bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune Responses to COVID-19 mRNA Vaccines in Patients with Solid Tumors on Active, Immunosuppressive Cancer Therapy
Authors: Shroff Rachna T. , Chalasani Pavani , Wei Ran , Pennington Daniel , Quirk Grace , Schoenle Marta V. , Peyton Kameron L. , Uhrlaub Jennifer L. , Ripperger Tyler J. , Jergović Mladen , Dalgai Shelby , Wolf Alexander , Whitmer Rebecca , Hammad Hytham , Carrier Amy , Scott Aaron J. , Nikolich-Žugich Janko , Worobey Michael , Sprissler Ryan , Dake Michael , LaFleur Bonnie J. , Bhattacharya Deepta 
Published: May 2021

AbstractVaccines against SARS-CoV-2 have shown high efficacy, but immunocompromised participants were excluded from controlled clinical trials. We compared immune responses to the Pfizer/BioNTech mRNA vaccine in solid tumor patients (n=53) on active cytotoxic anti-cancer therapy to a control cohort (n=50) as an observational study. Using live SARS-CoV-2 assays, neutralizing antibodies were detected in 67% and 80% of cancer patients after the first and second immunizations, respectively, with a 3-fold increase in median titers after the booster. Similar trends were observed in serum antibodies against the receptor-binding domain (RBD) and S2 regions of Spike protein, and in IFNγ+ Spike-specific T cells. Yet the magnitude of each of these responses was diminished relative to the control cohort. We therefore quantified RBD- and Spike S1-specific memory B cell subsets as predictors of anamnestic responses to additional immunizations. After the second vaccination, Spike-specific plasma cell-biased memory B cells were observed in most cancer patients at levels similar to those of the control cohort after the first immunization. We initiated an interventional phase 1 trial of a third booster shot (NCT04936997); primary outcomes were immune responses with a secondary outcome of safety. After a third immunization, the 20 participants demonstrated an increase in antibody responses, with a median 3-fold increase in virus-neutralizing titers. Yet no improvement was observed in T cell responses at 1 week after the booster immunization. There were mild adverse events, primarily injection site myalgia, with no serious adverse events after a month of follow-up. These results suggest that a third vaccination improves humoral immunity against COVID-19 in cancer patients on active chemotherapy with no severe adverse events.
The impact of COVID-19 non-pharmaceutical interventions on the lived experiences of people living in Thailand, Malaysia, Italy and the United Kingdom: a cross-country qualitative study
Authors: Schneiders Mira L. , Naemiratch Bhensri , Cheah Phaik Kin , Cuman Giulia , Poomchaichote Tassawan , Ruangkajorn Supanat , Stoppa Silvia , Osterrieder Anne , Cheah Phee-Kheng , Ongkili Darlene , Pan-ngum Wirichada , Mackworth-Young Constance R.S. , Cheah Phaik Yeong 
Published: May 2021

AbstractThis qualitative study explores the impact of non-pharmaceutical interventions (NPIs) on lived experiences during the first wave of the COVID-19 pandemic on people’s lives in Thailand, Malaysia, Italy and the United Kingdom. A total of 86 interviews were conducted with members of the public, including healthcare workers. Participants across countries held strong views on NPIs, with many feeling measures lacked clarity. Most participants reported primarily negative impacts of NPIs on their lives, including through separation, isolation and grief over missed milestones; work-related challenges and income loss; and poor mental health and wellbeing. Nonetheless, many also experienced inadvertent positive consequences, including more time at home to focus on what they most valued in life; a greater sense of connectedness; and benefits to working life. Commonly employed coping strategies focused on financial coping; psycho-emotional coping; social coping and connectedness; reducing and mitigating risks; and limiting exposure to the news. Importantly, the extent to which participants’ lived experiences were positive or negative, and their ability to cope was underpinned by individual, social and economic factors. In order to mitigate negative and unequal impacts of NPIs, COVID-19 policies will benefit from paying closer attention to the social, cultural and psychological—not just biological—vulnerabilities to, and consequences of public health measures.
Metabolomic profiling in small vessel disease identifies multiple associations with disease severity
Authors: Harshfield Eric L. , Sands Caroline J. , Tuladhar Anil M. , de Leeuw Frank-Erik , Lewis Matthew R. , Markus Hugh S. 
Published: May 2021

AbstractCerebral small vessel disease (SVD) is a major cause of vascular cognitive impairment and dementia. There are few treatments, largely reflecting limited understanding of the underlying pathophysiology. Metabolomics can be used to identify novel risk factors in order to better understand pathogenesis and to predict disease progression and severity.We analysed data from 624 patients with symptomatic cerebral SVD from two prospective cohort studies. Serum samples were collected at baseline and patients underwent MRI scans and cognitive testing at regular intervals with up to 14 years of follow-up. Using ultra-performance liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy, we obtained metabolic and lipidomic profiles from 369 annotated metabolites and 54,764 unannotated features and examined their association with respect to disease severity, assessed using MRI SVD markers, cognition, and future risk of all-cause dementia.Over 100 annotated metabolites were significantly associated with SVD imaging markers, cognition, and progression to dementia. Decreased levels of multiple glycerophospholipids, sphingolipids, and sterol lipids were associated with increased SVD load as evidenced by higher white matter hyperintensities (WMH) volume, lower mean diffusivity normalised peak height (MDNPH), greater brain atrophy, and impaired cognition. Higher levels of several amino acids and nucleotides were associated with higher WMH volume, greater atrophy, and lower MDNPH. Lower baseline levels of carnitines and creatinine were associated with higher annualised change in peak width of skeletonised mean diffusivity (PSMD), and several metabolites, including lower levels of valine, caffeine, and VLDL analytes, were associated with future dementia incidence. Additionally, we identified 1,362 unannotated features associated with lower MDNPH and 2,474 unannotated features associated with increased WMH volume.Our results show multiple distinct metabolic signatures that are associated with imaging markers of SVD, cognition, and conversion to dementia. Further research should assess causality and the use of metabolomic screening to improve the ability to predict future disease severity and dementia risk in SVD. The metabolomic profiles may also provide novel insights into disease pathogenesis and help identify novel treatment approaches.
Deep protein representations enable recombinant protein expression prediction
Authors: Martiny Hannah-Marie , Armenteros Jose Juan Almagro , Johansen Alexander Rosenberg , Salomon Jesper , Nielsen Henrik 
Published: May 2021

AbstractA crucial process in the production of industrial enzymes is recombinant gene expression, which aims to induce enzyme overexpression of the genes in a host microbe. Current approaches for securing overexpression rely on molecular tools such as adjusting the recombinant expression vector, adjusting cultivation conditions, or performing codon optimizations. However, such strategies are time-consuming, and an alternative strategy would be to select genes for better compatibility with the recombinant host. Several methods for predicting soluble expression are available; however, they are all optimized for the expression host Escherichia coli and do not consider the possibility of an expressed protein not being soluble. We show that these tools are not suited for predicting expression potential in the industrially important host Bacillus subtilis. Instead, we build a B. subtilis-specific machine learning model for expressibility prediction. Given millions of unlabelled proteins and a small labeled dataset, we can successfully train such a predictive model. The unlabeled proteins provide a performance boost relative to using amino acid frequencies of the labeled proteins as input. On average, we obtain a modest performance of 0.64 area-under-the-curve (AUC) and 0.2 Matthews correlation coefficient (MCC). However, we find that this is sufficient for the prioritization of expression candidates for high-throughput studies. Moreover, the predicted class probabilities are correlated with expression levels. A number of features related to protein expression, including base frequencies and solubility, are captured by the model.
Mechanistic of Rac and Cdc42 synchronization at the cell edge by ARHGAP39-dependent signaling nodules and the impact on protrusion dynamics
Authors: Howell Michael , Delorme-Walker Violaine , Welch Christopher , Pathak Ritu , Hahn Klaus M. , DerMardirossian Céline 
Published: May 2021

SUMMARYCompartmentalization of GTPase regulators into signaling nodules dictates the GTPase pathways selected. Rac and Cdc42 are synchronized at the cell edge for effective protrusion in motile cells but how their activity is coordinated remains elusive. Here, we discovered that ARHGAP39, a Rac and Cdc42 GTPase-activating protein, sequentially interacts with WAVE and mDia2 to control Rac/lamellipodia and Cdc42/filopodia protrusions, respectively. Mechanistically, ARHGAP39 binds to WAVE and, upon phosphorylation by Src kinase, inactivates Rac to promote Cdc42-induced filopodia formation. With our optimized FRET biosensor, we detected active Cdc42 at the filopodia tips that controls filopodia extension. ARHGAP39 is transported to filopodia tips by Myosin-X where it binds mDia2 and inactivates Cdc42 leading to filopodia retraction. Failure in lamellipodia to filopodia switch by defective ARHGAP39 impairs cell invasion and metastasis. Our study reveals that compartmentalization of ARHGAP39 within Rac/Cdc42 signaling nodules orchestrates the synchronization of lamellipodia/filopodia crosstalk and highlights the intricate regulation of leading edge dynamics in migrating cells.
T cell receptor (TCR) repertoire analysis reveals a highly conserved TCR repertoire in a bilateral tumor mouse model
Authors: Tsunoda Mikiya , Aoki Hiroyasu , Shimizu Haruka , Shichino Shigeyuki , Matsushima Kouji , Ueha Satoshi 
Published: May 2021

AbstractTemporal analysis of the T cell receptor (TCR) repertoire has been used to monitor treatment-induced changes in antigen-specific T cells in patients with cancer. However, the lack of experimental models that allow temporal analysis of the TCR repertoire in the same individual in a homogeneous population limits the understanding of the causal relationship between changes in TCR repertoire and antitumor responses. A bilateral tumor model, where tumor cells were inoculated bilaterally into the backs of mice, could be used for temporal analysis of the TCR repertoire. This study examined the prerequisite for this strategy: the TCR repertoire is conserved between bilateral tumors with the same growth rate. Bilateral tumors with equivalent size and draining lymph nodes (dLNs) were collected 13 days after tumor inoculation to analyze the TCR repertoire of CD4+ and CD8+ T cells. The tumor-infiltrating T cell clones were highly conserved between the bilateral tumors, and the extent of clonal expansion was equivalent. In addition, the similarity between the bilateral tumors was equivalent to heterogeneity on one side of the tumor. The similarity of the TCR repertoire in the bilateral dLNs was markedly lower than that in the tumor, suggesting that tumor-reactive T cell clones induced independently in each dLN integrated during recirculation and then infiltrated the tumor. These findings suggest that our bilateral tumor model is suitable for temporal monitoring of the TCR repertoire to evaluate temporal and treatment-induced changes in tumor-reactive T cell clones.Significance StatementThe bilateral subcutaneous tumor model, where tumor cells were inoculated bilaterally into the backs of mice, is a promising model for temporal analysis of the antitumor response in cancer immunotherapy. This study demonstrated a highly conserved TCR repertoire in bilateral tumors and provided the basis for using a bilateral tumor model for evaluating temporal and treatment-induced changes in tumor-responsive T cell clones in individual mice. In humans, accurate statistical analysis is hampered by various background factors, including cancer type and stage and history of treatment. Moreover, temporal tumor biopsy in patients is highly invasive. Our bilateral tumor model overcomes these clinical issues and is expected to be a valuable tool for the development of novel immune monitoring and therapeutic strategies.
Microfluidic Streptomyces Cultivation for Whole Lifecycle Characterization and Phenotypic Assays Enabled by Nanogap-stabilized Air-Water Interface
Authors: Chen Dongwei , Nie Mengyue , Tang Wei , Zhang Yuwei , Qiao Yuxin , Yun Juanli , Wang Jian , Lan Ying , Ma Liang , Chen Yihua , Du Wenbin 
Published: May 2021

ABSTRACTStreptomyces is a model filamentous prokaryote to study multicellular differentiation and a rich reservoir for antibiotics discovery. In their natural conditions, Streptomyces grows at the interface of porous soil, air, and water. The morphological development of Streptomyces is traditionally performed on agar plates and mostly studied at the population levels. However, the detailed lifecycle of Streptomyces has not been well studied due to its complexity and lack of research tools which can mimic their natural conditions in the soil. Here, we developed a simple assembled microfluidic device for cultivation and the entire lifecycle observation of Streptomyces development from single-cell level. The microfluidic device composed of a microchannel for loading samples and supplying nutrients, microwell arrays for seeding and growth of single spores, and air-filled chambers aside of the microwells that facilitate growth of aerial hyphae and spores. A unique feature of this device is that each microwell is surrounded by a 1.5 µm gap connected to an air-filled chamber which provide stabilized water-air interface. We used this device to observe the development of single Streptomyces spores and found that unlike those in bulk liquid culture, Streptomyces can differentiate at water-air interfaces in microscale liquid culture. Finally, we demonstrated that phenotypic A-Factor assay can be performed at defined time point of its lifecycle. This microfluidic device could become a robust tool for studying Streptomyces multi-cellular differentiation and interaction at single cell level.IMPORTANCEWe describe a microfluidic device that mimics the natural porous environment for the growth and development of Streptomyces, the model system for bacterial multicellularity. The microfluidic device is used for cultivation and the entire lifecycle observation of Streptomyces development from single-cell level, including growth of aerial filaments. The aerial hyphae development of Streptomyces at the water-air interface was observed at real time in the microfluidic device. The early growth, opportunistic transformation (in the gap), and merging of aerial hyphae of Streptomyces in the microfluidic device were observed for the first time. It will play an important role in finding single-cell heterogeneity to study secondary metabolites related to the complex lifecycle of Streptomyces.
SCRaPL: hierarchical Bayesian modelling of associations in single cell multi-omics data
Authors: Maniatis Christos , Vallejos Catalina A , Sanguinetti Guido 
Published: May 2021

AbstractSingle-cell multi-omics assays offer unprecedented opportunities to explore gene regulation at cellular level. However, high levels of technical noise and data sparsity frequently lead to a lack of statistical power in correlative analyses, identifying very few, if any, significant associations between different molecular layers. Here we propose SCRaPL, a novel computational tool that increases power by carefully modelling noise in the experimental systems. We show on real and simulated multi-omics single-cell data sets that SCRaPL achieves higher sensitivity and better robustness in identifying correlations, while maintaining a similar level of false positives as standard analyses based on Pearson correlation.
Polygene control and trait dominance in death-feigning syndrome in the red flour beetle Tribolium castaneum
Authors: Matsumura Kentarou , Miyatake Takahisa 
Published: May 2021

AbstractDeath-feigning behavior is an anti-predator behavior in a wide range of animal taxa, and it often correlates with the movement (i.e. death-feigning syndrome). In the present study, we performed reciprocal crossing among strains with genetically longer (L strain) and shorter (S strain) duration of death feigning, and investigated related heritable factors in the F1 and F2 populations. We also investigated moving activity which negatively responded to artificial selection for death feigning in T. castaneum. Our results showed that death feigning occurred more frequently and for shorter periods in the F1 population. In the F2 population, death feigning and movement showed continuous segregation. The distribution of each trait value in the F2 generation was different from the distribution of trait values in the parental generation, and no individuals transgressing the distribution of trait values in the parental generation emerged in the F2 generation. Chi-square analysis of the observed death feigning and movement of F1 and F2 progenies rejected the hypothesis of mono-major gene inheritance. These results suggest that death-feigning syndrome is controlled in a polygenic manner. Our study indicated that reciprocal crossing experiments are useful in assessing the quantitative inheritance of behavioral traits.
Microgravity effect on murine T cells exposed to suborbital flight aboard Blue Origin’s New Shepard vehicle
Authors: Llanos Pedro J. , Andrijauskaite Kristina , Duraisamy Vijay Vishal , Gangadharan Sathya , Morris Jay , Wargovich Michael J. 
Published: May 2021

AbstractNumerous scientific experiments have been conducted in space. However, the precise mechanisms mediating successful human body adaption to the hostile space environment are still not delineated. The cost and logistic challenges of sending biological payloads to International Space Station are forcing scientists to find alternative research platforms. In this study, we investigated whether brief exposure to microgravity during the suborbital flight aboard Blue Origin’s New Shepard rocket modulated the behavior of the gravity-sensitive murine T cells. We assessed the effect of suborbital environment on different T cell subsets, activation markers, functionality, and cytokine secretion capabilities. Thus, to optimize the potential response of T cells, we cultured them in interleukin IL-2 alone or combined with IL-12. We found that exposure to microgravity decreased the expression of T cells with CD4+ cells being more sensitive to suborbital flight as compared to CD8+ cells. Our data indicate that the functional capabilities of flown T cells were reduced. Also, our findings suggest that supplementing cells with IL-2 and IL-12 cytokines may restore microgravity-mediated cellular alterations. Finally, our study provides insights on the microgravity effect on the murine T cells by utilizing a novel suborbital research platform.
Homogeneous environmental selection overturns distance-decay relationship of soil prokaryotic community
Authors: Zhang Biao , Xue Kai , Zhou Shutong , Wang Kui , Liu Wenjing , Xu Cong , Cui Lizhen , Li Linfeng , Ran Qinwei , Hu Ronghai , Hao Yanbin , Cui Xiaoyong , Wang Yanfen 
Published: May 2021

AbstractThough being fundamental to global diversity distribution, little is known about the geographic pattern of soil microorganisms across different biomes on a large scale. Here, we investigated soil prokaryotic communities from Chinese northern grasslands on a scale up to 4,000 km in both alpine and temperate biomes. Surprisingly, prokaryotic similarities increased with geographic distance after tipping points of 1,760 - 1,920 km, overturning the well-accepted distance-decay relationship and generating a significant U-shape pattern. Such U-shape pattern was likely due to decreased disparities in environmental heterogeneity along with geographic distance when across biomes, as homogeneous environmental selection dominated prokaryotic assembly based on βNTI analysis. Consistently, short-term environmental heterogeneity also followed the U-shape pattern spatially, mainly attributed to dissolved nutrients. In sum, these results demonstrate that homogeneous environmental selection via dissolved nutrients overwhelmed the “distance” effect when across biomes, subverting the previously well-accepted geographic pattern for microbes on a large scale.
Increasing temperature weakens the positive effect of genetic diversity on population growth
Authors: Singleton Alexandra L. , Votzke Samantha , Yammine Andrea , Gibert Jean P. 
Published: May 2021

ABSTRACTGenetic diversity and temperature increases associated with global climate change, are known to independently influence population growth and extinction risk. Whether increasing temperature may influence the effect of genetic diversity on population growth, however, is not known. We address this issue in the model protist system Tetrahymena thermophila. We test the hypothesis that at temperatures closer to the species thermal optimum (i.e., the temperature at which population growth is maximal), genetic diversity should have a weaker effect on population growth compared to temperatures away from the thermal optimum. To do so, we grew populations of T. thermophila with varying levels of genetic diversity at increasingly warmer temperatures and quantified their intrinsic population growth rate, r. We found that genetic diversity increases population growth at cooler temperatures, but that as temperature increases, this effect almost completely disappears. We also show that a combination of changes in the amount of expressed genetic diversity (G), plastic changes in population growth across temperatures (E), and strong GxE interactions, underlie this temperature effect. Our results uncover important but largely overlooked temperature effects that have implications for the management of small populations with depauperate genetic stocks in an increasingly warming world.
Potent macrocycle inhibitors of the human SAGA deubiquitinating module
Authors: Morgan Michael , Ikenoue Tatsuya , Suga Hiroaki , Wolberger Cynthia 
Published: May 2021

AbstractThe SAGA transcriptional coactivator contains a four-protein subcomplex called the DUB module that removes ubiquitin from histone H2B-K120. The human DUB module contains the catalytic subunit, USP22, which is overexpressed in a number of cancers that are resistant to available therapies. We screened a massive combinatorial library of cyclic peptides and identified potent inhibitors of USP22. The top hit was highly specific for USP22 as compared to a panel of 44 other human DUBs. Cells treated with peptide had increased levels of H2B monoubiquitination, demonstrating the ability of the cyclic peptides to enter human cells and inhibit H2B deubiquitination. These macrocycle inhibitors are, to our knowledge, the first reported inhibitors of USP22/SAGA DUB module and show promise for development.