bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Performance of Satellite-Based Precipitation Products in Simulating Streamflow and Water Quality During Hydrometeorological Extremes
Authors: Solakian Jennifer , Maggioni Viviana , Godrej Adil N.
Published: January 2021

This study provides a comprehensive evaluation of streamflow and water quality simulated by a hydrological model using three different Satellite Precipitation Products (SPPs) with respect to observations from a dense rain gauge network over the Occoquan Watershed, located in Northern Virginia, suburbs to Washington, D.C., U.S. Eight extreme hydrometeorological events within a 5-year period between 2008 and 2012 are evaluated using SPPs, TMPA 3B42-V7, CMORPH V1. 0, and PERSIANN-CCS, which are based on different retrieval algorithms with varying native spatial and temporal resolutions. A Hydrologic Simulation Program FORTRAN (HSPF) hydrology and water quality model was forced with the three SPPs to simulate output of streamflow (Q), stream temperature (TW), and concentrations of total suspended solids (TSS), orthophosphate phosphorus (OP), total phosphorus (TP), ammonium-nitrate (NH4-N), nitrate-nitrogen (NO3-N), dissolved oxygen (DO), and biochemical oxygen demand (BOD) at six evaluation points within the watershed. Results indicate fairly good agreement between gauge- and SPP-simulated Q for TMPA and CMORPH, however, PERSIANN-simulated Q is lowest among SPPs, due to its inability to accurately measure stratiform precipitation between intense periods of precipitation during an extreme event. Correlations of water quality indicators vary considerably, however, TW has the strongest positive linear relationship compared to other indicators evaluated in this study. SPP-simulated TSS, a flow-dependent variable, has the weakest relationship to gauge-simulated TSS among all water quality indicators, with CMORPH performing slightly better than TMPA and PERSIANN. This study demonstrated that the spatiotemporal variability of SPPs, along with their algorithms to estimate precipitation, have an influence on water quality simulations during extreme hydrometeorological events.
Genome-Wide Histone Modifications and CTCF Enrichment Predict Gene Expression in Sheep Macrophages
Authors: Massa Alisha T. , Mousel Michelle R. , Herndon Maria K. , Herndon David R. , Murdoch Brenda M. , White Stephen N.
Published: January 2021

Alveolar macrophages function in innate and adaptive immunity, wound healing, and homeostasis in the lungs dependent on tissue-specific gene expression under epigenetic regulation. The functional diversity of tissue resident macrophages, despite their common myeloid lineage, highlights the need to study tissue-specific regulatory elements that control gene expression. Increasing evidence supports the hypothesis that subtle genetic changes alter sheep macrophage response to important production pathogens and zoonoses, for example, viruses like small ruminant lentiviruses and bacteria like Coxiella burnetii. Annotation of transcriptional regulatory elements will aid researchers in identifying genetic mutations of immunological consequence. Here we report the first genome-wide survey of regulatory elements in any sheep immune cell, utilizing alveolar macrophages. We assayed histone modifications and CTCF enrichment by chromatin immunoprecipitation with deep sequencing (ChIP-seq) in two sheep to determine cis-regulatory DNA elements and chromatin domain boundaries that control immunity-related gene expression. Histone modifications included H3K4me3 (denoting active promoters), H3K27ac (active enhancers), H3K4me1 (primed and distal enhancers), and H3K27me3 (broad silencers). In total, we identified 248,674 reproducible regulatory elements, which allowed assignment of putative biological function in macrophages to 12% of the sheep genome. Data exceeded the FAANG and ENCODE standards of 20 million and 45 million useable fragments for narrow and broad marks, respectively. Active elements showed consensus with RNA-seq data and were predictive of gene expression in alveolar macrophages from the publicly available Sheep Gene Expression Atlas. Silencer elements were not enriched for expressed genes, but rather for repressed developmental genes. CTCF enrichment enabled identification of 11,000 chromatin domains with mean size of 258 kb. To our knowledge, this is the first report to use immunoprecipitated CTCF to determine putative topological domains in sheep immune cells. Furthermore, these data will empower phenotype-associated mutation discovery since most causal variants are within regulatory elements.
Cytokines in CAR T Cell–Associated Neurotoxicity
Authors: Gust Juliane , Ponce Rafael , Liles W. Conrad , Garden Gwenn A. , Turtle Cameron J.
Published: January 2021

Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell–associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.
Genetic Modification of Tumor-Infiltrating Lymphocytes via Retroviral Transduction
Authors: Weinstein-Marom Hadas , Gross Gideon , Levi Michal , Brayer Hadar , Schachter Jacob , Itzhaki Orit , Besser Michal J.
Published: January 2021

Adoptive T cell therapy (ACT) holds great promise for cancer treatment. One approach, which has regained wide interest in recent years, employs antitumor T cells isolated from tumor lesions (“tumor-infiltrating lymphocytes” or TIL). It is now appreciated that a considerable proportion of anti-melanoma TIL recognize new HLA-binding peptides resulting from somatic mutations, which occurred during tumor progression. The clinical efficacy of TIL can potentially be improved via their genetic modification, designed to enhance their survival, homing capacity, resistance to suppression, tumor killing ability and additional properties of clinical relevance. Successful implementation of such gene-based strategies critically depends on efficient and reproducible protocols for gene delivery into clinical TIL preparations. Here we describe an optimized protocol for the retroviral transduction of TIL. As the experimental system we employed anti-melanoma TIL cultures prepared from four patients, recombinant retrovirus encoding an anti-CD19 chimeric antigen receptor (CAR) as a model gene of interest and CD19+ and CD19- human cell lines serving as target cells. Transduction on day 7 of the rapid expansion protocol (REP) resulted in 69 ± 8% CAR positive TIL. Transduced, but not untransduced TIL, from the four patients responded robustly to CD19+, but not CD19- cell lines, as judged by substantial secretion of IFN-γ following co-culture. In light of the rekindled interest in antitumor TIL, this protocol can be incorporated into a broad range of gene-based approaches for improving the in-vivo survival and functionality of TIL in the clinical setting.
Decreased Type I Interferon Production by Plasmacytoid Dendritic Cells Contributes to Severe Dengue
Authors: Upasani Vinit , Scagnolari Carolina , Frasca Federica , Smith Nikaïa , Bondet Vincent , Vanderlinden Axelle , Lay Sokchea , Auerswald Heidi , Heng Sothy , Laurent Denis , Ly Sowath , Duong Veasna , Antonelli Guido , Dussart Philippe , Duffy Darragh , Cantaert Tineke
Published: January 2021

The clinical presentation of dengue virus (DENV) infection is variable. Severe complications mainly result from exacerbated immune responses. Type I interferons (IFN-I) are important in antiviral responses and form a crucial link between innate and adaptive immunity. Their contribution to host defense during DENV infection remains under-studied, as direct quantification of IFN-I is challenging. We combined ultra-sensitive single-molecule array (Simoa) digital ELISA with IFN-I gene expression to elucidate the role of IFN-I in a well-characterized cohort of hospitalized Cambodian children undergoing acute DENV infection. Higher concentrations of type I IFN proteins were observed in blood of DENV patients, compared to healthy donors, and correlated with viral load. Stratifying patients for disease severity, we found a decreased expression of IFN-I in patients with a more severe clinical outcome, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). This was seen in parallel to a correlation between low IFNα protein concentrations and decreased platelet counts. Type I IFNs concentrations were correlated to frequencies of plasmacytoid DCs, not DENV-infected myloid DCs and correlated inversely with neutralizing anti-DENV antibody titers. Hence, type I IFN produced in the acute phase of infection is associated with less severe outcome of dengue disease.
Current Preventions and Treatments of aGVHD: From Pharmacological Prophylaxis to Innovative Therapies
Authors: Naserian Sina , Leclerc Mathieu , Shamdani Sara , Uzan Georges
Published: January 2021

Graft versus host disease (GVHD) is one of the main causes of mortality and the reason for up to 50% of morbidity after hematopoietic stem cell transplantations (HSCT) which is the treatment of choice for many blood malignancies. Thanks to years of research and exploration, we have acquired a profound understanding of the pathophysiology and immunopathology of these disorders. This led to the proposition and development of many therapeutic approaches during the last decades, some of them with very promising results. In this review, we have focused on the recent GVHD treatments from classical chemical and pharmacological prophylaxis to more innovative treatments including gene therapy and cell therapy, most commonly based on the application of a variety of immunomodulatory cells. Furthermore, we have discussed the advantages and potentials of cell-free therapy as a newly emerging approach to treat GVHD. Among them, we have particularly focused on the implication of the TNFα-TNFR2 axis as a new immune checkpoint signaling pathway controlling different aspects of many immunoregulatory cells.
Infusion of Host-Derived Unlicensed NK Cells Improves Donor Engraftment in Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation
Authors: Alvarez Maite , Pierini Antonio , Simonetta Federico , Baker Jeanette , Maas-Bauer Kristina , Hirai Toshihito , Negrin Robert S.
Published: January 2021

Allogeneic hematopoietic cell transplantation (allo-HCT) is an efficacious and frequently the only treatment option for some hematological malignances. However, it often faces severe morbidities and/or mortalities due to graft versus host disease, and the severity of the conditioning regiment needed, that result in toxicity-related issues poorly tolerable for some patients. These shortcomings have led to the development of less aggressive alternatives like non-myeloablative (NMAC) or reduced-intensity conditioning regiments (RIC). However, these approaches tend to have an increase of cancer relapse and limited persistence of donor-specific chimerism. Thus, strategies that lead towards an accelerated and more durable donor engraftment are still needed. Here, we took advantage of the ability of host-derived unlicensed NK (UnLicNK) cells to favor donor cell engraftment during myeloablative allo-HCT, and evaluated if the adoptive transfer of this cell type can improve donor chimerism in NAMC settings. Indeed, the infusion of these cells significantly increased mixed chimerism in a sublethal allo-HCT mouse model, resulting in a more sustainable donor cell engraftment when compared to the administration of licensed NK cells or HCT controls. We observed an overall increase in the total number and proportion of donor B, NK and myeloid cells after UnLicNK cell infusion. Additionally, the extension and durability of donor chimerism was similar to the one obtained after the tolerogenic Tregs infusion. These results serve as the needed bases for the implementation of the adoptive transfer of UnLicNK cells to upgrade NMAC protocols and enhance allogeneic engraftment during HCT.
Stony Coral Tissue Loss Disease in Florida Is Associated With Disruption of Host–Zooxanthellae Physiology
Authors: Landsberg Jan H. , Kiryu Yasunari , Peters Esther C. , Wilson Patrick W. , Perry Noretta , Waters Yvonne , Maxwell Kerry E. , Huebner Lindsay K. , Work Thierry M.
Published: January 2021

Samples from eight species of corals (Colpophyllia natans, Dendrogyra cylindrus, Diploria labyrinthiformis, Meandrina meandrites, Montastraea cavernosa, Orbicella faveolata, Pseudodiploria strigosa, and Siderastrea siderea) that exhibited gross clinical signs of acute, subacute, or chronic tissue loss attributed to stony coral tissue loss disease (SCTLD) were collected from the Florida Reef Tract during 2016–2018 and examined histopathologically. The hallmark microscopic lesion seen in all eight species was focal to multifocal lytic necrosis (LN) originating in the gastrodermis of the basal body wall (BBW) and extending to the calicodermis, with more advanced lesions involving the surface body wall. This was accompanied by other degenerative changes in host cells such as mucocyte hypertrophy, degradation and fragmentation of gastrodermal architecture, and disintegration of the mesoglea. Zooxanthellae manifested various changes including necrosis (cytoplasmic hypereosinophilia, pyknosis); peripheral nuclear chromatin condensation; cytoplasmic vacuolation accompanied by deformation, swelling, or atrophy; swollen accumulation bodies; prominent pyrenoids; and degraded chloroplasts. Polyhedral intracytoplasmic eosinophilic periodic acid–Schiff-positive crystalline inclusion bodies (∼1–10 μm in length) were seen only in M. cavernosa and P. strigosa BBW gastrodermis in or adjacent to active lesions and some unaffected areas (without surface lesions) of diseased colonies. Coccoidlike or coccobacilloidlike structures (Gram-neutral) reminiscent of microorganisms were occasionally associated with LN lesions or seen in apparently healthy tissue of diseased colonies along with various parasites and other bacteria all considered likely secondary colonizers. Of the 82 samples showing gross lesions of SCTLD, 71 (87%) were confirmed histologically to have LN. Collectively, pathology indicates that SCTLD is the result of a disruption of host–symbiont physiology with lesions originating in the BBW leading to detachment and sloughing of tissues from the skeleton. Future investigations could focus on identifying the cause and pathogenesis of this process.
Genomic and Phenotypic Insights Into the Potential of Rock Phosphate Solubilizing Bacteria to Promote Millet Growth in vivo
Authors: Silva Ubiana C. , Cuadros-Orellana Sara , Silva Daliane R. C. , Freitas-Júnior Luiz F. , Fernandes Ana C. , Leite Laura R. , Oliveira Christiane A. , Dos Santos Vera L.
Published: January 2021

Rock phosphate (RP) is a natural source of phosphorus for agriculture, with the advantage of lower cost and less impact on the environment when compared to synthetic fertilizers. However, the release of phosphorus (P) from RP occurs slowly, which may limit its short-term availability to crops. Hence, the use of P-solubilizing microorganisms to improve the availability of P from this P source is an interesting approach, as microorganisms often perform other functions that assist plant growth, besides solubilizing P. Here, we describe the characterization of 101 bacterial isolates obtained from the rhizosphere and endosphere of maize plants for their P solubilizing activity in vitro, their growth-promoting activity on millet plants cultivated in soil amended with RP, and their gene content especially associated with phosphate solubilization. For the in vitro solubilization assays, two mineral P sources were used: rock phosphate from Araxá (Brazil) mine (AP) and iron phosphate (Fe-P). The amounts of P released from Fe–P in the solubilization assays were lower than those released from AP, and the endophytic bacteria outperformed the rhizospheric ones in the solubilization of both P sources. Six selected strains were evaluated for their ability to promote the growth of millet in soil fertilized with a commercial rock phosphate (cRP). Two of them, namely Bacillus megaterium UFMG50 and Ochrobactrum pseudogrignonense CNPMS2088, performed better than the others in the cRP assays, improving at least six physiological traits of millet or P content in the soil. Genomic analysis of these bacteria revealed the presence of genes related to P uptake and metabolism, and to organic acid synthesis. Using this approach, we identified six potential candidates as bioinoculants, which are promising for use under field conditions, as they have both the genetic potential and the experimentally demonstrated in vivo ability to improve rock phosphate solubilization and promote plant growth.
Wine Terroir and the Soil Bacteria: An Amplicon Sequencing–Based Assessment of the Barossa Valley and Its Sub-Regions
Authors: Zhou Jia , Cavagnaro Timothy R. , De Bei Roberta , Nelson Tiffanie M. , Stephen John R. , Metcalfe Andrew , Gilliham Matthew , Breen James , Collins Cassandra , López Carlos M. Rodríguez
Published: January 2021

A wines’ terroir, represented as wine traits with regional distinctiveness, is a reflection of both the biophysical and human-driven conditions in which the grapes were grown and wine made. Soil is an important factor contributing to the uniqueness of a wine produced by vines grown in specific conditions. Here, we evaluated the impact of environmental variables on the soil bacteria of 22 Barossa Valley vineyard sites based on the 16S rRNA gene hypervariable region 4. In this study, we report that both dispersal isolation by geographic distance and environmental heterogeneity (soil plant-available P content, elevation, rainfall, temperature, spacing between row and spacing between vine) contribute to microbial community dissimilarity between vineyards. Vineyards located in cooler and wetter regions showed lower beta diversity and a higher ratio of dominant taxa. Differences in soil bacterial community composition were significantly associated with differences in fruit and wine composition. Our results suggest that environmental factors affecting wine terroir, may be mediated by changes in microbial structure, thus providing a basic understanding of how growing conditions affect interactions between plants and their soil bacteria.
Effect of Temperature on Acetate Mineralization Kinetics and Microbial Community Composition in a Hydrocarbon-Affected Microbial Community During a Shift From Oxic to Sulfidogenic Conditions
Authors: Bin Hudari Mohammad Sufian , Vogt Carsten , Richnow Hans Hermann
Published: January 2021

Aquifer thermal energy storage (ATES) allows for the seasonal storage and extraction of heat in the subsurface thus reducing reliance on fossil fuels and supporting decarbonization of the heating and cooling sector. However, the impacts of higher temperatures toward biodiversity and ecosystem services in the subsurface environment remain unclear. Here, we conducted a laboratory microcosm study comprising a hydrocarbon-degrading microbial community from a sulfidic hydrocarbon-contaminated aquifer spiked with 13C-labeled acetate and incubated at temperatures between 12 and 80°C to evaluate (i) the extent and rates of acetate mineralization and (ii) the resultant temperature-induced shifts in the microbial community structure. We observed biphasic mineralization curves at 12, 25, 38, and 45°C, arising from immediate and fast aerobic mineralization due to an initial oxygen exposure, followed by slower mineralization at sulfidogenic conditions. At 60°C and several replicates at 45°C, acetate was only aerobically mineralized. At 80°C, no mineralization was observed within 178 days. Rates of acetate mineralization coupled to sulfate reduction at 25 and 38°C were six times faster than at 12°C. Distinct microbial communities developed in oxic and strictly anoxic phases of mineralization as well as at different temperatures. Members of the Alphaproteobacteria were dominant in the oxic mineralization phase at 12–38°C, succeeded by a more diverse community in the anoxic phase composed of Deltaproteobacteria, Clostridia, Spirochaetia, Gammaproteobacteria and Anaerolinea, with varying abundances dependent on the temperature. In the oxic phases at 45 and 60°C, phylotypes affiliated to spore-forming Bacilli developed. In conclusion, temperatures up to 38°C allowed aerobic and anaerobic acetate mineralization albeit at varying rates, while mineralization occurred mainly aerobically between 45 and 60°C; thermophilic sulfate reducers being active at temperatures > 45°C were not detected. Hence, temperature may affect dissolved organic carbon mineralization rates in ATES while the variability in the microbial community composition during the transition from micro-oxic to sulfidogenic conditions highlights the crucial role of electron acceptor availability when combining ATES with bioremediation.
Culturing of “Unculturable” Subsurface Microbes: Natural Organic Carbon Source Fuels the Growth of Diverse and Distinct Bacteria From Groundwater
Authors: Wu Xiaoqin , Spencer Sarah , Gushgari-Doyle Sara , Yee Mon Oo , Voriskova Jana , Li Yifan , Alm Eric J. , Chakraborty Romy
Published: January 2021

Recovery and cultivation of diverse environmentally-relevant microorganisms from the terrestrial subsurface remain a challenge despite recent advances in modern molecular technology. Here, we applied complex carbon (C) sources, i.e., sediment dissolved organic matter (DOM) and bacterial cell lysate, to enrich groundwater microbial communities for 30 days. As comparisons, we also included enrichments amended with simple C sources including glucose, acetate, benzoate, oleic acid, cellulose, and mixed vitamins. Our results demonstrate that complex C is far more effective in enriching diverse and distinct microorganisms from groundwater than simple C. Simple C enrichments yield significantly lower biodiversity, and are dominated by few phyla (e.g., Proteobacteria and Bacteroidetes), while microcosms enriched with complex C demonstrate significantly higher biodiversity including phyla that are poorly represented in published culture collections (e.g., Verrucomicrobia, Planctomycetes, and Armatimonadetes). Subsequent isolation from complex C enrichments yielded 228 bacterial isolates representing five phyla, 17 orders, and 56 distinct species, including candidate novel, rarely cultivated, and undescribed organisms. Results from this study will substantially advance cultivation and isolation strategies for recovering diverse and novel subsurface microorganisms. Obtaining axenic representatives of “once-unculturable” microorganisms will enhance our understanding of microbial physiology and function in different biogeochemical niches of terrestrial subsurface ecosystems.
Biocontrol Potential of Grapevine Endophytic and Rhizospheric Fungi Against Trunk Pathogens
Authors: Silva-Valderrama Isidora , Toapanta Diana , Miccono Maria de los Angeles , Lolas Mauricio , Díaz Gonzalo A. , Cantu Dario , Castro Alvaro
Published: January 2021

Grapevine Trunk Diseases (GTDs) are a major challenge to the grape industry worldwide. GTDs are responsible for considerable loss of quality, production, and vineyard longevity. Seventy-five percent of Chilean vineyards are estimated to be affected by GTDs. GTDs are complex diseases caused by several fungi species, including members of the Botryosphaeriaceae family andPhaeomoniella chlamydospora, considered some of the most important causal agents for these diseases in Chile. In this study, we isolated 169 endophytic and 209 rhizospheric fungi from grapevines grown under organic and conventional farming in Chile. Multiple isolates ofChaetomiumsp.,Cladosporiumsp.,Clonostachys rosea, Epicoccum nigrum, Purpureocillium lilacinum, andTrichodermasp. were evaluated for their potential of biocontrol activity againstDiplodia seriata,Neofusicoccum parvum, andPa. chlamydospora.Tests of antagonism were carried out using two dual-culture-plate methods with multiple media types, including agar containing grapevine wood extract to simulatein plantanutrient conditions. Significant pathogen growth inhibition was observed by all isolates tested.Clonostachys roseashowed 98.2% inhibition of all pathogens in the presence of grapevine wood extract. We observed 100% pathogen growth inhibition when autoclaved lignified grapevine shoots were pre-inoculated with eitherC. roseastrains orTrichodermasp. Overall, these results show thatC. roseastrains isolated from grapevines are promising biocontrol agents against GTDs.
Investigating the Impact of the Missing Significant Objects in Scene Recognition Using Multivariate Pattern Analysis
Authors: Gu Jin , Liu Baolin , Yan Weiran , Miao Qiaomu , Wei Jianguo
Published: January 2021

Significant objects in a scene can make a great contribution to scene recognition. Besides the three scene-selective regions: parahippocampal place area (PPA), retrosplenial complex (RSC), and occipital place area (OPA), some neuroimaging studies have shown that the lateral occipital complex (LOC) is also engaged in scene recognition processing. In this study, the multivariate pattern analysis was adopted to explore the object-scene association in scene recognition when different amounts of significant objects were masked. The scene classification only succeeded in the intact scene in the ROIs. In addition, the average signal intensity in LOC [including the lateral occipital cortex (LO) and the posterior fusiform area (pF)] decreased when there were masked objects, but such a decrease was not observed in scene-selective regions. These results suggested that LOC was sensitive to the loss of significant objects and mainly involved in scene recognition by the object-scene semantic association. The performance of the scene-selective areas may be mainly due to the fact that they responded to the change of the scene's entire attribute, such as the spatial information, when they were employed in the scene recognition processing. These findings further enrich our knowledge of the significant objects' influence on the activation pattern during the process of scene recognition.
Comorbidity Between Math and Reading Problems: Is Phonological Processing a Mutual Factor?
Authors: Amland Tonje , Lervåg Arne , Melby-Lervåg Monica
Published: January 2021

There is a relationship between reading and math skills, as well as comorbidity between reading and math disorders. A mutual foundation for this comorbidity could be that the quality of phonological representations is important for both early reading and arithmetic. In this study, we examine this hypothesis in a sample traced longitudinally from preschool to first grade (N = 259). The results show that phonological awareness does not explain development in arithmetic, but that there is an indirect effect between phoneme awareness in preschool and arithmetic in first grade via phoneme awareness in first grade. This effect is, however, weak and restricted to verbal arithmetic and not arithmetic fluency. This finding is only partly in line with other studies, and a reason could be that this study more strongly controls for confounders and previous skills than other studies.
Monitoring of Heart Rate and Activity Using Telemetry Allows Grading of Experimental Procedures Used in Neuroscientific Rat Models
Authors: Wassermann Laura , Helgers Simeon O. A. , Riedesel Ann-Kristin , Talbot Steven R. , Bleich André , Schwabe Kerstin , Häger Christine
Published: January 2021

In animal experimentation, welfare and severity assessments of all procedures applied to animals are necessary to meet legal and ethical requirements, as well as public interests. So far, the methods suggested for this purpose are time consuming and personnel intensive. Also, evidence-based biostatistical methods for this purpose are still rare. We here tested whether the classification of heart rate (HR) and activity (Act) data monitored by telemetry in the home cage by unsupervised k-means-based class-labeling and subsequent Support Vector Machine (SVM) analysis allows severity assessment and grading of experimental procedures of different domains, including surgery, injection, behavioral testing, and routine handling for maintenance. Telemetric devices were subcutaneously implanted in young adult male Crl:CD(SD) and BDIX/UImHanZtm rats. After recovery, rats were randomly subjected to different experimental procedures, i.e., handling and cage change as routine maintenance, Rat Grimace Scale, burrowing, and social interaction for welfare assessment, as well as repeated subcutaneous injections. Thereafter, rats were either intracranially implanted with electrodes or injected with tumor cells. Directly after each procedure, HR and Act were monitored by telemetry in the home cage for 4 h. Application of k-means and SVM algorithms on the obtained data sets from baseline (as no stress), cage change (exploratory Act), and intracranial surgery (as burden) measurements computed three classes described as low HR/low Act, high HR/high Act, and high HR/low Act, respectively. Validation of the SVM model by entering data from all procedures confirmed the allocation to the high HR/low Act class (burden) after surgery, which lasted longer after subcutaneous transmitter implantation than after intracranial surgery. The majority of data points from repeated injections, behavioral testing, and maintenance handling were allocated to the low HR/low Act and high HR/high Act classes. Overall, the SVM model based on HR and Act data monitored in home cage after procedures may be useful for the classification and grading of experimental procedures of different domains.
Somatotopic Arrangement of the Human Primary Somatosensory Cortex Derived From Functional Magnetic Resonance Imaging
Authors: Willoughby W. R. , Thoenes Kristina , Bolding Mark
Published: January 2021

Functional magnetic resonance imaging (fMRI) was used to estimate neuronal activity in the primary somatosensory cortex of six participants undergoing cutaneous tactile stimulation on skin areas spread across the entire body. Differences between the accepted somatotopic maps derived from Penfield's work and those generated by this fMRI study were sought, including representational transpositions or replications across the cortex. MR-safe pneumatic devices mimicking the action of a Wartenberg wheel supplied touch stimuli in eight areas. Seven were on the left side of the body: foot, lower, and upper leg, trunk beneath ribcage, anterior forearm, middle fingertip, and neck above the collarbone. The eighth area was the glabella. Activation magnitude was estimated as the maximum cross-correlation coefficient at a certain phase shift between ideal time series and measured blood oxygen level dependent (BOLD) time courses on the cortical surface. Maximally correlated clusters associated with each cutaneous area were calculated, and cortical magnification factors were estimated. Activity correlated to lower limb stimulation was observed in the paracentral lobule and superomedial postcentral region. Correlations to upper extremity stimulation were observed in the postcentral area adjacent to the motor hand knob. Activity correlated to trunk, face and neck stimulation was localized in the superomedial one-third of the postcentral region, which differed from Penfield's cortical homunculus.
Challenging the Integrity of Rhythmic Maternal Signals Revealed Gene-Specific Responses in the Fetal Suprachiasmatic Nuclei
Authors: Lužná Vendula , Houdek Pavel , Liška Karolína , Sumová Alena
Published: January 2021

During fetal stage, maternal circadian system sets the phase of the developing clock in the suprachiasmatic nuclei (SCN) via complex pathways. We addressed the issue of how impaired maternal signaling due to a disturbed environmental light/dark (LD) cycle affects the fetal SCN. We exposed pregnant Wistar rats to two different challenges – a 6-h phase shift in the LD cycle on gestational day 14, or exposure to constant light (LL) throughout pregnancy – and detected the impact on gene expression profiles in 19-day-old fetuses. The LD phase shift, which changed the maternal SCN into a transient state, caused robust downregulation of expression profiles of clock genes (Per1, Per2, and Nr1d1), clock-controlled (Dbp) genes, as well as genes involved in sensing various signals, such as c-fos and Nr3c1. Removal of the rhythmic maternal signals via exposure of pregnant rats to LL abolished the rhythms in expression of c-fos and Nr3c1 in the fetal SCN. We identified c-fos as the gene primarily responsible for sensing rhythmic maternal signals because its expression profile tracked the shifted or arrhythmic maternal SCN clock. Pathways related to the maternal rhythmic behavioral state were likely not involved in driving the c-fos expression rhythm. Instead, introduction of a behavioral rhythm to LL-exposed mothers via restricted feeding regime strengthened rhythm in Vip expression in the fetal SCN. Our results revealed for the first time that the fetal SCN is highly sensitive in a gene-specific manner to various changes in maternal signaling due to disturbances of environmental cycles related to the modern lifestyle in humans.
Targeting Tumor-Associated Macrophages in the Pediatric Sarcoma Tumor Microenvironment
Authors: Koo Jane , Hayashi Masanori , Verneris Michael R. , Lee-Sherick Alisa B.
Published: January 2021

For many pediatric sarcoma patients, multi-modal therapy including chemotherapy, radiation, and surgery is sufficient to cure their disease. However, event-free and overall survival rates for patients with more advanced disease are grim, necessitating the development of novel therapeutic approaches. Within many pediatric sarcomas, the normal immune response, including recognition and destruction of cancer cells, is lost due to the highly immune suppressive tumor microenvironment (TME). In this setting, tumor cells evade immune detection and capitalize on the immune suppressed microenvironment, leading to unchecked proliferation and metastasis. Recent preclinical and clinical approaches are aimed at understanding this immune suppressive microenvironment and employing cancer immunotherapy in an attempt to overcome this, by renewing the ability of the immune system to recognize and destroy cancer cells. While there are several factors that drive the attenuation of immune responses in the sarcoma TME, one of the most remarkable are tumor associated macrophage (TAMs). TAMs suppress immune cytolytic function, promote tumor growth and metastases, and are generally associated with a poor prognosis in most pediatric sarcoma subtypes. In this review, we summarize the mechanisms underlying TAM-facilitated immune evasion and tumorigenesis and discuss the potential therapeutic application of TAM-focused drugs in the treatment of pediatric sarcomas.
Long-Term Survival in Nonsurgical Esophageal Cancer Patients Who Received Consolidation Chemotherapy Compared With Patients Who Received Concurrent Chemoradiotherapy Alone: A Systematic Review and Meta-Analysis
Authors: Xia Xiaojie , Liu Zeyuan , Qin Qin , Di Xiaoke , Zhang Zhaoyue , Sun Xinchen , Ge Xiaolin
Published: January 2021

Background

Concurrent chemoradiotherapy (CCRT) is the standard treatment for nonsurgical esophageal cancer (EC). However, esophageal cancer patients receiving CCRT alone are still unsatisfactory in terms of local control and overall survival (OS) benefit. Clinicians generally add consolidation chemotherapy (CCT) after CCRT. It remains controversial whether CCT following CCRT is beneficial for esophageal cancer. We, therefore, undertook a meta-analysis to assess the need for CCT in inoperable esophageal cancer.

Materials and Methods

We combed PubMed, Embase, Cochrane Library, Web of Science, and CNKI for relevant published articles up to July 2020 that compared CCRT plus CCT to CCRT alone for patients with nonsurgical EC. Our primary endpoint was OS and progression-free survival (PFS), and the secondary endpoint was treatment toxicity. We analyzed the hazard ratio (HR) to estimate the time-to-event data and the odds ratio (OR) to compare the treatment-related effect. To assess heterogeneity, we performed the I2 test and examined publication bias using funnel plots analysis.

Results

The 11 retrospective studies involved 2008 patients. Of these 2008 patients, 1018 received CCRT plus CCT, and 990 received CCRT. Compared to CCRT alone, CCT after CCRT did not improve disease control rate (DCR) (OR 1.66; 95% CI 0.53–5.15, p=0.384) and objective response rate (ORR) (OR 1.44; 95% CI 0.62–3.35, p=0.393). However, OS (HR 0.72; 95% CI 0.59–0.86, p < 0.001) and PFS (HR 0.61; 95% CI 0.44–0.84, p=0.003) did increase. Our results show that CCT plus CCRT had a clear survival advantage over CCRT alone. The risk of treatment toxicity did not increase for EC patients who received CCT.

Conclusion

CCT after CCRT significantly increases OS and PFS in patients with nonsurgical EC and could provide them remarkable survival benefits. The results provide an evidence-based framework for the use of CCT after CCRT.
A Novel Ex Vivo Model of Aortic Valve Calcification. A Preliminary Report
Authors: Zabirnyk Arsenii , Perez Maria del Mar , Blasco Marc , Stensløkken Kåre-Olav , Ferrer Miguel D. , Salcedo Carolina , Vaage Jarle
Published: January 2021

Background: No pharmacological treatment exists to prevent or stop the calcification process of aortic valves causing aortic stenosis. The aim of this study was to develop a robust model of induced calcification in whole aortic valve leaflets which could be suitable for studies of the basic mechanisms and for testing potentially inhibitory drugs.

Methods: Pig hearts were obtained from a commercial abattoir. The aortic valve leaflets were dissected free and randomized between experimental groups. Whole leaflets were cultured in individual wells. Two growth media were used for cultivation: standard growth medium and an antimyofibroblastic growth medium. The latter was employed to inhibit contraction of the leaflet into a ball-like structure. Calcification was induced in the growth medium by supplementation with an osteogenic medium. Leaflets were cultivated for four weeks and medium was changed every third day. To block calcification, the inhibitor SNF472 (a formulation of the hexasodium salt of myo-inositol hexaphosphate hexasodium salt) was used at concentrations between 1 and 100 µM. After cultivation for four weeks the leaflets were snap frozen in liquid nitrogen and kept at −80 °C until blind assessment of the calcium amount in leaflets by inductively coupled plasma optical emission spectroscopy. For statistical analysis, a Kruskal–Wallis test with Dunn’s post-test was applied.

Results: Osteodifferentiation with calcium accumulation was in principle absent when standard medium was used. However, when the antimyofibroblastic medium was used, a strong calcium accumulation was induced (p = 0.006 compared to controls), and this was blocked in a dose-dependent manner by the calcification inhibitor SNF472 (p = 0.008), with an EC50 of 3.3 µM.

Conclusion: A model of experimentally induced calcification in cultured whole leaflets from porcine aortic valves was developed. This model can be useful for studying the basic mechanisms of valve calcification and to test pharmacological approaches to inhibit calcification.
Metastasis Initiation Precedes Detection of Primary Cancer—Analysis of Metastasis Growth in vivo in a Colorectal Cancer Test Case
Authors: Hochman Gili , Shacham-Shmueli Einat , Raskin Stephen P. , Rosenbaum Sara , Bunimovich-Mendrazitsky Svetlana
Published: January 2021

Most cases of deaths from colorectal cancer (CRC) result from metastases, which are often still undetectable at disease detection time. Even so, in many cases, shedding is assumed to have taken place before that time. The dynamics of metastasis formation and growth are not well-established. This work aims to explore CRC lung metastasis growth rate and dynamics. We analyzed a test case of a metastatic CRC patient with four lung metastases, with data of four serial computed tomography (CT) scans measuring metastasis sizes while untreated. We fitted three mathematical growth models—exponential, logistic, and Gompertzian—to the CT measurements. For each metastasis, a best-fitted model was determined, tumor doubling time (TDT) was assessed, and metastasis inception time was extrapolated. Three of the metastases showed exponential growth, while the fourth showed logistic restraint of the growth. TDT was around 93 days. Predicted metastasis inception time was at least 4–5 years before the primary tumor diagnosis date, though they did not reach detectable sizes until at least 1 year after primary tumor resection. Our results support the exponential growth approximation for most of the metastases, at least for the clinically observed time period. Our analysis shows that metastases can be initiated before the primary tumor is detectable and implies that surgeries accelerate metastasis growth.
Unique Members of the Adipokinetic Hormone Family in Butterflies and Moths (Insecta, Lepidoptera)
Authors: Marco Heather G. , Šimek Petr , Gäde Gerd
Published: January 2021

Lepidoptera is amongst one of the four most speciose insect orders and ecologically very successful because of their ability to fly. Insect flight is always aerobic and exacts a high metabolic demand on the animal. A family of structurally related neuropeptides, generically referred to as adipokinetic hormones (AKHs), play a key role in triggering the release of readily utilizable fuel metabolites into the hemolymph from the storage forms in the fat body. We used mass spectrometry to elucidate AKH sequences from 34 species of Lepidoptera and searched the literature and publicly available databases to compile (in a phylogenetic context) a comprehensive list of all Lepidoptera sequences published/predicted from a total of 76 species. We then used the resulting set of 15 biochemically characterized AKHs in a physiological assay that measures lipid or carbohydrate mobilization in three different lepidopteran species to learn about the functional cross-activity (receptor-ligand interactions) amongst the different butterfly/moth families. Our results include novel peptide structures, demonstrate structural diversity, phylogenetic trends in peptide distribution and order-specificity of Lepidoptera AKHs. There is almost an equal occurrence of octa-, nona-, and decapeptides, with an unparalleled emphasis on nonapeptides than in any insect order. Primitive species make Peram-CAH-II, an octapeptide found also in other orders; the lepidopteran signature peptide is Manse-AKH. Not all of the 15 tested AKHs are active inPieris brassicae; this provides insight into structure-activity specificity and could be useful for further investigations into possible biorational insecticide development.
AMPK/mTOR Signaling in Autophagy Regulation During Cisplatin-Induced Acute Kidney Injury
Authors: Wang Ying , Liu Zhiwen , Shu Shaoqun , Cai Juan , Tang Chengyuan , Dong Zheng
Published: January 2021

Autophagy is a conserved, multistep pathway that degrades and recycles dysfunctional organelles and macromolecules to maintain cellular homeostasis. Mammalian target of rapamycin (mTOR) and adenosine-monophosphate activated-protein kinase (AMPK) are major negative and positive regulators of autophagy, respectively. In cisplatin-induced acute kidney injury (AKI) or nephrotoxicity, autophagy is rapidly induced in renal tubular epithelial cells and acts as a cytoprotective mechanism for cell survival. Both mTOR and AMPK have been implicated in the regulation of autophagy in cisplatin-induced AKI. Targeting mTOR and/or AMPK may offer effective strategies for kidney protection during cisplatin-mediated chemotherapy.
Spatial Models With Inter-Tree Competition From Airborne Laser Scanning Improve Estimates of Genetic Variance
Authors: Pont David , Dungey Heidi S. , Suontama Mari , Stovold Grahame T.
Published: January 2021

Phenotyping individual trees to quantify interactions among genotype, environment, and management practices is critical to the development of precision forestry and to maximize the opportunity of improved tree breeds. In this study we utilized airborne laser scanning (ALS) data to detect and characterize individual trees in order to generate tree-level phenotypes and tree-to-tree competition metrics. To examine our ability to account for environmental variation and its relative importance on individual-tree traits, we investigated the use of spatial models using ALS-derived competition metrics and conventional autoregressive spatial techniques. Models utilizing competition covariate terms were found to quantify previously unexplained phenotypic variation compared with standard models, substantially reducing residual variance and improving estimates of heritabilities for a set of operationally relevant traits. Models including terms for spatial autocorrelation and competition performed the best and were labelled ACE (autocorrelation-competition-error) models. The best ACE models provided statistically significant reductions in residuals ranging from −65.48% for tree height (H) to −21.03% for wood stiffness (A), and improvements in narrow sense heritabilities from 38.64% for H to 14.01% for A. Individual tree phenotyping using an ACE approach is therefore recommended for analyses of research trials where traits are susceptible to spatial effects.