bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting AKT elicits tumor suppressive functions of FOXO transcription factors and GSK3 kinase in Multiple Myeloma
Authors: Bloedjes Timon A. , de Wilde Guus , Maas Chiel , Eldering Eric E. , Bende Richard J. , van Noesel Carel J.M. , Pals Steven T. , Spaargaren Marcel , Guikema Jeroen E.J.
Published: October 2019

The phosphatidylinositide-3 kinases (PI3K) and the downstream mediator AKT drive survival and proliferation of multiple myeloma (MM) cells and several AKT inhibitors are currently being tested in clinical trials for MM patients. AKT inhibition has pleiotropic effects, and the key aspects that determine therapeutic efficacy are not fully clear. Therefore, we investigated the antimyeloma mechanism(s) of AKT inhibition. Among the various downstream AKT targets are Forkhead box O (FOXO) transcription factors, and we demonstrate that they are crucial for changes in gene expression upon AKT inhibition. Based on gene expression profiling we defined an AKT-induced FOXO-dependent gene set that has prognostic significance in a large cohort of MM patients, where low FOXO activity correlates with inferior survival. We show that cell cycle exit and cell death of MM cells after AKT inhibition required FOXO. In addition, glycogen synthase kinase 3 (GSK3), a negatively regulated AKT substrate, proved to be pivotal to induce cell death and to inhibit cell cycle progression after AKT inhibition. Finally, we demonstrate that FOXO and GSK3 induced cell death by increasing the turnover of the myeloid cell leukemia 1 (MCL1) protein. In concordance, the AKT inhibitor MK2206 greatly sensitized MM cells for the MCL1 inhibitor S63845. Thus, our results indicate that FOXO and GSK3 are crucial mediators of the antimyeloma effects of AKT inhibition, and suggest combination therapies that may have therapeutic potential in MM.

KEYPOINTS

FOXO transcription factors and the GSK3 kinase are pivotal tumor suppressors downstream of AKT inhibition in MM cells.

FOXO and GSK3 activation after AKT inhibition leads to a decrease in MCL1 levels in MM cells resulting in cell death.
Sensory substitution reveals a manipulation bias
Authors: Zai AT , Cavé-Lopez S , Rolland M , Giret N , Hahnloser RHR
Published: October 2019

Sensory substitution is a promising therapeutic approach for replacing a missing or diseased sensory organ by translating inaccessible information into another sensory modality. What aspects of substitution are important such that subjects accept an artificial sense and that it benefits their voluntary action repertoire? To obtain an evolutionary perspective on affective valence implied in sensory substitution, we introduce an animal model of deaf songbirds. As a substitute of auditory feedback, we provide binary visual feedback. Deaf birds respond appetitively to song-contingent visual stimuli, they skillfully adapt their songs to increase the rate of visual stimuli, showing that auditory feedback is not required for making targeted changes to a vocal repertoire. We find that visually instructed song learning is basal-ganglia dependent. Because hearing birds respond aversively to the same visual stimuli, sensory substitution reveals a bias for actions that elicit feedback to meet animals’ manipulation drive, which has implications beyond rehabilitation.
Use of a counterselectable transposon to create markerless knockouts from a 18,432-clone orderedM. bovisBCG mutant resource
Authors: Borgers Katlyn , Vandewalle Kristof , Van Hecke Annelies , Michielsen Gitte , Plets Evelyn , van Schie Loes , Vanmarcke Sandrine , Schindfessel Laurent , Festjens Nele , Callewaert Nico
Published: October 2019

Mutant resources are essential to improve our understanding of the biology of slow-growing mycobacteria, which include the causative agents of tuberculosis in various species, including humans. The generation of deletion mutants in slow-growing mycobacteria in a gene-by-gene approach in order to make genome-wide ordered mutant resources is still a laborious and costly approach; despite the recent development of improved methods. On the other hand, transposon mutagenesis in combination with Cartesian Pooling-Coordinate Sequencing allows the creation of large archivedMycobacteriumtransposon insertion libraries. However, such mutants contain selection marker genes with a risk of polar gene effects, which is undesired both for research and for use of these mutants as live attenuated vaccines. In this paper, a derivative of the Himar1 transposon is described, which allows the generation of clean, markerless knockouts from archived transposon libraries. By incorporatingFRTsites for FlpE/FRT-mediated recombination andI-SceIsites for ISceIM-based transposon removal, we enable two thoroughly experimentally validated possibilities to create unmarked mutants from such marked transposon mutants. TheFRTapproach is highly efficient but leaves anFRTscar in the genome, whereas theI-SceImediated approach can create mutants without any heterologous DNA in the genome. The combined use of CP-CSeq and this optimized transposon was applied in the BCG Danish 1331 vaccine strain (WHO reference 07/270), creating the largest ordered, characterized resource of mutants in a member of theM. tbcomplex (18,432 clones, mutating 83% of the non-essentialM. tbhomologues), from which clean knockouts can be generated.

Importance

While speeding up research for many fields of biology (e.g. yeast, plant, andC. elegans), genome-wide ordered mutant collections are still elusive in mycobacterial research. We developed methods to generate such resources in a time- and cost-effective manner, and developed a newly engineered transposon from which unmarked mutants can be efficiently generated. Our library in the WHO reference vaccine strain ofM. bovisBCG Danish targets 83% of all non-essential genes and was made publicly available via the BCCM/ITM Mycobacteria Collection. This resource will speed upMycobacteriumresearch (e.g. drug resistance research, vaccine development) and paves the way to similar genome-wide mutant collections in other strains of theM. tbcomplex. The stretch to a full collection of mutants in all non-essential genes is now much shorter, with just 17% remaining genes to be targeted using gene-by-gene approaches, for which highly effective methods have recently also been described.
Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis
Authors: Bolte Ashley C. , Hurt Mariah E. , Smirnov Igor , Kovacs Michael A. , McKee Celia A. , Natale Nick , Ennerfelt Hannah E. , Frost Elizabeth L. , Lammert Catherine E. , Kipnis Jonathan , Lukens John R.
Published: October 2019

Traumatic brain injury (TBI) has emerged as a leading cause of death and disability. Despite being a growing medical issue, the biological factors that promote central nervous system (CNS) pathology and neurological dysfunction following TBI remain poorly characterized. Recently, the meningeal lymphatic system was identified as a critical mediator of drainage from the CNS. In comparison to other peripheral organs, our understanding of how defects in lymphatic drainage from the CNS contribute to disease is limited. It is still unknown how TBI impacts meningeal lymphatic function and whether disruptions in this drainage pathway are involved in driving TBI pathogenesis. Here we demonstrate that even mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that can last out to at least two weeks post-injury. To investigate a mechanism behind impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics, as increased ICP commonly occurs in TBI. We demonstrate that increased ICP is capable of provoking meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction mediated by targeted photoablation before TBI leads to increased neuroinflammation and cognitive deficits. These findings provide new insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.
Closing and opening of the RNA polymerase trigger loop
Authors: Mazumder Abhishek , Lin Miaoxin , Kapanidis Achillefs N. , Ebright Richard H.
Published: October 2019

The RNA polymerase (RNAP) trigger loop (TL) is a mobile structural element of the RNAP active center that, based on crystal structures, has been proposed to cycle between an “unfolded”/“open” state that allows an NTP substrate to enter the active center and a “folded”/“closed” state that holds the NTP substrate in the active center. Here, by quantifying single-molecule fluorescence resonance energy transfer between a first fluorescent probe in the TL and a second fluorescent probe elsewhere in RNAP or in DNA, we detect and characterize TL closing and opening in solution. We show that the TL closes and opens on the millisecond timescale; we show that TL closing and opening provides a checkpoint for NTP complementarity, NTP ribo/deoxyribo identity, and NTP tri/di/monophosphate identity, and serves as a target for inhibitors; and we show that one cycle of TL closing and opening typically occurs in each nucleotide addition cycle in transcription elongation.
Kia kaua te reo e rite ki te moa, ka ngaro: Do not let the language suffer the same fate as the moa
Authors: Barrett-Walker Tessa , Plank Michael J. , Ka’ai-Mahuta Rachael , Hikuroa Daniel , James Alex
Published: October 2019

More than a third of the world’s languages are currently classified as endangered and more than half are expected to go extinct by 2100. Strategies aimed at revitalising endangered languages have been implemented in numerous countries, with varying degrees of success. Here, we develop a new model regarding language transmission by dividing the population into defined proficiency categories and dynamically quantifying transition rates between categories. The model can predict changes in proficiency levels over time and, ultimately, whether a given endangered language is on a long-term trajectory towards extinction or recovery. We calibrate the model using data from Wales and show that the model predicts that the Welsh language will thrive in the long term. We then apply the model to te reo Māori, the Indigenous language of New Zealand, as a case study. Initial conditions for this model are estimated using New Zealand census data. We modify the model to describe a country, such as New Zealand, where the endangered language is associated with a particular subpopulation representing the Indigenous People. We conclude that, with current learning rates, te reo Māori is on a pathway towards extinction, but identify strategies that could help restore it to an upward trajectory.
A missense variant impairing TRMT1 function in tRNA modification is linked to intellectual disability
Authors: Zhang Kejia , Lentini Jenna M , Prevost Christopher T , Hashem Mais O , Alkuraya Fowzan S , Fu Dragony
Published: October 2019

The humanTRMT1gene encodes a tRNA methyltransferase enzyme responsible for the formation of the dimethylguanosine (m2,2G) modification in cytoplasmic and mitochondrial tRNAs. Frameshift mutations in theTRMT1gene have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Moreover, the impact of ID-associated TRMT1 mutations on m2,2G levels in ID-affected patients is unknown. Here, we describe a homozygous missense variant inTRMT1in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes a conserved arginine residue to a cysteine (R323C) within the methyltransferase domain of TRMT1 and is expected to perturb protein folding. Patient cells expressing the TRMT1-R323C variant exhibit a severe deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss-of-function. Notably, the TRMT1 R323C mutant retains the ability to bind tRNA but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that severely perturbs tRNA modification activity, and provide the first demonstration that m2,2G modifications are disrupted in patients with TRMT1-associated ID disorders.
Integrating somatosensory information over time
Authors: Hernández-Pérez Raúl , Rojas-Hortelano Eduardo , de Lafuente Victor
Published: October 2019

Our choices are often informed by temporally integrating streams of sensory information. This has been well demonstrated in the visual and auditory domains, but the integration of tactile information over time has been less studied. We designed an active touch task in which subjects explored a spheroid-shaped object to determine its inclination with respect to the horizontal plane (inclined to the left or to the right). In agreement with previous findings, our results show that more errors, and longer decision times, accompany difficult decisions (small inclination angles). To gain insight into the decision-making process, we used a task in which the time available for tactile exploration was varied by the experimenter, in a trial-by-trial basis. The behavioral results were fit with a model of bounded accumulation, and also with an independent-sampling model which assumes no sensory accumulation. The results of model fits favor an accumulation-to-bound mechanism, and suggest that participants integrate the first 600 ms of 1800 ms-long stimuli. This means that the somatosensory system benefits from longer streams of information although it does not make use of all available evidence.

Highlights

The somatosensory system integrates information streams through time.

Somatosensory discrimination thresholds decrease with longer stimuli.

A bounded accumulation model is favored over independent sampling.

Humans accumulate up to 600 ms, out of 1800 ms-long stimuli.
Mutant evolution in spatially structured and fragmented populations
Authors: Wodarz Dominik , Komarova Natalia L
Published: October 2019

Understanding mutant evolution in spatially structured systems is crucially important for a range of biological systems, including bacterial populations and cancer. While previous work has shown that the mutation load is higher in spatially structured compared to well-mixed systems for neutral mutants in the absence of cell death, we demonstrate a significantly higher degree of complexity, using a comprehensive computational modeling approach that takes into account different mutant fitness, cell death, and different population structures. While an agent-based model assuming nearest neighbor interactions predicts a higher abundance of neutral or advantageous mutants compared to well-mixed systems of the same size, we show that for disadvantageous mutants, results depend on the nature of the disadvantage. In particular, if the disadvantage occurs through higher death rates, as opposed to lower reproduction rates, the result is the opposite, and a lower mutation load occurs in spatial compared to mixed systems. Interestingly, we show that in all cases, the same results are observed in fragmented patch models, where individuals can migrate to randomly chosen patches, thus lacking a strict spatial component. Hence, the results reported for spatial models are the consequence of population fragmentation, and not spatial restrictions per se. We further derive growth laws that characterize the expansion of wild type and mutant populations in different dimensionalities. For example, we find that while disadvantageous mutant abundance scales with the total population size, N, neutral mutants grow faster (as N2for 1D, as N3/2in 2D, and as N4/3in 3D). Advantageous mutants scale with the cube of N in 1D and with the square of N in higher dimensions. These laws are universal (as long as mutants remain a minority) and independent of “microscopic” modeling details.
Dynamic shifts of visual and saccadic signals in prefrontal cortical regions 8Ar and FEF
Authors: Khanna Sanjeev B. , Scott Jonathan A. , Smith Matthew A.
Published: October 2019

Active vision is a fundamental process by which primates gather information about the external world. Multiple brain regions have been studied in the context of simple active vision tasks in which a visual target’s appearance is temporally separated from saccade execution. Most neurons have tight spatial registration between visual and saccadic signals, and in areas such as prefrontal cortex (PFC) some neurons show persistent delay activity that links visual and motor epochs and has been proposed as a basis for spatial working memory. Many PFC neurons also show rich dynamics, which have been attributed to alternative working memory codes and the representation of other task variables. Our study investigated the transition between processing a visual stimulus and generating an eye movement in populations of PFC neurons in macaque monkeys performing a memory guided saccade task. We found that neurons in two subregions of PFC, the frontal eye fields (FEF) and area 8Ar, differed in their dynamics and spatial response profiles. These dynamics could be attributed largely to shifts in the spatial profile of visual and motor responses in individual neurons. This led to visual and motor codes for particular spatial locations that were instantiated by different mixtures of neurons, which could be important in PFC’s flexible role in multiple sensory, cognitive, and motor tasks.

New and Noteworthy

A central question in neuroscience is how the brain transitions from sensory representations to motor outputs. The prefrontal cortex contains neurons that have long been implicated as important in this transition and in working memory. We found evidence for rich and diverse tuning in these neurons, that was often spatially misaligned between visual and saccadic responses. This feature may play an important role in flexible working memory capabilities.
High quality genome sequence reveals the 12 pseudo-chromosomes of Ganoderma boninense
Authors: Utomo Condro , Tanjung Zulfikar Achmad , Aditama Redi , Nurani Buana Rika Fithri , Madu Pratomo Antonius Dony , Tryono Reno , Liwang Tony
Published: October 2019

Ganoderma boninense is the dominant fungal pathogen in causing Basal Stem Rot (BSR) disease on oil palm. The whole genome of this fungus was sequenced using PacBio RS II platforms to gain the whole-genome shotgun libraries. These libraries were smoothed with Illumina Hiseq 4000 paired end sequencing to polish the genome assembly. Subsequently, a combination of Dovetail Chicago and HiC libraries with the HiRise assembly pipeline revealed the 12 pseudo-chromosomes of G. boninense. This is the first report of chromosomal-scale genome assembly for the most important fungal pathogen on oil palm.
Identification and characterization of zebrafish Tlr4 co-receptor Md-2
Authors: Loes Andrea N. , Hinman Melissa N. , Farnsworth Dylan R. , Miller Adam C. , Guillemin Karen , Harms Michael J.
Published: October 2019

The zebrafish (Danio rerio) is a powerful model organism for studies of the innate immune system. One apparent difference between human and zebrafish innate immunity is the cellular machinery for LPS-sensing. In amniotes, the protein complex formed by Toll-like receptor 4 and myeloid differentiation factor 2 (Tlr4/Md-2) recognizes the bacterial molecule lipopolysaccharide (LPS) and triggers an inflammatory response. It is believed that zebrafish have neither Md-2 nor Tlr4: Md-2 has not been identified outside of amniotes, while the zebrafishtlr4genes appear to be paralogs, not orthologs, of amnioteTLR4s. We revisited these conclusions. We identified a zebrafish gene encoding Md-2,ly96. Using single-cell RNA-Seq, we found thatly96is transcribed in cells that also transcribe genes diagnostic for innate immune cells, including the zebrafishtlr4-like genes. Unlike amnioteLY96, zebrafishly96expression is restricted to a small number of macrophage-like cells. In a functional assay, zebrafish Md-2 and Tlr4a form a complex that activates NF-κB signaling in response to LPS, butly96loss-of-function mutations gave little protection against LPS-toxicity in larval zebrafish. Finally, by analyzing the genomic context oftlr4genes in eleven jawed vertebrates, we found thattlr4arose prior to the divergence of teleosts and tetrapods. Thus, an LPS-sensitive Tlr4/Md-2 complex is likely an ancestral feature shared by mammals and zebrafish, rather than ade novoinvention on the tetrapod lineage. We hypothesize that zebrafish retain an ancestral, low-sensitivity Tlr4/Md-2 complex that confers LPS-responsiveness to a specific subset of innate immune cells.
Learning to learn persistently modifies an entorhinal-hippocampal excitatory-inhibitory subcircuit
Authors: Chung Ain , Jou Claudia , Grau-Perales Alejandro , Levy Eliott , Dvorak Dino , Hussain Nida , Fenton André A.
Published: October 2019

Cognitive control, the judicious use of relevant information while ignoring distractions, is a feature of everyday cognitive experience, but its neurobiology is understudied. We investigated whether cognitive control training (CCT) changes hippocampal neural circuit function in mice, beyond the changes caused by place learning and memory formation. Mice learned and remembered a conditioned place avoidance during CCT that required ignoring irrelevant locations of shock. They were compared to controls that learned the same place avoidance under lower cognitive control demands. Weeks after CCT, mice learn new tasks in novel environments faster than controls; they learned to learn. We investigated entorhinal cortex-to-dentate gyrus neural circuit changes and report that CCT rapidly changes synaptic circuit function, resulting in an excitatory-inhibitory subcircuit change that persists for months. CCT increases inhibition that attenuates the dentate response to medial entorhinal cortical input, and through disinhibition, potentiates the response to strong inputs, pointing to overall signal-to-noise enhancement. These neurobiological findings support a neuroplasticity hypothesis that, beyond storing item/event associations, CCT persistently optimizes neural circuit information processing.
The novel shapeshifting bacterial phylumSaltatorellota
Authors: Wiegand Sandra , Jogler Mareike , Kohn Timo , Awal Ram Prasad , Oberbeckmann Sonja , Kesy Katharina , Jeske Olga , Schumann Peter , Peeters Stijn H. , Kallscheuer Nicolai , Strauss Mike , Heuer Anja , Jetten Mike S. M. , Labrenz Matthias , Rohde Manfred , Boedeker Christian , Engelhardt Harald , Schüler Dirk , Jogler Christian
Published: October 2019

Our current understanding of a free-living bacterium - capable of withstanding a variety of environmental stresses-is represented by the image of a peptidoglycan-armored rigid casket. The making and breaking of peptidoglycan greatly determines cell shape. The cytoplasmic membrane follows this shape, pressed towards the cell wall by turgor pressure. Consequently, bacteria are morphologically static organisms, in contrast to eukaryotic cells that can facilitate shape changes. Here we report the discovery of the novel bacterial phylumSaltatorellota, that challenges this concept of a bacterial cell. Members of this phylum can change their shape, are capable of amoeba-like locomotion and trunk-formation through the creation of extensive pseudopodia-like structures. Two independentSaltatorellotacells can fuse, and they employ various forms of cell division from budding to canonical binary fission. Despite their polymorphisms, members of theSaltatorellotado possess a peptidoglycan cell wall. Their genomes encode flagella and type IV pili as well as a bacterial actin homolog, the ‘saltatorellin’. This protein is most similar to MamK, a dynamic filament-forming protein, that aligns and segregates magnetosome organelles via treadmilling. We found saltatorellin to form filaments in both,E. coliandMagnetospirillum gryphiswaldense, leading to the hypothesis that shapeshifting and pseudopodia formation might be driven by treadmilling of saltatorellin.
Active sensing in groups: (what) do bats hear in the sonar cocktail party nightmare?
Authors: Beleyur Thejasvi , Goerlitz Holger R.
Published: October 2019

Active sensing animals perceive their surroundings by emitting probes of energy and analyzing how the environment modulates these probes. However, the probes of conspecifics can jam active sensing, which should cause problems for groups of active sensing animals. This problem was termed the cocktail party nightmare for echolocating bats: as bats listen for the faint returning echoes of their loud calls, these echoes will be masked by the loud calls of other close-by bats. Despite this problem, many bats echolocate in groups and roost socially. Here, we present a biologically parametrized framework to quantify echo detection in groups. Incorporating known properties of echolocation, psychoacoustics, spatial acoustics and group flight, we quantify how well bats flying in groups can detect each other despite jamming. A focal bat in the center of a group can detect neighbors for group sizes of up to 100 bats. With increasing group size, fewer and only the closest and frontal neighbors are detected. Neighbor detection is improved for longer call intervals, shorter call durations, denser groups and more variable flight and sonar beam directions. Our results provide the first quantification of the sensory input of echolocating bats in collective group flight, such as mating swarms or emergences. Our results further generate predictions on the sensory strategies bats may use to reduce jamming in the cocktail party nightmare. Lastly, we suggest that the spatially limited sensory field of echolocators leads to limited interactions within a group, so that collective behavior is achieved by following only nearest neighbors.

SIGNIFICANCE STATEMENT

Close-by active sensing animals may interfere with each other. We investigated if and what many echolocators fly in a group hear – can they detect each other after all? We modelled acoustic and physical properties in group echolocation to quantify neighbor detection probability as group size increases. Echolocating bats can detect at least one of their closest neighbors per call up to group sizes of even 100 bats. Call parameters such as call rate and call duration play a strong role in how much echolocators in a group interfere with each other. Even when many bats fly together, they are indeed able to detect at least their nearest frontal neighbors – and this prevents them from colliding into one another.
“And if you gaze long into an abyss, the abyss gazes also into thee”: four morphs of Arctic charr adapting to a depth-gradient in Lake Tinnsjøen
Authors: Østbye Kjartan , Hassve Marius Hagen , Peris Ana-Maria Tamayo , Hagenlund Mari , Vogler Thomas , Præbel Kim
Published: October 2019

Background

The origin of species is a central topic in biology aiming at understanding mechanisms, level and rate of diversification. Ecological speciation is an important driver in adaptive radiation during post-glacial intra-lacustrine niche diversification in fishes. The Arctic charrSalvelinus alpinusL. species complex in the Northern hemisphere freshwater systems display huge morphological and life history divergence in lakes with one or several morphs present, thus offering a unique opportunity to address ongoing speciation mechanisms.

We studied Arctic charr in Lake Tinnsjøen by fishing in four nominal lake habitats (pelagial, littoral, shallow-moderate profundal, and deep-profundal habitats) down to 350 meters depth. Research topics addressed were; (1) to illuminate Holarctic phylogeography and lineages colonizing Lake Tinnsjøen, (2) to estimate reproductive isolation of morphs or fish using unbiased methods, and (3) to document eco-morphological and life history trait divergence. Also, we compared Lake Tinnsjøen with four Norwegian outgroup populations of Arctic charr.

Results

Four field-assigned morphs were identified in Lake Tinnsjøen; the planktivore morph in all habitats except deep-profundal, the dwarf morph in shallow-moderate profundal, the piscivore morph in shallow-moderate profundal (less in littoral and deep-profundal), and an undescribed new morph – the abyssal morph in the deep-profundal only. The morphs displayed extensive life history variation based on age and size patterns. A moderate to high concordance was observed between field-assigned morphs and four unbiased genetic clusters obtained from microsatellite variation. MtDNA suggested the occurrence of two minor endemic clades in Lake Tinnsjøen likely originating from one widespread colonizing clade in the Holarctic. All morphs were genetically differentiated at microsatellites (FST: 0.12-0.20; with some ongoing gene flow among morphs, and for most mtDNA comparisons (FST: 0.04-0.38). Analyses of Norwegian outgroup lakes implied colonization from a river system below Lake Tinnsjøen.

Conclusion

Our findings suggest post-glacial adaptive radiation of one colonizing mtDNA lineage with divergent niche specialization along a depth-temperature-productivity-pressure gradient. Concordance between reproductive isolation and the realized habitat of the morphs imply that ecological speciation may be the mechanism of divergence. Particularly novel is the extensive morph diversification with depth into the often unexplored deep-water profundal habitat, suggesting we may have systematically underestimated biodiversity present in lakes.
m6A minimally impacts the structure, dynamics, and Rev ARM binding properties of HIV-1 RRE stem IIB
Authors: Chu Chia-Chieh , Liu Bei , Plangger Raphael , Kreutz Christoph , Al-Hashimi Hashim M.
Published: October 2019

N6-methyladenosine (m6A) is a ubiquitous RNA post-transcriptional modification found in coding as well as non-coding RNAs. m6A has also been found in viral RNAs where it is proposed to modulate host-pathogen interactions. Two m6A sites have been reported in the HIV-1 Rev response element (RRE) stem IIB, one of which was shown to enhance binding to the viral protein Rev and viral RNA export. However, because these m6A sites have not been observed in other studies mapping m6A in HIV-1 RNA, their significance remains to be firmly established. Here, using optical melting experiments, NMR spectroscopy, andin vitrobinding assays, we show that m6A minimally impacts the stability, structure, and dynamics of RRE stem IIB as well as its binding affinity to the Rev arginine-rich-motif (ARM). Our results indicate that if present in stem IIB, m6A is unlikely to modulate RRE-Rev interaction by altering the conformational properties of the RNA. Our results add to a growing view that the impact of m6A on RNA depends on sequence context and Mg2+.
Antagonistic activity ofBacillus amyloliquefacienssubsp.amyloliquefaciensagainst multidrug resistantSerratia rubidaea
Authors: Afrin Sadia , Islam Bhuiyan Mohammad Nazrul
Published: October 2019

Serratia rubidaeaa member of the Enterobacteriaceae family, is a Gram-negative opportunistic pathogen, known to survive harsh environmental conditions and responsible for hospital associated infections. Specifically,S. rubidaeacan withstand desiccation and survive on hospital surfaces and equipments as well as have acquired antimicrobial resistance determinants for different commercial antibiotics. The expansion of this multidrug resistant pattern suggests that the treatment ofS. rubidaeainfections will become increasingly difficult in near future. Although some measures were taken to control this species, an inhibition mechanism is remaining unknown. To design effective means to control the dissemination ofS. rubidaea, an in-depth analysis is required. In the present study, one possible candidate was isolated from the soil of Sundarban Mangroove Forest (Bangladesh) that has important physiological effects to inhibit this pathogenic bacterium. The bacterial isolate was initially identified asBacillus amyloliquefacienssubsp.amyloliquefaciensusing BIOLOG™ identification system and confirmed to beB. amyloliquefaciensstrain through 16SrDNA sequence analysis. The growth and antagonistic activity of this potential strain was shown to be stable under wide range of pH, temperature and salinity (NaCl). Moreover, the novelB. amyloliquefaciensisolate can also inhibitStaphylococcus aureus, Escherichia coli, Pseudomonas aeruginosaand other pathogenic bacteria. These results suggest thatB. amyloliquefaciensmight have potential antimicrobial properties and further research is required for future use of this bacterium as biological controls ofS. rubidaeaor development as new drugs for pathogenic bacteria.
p53 induces senescence in the unstable progeny of aneuploid cells
Authors: Giam Maybelline , Wong Cheng Kit , Low Jun Siong , Sinelli Matteo , Dreesen Oliver , Rancati Giulia
Published: October 2019

Aneuploidy is the condition of having an imbalanced karyotype, which is strongly associated with tumor initiation, evolution, and acquisition of drug-resistant features, possibly by generating heterogeneous populations of cells with distinct genotypes and phenotypes. Multicellular eukaryotes have therefore evolved a range of extrinsic and cell-autonomous mechanisms for restraining proliferation of aneuploid cells, including activation of the tumor suppressor protein p53. However, accumulating evidence indicates that a subset of aneuploid cells can escape p53-mediated growth restriction and continue proliferating in vitro. Here we show that such aneuploid cell lines display a robust modal karyotype and low frequency of chromosomal aberrations despite ongoing chromosome instability. Indeed, while these aneuploid cells are able to survive for extended periods in vitro, their chromosomally unstable progeny remain subject to p53-induced senescence and growth restriction, leading to subsequent elimination from the aneuploid pool. This mechanism helps maintain low levels of heterogeneity in aneuploid populations and may prevent detrimental evolutionary processes such as cancer progression and development of drug resistance.
Circumvention of common labeling artifacts using secondary nanobodies
Authors: Sograte-Idrissi Shama , Schlichthaerle Thomas , Duque-Afonso Carlos J. , Alevra Mihai , Strauss Sebastian , Moser Tobias , Jungmann Ralf , Rizzoli Silvio , Opazo Felipe
Published: October 2019

The most common procedure to reveal the location of specific (sub)cellular elements in biological samples is via immunostaining followed by optical imaging. This is typically performed with target-specific primary antibodies (1.Abs), which are revealed by fluorophore-conjugated secondary antibodies (2.Abs). However, at high resolution this methodology can induce a series of artifacts due to the large size of antibodies, their bivalency, and their polyclonality. Here we use STED and DNA-PAINT super-resolution microscopy or light sheet microscopy on cleared tissue to show how monovalent secondary reagents based on camelid single-domain antibodies (nanobodies; 2.Nbs) attenuate these artifacts. We demonstrate that monovalent 2.Nbs have four additional advantages: 1) they increase localization accuracy with respect to 2.Abs; 2) they allow direct pre-mixing with 1.Abs before staining, reducing experimental time, and enabling the use of multiple 1.Abs from the same species; 3) they penetrate thick tissues efficiently; and 4) they avoid the artificial clustering seen with 2.Abs both in live and in poorly fixed samples. Altogether, this suggests that 2.Nbs are a valuable alternative to 2.Abs, especially when super-resolution imaging or staining of thick tissue samples are involved.
How do species barriers decay? Concordance and local introgression in mosaic hybrid zones of mussels
Authors: Simon Alexis , Fraïsse Christelle , Ayari Tahani El , Liautard-Haag Cathy , Strelkov Petr , Welch John J. , Bierne Nicolas
Published: October 2019

TheMytiluscomplex of marine mussel species forms a mosaic of hybrid zones, found across temperate regions of the globe. This allows us to study “replicated” instances of secondary contact between closely-related species. Previous work on this complex has shown that local introgression is both widespread and highly heterogeneous, and has identified SNPs that are outliers of differentiation between lineages. Here, we developed an ancestry-informative panel of such SNPs. We then compared their frequencies in newly-sampled populations, including samples from within the hybrid zones, and parental populations at different distances from the contact. Results show that close to the hybrid zones, some outlier loci are near to fixation for the heterospecific allele, suggesting enhanced local introgression, or the local sweep of a shared ancestral allele. Conversely, genomic cline analyses, treating local parental populations as the reference, reveal a globally high concordance among loci, albeit with a few signals of asymmetric introgression. Enhanced local introgression at specific loci is consistent with the early transfer of adaptive variants after contact, possibly including asymmetric bistable variants (Dobzhansky-Muller incompatibilities), or haplotypes loaded with fewer deleterious mutations. Having escaped one barrier, however, these variants can be trapped or delayed at the next barrier, confining the introgression locally. These results shed light on the decay of species barriers during phases of contact.
Service innovation, corporate reputation and word-of-mouth in the banking sector
Authors: Manohar Sridhar , Mittal Amit , Marwah Sanjiv
Published: October 2019

Purpose

The purpose of this paper is to establish the link between three constructs, namely, service innovation, corporate reputation (CR), and word-of-mouth (hereinafter WOM). Primarily, the aim is to understand whether innovation in a service firm drives its reputation, thereby resulting in positive WOM where the direct effect of service innovation of a firm on WOM is mediated by reputation. Furthermore, the study also seeks to understand whether the type of service firm has an effect on determining the level of the mediation effect.

Design/methodology/approach

This study adopts an integrated approach where the measure for the construct service innovation is explored through a qualitative approach, and the conceptual model is estimated through path analysis. The service industry taken for this study is banking, and the through non-probability criterion sampling technique, 252 customers responded to their level of agreement. The PLS-SEM technique was used to estimate the path coefficient by following the two-stage approach. The multigroup moderation analysis is performed to determine whether the type of the bank plays a major role in determining the direct effects and the mediation effect of CR between service innovation and WOM.

Findings

The result of this study indicates that there is a strong positive association between the three constructs. Further, the direct relationship between service innovation and WOM is partially mediated by reputation. The result of the multigroup moderation indicates that the type of the bank plays a major role in determining the mediation effect of reputation.

Practical implications

The study helps the decision makers and the managers of the bank to understand that frequent innovation within the firm would help to gain reputation, and thereby customers would tend to give a positive WOM. Further, non-reputable firms can still gain a positive WOM if they continuously innovate new services. In the Indian context, it is noted that there is a difference between private and public banks in determining the mediation effect of reputation between service innovation and WOM.

Originality/value

The originality of the study is based on the following: development of a unique scale to measure service innovation in the banking industry overcoming the existing scales which are based on goods-dominant logic; estimating empirically the combined effect of service innovation and CR on WOM; the process of evaluating the moderated mediation effect; how the mediating effect of CR varies from private sector banks to public sector banks.
Process management framework for chemical waste treatment laboratories
Authors: Leoneti Alexandre Bevilacqua , Vitorino dos Santos Danilo , da Silva Renato Santos , Henriques Ferreira Alessandra , César Pimenta Adriano , Valle Walter Borges de Oliveira Sonia
Published: October 2019

Purpose

The purpose of this paper is to propose a process management framework for Chemical Waste Treatment Laboratories (CWTL) that can be used as a management tool to identify and manage critical process.

Design/methodology/approach

Proposition of a generic classification for categories of chemical waste; use of the ABC analysis as a tool for analysis of priority in relation to the inputs of an CWTL; use of the process matrix (variety vs volume) to identify the key resources required to perform the activities of a CWTL; and use of mapping process techniques to map the processes defined and calculate times.

Findings

The proposed framework was applied to a CWTL at University of São Paulo, Brazil, and showed that the high variability of demand is a significant factor in the management of this laboratory, requiring processes that are flexible to meet this demand. The results showed that the applicability of the production and operations management theories within the scope of process management of CWTLs, proved to be useful tools for improving the treatment efficiency of chemical waste in these facilities.

Originality/value

The novelty of this work is in the fact of using production and operations management tools in the management of CWTLs to propose diagnoses to improve the management of their processes. The proposition of a comprehensive classification for chemical wastes generated in CWTLs is also highlighted.
Leadership preferences and ethnic bargaining: theory and illustrations
Authors: Horowitz Shale , Ye Min
Published: October 2019

Purpose

In explaining ethno-territorial conflicts, leadership preferences have an odd status. In case studies, leadership preferences are often viewed as highly significant causes but are not usually defined and measured explicitly. In large-sample statistical studies, leadership preferences are only captured by weakly related proxy variables. This paper aims to fill this gap by developing suitable theory, which can be used consistently in both case study and statistical applications.

Design/methodology/approach

Formal bargaining models are used to examine the expected impact of variation in leadership preferences. Relevant leadership characteristics are then used to construct measures of variation in leadership preferences, which are applied in case studies.

Findings

In bargaining models, variation in leadership preferences is expected to have a significant impact on ethno-territorial conflict outcomes. More extreme nationalist leaders and, more conditionally, strongly power-seeking leaders, should be more likely to be willing to use force to modify the status quo – although more moderate nationalist leaderships are also willing to do so under certain conditions. In five case studies, these formally derived hypotheses receive initial empirical support.

Originality/value

Theoretically and empirically, further refinement of research on variation in leadership preferences promises to add significant value. Formally, it is worth investigating the expected impact of additional preference types. Empirically, it is important to invest in measures of leadership preferences across large samples.
Social media marketing management: an application to small restaurants in the US
Authors: Lepkowska-White Elzbieta , Parsons Amy , Berg William
Published: October 2019

Purpose

This study aims to use a social media management framework and strategic orientation framework to explore how small restaurants manage social media.

Design/methodology/approach

The authors content-analyzed social media activity and interviews with 14 managers of social media in small independent restaurants in the northeast region of the USA that employed fewer than 20 employees.

Findings

The results of the study show that most small restaurants can be classified as anarchic, hierarchical and conservative defenders, and that they mainly focus on promotional activities on social media. The majority use social media also to drive traffic to a restaurant and, thus, act as calculative pragmatists. Very few use social media strategically or creatively in any of the social media management stages, and very few monitor or use social media information to improve their operations.

Research limitations/implications

This study shows that the adopted theoretical framework in this study for social media management helps analyze social media operations in small restaurants, points to the strategic orientations applied in small restaurants, shows the intricacies of each stage and helps show what small restaurants do well and how they can improve. Future research may use larger samples, investigate frameworks particularly relevant to small restaurants, such as the resource-based view (RBV) framework, and may focus on creative and diverse strategic approaches toward social media management for small establishments.

Practical implications

As customers continue shifting to social media and review sites, more restaurants may want to invest in developing more creative approaches toward social media and do it in more structured, integrated and continuous ways. The study describes a process they may want to follow and specific tactics that could be implemented to use social media more strategically in all stages of social media management.

Social implications

Not only are small business establishments the backbone of the restaurant industry, but they also appeal to customers more than large chains. This study shows how these small businesses can utilize social media to attract more customers, engage them, learn about them and their competitive environment to market and improve their operations.

Originality/value

The authors focus on the supplier side of social media for restaurants, a perspective lacking in the literature, and specifically small restaurants that receive less attention in prior research. Few studies exist that explore how social media is incorporated in all stages of social media management. The study points to the unique challenges that small restaurants experience in the process of using social media for marketing, monitoring and using social media to improve their operations. The study uses a relatively large sample of qualitative interviews conducted with managers of small restaurants and a content analysis of their actual social media activity.
How do talented managers view dividend policy? Further evidence from Chinese equity market
Authors: Sarwar Bushra , Kutan Ali , Ming Xiao , Husnain Muhammad
Published: October 2019

Purpose

The purpose of this paper is to examine the importance of market imperfection, namely, variation in managerial ability (MA), on dividend policy in China. The authors focus on the Chinese market as it is dominated by state-owned enterprises and test whether the association between MA and dividend policy varies systematically with the degree of state ownership.

Design/methodology/approach

To measure MA, this study exploits a novel measure developed by Demerjianet al.(2012) to estimate how efficiently manager utilizes firm’s resources. Manager efficiency is defined in terms of output a manager produces based on inputs available within firm.

Findings

The authors find that relationship between MA and dividend policy is primarily driven by non-state own enterprises compare to state own enterprises, more prevalent for financially unconstrained firms with strong balance sheet and more pronounced under high marketized groups as compare to low marketized groups. These finding are robust under battery of robustness checks. This research adds new insight for the policy makers and investors to pay more attention on MA.

Practical implications

This research adds new insight for the policy makers and investors to pay more attention on MA.

Originality/value

This study augments the dividend policy literature by relaxing perfect capital market assumption of Miller and Modigliani, and neo-classic view of firms by incorporating a new novel factor – variation in MA – and applies it to the emerging market of China.