bluuebunny/crossref_metadata_2025 huggingface dataset:
Albendazole and antibiotics synergize to deliver short-course anti-
Wolbachia
curative treatments in preclinical models of filariasis
Authors: Turner Joseph D. , Sharma Raman , Al Jayoussi Ghaith , Tyrer Hayley E. , Gamble Joanne , Hayward Laura , Priestley Richard S. , Murphy Emma A. , Davies Jill , Waterhouse David , Cook Darren A. N. , Clare Rachel H. , Cassidy Andrew , Steven Andrew , Johnston Kelly L. , McCall John , Ford Louise , Hemingway Janet , Ward Stephen A. , Taylor Mark J.
Published: October 2017

Significance

Filarial nematode infections, caused by
Wuchereria bancrofti
,
Brugia malayi
(elephantiasis), and
Onchocerca volvulus
(river blindness) infect 150 million of the world’s poorest populations and cause profound disability. Standard treatments require repetitive, long-term, mass drug administrations and have failed to interrupted transmission in certain sub-Saharan African regions. A drug cure using doxycycline, which targets the essential filarial endosymbiont
Wolbachia
, is clinically effective but programmatically challenging to implement due to long treatment durations and contraindications. Here we provide proof-of-concept of a radical improvement of targeting
Wolbachia
via identification of drug synergy between the anthelmintic albendazole and antibiotics. This synergy enables the shortening of treatment duration of macrofilaricidal anti-
Wolbachia
based treatments from 4 wk to 7 d with registered drugs ready for clinical testing.
Fluorothreonyl-tRNA deacylase prevents mistranslation in the organofluorine producer
Streptomyces cattleya
Authors: McMurry Jonathan L. , Chang Michelle C. Y.
Published: October 2017

Significance

Fluorine is an element that has been exploited for its unique properties in the design of therapeutic small molecules. As such, there is significant interest in understanding the interaction of organofluorine compounds with living systems. Here, we explore the metabolism of one of the few known fluorinated natural products, fluorothreonine, in its native host
Streptomyces cattleya
. While this amino acid is efficiently incorporated into protein in place of threonine, mistranslation is avoided through the action of a
trans
-acting aminoacyl-transfer RNA deacylase with 670-fold selectivity for the fluorine substituent. This finding demonstrates how new enzyme activities can be recruited to biosynthetic gene clusters to enable the evolution of biosynthetic capacity and expands the range of known organofluorine biochemistry.
Clinical validation of a nanodiamond-embedded thermoplastic biomaterial
Authors: Lee Dong-Keun , Kee Theodore , Liang Zhangrui , Hsiou Desiree , Miya Darron , Wu Brian , Osawa Eiji , Chow Edward Kai-Hua , Sung Eric C. , Kang Mo K. , Ho Dean
Published: October 2017

Significance

There is a continued need to advance novel nanomedicine platforms into the clinic to address treatment challenges in oncology, infection, and regenerative medicine, among other areas. As such, this work demonstrates the in-human validation of nanodiamonds through their incorporation into gutta percha [nanodiamond-embedded gutta percha (NDGP)], a polymer that repairs root canal treatment sites following tissue disinfection. A randomized, dual-arm clinical trial was implemented, and study endpoints included confirmation of lesion healing, postoperative pain reduction, and the absence of reinfection. To date, the NDGP-treated patients successfully met the study endpoints. Therefore, these findings support the potential expansion of nanodiamonds, and the broader nanomedicine field, into other disease indications.
Neurobiology of culturally common maternal responses to infant cry
Authors: Bornstein Marc H. , Putnick Diane L. , Rigo Paola , Esposito Gianluca , Swain James E. , Suwalsky Joan T. D. , Su Xueyun , Du Xiaoxia , Zhang Kaihua , Cote Linda R. , De Pisapia Nicola , Venuti Paola
Published: October 2017

Significance

We undertook an interdisciplinary exploration that unites evolutionary biology, neuroscience, and developmental cultural psychology. Based on extensive and detailed behavioral analyses of 684 new mothers in 11 countries and complementary functional magnetic resonance imaging (fMRI) analyses of brain responses in 43 first-time new US mothers to their own infants’ cries, 44 experienced Chinese mothers to infant cries and control emotional sounds, and 12 Italian mothers and nonmothers to generic infant cries, we identified specific behavior repertoires and specific corresponding activated brain regions in human caregivers that constitute primary responses to infant distress. This study set will appeal to scientific and general audiences because it elucidates the foundations of core parenting practices in response to infant vocal distress.
Dephosphorylation by protein phosphatase 2A regulates visual pigment regeneration and the dark adaptation of mammalian photoreceptors
Authors: Kolesnikov Alexander V. , Orban Tivadar , Jin Hui , Brooks Celine , Hofmann Lukas , Dong Zhiqian , Sokolov Maxim , Palczewski Krzysztof , Kefalov Vladimir J.
Published: October 2017

Significance

Resetting G-protein–coupled receptors (GPCRs) from their active state to their biologically inert ground state driven by reversible phosphorylation and arrestin binding is an integral part of GPCR signaling. Visual pigments in retinal rod and cone photoreceptors represent a classic example of GPCR signaling. Although pigment inactivation by phosphorylation is well understood, the enzyme(s) responsible for pigment dephosphorylation and the functional significance of this reaction remain largely unknown. Here, we show that protein phosphatase 2A (PP2A) is expressed in mouse photoreceptors and that its targeted ablation compromises, but does not fully block, their pigment dephosphorylation, visual chromophore recycling, and dark adaptation after >90% bleach. We conclude that visual pigments are dephosphorylated by PP2A and that this reaction regulates dark adaptation of photoreceptors.
Controlling orientational order in block copolymers using low-intensity magnetic fields
Authors: Gopinadhan Manesh , Choo Youngwoo , Kawabata Kohsuke , Kaufman Gilad , Feng Xunda , Di Xiaojun , Rokhlenko Yekaterina , Mahajan Lalit H. , Ndaya Dennis , Kasi Rajeswari M. , Osuji Chinedum O.
Published: October 2017

Significance

Magnetic field interactions with condensed matter can produce orientationally ordered states that are important for fundamental research and technological applications. Block copolymer (BCP) mesophases typically exhibit weak field coupling, requiring high-intensity fields generated by superconducting magnets to produce such states. This work advances a strategy for circumventing such field intensity limitations and creates highly aligned mesophases using fields an order of magnitude smaller than typically required and that can be produced by simple permanent magnets. We elucidate the roles of molecular mobility, grain size, and ordering kinetics on the mesophase field response. Low-intensity field-directed BCP ordering has potentially profound implications for processing functional materials and developing complex textures by field shaping.
Large G protein α-subunit XLαs limits clathrin-mediated endocytosis and regulates tissue iron levels in vivo
Authors: He Qing , Bouley Richard , Liu Zun , Wein Marc N. , Zhu Yan , Spatz Jordan M. , Wang Chia-Yu , Divieti Pajevic Paola , Plagge Antonius , Babitt Jodie L. , Bastepe Murat
Published: October 2017

Significance

Mutations in the gene encoding XLαs and Gsα (
GNAS
) cause several genetic diseases and various tumors. Although alterations in XLαs activity/levels are implicated in some of these disorders, cellular actions of XLαs have remained poorly defined. We identified dynamins and sorting nexin-9, key components of clathrin-mediated endocytosis, as binding partners of XLαs and showed that XLαs, but not Gsα, restricts clathrin-mediated endocytosis and plays a role in iron/transferrin uptake in vivo. Thus, impaired or enhanced endocytosis may be involved in the pathogenesis of some of the
GNAS
-related diseases. Our findings also provide insights into the roles of heterotrimeric G proteins and the mechanisms underlying endocytosis, a fundamental cellular process required for nutrient uptake and regulation of cell signaling.
Living supramolecular polymerization achieved by collaborative assembly of platinum(II) complexes and block copolymers
Authors: Zhang Kaka , Yeung Margaret Ching-Lam , Leung Sammual Yu-Lut , Yam Vivian Wing-Wah
Published: October 2017

Significance

Living supramolecular polymerization has emerged as an efficient pathway for the fabrication of supramolecular assemblies with precisely controlled dimensions and diverse architectures. This work achieves living supramolecular polymerization by the collaborative assembly of two structurally dissimilar components, namely, the platinum(II) complexes and the block copolymers. This work largely broadens the scope of supramolecular monomers for living supramolecular polymerization and in the construction of supramolecular-based heterojunctions with large lattice mismatch, which represents a distinct advantage over the existing methods based on single-component systems in devising living supramolecular polymerization. This work may open up new, simple one-pot strategies for the fabrication of segmented supramolecular-based heterojunctions with different optical, charge transport, and catalytic properties for directional excitation energy, and electron and hole transport.
Organizing principles for the cerebral cortex network of commissural and association connections
Authors: Swanson Larry W. , Hahn Joel D. , Sporns Olaf
Published: October 2017

Significance

The cerebral cortex supports cognition and is a structure common to all mammals. The major cortical subdivisions (its gray matter regions) are connected by a complex network of axonal connections that includes connections between regions in the same hemisphere (association connections on the right or left side) and those between hemispheres (commissural connections between opposite sides). A database of over 5,000 connections in the cortical network was extracted from the literature, and network analysis revealed three identical cortical modules (neural subsystems) on each side. One appears to deal especially with the external world, one with the viscera, and one with planning, prioritization, and self-awareness. A set of general organizing principles for association and commissural connections also emerged from the analysis.
Strong attractions and repulsions mediated by monovalent salts
Authors: Li Yaohua , Girard Martin , Shen Meng , Millan Jaime Andres , Olvera de la Cruz Monica
Published: October 2017

Significance

The physical properties of proteins and polyions in electrolyte solutions are of crucial importance for understanding biological processes and for controlling biotechnological processes. The concentration of salt controls the range and strength of the interactions in these complex electrolytes. Here, multiscale coarse-grained molecular dynamics simulations reveal long-range interactions between nanoparticles in aqueous solutions at high monovalent salt concentrations. The simulations explain the crystallization of nanoparticles even when they are strongly charged and explain the reentrant attractive to repulsive to attractive interactions as the nanoparticle charge density increases in high monovalent salt-concentration conditions.
Individual differences in associative memory among older adults explained by hippocampal subfield structure and function
Authors: Carr Valerie A. , Bernstein Jeffrey D. , Favila Serra E. , Rutt Brian K. , Kerchner Geoffrey A. , Wagner Anthony D.
Published: October 2017

Significance

Older adults differ in the degree to which they experience memory impairments, but the underlying factors contributing to this variability remain unclear. Motivated by the essential role of the medial temporal lobe (MTL) in declarative memory, we investigated whether episodic memory differences among older adults can be explained by differences in MTL subfield structure and function. Using high-resolution magnetic resonance imaging, we demonstrated that a combination of structural and functional subfield measures significantly accounted for differences in memory performance. These findings advance understanding of how independent but converging influences of both MTL structure and function contribute to age-related impairment in episodic memory, complementing findings in the rodent and human postmortem literatures.
Integrated field, laboratory, and theoretical study of PKD spread in a Swiss prealpine river
Authors: Carraro Luca , Bertuzzo Enrico , Mari Lorenzo , Fontes Inês , Hartikainen Hanna , Strepparava Nicole , Schmidt-Posthaus Heike , Wahli Thomas , Jokela Jukka , Gatto Marino , Rinaldo Andrea
Published: October 2017

Significance

Predicting how temperature, climate change, and emerging infectious diseases interact to drive local extinction risk for natural populations requires complex integrated approaches involving field data [fish and environmental DNA (eDNA) sampling and hydrological and geomorphological surveys], laboratory studies (eDNA analyses and disease prevalence assessment), and metacommunity modeling. Together, these tools reproduce all of the relevant biological and ecohydrological features of proliferative kidney disease, a major emerging disease impacting native salmonid stocks. We thus provide a predictive framework, applicable to other aquatic pathogens, that may function as a baseline for environmental management decisions aimed at preserving declining and iconic salmonid species.
Silent memory engrams as the basis for retrograde amnesia
Authors: Roy Dheeraj S. , Muralidhar Shruti , Smith Lillian M. , Tonegawa Susumu
Published: October 2017

Significance

We previously discovered that memory is retrieved robustly from protein synthesis inhibitor-induced retrograde amnesia by optogenetic activation of engram cells. Connectivity of engram cells correlates with memory information storage under amnesia, even though these amnesic engram cells lack learning-induced augmented synaptic strength. We term this state of engrams as “silent engrams.” The significance of this study is threefold: first, the silent state of the engram can last for a prolonged period (at least 8 d post encoding); second, connectivity between engram cell ensembles is causally linked to optogenetic recall and hence memory information storage; and third, there is a molecular genetic method to convert an engram from a silent state to an active state.
Intersectin associates with synapsin and regulates its nanoscale localization and function
Authors: Gerth Fabian , Jäpel Maria , Pechstein Arndt , Kochlamazashvili Gaga , Lehmann Martin , Puchkov Dmytro , Onofri Franco , Benfenati Fabio , Nikonenko Alexander G. , Fredrich Kristin , Shupliakov Oleg , Maritzen Tanja , Freund Christian , Haucke Volker
Published: October 2017

Significance

Mutations in genes regulating neurotransmission in the brain are implicated in neurological disorders and neurodegeneration. Synapsin is a crucial regulator of neurotransmission and allows synapses to maintain a large reserve pool of synaptic vesicles. Human mutations in synapsin genes are linked to epilepsy and autism. How synapsin function is regulated to allow replenishment of synaptic vesicles and sustain neurotransmission is largely unknown. Here we identify a function for the endocytic scaffold protein intersectin, a protein overexpressed in patients with Down syndrome, as a regulator of synapsin nanoscale distribution and function that is controlled by a phosphorylation-dependent autoinhibitory switch. Our results unravel a hitherto unknown molecular connection between the machineries for synaptic vesicle reserve pool organization and endocytosis.
PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP
Authors: Wang Huibing , Meng Huyan , Li Xingyan , Zhu Kezhou , Dong Kangyun , Mookhtiar Adnan K. , Wei Huiting , Li Ying , Sun Shao-Cong , Yuan Junying
Published: October 2017

Significance

This study demonstrates Pellino 1 (PELI1) as an important modulator that exerts opposite regulatory functions on apoptosis and necroptosis, two distinct forms of regulated cell death mechanisms. K63 ubiquitination of RIPK1 mediated by PELI1 depends on the kinase activity of RIPK1, which provides a mechanism to explain why inhibition of RIPK1 kinase activity by Nec-1s can also reduce its ubiquitination during necroptosis.
What, no rats? The solar bird tradition and its relevance to the Pied Piper legend
Authors: Kline Jim
Published: October 2017

For over seven hundred years, the legend of the Pied Piper has inspired folk tales, poems, songs, and theatrical productions, as well as speculations about whether the legend is based upon actual events that occurred on 26 June 1284, the date given to the incident according to several commemorative documents and monuments found in the town of Hamelin, Germany, where the legend originated. Many scholars who have studied the legend believe it has little to do with a Pied Piper ridding the town of rats and later enticing the town's children to follow him out of town where they all disappear; instead, they believe the incident refers to a military recruiter who either led a troupe of young men to the Baltic or to Transylvania to establish settlements there. However, other scholars put great significance upon the date of the event and how it might be related to a summer solstice celebration gone awry. The following article provides evidence to support the summer solstice theory, presenting information relating to ancient solar bird traditions that link the piper with shamanic rites in which shamans dress as birds and perform bird sacrifices associated with both summer and winter solstice celebrations.
Retromer revisited: Evolving roles for retromer in endosomal sorting
Authors: Chamberland John P. , Ritter Brigitte
Published: October 2017

The highly conserved retromer complex has been linked to cargo retrieval from endosomes to the trans-Golgi network. In this issue, Kvainickas et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201702137) and Simonetti et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201703015) fundamentally question the current retromer model and demonstrate that in mammalian cells, the individual retromer subcomplexes have functionally diverged to organize multiple distinct sorting pathways.
Alzheimer’s disease: A matter of blood–brain barrier dysfunction?
Authors: Montagne Axel , Zhao Zhen , Zlokovic Berislav V.
Published: October 2017

The blood–brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been shown in Alzheimer’s disease (AD) before dementia, neurodegeneration and/or brain atrophy occur. However, the role of BBB breakdown in neurodegenerative disorders is still not fully understood. Here, we examine BBB breakdown in animal models frequently used to study the pathophysiology of AD, including transgenic mice expressing human amyloid-β precursor protein, presenilin 1, and tau mutations, and apolipoprotein E, the strongest genetic risk factor for AD. We discuss the role of BBB breakdown and dysfunction in neurodegenerative process, pitfalls in BBB measurements, and how targeting the BBB can influence the course of neurological disorder. Finally, we comment on future approaches and models to better define, at the cellular and molecular level, the underlying mechanisms between BBB breakdown and neurodegeneration as a basis for developing new therapies for BBB repair to control neurodegeneration.
A symporter’s secrets shown
Authors: Sedwick Caitlin
Published: October 2017

New JGP study explores the thermodynamic cycle and cation preference of the sugar symporter MelB.
Abhyankar’s conjectures in Galois theory: Current status and future directions
Authors: Harbater David , Obus Andrew , Pries Rachel , Stevenson Katherine
Published: October 2017

In this paper we survey the major contributions of Abhyankar to the development of the theory of fundamental groups and Galois covers in positive characteristic. We first discuss the current status of four conjectures of Abhyankar about Galois covers in positive characteristic. Then we discuss research directions inspired by Abhyankar’s work, including many open problems.
Anchoring Bias in Recall Data: Evidence from Central America
Authors: Godlonton Susan , Hernandez Manuel A , Murphy Mike
Published: October 2017

Self‐reported retrospective survey data is widely used in empirical work but may be subject to cognitive biases, even over relatively short recall periods. This paper examines the role of anchoring bias in self‐reports of objective and subjective outcomes under recall. We use a unique panel‐survey dataset of smallholder farmers from four countries in Central America collected over a period of three years. We exploit differences between recalled and concurrent responses to quantify the degree of mental anchoring in survey recall data. We assess whether respondents use their reported value for the most recent period as a cognitive heuristic when recalling the value from a previous period, while controlling for the value they reported earlier. The results show strong evidence of sizeable anchoring bias in self‐reported retrospective indicators for both objective measures (income, wages, and working hours) and subjective measures (reports of happiness, health, stress, and well‐being). We also generally observe a larger bias in response to negative changes for objective indicators and a larger bias in response to positive changes for subjective indicators.
Iterative reconstruction of rank-one matrices in noise
Authors: Fletcher Alyson K , Rangan Sundeep
Published: October 2017

We consider the problem of estimating a rank-one matrix in Gaussian noise under a probabilistic model for the left and right factors of the matrix. The probabilistic model can impose constraints on the factors including sparsity and positivity that arise commonly in learning problems. We propose a family of algorithms that reduce the problem to a sequence of scalar estimation computations. These algorithms are similar to approximate message-passing techniques based on Gaussian approximations of loopy belief propagation that have been used recently in compressed sensing. Leveraging analysis methods by Bayati and Montanari, we show that the asymptotic behavior of the algorithm is described by a simple scalar equivalent model, where the distribution of the estimates at each iteration is identical to certain scalar estimates of the variables in Gaussian noise. Moreover, the effective Gaussian noise level is described by a set of state evolution equations. The proposed approach to deriving algorithms thus provides a computationally simple and general method for rank-one estimation problems with a precise analysis in certain high-dimensional settings.
Characterization of Foliar Web Blight of Spinach, Caused by Pythium aphanidermatum, in the Desert Southwest of the United States
Authors: Liu Bo , Feng Chunda , Matheron Michael E. , Correll James C.
Published: October 2017

A unique foliar disease of spinach, determined to be caused by Pythium aphanidermatum, was observed on spinach in Yuma County, AZ and Imperial County, CA desert spinach production areas in both 2015 and 2016. The foliar symptoms of the disease included water-soaked foliage, rapid collapse of young plants, and white, aerial, cottony mycelia. The disease was associated with hot (27 to 42°C) and wet conditions associated with overhead irrigation under high-density plantings (>8.0 million seeds/ha). Isolations were performed on symptomatic tissue, and DNA was recovered from pure culture of the isolates recovered and sequenced using the internal transcribed spacer (ITS) ribosomal DNA (rDNA) primers ITS1/ITS4 and gene cytochrome oxidase I (COXI) primers FM55 and FM59. BLAST searches in GenBank indicated that the isolates were P. aphanidermatum based on 99 to 100% homology of ITS rDNA. Moreover, the DNA sequences of the ITS and COXI were identical for the five representative isolates. The objective of this research was to determine whether P. aphanidermatum recovered from symptomatic spinach tissue was able to cause foliar web blight and damping-off of spinach and other crops. In addition to spinach, other hosts evaluated included cotton, soybean, pepper, tomato, cucumber, melon, squash, lettuce, corn, wheat, and rice in greenhouse trials. Inoculations were performed by either foliar inoculations or infesting the soil with plugs of potato dextrose agar colonized by the P. aphanidermatum. Web blight symptoms were severe on spinach and all other dicotyledonous hosts tested, except lettuce. No web blight symptoms were observed on corn or rice, and only minor symptoms were observed on 10-day-old seedlings of wheat. P. aphanidermatum caused severe preemergence damping-off of all dicotyledonous plant species tested but only caused limited seedling size reduction in corn and wheat. Mefenoxam treatment of spinach seed provided complete protection against preemergence damping-off of spinach at both low (0.15 g a.i./kg of seed) and high (0.70 g a.i./kg of seed) rates of application, and the high rate of the application resulted in complete protection against web blight of spinach for 10 to 20 days after planting.
Isolation and characterization of Leptospira interrogans serovar Copenhageni from a dog from Saint Kitts
Authors: Larson Christopher R. , Dennis Michelle , Nair Rajeev V. , Llanes Alejandro , Peda Andrea , Welcome Shamara , Rajeev Sreekumari
Published: October 2017

Introduction. Leptospirosis is a zoonotic bacterial disease of global distribution affecting humans and animals. The initial phase of leptospirosis resembles many other febrile illness and due to its broad and biphasic clinical manifestations, selection and implementation of appropriate diagnostic tests can be challenging.

Case presentation. This report describes a case investigation of a 14 weeks old male, orphan puppy, presented with generalised jaundice, anemia, weakness, and anorexia. Clinical abnormalities included the evidence of renal and hepatic failure. Antemortem and postmortem diagnostic investigations were conducted to identify the cause of illness. PCR testing and culture of blood was positive for Leptospira sp. Necropsy followed by histopathology evaluation revealed lesions compatible with liver and kidney damage consisting of marked diffuse hepatocellular dissociation, acute renal tubular necrosis, and mild interstitial nephritis.

Conclusion. Multiple diagnostic techniques including bacterial isolation confirmed Leptospira infection in this puppy. Whole genome sequencing and analysis identified the Leptospira sp. isolated from this puppy as Leptospira interrogans serovar Copenhageni. To our knowledge, this case report describes the first isolation of Leptospira from Saint Kitts. This case highlights the usefulness of including multiple diagnostic tests for the diagnosis and epidemiological investigation of Leptospira infection. Accurate diagnosis followed by timely intervention can prevent case fatality and mortality in infected patients.
NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma
Authors: Brennan Kevin , Shin June Ho , Tay Joshua K. , Prunello Marcos , Gentles Andrew , Sunwoo John B. , Gevaert Olivier
Published: October 2017

Chromatin modifying enzymes are frequently mutated in cancer, resulting in a cascade of epigenetic deregulation. Recent reports indicate that inactivating mutations in the histone methyltransferase NSD1 define an intrinsic subtype of head and neck squamous cell carcinoma (HNSC) that features widespread DNA hypomethylation. Here, we describe a similar DNA hypomethylated subtype of lung squamous cell carcinoma (LUSC) that is enriched for both inactivating mutations and deletions inNSD1. The ‘NSD1 subtype’ of HNSC and LUSC are highly correlated at the DNA methylation and gene expression levels, with concordant DNA hypomethylation and overexpression of a strongly overlapping set of genes, a subset of which are also hypomethylated in Sotos syndrome, a congenital growth disorder caused by germlineNSD1mutations. Further, the NSD1 subtype of HNSC displays an ‘immune cold’ phenotype characterized by low infiltration of tumor-associated leukocytes, particularly macrophages and CD8+T cells, as well as low expression of genes encoding the immunotherapy target PD-1 immune checkpoint receptor and its ligands PD-L1 and PD-L2. Using anin vivomodel, we demonstrate that NSD1 inactivation results in a reduction in the degree of T cell infiltration into the tumor microenvironment, implicating NSD1 as a tumor cell-intrinsic driver of an immune cold phenotype. These data have important implications for immunotherapy and reveal a general role of NSD1 in maintaining epigenetic repression.
The ABCE1 capsid assembly pathway is conserved between primate lentiviruses and the non-primate lentivirus feline immunodeficiency virus
Authors: Reed Jonathan C. , Westergreen Nick , Barajas Brook C. , Ressler Dylan , Phuong Daryl , Swain John V. , Lingappa Vishwanath R. , Lingappa Jaisri R.
Published: October 2017

During immature capsid assembly in cells, the Gag protein of HIV-1 and other primate lentiviruses co-opts a host RNA granule, forming a pathway of assembly intermediates that contains host components, including two cellular enzymes shown to facilitate assembly, ABCE1 and DDX6. Here we asked whether a non-primate lentivirus, feline immunodeficiency virus (FIV), also forms such RNA-granule-derived intracellular capsid assembly intermediates. First, we found that, unlike for HIV-1, the FIV completed immature capsid and the largest putative assembly intermediate are unstable during analysis. Next, we identifiedin situcross-linking conditions that overcame this problem and revealed the presence of FIV Gag complexes that correspond in size to early and late HIV-1 assembly intermediates. Because assembly-defective HIV-1 Gag mutants are arrested at specific intracellular assembly intermediates, we asked if a similar arrest is also observed for FIV. We analyzed four FIV Gag mutants, including three not previously studied that we identified based on sequence and structural similarity to HIV-1 Gag, and found that each is assembly-defective and arrested at the same intermediate as the corresponding HIV-1 mutant. Further evidence that these FIV Gag-containing complexes correspond to assembly intermediates came from co-immunoprecipitation studies demonstrating that FIV Gag is associated with ABCE1 and DDX6, as shown previously for HIV-1. Finally, we validated these co-immunoprecipitations with a proximity ligation assay that revealed co-localization between assembly-competent FIV Gag and ABCE1in situ. Together, these data offer novel structure-function insights and indicate that primate and non-primate lentiviruses form intracellular capsid assembly intermediates derived from ABCE1-containing RNA granules.

Importance

Like HIV-1, FIV Gag assembles into immature capsids; however, it is not known whether FIV Gag progresses through a pathway of immature capsid assembly intermediates derived from host RNA granules, as shown for HIV-1 Gag. Here we asked whether FIV Gag forms complexes similar in size to HIV-1 assembly intermediates and if FIV Gag is associated with ABCE1 and DDX6, two host enzymes that facilitate HIV-1 immature capsid assembly that are found in HIV-1 assembly intermediates. Our studies identified FIV Gag-containing complexes that closely resemble HIV-1 capsid assembly intermediates, showed that known and novel assembly-defective FIV Gag mutants fail to progress past these putative intermediates, and utilized biochemical and imaging approaches to demonstrate association of FIV Gag with ABCE1 and DDX6. Thus, we conclude that viral-host interactions important for immature capsid assembly are conserved between primate and non-primate lentiviruses, and could yield important targets for future antiviral strategies.
Association of a biomarker-based frailty index with telomere length in older US adults: Findings from NHANES 1999-2002
Authors: Bello Ghalib A. , Chiu Yueh-Hsiu M. , Dumancas Gerard G.
Published: October 2017

Objectives

To study the link between frailty and cellular senescence, we examine the association of leukocyte telomere length (LTL) with a recently introduced measure of subclinical frailty that is based entirely on laboratory test biomarkers (FI-LAB).

Methods

This study was conducted on a random sample of 1890 Americans aged 60+. Multiple Linear Regression was used to examine the relationship between FI-LAB and LTL.

Results

A statistically significant association was found between FI-LAB and LTL after adjusting for multiple covariates, indicating that higher FI-LAB scores are associated with shorter telomeres.

Discussion

Our study results establish a link between subclinical frailty (FI-LAB) and cellular aging, which may help elucidate the pathophysiological mechanisms giving rise to frailty.
Reduced transmission ofMycobacterium africanumcompared toM. tuberculosisin urban West Africa
Authors: Asare Prince , Asante-Poku Adwoa , Prah Diana Ahu , Borrell Sonia , Osei-Wusu Stephen , Otchere Isaac Darko , Forson Audrey , Adjapong Gloria , Koram Kwadwo Ansah , Gagneux Sebastien , Yeboah-Manu Dorothy
Published: October 2017

Background

Understanding transmission dynamics is useful for tuberculosis (TB) control. We conducted a population-based molecular epidemiological study to understand TB transmission in Ghana.

Methods

Mycobacterium tuberculosiscomplex (MTBC) isolates obtained from prospectively-sampled pulmonary TB patients between July, 2012 and December, 2015 were confirmed as MTBC using IS6110PCR. MTBC lineages were identified by large sequence polymorphism and single nucleotide polymorphism assays and further characterized using spoligotyping and standard 15-loci MIRU-VNTR typing. We used the n-1 method to estimate recent TB transmission and identified associated risk factors using logistic regression analysis.

Findings

Out of 2,309 MTBC isolates, we identified 1,082 (46·9%) single cases with 1,227 (53·1%) isolates belonging to one of 276 clustered cases (clustering range; 2-35). Recent TB transmission rate was estimated to be 41·2%. While we see no significant difference in the recent transmission rates between lineages ofMycobacterium africanum(lineage-5 (31·8%); lineage-6 (24·7%), p=0·118), we found that lineage-4 belonging to theM. tuberculosistransmitted significantly higher (44·9%, p<0·001). Finally, apart from age being significantly associated with recent TB transmission (p=0·007), we additionally identified a significant departure in the male/female ratio among very large clustered cases compared to the general TB patient population (3:1 vs. 2:1, p=0·022).

Interpretations

Our findings indicate high recent TB transmission suggesting occurrences of unsuspected outbreaks. The observed reduced transmission rate ofM. africanumsuggests other factor(s) may be responsible for its continuous presence in West Africa.

Funding

Wellcome Trust Intermediate Fellowship Grant 097134/Z/11/Z to Dorothy Yeboah-Manu.
Game theoretic consideration of transgenic bacteria in the human gut microbiota as a pro-biotic prophylactic for metabolic syndrome
Authors: Ibrahim Ahmed M. , Smith James
Published: October 2017

A game theoretic treatment is introduced to explore the role of nutrition of the gut bacterial microflora as a potential pro-biotic therapy. Rational design of functional foods and nutraceuticals has far reaching public health and therapeutic benefits. Understanding ecological dynamics and how phenotypic manipulations of microbe-microbe interactions of the gut microbiota can provide direct health benefit is currently a fundamental question in bioengineering and more widely in the food, diet and health industries. This work considers a hypothetical adjustment of the microbiome by introducing a transgenic bacterial species that contributes to increased exposure of omega 3 fats in the gut by converting them from the omega 6 fats, dominant in the Western diet. The ratio of the two fats circulating in blood are risk markers, indicators of metabolic syndrome and related conditions. In this work, we consider nutritional exposure to a pro-biotic, a live culture of transgenic bacteria contributing omega 3 fats from omega 6 in the diet. Maintaining a long-term co-existence between native (indigenous) and transgenic bacteria is a challenge. Game theory is the appropriate tool for handling this conflict. The long-term co-existence is guaranteed if the two strains engage in the Snowdrift game. Our game theoretic treatment provides the basis of a model mechanism for prophylactic nutritional therapy for metabolic syndrome by the transgenic bacteria, providing support of indigenous gut microbiota and additional supplementation of a pro-biotic.
An Observational Study of Ballooning in Large Spiders: Nanoscale Multi-Fibers Enable Large Spiders’ Soaring Flight
Authors: Cho Moonsung , Neubauer Peter , Fahrenson Christoph , Rechenberg Ingo
Published: October 2017

The physical mechanism of aerial dispersal of spiders, “ballooning behavior,” is still unclear because of the lack of serious scientific observations and experiments. Therefore, as a first step in clarifying the phenomenon, we studied the ballooning behavior of relatively large spiders (heavier than 5 mg) in nature. Additional wind tunnel tests to identify ballooning silks were implemented in the laboratory. From our observation, it seems obvious that spiders actively evaluate the condition of the wind with their front leg (leg I) and wait for the preferable wind condition for their ballooning takeoff. In the wind tunnel tests, as yet unknown physical properties of ballooning fibers (length, thickness and number of fibers) were identified. Large spiders, 16–20 mgXysticusspecies, spun 50 to 60 nanoscale fibers, with a diameter of 121 to 323 nm. The length of these threads was 3.22 ± 1.31 m (N = 22). These physical properties of ballooning fibers can explain the ballooning of large spiders with relatively light updrafts, 0.1–0.5 m s-1, which exist in a light breeze of 1.5–3.3 m s-1. Additionally, in line with previous research on turbulence in atmospheric boundary layers and from our wind measurements, it is hypothesized that spiders use the ascending air current for their aerial dispersal, the “ejection” regime, which is induced by hairpin vortices in the atmospheric boundary layer turbulence. This regime is highly correlated with lower wind speeds. This coincides well with the fact that spiders usually balloon when the wind speed is lower than 3 m s-1.
Leveraging heterogeneity across multiple data sets increases accuracy of cell-mixture deconvolution and reduces biological and technical biases
Authors: Vallania Francesco , Tam Andrew , Lofgren Shane , Schaffert Steven , Azad Tej D , Bongen Erika , Alsup Meia , Alonso Michael , Davis Mark , Engleman Edgar , Khatri Purvesh
Published: October 2017

In silico quantification of cell proportions from mixed-cell transcriptomics data (deconvolution) requires a reference expression matrix, called basis matrix. We hypothesized that matrices created using only healthy samples from a single microarray platform would introduce biological and technical biases in deconvolution. We show presence of such biases in two existing matrices, IRIS and LM22, irrespective of the deconvolution method used. Here, we present immunoStates, a basis matrix built using 6160 samples with different disease states across 42 microarray platforms. We found that immunoStates significantly reduced biological and technical biases. We further show that cellular proportion estimates using immunoStates are consistently more correlated with measured proportions than IRIS and LM22, across all methods. Importantly, we found that different methods have virtually no effect once the basis matrix is chosen. Our results demonstrate the need and importance of incorporating biological and technical heterogeneity in a basis matrix for achieving consistently high accuracy.
Machine Learning for Population Genetics: A New Paradigm
Authors: Schrider Daniel R. , Kern Andrew D.
Published: October 2017

As population genomic datasets grow in size, researchers are faced with the daunting task of making sense of a flood of information. To keep pace with this explosion of data, computational methodologies for population genetic inference are rapidly being developed to best utilize genomic sequence data. In this review we discuss a new paradigm that has emerged in computational population genomics: that of supervised machine learning. We review the fundamentals of machine learning, discuss recent applications of supervised machine learning to population genetics that outperform competing methods, and describe promising future directions in this area. Ultimately, we argue that supervised machine learning is an important and underutilized tool that has considerable potential for the world of evolutionary genomics.
Structural lipids enable the formation of functional oligomers of the eukaryotic purine symporter UapA
Authors: Pyle Euan , Kalli Antreas C. , Amillis Sotiris , Hall Zoe , Hanyaloglu Aylin C. , Diallinas George , Byrne Bernadette , Politis Argyris
Published: October 2017

The role of membrane lipids in modulating eukaryotic transporter structure and function remains poorly understood. We used native mass spectrometry in combination with molecular dynamics simulations andin vivoanalyses to investigate the roles of membrane lipids in the structure and transport activity of the purine transporter, UapA, fromAspergillus nidulans. We revealed that UapA exists mainly as a dimer and that two lipid molecules bind per UapA dimer. We identified three classes of phospholipids: phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) which co-purified with UapA. Delipidation of UapA caused dissociation of the dimer into individual protomers. Subsequent addition of PI or PE rescued the UapA dimer and allowed recovery of bound lipids, suggesting a central role of these lipids in stabilising the dimer. We predicted a putative lipid-binding site near the UapA dimer interface. Mutational analyses established that lipid binding at this site is essential for formation of functional UapA dimers. Our findings reveal unprecedented level of detail into the nature of UapA-lipid interactions and provide a framework for studying similar eukaryotic systems.
SALP, a new single-stranded DNA library preparation method especially useful for the high-throughput characterization of chromatin openness states
Authors: Wu Jian , Dai Wei , Wu Ling , Wang Jinke
Published: October 2017

Based on a novel kind of single strand adaptor (SSA), this study developed a new method to construct next-generation sequencing (NGS) library, named as SALP, representing Single strand Adaptor Library Preparation. The key creativity of the method lies in the design and verification of a special adaptor that can be efficiently linked to the 3′ end of single-stranded DNA, which is a double-stranded oligonucleotide with a 3′ overhang of 3 random nucleotides. This method can start with the denatured DNAs or chromatins fragmented by different methods such as Tn5 tagmentation, enzyme digestion and sonication. When applied to Tn5-tagmented chromatin, SALP overcomes the key limitation of the current ATAC-seq method and develops a high-throughput NGS library construction and sequencing approach, SALP-seq, which can be used to comparatively characterize the chromatin openness state of multiple cells simply and unbiasly. In this way, the comparative chromatin openness states of four different cell lines, including GM12878, HepG2, HeLa and 293T, were successfully characterized. This study also demonstrated that SALP-seq could characterize the chromatin openness states with 105to 500 cells, indicating the high sensitivity of SALP-seq in characterizing chromatin state of cells. SALP should have wide applications in the future biological sciences and biomedicine.
Drosophila species learn dialects through communal living
Authors: Kacsoh Balint Z , Bozler Julianna , Bosco Giovanni
Published: October 2017

Many species are able to share information about their environment by communicating through auditory, visual, and olfactory cues. In Drosophila melanogaster, exposure to parasitoid wasps leads to a decline in egg laying, and exposed females communicate this threat to naïve flies, which also depress egg laying. We find that species across the genus Drosophila respond to wasps by egg laying reduction, activate cleaved caspase in oocytes, and communicate the presence of wasps to naïve individuals. communication within a species and between closely related species is efficient, while more distantly related species exhibit partial communication. Remarkably, partial communication between some species is enhanced after a cohabitation period that requires exchange of visual and olfactory signals. This interspecies “dialect learning” requires neuronal cAMP signaling in the mushroom body, suggesting neuronal plasticity facilitates dialect learning and memory. These observations establish Drosophila as genetic models for inter-species social communication and evolution of dialects.
Subtle Changes in Clonal Dynamics Underlie the Age-Related Decline in Neurogenesis
Authors: Bast Lisa , Calzolari Filippo , Strasser Michael , Hasenauer Jan , Theis Fabian , Ninkovic Jovica , Marr Carsten
Published: October 2017

Neural stem cells in the adult murine brain have only a limited capacity to self-renew, and the number of neurons they generate drastically declines with age. How cellular dynamics sustain neurogenesis and how alterations with age may result in this decline, are both unresolved issues. Therefore, we clonally traced neural stem cell lineages using confetti reporters in young and middle-aged adult mice. To understand underlying mechanisms, we derived mathematical population models of adult neurogenesis that explain the observed clonal cell type abundances. Models fitting the data best consistently show self renewal of transit amplifying progenitors and rapid neuroblast cell cycle exit. Most importantly, we identified an increase of asymmetric stem cell divisions at the expense of symmetric stem cell differentiation with age. Beyond explaining existing longitudinal population data, our model identifies a particular cellular strategy underlying adult neural stem cell homeostasis that gives insights into the aging of a stem cell compartment.