl oysters, edible oysters and mussels. In this study, we have characterized the shell organic matrix from the crocus clam, Tridacna crocea, (Heterodonta) using various biochemical techniques, including SDS-PAGE, FT-IR, monosaccharide analysis, and enzyme-linked lectin assay (ELLA). Furthermore, we have identified a number of shell matrix proteins (SMPs) using a comprehensive proteomics approach combined to RNA-seq. The biochemical studies confirmed the presence of proteins, polysaccharides, and sulfates in the T. crocea shell organic matrix. Proteomics analysis revealed that the majority of the T. crocea SMPs are novel and dissimilar to known SMPs identified from the other bivalve species. Meanwhile, the SMP repertoire of the crocus clam also includes proteins with conserved functional domains such as chitin-binding domain, VWA domain, and protease inhibitor domain. We also identified BMSP (Blue Mussel Shell Protein, originally reported from Mytilus), which is widely distributed among molluscan shell matrix proteins. Tridacna SMPs also include low-complexity regions (LCRs) that are absent in the other molluscan genomes, indicating that these genes may have evolved in specific lineage. These results highlight the diversity of the organic molecules – in particular proteins – that are essential for molluscan shell formation.
Quantitative and Correlational Analysis of Brain and Spleen Immune Cellular Responses Following Cerebral Ischemia
Authors: Liu Qingkun , Sorooshyari Siamak K.
Published: June 2021

Stroke is a multiphasic process, and the initial ischemic phase of neuronal damage is followed by secondary innate and adaptive responses that unfold over days after stroke, offer a longer time frame of intervention, and represent a novel therapeutic target. Therefore, revealing the distinct functions of immune cells in both brain and periphery is important for identification of immunotherapeutic targets for stroke to extend the treatment time window. In this paper an examination of the cellular dynamics of the immune response in the central nervous system (CNS) and periphery provoked by cerebral ischemia is provided. New data is presented for the number of immune cells in brain and spleen of mice during the 7 days following middle cerebral artery occlusion (MCAO). A novel analysis of the correlation among various cell types in the brain and spleen following stroke is presented. It is found that the infiltrated macrophages in the ischemic hemisphere positively correlate with neutrophils which implies their synergic effect in migrating into the brain after stroke onset. It is noted that during infiltration of adaptive immune cells, the number of neutrophils correlate positively with T cells, which suggests neutrophils contribute to T cell infiltration in the stroked brain. Furthermore, the correlation among neurological deficit and various immune cells suggests that microglia and splenic adaptive immune cells (T and B cells) are protective while infiltrating peripheral myeloid cells (macrophage and neutrophils) worsen stroke outcome. Comprehension of such immune responses post cerebral ischemia is crucial for differentiating the drivers of outcomes and also predicting the stroke outcome.
lncRNA-HEIM Facilitated Liver Fibrosis by Up-Regulating TGF-β Expression in Long-Term Outcome of Chronic Hepatitis B
Authors: Yao Jian , Lin Chenhong , Jiang Jingjing , Zhang Xujun , Li Fengxia , Liu Tianxing , Diao Hongyan
Published: June 2021

Background

Chronic liver fibrosis is an inevitable stage for the development of patients with chronic hepatitis B (CHB). However, anti-fibrotic therapies have been unsuccessful so far. The biological functions and molecular mechanisms of long non-coding RNAs (lncRNAs) in the host immune system during chronic hepatitis B virus (HBV) infection, especially in fibrosis, are still largely unknown.

Method

The total RNA of peripheral blood mononuclear cells (PBMCs) from asymptomatic carriers (ASCs) or CHB receiving at least 8 years of anti-viral treatments was analyzed using Arraystar microarray and validated via quantitative real-time PCR (qRT-PCR). Correlation analysis was conducted based on correlation coefficients, Clusterprofile, and RNA Interactome Database (RAID). The functions of lncRNA in monocytes were determined via loss-of-function RNAi or gain-of-function lentivirus assays. The expression levels of mRNAs or proteins were evaluated using qRT-PCR, western blotting assay, or enzyme linked immunosorbent assays (ELISA).

Results

A total of 1,042 mRNA transcripts (630 up-regulated and 412 down-regulated) were identified being differentially expressed between ASC and CHB patients. Through enrichment analysis we focused on the transforming growth factor beta (TGF-β) signaling pathway and validated their expression in a larger cohort. Moreover, we found that lncRNA ENST00000519726 (lncRNA-HEIM) was highly expressed in monocytes and further up-regulated upon HBV infection. LncRNA-HEIM played an important role in CHB patients with long-term antiviral treatments, and its elevated expression was remarkably correlated with the TGF-β signaling pathway, especially with the two members namely TGF-β and SMAD4. Furthermore, altering the endogenous lncRNA-HEIM level in monocytes significantly affected the production of TGF-β, as well as the fibrosis of hepatic stellate cells by affecting the expression of collagen I and α-smooth muscle actin (α-SMA).

Conclusion

These findings not only added knowledge to the understanding of the roles of which lncRNA-HEIM played in the activation of HSCs in CHB patients with long-term medication, but also provided a promising therapeutic target in the future treatment for liver fibrosis.
Gene Expression Profiling of Lymph Node Sub-Capsular Sinus Macrophages in Cancer
Authors: Pellin Danilo , Claudio Natalie , Guo Zihan , Ziglari Tahereh , Pucci Ferdinando
Published: June 2021

Lymph nodes are key lymphoid organs collecting lymph fluid and migratory cells from the tissue area they survey. When cancerous cells arise within a tissue, the sentinel lymph node is the first immunological organ to mount an immune response. Sub-capsular sinus macrophages (SSMs) are specialized macrophages residing in the lymph nodes that play important roles as gatekeepers against particulate antigenic material. In the context of cancer, SSMs capture tumor-derived extracellular vesicles (tEVs), a form of particulate antigen released in high amounts by tumor cells. We and others have recently demonstrated that SSMs possess anti-tumor activity because in their absence tumors progress faster. A comprehensive profiling of SSMs represents an important first step to identify the cellular and molecular mechanisms responsible for SSM anti-tumor activity. Unfortunately, the isolation of SSMs for molecular analyses is very challenging. Here, we combined an optimized dissociation protocol, careful marker selection and stringent gating strategies to highly purify SSMs. We provide evidence of decreased T and B cell contamination, which allowed us to reveal the gene expression profile of this elusive macrophage subset. Squamous cell carcinomas induced an increase in the expression of Fc receptors, lysosomal and proteasomal enzymes in SSMs. Imaging of mouse and patient lymph nodes confirmed the presence of the top differentially expressed genes. These results suggest that SSMs respond to tumor formation by upregulating the machinery necessary for presentation of tumor particulate antigens to B cells.
Memory B Cells in Multiple Sclerosis: Emerging Players in Disease Pathogenesis
Authors: DiSano Krista D. , Gilli Francesca , Pachner Andrew R.
Published: June 2021

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Once thought to be primarily driven by T cells, B cells are emerging as central players in MS immunopathogenesis. Interest in multiple B cell phenotypes in MS expanded following the efficacy of B cell-depleting agents targeting CD20 in relapsing-remitting MS and inflammatory primary progressive MS patients. Interestingly, these therapies primarily target non-antibody secreting cells. Emerging studies seek to explore B cell functions beyond antibody-mediated roles, including cytokine production, antigen presentation, and ectopic follicle-like aggregate formation. Importantly, memory B cells (Bmem) are rising as a key B cell phenotype to investigate in MS due to their antigen-experience, increased lifespan, and rapid response to stimulation. Bmem display diverse effector functions including cytokine production, antigen presentation, and serving as antigen-experienced precursors to antibody-secreting cells. In this review, we explore the cellular and molecular processes involved in Bmem development, Bmem phenotypes, and effector functions. We then examine how these concepts may be applied to the potential role(s) of Bmem in MS pathogenesis. We investigate Bmem both within the periphery and inside the CNS compartment, focusing on Bmem phenotypes and proposed functions in MS and its animal models. Finally, we review how current immunomodulatory therapies, including B cell-directed therapies and other immunomodulatory therapies, modify Bmem and how this knowledge may be harnessed to direct therapeutic strategies in MS.
Integrative Multi-Omics Reveals Serum Markers of Tuberculosis in Advanced HIV
Authors: Krishnan Sonya , Queiroz Artur T. L. , Gupta Amita , Gupte Nikhil , Bisson Gregory P. , Kumwenda Johnstone , Naidoo Kogieleum , Mohapi Lerato , Mave Vidya , Mngqibisa Rosie , Lama Javier R. , Hosseinipour Mina C. , Andrade Bruno B. , Karakousis Petros C.
Published: June 2021

Tuberculosis (TB) accounts for disproportionate morbidity and mortality among persons living with HIV (PLWH). Conventional methods of TB diagnosis, including smear microscopy and Xpert MTB/RIF, have lower sensitivity in PLWH. Novel high-throughput approaches, such as miRNAomics and metabolomics, may advance our ability to recognize subclinical and difficult-to-diagnose TB, especially in very advanced HIV. We conducted a case-control study leveraging REMEMBER, a multi-country, open-label randomized controlled trial comparing 4-drug empiric standard TB treatment with isoniazid preventive therapy in PLWH initiating antiretroviral therapy (ART) with CD4 cell counts <50 cells/μL. Twenty-three cases of incident TB were site-matched with 32 controls to identify microRNAs (miRNAs), metabolites, and cytokines/chemokines, associated with the development of newly diagnosed TB in PLWH. Differentially expressed miRNA analysis revealed 11 altered miRNAs with a fold change higher than 1.4 or lower than -1.4 in cases relative to controls (p<0.05). Our analysis revealed no differentially abundant metabolites between cases and controls. We found higher TNFα and IP-10/CXCL10 in cases (p=0.011, p=0.0005), and higher MDC/CCL22 in controls (p=0.0072). A decision-tree algorithm identified gamma-glutamylthreonine and hsa-miR-215-5p as the optimal variables to classify incident TB cases (AUC 0.965; 95% CI 0.925-1.000). hsa-miR-215-5p, which targets genes in the TGF-β signaling pathway, was downregulated in cases. Gamma-glutamylthreonine, a breakdown product of protein catabolism, was less abundant in cases. To our knowledge, this is one of the first uses of a multi-omics approach to identify incident TB in severely immunosuppressed PLWH.
The Status and Prospects of Epstein–Barr Virus Prophylactic Vaccine Development
Authors: Sun Cong , Chen Xin-chun , Kang Yin-feng , Zeng Mu-sheng
Published: June 2021

Epstein–Barr virus (EBV) is a human herpesvirus that is common among the global population, causing an enormous disease burden. EBV can directly cause infectious mononucleosis and is also associated with various malignancies and autoimmune diseases. In order to prevent primary infection and subsequent chronic disease, efforts have been made to develop a prophylactic vaccine against EBV in recent years, but there is still no vaccine in clinical use. The outbreak of the COVID-19 pandemic and the global cooperation in vaccine development against SARS-CoV-2 provide insights for next-generation antiviral vaccine design and opportunities for developing an effective prophylactic EBV vaccine. With improvements in antigen selection, vaccine platforms, formulation and evaluation systems, novel vaccines against EBV are expected to elicit dual protection against infection of both B lymphocytes and epithelial cells. This would provide sustainable immunity against EBV-associated malignancies, finally enabling the control of worldwide EBV infection and management of EBV-associated diseases.
The cGAS/STING–TBK1–IRF Regulatory Axis Orchestrates a Primitive Interferon-Like Antiviral Mechanism in Oyster
Authors: Qiao Xue , Zong Yanan , Liu Zhaoqun , Wu Zhaojun , Li Yuanmei , Wang Lingling , Song Linsheng
Published: June 2021

Interferon (IFN) system is considered as the first defense line against viral infection, and it has been extensively studied in vertebrates from fish to mammals. In invertebrates, Vagos from arthropod and IFN-like protein (CgIFNLP) from Crassostrea gigas appeared to function as IFN-like antiviral cytokines. In the present study, the CgIFNLP protein in hemocytes was observed to increase after Poly (I:C) stimulation. After CgIFNLP was knocked down by RNAi, the mRNA expression of IFN-stimulated genes (CgISGs) was significantly inhibited. Both cyclic GMP-AMP synthase (CgcGAS) and stimulator of interferon gene (CgSTING) identified from oyster were able to recognize the double-stranded nucleic acid [Poly (I:C) and dsDNA] and expressed at high level after Poly (I:C) stimulation. The expression of CgIFNLP and interferon regulatory factors (CgIRF1/8) and the nuclear translocation of CgIRF8 were all suppressed in CgcGAS-RNAi or CgSTING-RNAi oysters after Poly (I:C) stimulation. The expression level of CgSTING and TANK binding kinase1 (CgTBK1) did not decrease in CgcGAS-RNAi oysters. After CgSTING was knocked down, the high expression of CgTBK1 induced by Poly (I:C) was prevented significantly. These results indicated that there was a primitive IFN-like antiviral mechanism dependent on the cGAS/STING–TBK1–IRFs regulatory axis in mollusks, which was different from the classic cGAS–STING–TBK1 signal pathway in mammals.
PRMT5 Promotes Cyclin E1 and Cell Cycle Progression in CD4 Th1 Cells and Correlates With EAE Severity
Authors: Amici Stephanie A. , Osman Wissam , Guerau-de-Arellano Mireia
Published: June 2021

Multiple Sclerosis (MS) is a debilitating central nervous system disorder associated with inflammatory T cells. Activation and expansion of inflammatory T cells is thought to be behind MS relapses and influence disease severity. Protein arginine N-methyltransferase 5 (PRMT5) is a T cell activation-induced enzyme that symmetrically dimethylates proteins and promotes T cell proliferation. However, the mechanism behind PRMT5-mediated control of T cell proliferation and whether PRMT5 contributes to diseases severity is unclear. Here, we evaluated the role of PRMT5 on cyclin/cdk pairs and cell cycle progression, as well as PRMT5’s link to disease severity in an animal model of relapsing-remitting MS. Treatment of T helper 1 (mTh1) cells with the selective PRMT5 inhibitor, HLCL65, arrested activation-induced T cell proliferation at the G1 stage of the cell cycle, suggesting PRMT5 promotes cell cycle progression in CD4+ T cells. The Cyclin E1/Cdk2 pair promoting G1/S progression was also decreased after PRMT5 inhibition, as was the phosphorylation of retinoblastoma. In the SJL mouse relapsing-remitting model of MS, the highest PRMT5 expression in central nervous system-infiltrating cells corresponded to peak and relapse timepoints. PRMT5 expression also positively correlated with increasing CD4 Th cell composition, disease severity and Cyclin E1 expression. These data indicate that PRMT5 promotes G1/S cell cycle progression and suggest that this effect influences disease severity and/or progression in the animal model of MS. Modulating PRMT5 levels may be useful for controlling T cell expansion in T cell-mediated diseases including MS.
Understanding Sea Level Processes During Western Mediterranean Storm Gloria
Authors: Pérez-Gómez Begoña , García-León Manuel , García-Valdecasas Javier , Clementi Emanuela , Mösso Aranda César , Pérez-Rubio Susana , Masina Simona , Coppini Giovanni , Molina-Sánchez Rafael , Muñoz-Cubillo Angel , García Fletcher Ana , Sánchez González José Francisco , Sánchez-Arcilla Agustín , Álvarez Fanjul Enrique
Published: June 2021

In January 2020, the storm Gloria hit the Western Mediterranean Sea causing severe coastal damages, destruction of infrastructures, flooding and several casualties. This extreme event was characterized by strong Eastern winds, record-breaking waves heights and periods, and a storm surge that locally beat the record along Valencia’s coastline. This paper analyses the dynamic evolution of sea level during this storm. The study employs both the in situ data and the operational forecasts of the PORTUS early warning system. Tide gauge data are analyzed on the different temporal scales that contribute to total sea level: long-term and seasonal, tides and storm surges, and higher frequency oscillations. It was found that, due to the unusual long wave periods, infragravity waves were generated and dominate the high frequency energy band, contributing significantly to extreme sea level records. This is a relevant finding, since this kind of oscillations are usually associated with larger basins, where swell can develop and propagate. The impact of sea level rise is also analyzed and considered relevant. A multi-model ensemble storm surge forecasting system is employed to study the event. The system was able to correctly forecast the surge, and the measured data were always inside the confidence bands of the system. The differences of the results obtained by the available operational forecasting system integrated into the ensemble, including those from Copernicus Marine Service, are described. All the models provided useful forecasts during the event, but differences with measured data are described and connected with the known limitations in physics (for example, barotropic vs. baroclinic) and set-up of the models (model domain, lack of tides and different inverse barometer implementations at the open boundaries amongst others).
Efficient Detection of Longitudinal Bacteria Fission Using Transfer Learning in Deep Neural Networks
Authors: Garcia-Perez Carlos , Ito Keiichi , Geijo Javier , Feldbauer Roman , Schreiber Nico , zu Castell Wolfgang
Published: June 2021

A very common way to classify bacteria is through microscopic images. Microscopic cell counting is a widely used technique to measure microbial growth. To date, fully automated methodologies are available for accurate and fast measurements; yet for bacteria dividing longitudinally, as in the case of Candidatus Thiosymbion oneisti, its cell count mainly remains manual. The identification of this type of cell division is important because it helps to detect undergoing cellular division from those which are not dividing once the sample is fixed. Our solution automates the classification of longitudinal division by using a machine learning method called residual network. Using transfer learning, we train a binary classification model in fewer epochs compared to the model trained without it. This potentially eliminates most of the manual labor of classifying the type of bacteria cell division. The approach is useful in automatically labeling a certain bacteria division after detecting and segmenting (extracting) individual bacteria images from microscopic images of colonies.
Transcriptome Dynamics Underlying Chlamydospore Formation in Trichoderma virens GV29-8
Authors: Peng Xinhong , Wu Beilei , Zhang Shuaihu , Li Mei , Jiang Xiliang
Published: June 2021

Trichoderma spp. are widely used biocontrol agents which are antagonistic to a variety of plant pathogens. Chlamydospores are a type of propagules produced by many fungi that have thick walls and are highly resistant to adverse environmental conditions. Chlamydospore preparations of Trichoderma spp. can withstand various storage conditions, have a longer shelf life than conidial preparations and have better application potential. However, large-scale production of chlamydospores has proven difficult. To understand the molecular mechanisms governing chlamydospore formation (CF) in Trichoderma fungi, we performed a comprehensive analysis of transcriptome dynamics during CF across 8 different developmental time points, which were divided into 4 stages according to PCA analysis: the mycelium growth stage (S1), early and middle stage of CF (S2), flourishing stage of CF (S3), and late stage of CF and mycelia initial autolysis (S4). 2864, 3206, and 3630 DEGs were screened from S2 vs S1, S3 vs S2, and S4 vs S3, respectively. We then identified the pathways and genes that play important roles in each stage of CF by GO, KEGG, STC and WGCNA analysis. The results showed that DEGs in the S2 vs S1 were mainly enriched in organonitrogen compound metabolism, those in S3 vs S2 were mainly involved in secondary metabolite, cell cycle, and N-glycan biosynthesis, and DEGs in S4 vs S3 were mainly involved in lipid, glycogen, and chitin metabolic processes. We speculated that mycelial assimilation and absorption of exogenous nitrogen in the early growth stage (S1), resulted in subsequent nitrogen deficiency (S2). At the same time, secondary metabolites and active oxygen free radicals released during mycelial growth produced an adverse growth environment. The resulting nitrogen-deficient and toxin enriched medium may stimulate cell differentiation by initiating cell cycle regulation to induce morphological transformation of mycelia into chlamydospores. High expression of genes relating to glycogen, lipid, mannan, and chitin synthetic metabolic pathways during the flourishing (S3) and late stages (S4) of CF may be conducive to energy storage and cell wall construction in chlamydospores. For further verifying the functions of the amino sugar and nucleotide sugar metabolism (tre00520) pathway in the CF of T. virens GV29-8 strain, the chitin synthase gene (TRIVIDRAFT_90152), one key gene of the pathway, was deleted and resulted in the dysplasia of mycelia and an incapability to form normal chlamydospores, which illustrated the pathway affecting the CF of T. virens GV29-8 strain. Our results provide a new perspective for understanding the genetics of biochemical pathways involved in CF of Trichoderma spp.
Why Plants Harbor Complex Endophytic Fungal Communities: Insights From Perennial Bunchgrass Stipagrostis sabulicola in the Namib Sand Sea
Authors: Wenndt Anthony J. , Evans Sarah E. , van Diepeningen Anne D. , Logan J. Robert , Jacobson Peter J. , Seely Mary K. , Jacobson Kathryn M.
Published: June 2021

All perennial plants harbor diverse endophytic fungal communities, but why they tolerate these complex asymptomatic symbioses is unknown. Using a multi-pronged approach, we conclusively found that a dryland grass supports endophyte communities comprised predominantly of latent saprophytes that can enhance localized nutrient recycling after senescence. A perennial bunchgrass, Stipagrostis sabulicola, which persists along a gradient of extreme abiotic stress in the hyper-arid Namib Sand Sea, was the focal point of our study. Living tillers yielded 20 fungal endophyte taxa, 80% of which decomposed host litter during a 28-day laboratory decomposition assay. During a 6-month field experiment, tillers with endophytes decomposed twice as fast as sterilized tillers, consistent with the laboratory assay. Furthermore, profiling the community active during decomposition using next-generation sequencing revealed that 59–70% of the S. sabulicola endophyte community is comprised of latent saprophytes, and these dual-niche fungi still constitute a large proportion (58–62%) of the litter community more than a year after senescence. This study provides multiple lines of evidence that the fungal communities that initiate decomposition of standing litter develop in living plants, thus providing a plausible explanation for why plants harbor complex endophyte communities. Using frequent overnight non-rainfall moisture events (fog, dew, high humidity), these latent saprophytes can initiate decomposition of standing litter immediately after tiller senescence, thus maximizing the likelihood that plant-bound nutrients are recycled in situ and contribute to the nutrient island effect that is prevalent in drylands.
Gene Expression Profiles of Human Cerebral Organoids Identify PPAR Pathway and PKM2 as Key Markers for Oxygen-Glucose Deprivation and Reoxygenation
Authors: Iwasa Naoki , Matsui Takeshi K. , Iguchi Naohiko , Kinugawa Kaoru , Morikawa Naritaka , Sakaguchi Yoshihiko M. , Shiota Tomo , Kobashigawa Shinko , Nakanishi Mari , Matsubayashi Masaya , Nagata Riko , Kikuchi Sotaro , Tanaka Tatsuhide , Eura Nobuyuki , Kiriyama Takao , Izumi Tesseki , Saito Kozue , Kataoka Hiroshi , Saito Yuichi , Kimura Wataru , Wanaka Akio , Nishimura Yuhei , Mori Eiichiro , Sugie Kazuma
Published: June 2021

Ischemic stroke is one of the most common neurological diseases. However, the impact of ischemic stroke on human cerebral tissue remains largely unknown due to a lack of ischemic human brain samples. In this study, we applied cerebral organoids derived from human induced pluripotent stem cells to evaluate the effect of oxygen-glucose deprivation/reoxygenation (OGD/R). Pathway analysis showed the relationships between vitamin digestion and absorption, fat digestion and absorption, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and complement and coagulation cascades. Combinational verification with transcriptome and gene expression analysis of different cell types revealed fatty acids-related PPAR signaling pathway and pyruvate kinase isoform M2 (PKM2) as key markers of neuronal cells in response to OGD/R. These findings suggest that, although there remain some limitations to be improved, our ischemic stroke model using human cerebral organoids would be a potentially useful tool when combined with other conventional two-dimensional (2D) mono-culture systems.
Analysis of Fine Motor Skills in Essential Tremor: Combining Neuroimaging and Handwriting Biomarkers for Early Management
Authors: Lopez-de-Ipina Karmele , Solé-Casals Jordi , Sánchez-Méndez José Ignacio , Romero-Garcia Rafael , Fernandez Elsa , Requejo Catalina , Poologaindran Anujan , Faúndez-Zanuy Marcos , Martí-Massó José Félix , Bergareche Alberto , Suckling John
Published: June 2021

Essential tremor (ET) is a highly prevalent neurological disorder characterized by action-induced tremors involving the hand, voice, head, and/or face. Importantly, hand tremor is present in nearly all forms of ET, resulting in impaired fine motor skills and diminished quality of life. To advance early diagnostic approaches for ET, automated handwriting tasks and magnetic resonance imaging (MRI) offer an opportunity to develop early essential clinical biomarkers. In this study, we present a novel approach for the early clinical diagnosis and monitoring of ET based on integrating handwriting and neuroimaging analysis. We demonstrate how the analysis of fine motor skills, as measured by an automated Archimedes’ spiral task, is correlated with neuroimaging biomarkers for ET. Together, we present a novel modeling approach that can serve as a complementary and promising support tool for the clinical diagnosis of ET and a large range of tremors.
MR Tractography-Based Targeting and Physiological Identification of the Cuneiform Nucleus for Directional DBS in a Parkinson’s Disease Patient With Levodopa-Resistant Freezing of Gait
Authors: Chang Stephano J. , Cajigas Iahn , Guest James D. , Noga Brian R. , Widerström-Noga Eva , Haq Ihtsham , Fisher Letitia , Luca Corneliu C. , Jagid Jonathan R.
Published: June 2021

Background

Freezing of gait (FOG) is a debilitating motor deficit in a subset of Parkinson’s Disease (PD) patients that is poorly responsive to levodopa or deep brain stimulation (DBS) of established PD targets. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN), to address FOG was based on its observed neuropathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region (MLR). Initial reports of PPN DBS were met with enthusiasm; however, subsequent studies reported mixed results. A closer review of the MLR basic science literature, suggests that the closely related cuneiform nucleus (CnF), dorsal to the PPN, may be a superior site to promote gait. Although suspected to have a conserved role in the control of gait in humans, deliberate stimulation of a homolog to the CnF in humans using directional DBS electrodes has not been attempted.

Methods

As part of an open-label Phase 1 clinical study, one PD patient with predominantly axial symptoms and severe FOG refractory to levodopa therapy was implanted with directional DBS electrodes (Boston Science Vercise CartesiaTM) targeting the CnF bilaterally. Since the CnF is a poorly defined reticular nucleus, targeting was guided both by diffusion tensor imaging (DTI) tractography and anatomical landmarks. Intraoperative stimulation and microelectrode recordings were performed near the targets with leg EMG surface recordings in the subject.

Results

Post-operative imaging revealed accurate targeting of both leads to the designated CnF. Intraoperative stimulation near the target at low thresholds in the awake patient evoked involuntary electromyography (EMG) oscillations in the legs with a peak power at the stimulation frequency, similar to observations with CnF DBS in animals. Oscillopsia was the primary side effect evoked at higher currents, especially when directed posterolaterally. Directional DBS could mitigate oscillopsia.

Conclusion

DTI-based targeting and intraoperative stimulation to evoke limb EMG activity may be useful methods to help target the CnF accurately and safely in patients. Long term follow-up and detailed gait testing of patients undergoing CnF stimulation will be necessary to confirm the effects on FOG.

Clinical Trial Registration

Clinicaltrials.gov identifier: NCT04218526.
Profiling of 520 Candidate Genes in 50 Surgically Treated Chinese Small Cell Lung Cancer Patients
Authors: Yuan Ting , Wang Xin , Sun Sijin , Cao Zheng , Feng Xiaoli , Gao Yibo
Published: June 2021

Small cell lung cancer (SCLC) is one of the severe malignancies with high mortality. Surgically resected tumor tissues from 50 Chinese SCLC patients were collected for next-generation sequencing to detect 520 cancer‐related genes. The most frequently altered genes were TP53 (94.0%), RB1 (86.0%), LRP1B (44.0%), SPTA1 (26.0%) and KMT2D (24.0%). We detected that NOTCH2, JAK2 and CDK12 (P<0.05) had a significantly higher mutation frequency in Chinese SCLC compared to the Cologne and MSKCC. The single nucleotide variation (SNV) is dominated by C>A (34.1%). We found a significant association between TMB-H (≥10.3muts/Mb) and ATM (P=0.023), CREBBP (P=0.010), KMT2D(P=0.050) and LRP1B (P=0.005) gene mutations in Chinese SCLC patients. Immunostaining was performed using the following antibodies: TTF-1, CgA, CD56, Syn, and Ki-67. Correlation analysis between the expression of 6 markers and mutations in signaling pathways showed that Syn and CgA expression were associated with 4 (cGMP-PKG, Chemokine, TGF-β and Phospholipase D) and 2 (cGMP-PKG and Phosphatidylinositol) signaling pathway mutations. Kaplan-Meier curve showed that age<55 years, mutant ARID2 and high TMB (≥7muts/Mb) were associated with a better prognosis, while the prognosis of patients with mutations in the Ras pathway was significantly improved. High TMB is an important prognostic factor for SCLC patients showed by multivariate analysis. In the combined cohort composed of current and two previous studies, survival analysis showed that SCLC patients with mutant LRP1B demonstrated better OS (P=0.0017). Patients with a high TMB (≥7muts/Mb) have a better prognosis (P=0.0053), consistent with our results in the Chinese cohort. We characterized the genomic alterations profile of Chinese SCLC patients and analyzed the correlation between genomic changes and immunohistochemical phenotypes at the signaling pathway level. Our data might provide useful information in the diagnosis and treatment for Chinese SCLC patients.
Phase 2 Study of Pomalidomide (CC-4047) Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors
Authors: Fangusaro Jason , Cefalo Maria Giuseppina , Garré Maria Luisa , Marshall Lynley V. , Massimino Maura , Benettaib Bouchra , Biserna Noha , Poon Jennifer , Quan Jackie , Conlin Erin , Lewandowski John , Simcock Mathew , Jeste Neelum , Hargrave Darren R. , Doz François , Warren Katherine E.
Published: June 2021

Introduction

Treatment of recurrent primary pediatric brain tumors remains a major challenge, with most children succumbing to their disease. We conducted a prospective phase 2 study investigating the safety and efficacy of pomalidomide (POM) in children and young adults with recurrent and progressive primary brain tumors.

Methods

Patients with recurrent and progressive high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), ependymoma, or medulloblastoma received POM 2.6 mg/m2/day (the recommended phase 2 dose [RP2D]) on days 1-21 of a 28-day cycle. A Simon’s Optimal 2-stage design was used to determine efficacy. Primary endpoints included objective response (OR) and long-term stable disease (LTSD) rates. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety.

Results

46 patients were evaluable for response (HGG, n = 19; DIPG, ependymoma, and medulloblastoma, n = 9 each). Two patients with HGG achieved OR or LTSD (10.5% [95% CI, 1.3%-33.1%]; 1 partial response and 1 LTSD) and 1 patient with ependymoma had LTSD (11.1% [95% CI, 0.3%-48.2%]). There were no ORs or LTSD in the DIPG or medulloblastoma cohorts. The median PFS for patients with HGG, DIPG, ependymoma, and medulloblastoma was 7.86, 11.29, 8.43, and 8.43 weeks, respectively. Median OS was 5.06, 3.78, 12.02, and 11.60 months, respectively. Neutropenia was the most common grade 3/4 adverse event.

Conclusions

Treatment with POM monotherapy did not meet the primary measure of success in any cohort. Future studies are needed to evaluate if POM would show efficacy in tumors with specific molecular signatures or in combination with other anticancer agents.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT03257631; EudraCT, identifier 2016-002903-25.
Novel MRPS9-ALK Fusion Mutation in a Lung Adenocarcinoma Patient: A Case Report
Authors: Zhou Huamiao , Xu Binyue , Xu Jili , Zhu Guomeng , Guo Yong
Published: June 2021

Anaplastic lymphoma kinase (ALK) rearrangements account for approximately 5–6% of non–small-cell lung cancer (NSCLC) patients. In this study, a case of lung adenocarcinoma harboring a novel MRPS9-ALK fusion is reported. The patient responded well to the first and second generation of ALK-tyrosine kinase inhibitors (ALK-TKIs) (crizotinib then alectinib), as her imaging findings and clinical symptoms significantly improved. At last follow-up, over 21 months of overall survival (OS) has been achieved since ALK-TKI treatment. The progression-free survival (PFS) is already ten months since alectinib. The adverse effects were manageable. The case presented here provides first clinical evidence of the efficacy of ALK-TKIs in NSCLC patients with MRPS9-ALK fusion.
Texture Analysis Using Semiquantitative Kinetic Parameter Maps from DCE-MRI: Preoperative Prediction of HER2 Status in Breast Cancer
Authors: Song Lirong , Li Chunli , Yin Jiandong
Published: June 2021

Objective

To evaluate whether texture features derived from semiquantitative kinetic parameter maps based on breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can determine human epidermal growth factor receptor 2 (HER2) status of patients with breast cancer.

Materials and Methods

This study included 102 patients with histologically confirmed breast cancer, all of whom underwent preoperative breast DCE-MRI and were enrolled retrospectively. This cohort included 48 HER2-positive cases and 54 HER2-negative cases. Seven semiquantitative kinetic parameter maps were calculated on the lesion area. A total of 55 texture features were extracted from each kinetic parameter map. Patients were randomly divided into training (n = 72) and test (n = 30) sets. The least absolute shrinkage and selection operator (LASSO) was used to select features in the training set, and then, multivariate logistic regression analysis was conducted to establish the prediction models. The classification performance was evaluated by receiver operating characteristic (ROC) analysis.

Results

Among the seven prediction models, the model with features extracted from the early signal enhancement ratio (ESER) map yielded an area under the ROC curve (AUC) of 0.83 in the training set (sensitivity of 70.59%, specificity of 92.11%, and accuracy of 81.94%), and the highest AUC of 0.83 in the test set (sensitivity of 57.14%, specificity of 100.00%, and accuracy of 80.00%). The model with features extracted from the slope of signal intensity (SIslope) map yielded the highest AUC of 0.92 in the training set (sensitivity of 82.35%, specificity of 97.37%, and accuracy of 90.28%), and an AUC of 0.79 in the test set (sensitivity of 92.86%, specificity of 68.75%, and accuracy of 80.00%).

Conclusions

Texture features derived from kinetic parameter maps, calculated based on breast DCE-MRI, have the potential to be used as imaging biomarkers to distinguish HER2-positive and HER2-negative breast cancer.
Can Smoking Cause Differences in Urine Microbiome in Male Patients With Bladder Cancer? A Retrospective Study
Authors: Ma Wenchao , Zhang Wentao , Shen Liliang , Liu Ji , Yang Fuhang , Maskey Niraj , Wang Hong , Zhang Junfeng , Yan Yang , Yao Xudong
Published: June 2021

Background

Tobacco smoking is a carcinogen for many cancers including bladder cancer. The microbiota is involved in the occurrence, development, and treatment of tumors. We explored the composition of male urinary microbiome and the correlation between tobacco smoking and microbiome in this study.

Methods

Alpha diversity, principal component analysis (PCA) and Adonis analysis, linear discriminant analysis (LDA) coupled with effect size measurement, and PICRUSt function predictive analysis were used to compare different microbiome between smokers and non-smokers in men.

Results

There were 26 qualified samples included in the study. Eleven of them are healthy controls, and the others are from men with bladder cancer. Simpson index and the result of PCA analysis between smokers and non-smokers were not different (P > 0.05) in healthy men. However, the abundance of Bacteroidaceae, Erysipelotrichales, Lachnospiraceae, Bacteroides, and so on in the urinary tract of smokers is much higher than that of non-smokers. Compared to non-smokers, the alpha diversity in smokers was elevated in patients with bladder cancer (P < 0.05). PCA analysis showed a significant difference between smokers and non-smokers (P < 0.001), indicating that tobacco smoking plays a vital role in urinary tract microbial composition.

Conclusion

The composition of microbiome in the urinary tract is closely related to tobacco smoking. This phenomenon is more significant in patients with bladder cancer. This indicates tobacco smoking may promote the occurrence and development of bladder cancer by changing urinary tract microbiome.
Functionalized Selenium Nanotherapeutics Synergizes With Zoledronic Acid to Suppress Prostate Cancer Cell Growth Through Induction of Mitochondria-Mediated Apoptosis and Cell Cycle S Phase Arrest
Authors: An Yulin , Zhao Jianfu
Published: June 2021

The use of established drugs in new therapeutic applications has great potential for the treatment of cancers. Nanomedicine has the advantages of efficient cellular uptake and specific cell targeting. In this study, we investigate using lentinan-functionalized selenium nanoparticles (LET-SeNPs) for the treatment of prostate cancer (PCa). We used assays to demonstrate that a combination of LET-SeNPs and zoledronic acid (ZOL) can reduce PCa cell viability in vitro. Stability and hemocompatibility assays were used to determine the safety of the combination of LET-SeNPs and ZOL. The localization of LET-SeNPs was confirmed using fluorescence microscopy. JC-1 was used to measure the mitochondrial membrane potential, while the cellular uptake, cell cycle and apoptosis were evaluated by flow cytometry. Finally, cell migration and invasion assays were used to evaluate the effects of the combination treatment on cell migration and invasion. Under optimized conditions, we found that LET-SeNPs has good stability. The combination of LET-SeNPs and ZOL can effectively inhibit metastatic PCa cells in a concentration-dependent manner, as evidenced by cytotoxicity testing, flow cytometric analysis, and mitochondria functional test. The enhanced anti-cancer effect of LET-SeNPs and ZOL may be related to the regulation of BCL2 family proteins that could result in the release of cytochrome C from the inner membranes of mitochondria into the cytosol, accompanied by induction of cell cycle arrest at the S phase, leading to irreversible DNA damage and killing of PCa cells. Collectively, the results of this study suggest that the combination of SeNPs and ZOL can successfully inhibit the growth of PCa cells.