bluuebunny/crossref_metadata_2025 huggingface dataset:
Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform
Authors: Helman Guy , Takanohashi Asako , Hagemann Tracy L. , Perng Ming D. , Walkiewicz Marzena , Woidill Sarah , Sase Sunetra , Cross Zachary , Du Yangzhu , Zhao Ling , Waldman Amy , Haake Bret C. , Fatemi Ali , Brenner Michael , Sherbini Omar , Messing Albee , Vanderver Adeline , Simons Cas
Published: November 2019

Alexander disease results from gain of function mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament protein expressed in astrocytes. At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for approximately 90% of GFAP protein in the central nervous system. Here we describe exonic variants identified in three unrelated families with Type II Alexander disease that alter the splicing of GFAP pre-mRNA and result in upregulation of a previously uncharacterized GFAP lambda isoform (NM 001363846.1). Affected members of Family 1 and Family 2 shared the same missense variant, NM 001363846.1:c.1289G>A;p.(Arg430His) while in Family 3 we identified a synonymous variant in the adjacent nucleotide, NM 001363846.1:c.1290C>A;p.(Arg430Arg). Using RNA and protein analysis of brain autopsy samples, and a mini-gene splicing reporter assay, we demonstrate both variants result in upregulation of the lambda isoform. We assessed other GFAP variants in the ClinVar database for predicted aberrant splicing and using the same assay demonstrated significant changes to splicing for two selected variants. Our approach demonstrates the importance of characterizing the effect of GFAP variants on mRNA splicing in order to inform future pathophysiologic and therapeutic study for Alexander disease.
Dynamic evolution of euchromatic satellites on the X chromosome inDrosophila melanogasterand thesimulansclade
Authors: Sproul J.S. , Khost D.E. , Eickbush D.G. , Negm S. , Wei X. , Wong I. , Larracuente A.M.
Published: November 2019

Satellite DNAs (satDNAs) are among the most dynamically evolving components of eukaryotic genomes and play important roles in genome regulation, genome evolution, and speciation. Despite their abundance and functional impact, we know little about the evolutionary dynamics and molecular mechanisms that shape satDNA distributions in genomes. Here we use high-quality genome assemblies to study evolutionary dynamics of two complex satDNAs,Rsp-likeand1.688gm/cm3, inDrosophila melanogasterand its three nearest relatives in thesimulansclade. We show that large blocks of these repeats are highly dynamic in the heterochromatin, where their genomic location varies across species. We discovered that small blocks of satDNA that are abundant in X chromosome euchromatin are similarly dynamic, with repeats changing in abundance, location, and composition among species. We detail the proliferation of a rare satellite (Rsp-like) across the X chromosome inD. simulansandD. mauritiana. Rsp-likespreads by inserting into existing clusters of the older, more abundant1.688satellite, in events that were likely facilitated by microhomology-mediated repair pathways. We show thatRsp-likeis abundant on extrachromosomal circular DNA inD. simulans, which may have contributed to its dynamic evolution. Intralocus satDNA expansions via unequal exchange and the movement of higher-order repeats also contribute to the fluidity of the repeat landscape. We find evidence that euchromatic satDNA repeats experience cycles of proliferation and diversification somewhat analogous to bursts of transposable element proliferation. Our study lays a foundation for mechanistic studies of satDNA proliferation and the functional and evolutionary consequences of satDNA movement.
A highly sensitive and specific SYBR Green quantitative polymerase chain reaction (qPCR) method for rapid detection of scale drop disease virus in Asian sea bass, Lates calcarifer
Authors: Sriisan Sukhontip , Boonchird Chuenchit , Thitamadee Siripong , Sonthi Molruedee , Dong Ha Thanh , Senapin Saengchan
Published: November 2019

Scale drop disease virus (SDDV) is a novel Megalocytivirus causing scale drop disease (SDD) in Asian sea bass in Southeast Asia. In order to support disease diagnosis and surveillance, the present study developed a highly sensitive and specific SYBR Green qPCR assay for rapid detection of SDDV. Specific primers targeting a 135-bp fragment of ATPase coding gene of the SDDV genome were newly designed and subsequent gradient PCR assays were conducted to investigate their optimal annealing temperature. The optimized qPCR assay could detect as low as 2 viral copies per reaction and showed no cross amplification with DNA extracted from 12 viruses and bacteria commonly found in aquatic animals. The SDDV ATPase qPCR method was subsequently validated with field samples (n= 86). The results revealed that all clinically sick fish (n=34) from 5 affected farms gave positive results. Interestingly, 30/52 samples of apparently healthy fish from 8 unaffected farms which previously tested negative for SDDV by semi-nested PCR assay were positive by the newly developed qPCR method. This suggested that qPCR method is highly sensitive and suitable for early screening of SDDV from clinically healthy fish and for disease confirmation of sick fish. Investigation of tissue tropism and viral load of SDDV revealed systemic viral infection with relatively high viral load (8 × 102 to 6.8 × 104 copies per 200 ng of DNA template) in all 9 tested organs including eyes, brain, fin, gills, kidney, liver, kidney, spleen, and muscle. The newly developed qPCR method in this study delivered an accurate and reliable method for rapid detection of SDDV that may facilitate active surveillance and prevent widespread of the virus.

Highlights

This study developed a SYBR Green qPCR assay for rapid detection of SDDV

The developed qPCR assay is specific for SDDV with limit of detection of 2 viral copies per reaction

The assay could detect the virus from subclinically infected fish with low viral load

We recommend this qPCR assay for active surveillance and early screening of SDDV
Differential transcription of expanded gene families in central carbon metabolism of Streptomyces coelicolor A3(2)
Authors: Schniete Jana K , Reumerman Richard , Kerr Leena , Tucker Nicholas P , Hunter Iain S , Herron Paul R , Hoskisson Paul A
Published: November 2019

Background

Streptomycete bacteria are prolific producers of specialised metabolites, many of which have clinically relevant bioactivity. A striking feature of their genomes is the expansion of gene families that encode the same enzymatic function. Genes that undergo expansion events, either by horizontal gene transfer or duplication, can have a range of fates: genes can be lost, or they can undergo neo-functionalisation or sub-functionalisation. To test whether expanded gene families in Streptomyces exhibit differential expression, an RNA-Seq approach was used to examine cultures of wild-type Streptomyces coelicolor grown with either glucose or tween as the sole carbon source.

Results

RNA-Seq analysis showed that two-thirds of genes within expanded gene families show transcriptional differences when strains were grown on tween compared to glucose. In addition, expression of specialised metabolite gene clusters (actinorhodin, isorenieratane, coelichelin and a cryptic NRPS) was also influenced by carbon source.

Conclusions

Expression of genes encoding the same enzymatic function had transcriptional differences when grown on different carbon sources. This transcriptional divergence enables partitioning to function under different physiological conditions. These approaches can inform metabolic engineering of industrial Streptomyces strains and may help develop cultivation conditions to activate the so-called silent biosynthetic gene clusters.
G-Quadruplexes Act as Sequence Dependent Chaperones via Protein Oligomerization
Authors: Begeman Adam , Litberg Theodore J. , Bourne Jennifer , Xuan Zhenyu , Horowitz Scott
Published: November 2019

Maintaining proteome health is important for cell survival. Nucleic acids possess the ability to prevent aggregation up to 300-fold more efficiently than traditional chaperone proteins. In this study, we explore the sequence specificity of the chaperone activity of nucleic acids. Evaluating over 500 nucleic acid sequences’ effects on aggregation, we demonstrate that the holdase chaperone effect of nucleic acids is highly sequence dependent. Quadruplexes are found to have especially potent effects on aggregation with many different proteins via quadruplex:protein oligomerization. These observations contextualize recent reports of quadruplexes playing important roles in aggregation-related diseases, such as Fragile X and Amyotrophic lateral sclerosis (ALS).
Bacterial quorum sensing allows graded and bimodal cellular responses to variations in population density
Authors: Rattray Jennifer B. , Thomas Stephen A. , Wang Yifei , Molotkova Evgeniya , Gurney James , Varga John J. , Brown Sam P.
Published: November 2019

Quorum sensing (QS) is a mechanism of cell–cell communication that connects gene expression to environmental conditions (e.g. density) in many bacterial species, mediated by diffusible signal molecules. Current functional studies focus on a dichotomy of QS on/off (or, quorate / sub-quorate) states, overlooking the potential for intermediate, graded responses to shifts in the environment. Here, we track QS regulated protease (lasB) expression and show that Pseudomonas aeruginosa can deliver a graded behavioral response to fine-scale variation in population density, on both the population and single-cell scales. On the population scale, we see a graded response to variation in environmental population density. On the single-cell scale, we see significant bimodality at higher densities, with separate OFF and ON sub-populations that respond differentially to changes in density; static OFF cells and increasing intensity of expression among ON cells. Together these results indicate that QS can tune gene expression to graded environmental change, with no critical cell mass or ‘quorum’ at which behavioral responses are activated on either the individual cell or population scale. In an infection context, our results indicate there is not a hard threshold separating sub-quorate ‘stealth’ mode and a quorate ‘attack’ mode.
Cyclic peptides can engage a single binding pocket through multiple, entirely divergent modes
Authors: Patel Karishma , Walport Louise J , Walshe James L , Solomon Paul , Low Jason K K , Tran Daniel H , Mouradian Kevork S , Silva Ana P G , Wilkinson-White Lorna , Matthews Jacqueline M , Mitchell Guss J , Payne Richard J , Passioura Toby , Suga Hiroaki , Mackay Joel P
Published: November 2019

Cyclic peptide display screening techniques can identify drug leads and biological probes with exceptional affinity and specificity. To date, however, the structural and functional diversity encoded in such peptide libraries remains unexplored. We have used the Random nonstandard Peptide Integrated Discovery (RaPID) system to develop cyclic peptide inhibitors of several acetyllysine-binding bromodomains from the Bromodomain and Extra-Terminal domain (BET) family of epigenetic regulators. These peptides have very high affinities for their targets and exhibit extraordinary selectivity (up to 106-fold), making them the highest-affinity and most specific BET-binding molecules discovered to date. Crystal structures of 13 distinct peptide-bromodomain complexes, which all target the acetyllysine-binding pocket, reveal remarkable diversity in both peptide structure and binding mode, and include both α-helical and β-sheet type structures. The peptides can exhibit a high degree of structural pre-organization and bivalent binding of two BDs by one peptide was common, flagging the potential for a new direction in inhibitor design that could bring stronger discrimination between BET-family paralogues. Our data demonstrate for the first time the enormous potential held in these libraries to provide a wide array of modes against a single target, maximizing the opportunity to attain high potency and specificity ligands to a wide variety of proteins.
Learning mutational signatures and their multidimensional genomic properties with TensorSignatures
Authors: Vöhringer Harald , van Hoeck Arne , Cuppen Edwin , Gerstung Moritz
Published: November 2019

Mutational signature analysis is an essential part of the cancer genome analysis toolkit. Conventionally, mutational signature analysis extracts patterns of different mutation types across many cancer genomes. Here we present TensorSignatures, an algorithm to learn mutational signatures jointly across all variant categories and their genomic context. The analysis of 2,778 primary and 3,824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that practically all signatures operate dynamically in response to various genomic and epigenomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis, which is detected in 7 different cancer types. The analysis also unmasks replication- and double strand break repair-driven APOBEC mutagenesis, which manifests with differential numbers and length of mutation clusters indicating a differential processivity of the two triggers. As a fourth example, TensorSignatures detects a signature of somatic hypermutation generating highly clustered variants around the transcription start sites of active genes in lymphoid leukaemia, distinct from a more general and less clustered signature of Polη-driven translesion synthesis found in a broad range of cancer types.

Key findings

Simultaneous inference of mutational signatures across mutation types and genomic features refines signature spectra and defines their genomic determinants.

Analysis of 6,602 cancer genomes reveals pervasive intra-genomic variation of mutational processes.

Distinct mutational signatures found in quiescent and active regions of the genome reveal differential repair and mutagenicity of UV- and tobacco-induced DNA damage.

APOBEC mutagenesis produces two signatures reflecting highly clustered, double strand break repair-initiated and lowly clustered replication-driven mutagenesis, respectively.

Somatic hypermutation in lymphoid cancers produces a strongly clustered mutational signature localised to transcription start sites, which is distinct from a weakly clustered translesion synthesis signature found in multiple tumour types.
Reconciling global priorities for conserving biodiversity habitat
Authors: Mokany K. , Ferrier S. , Harwood T.D. , Ware C. , Di Marco M. , Grantham H.S. , Venter O. , Hoskins A.J. , Watson J.E.M.
Published: November 2019

Degradation and loss of natural habitat is the major driver of the current global biodiversity crisis. Most habitat conservation efforts to date have targeted small areas of highly threatened habitat, but emerging debate suggests retaining large intact natural systems may be just as important. We reconcile these perspectives by integrating fine-resolution global data on habitat condition and species assemblage turnover, to identify Earth’s high-value biodiversity habitat. These are areas in better condition than most other locations once supporting a similar assemblage of species, and are found within both intact regions and human dominated landscapes. However, only 18.6 % of this high-value habitat is currently protected globally. Averting permanent biodiversity loss requires clear spatially explicit targets for retaining these unprotected high-value habitats.
Quantitative Detection of Cell Activity by Measuring the Fluctuation of Intracellular Motility
Authors: Sakuma Morito , Kondo Yuichi , Higuchi Hideo
Published: November 2019

The measurement of cell activity changes during damage is important to understand the process of cell death and evaluate the effect of medicines. To evaluate cell activity generally, we extended the method of intensity fluctuation in which intensity change in the pixel induced by the movement of organelles was calculated. Cancer, endothelial and iPS cells were damaged by reactive oxygen species (ROS) generated by a fluorescent dye (IR700), hydrogen peroxide, and ultraviolet light. The intensity fluctuation in damaged cells gradually decreased independent of the kind of cell, indicating that the decrease in the fluctuation is a general phenomenon in damaged cells. The rupture of vesicles and mitochondria in the cells were observed upon ROS production. The motility of purified kinesin and dynein which transport vesicles and organelles was inhibited by ROS. These suggest that ROS and cytotoxic molecules spreading from ruptured organelles contribute to the reduction in cell activity which brings about the decrease in the motility and intensity fluctuation of organelles driven by kinesin and dynein.
Computing Skin Cutaneous Melanoma Outcome from the HLA-alleles and Clinical Characteristics
Authors: Dhall Anjali , Patiyal Sumeet , Kaur Harpreet , Bhalla Sherry , Arora Chakit , Raghava G.P.S.
Published: November 2019

Human Leukocyte Antigen (HLA) is an essential component of the immune system which stimulates immune cells to provide protection and defense against cancer. More than thousands of HLA alleles have been reported in the literature; but, only a specific set of HLA alleles expressed in an individual. Recognition of cancer-associated mutations by the immune system depends on the presence of a particular set of alleles, that elicit an immune response to fight against cancer. It indicates that the occurrence of specific HLA alleles also affects the outcome of the cancer patients. In the current study, prediction models have been developed using 415 skin cutaneous melanoma (SKCM) patients for predicting the overall survival of patients from their HLA-alleles. It has been observed that, the presence of certain superalleles in the patients, is responsible for improved overall survival which were referred as favourable superalleles like HLA-B*55 (HR=0.15, 95% CI 0.034 to 0.67), HLA-A*01 (HR=0.5, 95% CI 0.3 to 0.8). In contrast, presence of certain superalleles in the patients is responsible for their poor survival, those superalleles were referred as unfavourable superalleles such as HLA-B*50 (HR=2.76, 95% CI 1.284 to 5.941), HLA-DRB1*12 (HR=3.44, 95% CI 1.64 to 7.2). We developed prediction models using 14 HLA-superalleles and five clinical characteristics for predicting high-risk SKCM patients and achieve HR=4.52 (95% CI 3.088-6.609) with p-value = 8.01E-15. Lastly, we provide a web-based service to community for predicting the risk in SKCM patients (https://webs.iiitd.edu.in/raghava/skcmhrp/)
Low iron-induced small RNA BrrF regulates central metabolism and oxidative stress responses inBurkholderia cenocepacia
Authors: Sass Andrea , Coenye Tom
Published: November 2019

BrrF is a Fur-regulated small RNA highly upregulated inBurkholderia cenocepaciaunder conditions of iron depletion. Its computationally predicted targets include iron-containing enzymes of the tricarboxylic acid (TCA) cycle such as aconitase and succinate dehydrogenase, as well as iron-containing enzymes responsible for the oxidative stress response, such as superoxide dismutase and catalase. Phenotypic and gene expression analysis of BrrF deletion and overexpression mutants show that the regulation of these genes is BrrF-dependent. Expression ofacnA,fumA,sdhAandsdhCwas downregulated during iron depletion in the wild type strain, but not in a BrrF deletion mutant. TCA cycle genes not predicted as target for BrrF were not affected in the same manner by iron depletion. Likewise, expression ofsodBandkatBwas dowregulated during iron depletion in the wild type strain, but not in a BrrF deletion mutant. BrrF overexpression reduced aconitase and superoxide dismutase activities and increased sensitivity to hydrogen peroxide. All phenotypes and gene expression changes of the BrrF deletion mutant could be complemented by overexpressing BrrFin trans. Overall, BrrF acts as a regulator of central metabolism and oxidative stress response, possibly as an iron-sparing measure to maintain iron homeostasis under conditions of iron starvation.

Importance

Regulatory small RNAs play an essential role in maintaining cell homeostasis in bacteria in response to environmental stresses such as iron starvation. Prokaryotes generally encode a large number of RNA regulators, yet their identification and characterisation is still in its infancy for most bacterial species.Burkholderia cenocepaciais an opportunistic pathogen with high innate antimicrobial resistance, which can cause the often fatal cepacia syndrome in individuals with cystic fibrosis. In this study we characterise a small RNA which is involved in the response to iron starvation, a condition that pathogenic bacteria are likely to encounter in the host.
Exploring groundwater microbial communities for natural attenuation potential of micropollutants
Authors: Aldas-Vargas Andrea , Hauptfeld Ernestina , Hermes Gerben D.A. , Atashgahi Siavash , Smidt Hauke , Rijnaarts Huub H.M. , Sutton Nora B.
Published: November 2019

Groundwater is a key water resource, with 45.7% of all drinking water globally being extracted from groundwater. Maintaining good groundwater quality is thus crucial to secure drinking water. Micropollutants, such as pesticides, threaten groundwater quality which can be mitigated by biodegradation. Hence, exploring microbial communities in aquifers used for drinking water production is essential for understanding micropollutants biodegradation capacity. This study aimed at understanding the interaction between groundwater geochemistry, pesticide presence, and microbial communities in aquifers used for drinking water production. Two groundwater monitoring wells located in the northeast of The Netherlands and at 500 m distance from each other were sampled in 2014, 2015, 2016 and 2018. In both wells, water was extracted from five discrete depths ranging from 13 to 54 m and used to analyze geochemical parameters, pesticide concentrations and microbial community dynamics using 16S rRNA gene sequencing and qPCR. Groundwater geochemistry was stable throughout the study period and pesticides were heterogeneously distributed at low concentrations (μg/L range). Integration of the groundwater chemical and microbial data showed that geochemical parameters and pesticides exerted selective pressure on microbial communities. Furthermore, microbial communities in both wells showed a more similar composition in the deeper part of the aquifer as compared to shallow sections, suggesting vertical differences in hydrological connection. This study provides initial insights into microbial community composition and distribution in groundwater systems in relation to geochemical parameters. This information can contribute for the implementation of bioremediation technologies that guarantee safe drinking water production from clean aquifers.

Importance section

Groundwater is an essential source of drinking water. However, its quality is threathened by the presence of micropollutants. Certain microorganisms are capable of degrading micropollutants. However, groundwater is an unexplored environment, where the biodegradation potential of naturally-present microorganisms is unknown. We thus explore how groundwater microbial ecology in shaped by groundwater composition, namely geochemical parameters and micropollutants. This is a first step towards understanding which microbial communities and environmental conditions support natural attenuation of micropollutants. This study thus provides a first step towards developing in situ bioremediation strategies to remove micropollutants from groundwater used for drinking water production.
Genome-enabled prediction models for black tea (Camellia sisnesnsis) quality and drought tolerance traits
Authors: Koech Robert. K. , Malebe Pelly M. , Nyarukowa Christopher , Mose Richard , Kamunya Samson M. , Loots Theodor , Apostolides Zeno
Published: November 2019

Genomic selection in tea (Camellia sinensis) breeding has the potential to accelerate efficiency of choosing parents with desirable traits at the seedling stage.

The study evaluated different genome-enabled prediction models for black tea quality and drought tolerance traits in discovery and validation populations. The discovery population comprised of two segregating tea populations (TRFK St. 504 and TRFK St. 524) with 255 F1 progenies and 56 individual tea cultivars in validation population genotyped using 1 421 DArTseq markers.

Two-fold cross-validation was used for training the prediction models in discovery population, and the best prediction models were consequently, fitted to the validation population.

Of all the four based prediction approaches, putative QTLs (Quantitative Trait Loci) + annotated proteins + KEGG (Kyoto Encyclopaedia of Genes and Genomes) pathway-based prediction approach, showed robustness and usefulness in prediction of phenotypes.

Extreme Learning Machine model had better prediction ability for catechin, astringency, brightness, briskness, and colour based on putative QTLs + annotated proteins + KEGG pathway approach.

The percent variables of importance of putatively annotated proteins and KEGG pathways were associated with the phenotypic traits. The findings has for the first time opened up a new avenue for future application of genomic selection in tea breeding.
Dynamic expression of MMP28 during cranial morphogenesis
Authors: Gouignard Nadege , Theveneau Eric , Saint-Jeannet Jean-Pierre
Published: November 2019

Matrix metalloproteinases (MMP) are a large family of proteases comprising 24 members in vertebrates. They are well known for their extracellular matrix remodelling activity. MMP28 is the last member of the family to be discovered. It is a secreted MMP involved in wound healing, immune system maturation, cell survival and migration. MMP28 is also expressed during embryogenesis in human and mouse. Here we describe the detailed expression profile of MMP28 inXenopus laevisembryos. We show that MMP28 is expressed maternally and accumulates at neurula and tailbud stages specifically in the cranial placode territories adjacent to migrating neural crest cells. As a secreted MMP, MMP28 may be required in normal neural crest-placode interactions.
Object Recognition in P14 mice
Authors: Chandrakantan Arvind , Adler Adam C. , Pereira Fred A.
Published: November 2019

Object Recognition is a task which involves multiple brain areas for successful completion. This assay is non-invasive, is an enriched learning task, and relies upon on encoded memory for successful completion. In this study, we have demonstrated that neonatal mice can perform the task
In vivodiversification of target genomic sites using processive T7 RNA polymerase-base deaminase fusions blocked by RNA-guided dCas9
Authors: Álvarez Beatriz , Mencía Mario , de Lorenzo Víctor , Fernández Luis Ángel
Published: November 2019

Diversification of specific DNA segments typically involvein vitrogeneration of large sequence libraries and their introduction in cells for selection. Alternativein vivomutagenesis systems on cells often show deleterious offsite mutations and restricted capabilities. To overcome these limitations, we have developed anin vivoplatform to diversify specific DNA segments based on protein fusions between various base deaminases (BD) and the T7 RNA polymerase (T7RNAP) that recognizes a cognate promoter oriented towards the target sequence. The transcriptional elongation of these fusions generates transitions C to T or A to G on both DNA strands and in long DNA segments. To delimit the boundaries of the diversified DNA, the catalytically dead Cas9 (dCas9) is tethered with custom-designed crRNAs as a “roadblock” for BD-T7RNAP elongation. While the efficiency of this platform is demonstrated inE. coli, the system can be adapted to a variety of bacterial and eukaryotic hosts.
Discovery of the First Human Retro-Giant Virus: Description of its morphology, retroviral kinase and ability to induce tumours in mice
Authors: Lusi Elena Angela , Caicci Federico
Published: November 2019

Background

The study of retroviruses dates back to the early 1900s during investigations on neoplastic diseases in chickens. Subsequently, Robert Gallo reported the first human retrovirus HLTV in 1980. What we report here is not an archetypal retrovirus, but the discovery of an oncogenic giant microbial agent with a mega-genome, where the transforming retroviral nature co-exists with multiple archaeal oncogenes.

Methods

After their isolation from human T cells Leukaemia, these organisms were examined at electron microscopy, tested for reverse transcriptase activity, fully sequenced, used for transformation tests on NIH-3T3 cells in vitro and tumours formation in mice. Same type of particles were also isolated from Canine Transmissible Venereal Tumour (CTVT), the oldest contagious cancer in nature.

Results

EM showed the presence of giant viral particles displaying retroviral antigens. These microbial entities harbour in their mega-genome a transforming retroviral kinase, cell-based oncogenes and have reverse transcriptase activity. The purified viral particles transformed NIH-3T3 cells and induced metastatic tumours in nude mice, three weeks post infection. Ruling out the possible presence of filterable retroviruses, a filtered supernatant did not display RT activity and did not transforms.

Conclusions

We discovered an ancestral microbial agent, acutely transforming. For its giant dimensions, the ability to retain the Gram stain, the presence of a mega-genome and its retroviral nature, we tentatively named the agent Retro-Giant-Virus (RGV). However, distinct from amoeba giant Mimiviruses, this transforming human agent has a different nature and does not require for its isolation amoeba co-culture, since amoeba is not its natural host.

The morphology, biology and genetic features allocate this mammalian giant microbe halfway in between a classic oncogenic virus and an infectious cancer cell. Its transforming nature goes with its constant ability to induce tumours formation in mice.
Family History of Depression is Associated with Alterations in Task-Dependent Connectivity between the Cerebellum and Ventromedial Prefrontal Cortex
Authors: Tepfer Lindsey J. , Alloy Lauren B. , Smith David V.
Published: November 2019

Background

A family history of major depressive disorder (MDD) increases the likelihood of a future depressive episode, which itself poses a significant risk for disruptions in reward processing and social cognition. However, it is unclear whether a family history of MDD is associated with alterations in the neural circuitry underlying reward processing and social cognition.

Methods

We subdivided 279 participants from the Human Connectome Project into three groups: 71 with a lifetime history of MDD, 103 with a family history of MDD (FH), and 105 healthy controls (HC). We then evaluated task-based fMRI data on a social cognition and a reward processing task and found a region of the ventromedial prefrontal cortex (vmPFC) that responded to both tasks, independent of group. To investigate whether the vmPFC shows alterations in functional connectivity between groups, we conducted psychophysiological interaction (PPI) analyses using the vmPFC as a seed region.

Results

We found that FH (relative to HC) was associated with increased sadness scores, and MDD (relative to both FH and HC) was associated with increased sadness and MDD symptoms. Additionally, the FH group had increased vmPFC functional connectivity within the nucleus accumbens, left dorsolateral PFC, and subregions of the cerebellum relative to HC during the social cognition task.

Conclusions

These findings suggest that aberrant neural mechanisms among those with a familial risk of MDD may underlie vulnerability to altered social cognition.
The structure and function of the sucker systems of hill stream loaches
Authors: Willis Jay , Burt de Perera Theresa , Newport Cait , Poncelet Guillaume , Sturrock Craig J , Thomas Adrian
Published: November 2019

Hill stream loaches (familyBalitoridaeandGastromyzontidae) are thumb-sized fish that effortlessly exploit environments where flow rates are so high that potential competitors would be washed away. To cope with these extreme flow rates hill stream loaches have evolved adaptations to stick to the bottom, equivalent to the downforce generating wings and skirts of F1 racing cars, and scale architecture reminiscent of the drag-reducing riblets of Mako sharks. Hill stream loaches exhibit far more diverse flow-modifying morphological features than fast pelagic predators, suggesting as yet unknown drag reducing systems remain to be discovered. Here we describe the skeletal structure ofSewellia lineolataandGastromyzon punctulatusand contrast that with other fish that face similar hydrodynamic challenges. We identify a major structural variation withinBalitoridaepelvic sucker attachment positions which may explain fundamental constraints on the parallel development of different genera and which has not been described before. We also use high speed video capture, CT scans and Frustrated Total Internal Reflection to image and measure the sucker system in live operation and describe how it functions on a familiar activity for hill stream loaches (climbing waterfalls). We show how they can drag 3 to 4 times their own bodyweight up a vertical glass waterfall. Adaptations to high flow rates are the inspiration for this study, because there are many engineering applications where the ability to deal with high flow rates are important - either by reducing drag, or by generating the forces needed to hold an animal in place.
Axon-dependent expression of YAP/TAZ mediates Schwann cell remyelination but not proliferation after nerve injury
Authors: Grove Matthew , Lee Hyunkyoung , Zhao Huaqing , Son Young-Jin
Published: November 2019

Previously we showed that YAP/TAZ promote not only proliferation but also differentiation of immature Schwann cells (SCs), thereby forming and maintaining the myelin sheath around peripheral axons (Grove et al., 2017). Here we show that YAP/TAZ are required for mature SCs to restore peripheral myelination, but not to proliferate, after nerve injury. We find that YAP/TAZ dramatically disappear from SCs of adult mice concurrent with axon degeneration after nerve injury. They reappear in SCs only if axons regenerate. YAP/TAZ ablation does not impair SC proliferation or transdifferentiation into growth promoting repair SCs. SCs lacking YAP/TAZ, however, fail to upregulate myelin-associated genes and completely fail to remyelinate regenerated axons. We also show that both YAP and TAZ are redundantly required for optimal remyelination. These findings suggest that axons regulate transcriptional activity of YAP/TAZ in adult SCs and that YAP/TAZ are essential for functional regeneration of peripheral nerve.
Predator complementarity dampens variability of phytoplankton biomass in a diversity-stability trophic cascade
Authors: Rakowski Chase J. , Farrior Caroline E. , Manning Schonna R. , Leibold Mathew A.
Published: November 2019

Trophic cascades – indirect effects of predators that propagate down through food webs – have been extensively documented. It has also been shown that predator diversity can mediate these trophic cascades, and separately, that herbivore biomass can influence the stability of primary producers. However, whether predator diversity can cause cascading effects on the stability of lower trophic levels has not yet been studied. We conducted a laboratory microcosm experiment and a field mesocosm experiment manipulating the presence and coexistence of two heteropteran predators and measuring their effects on zooplankton herbivores and phytoplankton basal resources. We predicted that if the predators partitioned their zooplankton prey, for example by size, then co-presence of the predators would reduce zooplankton prey mass and lead to 1) increased average values and 2) decreased temporal variability of phytoplankton basal resources. We present evidence that the predators partitioned their zooplankton prey, leading to a synergistic suppression of zooplankton; and that in turn, this suppression of zooplankton reduced the variability of phytoplankton biomass. However, mean phytoplankton biomass was unaffected. Our results demonstrate that predator diversity may indirectly stabilize basal resource biomass via a “diversity-stability trophic cascade,” seemingly dependent on predator complementarity, but independent of a classic trophic cascade in which average biomass is altered. Therefore predator diversity, especially if correlated with diversity of prey use, could play a role in regulating ecosystem stability. Furthermore, this link between predator diversity and producer stability has implications for potential biological control methods for improving the reliability of crop yields.
Activation of GPR56, a novel adhesion GPCR, is necessary for nuclear androgen receptor signaling in prostate cells
Authors: Singh Julie Pratibha , Dagar Manisha , Dagar Gunjan , Rawal Sudhir , Sharma Ravi Datta , Tyagi Rakesh Kumar , Bagchi Gargi
Published: November 2019

The androgen receptor (AR) is activated in patients with castration resistant prostate cancer (CRPC) despite low circulating levels of androgen, suggesting that intracellular signaling pathways and non-androgenic factors may contribute to AR activation. Many G-protein coupled receptors (GPCR) and their ligands are also activated in these cells indicating a role for these in CRPC. Although a cross talk has been suggested between the two pathways, yet, the identity of GPCRs which may play a role in androgen signaling, is not established yet. We demonstrate that adhesion GPCR 205, also known as GPR56, can be activated by androgens to stimulate the Rho signaling pathway, a pathway that plays an important role in prostate tumor cell metastasis. Testosterone stimulation of GPR56 also activates the cAMP/ Protein kinase A (PKA) pathway, that is necessary for AR signaling. Knocking down the expression of GPR56 using siRNA, disrupts nuclear translocation of AR and transcription of prototypic AR target genes such as PSA. GPR56 expression is higher in all prostate tumor samples tested and cells expressing GPR56 exhibit increased proliferation. These findings provide new insights about androgen signaling and identify GPR56 as a possible therapeutic target in advanced prostate cancer patients.
Rare Rewards Amplify Dopamine Learning Responses
Authors: Rothenhoefer Kathryn M. , Hong Tao , Alikaya Aydin , Stauffer William R.
Published: November 2019

Dopamine neurons drive learning by coding reward prediction errors (RPEs), which are formalized as subtractions of predicted values from reward values. Subtractions accommodate point estimate predictions of value, such as the average value. However, point estimate predictions fail to capture many features of choice and learning behaviors. For instance, reaction times and learning rates consistently reflect higher moments of probability distributions. Here, we demonstrate that dopamine RPE responses code probability distributions. We presented monkeys with rewards that were drawn from the tails of normal and uniform reward size distributions to generate rare and common RPEs, respectively. Behavioral choices and pupil diameter measurements indicated that monkeys learned faster and registered greater arousal from rare RPEs, compared to common RPEs of identical magnitudes. Dopamine neuron recordings indicated that rare rewards amplified RPE responses. These results demonstrate that dopamine responses reflect probability distributions and suggest a neural mechanism for the amplified learning and enhanced arousal associated with rare events.
Derivatives of the antimalarial drug mefloquine are broad spectrum antifungal molecules with activity against drug-resistant clinical isolates
Authors: Montoya Marhiah C. , Beattie Sarah , Alden Kathryn M. , Krysan Damian J.
Published: November 2019

The antifungal pharmacopeia is critically small, particularly in light of the recent emergence of multi-drug-resistant pathogens such as Candida auris. Herein, we report that derivatives of the anti-malarial drug mefloquine have broad spectrum antifungal activity against pathogenic yeasts and molds. In addition, the mefloquine derivatives have activity against clinical isolates that are resistant to one or more of the three classes of drugs currently used to treat invasive fungal infections, indicating that they have a novel mechanism of action. Importantly, the in vitro toxicity profiles using human cell lines indicate that the mefloquine derivatives are very similar to the parent mefloquine despite being up to 64-fold more active against fungal cells. In addition to direct antifungal activity, sub-inhibitory concentrations of the mefloquine derivatives inhibit the expression of virulence traits including filamentation in C. albicans and capsule formation/melanization in C. neoformans. Mode/mechanism of action experiments indicate that the mefloquine derivatives interfere with both mitochondrial and vacuolar function as part of a multi-target mechanism of action. The broad-spectrum scope of activity, blood-brain-barrier penetration, and large number of previously synthesized analogs available combine to support the further optimization and development of the antifungal activity of this general class of drug-like molecules.
Protein adlayer thickness on colloidal nanoparticle determined by Rayleigh-Gans-Debye approximation
Authors: Yuan L , Zhai Z , Chen L , Ge X , Li D , Ge G
Published: November 2019

Reference materials (RM)-assisted Rayleigh-Gans-Debye approximation (rm-RGDA) has been developed and used to in situ determine the size and thickness of the adlayer on the particles in solution. The particle size determined by rm-RGDA is quite close to that measured by electron microscopy but significantly smaller than that measured by DLS. The BSA adlayer absorbed on PS50, PS100 and SiO2 NPs is 3.3, 0.9 and 1.2 nm, respectively, and close to those observed by SEM, which is 4.6, 1.3 and 3.8 nm, respectively. The FTIR analysis results show that the BSA absorbed on larger particles or hydroxyl-abundant surface, e.g. PS100 and SiO2 NPs can lose its secondary structure, e.g. α-helix, to a great extent and that absorbed on a more curve surface, e.g. smaller PS50 particles can largely preserve its secondary structure as its free state. The measurement results show the curvature of the NPs is closely related to the structure change of the adsorbed protein. This method provide a facile and new approach to measure the size and its adlayer change of the hybrid and core-shell structured nanoparticles in a wide range of wavelength.

SIGNIFICANCE

Quantitative study on the adsorption of the protein on colloidal nanoparticles is an important approach to understand the biophysical effect, compared with other ex situ methods such as TEM and SEM, where the specimen are undergone pre-processing and no longer the original state in measurement. It is, therefore, a big challenge. In order to cope with this challenge, UV-vis based RGDA has been developed and applied to in situ measure the size of the dispersed colloidal nanoparticles and their protein adlayer thickness, where the protein adlayer thickness on the colloidal nanoparticles can be easily determined. We believe this method provide a facile and sensitive way to in situ measure the dimension change of hybrid colloidal nanoparticles.
Comparison of the crystal structures and physicochemical properties of novel resveratrol cocrystals
Authors: Peng Bo , He Hongyan , Li Meiqi , Wang Jian-Rong , Mei Xuefeng
Published: November 2019

Resveratrol (RSV) is one of the most extensively investigated natural polyphenol with potential cardioprotective effects and various biological activities. However, the polymorphism and solvates of RSV cocrystals have not been studied comprehensively. In addition, the relationship between the crystal packing modes and their physicochemical properties of RSV cocrystals remains poorly understood. In this paper, seven novel RSV cocrystals were prepared and characterized by powder X-ray diffraction, single-crystal X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, dynamic vapor sorption, Raman and Fourier transform infrared spectroscopy. Five RSV–4,4′-vinylenedipyridine (DPE) cocrystals were synthesized with polymorphs and solvates, such as RSV–DPE (1:2) in form (I) [RSV–2DPE form (I)], RSV–DPE (1:2) in form (II) [RSV–2DPE form (II)], RSV–DPE (1:1) (RSV–DPE), RSV–DPE (2:3)·acetone (RSV–1.5DPE·0.5ACE), RSV–DPE (1:1.5)·MeOH (RSV–1.5DPE·MeOH). However, RSV–4,4′-ethylenedipyridine (BPE) and RSV–4,4′-azobispyridine (AZPY) cocrystals were prepared as their single crystal forms, that is, RSV–BPE (1:1.5) (RSV–1.5BPE) and RSV–AZPY (1:2) (RSV–2AZPY). RSV–2DPE form (II) can be transformed from RSV–2DPE form (I) during the heating process from single crystal to single crystal. The physicochemical properties of RSV cocrystals are closely related to their crystal packing modes. Also, the conformation and molecular packing of RSV among different cocrystals is flexible. The solubility of RSV–1.5BPE and RSV–2DPE form (II) exhibit higher than RSV in the buffer solution of pH 4.6 and 2.0, respectively. This study may provide a valuable insight into the crystal packing modes of cocrystals which may affect their physicochemical properties.
Islamic marketing ethics for Islamic financial institutions
Authors: Aman Ameenullah
Published: November 2019

Purpose

To wipe out the criticism of being a replica of conventional financial institution, Islamic financial institutions (IFIs) need to comply with Islamic principles not only on financial side but also while branding and marketing their products and services. This will bring the coherence between their overall market image and core business activities. This paper aims to discuss in detail the Islamic marketing traits relevant to the IFIs for positioning and offering their products.

Design/methodology/approach

This study follows the research design based on reviewing existing sources of Qura’an and Hadith, the secondary research literature on this novel topic and substantial intellectual discourse with the field experts.

Findings

It is criticized that IFIs lack the spirit of Islamic values for marketing and branding a commercial business entity. Therefore, this paper outline the differences between Islamic and conventional marketing. Also, it contributes to explain the traits of Islamic marketing mix relevant to the IFIs based on Islamic established principles.

Research limitations/implications

This study gives valuable practical guidelines for the marketing policymakers of Islamic financial institutions. Islamic marketing mix; product, price, place and promotion, related strategies can be designed and branded keeping the true spirit of Islamic marketing values intact.

Practical implications

This study is practically important for Islamic financial intuitions to sustain their “Islamic” image by making sure of Islamic principles in their product development, pricing, promotions and distribution.

Social implications

The socioeconomic system is the brand of Islamic economics and finance. IFIs being the stakeholders of this brand can contribute to the well-being of the society by enhancing their acceptability with the help of divine image and operations.

Originality/value

Literature on practical Islamic marketing approach in particular to the IFIs is very limited. This study gives comprehensive findings on all the major aspects of marketing based on Islamic values for Islamic financial institutions.