bluuebunny/crossref_metadata_2025 huggingface dataset:
A Deep Learning approach predicts the impact of point mutations in intronic flanking regions on micro-exon splicing definition
Authors: DaSilva Lucas F. , Tahira Ana C. , Mesel Vinicius , Verjovski-Almeida Sergio
Published: December 2019

While mammalian exons are on average 140-nt-long, thousands of human genes harbor micro-exons (≤ 39 nt). Large numbers of micro-exons have their splicing altered in diseases such as autism and cancer, and yet there is no systematic assessment of the impact of point mutations in intronic flanking-sequences on the splicing of a neighboring micro-exon. Here, we constructed a model using the Convolutional Neural Network (CNN) to predict the impact of point mutations in intronic-flanking-sequences on the splicing of a neighboring micro-exon. The prediction model was based on both the sequence contents and conservation among species of the two 100-nt intronic regions (5’ and 3’) that flank all human micro-exons and a set with the same number of randomly selected long exons. After training our CNN model, the micro-exon splicing event prediction accuracy, using an independent validation dataset, was 0.71 with an area under the ROC curve of 0.76, showing that our model had identified sequence patterns that have been conserved in evolution in the introns that flank micro-exons. Next, we introduced in silico point mutations at each of the 200 nucleotides in the introns that flank a micro-exon and used the trained CNN algorithm to predict splicing for every mutated intronic sequence version. This analysis identified thousands of point mutations in the flanking introns that significantly decreased the power of the CNN model to correctly predict a neighboring micro-exon splicing event, thus pointing to predictive bases in intronic regions important for micro-exon splicing signaling. We found these predictive bases to locate within conserved RNA-binding-motifs for RNA-binding-proteins (RBPs) known to relate to micro-exon splicing. Experimental data of minigene splicing reporter changes upon intron-base point-mutation confirmed the effect predicted by the CNN model for some of the micro-exon splicing events. The model can be used for validating novel micro-exons de novo assembled from RNA-seq data, and for an unbiased screening of introns, identifying genomic bases that have high micro-exon-splicing predictive power, possibly revealing critical point mutations that would be related in a yet unknown manner to a given disease.
Factors Affecting Detection Of GMO Traces In Food And Crop Samples
Authors: Hassan Waqar , Jamil Nadia , Siddiqui Shehzaib , Ali Anam , Quadri Owais , Wajeeh Maliha , Khan Aftab Ahmed , Khan Saifullah
Published: December 2019

Rice is one of the highly consumable and demanded food crops throughout the world. To meet this requirement, genetically modified (GM) crops were introduced, which were met with sturdy and frequently angry opposition by the user. To handle the situation labeling of GM food / crop was advised, thus demand for traceability and detection of unknown modified genes increased.

Modified genes are detected by various methods; these methods are affected by several factors as reported in international standards. Those factors include presence / absence of shells, husk, and dust, method of DNA extraction and different PCR primers. These factors ultimately pose hindrance in detection of modified genes.

This study was conducted to analyze the effects of the above mentioned factors on detection of GM rice samples. Furthermore two different sets of primers were used with same samples and their impact on the PCR detection was observed.

The results showed a significant difference in DNA concentration between the rice samples with husk, without husk and after seed germination. Furthermore, the change of PCR primer set also affected the detection of genetic modifications. This allows analysis of the potential factors that may have impact on the final results.
Discovery of a Selective, State-Independent Inhibitor of NaV1.7 by Modification of Guanidinium Toxins
Authors: Pajouhesh H , Beckley JT , Delwig A , Hajare HS , Luu G , Monteleone D , Zhou X , Ligutti J , Amagasu S , Moyer BD , Yeomans D , Du Bois J , Mulcahy JV
Published: December 2019

The voltage-gated sodium channel isoform NaV1.7 is highly expressed in small diameter dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-function and loss-of-function NaV1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These findings implicate NaV1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting NaV1.7 have been advanced to clinical development, no NaV1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a NaV1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC50 of 72 nM and greater than 200-fold selectivity over off-target sodium channel isoforms, NaV1.1–1.6 and NaV1.8. In contrast to other NaV1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent against resting and inactivated protein conformers. In a non-human primate model, animals treated with ST-2262 exhibit markedly reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for selective ligand design and provide insight into the pharmacology of state-independent inhibition of NaV1.7.

Significance Statement

Pain is among the most common reasons for seeking medical care, yet many frequently prescribed drugs, particularly the opioids, cause problematic side effects and carry a risk of addiction. Voltage-gated sodium ion channels (NaVs) have emerged as promising targets for the development of non-opioid pain medicines. NaVs are involved in the propagation of electrical signals along neurons throughout the body. Humans born without a functional copy of one sodium channel subtype, NaV1.7, are unable to experience most types of pain. In the present work, we disclose the discovery and characterization of a selective inhibitor of NaV1.7 that reduces sensitivity to a painful thermal stimulus in non-human primates. Findings from this work may help guide the development of novel, non-addictive drug candidates as alternatives to opioids.
Acid sensing ion channel 1a is a key mediator of cardiac ischemia-reperfusion injury
Authors: Redd Meredith A. , Scheuer Sarah E. , Saez Natalie J. , Gao Ling , Hicks Mark , Villanueva Jeanette E. , Reichelt Melissa E. , Peart Jason N. , See Hoe Louise E. , Chiu Han S. , Chen Xiaoli , Sun Yuliangzi , Suen Jacky Y. , Hatch Robert J , Rollo Ben , Alzubaidi Mubarak A.H. , Maljevic Snezana , Quaife-Ryan Greg A. , Thomas Walter G. , Hudson James E. , Porrello Enzo R. , Cuellar-Partida Gabriel , Fraser John F. , Petrou Steven , King Glenn F. , Macdonald Peter S. , Palpant Nathan J.
Published: December 2019

The proton-gated acid-sensing ion channel 1a (ASIC1a) is implicated in the injury response to cerebral ischemia but little is known about its role in cardiac ischemia. We provide genetic evidence that ASIC1a is involved in myocardial ischemia-reperfusion injury (IRI) and show that pharmacological inhibition of ASIC1a yields robust cardioprotection in rodent and human models of cardiac ischemia, resulting in improved post-IRI cardiac viability and function. Consistent with a key role for ASIC1a in cardiac ischemia, we show that polymorphisms in the ASIC1 genetic locus are strongly associated with myocardial infarction. Collectively, our data provide compelling evidence that ASIC1a is a key target for cardioprotective drugs to reduce the burden of disease associated with myocardial ischemia.
Analytical solution of linearized equations of the Morris-Lecar neuron model at large constant stimulation
Authors: Paraskevov A.V. , Zemskova T.S.
Published: December 2019

The classical biophysical Morris-Lecar model of neuronal excitability predicts that upon stimulation of the neuron with a sufficiently large constant depolarizing current there exists a finite interval of the current values where periodic spike generation occurs. Above the upper boundary of this interval, there is four-stage damping of the spike amplitude: 1) minor primary damping, which reflects a typical transient to stationary dynamic state, 2) plateau of nearly undamped periodic oscillations, 3) strong damping, and 4) reaching a constant asymptotic value of the neuron potential. We have shown that in the vicinity of the asymptote the Morris-Lecar equations can be reduced to the standard equation for exponentially damped harmonic oscillations. Importantly, all coefficients of this equation can be explicitly expressed through parameters of the original Morris-Lecar model, enabling direct comparison of the numerical and analytical solutions for the neuron potential dynamics at later stages of the spike amplitude damping.
Region-specific and dose-specific effects of chronic haloperidol exposure on [3H]-Flumazenil and [3H]-Ro15-4513 GABAA receptor binding sites in the rat brain
Authors: Peris-Yague Alba , Kiemes Amanda , Cash Diana , Cotel Marie-Caroline , Singh Nisha , Vernon Anthony C. , Modinos Gemma
Published: December 2019

Post-mortem studies suggest that schizophrenia is associated with abnormal expression of specific GABAA receptor (GABAAR) α subunits, including α5GABAAR. Positron emission tomography (PET) measures of GABAAR availability in schizophrenia, however, have not revealed consistent alterations in vivo. Animal studies using the GABAAR agonist [3H]-muscimol provide evidence that antipsychotic drugs influence GABAAR availability, in a region-specific manner, suggesting a potential confounding effect of these drugs. No such data, however, are available for more recently developed subunit-selective GABAAR radioligands. To address this, we therefore combined a rat model of clinically relevant antipsychotic drug exposure with quantitative receptor autoradiography. Haloperidol (0.5 and 2 mg/kg/day) or drug vehicle were administered continuously to adult male Sprague-Dawley rats via osmotic mini-pumps for 28 days. Quantitative receptor autoradiography was then performed post-mortem using the GABAAR subunit-selective radioligand [3H]-Ro15-4513 and the non-subunit selective radioligand [3H]-flumazenil. Chronic haloperidol exposure increased [3H]-Ro15-4513 binding in the CA1 sub-field of the rat dorsal hippocampus (p<0.01; q<0.01; d = +1.3), which was not dose-dependent. [3H]-flumazenil binding also increased in most rat brain regions (p<0.05; main effect of treatment), irrespective of the haloperidol dose. These data confirm previous findings that chronic haloperidol exposure influences the specific binding of non-subtype selective GABAAR radioligands and is the first to demonstrate a potential effect of haloperidol on the binding of a α1/5GABAAR-selective radioligand. Although caution should be exerted when extrapolating results from animals to patients, our data support a view that exposure to antipsychotics may be a confounding factor in PET studies of GABAAR in the context of schizophrenia.
Natural transformation of the filamentous cyanobacterium Phormidium lacuna
Authors: Nies Fabian , Mielke Marion , Pochert Janko , Lamparter Tilman
Published: December 2019

Research for biotechnological applications of cyanobacteria focuses on synthetic pathways and bioreactor design, while little effort is devoted to introduce new, promising organisms in the field. Applications are most often based on recombinant work, and the establishment of transformation can be a risky, time-consuming procedure. In this work we demonstrate the natural transformation of the filamentous cyanobacterium Phormidium lacuna and insertion of a selection marker into the genome by homologous integration. This is the first example for natural transformation of a member of the order Oscillatoriales. We found that Phormidium lacuna is polyploid, each cell has about 20-100 chromosomes. Transformed filaments were resistant against up to 15 mg/ml of kanamycin, and the high resistance feature allowed for rapid segregation into all chromosomes. Formerly, natural transformation in cyanobacteria has been considered a rare and exclusive feature of a few unicellular species. Our finding suggests that natural competence is more distributed among cyanobacteria than previously thought. This is supported by bioinformatic analyses which show that all protein factors for natural transformation are present in the majority of the analyzed cyanobacteria.
Adverse caregiving in infancy blunts neural processing of the mother: Translating across species
Authors: Opendak Maya , Theisen Emma , Blomkvist Anna , Hollis Kaitlin , Lind Teresa , Sarro Emma , Lundström Johan N. , Tottenham Nim , Dozier Mary , Wilson Donald A , Sullivan Regina M
Published: December 2019

The roots of psychopathology frequently take shape during infancy in the context of parent-infant interactions and adversity. Yet, neurobiological mechanisms linking these processes during infancy remain elusive. Here, using responses to attachment figures among infants who experienced adversity as a benchmark, we assessed rat pup cortical Local Field Potentials (LFP) and behaviors exposed to adversity in response to maternal rough and nurturing handling by examining its impact on pup separation-reunion with the mother. We show that during adversity, pup cortical LFP dynamic range decreased during nurturing maternal behaviors, but was minimally impacted by rough handling. During reunion, adversity-experiencing pups showed aberrant interactions with mother and blunted cortical LFP. Blocking pup stress hormone during either adversity or reunion restored typical behavior, LFP power, and cross-frequency coupling. This translational approach suggests adversity-rearing produces a stress-induced aberrant neurobehavioral processing of the mother, which can be used as an early biomarker of later-life pathology.
The Genomic Loci of Specific Human tRNA Genes Exhibit Ageing-Related DNA Hypermethylation
Authors: Acton Richard J. , Yuan Wei , Gao Fei , Xia Yudong , Bourne Emma , Wozniak Eva , Bell Jordana , Lillycrop Karen , Wang Jun , Dennison Elaine , Harvey Nicholas , Mein Charles A. , Spector Tim D. , Hysi Pirro G. , Cooper Cyrus , Bell Christopher G.
Published: December 2019

The epigenome deteriorates with age, potentially impacting on ageing-related disease.

Here, we interrogate the DNA methylation state of the genomic loci of human tRNA. Whilst arising from only ~46kb (<0.002% genome), this information transfer machinery is the second most abundant cellular transcript. tRNAs also control metabolic processes known to affect ageing, through core translational and additional regulatory roles.

We identified a genomic enrichment for age-related DNA hypermethylation at tRNA loci. Analysis in 4,350 MeDIP-seq peripheral-blood DNA methylomes (16-82 years), classified 44 and 21 hypermethylating specific tRNAs at study- and genome-wide significance, respectively, contrasting with 0 hypomethylating. Validation and replication (450k array & independent targeted Bisuphite-sequencing) supported thehypermethylation of this functional unit. The strongest consistent signals, also independent of major cell-type change, occur in tRNA-iMet-CAT-1-4 and tRNA-Ser-AGA-2-6.

This study is this first comprehensive evaluation of the genomic DNA methylation state of human tRNA genes and reveals a discreet hypermethylation with advancing age.
The Role of Central Amygdala Corticotropin-Releasing Factor in Predator Odor Stress-Induced Avoidance Behavior and Escalated Alcohol Drinking in Rats
Authors: Weera Marcus M. , Schreiber Allyson L. , Avegno Elizabeth M. , Gilpin Nicholas W.
Published: December 2019

Post-traumatic stress disorder (PTSD) is characterized by avoidance of trauma-associated stimuli and amygdala hyperreactivity, and is highly co-morbid with alcohol use disorder (AUD). Our lab uses a predator odor (bobcat urine) stress model that produces conditioned avoidance of an odor-paired context in a subset of rats, mirroring avoidance symptoms that manifest in some but not all humans exposed to trauma. We previously showed that after predator odor stress, Avoiders exhibit escalated alcohol drinking, higher aversion-resistant operant alcohol responding, hyperalgesia, and greater anxiety-like behavior compared to unstressed Controls. We also showed that systemic antagonism of corticotropin-releasing factor-1 receptors (CRFR1) reduced escalation of alcohol drinking in rats not indexed for avoidance, that corticotropin-releasing factor (CRF) infusions into the central amygdala (CeA) produced conditioned place avoidance in stress-naïve rats, and that intra-CeA infusion of a CRFR1 antagonist reduced hyperalgesia in Avoiders. Here, we show that avoidance behavior is persistent after repeated predator odor exposure and is resistant to extinction. In addition, Avoiders showed lower weight gain than Controls after predator odor re-exposure. In the brain, higher avoidance was correlated with higher number of c-Fos+ cells and CRF immunoreactivity in the CeA. Finally, we show that intra-CeA CRFR1 antagonism reversed post-stress escalation of alcohol drinking and reduced avoidance behavior in Avoiders. Collectively, these findings suggest that elucidation of the mechanisms by which CRFR1-gated CeA circuits regulate avoidance behavior and alcohol drinking may lead to better understanding of the neural mechanisms underlying co-morbid PTSD and AUD.
The Dopamine Receptor Antagonist TFP Prevents Phenotype Conversion and Improves Survival in Mouse Models of Glioblastoma
Authors: Bhat Kruttika , Saki Mohammad , Vlashi Erina , Cheng Fei , Duhachek-Muggy Sara , Alli Claudia , Yu Garrett , Medina Paul , He Ling , Damoiseaux Robert , Pellegrini Matteo , Zemke Nathan R. , Nghiemphu Phioanh Leia , Cloughesy Timothy F. , Liau Linda M. , Kornblum Harley I. , Pajonk Frank
Published: December 2019

Glioblastoma (GBM) is the deadliest adult brain cancer and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 months over surgery alone but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP caused loss of radiation-induced Nanog mRNA expression, activation of GSK3 with consecutive post-translational reduction in p-Akt, Sox2 and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICsin vivoand prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment resistant, induced GICs.

Significance

GBM is the most common and most deadly adult brain cancer. The current standard-of-care is surgery followed by RT and temozolomide, which results in a median survival time of only 15 months. The efficacy of chemotherapies and targeted therapies in GBM is very limited because most of these drugs do not pass the blood-brain-barrier. Ultimately, all patients succumb to the disease. Our study describes radiation-induced cellular plasticity as a novel resistance mechanism in GBM. We identified a dopamine receptor antagonist as a readily available, FDA-approved drug known to penetrate the blood-brain-barrier which prevents phenotype conversion of glioma cells into glioma-initiating cells and prologs survival in mouse models of GBM, thus suggesting that it will improve the efficacy of RT without increasing toxicity.
Effectiveness of topical antibiotics in treating corals affected by Stony Coral Tissue Loss Disease
Authors: Neely K.L. , Macaulay K.A. , Hower E.K. , Dobler M.A.
Published: December 2019

Since 2014, Stony Coral Tissue Loss Disease (SCTLD) has led to mass mortality of the majority of hard coral species on the Florida Reef Tract. Following the successful treatment of SCTLD lesions on corals in closed aquaria using water dosed with antibiotics, two pastes were developed as vehicles for direct antibiotic treatments on wild corals. These pastes were tested as placebos and with additions of amoxicillin via topical applications over active SCTLD margins on multiple coral species. The effectiveness of the pastes without antibiotics (placebo treatments) was less than 10%. Adding amoxicillin to both pastes increased effectiveness. For one of the two pastes, which was silicone based with a time-release mechanism for the antibiotics, effectiveness in halting disease lesions reached 86% when amoxicillin was added. Topical antibiotic application is a viable tool for the preservation of priority corals affected by SCTLD.
Elevated rates of positive selection drive the evolution of pestiferousness in the Colorado potato beetle (Leptinotarsa decemlineata, Say)
Authors: Cohen Zachary P. , Brevik Kristian , Chen Yolanda H. , Hawthorne David J. , Weibel Benjamin D. , Schoville Sean D.
Published: December 2019

Insect pests are characterized by expansion, preference and performance on agricultural crops, high fecundity and rapid adaptation to control methods, which we collectively refer to as pestiferousness. Which organismal traits and evolutionary processes facilitate certain taxa becoming pests remains an outstanding question for evolutionary biologists. In order to understand these features, we set out to test the relative importance of genomic properties that underlie the rapid evolution of pestiferousness in the emerging pest model: the Colorado potato beetle (CPB),Leptinotarsa decemlineataSay. Within theLeptinotarsagenus, only CPB has risen to pest status on cultivatedSolanum. Using whole genomes from ten closely relatedLeptinotarsaspecies, we reconstructed a high-quality species tree of this genus. Within this phylogenetic framework, we tested the relative importance of four drivers of rapid adaptation: standing genetic variation, gene family expansion and contraction, transposable element variation, and protein evolution. Throughout approximately 20 million years of divergence,Leptinotarsashow little evidence of gene family turnover or transposable element variation contributing to pest evolution. However, there is a clear pattern of pest lineages experiencing greater rates of positive selection on protein coding genes, as well as retaining higher levels of standing genetic variation. We also identify a suite of positively selected genes unique to the Colorado potato beetle that are directly associated with pestiferousness. These genes are involved in xenobiotic detoxification, chemosensation, and hormones linked with pest behavior and physiology.
Conserved Ark1-related kinases control TORC2 signaling
Authors: Alcaide-Gavilán Maria , Banuelos Selene , Lucena Rafael , Kellogg Douglas R.
Published: December 2019

In all orders of life, cell cycle progression is dependent upon cell growth, and the extent of growth required for cell cycle progression is proportional to growth rate. Thus, cells growing rapidly in rich nutrients are substantially larger than slow growing cells. In budding yeast, a conserved signaling network surrounding Tor complex 2 (TORC2) controls growth rate and cell size in response to nutrient availability. Here, a search for new components of the TORC2 network identified a pair of redundant kinase paralogs called Ark1 and Prk1. Previous studies found that Ark/Prk play roles in endocytosis. Here, we show that Ark/Prk are embedded in the TORC2 network, where they appear to influence TORC2 signaling independently of their roles in endocytosis. We also show that reduced endocytosis leads to increased cell size, which indicates that cell size homeostasis requires coordinated control of plasma membrane growth and endocytosis. The discovery that Ark/Prk are embedded in the TORC2 network suggests a model in which TORC2-dependent signals control both plasma membrane growth and endocytosis, which would ensure that the rates of each process are matched to each other and to the availability of nutrients so that cells achieve and maintain an appropriate size.
Anti-PD-1 treatment as a neurotherapy to enhance neuronal excitability, synaptic plasticity and memory
Authors: Zhao Junli , Ji Ru-Rong
Published: December 2019

Emerging immunotherapy using anti-PD-1 antibodies have improved survival in cancer patients by immune activation. Here we show that functional PD-1 receptor is present in hippocampal CA1 neurons and loss of PD-1 or local anti-PD-1 treatment with nivolumab enhances neuronal excitability and long-term potentiation in CA1 neurons, leading to enhanced learning and memory. Our findings suggest that anti-PD-1 antibody also acts as a neurotherapy for improving memory and counteracting cognitive decline.
An RNA Degradation Complex Required for Spreading and Epigenetic Inheritance of Heterochromatin
Authors: Shipkovenska Gergana , Durango Alexander , Kalocsay Marian , Gygi Steven P. , Moazed Danesh
Published: December 2019

Heterochromatin assembly requires the methylation of histone H3 lysine 9 by the Clr4(Suv39h) methyltransferase and both the spreading and epigenetic inheritance of heterochromatin involve the recognition of H3K9me-containing nucleosomes by Clr4 and catalysis of H3K9me on adjacent nucleosomes. How this read-write mechanism overcomes obstacles posed by RNA polymerase II and nascent RNA in its path is not fully understood. Here we identify a role for the highly conserved and essential Rix1-containing complex (here referred to as the rixosome), with known RNA endonuclease and polynucleotide kinase activities required for ribosomal RNA (rRNA) processing, in spreading and epigenetic inheritance of heterochromatin. Viable mutations in rixosome subunits that disrupt its association with Swi6/HP1 fail to localize to heterochromatin, lead to accumulation of heterochromatic RNAs, and block spreading of H3K9me and silencing away from nucleation sites into actively transcribed regions. These findings reveal a new pathway for degradation of heterochromatic RNAs with essential roles in heterochromatin spreading and inheritance.
Antibiotic degradation by commensal microbes shields pathogens
Authors: Gjonbalaj Mergim , Keith James W. , Do Mytrang , Hohl Tobias M. , Pamer Eric G. , Becattini Simone
Published: December 2019

The complex bacterial populations that constitute the gut microbiota can harbor antibiotic-resistance genes (ARGs), including those encoding for β-lactamase enzymes (BLA), which degrade commonly prescribed antibiotics such as ampicillin. While it is known that ARGs can be transferred between bacterial species, with dramatic public health implications, whether expression of such genes by harmless commensal bacterial species shields antibiotic-sensitive pathogens in trans by destroying antibiotics in the intestinal lumen is unknown. To address this question, we colonized GF mice with a model intestinal commensal strain of E. coli that produces either functional or defective BLA. Mice were subsequently infected with Listeria monocytogenes or Clostridioides difficile followed by treatment with oral ampicillin. Production of functional BLA by commensal E. coli markedly reduced clearance of these pathogens and enhanced systemic dissemination during ampicillin treatment. Pathogen resistance was independent of ARG acquisition via horizontal gene transfer but instead relied on antibiotic degradation in the intestinal lumen by BLA. We conclude that commensal bacteria that have acquired ARGs can mediate shielding of pathogens from the bactericidal effects of antibiotics.
Mitochondrial translation and dynamics synergistically extend lifespan inC. elegansthrough HLH-30
Authors: Liu Yasmine J. , McIntyre Rebecca L. , Janssens Georges E. , Williams Evan G. , Lan Jiayi , van der Veen Henk , van der Wel Nicole N. , Mair William B. , Aebersold Ruedi , MacInnes Alyson W. , Houtkooper Riekelt H.
Published: December 2019

Mitochondrial form and function, such as translation, are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan inC. elegans, which is accompanied by a fragmented mitochondrial network. However, the causality between mitochondrial translation and morphology in longevity remains uncharacterized. Here, we show inC. elegansthat disrupting mitochondrial network homeostasis by either blocking fission or fusion synergizes with the reduced mitochondrial translation to substantially prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous abrogation of fission and fusion reverses the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic connections between mitochondrial translation and dynamics in regulating longevity.

Mitochondrial form and function are intimately intertwined. Liu et al. find the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan. This synergy is dependent on the induction of lysosome biogenesis through the nuclear localization of HLH-30.
A stomatal model of anatomical tradeoffs between gas exchange and pathogen colonization
Authors: Muir Christopher D.
Published: December 2019

Stomatal pores control both leaf gas exchange and are one route for infection of internal plant tissues by many foliar pathogens, setting up the potential for tradeoffs between photosynthesis and defense. Anatomical shifts to lower stomatal density and/or size may also limit pathogen colonization, but such developmental changes could permanently reduce the gas exchange capacity for the life of the leaf. I developed and analyzed a spatially explicit model of pathogen colonization on the leaf as a function of stomatal size and density, anatomical traits which partially determine maximum rates of gas exchange. The model predicts greater stomatal size or density increases the probability of colonization, but the effect is most pronounced when the fraction of leaf surface covered by stomata is low. I also derived scaling relationships between stomatal size and density that preserves a given probability of colonization. These scaling relationships set up a potential anatomical conflict between limiting pathogen colonization and minimizing the fraction of leaf surface covered by stomata. Although a connection between gas exchange and pathogen defense has been suggested empirically, this is the first mathematical model connecting gas exchange and pathogen defense via stomatal anatomy. A limitation of the model is that it does not include variation in innate immunity and stomatal closure in response to pathogens. Nevertheless, the model makes predictions that can be tested with experiments and may explain variation in stomatal anatomy among plants. The model is generalizable to many types of pathogens, but lacks significant biological realism that may be needed for precise predictions.
Pragmatic Language Processing in the Adolescent Brain
Authors: Asaridou Salomi S. , Demir-Lira Ö. Ece , Uddén Julia , Goldin-Meadow Susan , Small Steven L.
Published: December 2019

Adolescence is a developmental period in which social interactions become increasingly important. Successful social interactions rely heavily on pragmatic competence, the appropriate use of language in different social contexts, a skill that is still developing in adolescence. In the present study, we used fMRI to characterize the brain networks underlying pragmatic language processing in typically developing adolescents. We used an indirect speech paradigm whereby participants were presented with question/answer dialogues in which the meaning of the answer had to be inferred from the context, in this case the preceding question. Participants were presented with three types of answers: (1) direct replies, i.e., simple answers to open-ended questions, (2) indirect informative replies, i.e., answers in which the speaker’s intention was to add more information to a yes/no question, and (3) indirect affective replies, i.e., answers in which the speaker’s intention was to express polite refusals, negative opinions or to save face in response to an emotionally charged question. We found that indirect affective replies elicited the strongest response in brain areas associated with language comprehension (superior temporal gyri), theory of mind (medial prefrontal cortex, temporo-parietal junction, and precuneus), and attention/working memory (inferior frontal gyri). The increased activation to indirect affective as opposed to indirect informative and direct replies potentially reflects the high salience of opinions and perspectives of others in adolescence. Our results add to previous findings on socio-cognitive processing in adolescents and extend them to pragmatic language comprehension.
Acidic pH reducesVibrio choleraemotility in mucus by weakening flagellar motor torque
Authors: Nhu Nguyen T. Q. , Wang Helen J. , Dufour Yann S.
Published: December 2019

Intestinal mucus is the first line of defense against intestinal pathogens. It acts as a physical barrier between the epithelial tissues and luminal microbes. Enteropathogens, such asVibrio cholerae, must compromise or circumvent the mucus barrier to establish a successful infection. We investigated how motileV. choleraeis able to penetrate mucus using single cell tracking in unprocessed porcine intestinal mucus. We found that changes in pH within the range of what has been measured in the human small intestine indirectly affectV. choleraeflagellar motor torque, and consequently, mucus penetration. Microrheological measurements indicate that the viscoelasticity of mucus does not change substantially within the physiological pH range and that commercially available mucins do not form gels when rehydrated. Finally, we found that besides the reduction in motor torque, El Tor and Classical biotypes have different responses to acidic pH. For El Tor, acidic pH promotes surface attachment that is mediated by activation of the mannose-sensitive haemagglutinin (MshA) pilus without a measurable change in the total cellular concentration of the secondary messenger cyclic dimeric guanosine monophosphate (c-di-GMP). Overall, our results support that the high torque ofV. choleraeflagellar motor is critical for mucus penetration and that the pH gradient in the small intestine is likely an important factor in determining the preferred site of infection.

Author summary

The diarrheal disease cholera is still a burden for populations in developing countries with poor sanitation. To develop effective vaccines and prevention strategies againstVibrio cholerae, we must understand the initial steps of infection leading to the colonization of the small intestine. To infect the host and deliver the cholera toxin,V. choleraehas to penetrate the mucus layer protecting the intestinal tissues. However,V. cholerae’sinteractions with intestinal mucus has not been extensively investigated. In this report, we demonstrate using single cell tracking thatV. choleraeis able to penetrate native intestinal mucus using flagellar motility. In addition, we found that a strong motor torque is required for mucus penetration and, that torque is weakened in acidic environments even though the motor is powered by a sodium potential. This finding has important implications for understanding the dynamics of infection because pH varies significantly along the small intestine, between individuals, and between species. Blocking mucus penetration by interfering withV. cholerae’sflagellar motility, reinforcing the mucosa, controlling intestinal pH, or manipulating the intestinal microbiome, will offer new strategies to fight cholera.
The Vitamin D Receptor (VDR) Regulates Mitochondrial Function in C2C12 Myoblasts
Authors: Ashcroft Stephen P. , Bass Joseph J. , Kazi Abid A. , Atherton Philip J. , Philp Andrew
Published: December 2019

Vitamin D deficiency has been linked to a reduction in skeletal muscle function and oxidative capacity, however, the mechanistic basis of these impairments are poorly understood. The biological actions of vitamin D are carried out via the binding of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) to the vitamin D receptor (VDR). Recent evidence has linked 1α,25(OH)2D3 to the regulation of skeletal muscle mitochondrial function in vitro, however, little is known with regard to the role of the VDR in this process. To examine the regulatory role of the VDR in skeletal muscle mitochondrial function, we utilised lentiviral mediated shRNA silencing of the VDR in C2C12 myoblasts (VDR-KD) and examined mitochondrial respiration and protein content compared to shRNA scrambled control. VDR protein content was reduced by ~95% in myoblasts and myotubes (P < 0.001). VDR-KD myoblasts displayed a 30%, 30% and 36% reduction in basal, coupled and maximal respiration respectively (P < 0.05). This phenotype was maintained in VDR-KD myotubes, displaying a 34%, 33% and 48% reduction in basal, coupled and maximal respiration (P < 0.05). Furthermore, ATP production derived from oxidative phosphorylation (ATPox) was reduced by 20% suggesting intrinsic impairments within the mitochondria following VDR-KD. However, despite the observed functional decrements, mitochondrial protein content as well as markers of fusion and fission were unchanged. In summary, we highlight a direct role for the VDR in regulating skeletal muscle mitochondrial respiration in vitro, providing a potential mechanism as to how vitamin D deficiency might impact upon skeletal muscle oxidative capacity.
A conserved translation factor is required for optimal synthesis of a membrane protein family in mycobacteria
Authors: Fishbein Skye R.S. , Wolf Ian D. , Dulberger Charles L. , Wang Albert , Keshishian Hasmik , Wallace Luke , Carr Steven A. , Ioerger Thomas R. , Rego E. Hesper , Rubin Eric J.
Published: December 2019

Ribosomes require the activity of associated GTPases to synthesize proteins. Despite strong evolutionary conservation, the roles of many of these remain unknown. For example, LepA (also known as elongation factor 4) is a ribosome-associated GTPase found in bacteria, mitochondria, and chloroplasts, yet its physiological contribution to cell survival is not clear. Recently, we found that loss of lepA in Mycobacterium smegmatis (Msm) altered tolerance to rifampin, a drug that targets a non-ribosomal cellular process. To uncover the determinants of LepA-mediated drug tolerance, we characterized the whole-cell proteomes and transcriptomes of a lepA deletion mutant relative to a wild-type strain. We find that LepA is important for the steady-state abundance of an outer membrane porin, which is integral to nutrient uptake and drug susceptibility. Loss of LepA leads to a decreased amount of porin in the membrane, resulting in the drug tolerance phenotype of the lepA mutant. LepA control requires a sequence motif in the 5’ region of the porin transcript. Thus, LepA controls the abundance of specific proteins, likely through its activity during translation.

Importance

Our understanding of how ribosomes properly synthesis an entire cellular proteome, in all its complexity, is still evolving. Ribosomal GTPases are often highly conserved, but the roles of many are not well understood. For example, elongation factor 4, or LepA, is a ribosome-associated GTPase conserved across bacteria, mitochondria, and chloroplasts. Using whole-cell proteomics and RNA-sequencing of wild type and a lepA deletion mutant, we find that LepA improves translation of mycobacterial porins in a message-specific manner. As porins play a key role in cell wall permeability, loss of LepA produces a plethora of phenotypic changes. These findings underline the problem of building proteins into a complex cell wall, such as that of mycobacteria, and point to a solution in the use of GTPases such as LepA, that have evolved to aid in specific protein synthesis.
Towards a systematic map of the functional role of protein phosphorylation
Authors: Viéitez Cristina , Busby Bede P. , Ochoa David , Mateus André , Galardini Marco , Jawed Areeb , Memon Danish , Potel Clement M. , Vonesch Sibylle C. , Tu Chelsea Szu , Shahraz Mohammed , Stein Frank , Steinmetz Lars M. , Savitski Mikhail M. , Typas Athanasios , Beltrao Pedro
Published: December 2019

Phosphorylation is a critical post-translational modification involved in the regulation of almost all cellular processes. However, less than 5% of thousands of recently discovered phosphorylation sites have a known function. Here, we devised a chemical genetic approach to study the functional relevance of phosphorylation in S. cerevisiae. We generated 474 phospho-deficient mutants that, along with the gene deletion library, were screened for fitness in 102 conditions. Of these, 42% exhibited growth phenotypes, suggesting these phosphosites are likely functional. We inferred their function based on the similarity of their growth profiles with that of gene deletions, and validated a subset by thermal proteome profiling and lipidomics. While some phosphomutants showed loss-of-function phenotypes, a higher fraction exhibited phenotypes not seen in the corresponding gene deletion suggestive of a gain-of-function effect. For phosphosites conserved in humans, the severity of the yeast phenotypes is indicative of their human functional relevance. This study provides a roadmap for functionally characterizing phosphorylation in a systematic manner.
Marketability, profitability, and profit-loss sharing: evidence from sharia banking in Indonesia
Authors: Abbas Ahmad , Arizah Ainun
Published: December 2019

Purpose

The purpose of this paper is to analyze marketability constructed from market share and concentration and to test its effect on the profitability and the mediation effects of profit‒loss sharing under stewardship theory.

Design/methodology/approach

This research employs data of financial statements published by ten sharia commercial banks listed in the Indonesia Financial Services Authority during the period 2011–2016. The data are analyzed into path analysis model using multiple mediators.

Findings

The result reveals that sharia banks’ marketability in Indonesia tends to be low. Based on the test of significance through Partial Least Square, it is found that marketability has a positive effect on the level of profitability, indicating that market share and concentration of sharia banks positively lead the change on the level of Return on Asset and Return on Equity. This paper further identifies the mediation effects emerged through mudharabah and musharakah. The results point out that mudharabah has a partial effect and musharakah has a competitive effect on the relationship between market share and profitability.

Practical implications

This paper can be a decision-maker for Central Bank and Financial Services Authority for encouraging sharia banks to enhance the power market through the mode of finances with profit‒loss sharing.

Originality/value

The growth of sharia banks is currently becoming highlight of the literature of sharia banks. This paper provides insights into stewardship theory that sharia banking management provides the concept of the alignment of interest.
Mobile shopping platform characteristics as consumer behavior determinants
Authors: Liu Yang , Li Qi , Edu Tudor , Jozsa Laszlo , Negricea Iliuta Costel
Published: December 2019

Purpose

The purpose of this paper is to appraise the impact of mobile shopping platform characteristics on consumer’s emotions, the relationship between emotions and their impact on impulsive buying.

Design/methodology/approach

Mobile shopping platform characteristics were grouped into five dimensions: information, entertainment, personalization, visuality and economic benefits, and integrated in a model built on the Stimulus-organism-response theory to evaluate the influence on arousal (excitement) and pleasure, the relationship between arousal and pleasure and their impact on impulsive buying. In total, 303 valid questionnaires were collected from Chinese mobile shoppers. The research hypotheses were tested through confirmatory factor analysis and structural equation modeling.

Findings

Entertainment and personalization had significant positive influences on consumer’s arousal and pleasure. Information, visuality and economic benefits had significant positive influences on consumer’s arousal. Arousal had a significant positive impact on consumer’s pleasure. Arousal and pleasure had significant positive influences on impulsive buying.

Research limitations/implications

New insights can be obtained by investigating other consumer’s profiles. The model can be improved by including other mobile platform characteristics (product availability, platform ease-of-use and interactivity) and broadening the impulsive buying perspective through assessing flow experience and virtual atmosphere.

Practical implications

Marketing strategies are proposed based on the mobile platform characteristics and considering Chinese customer values, for generating positive emotions and impulsive buying.

Originality/value

This study enriches the literature by recommending a classification for mobile shopping platform characteristics and proposing a model to investigate the characteristics, emotions and impulsive buying nexus.
The effects of creator credibility and backer endorsement in donation crowdfunding campaigns success
Authors: Bukhari Farasat Ali Shah , Usman Sardar Muhammad , Usman Muhammad , Hussain Khalid
Published: December 2019

Purpose

The purpose of this paper is to investigate the effects of creator credibility and backer endorsement on the levels of donation to crowdfunding campaigns in a focal muslim community and to determine the success factors of projects in developing and developed countries.

Design/methodology/approach

This research adopts a quantitative approach, utilizing 223 crowdfunding projects from LaunchGood to examine the expected connections. The crowdfunding projects in the distinctive data set (Ramadan) are similar, permitting exploration of the role of creator credibility and backer endorsement in a unique context of religious-based crowdfunding activity.

Findings

Creators’ credibility and backers’ endorsements are decisive factors in crowdfunding success. Results from an additional test related to location (developing and developed countries) suggest that creators’ credibility is more important than backers’ endorsements, especially in developing countries.

Research limitations/implications

The projects used in the data set are homogenous and take place in a specific context. The limited number of available observations influences the testing function and capacity of the models and variables. Further, the investigation is related to a specific community, so might not be applicable to all communities.

Social implications

Potential supporters from the community are vital for the success of crowdfunding projects. This study informs campaign efforts in a religious community by stressing the importance of creators’ credibility and backers’ endorsements. The study also sheds light on factors that affect crowdfunding success in developing and developed countries.

Originality/value

This study helps to explain successful crowdfunding practices in donation-based crowdfunding projects within a religious community context. Results improve scholars’ ability to comprehend individuals’ supporting behavior, providing empirical evidence of creators’ credibility and backers’ endorsement on project success. The study also addresses the determinants of crowdfunding success in developing and developed countries.