bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel start codons introduce novel coding sequences in the human genomes
Authors: Zhang He , Xie Yang 
Published: November 2020

AbstractStart-gain mutations can introduce novel start codons and generate novel coding sequences that may affect the function of genes. In this study, we systematically investigated the novel start codons that were either polymorphic or fixed in the human genomes. 829 polymorphic start-gain SNVs were identified in the human populations, and the novel start codons introduced by these SNVs have significantly higher activity in translation initiation. Some of these start-gain SNVs were reported to be associated with phenotypes and diseases in previous studies. By comparative genomic analysis, we found 26 human-specific start codons that were fixed after the divergence between the human and chimpanzee, and high-level translation initiation activity was observed on them. The negative selection signal was detected in the novel coding sequences introduced by these human-specific start codons, indicating the important function of these novel coding sequences. This study reveals start-gain mutations are keeping appearing in the human genomes during the evolution and may be important sources altering the function of genes which may further affect the phenotypes or cause diseases.
AMiGA: software for automated Analysis of Microbial Growth Assays
Authors: Midani Firas S. , Collins James , Britton Robert A. 
Published: November 2020

ABSTRACTThe analysis of microbial growth is one of the central methods in the field of microbiology. Microbial growth dynamics can be characterized by growth parameters including carrying capacity, exponential growth rate, and growth lag. However, growth assays with clinical isolates, fastidious organisms, or microbes under stress often produce atypical growth shapes that do not follow the classical microbial growth pattern. Here, we introduce the Analysis of Microbial Growth Assays (AMiGA) software which streamlines the analysis of growth curves without any assumptions about their shapes. AMiGA can pool replicates of growth curves and infer summary statistics for biologically meaningful growth parameters. In addition, AMiGA can quantify death phases and characterize diauxic shifts. It can also statistically test for differential growth under distinct experimental conditions. Altogether, AMiGA streamlines the organization, analysis, and visualization of microbial growth assays.IMPORTANCEOur current understanding of microbial physiology relies on the simple method of measuring microbial populations’ size over time and under different conditions. Many advances have increased the throughput of those assays and enabled the study of non-lab adapted microbes under diverse conditions that widely affect their growth dynamics. Our software provides an all-in-one tool for estimating the growth parameters of microbial cultures and testing for differential growth in a high-throughput and user-friendly fashion without any underlying assumptions about how microbes respond to their growth conditions.
Cytokinin inhibits fungal development and virulence by targeting the cytoskeleton and cellular trafficking
Authors: Gupta Rupali , Anand Gautam , Pizarro Lorena , Laor Dana , Kovetz Neta , Sela Noa , Yehuda Tal , Gazit Ehud , Bar Maya 
Published: November 2020

AbstractCytokinin (CK) is an important plant developmental regulator, having activities in many aspects of plant life and its response to the environment. CKs are involved in diverse processes in the plant, including stem-cell maintenance, vascular differentiation, growth and branching of roots and shoots, leaf senescence, nutrient balance and stress tolerance. In some cases, phytopathogens secrete CKs. It has been suggested that to achieve pathogenesis in the host, CK-secreting biotrophs manipulate CK signaling to regulate the host cell cycle and nutrient allocation. CK is known to induce host plant resistance to several classes of phytopathogens from a handful of works, with induced host immunityviasalicylic acid signaling suggested to be the prevalent mechanism for this host resistance.Here, we show that CK directly inhibits the growth, development, and virulence of fungal phytopathogens. Focusing onBotrytis cinerea (Bc), we demonstrate that various aspects of fungal development can be reversibly inhibited by CK. We also found that CK affects both budding and fission yeast in a similar manner. Investigating the mechanism by which CK influences fungal development, we conducted RNA-NGS on mock and CK treatedB. cinereasamples, finding that CK inhibits the cell cycle, cytoskeleton, and endocytosis. Cell biology experiments demonstrated that CK affects cytoskeleton structure and cellular trafficking inBc, lowering endocytic rates and endomembrane compartment sizes, likely leading to reduced growth rates and arrested developmental programs. Mutant analyses in yeast confirmed that the endocytic pathway is altered by CK.Our work uncovers a remarkably conserved role for a plant growth hormone in fungal biology, suggesting that pathogen-host interactions resulted in fascinating molecular adaptations on fundamental processes in eukaryotic biology.ImportanceCytokinins (CKs), important plant growth/ developmental hormones, have previously been associated with host disease resistance. Here, we demonstrate that CK directly inhibits the growth, development, and virulence ofB. cinerea(Bc) and many additional phytopathogenic fungi. Molecular and cellular analyses revealed that CK is not toxic toBc, but rather,Bclikely recognizes CK and responds to it, resulting in cell cycle and individual cell growth retardation, via downregulation of cytoskeletal components and endocytic trafficking. Mutant analyses in yeast confirmed that the endocytic pathway is a CK target. Our work demonstrates a conserved role for CK in yeast and fungal biology, suggesting that suggesting that pathogen-host interactions may cause molecular adaptations on fundamental processes in eukaryotic biology.
Remote effects of temporal lobe epilepsy surgery: long-term morphological changes after surgical resection
Authors: Arnold T. Campbell , Kini Lohith G. , Bernabei John M. , Revell Andrew Y. , Das Sandhitsu R. , Stein Joel M. , Lucas Tim H. , Englot Dario J. , Morgan Victoria L. , Litt Brian , Davis Kathryn A. 
Published: November 2020

ABSTRACTObjectiveWe present a semi-automated method for quantifying structural changes after epilepsy surgery that accounts for tissue deformation caused by resection. We demonstrate its utility by comparing the remote structural effects of two surgical approaches, the anterior temporal lobectomy (ATL) and the selective amygdalohippocampectomy (SAH).MethodsWe studied 37 temporal lobe epilepsy (TLE) patients who underwent resective surgery. Patients were treated with either an anterior temporal lobectomy (ATL, N=21) or a selective amygdalohippocampectomy (SAH, N=16). All patients received same-scanner MR imaging preoperatively and postoperatively (5+ months after surgery). To analyze structural changes in remote brain regions, we (1) implemented an automated method for segmenting resections with manual review, (2) applied cost function masking to the resection zone, and (3) estimated longitudinal cortical thickness changes using Advanced Normalization Tools (ANTs). We then compared post-operative changes in cortical thickness between the two surgical groups in brain regions outside the resected area.ResultsPatients treated with ATL exhibited significantly greater cortical thinning globally when compared to patients treated with SAH (p = 0.049). There were significant focal differences between the two treatment groups in the ipsilateral frontal lobe (superior medial and medial orbital regions) and insula (p > 0.001, α = 0.05 Bonferroni corrected). No significant effects were seen in the contralateral hemisphere.SignificanceWe present and share a semi-automated pipeline for quantifying remote longitudinal changes in cortical thickness after neurosurgery. The technique is applicable to a broad array of applications, including surgical planning and mapping neuropsychological function to brain structure. Using this tool, we demonstrate that patients treated with SAH for refractory temporal lobe epilepsy have less postoperative cortical thinning in remote brain regions than those treated with ATL. We share all algorithm code and results to accelerate collaboration and clinical translation of our work.KEY POINTS BOXDifferent epilepsy surgical approaches lead to distinct patterns of postoperative cortical atrophy in remote brain regionsPatients treated with SAH have less postoperative cortical thinning than patients treated with ATLThe insula and frontal lobe demonstrated the greatest focal differences in postoperative cortical thinning when comparing SAH and ATLPostoperative cortical thinning analyses may inform surgical planning and our understanding of cognitive sequelae
Changes in physical activity, sitting and sleep across the COVID-19 national lockdown period in Scotland
Authors: Janssen Xanne , Fleming Leanne , Kirk Alison , Rollins Lesley , Young David , Grealy Madeleine , MacDonald Bradley , Flowers Paul , Williams Lynn 
Published: November 2020

AbstractWe examine the impact of the COVID-19 outbreak and concomitant restrictions (i.e. lockdown) on 24-hour movement behaviors (i.e. physical activity, sitting, sleep) in a purposive sample of people (n=3230) reporting change recruited on-line. Participants’ self-reported time spent in moderate-to-vigorous physical activity (MVPA), walking, sitting and sleep prior to lockdown (T1), during the first national lockdown (T2) and as restrictions initially started to ease (T3). For each 24-hour movement behavior, category-shifts are reported (positive, negative or did not change), as well as the percentage of participants recording positive/negative changes across clusters of behaviors and the percentage of participants recording improvement or maintenance of change across time. From T1 to T2 walking decreased, whereas MVPA, sitting and sleep increased, from T2 to T3 levels returned to pre-lockdown for all but MVPA. Participants who changed one behavior positively were more likely to report a positive change in another and 50% of those who reported positive changes from T1 to T2 maintained or improved further when restrictions started to ease. The current study showed that a large proportion of the sample reported positive changes, most notably those displaying initially poor levels of each behavior. These findings will inform salutogenic intervention development.
Single-cell RNA-seq uncovers shared and distinct axes of variation in dorsal LGN neurons in mice, non-human primates and humans
Authors: Bakken Trygve E. , van Velthoven Cindy T.J. , Menon Vilas , Hodge Rebecca D. , Yao Zizhen , Nguyen Thuc Nghi , Graybuck Lucas T. , Horwitz Gregory D. , Bertagnolli Darren , Goldy Jeff , Garren Emma , Parry Sheana , Casper Tamara , Shehata Soraya I. , Barkan Eliza R. , Szafer Aaron , Levi Boaz P. , Dee Nick , Smith Kimberly A. , Sunkin Susan M. , Bernard Amy , Phillips John W. , Hawrylycz Michael , Koch Christof , Murphy Gabe , Lein Ed , Zeng Hongkui , Tasic Bosiljka 
Published: November 2020

ABSTRACTAbundant anatomical and physiological evidence supports the presence of at least three distinct types of relay glutamatergic neurons in the primate dorsal lateral geniculate nucleus (dLGN) of the thalamus, the brain region that conveys visual information from the retina to the primary visual cortex. Relay neuron diversity has also been described in the mouse dLGN (also known as LGd). Different types of relay neurons in mice, humans and macaques have distinct morphologies, distinct connectivity patterns, and convey different aspects of visual information to the cortex. To investigate the molecular underpinnings of these cell types, and how these relate to other cellular properties and differences in dLGN between human, macaque, and mice, we profiled gene expression in single nuclei and cells using RNA-sequencing. These efforts identified four distinct types of relay neurons in the primate dLGN, magnocellular neurons, parvocellular neurons, and two cell types expressing canonical marker genes for koniocellular neurons. Surprisingly, despite extensive documented morphological and physiological differences between magno- and parvocellular neurons, we identified few genes with significant differential expression between transcriptomic cell types corresponding to these two neuronal populations. We also detected strong donor-specific gene expression signatures in both macaque and human relay neurons. Likewise, the dominant feature of relay neurons of the adult mouse dLGN is high transcriptomic similarity, with an axis of heterogeneity that aligns with core vs. shell portions of mouse dLGN. Together, these data show that transcriptomic differences between principal cell types in the mature mammalian dLGN are subtle relative to striking differences in morphology and cortical projection targets. Finally, we align cellular expression profiles across species and find homologous types of relay neurons in macaque and human, and distinct relay neurons in mouse.
PDE1 inhibition modulates Cav1.2 channel to stimulate cardiomyocyte contraction
Authors: Muller Grace K , Song Joy , Jani Vivek , Wu Yuejin , Anderson Mark E , Kass David A 
Published: November 2020

ABSTRACTRationaleCyclic adenosine monophosphate (cAMP) activation of protein kinase A (PKA) stimulates excitation-contraction coupling, increasing cardiac contractility. This is clinically leveraged by beta-adrenergic stimulation (β-ARs) or phosphodiesterase-3 inhibition (PDE3i), though both approaches are limited by arrhythmia and chronic myocardial toxicity. Phosphodiesterase-1 inhibition (PDE1i) also augments cAMP and was recently shown in rabbit cardiomyocytes to augment contraction independent of β-AR stimulation or blockade, and with less intracellular calcium rise than β-ARs or PDE3i. Early testing of PDE1 inhibition in humans with neuro-degenerative disease and dilated heart failure has commenced. Yet, the molecular mechanisms for PDE1i inotropic effects remain largely unknown.ObjectiveDefine the mechanism(s) whereby PDE1i increases contractility.Methods and ResultsPrimary guinea pig myocytes which express the cAMP-hydrolyzing PDE1C isoform found in larger mammals and humans were studied. The potent, selective PDE1i (ITI-214) did not alter cell shortening or Ca2+transients under resting conditions whereas both increased with β-ARs or PDE3i. However, PDE1i enhanced shortening with less Ca2+rise in a PKA-dependent manner when combined with low-dose adenylate cyclase stimulation (Forskolin). Unlike PDE3i, PDE1i did not augment β-AR responses. Whereas β-ARs reduced myofilament Ca2+sensitivity and increased sarcoplasmic reticular Ca2+content in conjunction with greater phosphorylation of troponin I, myosin binding protein C, and phospholamban, PDE1i did none of this. However, PDE1i increased Cav1.2 channel conductance similar to PDE3i in a PKA-dependent manner. Myocyte shortening and peak Ca2+transients were more sensitive to Cav1.2 blockade with nitrendipine combined with PDE1i versus PDE3i. Lastly, PDE1i was found to be far less arrythmogenic than PDE3i.ConclusionsPDE1i enhances contractility by a PKA-dependent increase in Cav1.2 conductance without concomitant myofilament desensitization. The result is less rise in intracellular Ca2+and arrhythmia compared to β-ARs and/or PDE3i. PDE1i could be a novel positive inotrope for failing hearts without the toxicities of β-ARs and PDE3i.
Aryl hydrocarbon receptor and TGF-β inducible early gene mediate a transcriptional axis modulating immune homeostasis in mosquitoes
Authors: Kulkarni Aditi , Pandey Ashmita , Trainor Patrick , Carlisle Samantha , Yu Wanqin , Kukutla Phanidhar , Xu Jiannong 
Published: November 2020

AbstractImmune homeostasis ensures effective pathogen defense and avoids overactivity, which is achieved through an orchestrated transcriptional network. Here we demonstrate that mosquito AhR and TIEG mediate a transcriptional axis to modulate the immune response. The AhR agonist compromised the immunity with reduced survival upon the challenge with bacteriumSerratia fonticola, while the AhR antagonists enhanced the immunity with increased survival. The phenotype of pharmacological immune enhancement was corroborated genetically by theAhRgene silencing. The transcriptome comparison following AhR manipulations highlighted a set of AhR regulated genes, from which transcription factor TIEG, the ortholog of Krüppel-like factor 10, was chosen for further study. TIEG was required for the AhR mediated immune modulation. SilencingTIEGincreased survival and reversed the immune suppression mediated by agonist-activated AhR. Among the transcriptomes, there were genes sharing co-expression patterns in the cohorts with AhR manipulation pharmacologically or genetically. Moreover, the mosquitoes with silencedTIEGandAhRshared ~68% altered genes upon infection. Together, the data suggest TIEG is downstream of AhR, acting as a major transcription factor mediating the immune modulation. The TIEG targets include genes involved in sugar metabolism and circadian rhythms, both processes are critical for immune homeostasis. In the naïve mosquitoes, the AhR-TIEG axis prevents the adverse effect of the overactivated IMD pathway created by silencing the inhibitorCaspar. In summary, AhR and TIEG constitute a transcriptional axis that mediates a gene network critical for maintaining immune homeostasis.SignificanceImmune homeostasis is sustained by various parameters involving different transcriptional regulatory networks. Such knowledge in mosquitoes remains scarce. Here, using AhR manipulation and transcriptome interrogation, we demonstrate that AhR and TIEG (a KLF10 ortholog) constitute a transcriptional axis to mediate immune modulation using an antibacterial immune model in the malaria vectorAnopheles gambiae. AhR is a ligand-activated transcription factor that senses environmental signals and transcribes relevant genes to modulate immune responses. TIEG/KLF10, conserved from invertebrates to mammals, mediates various transcriptional networks. Our data show that the AhR-TIEG axis controls the genes involving in sugar sensing and circadian rhythms in the infection context. This finding warrants further study to elucidate the transcriptional control of metabolic and circadian behind immune homeostasis.
Metabolomic investigation of the pseudouridimycin producer, a prolific streptomycete
Authors: Iorio Marianna , Davatgarbenam Sahar , Serina Stefania , Criscenzo Paolo , Zdouc Mitja M. , Simone Matteo , Maffioli Sonia I. , Ebright Richard H. , Donadio Stefano , Sosio Margherita 
Published: November 2020

ABSTRACTWe report a metabolomic analysis of Streptomyces sp. ID38640, a soil isolate that produces the bacterial RNA polymerase inhibitor pseudouridimycin. The analysis was performed on the wild type and on ten different pum mutants blocked at different steps in pseudouridimycin biosynthesis. The results indicate that Streptomyces sp. ID38640 is able to produce, in addition to pseudouridimcyin, lydicamycins and deferroxiamines, as previously reported, also the lassopeptide ulleungdin, the non-ribosomal peptide antipain and the osmoprotectant ectoine. The corresponding biosynthetic gene clusters were readily identified in the strain genome. We also detected the known compound pyridindolol, for which we propose a previously unreported biosynthetic gene cluster, as well as three families of unknown metabolites. Remarkably, the levels of the different metabolites varied strongly in the different mutant strains, allowing detection of metabolites not normally seen in the wild type. Three newly constructed pum mutants, along with systematic investigation of the accumulated metabolites, shed further lights on pseudouridimycin biosynthesis. We also show that several Streptomyces strains, harboring the pum biosynthetic gene cluster and unrelated to ID38640, readily produce pseudouridimycin.
A Fast Lysine Cross-linker DOPA Enables Mass Spectrometry Analyses of Protein Unfolding and Weak Protein-protein Interactions
Authors: Wang Jian-Hua , Tang Yu-Liang , Jain Rohit , Xiao Fan , Gong Zhou , Zhou Yu , Tan Dan , Li Qiang , Dong Xu , Liu Shu-Qun , Tang Chun , Huang Niu , Ye Keqiong , Dong Meng-Qiu , Lei Xiaoguang 
Published: November 2020

AbstractChemical cross-linking of proteins coupled with mass spectrometry analysis (CXMS) has become a widely used method for protein structure analysis. Central to this technology are chemical cross-linkers. The most popular cross-linkers are N-hydroxysuccinimide (NHS) esters, which react with protein amino groups relatively slowly over 10 minutes or more while in competition with the hydrolysis reaction of NHS esters. To improve the speed of cross-linking, we developed a new class of amine-selective and non-hydrolyzabledi-ortho-phthalaldehyde (DOPA) cross-linkers. DOPA can cross-link proteins in 10 seconds under near physiological conditions, which is 60 times faster than the NHS ester cross-linker DSS. DOPA also works at low pH, low temperature, or in the presence of high concentrations of denaturants such as 8 M urea or 6 M guanidine hydrochloride. Further, DOPA-mediated pulse cross-linking captured the dynamic conformational changes associated with RNase A unfolding. Lastly, DOPA outperformed DSS at capturing weak but specific protein-protein interactions.
Liver FoxO1 overexpression is positively associated with the degree of liver injury in cirrhotic patients
Authors: Fernandez-Galán Esther , Sandalinas Silvia , Morales-Romero Blai , Macias Laura , Pauta Montse , Ribera Jordi , Casals Gregori , Boix Loreto , Bruix Jordi , Jimenez Wladimiro , Morales-Ruiz Manuel 
Published: November 2020

ABSTRACTIntroductionChronic liver disease is associated with high mortality. Liver transplantation is the definitive treatment for patients with end-stage liver disease, improving their survival and quality of life. However, chronic rejection of the graft and the imbalance between the demand and the availability of organs limit its applicability. Therefore, finding therapeutic and/or diagnostic alternatives for these patients is a priority. In this context, preclinical studies in rodents have demonstrated that Akt plays a key role in liver dysfunction. Even with all this evidence, the activation status of Akt and its downstream targets in the liver of patients with chronic hepatopathy is still unknown. Hence, the present study aims to determine the activation status of the molecules involved in the Akt signaling pathway in livers of cirrhotic patients.Materials and MethodsIn this study, 36 liver tissue samples from a cohort of 27 cirrhotic patients and 9 patients without cirrhosis were included. A total of 10 proteins involved in Akt/mTOR pathway (GSK3β, IGF1R, IRS1, mTOR, p70S6K, IR, PTEN, GSK3α, TSC2, and RPS6) were analyzed using a multiplex immunoassay based on Luminex® technology.ResultsSignificant differences were found in several Akt/mTOR target proteins between the groups of cirrhotic patients vs. non-cirrhotic: FoxO1 (9.5 vs. 4.4;p<0.01), p-Akt (2.1 vs. 1.0;p<0.01), PTEN (3.061 vs. 1.877;p<0.05) and p70S6K (196.3 vs. 270.5;p<0.001). FoxO1 showed the best correlation with biochemical markers of liver injury aspartate aminotransferase and serum alanine aminotransferase (ASAT: r=0.51,p<0.05; ALAT: r=0.49,p<0.05). Moreover, the individual influence of FoxO1 on these parameters was confirmed by multiple regression analysis. It was the only enzyme in the Akt signaling pathway identified as a positive independent predictor of increased ASAT and ALAT levels.ConclusionFoxO1 is overexpressed in the liver of cirrhotic patients after partial hepatectomy. FoxO1 levels are also associated with the degree of liver injury, showing a positive correlation with current biomarkers used in clinical practice to detect liver injury.