bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia
Authors: Wang Huabo , Lu Jie , Alencastro Frances , Roberts Alexander , Fiedor Julia , Carroll Patrick , Eisenman Robert N. , Ranganathan Sarangarajan , Torbenson Michael , Duncan Andrew W. , Prochownik Edward V. 
Published: August 2021

AbstractBackground & AimsThe c-Myc (Myc) bHLH-ZIP transcription factor is deregulated in most cancers. In association with Max, Myc controls target genes that supervise metabolism, ribosome biogenesis, translation and proliferation. This “Myc Network” cross-talks with the “Mlx Network”, which consists of the Myc-like proteins MondoA and ChREBP and Max-like Mlx. Together, this “Extended Myc Network” regulates both common and distinct genes targets. Here we studied the consequence of Myc and/or Mlx ablation in the liver, particularly those pertaining to hepatocyte proliferation, metabolism and spontaneous tumorigenesis.MethodsWe examined the ability of hepatocytes lacking Mlx (MlxKO) or Myc+Mlx (double KO or DKO) to repopulate the liver over an extended period of time in a murine model of Type I tyrosinemia. We also compared this and other relevant behaviors, phenotypes and transcriptomes of the livers to those from previously characterized MycKO, ChrebpKO and MycKO x ChrebpKO mice.ResultsHepatocyte regenerative potential deteriorated as the Extended Myc Network was progressively dismantled. Genes and pathways dysregulated in MlxKO and DKO hepatocytes included those pertaining to translation, mitochondrial function and non-alcoholic fatty liver disease (NAFLD). The Myc and Mlx Networks were shown to cross-talk, with the latter playing a disproportionate role in target gene regulation. All cohorts also developed NAFLD and molecular evidence of early steatohepatitis. Finally, MlxKO and DKO mice displayed extensive hepatic adenomatosis.ConclusionsIn addition to demonstrating cooperation between the Myc and Mlx Networks, this study revealed the latter to be more important in maintaining proliferative, metabolic and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis.SynopsisThe Myc and Mlx Networks exhibit extensive cross-talk and regulate distinct but overlapping sets of transcriptional targets. The current work demonstrates the cooperation between these two Networks in supporting the regenerative capabilities of normal hepatocytes while also revealing that the Mlx Network serves as a suppressor of spontaneous hepatic adenomatosis
Expression of soluble methane monooxygenase in Escherichia coli enables methane conversion
Authors: Bennett R. Kyle , Dzvova Nyaradzo , Dillon Michael , Jones Stephanie , Hestmark Kelley , Zhu Baolong , Helman Noah , Greenfield Derek , Clarke Elizabeth , Papoutsakis Eleftherios T. 
Published: August 2021

AbstractNatural gas and biogas provide an opportunity to harness methane as an industrial feedstock. Bioconversion is a promising alternative to chemical catalysis, which requires extreme operating conditions and exhibits poor specificities. Though methanotrophs natively utilize methane, efforts have been focused on engineering platform organisms like Escherichia coli for synthetic methanotrophy. Here, a synthetic E. coli methanotroph was developed by engineering functional expression of the Methylococcus capsulatus soluble methane monooxygenase in vivo via expression of its cognate GroESL chaperone. Additional overexpression of E. coli GroESL further improved activity. Incorporation of an acetone formation pathway then enabled the conversion of methane to acetone in vivo, as validated via 13C tracing. This work provides the first reported demonstration of methane bioconversion to liquid chemicals in a synthetic methanotroph.
A single layer artificial neural network type architecture with molecular engineered bacteria for complex conventional and reversible computing
Authors: Sarkar Kathakali , Bonnerjee Deepro , Srivastava Rajkamal , Bagh Sangram 
Published: August 2021

AbstractHere, we adapted the basic concept of artificial neural networks (ANN) and experimentally demonstrate a broadly applicable single layer ANN type architecture with molecular engineered bacteria to perform complex irreversible computing like multiplexing, de-multiplexing, encoding, decoding, majority functions, and reversible computing like Feynman and Fredkin gates. The encoder and majority functions and reversible computing were experimentally implemented within living cells for the first time. We created molecular-devices, which worked as artificial neuro-synapses in bacteria, where input chemical signals were linearly combined and processed through a non-linear activation function to produce fluorescent protein outputs. To create such molecular devices, we established a set of rules by corelating truth tables, mathematical equations of ANN, and molecular-device design, which unlike molecular computing, does not require circuit diagram and the equation directly correlates the design of the molecular-device. To our knowledge this is the first adaptation of ANN type architecture with engineered cells. This work may have significance in new platform for biomolecular computing, reversible computing and in transforming living cells as ANN-enabled hardware.
One Health or Three? Transmission modelling ofKlebsiellaisolates reveals ecological barriers to transmission between humans, animals and the environment
Authors: Thorpe Harry , Booton Ross , Kallonen Teemu , Gibbon Marjorie J. , Couto Natacha , Passet Virginie , Fernandez Juan Sebastian Lopez , Rodrigues Carla , Matthews Louise , Mitchell Sonia , Reeve Richard , David Sophia , Merla Cristina , Corbella Marta , Ferrari Carolina , Comandatore Francesco , Marone Piero , Brisse Sylvain , Sassera Davide , Corander Jukka , Feil Edward J. 
Published: August 2021

AbstractTheKlebsiellagroup is highly diverse both genetically and ecologically, being commonly recovered from humans, livestock, plants, soil, water, and wild animals. Many species are opportunistic pathogens, and can harbour diverse classes of antimicrobial resistance (AMR) genes.K. pneumoniaeis responsible for a high public-health burden, due in part to the rapid spread of health-care associated clones that are non-susceptible to carbapenems.Klebsiellathus represents a highly pertinent taxon for assessing the risk to public health posed by animal and environmental reservoirs. Here we report an analysis of 6548 samples and 3,482 genome sequences representing 15Klebsiellaspecies sampled over a 15-month period from a wide range of clinical, community, animal and environmental settings in and around the city of Pavia, in the northern Italian region of Lombardy. Despite carbapenem-resistant clones circulating at a high frequency in the hospitals, we find no genotypic or phenotypic evidence for non-susceptibility to carbapenems outside of the clinical environment. The non-random distribution of species and strains across sources point to ecological barriers that are likely to limit AMR transmission. Although we find evidence for occasional transmission between settings, hierarchical modelling and intervention analysis suggests that direct transmission from the multiple non-human (animal and environmental) sources included in our sample accounts for less than 1% of hospital disease, with the vast majority of clinical cases originating from other humans.
Evolution of the folding landscape of effector caspases
Authors: Shrestha Suman , Clark A. Clay 
Published: August 2021

AbstractCaspases are a family of cysteinyl proteases that control programmed cell death and maintain homeostasis in multicellular organisms. The caspase family is an excellent model to study protein evolution because all caspases are produced as zymogens (procaspases) that must be activated to gain full activity; the protein structures are conserved through hundreds of millions of years of evolution; and some allosteric features arose with the early ancestor while others are more recent evolutionary events. The apoptotic caspases evolved from a common ancestor into two distinct subfamilies: monomers (initiator caspases) or dimers (effector caspases). Differences in activation mechanisms of the two subfamilies, and their oligomeric forms, play a central role in the regulation of apoptosis. Here, we examine changes in the folding landscape by characterizing human effector caspases and their common ancestor. The results show that the effector caspases unfold by a minimum three-state equilibrium model at pH 7.5, where the native dimer is in equilibrium with a partially folded monomeric (procaspase-7, common ancestor) or dimeric (procaspase-6) intermediate. In comparison, the unfolding pathway of procaspase-3 contains both oligomeric forms of the intermediate. Overall, the data show that the folding landscape was first established with the common ancestor and was then retained for >650 million years. Partially folded monomeric or dimeric intermediates in the ancestral ensemble provide mechanisms for evolutionary changes that affect stability of extant caspases. The conserved folding landscape allows for the fine-tuning of enzyme stability in a species-dependent manner while retaining the overall caspase-hemoglobinase fold.
Integrating omics approaches to discover and prioritize candidate genes involved in oil biosynthesis in soybean
Authors: Turquetti-Moraes Dayana K. , Moharana Kanhu C. , Almeida-Silva Fabricio , Pedrosa-Silva Francisnei , Venancio Thiago M. 
Published: August 2021

AbstractSoybean is one of the major sources of edible protein and oil. Oil content is a quantitative trait that is significantly determined by genetic and environmental factors. Over the past 30 years, a large volume of soybean genetic, genomic, and transcriptomic data have been accumulated. Nevertheless, integrative analyses of such data remain scarce, in spite of their importance for crop improvement. We hypothesized that the co-occurrence of genomic regions for oil-related traits in different studies may reveal more stable regions encompassing important genetic determinants of oil content and quality in soybean. We integrated publicly available data, obtained with distinct techniques, to discover and prioritize candidate genes involved in oil biosynthesis and regulation in soybean. We detected key fatty acid biosynthesis genes (e.g., BCCP and ACCase, FADs, KAS family proteins) and several transcripton factors, which are likely regulators of oil biosynthesis. In addition, we identified new candidates for seed oil accumulation and quality, such as Glyma.03G213300 and Glyma.19G160700, which encode a translocator protein and a histone acetyltransferase, respectively. Further, oil and protein genomic hotspots are strongly associated with breeding and not with domestication, suggesting that soybean domestication prioritized other traits. The genes identified here are promising targets for breeding programs and for the development of soybean lines with increased oil content and quality.
Structure of PINK1 reveals autophosphorylation dimer and provides insights into binding to the TOM complex
Authors: Rasool Shafqat , Veyron Simon , Soya Naoto , Eldeeb Mohamed , Lukacs Gergely L. , Fon Edward A. , Trempe Jean-François 
Published: August 2021

SummaryMutations in PINK1 causes autosomal-recessive Parkinson’s disease. Mitochondrial damage results in PINK1 import arrest on the Translocase of the Outer Mitochondrial Membrane (TOM) complex, resulting in the activation of its ubiquitin kinase activity by autophosphorylation and initiation of Parkin-dependent mitochondrial clearance. Herein we report crystal structures of the entire cytosolic domain of insect PINK1. Our structures reveal a dimeric autophosphorylation complex targeting phosphorylation at the invariant Ser205 (human Ser228). The dimer interface requires insert 2, which is unique to PINK1. The structures also reveal how an N-terminal helix binds to the C-terminal extension and provide insights into stabilization of PINK1 on the core TOM complex.
Fat specific adipose triglyceride lipase is necessary for iron-mediated lipolysis and lipid mobilization in response to negative energy balance
Authors: Romero Alicia R. , Mu Andre , Ayres Janelle S. 
Published: August 2021

SummaryMaintenance of energy balance is essential for the overall health of an organism. In mammals, both negative and positive energy balance are associated with disease states. To maintain their energy balance within a defined homeostatic setpoint, mammals have evolved complex regulatory mechanisms that control energy intake and expenditure. Traditionally, studies have focused on understanding the role of macronutrient physiology in energy balance. In the present study, we examined the role of the essential micronutrient iron in regulating energy balance. Using a dietary model, we found that a short course of excess dietary iron caused a negative energy balance resulting in a severe whole body wasting phenotype. This disruption in energy balance was due to an iron dependent increase in energy expenditure caused by a heightened basal metabolic rate and activity level. Using a transgenic mouse model lacking adipose triglyceride lipase (ATGL) specifically in fat tissue, we found that to meet the increased energetic demands, dietary iron caused increased lipid utilization that required fat specific ATGL-mediated lipid mobilization and wasting of subcutaneous white adipose tissue deposits. When fed dietary iron, mice lacking fat-specific ATGL activity were protected from fat wasting, and developed a severe cachectic response that is necessary to meet the increased energetic demands caused by the dietary regimen. Our work highlights the multi-faceted role of iron regulation of organismal metabolism and provides a novel in vivo mechanism for micronutrient control of lipolysis that is necessary for regulating mammalian energy balance.
Physiological Magnesium Concentrations Increase Fidelity of Diverse Reverse Transcriptases from HIV-1, HIV-2, and Foamy Virus, but not MuLV or AMV
Authors: Wang Ruofan , Belew Ashton T. , Achuthan Vasudevan , Sayed Najib El , DeStefano Jeffrey J. 
Published: August 2021

AbstractReverse transcriptases (RTs) are typically assayed in vitro using optimized Mg2+ concentrations (∼5-10 mM) several-fold higher than physiological cellular free Mg2+ (∼0.5 mM). Analysis of fidelity using lacZα-based α-complementation assays showed that tested HIV RTs, including HIV-1 from subtype B (HXB2-derived), HIV-2, subtype A/E, and several drug-resistant HXB2 derivatives all showed significantly higher fidelity using physiological Mg2+. This also occurred with prototype foamy virus (PFV) RT. In contrast, Moloney murine leukemia virus (MuLV) and avian myeloblastosis virus (AMV) RTs demonstrated equivalent fidelity in both low and high Mg2+. In 0.5 mM Mg2+, all RTs demonstrated ≈ equal fidelity, except for PFV RT which showed higher fidelity. A Next Generation Sequencing (NGS) approach that used barcoding to accurately determine mutation rates and profiles was used to examine the types of mutations made by HIV-1 (subtype B, wild type) in low (0.5 mM) and high (6 mM) Mg2+ with DNA or RNA that coded for lacZα. Unlike the α-complementation assay, which is dependent on LacZα activity, the NGS assay scores mutations at all positions and of every type. Consistent with α-complementation assays, a ∼4-fold increase in mutations was observed in high Mg2+. These findings help explain why HIV RT displays lower fidelity in vitro (with high Mg2+ concentrations) than other RTs (e.g., MuLV and AMV), yet cellular fidelity for these viruses is comparable. Establishing in vitro conditions that accurately represent RT’s activity in cells is pivotal to determining the contribution of RT and other factors to the mutation profile observed with HIV.
Design of Transmembrane Mimetic Structural Probes to Trap Different Stages of γ-Secretase-Substrate Interaction
Authors: Bhattarai Sanjay , Devkota Sujan , Wolfe Michael S. 
Published: August 2021

ABSTRACTThe transmembrane domain (TMD) of the amyloid precursor protein of Alzheimer’s disease is processively cut by γ-secretase through endoproteolysis and tricarboxypeptidase “trimming”. We recently developed a prototype substrate TMD mimetic for structural analysis—composed of a helical peptide inhibitor linked to a transition-state analog—that simultaneously engages a substrate exosite and the active site and is pre-organized to trap the carboxypeptidase transition state. Here we developed variants of this prototype designed to allow visualization of transition states for endoproteolysis, TMD helix unwinding, and lateral gating of substrate, identifying potent inhibitors for each class. These TMD mimetics exhibited non-competitive inhibition and occupy both exosite and active site as demonstrated by inhibitor cross competition experiments and photoaffinity probe binding assays. The new probes should be important structural tools for trapping different stages of substrate recognition and processing via ongoing cryo-electron microscopy with γ-secretase, ultimately aiding rational drug design.
The orphan drug dichloroacetate reduces amyloid beta-peptide production whilst promoting non-amyloidogenic proteolysis of the amyloid precursor protein
Authors: Parkin Edward T. , Hammond Jessica E. , Hodges Matthew D. 
Published: August 2021

AbstractThe amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer’s disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by β- and γ-secretases in the ‘amyloidogenic’ proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the ‘non-amyloidogenic’ pathway which, through the action of the α-secretaseadisintegrinandmetalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting β-secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the β-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. As the drug is already used for the treatment of lactic acidosis and is known to cross the blood-brain-barrier, it might represent a cheap and effective therapy for slowing the progression of Alzheimer’s disease.
Effects of enhanced insect feeding on the faecal microbiota and transcriptome of a family of captive common marmosets (Callithrix jacchus)
Authors: Yamazaki Yumiko , Moriya Shigeharu , Kawarai Shinpei , Morita Hidetoshi , Kikusui Takefumi , Iriki Atsushi 
Published: August 2021

AbstractCommon marmosets have been widely used in biomedical research for years. Nutritional control is an important factor in managing their health, and insect intake would be beneficial for that purpose because common marmosets frequently feed on insects in natural habitats. Here, we examined the effect of enhanced insect feeding on the gut by analysing the faecal microbiota and transcripts of captive marmosets. A family consisting of six marmosets was divided into two groups. During the seven-day intervention period, one group (the insect feeding group, or Group IF) was fed one cricket and one giant mealworm per marmoset per day, while the other (the control group, or Group C) was not fed these insects. RNA was extracted from faecal samples to evaluate the ecology and transcripts of the microbiota, which were then compared among time points before (Pre), immediately after (Post), and two weeks after intervention (After) by total RNA sequencing. The gut microbiota of marmosets showedFirmicutes,Actinobacteria,Bacteroidetes, andProteobacteriaas dominant phyla. Linear discriminant analysis showed differential characteristics of microbiota with and without insect feeding treatment. Further analysis of differentially expressed genes revealed increases and decreases inBacteroidetesandFirmicutes, respectively, corresponding to the availability of insects under both Post and After conditions. Significant changes specific to insect feeding were also detected within the transcriptome, some of which were synchronized with the fluctuations in the microbiota, suggesting a functional correlation or interaction between the two. The rapid changes in the microbiota and transcripts may be deeply connected to the original microbiota community shaped by marmoset feeding ecology in the wild. The results were informative for identifying the physiological impact of insect feeding to produce a better food regimen and for detecting transcripts that are currently unidentifiable.
The pink salmon genome: uncovering the genomic consequences of a strict two-year life-cycle
Authors: Christensen Kris A. , Rondeau Eric B. , Sakhrani Dionne , Biagi Carlo A. , Johnson Hollie , Joshi Jay , Flores Anne-Marie , Leelakumari Sreeja , Moore Richard , Pandoh Pawan K. , Withler Ruth E. , Beacham Terry D. , Leggatt Rosalind A. , Tarpey Carolyn M. , Seeb Lisa W. , Seeb James E. , Jones Steven J.M. , Devlin Robert H. , Koop Ben F. 
Published: August 2021

AbstractPink salmon (Oncorhynchus gorbuscha) adults are the smallest of the five Pacific salmon native to the western Pacific Ocean. Pink salmon are also the most abundant of these species and account for a large proportion of the commercial value of the salmon fishery worldwide. A strict two-year life-history of most pink salmon generates temporally isolated populations that spawn either in even-years or odd-years. To uncover the influence of this genetic isolation, reference genome assemblies were generated for each year-class and whole genome re-sequencing data was collected from salmon of both year-classes. The salmon were sampled from six Canadian rivers and one Japanese river. At multiple centromeres we identified peaks of Fst between year-classes that were millions of base-pairs long. The largest Fst peak was also associated with a million base-pair chromosomal polymorphism found in the odd-year genome near a centromere. These Fst peaks may be the result of centromere drive or a combination or reduced recombination and genetic drift, and they could influence speciation. Other regions of the genome influenced by odd-year and even-year temporal isolation and tentatively under selection were mostly associated with genes related to immune function, organ development/maintenance, and behaviour.