bluuebunny/crossref_metadata_2025_split huggingface dataset:
uniForest: an unsupervised machine learning technique to detect outliers and restrict variance in microbiome studies
Authors: Leigh R.J. , Murphy R.A. , Walsh F. 
Published: May 2021

AbstractIsolation Forests is an unsupervised machine learning technique for detecting outliers in continuous datasets that does not require an underlying equivariant or Gaussian distribution and is suitable for use on small datasets. While this procedure is widely used across quantitative fields, to our knowledge, this is the first attempt to solely assess its use for microbiome datasets. Here we present uniForest, an interactive Python notebook (which can be run from any desktop computer using the Google Colaboratory web service) for the processing of microbiome outliers. We used uniForest to apply Isolation Forests to the Healthy Human Microbiome project dataset and imputed outliers with the mean of the remaining inliers to maintain sample size and assessed its prowess in variance reduction in both community structure and derived ecological statistics (α-diversity). We also assessed its functionality in anatomical site differentiation (pre- and postprocessing) using principal component analysis, dissimilarity matrices, and ANOSIM. We observed a minimum variance reduction of 81.17% across the entire dataset and in alpha diversity at the Phylum level. Application of Isolation Forests also separated the dataset to an extremely high specificity, reducing variance within taxa samples by a minimum of 81.33%.It is evident that Isolation Forests are a potent tool in restricting the effect of variance in microbiome analysis and has potential for broad application in studies where high levels of microbiome variance is expected. This software allows for clean analyses of otherwise noisy datasets.
BMP signaling underlies the craniofacial heterochrony in phyllostomid bats, a hyperdiverse mammal group
Authors: Camacho Jasmin , Lin Jacky D. , McCormack Michaela , Moon Rachel , Smith Samantha K. , Rasweiler John J. , Behringer Richard R. , Tabin Clifford J. , Abzhanov Arhat 
Published: May 2021

SummaryThe potential for variation and the capacity to evolve in response to ecological opportunity are important aspects of an adaptive radiation. Identifying the origin of phenotypic variation, in which natural selection might act upon, is a major goal of evolutionary developmental biology. The New World leaf-nosed bats (phyllostomids) are a textbook example of an adaptive radiation. Their cranial morphology is diverse along relative facial length, which is related to their diets. We previously used geometric morphometrics to reveal peramorphosis, a type of heterochrony, in the cranial evolution among phyllostomid bats. We then demonstrated that the mechanism of peramorphic diversity in phyllostomid rostrum length resulted from altered cellular proliferation. Here, we investigate the progenitors of the face, the cranial neural crest, and a key signaling pathway related to their proliferation and differentiation into mature tissues: the bone morphogenetic protein (BMP). With geometric morphometrics, immunofluorescence, and confocal imaging—in three phyllostomid species and one outgroup bat species—we show the molecular patterns that underlie the adaptive and innovative traits seen in phyllostomid bats. Then, with mouse genetics, we mimic the BMP molecular pattern observed in nectar feeding bats and recapitulate the elongated morphological variation in mice. Surprisingly, we also observe an expansion in the nose-tip of mice, akin to the expanding leaf-nose tissue in phyllostomid bats. These data, combined with the mouse genetics literature on BMP signaling, suggest the BMP developmental pathway plays a central role in shaping the craniofacial variation necessary for adaptation in bats. Further, we speculate that the BMP signaling pathway could underlie other bizarre facial phenotypes in mammals that are derived from frontonasal mesenchyme, such as the proboscis. Overall, this study combines a comparative framework to developmental data, with a genetic approach, to directly investigate the role of development on complex morphology.
T2R bitter taste receptors regulate apoptosis and may be associated with survival in head and neck squamous cell carcinoma
Authors: Carey Ryan M. , McMahon Derek B. , Rajasekaran Karthik , Gopallawa Indiwari , Newman Jason G. , Basu Devraj , White Elizabeth A. , Lee Robert J. 
Published: May 2021

AbstractBetter management of head and neck squamous cell carcinomas (HNSCCs) requires a clearer understanding of tumor biology and disease risk. Bitter taste receptors (T2Rs) have been studied in several cancers, including thyroid, salivary, and GI, but their role in HNSCC has not been explored. We found that HNSCC patient samples and cell lines expressed functional T2Rs on both the cell and nuclear membranes. Bitter compounds, including bacterial metabolites, activated T2R-mediated nuclear Ca2+ responses leading to mitochondrial depolarization, caspase activation and ultimately apoptosis. Buffering nuclear Ca2+ elevation blocked caspase activation. Furthermore, increased expression of T2Rs in HNSCCs from The Cancer Genome Atlas (TCGA) is associated with improved overall survival. This work suggests that T2Rs are potential biomarkers to predict outcomes and guide treatment selection, may be leveraged as therapeutic targets to stimulate tumor apoptosis, and may mediate tumor-microbiome crosstalk in HNSCC.
Empowering systems-guided drug target discovery with metabolic and structural analysis
Authors: Chowdhury Sourav , Zielinski Daniel C. , Dalldorf Christopher , Rodrigues Joao V , Palsson Bernhard O. , Shakhnovich Eugene I 
Published: May 2021

AbstractElucidating intracellular drug targets has been a difficult problem. While machine learning analysis of omics data has been a promising approach, going from large-scale trends to specific targets remains a challenge. Here, we developed a systems-guided hierarchic workflow that utilizes metabolic and structural analysis to narrow in on specific targets suggested by statistical and machine learning analysis of metabolomics data. Utilizing a novel multi-valent DHFR-targeting antibiotic compound, CD15-3, as a case study, we first measured global metabolomics and applied statistics and machine learning to locate broad areas of metabolic perturbation under antibiotic stress. We then tested the ability of suggested compounds to rescue growth and performed metabolic modelling to identify pathways whose inhibition was consistent with growth rescue patterns. Next, we utilized protein structural similarity to further prioritize candidate drug targets within these pathways. Overexpression and in vitro activity assays of a top candidate target, HPPK (folK), showed complete recovery from drug induced growth inhibition and with microscopy. As interest in ‘white-box’ machine learning methods continues to grow, this study demonstrates how established machine learning methods can be combined with mechanistic analyses to improve the resolution of drug target finding workflows.
High level production and characterization of truncated human angiotensin converting enzyme 2 in Nicotiana benthamiana plant as a potential therapeutic target in COVID-19
Authors: Mamedov Tarlan , Gürbüzaslan İrem , Ilgin Merve , Yuksel Damla , Mammadova Gunay , Ozkul Aykut , Hasanova Gulnara 
Published: May 2021

AbstractThe COVID-19 pandemic, which is caused by SARS-CoV-2 has rapidly spread to more than 222 countries and has put global public health at high risk. The world urgently needs safe, a cost-effective SARS-CoV-2 coronavirus vaccine, therapeutic and antiviral drugs to combat the COVID-19. Angiotensin-converting enzyme 2 (ACE2), as a key receptor for SARS-CoV-2 infections, has been proposed as a potential therapeutic target in COVID-19 patients. In this study, we report high level production (about ∼0.75 g /kg leaf biomass) of glycosylated and non-glycosylated forms of recombinant human truncated ACE2 in Nicotiana benthamiana plant. The plant produced recombinant human truncated ACE2s successfully bind to the SARC-CoV-2 spike protein, but deglycosylated ACE2 binds more strongly than the glycosylated counterpart. Importantly, both deglycosylated and glycosylated forms of AEC2 stable at elevated temperatures for prolonged periods and demonstrated strong anti-SARS-CoV-2 activity in vitro. The IC50 values of glycosylated and deglycosylated AEC2 were 0.4 and 24 μg/ml, respectively, for the pre-entry infection, when incubated with 100TCID50 of SARS-CoV-2. Thus, plant produced truncated ACE2s are promising cost-effective and safe candidate as a potential therapeutic targets in the treatment of COVID-19 patients.
Intrinsic timescales in the visual cortex change with selective attention and reflect spatial connectivity
Authors: Zeraati Roxana , Shi Yan-Liang , Steinmetz Nicholas A. , Gieselmann Marc A. , Thiele Alexander , Moore Tirin , Levina Anna , Engel Tatiana A. 
Published: May 2021

ABSTRACTIntrinsic timescales characterize dynamics of endogenous fluctuations in neural activity. Variation of intrinsic timescales across the neocortex reflects functional specialization of cortical areas, but less is known about how intrinsic timescales change during cognitive tasks. We measured intrinsic timescales of local spiking activity within columns of area V4 while monkeys performed spatial attention tasks. The ongoing spiking activity unfolded across at least two distinct timescales, fast and slow. The slow timescale increased when monkeys attended to the receptive fields location and correlated with reaction times. By evaluating predictions of several network models, we found that spatiotemporal correlations in V4 activity were best explained by the model in which multiple timescales arise from recurrent interactions shaped by spatially arranged connectivity, and attentional modulation of timescales results from an increase in the efficacy of recurrent interactions. Our results suggest that multiple timescales arise from the spatial connectivity in the visual cortex and flexibly change with the cognitive state due to dynamic effective interactions between neurons.
A systematic comparison of fibroblasts derived from postmortem human dura mater versus dermal epithelium for neurodegenerative disease modeling
Authors: Argouarch Andrea R. , Cosme Celica G. , Garcia Kristle , Corrales Christian I. , Nana Alissa L. , Karydas Anna M. , Spina Salvatore , Grinberg Lea T. , Miller Bruce , Goodarzi Hani , Seeley William W. , Kao Aimee W. 
Published: May 2021

ABSTRACTPatient-derived cells hold great promise for precision medicine approaches in human health. Fibroblast cells have been a major source of human cells for reprogramming and differentiating into specific cell types for disease modeling. Such cells can be isolated at various stages during life (presymptomatic, symptomatic, and postmortem) and thus can potentially be used to model different phases of disease progression. In certain circumstances, however, tissues are not collected during life and only postmortem tissues are the only available source of fibroblasts. Fibroblasts cultured from postmortem human dura mater of individuals with neurodegenerative diseases have been suggested as a primary source of cells for in vitro modeling of neurodegenerative diseases. Although fibroblast-like cells from human and mouse dura mater have been previously described, their utility for reprogramming and direct differentiation protocols requires further characterization. In this study, cells derived from dermal biopsies performed in living subjects were compared to cells derived from postmortem dura mater. In two instances, we have isolated and compared dermal and dural cell lines from the same subject. Notably, striking differences between the dermis and dura mater-derived cell lines were found. Compared to dermal fibroblasts, postmortem dura mater-derived cells demonstrated different morphology, exhibited slower growth rates, failed to express fibroblast protein markers, and exhibited significant differences in gene expression profiles. In addition, dura mater-derived cells were found to exhibit a high rate of chromosomal abnormalities, particularly in the loss of the Y chromosome. Our study highlights potential limitations of postmortem human dura mater-derived cells for disease modeling, argues for rigorous karyotyping prior to reprograming, and brings into question the identity of dura mater-derived cells as belonging to a fibroblast lineage.
Rescuable effect of R-salbutamol in LPS-induced immune dysfunction of sepsis
Authors: Beng Huimin , Wang Shanping , Hu Junhua , Liang Xinglong , Qin Haolong , Tan Wen 
Published: May 2021

AbstractSepsis is a severe life-threatening condition caused by a dysregulated host response to infection. So far, there are no pharmacotherapies to stop sepsis. Salbutamol, a commonly used β2-adrenoreceptor agonist, has found to be potential in regulating immune response dysfunction and exert anti-inflammatory effect. However, salbutamol exists two isomers. R-isomer exhibits the therapeutic effect and clinical benefit, while S-isomer proves to be detrimental rather than benign. So, in this study, we investigated the preventive and therapeutic effect of R-salbutamol (R-sal), S-salbutamol (S-sal) or racemic mixture in a mouse model of lipopolysaccharide (LPS)-induced sepsis. Dexamethasone (Dex) was set as comparison. The results showed that R-sal markedly improved seven-day survival rate of septic mice both administered before or after LPS. Whereas Dex showed toxic and accelerated the death of septic mice when given before LPS injection. Lung histological examination and lung function assay revealed that LPS challenge resulted in acute lung damage, including inflammatory cell infiltration, thickened alveolar septa and congestion, and decreased minute volume in septic mice. R-sal pretreatment efficiently inhibited these changes, accompanying by markedly reduced lung MPO level, serum cytokines levels and lactate release and significantly restored the lymphocytes and suppressed the percentage of monocytes. Racemic mixture exhibited diminished effects while S-sal showed enhanced cytokines release. In addition, R-sal pretreatment showed a better improvement in prognostic pulmonary function at day4 in survived mice than that of Rac-sal. Collectively, our results indicate the potential benefit of R-sal for sepsis and sepsis-induced lung injury.
Modulating the selective utilization of carbon sources by engineering the 3rd and 4th helices of the DNA-binding domain of catabolite control protein A (CcpA) in Bacillus licheniformis
Authors: Zhang Yupeng , Li Youran , Xiao Fengxu , Wang Hanrong , Zhang Liang , Ding Zhongyang , Gu Zhenghua , Xu Sha , Shi Guiyang 
Published: May 2021

AbstractThe gram-positive bacterium Bacillus licheniformis exhibits obvious selective utilization on carbon sources. This process is mainly governed by the global regulator catabolite control protein A (CcpA), which can recognize and bind to multiple target genes widely distributed in metabolic pathways. Although the DNA-binding domain of CcpA has been predicted, the influence of key amino acids on target gene recognition and binding remains elusive. In this study, the impact of Lys31, Ile42 and Leu56 on in vitro protein-DNA interactions and in vivo carbon source selective utilization was investigated. The results showed that alanine substitution of Lys31 and Ile42, located within the 3rd helices of the DNA-binding domain, significantly weakened the binding strength between CcpA and target genes. These mutations also lead to alleviated repression of xylose utilization in the presence of glucose. On the other hand, the Leu56Arg mutant in the 4th helices exhibited enhanced binding affinity compared with that of the wild-type one. When this mutant was used to replace the native one in B. licheniformis cells, the selective utilization of glucose over xylose increased. The above research results are helpful for a deep understanding of how microorganisms can flexibly sense and adapt to changes in the external environment. Additionally, they can provide important theoretical basis for the rational design of biomass utilization and environmental adaptability of B. licheniformis cell factories.ImportanceBacillus licheniformis is widely used in producing various valuable products, such as α enzymes, industrial chemicals and biocides. The carbon catabolite regulation process in the utilization of raw materials is crucial to maximizing the efficiency of this microbial cell factory. CcpA plays an important role in this process. This study represents a new paradigm to investigate the structure–function relationship in CcpA by fluorescence polarization experiments in vitro. The results also uncover key amino acids in the DNA-binding domain that affect the selective utilization of carbon sources. These results provide a theoretical basis for the rational design of industrial microorganisms.
Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Authors:   RECOVERY Collaborative Group, Horby Peter W , Campbell Mark , Spata Enti , Emberson Jonathan R , Staplin Natalie , Pessoa-Amorim Guilherme , Peto Leon , Wiselka Martin , Wiffen Laura , Tiberi Simon , Caplin Ben , Wroe Caroline , Green Christopher , Hine Paul , Prudon Benjamin , George Tina , Wight Andrew , Baillie J Kenneth , Basnyat Buddha , Buch Maya H , Chappell Lucy C , Day Jeremy N , Faust Saul N , Hamers Raph L , Jaki Thomas , Juszczak Edmund , Jeffery Katie , Lim Wei Shen , Montgomery Alan , Mumford Andrew , Rowan Kathryn , Thwaites Guy , Mafham Marion , Haynes Richard , Landray Martin J 
Published: May 2021

SUMMARYBackgroundColchicine has been proposed as a treatment for COVID-19 on the basis of its anti-inflammatory actions.MethodsIn this randomised, controlled, open-label trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus colchicine twice daily for 10 days or until discharge (or one of the other treatment arms) using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).FindingsBetween 27 November 2020 and 4 March 2021, 5610 patients were randomly allocated to receive colchicine and 5730 patients to receive usual care alone. Overall, 1173 (21%) patients allocated to colchicine and 1190 (21%) patients allocated to usual care died within 28 days (rate ratio 1.01; 95% confidence interval [CI] 0.93-1.10; p=0.77). Consistent results were seen in all pre-specified subgroups of patients. There was no significant difference in duration of hospitalisation (median 10 days vs. 10 days) or the proportion of patients discharged from hospital alive within 28 days (70% vs. 70%; rate ratio 0.98; 95% CI 0.94-1.03; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (25% vs. 25%; risk ratio 1.02; 95% CI 0.96-1.09; p=0.47).InterpretationIn adults hospitalised with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.FundingUK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056). Wellcome Trust (Grant Ref: 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator.
Nanoscale resolution imaging of the whole mouse embryos and larval zebrafish using expansion microscopy
Authors: Sim Jueun , Park Chan E , Cho In , Min Kyeongbae , Eom Minho , Han Seungjae , Jeon Hyungju , Cho Hyun-Ju , Cho Eun-Seo , Kumar Ajeet , Chong Yosep , Kang Jeong Seuk , Piatkevich Kiryl D. , Jung Erica E. , Kang Du-Seock , Kwon Seok-Kyu , Kim Jinhyun , Yoon Ki-Jun , Lee Jeong-Soo , Boyden Edward S. , Yoon Young-Gyu , Chang Jae-Byum 
Published: May 2021

ABSTRACTNanoscale resolution imaging of whole vertebrates is required for a systematic understanding of human diseases, but this has yet to be realized. Expansion microscopy (ExM) is an attractive option for achieving this goal, but the expansion of whole vertebrates has not been demonstrated due to the difficulty of expanding hard body components. Here, we demonstrate whole-body ExM, which enables nanoscale resolution imaging of anatomical structures, proteins, and endogenous fluorescent proteins (FPs) of whole zebrafish larvae and mouse embryos by expanding them fourfold. We first show that post-digestion decalcification and digestion kinetics matching are critical steps in the expansion of whole vertebrates. Then, whole-body ExM is combined with the improved pan-protein labeling approach to demonstrate the three-dimensional super-resolution imaging of antibody- or FP-labeled structures and all major anatomical structures surrounding them. We also show that whole-body ExM enables visualization of the nanoscale details of neuronal structures across the entire body.
Urbanisation, Bird Species Richness and Abundance Within Ibadan Metropolis, Nigeria
Authors: Adegbola Festus O. , Adeyanju Taiye Adeniyi , Iwajomo Soladoye B. , Ayodele Ibukunoluwa Augustine 
Published: May 2021

ABSTRACTUrbanisation is considered as one of the most profound threat to wildlife, with habitat loss and fragmentation being predominant. This study assessed the impacts of urbanisation on richness, abundance of bird species within Ibadan metropolis, Nigeria. A uniform grid of 500 square meters was installed on the map of Ibadan Metropolis using QGIS to produce 499 grid points distributed across the five urban local governments. 100 grids were selected randomly, identified with mapinR software application and surveyed with 5 point counts within each gird, established at 200m interval to avoid double counting. Each point count was observed for 5 minutes using a pair of 8×42mm binoculars within a 50m radius. Habitat variables like number of buildings, trees, paved roads, communication masts were also recorded.A total number of 56 species of birds were observed at the end of the assessment, classified into 30 families. The test of statistics showed that there was no statistically significant difference in bird species richness between the Local Governments. The test of statistics showed that there was no statistically significant difference in bird species abundance between the local governments. The test of between-subjects effects revealed that there were no statistical significant effects when all the habitat variables were computed in the model on species richness. The number of paved roads and number of vehicles showed a significant effect on bird species abundance while others variables in the model did not exact statistically significant effects on bird species abundance.The study therefore concluded that habitat actions due to urbanisation have not affected the richness and abundance of birds species found in all the local governments. The only habitat variables that have currently exacted significant effect on species abundance within the metropolis are number of vehicles and paved roads.
Using machine learning to design adeno-associated virus capsids with high likelihood of viral assembly
Authors: To Cuong T. , Wirsching Christian , Marques Andrew D. , Zolotukhin Sergei 
Published: May 2021

AbstractWe study the application of machine learning in designing adeno-associated virus (AAV) capsid sequences with high likelihood of viral assembly, i.e. capsid viability. Specifically, we design and implement Origami, a model-based optimization algorithm, to identify highly viable capsid sequences within the vast space of 2033 possibilities. Our evaluation shows that Origami performs well in terms of optimality and diversity of model-designed sequences. Moreover, these sequences are ranked according to their viability score. This helps designing experiments given budget constraint.