bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fate of a mutation in a fluctuating environment
Authors: Cvijović Ivana , Good Benjamin H. , Jerison Elizabeth R. , Desai Michael M. 
Published: August 2015

Significance
Evolution in variable environments depends crucially on the fates of new mutations in the face of fluctuating selection pressures. In constant environments, the relationship between the selective effect of a mutation and the probability that it will eventually fix or go extinct is well understood. However, our understanding of fixation probabilities in fluctuating environmental conditions is limited. Here, we show that temporal fluctuations in environmental conditions can have dramatic effects on the fate of each new mutation, reducing the efficiency of natural selection and increasing the fixation probability of all mutations, including those that are strongly deleterious on average. This makes it difficult for a population to maintain specialist adaptations, even if their benefits outweigh their costs.
Native root-associated bacteria rescue a plant from a sudden-wilt disease that emerged during continuous cropping
Authors: Santhanam Rakesh , Luu Van Thi , Weinhold Arne , Goldberg Jay , Oh Youngjoo , Baldwin Ian T. 
Published: August 2015

Significance
Plant roots associate with the diverse microbial community in soil and can establish mutualistic relationships with microbes. The genetic characterization of the plant microbiome (total microbiota of plants) has intensified, but we still lack experimental proof of the ecological function of the root microbiome. Without such an understanding, the use of microbial communities in sustainable agricultural practices will be poorly informed. Through continuous cropping of a seed-sterilized native plant, we inadvertently recapitulated a common agricultural dilemma: the accumulation of phytopathogens. Experimental inoculations of seeds with native bacterial consortium during germination significantly attenuated plant mortality, demonstrating that a plant’s opportunistic mutualistic associations with soil microbes have the potential to increase the resilience of crops.
IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation
Authors: Sosa Rebecca A. , Murphey Cathi , Robinson Rachel R. , Forsthuber Thomas G. 
Published: August 2015

SignificanceThe mechanisms guiding tissue repair in autoimmune-mediated diseases of the CNS are not fully understood, but cytokines are believed to play an important role. The proinflammatory cytokine IFN-γ has been implicated in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Paradoxically, knockout studies in mice showed that EAE is exacerbated when the cytokine’s signaling is disrupted, but its mechanism of protection has not been resolved. Here, we show a critical role for IFN-γ in activating antigen-presenting cells toward a protective phenotype in the CNS by removing extracellular myelin debris and limiting the availability of substrate for oxidative stress-generated neurotoxic lipid peroxidation products.
Instability of thermoremanence and the problem of estimating the ancient geomagnetic field strength from non-single-domain recorders
Authors: Shaar Ron , Tauxe Lisa 
Published: August 2015

Significance
The evolution of Earth’s magnetic field is one of the greatest riddles of Earth’s past. Despite decades of paleomagnetic research, some fundamental properties of the geomagnetic field, such as the nature of its intensity fluctuation (paleointensity), are still elusive. Paleointensity is recovered from ancient materials that were thermally magnetized in the presence of the ancient field. The paleointensity procedure is based on the assumption that the ancient magnetization is stable with time. Here we show that this assumption is violated for many of the widely used materials, such as, for example, crystalline volcanic rocks. Our results put in question the reliability of much of the available paleointensity information, posing new challenges to our understanding of the ancient Earth.
Structural basis of antizyme-mediated regulation of polyamine homeostasis
Authors: Wu Hsiang-Yi , Chen Shin-Fu , Hsieh Ju-Yi , Chou Fang , Wang Yu-Hsuan , Lin Wan-Ting , Lee Pei-Ying , Yu Yu-Jen , Lin Li-Ying , Lin Te-Sheng , Lin Chieh-Liang , Liu Guang-Yaw , Tzeng Shiou-Ru , Hung Hui-Chih , Chan Nei-Li 
Published: August 2015

Significance
Polyamines are small organic compounds that carry multiple positive charges at physiological pH. With a high capacity to interact with the acidic surface patches of proteins and nucleic acids, polyamines may regulate a variety of cellular processes, and the fluctuations in the intracellular polyamine levels are rigorously controlled during cell growth and differentiation through the interplay between the enzyme ornithine decarboxylase (ODC) and two regulatory proteins: antizyme (Az) and antizyme inhibitor (AzIN). ODC initiates the polyamine biosynthetic pathway, whereas Az decreases polyamine concentrations by both inhibiting ODC activity and channeling ODC for proteolytic degradation. AzIN neutralizes Az function to restore polyamine levels. Here we provide the long-sought structural information and previously unidentified functional insights into this delicate regulatory circuit.
Conserved mechanism for coordinating replication fork helicase assembly with phosphorylation of the helicase
Authors: Bruck Irina , Kaplan Daniel L. 
Published: August 2015

Significance
The replication fork helicase unwinds double-stranded DNA at a replication fork, and assembly and activation of this helicase are tightly controlled. This paper describes a biological mechanism to link two essential functions related to helicase assembly and activation. Sld3, a protein required for initiation of DNA replication, coordinates the assembly of the replication fork helicase with the chemical modification of a helicase protein subunit. This chemical modification is important for subsequent activation of the helicase.
Structure of an intermediate conformer of the spindle checkpoint protein Mad2
Authors: Hara Mayuko , Özkan Engin , Sun Hongbin , Yu Hongtao , Luo Xuelian 
Published: August 2015

Significance
The spindle checkpoint is a cellular surveillance system that ensures the fidelity of chromosome segregation and guards against aneuploidy and its associated disease states. The critical checkpoint protein mitotic arrest deficient 2 (Mad2) is an unusual protein with multiple, topologically distinct conformers, including the inactive, open conformer (O-Mad2) and the active, closed conformer (C-Mad2). C-Mad2 can form an asymmetric dimer with O-Mad2 to convert it to another C-Mad2, through an intermediate conformer (I-Mad2). This study determines the structure of the intermediate conformer of the multistate Mad2 protein, revealing how one Mad2 conformer molds the other into itself in a prion-like conformational propagation process.
Evasion of affinity-based selection in germinal centers by Epstein–Barr virus LMP2A
Authors: Minamitani Takeharu , Yasui Teruhito , Ma Yijie , Zhou Hufeng , Okuzaki Daisuke , Tsai Chiau-Yuang , Sakakibara Shuhei , Gewurz Benjamin E. , Kieff Elliott , Kikutani Hitoshi 
Published: August 2015

Significance
Epstein–Barr virus (EBV) is a human herpesvirus that establishes persistent infection of the B-cell compartment. EBV is associated with autoimmune diseases, including systemic lupus erythematosus (SLE). However, the molecular mechanisms by which EBV contributes to autoimmunity remain unclear. We used previously undescribed mouse models to study the role of EBV-encoded latent membrane protein 2A (LMP2A), which mimics B-cell receptor signaling. Interestingly, LMP2A not only enhanced B-cell survival but also upregulated the transcription factor zinc finger and bric-a-brac, tramtrack domain-containing protein 20 and promoted plasma cell differentiation. When expressed late in B-cell development, LMP2A also caused prominent features of SLE, including autoantibody production with kidney immune complex deposition. Our findings suggest that LMP2A has important roles in B-cell activation and differentiation and in the development of EBV-associated autoimmune diseases.
Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus
Authors: Prieto G. Aleph , Snigdha Shikha , Baglietto-Vargas David , Smith Erica D. , Berchtold Nicole C. , Tong Liqi , Ajami Dariush , LaFerla Frank M. , Rebek Julius , Cotman Carl W. 
Published: August 2015

Significance
There is a growing understanding that inflammation impairs synaptic plasticity and cognition and that the aged brain has an elevated sensitivity to cognitive impairment by the proinflammatory cytokine interleukin 1β (IL-1β). IL-1β activates different pathways via AcP (proinflammatory) or AcPb (prosurvival) IL-1 receptor subunits. This study demonstrates that the IL-1 receptor subunit system undergoes an age-dependent reconfiguration in hippocampal synapses. This previously undescribed reconfiguration, characterized by an increase in the AcP/AcPb ratio, is responsible for potentiating impairments of synaptic plasticity and memory by IL-1β. Our data reveal a previously unidentified mechanism that explains the age-related vulnerability of hippocampal function to impairment by inflammation and adds another dimension beyond glia to understanding how inflammation causes cognitive decline in aging.
Uterine activin receptor-like kinase 5 is crucial for blastocyst implantation and placental development
Authors: Peng Jia , Monsivais Diana , You Ran , Zhong Hua , Pangas Stephanie A. , Matzuk Martin M. 
Published: August 2015

SignificanceAlthough many studies have yielded tremendous insights into the roles of TGF-β superfamily signaling pathways in physiological and pathophysiological processes, the in vivo roles of TGF-β signaling pathways in many aspects of reproduction remain largely unknown. To address these functions in females, we conditionally deleted the TGF-β type 1 receptor (activin receptor-like kinase 5, ALK5) and demonstrated that absence of TGF-β signaling through ALK5 in the uterus leads to striking abnormalities at different stages of pregnancy, including delayed implantation, disorganization of the trophoblast cells, significantly fewer uterine natural killer cells, and defects in spiral artery remodeling. Our findings provide a mouse model to investigate TGF-β signaling in reproduction and pave the way toward a better understanding of the pathogenesis of pregnancy-related complications in women.
Role of PKA signaling in D2 receptor-expressing neurons in the core of the nucleus accumbens in aversive learning
Authors: Yamaguchi Takashi , Goto Akihiro , Nakahara Ichiro , Yawata Satoshi , Hikida Takatoshi , Matsuda Michiyuki , Funabiki Kazuo , Nakanishi Shigetada 
Published: August 2015

Significance
The nucleus accumbens (NAc) is a key neural substrate that controls aversive learning through D1 receptor-expressing direct pathway neurons and D2 receptor-expressing indirect pathway neurons. We explored how aversive learning is controlled by intracellular PKA signaling in these two types of neurons in the NAc. We approached this issue not only by pathway-specific inhibition of PKA in either direct or indirect pathway neurons, but also by microendoscopic analysis of FRET responses of the PKA biosensor distinctly expressed in the two types of neurons. We obtained consistent findings from these two different approaches, and demonstrate that activation of PKA in the indirect pathway neurons plays a pivotal role in both the formation and the retention of aversive memory.
Recognition and sequestration of ω-fatty acids by a cavitand receptor
Authors: Mosca Simone , Ajami Dariush , Rebek Julius 
Published: August 2015

Significance
We report on the design and synthesis of a deeper cavitand and its binding properties for biologically relevant long-chain unsaturated ω-fatty acids and structural analogues in aqueous media. Nature evolved fatty acid binding proteins (FABPs) for this purpose, embedding hydrophobic cavities into hydrophilic structures. Synthetic container molecules have lacked the capacity to accommodate guest molecules of the length and shape of the fatty acids. Abiotic structures capable of mimicking the complexation ability of FABPs can help identify the structural and dynamic features required for fatty acid recognition. Further development of cavitands as synthetic container compounds is expected to stimulate practical applications in sensing and sequestration of physiologically relevant fatty acids.
An integrated curriculum approach to increasing habitual physical activity in deprived South Asian children
Authors: Eyre E. L. J. , Cox V. M. , Birch S. L. , Duncan M. J. 
Published: August 2015

AbstractIntegrating physical activity (PA) within a school curriculum is a promising approach for increasing PA in children. To date, no research has examined its effectiveness in increasing the low levels of PA witnessed in deprived South Asian (SA) children. The study aims to ascertain whether an integrated school‐based curriculum and pedometer intervention could increase PA in children from deprived SA backgrounds. Following ethical approval and informed consent, 134 deprived SA children (63 boys, 71 girls, control (n = 40, mean age = 11.12 years, SD = 0.32 years) and intervention (n = 94, mean age = 9.48 years, SD = 0.62 years)) from a primary school in England, UK, completed a 6‐week integrated PA intervention based on virtually walking from their school (middle of the country) to the coast and back (March–July 2013). Habitual PA was determined at baseline and post 6 weeks intervention for both groups, and determined weekly during the intervention in the experimental group. The results indicated that average daily steps were significantly higher at post 6 weeks compared to baseline for the intervention group (intervention mean change = 8694 steps/day, SD = 7428 steps/day vs. control mean change = −1121 steps/day, SD = 5592 steps/day, 95% CI of difference, 6726–7428 steps/day, P = .001, d = 1.76). In addition, significant decreases in BF% and waist circumference were observed in the intervention group post 6 weeks (mean change for BF% = −4.5%, mean change for WC = −1.7 cm, P = .001). School‐based integrated curriculum and pedometer interventions provide a feasible and effective mechanism for increasing habitual PA in primary school children from deprived SA backgrounds.
Discovery of an essential nucleotidylating activity associated with a newly delineated conserved domain in the RNA polymerase-containing protein of all nidoviruses
Authors: Lehmann Kathleen C. , Gulyaeva Anastasia , Zevenhoven-Dobbe Jessika C. , Janssen George M. C. , Ruben Mark , Overkleeft Hermen S. , van Veelen Peter A. , Samborskiy Dmitry V. , Kravchenko Alexander A. , Leontovich Andrey M. , Sidorov Igor A. , Snijder Eric J. , Posthuma Clara C. , Gorbalenya Alexander E. 
Published: August 2015

AbstractRNA viruses encode an RNA-dependent RNA polymerase (RdRp) that catalyzes the synthesis of their RNA(s). In the case of positive-stranded RNA viruses belonging to the order Nidovirales, the RdRp resides in a replicase subunit that is unusually large. Bioinformatics analysis of this non-structural protein has now revealed a nidoviral signature domain (genetic marker) that is N-terminally adjacent to the RdRp and has no apparent homologs elsewhere. Based on its conservation profile, this domain is proposed to have nucleotidylation activity. We used recombinant non-structural protein 9 of the arterivirus equine arteritis virus (EAV) and different biochemical assays, including irreversible labeling with a GTP analog followed by a proteomics analysis, to demonstrate the manganese-dependent covalent binding of guanosine and uridine phosphates to a lysine/histidine residue. Most likely this was the invariant lysine of the newly identified domain, named nidovirus RdRp-associated nucleotidyltransferase (NiRAN), whose substitution with alanine severely diminished the described binding. Furthermore, this mutation crippled EAV and prevented the replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in cell culture, indicating that NiRAN is essential for nidoviruses. Potential functions supported by NiRAN may include nucleic acid ligation, mRNA capping and protein-primed RNA synthesis, possibilities that remain to be explored in future studies.
Protection and antibody responses in different strains of mouse immunized with plasmid DNAs encoding influenza virus haemagglutinin, neuraminidase and nucleoprotein
Authors: Chen Ze , Yoshikawa Tomoki , Kadowaki Shin-etsu , Hagiwara Yukari , Matsuo Kazutoshi , Asanuma Hideki , Aizawa Chikara , Kurata Takeshi , Tamura Shin-ichi 
Published: August 2015

Protection against influenza virus infection and antibody responses in mice vaccinated with plasmid DNAs encoding haemagglutinin (HA), neuraminidase (NA) and nucleoprotein (NP) were compared among BALB/c (H-2d), B10 (H-2b) and C3H (H-2k) mice. Mice were inoculated with each DNA construct twice, 3 weeks apart, at a dose of 1 μg per mouse by particle-mediated DNA transfer (gene gun) to the epidermis. They were challenged with a lethal dose of the homologous virus 7 days after the second vaccination. NA-DNA provided significant protection in all strains of mouse, whereas HA-DNA afforded significant protection only in BALB/c mice. The serum antibody titres against NA or HA molecules in BALB/c, C3H and B10 mice were high, intermediate and low, respectively. NP-DNA failed to provide protection in any strain of mouse, and elicited low titres of anti-NP antibodies. These results suggest that NA-DNA can be used as a vaccine component to provide effective protection against influenza virus infection in various strains of mouse.
Porcine adenovirus-3 as a helper-dependent expression vector
Authors: Reddy P. Seshidhar , Idamakanti Neeraja , Babiuk Lorne A. , Mehtali Majid , Tikoo Suresh K. 
Published: August 2015

Porcine adenovirus has been proposed as a potential vector for generating novel and effective vaccines for pigs. As a prerequisite for the generation of helper-dependent porcine adenovirus-3 (PAV-3) vectors, two E1-complementing porcine cell lines expressing E1 proteins of human adenovirus-5 (HAV-5) were made. These cell lines could be efficiently transfected with DNA and allowed the rescue and propagation of a PAV-3 recombinant, PAV201, containing a 0·597 kb E3 deletion and a 0·803 kb E1A deletion. Our data demonstrate that E1A proteins of HAV-5 have the capacity to transform foetal porcine retina cells and complement for the E1A proteins of PAV-3. The green fluorescent protein (GFP) gene placed under the control of a cytomegalovirus immediate early promoter was inserted into the E1A region of the PAV201 genome. Using these cell lines, a helper-dependent PAV-3 recombinant expressing GFP, PAV202, was constructed and characterized. The wild-type PAV-3 and the recombinant PAV202 expressing GFP were used to determine the ability of the virus to enter and replicate in cells of human and animal origin under cell culture conditions. Our results suggest that PAV-3 enters but does not replicate in dog, sheep, bovine and human cells.
The vaccinia virus A40R gene product is a nonstructural, type II membrane glycoprotein that is expressed at the cell surface
Authors: Wilcock Diane , Duncan Stephen A. , Traktman Paula , Zhang Wei-Hong , Smith Geoffrey L. 
Published: August 2015

Gene A40R from vaccinia virus (VV) strain Western Reserve has been characterized. The open reading frame (ORF) was predicted to encode a 159 amino acid, 18152 Da protein with amino acid similarity to C-type animal lectins and to the VV A34R protein, a component of extracellular enveloped virus (EEV). Northern blotting and S1 nuclease mapping showed that gene A40R is transcribed early during infection from a position 12 nucleotides upstream of the ORF, producing a transcript of approximately 600 nucleotides. Rabbit anti-sera were raised against bacterial fusion proteins containing parts of the A40R protein. These were used to identify an 18 kDa primary translation product andN- andO-glycosylated forms of 28, 35 and 38 kDa. The A40R proteins were detected early during infection, formed higher molecular mass complexes under non-reducing conditions and were present on the cell surface but absent from virions. The proteins partitioned with integral membrane proteins in Triton X-114. Canine pancreatic microsomal membranes protectedin vitro-translated A40R from proteinase K digestion, suggesting the A40R protein has type II membrane topology. A mutant virus with the A40R gene disrupted after amino acid 50, so as to remove the entire lectin-like domain, and a revertant virus were constructed. Disruption of the A40R gene did not affect virus plaque size,in vitrogrowth rate and titre, EEV formation, or virus virulence in a murine intranasal model.
Functional features of the bovine enterovirus 5′-non-translated region
Authors: Zell Roland , Sidigi Karim , Henke Andreas , Schmidt-Brauns Joachim , Hoey Elizabeth , Martin Sam , Stelzner Axel 
Published: August 2015

The bovine enterovirus (BEV) serotypes exhibit unique features of the non-translated regions (NTRs) which separate them from the other enteroviruses. Their most remarkable property is an additional genome region of 110 nt located between the 5′-cloverleaf and the internal ribosome entry site (IRES). This genome region has the potential to form an additional cloverleaf structure (domain I*) separated from the 5′-cloverleaf (domain I) by a small stem–loop (domain I**). Other characteristics involve the putative IRES domains III and VI. In order to investigate the features of the 5′-NTR, several full-length coxsackievirus B3 (CVB3) cDNA plasmids with hybrid 5′-NTRs were engineered. After exchange of the CVB3 cloverleaf with the BEV1 genome region representing both cloverleafs, a viable virus chimera was generated. Deletion of domain I** within the exchanged region also yielded viable virus albeit with reduced growth capacity. Deletion of sequences encoding either the first or the second BEV cloverleaf resulted in non-infectious constructs. Hybrid plasmids with exchanges of the IRES-encoding sequence or the complete 5′-NTR were non-infectious. Transfection experiments with SP6 transcripts containing 5′-NTRs fused to the luciferase message indicated that IRES-driven translation is enhanced by the presence of the CVB3 cloverleaf and both BEV1 cloverleaf structures, respectively. Deletion of either the first or the second BEV cloverleaf domain reduced but did not abolish enhanced luciferase expression. These results suggest that the substitution of two putative BEV cloverleaf structures for the putative coxsackieviral cloverleaf yields viable virus, while BEV sequences encoding the IRES fail to functionally replace CVB3 IRES-encoding sequences.
Replication of equine herpesvirus type 1 in freshly isolated equine peripheral blood mononuclear cells and changes in susceptibility following mitogen stimulation
Authors: van der Meulen Karen M. , Nauwynck Hans J. , Buddaert Wim , Pensaert Maurice B. 
Published: August 2015

In the present study, the outcome of an inoculation of equine peripheral blood mononuclear cells (PBMC) with equine herpesvirus type 1 (EHV-1) was studiedin vitro. Cytoplasmic and plasma membrane expression of viral antigens, intra- and extracellular virus titres, and plaque formation in co-culture were determined. EHV-1 replicated in monocytes, although in a highly restricted way. Viral antigens were found at maximum levels (8·7% of the monocytes) at 12 h post-infection. The infection was productive in 0·16% of the monocytes. The virus yield was 100·7TCID50per productive cell. In a population of resting lymphocytes, 0·9% of cells were infected and less than 0·05% produced infectious virus. After prestimulation with different mitogens, the number of infected lymphocytes increased four to twelve times. The susceptible lymphocytes were T-lymphocytes. In mitogen-stimulated lymphocytes, clear expression of viral antigens was found on the plasma membrane.