bluuebunny/crossref_metadata_2025 huggingface dataset:
Waste Matters: Compost, Domestic Practice, and the Transformation of Alternative Toilet Cultures around Skaneateles Lake, New York
Authors: Dimpfl Mike , Moran Sharon
Published: August 2014

The Skaneateles Lake Watershed Composting Toilet Project highlights the material and sociocultural challenges of developing new kinds of embodied practices that effectively utilize alternatives to traditional water-dependent plumbing. Practical, small-scale innovation is important to addressing the human dimensions of these changes, particularly given the widely held taboos informing discussion of what happens behind closed bathroom doors. In this example an innovative watershed policy placed composting toilets in seventy-five lakeside homes to prevent household blackwater from polluting an unfiltered drinking water source utilized by 250 000 people. Interviews with key informants and participating households illustrate the ways in which expectations of toileting practice sit in tension with the need to preserve the health of the local watershed, particularly over the long term. Understanding shifts in toileting practice must move past functional assessments of new or untested technology, taking into account sociocultural understandings of private, deeply embodied, yet resolutely pragmatic daily habits. As individuals seek to normalize new toilet technology as a part of daily routines, they encounter the body's materiality in ways that conflict with expectations of what belongs inside the home. In this case, the traditionally excluded effluence of the human body remains too close for comfort, forcing a renegotiation of the common boundary-making habits defining domestic space. The result is a shift in expectations about what of the body can or should belong in the home.
An Anatomy of Symbolic Power: Israeli Road-Sign Policy and the Palestinian Minority
Authors: Bigon Liora , Dahamshe Amer
Published: August 2014

Perceived as mundane and experienced as mere informative images, innocent and undisputable, road signs can constitute part of a highly invested political strategy for producing a linguistic landscape. This is especially true in multiethnic or multinational states, such as Israel, where the linguistic landscape is being constituted in a contested context. The focus of this paper is on the visual and linguistic representations of Arabic and Hebrew toponyms in the Israeli road-sign system of the Galilee region. They will be examined in terms of positioning and organisation, landscape salience, and modes of transcript. Embracing Pierre Bourdieu's concept of ‘symbolic power’, our detailed analysis exposes the very anatomy of a bipartite rhetorical policy on the part of Israeli governmental agencies: On the one hand is spatial exclusion of the Palestinian memory through various visual and linguistic manipulations, tactics, and mechanisms at the expense of its own rich toponymic corpus. On the other, there is the establishment of the identity and related imagery of the Hebrew-speaking majority, which supports the Zionist project, regional consciousness, and spatial appropriation.
Probability Cueing Influences Miss Rate and Decision Criterion in Visual Searches
Authors: Ishibashi Kazuya , Kita Shinichi
Published: August 2014

In visual search tasks, the ratio of target-present to target-absent trials has an important effect on miss rates. The low prevalence effect indicates that we are more likely to miss a target when it occurs rarely rather than frequently. In this study, we examined whether probability cueing modulates the miss rate and the observer's criterion. The results indicated that probability cueing affects miss rates, the average observer's criterion, and reaction time for target-absent trials. These results clearly demonstrate that probability cueing modulates two parameters (i.e., the decision criterion and the quitting threshold) and produces a low prevalence effect. Taken together, the current study and previous studies suggest that the miss rate is not just affected by global prevalence; it is also affected by probability cueing.
Regional seroprevalence of Toxoplasma gondii antibodies in feral and stray cats (Felis catus) from Tasmania
Authors: Fancourt Bronwyn A. , Jackson Robert B.
Published: August 2014

Toxoplasma gondii is a cosmopolitan protozoan parasite of felids that also has significant implications for the health of wildlife, livestock and humans worldwide. In Australia, feral, stray and domestic cats (Felis catus) are the most important definitive host of T. gondii as they are the only species that can excrete the environmentally resistant oocysts that provide a major source of infection for mammals and birds. In Tasmania, the rapid decline of the Tasmanian devil (Sarcophilus harrisii) may allow an increase in feral cat abundance, thereby increasing the risk of T. gondii infection to a range of susceptible wildlife species. At present, there is scant information on the prevalence of T. gondii infection in feral cat populations across Tasmania. We tested feral cats from 13 regions across Tasmania for the presence of T. gondii–specific IgG antibodies using a modified agglutination test. Results were combined with serosurveys from three previous studies to enable a comparison of seroprevalence among 14 regions across Tasmania. We found that 84.2% (224 of 266) of cats tested positive for T. gondii IgG antibodies. This is among the highest rates of prevalence recorded from Australia, and significantly higher than for most other countries. Adult cats had higher seroprevalence than kittens but there was no difference between sexes. In Tasmania, seroprevalence was high in 12 of 14 regions (range: 79.3–100.0%), with only two regions (Tasman Island and Southern Tasmania) recording significantly lower seroprevalence (≤50%). This suggests a high risk of infection across Tasmania, and has significant implications for wildlife conservation should feral cat abundance increase with the ongoing declines in Tasmanian devils.
Inhibitor of MYC identified in a Kröhnke pyridine library
Authors: Hart Jonathan R. , Garner Amanda L. , Yu Jing , Ito Yoshihiro , Sun Minghao , Ueno Lynn , Rhee Jin-Kyu , Baksh Michael M. , Stefan Eduard , Hartl Markus , Bister Klaus , Vogt Peter K. , Janda Kim D.
Published: August 2014

Significance

MYC is an essential transcriptional regulator that controls cell proliferation. Elevated MYC is a driving force in most human cancers, yet MYC has been an exceedingly challenging target for small-molecule inhibitors. Here we describe a novel MYC inhibitor that interacts directly with MYC and interferes with its transcriptional and oncogenic activities.
Primary cilia are required in a unique subpopulation of neural progenitors
Authors: Tong Cheuk Ka , Han Young-Goo , Shah Jugal K. , Obernier Kirsten , Guinto Cristina D. , Alvarez-Buylla Arturo
Published: August 2014

Significance

The primary cilium, an antenna-like extension on the surface of many cells, is considered essential for growth factor and morphogen reception and transduction. Here we asked, what is the function of primary cilia that projects from the apical surface of neural stem cells (NSCs) into the ventricle? Surprisingly, the removal of primary cilia from fetal and early postnatal NSCs had little effect on forebrain development. Primary cilia, however, were essential for the function of NSCs in a restricted region of a major postnatal germinal niche, the ventricular–subventricular zone. Our data are consistent with primary cilia being essential for the normal proliferation of a subset of Hedgehog-responsive postnatal progenitors.
Marine ammonia-oxidizing archaeal isolates display obligate mixotrophy and wide ecotypic variation
Authors: Qin Wei , Amin Shady A. , Martens-Habbena Willm , Walker Christopher B. , Urakawa Hidetoshi , Devol Allan H. , Ingalls Anitra E. , Moffett James W. , Armbrust E. Virginia , Stahl David A.
Published: August 2014

Significance

Ammonia-oxidizing archaea (AOA) influence the form and availability of nitrogen in marine environments and are a major contributor to N
2
O release and plausible indirect source of methane in the upper ocean. Thus, their sensitivity to ocean acidification and other physicochemical changes associated with climate change has global significance. Here, we report on the physiological response of marine AOA isolates to key environmental variables. Although reported as highly sensitive to reduction in ocean pH, we now show that some coastal marine AOA can remain active with increasing acidification of the oceans. All AOA isolates assimilate fixed carbon and two are obligate mixotrophs, suggesting this globally significant assemblage serves a significant function in coupling chemolithotrophy with organic matter assimilation in marine food webs.
Bioengineered functional brain-like cortical tissue
Authors: Tang-Schomer Min D. , White James D. , Tien Lee W. , Schmitt L. Ian , Valentin Thomas M. , Graziano Daniel J. , Hopkins Amy M. , Omenetto Fiorenzo G. , Haydon Philip G. , Kaplan David L.
Published: August 2014

Significance

A modular 3D brain-like cortical tissue is constructed with silk protein-based scaffold and ECM composite and primary cortical neurons. This tissue responds in vitro with biochemical and electrophysiological outcomes, mimicking observations of brain homeostasis and mechanical injury responses.
Enhanced killing of antibiotic-resistant bacteria enabled by massively parallel combinatorial genetics
Authors: Cheng Allen A. , Ding Huiming , Lu Timothy K.
Published: August 2014

Significance

Many complex biological phenotypes are multifactorial in nature, yet current strategies for studying biological systems are limited by the inability to generate and track complex combinatorial cellular perturbations in a scalable fashion. Here, we introduce a method, Combinatorial Genetics En Masse (CombiGEM), that allows both facile generation of high-order combinations and high-throughput characterization of pooled populations using next-generation sequencing. We apply CombiGEM to identify genetic combinations that enhance killing of highly antibiotic-resistant bacteria with antibiotics, thus providing potential targets for antimicrobial development. We envision that CombiGEM will be broadly useful for basic science and biotechnology applications, such as complex genetic screening, identification of novel drug targets, interactome mapping, and synthetic circuit characterization.
Autophagy protects
C. elegans
against necrosis during
Pseudomonas aeruginosa
infection
Authors: Zou Cheng-Gang , Ma Yi-Cheng , Dai Li-Li , Zhang Ke-Qin
Published: August 2014

Significance

The autophagy machinery functions as an innate immune defense mechanism to eliminate intracellular pathogens, including bacteria, viruses, and parasites. However, the alternative functions of autophagy in innate immunity remain unknown. Using the metazoan
Caenorhabditis elegans
as a model system, we show that autophagy plays a crucial role in host defense against a pathogenic bacterium
Pseudomonas aeruginosa
. The function of autophagy lies not to directly diminish
P. aeruginosa
, but instead to neutralize necrosis imposed by the pathogen. These findings indicate that autophagy possesses multifaceted functions that modulate infectious and inflammatory diseases.
Natural selection drives the evolution of ant life cycles
Authors: Wilson Edward O. , Nowak Martin A.
Published: August 2014

The genetic origin of advanced social organization has long been one of the outstanding problems of evolutionary biology. Here we present an analysis of the major steps in ant evolution, based for the first time, to our knowledge, on combined recent advances in paleontology, phylogeny, and the study of contemporary life histories. We provide evidence of the causal forces of natural selection shaping several key phenomena: (i) the relative lateness and rarity in geological time of the emergence of eusociality in ants and other animal phylads; (ii) the prevalence of monogamy at the time of evolutionary origin; and (iii) the female-biased sex allocation observed in many ant species. We argue that a clear understanding of the evolution of social insects can emerge if, in addition to relatedness-based arguments, we take into account key factors of natural history and study how natural selection acts on alleles that modify social behavior.
MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma
Authors: Gill Brian J. , Pisapia David J. , Malone Hani R. , Goldstein Hannah , Lei Liang , Sonabend Adam , Yun Jonathan , Samanamud Jorge , Sims Jennifer S. , Banu Matei , Dovas Athanassios , Teich Andrew F. , Sheth Sameer A. , McKhann Guy M. , Sisti Michael B. , Bruce Jeffrey N. , Sims Peter A. , Canoll Peter
Published: August 2014

Significance

Molecular analysis of surgically resected glioblastomas (GBM) samples has uncovered phenotypically and clinically distinct tumor subtypes. However, little is known about the molecular features of the glioma margins that are left behind after surgery. To address this key issue, we performed RNA-sequencing (RNA-seq) and histological analysis on MRI-guided biopsies from the contrast-enhancing core and nonenhancing margins of GBM. Computational deconvolution of the RNA-seq data revealed that cellular composition, including nonneoplastic cells, is a major determinant of the expression patterns at the margins of GBM. The different GBM subtypes show distinct expression patterns that relate the contrast enhancing centers to the nonenhancing margins of tumors. Understanding these patterns may provide a means to infer the molecular and cellular features of residual disease.
The Holocene temperature conundrum
Authors: Liu Zhengyu , Zhu Jiang , Rosenthal Yair , Zhang Xu , Otto-Bliesner Bette L. , Timmermann Axel , Smith Robin S. , Lohmann Gerrit , Zheng Weipeng , Elison Timm Oliver
Published: August 2014

Significance

Marine and terrestrial proxy records suggest global cooling during the Late Holocene, following the peak warming of the Holocene Thermal Maximum (∼10 to 6 ka) until the rapid warming induced by increasing anthropogenic greenhouses gases. However, the physical mechanism responsible for this global cooling has remained elusive. Here, we show that climate models simulate a robust global annual mean warming in the Holocene, mainly in response to rising CO
2
and the retreat of ice sheets. This model-data inconsistency demands a critical reexamination of both proxy data and models.
A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs
Authors: Prota Andrea E. , Bargsten Katja , Diaz J. Fernando , Marsh May , Cuevas Carmen , Liniger Marc , Neuhaus Christian , Andreu Jose M. , Altmann Karl-Heinz , Steinmetz Michel O.
Published: August 2014

Significance

Microtubules are dynamic protein filaments assembled from tubulin subunits, which play a key role for cell division. Ligands that target microtubules and affect their dynamics belong to the most successful classes of chemotherapeutic drugs against cancer by inhibiting cell proliferation. Here we have analyzed three structurally unrelated drugs that destabilize microtubules, using X-ray crystallography. The data reveal a new tubulin-binding site for these drugs, which renders their mechanism of action distinct from that of other types of microtubule assembly inhibitors. Similar key interactions with tubulin are observed for all three ligands, thus defining a common pharmacophore. Our results offer an opportunity for the rational design of potent tubulin modulators for the development of more efficient cancer therapies.
Fractal branching organizations of Ediacaran rangeomorph fronds reveal a lost Proterozoic body plan
Authors: Hoyal Cuthill Jennifer F. , Conway Morris Simon
Published: August 2014

Significance

Rangeomorph fronds characterize the late Ediacaran Period (575–541 Ma), representing some of the earliest large organisms. As such, they offer key insights into the early evolution of multicellular eukaryotes. However, their extraordinary branching morphology differs from all other organisms and has proved highly enigmatic. Here we provide a unified mathematical model of rangeomorph branching, allowing us to reconstruct 3D morphologies of 11 taxa and measure their functional properties. This reveals an adaptive radiation of fractal morphologies which maximized body surface area, consistent with diffusive nutrient uptake (osmotrophy). Rangeomorphs were adaptively optimal for the low-competition, high-nutrient conditions of Ediacaran oceans. With the Cambrian explosion in animal diversity (from 541 Ma), fundamental changes in ecological and geochemical conditions led to their extinction.
Native microbiome impedes vertical transmission of
Wolbachia
in
Anopheles
mosquitoes
Authors: Hughes Grant L. , Dodson Brittany L. , Johnson Rebecca M. , Murdock Courtney C. , Tsujimoto Hitoshi , Suzuki Yasutsugu , Patt Alyssa A. , Cui Long , Nossa Carlos W. , Barry Rhiannon M. , Sakamoto Joyce M. , Hornett Emily A. , Rasgon Jason L.
Published: August 2014

Significance

Factors influencing
Wolbachia
transfer into new species remain poorly understood. This is important as
Wolbachia
can influence speciation and is being developed as a novel arthropod-borne disease control approach. We show the native microbiota of
Anopheles
impede vertical transmission of
Wolbachia
. Antibiotic microbiome perturbation enables
Wolbachia
transmission in two
Anopheles
species. Mosquitoes with altered microbiomes do not exhibit blood meal-induced mortality associated with
Wolbachia
infection, suggesting that mosquitoes are killed by interactions between
Wolbachia
and other bacteria present in the mosquito. We identified
Asaia
as the bacterium responsible for inhibiting
Wolbachia
transmission, and partially responsible for blood meal-induced mortality. These results suggest that microbial interactions profoundly affect the host, and that microbiome incompatibility may influence distribution of
Wolbachia
in arthropods.
Chaperone-enhanced purification of unconventional myosin 15, a molecular motor specialized for stereocilia protein trafficking
Authors: Bird Jonathan E. , Takagi Yasuharu , Billington Neil , Strub Marie-Paule , Sellers James R. , Friedman Thomas B.
Published: August 2014

Significance

Mutations in unconventional myosin 15 cause nonsyndromic autosomal recessive deafness, a common form of hereditary hearing loss in humans. Myosin 15 is required for the development of hair cell mechanosensory stereocilia that detect sounds within the inner ear. To our knowledge, our work offers the first insight into the biophysical properties of purified myosin 15. Using ensemble and single molecule techniques, we show that myosin 15 is a high-duty ratio motor, which is a characteristic of myosins that can move processively along actin filaments. We also introduce a new strategy for producing myosins by chaperone coexpression in
Spodoptera frugiperda
insect cells. This approach may help optimize expression of skeletal and cardiac muscle myosins, which are emerging as translational drug targets but are presently refractory to larger-scale purification.
EFA6 controls Arf1 and Arf6 activation through a negative feedback loop
Authors: Padovani Dominique , Folly-Klan Marcia , Labarde Audrey , Boulakirba Sonia , Campanacci Valérie , Franco Michel , Zeghouf Mahel , Cherfils Jacqueline
Published: August 2014

Significance

EFA6, cytohesins, and BRAGs activate Arf GTPases in endocytic events. They carry a plasma membrane-binding PH domain in tandem with their catalytic Sec7 domain, which is autoinhibitory and mediates a positive feedback loop in cytohesins but not in BRAGs, and has an as-yet unknown role in EFA6 regulation. By reconstituting GDP/GTP exchange on membranes, we find that the PH domain of EFA6 is not autoinhibitory, but supports a negative feedback loop. This loop is controlled by interaction of Arf6-GTP with the PH-Ct domains of EFA6 and monitors Arf1 and Arf6 activation differentially. This suggests that EFA6 and cytohesins might be coupled in a mixed negative-positive feedback loop to shape the level and timing of Arf1 and Arf6 activation in endocytosis.
Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells
Authors: Sundberg Thomas B. , Choi Hwan Geun , Song Joo-Hye , Russell Caitlin N. , Hussain Mahmud M. , Graham Daniel B. , Khor Bernard , Gagnon John , O’Connell Daniel J. , Narayan Kavitha , Dančík Vlado , Perez Jose R. , Reinecker Hans-Christian , Gray Nathanael S. , Schreiber Stuart L. , Xavier Ramnik J. , Shamji Alykhan F.
Published: August 2014

Significance

IL-10 plays an essential role in maintaining gut immune homeostasis as evidenced by the link between genetic perturbation of this anti-inflammatory cytokine and inflammatory bowel disease (IBD). Here, we describe a small-molecule screen that identified inhibition of salt-inducible kinases (SIKs) as a strategy to enhance IL-10 production by macrophages and dendritic cells. Significantly, the IL-10–potentiating effects of SIK inhibition are associated with reduced secretion of the inflammatory cytokines IL-1β, IL-6, IL-12, and TNF-α, and these coordinated effects are observed in cells relevant to IBD including anti-inflammatory CD11c
+
CX
3
CR1
hi
cells from murine gut tissue and in human dendritic cells and macrophages. Collectively, these results identify SIK inhibition as a promising approach to treat IBD by increasing gut IL-10 levels.
Small RNA combination therapy for lung cancer
Authors: Xue Wen , Dahlman James E. , Tammela Tuomas , Khan Omar F. , Sood Sabina , Dave Apeksha , Cai Wenxin , Chirino Leilani M. , Yang Gillian R. , Bronson Roderick , Crowley Denise G. , Sahay Gaurav , Schroeder Avi , Langer Robert , Anderson Daniel G. , Jacks Tyler
Published: August 2014

Significance

Small RNAs can potently and precisely regulate gene expression; as a result, they have tremendous clinical potential. However, effective delivery of small RNAs to solid tumors has remained challenging. Here we report that a lipid/polymer nanoparticle can deliver small RNAs to treat autochthonous tumors in the so-called “KP” mouse model of lung cancer. Nanoparticles formulated with mimics of the p53-regulated miRNA miR-34a downregulated target genes and delayed tumor progression, while nanoparticles formulated with siRNA targeting Kirsten rat sarcoma viral oncogene homolog (siKras) slowed tumor growth and increased apoptosis. Notably, concurrent delivery of miR-34a and siKras increased anti-tumor effects, and led to tumor regression. These results demonstrate that small RNA therapies can impact solid lung tumor growth, and that targeted RNA combination therapies may be used to improve therapeutic response.
Quasi-resonant circulation regimes and hemispheric synchronization of extreme weather in boreal summer
Authors: Coumou Dim , Petoukhov Vladimir , Rahmstorf Stefan , Petri Stefan , Schellnhuber Hans Joachim
Published: August 2014

Significance

The recent decade has seen an exceptional number of boreal summer weather extremes, some causing massive damage to society. There is a strong scientific debate about the underlying causes of these events. We show that high-amplitude quasi-stationary Rossby waves, associated with resonance circulation regimes, lead to persistent surface weather conditions and therefore to midlatitude synchronization of extreme heat and rainfall events. Since the onset of rapid Arctic amplification around 2000, a cluster of resonance circulation regimes is observed involving wave numbers 7 and 8. This has resulted in a statistically significant increase in the frequency of high-amplitude quasi-stationary waves with these wave numbers. Our findings provide important insights regarding the link between Arctic changes and midlatitude extremes.
Mapping of SUMO sites and analysis of SUMOylation changes induced by external stimuli
Authors: Impens Francis , Radoshevich Lilliana , Cossart Pascale , Ribet David
Published: August 2014

Significance

Small ubiquitin-related modifier (SUMO) is a posttranslational modification essential for many functions in eukaryotic cells. A better understanding of the role of this ubiquitin-like modification, identification of proteins modified by SUMO, and knowledge of the exact sites of SUMO conjugation are critical but remain experimentally challenging. We have developed an innovative proteomic strategy allowing proteome-wide identification of SUMOylation sites and quantification of cell SUMOylation changes in response to diverse stimuli. Identification of yet unknown SUMO targets and characterization of SUMOylome alterations in response to environmental stresses, drugs, toxins, or bacterial and viral infections will help decipher previously unidentified roles of SUMOylation in cell physiology and disease.
Denying knowledge
Authors: Petersen Esben Nedenskov
Published: August 2014

Intuitions about contextualist cases such as Cohen’s airport case pose a problem for classical anti-skeptical versions of invariantism. Recently, Tim Black (2005), Jessica Brown (2006), and Patrick Rysiew (2001, 2005, 2007) have argued that the classical invariantist can respond by arguing that pragmatic aspects of epistemic discourse are responsible for the relevant problematic intuitions. This paper identifies the mechanisms of conversational implicature and impliciture as the basic sources of hope for this explanatory strategy. It then argues that neither of these sources provides the classical invariantist with a convincing response to the airport case and its analogs.
From the clarity of ideas to the validity of judgments: Kant’s farewell to epistemic perfectionism
Authors: Pollok Konstantin
Published: August 2014

Against the standard interpretation of Kant’s ‘Copernican revolution’ as the prioritization of epistemology over ontology, I argue in this paper that his critique of traditional metaphysics must be seen as a farewell to the perfectionism on which early modern rationalist ontology and epistemology are built. However, Kant does not simply replace ‘perfection’ with another fundamental concept of normativity. More radically, Kant realizes that it is not simply ideas but only the relation of ideas that can be subject to norms, and thus he shifts the focus from the reality of ideas to the validity of judgments. Section 1 of this paper clarifies the pre-Kantian role of the concept of perfection and examines Kant’s critical response to that concept. Section 2 identifies Kant’s point of departure from the Cartesian ‘way of ideas.’ Section 3 explains the key problem of his novel account of epistemic normativity. I conclude that Kant’s anti-perfectionism must be seen as the driving force behind his ‘Copernican revolution’ in order to fully appreciate his mature account of epistemic normativity.
Skookumchuck, Kiidk’yaas, Gibbard: normativity, meaning, and idealization (critical notice of Allan Gibbard Meaning and Normativity)
Authors: Morton Adam
Published: August 2014

Gibbard argues that ‘meaning is normative’. He explains the claim with an account of the normative which bases it on the process of planning, taken in part as issuing instructions to oneself. It seems to entail that the right kind of plans make norms. One ought to continue adding with plus rather than quus in a Kripkenstein horror story. I focus on Gibbard’s characterization of normativity: it is not what one might expect. The main purpose of this review article is to present the way of understanding normativity that makes most sense of what he says, and which makes some otherwise implausible assertions defensible and perhaps even true. I give reasons for thinking that Gibbard’s understanding of normativity-through-plans cannot do the work he wants it to. I also argue that he is onto something right, and it opens interesting new questions.
Do Family Policies Matter for Educational Outcomes?
Authors: Crettaz Eric , Jacot Cédric
Published: August 2014

The aim of this article is to shed some light on the impact of family policies on educational mobility; this link has been often debated, but rarely measured. Another aim of this contribution is to build a bridge between social mobility research and social policy analysis. We investigate whether the level of expenditure on family services in the 1980s and 1990s has had a positive impact on educational achievements and mobility in 11 European countries, by closely looking at a cohort of young adults aged 25–35. To this end, multilevel logistic regression models that control for other policies that have an impact on educational mobility are presented; fixed effects models are also provided. Our results suggest that, in terms of the likelihood of going to university, these policies seem to have reduced the gap between individuals whose parents are well educated, and those who have a more modest background.
The nebulin repeat protein Lasp regulates I-band architecture and filament spacing in myofibrils
Authors: Fernandes Isabelle , Schöck Frieder
Published: August 2014

Mutations in nebulin, a giant muscle protein with 185 actin-binding nebulin repeats, are the major cause of nemaline myopathy in humans. Nebulin sets actin thin filament length in sarcomeres, potentially by stabilizing thin filaments in the I-band, where nebulin and thin filaments coalign. However, the precise role of nebulin in setting thin filament length and its other functions in regulating power output are unknown. Here, we show that Lasp, the only member of the nebulin family in Drosophila melanogaster, acts at two distinct sites in the sarcomere and controls thin filament length with just two nebulin repeats. We found that Lasp localizes to the Z-disc edges to control I-band architecture and also localizes at the A-band, where it interacts with both actin and myosin to set proper filament spacing. Furthermore, introducing a single amino acid change into the two nebulin repeats of Lasp demonstrated different roles for each domain and established Lasp as a suitable system for studying nebulin repeat function.
Sac1–Vps74 structure reveals a mechanism to terminate phosphoinositide signaling in the Golgi apparatus
Authors: Cai Yiying , Deng Yongqiang , Horenkamp Florian , Reinisch Karin M. , Burd Christopher G.
Published: August 2014

Sac1 is a phosphoinositide phosphatase of the endoplasmic reticulum and Golgi apparatus that controls organelle membrane composition principally via regulation of phosphatidylinositol 4-phosphate signaling. We present a characterization of the structure of the N-terminal portion of yeast Sac1, containing the conserved Sac1 homology domain, in complex with Vps74, a phosphatidylinositol 4-kinase effector and the orthologue of human GOLPH3. The interface involves the N-terminal subdomain of the Sac1 homology domain, within which mutations in the related Sac3/Fig4 phosphatase have been linked to Charcot–Marie–Tooth disorder CMT4J and amyotrophic lateral sclerosis. Disruption of the Sac1–Vps74 interface results in a broader distribution of phosphatidylinositol 4-phosphate within the Golgi apparatus and failure to maintain residence of a medial Golgi mannosyltransferase. The analysis prompts a revision of the membrane-docking mechanism for GOLPH3 family proteins and reveals how an effector of phosphoinositide signaling serves a dual function in signal termination.
Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery
Authors: Murphy Anar K. , Fitzgerald Michael , Ro Teresa , Kim Jee Hyun , Rabinowitsch Ariana I. , Chowdhury Dipanjan , Schildkraut Carl L. , Borowiec James A.
Published: August 2014

Phosphorylation of replication protein A (RPA) by Cdk2 and the checkpoint kinase ATR (ATM and Rad3 related) during replication fork stalling stabilizes the replisome, but how these modifications safeguard the fork is not understood. To address this question, we used single-molecule fiber analysis in cells expressing a phosphorylation-defective RPA2 subunit or lacking phosphatase activity toward RPA2. Deregulation of RPA phosphorylation reduced synthesis at forks both during replication stress and recovery from stress. The ability of phosphorylated RPA to stimulate fork recovery is mediated through the PALB2 tumor suppressor protein. RPA phosphorylation increased localization of PALB2 and BRCA2 to RPA-bound nuclear foci in cells experiencing replication stress. Phosphorylated RPA also stimulated recruitment of PALB2 to single-strand deoxyribonucleic acid (DNA) in a cell-free system. Expression of mutant RPA2 or loss of PALB2 expression led to significant DNA damage after replication stress, a defect accentuated by poly-ADP (adenosine diphosphate) ribose polymerase inhibitors. These data demonstrate that phosphorylated RPA recruits repair factors to stalled forks, thereby enhancing fork integrity during replication stress.
Vps74 gives phosphatase directions
Authors: Short Ben
Published: August 2014

Study reveals how the Sac1 phosphatase removes PtdIns4P from early Golgi membranes.
Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells
Authors: Lancini Cesare , van den Berk Paul C.M. , Vissers Joseph H.A. , Gargiulo Gaetano , Song Ji-Ying , Hulsman Danielle , Serresi Michela , Tanger Ellen , Blom Marleen , Vens Conchita , van Lohuizen Maarten , Jacobs Heinz , Citterio Elisabetta
Published: August 2014

Histone ubiquitination at DNA breaks is required for activation of the DNA damage response (DDR) and DNA repair. How the dynamic removal of this modification by deubiquitinating enzymes (DUBs) impacts genome maintenance in vivo is largely unknown. To address this question, we generated mice deficient for Ub-specific protease 3 (USP3; Usp3Δ/Δ), a histone H2A DUB which negatively regulates ubiquitin-dependent DDR signaling. Notably, USP3 deletion increased the levels of histone ubiquitination in adult tissues, reduced the hematopoietic stem cell (HSC) reserves over time, and shortened animal life span. Mechanistically, our data show that USP3 is important in HSC homeostasis, preserving HSC self-renewal, and repopulation potential in vivo and proliferation in vitro. A defective DDR and unresolved spontaneous DNA damage contribute to cell cycle restriction of Usp3Δ/Δ HSCs. Beyond the hematopoietic system, Usp3Δ/Δ animals spontaneously developed tumors, and primary Usp3Δ/Δ cells failed to preserve chromosomal integrity. These findings broadly support the regulation of chromatin ubiquitination as a key pathway in preserving tissue function through modulation of the response to genotoxic stress.
Increased severity of respiratory infections associated with elevated anti-LPS IgG2 which inhibits serum bactericidal killing
Authors: Wells Timothy J. , Whitters Deborah , Sevastsyanovich Yanina R. , Heath Jennifer N. , Pravin John , Goodall Margaret , Browning Douglas F. , O’Shea Matthew K. , Cranston Amy , De Soyza Anthony , Cunningham Adam F. , MacLennan Calman A. , Henderson Ian R. , Stockley Robert A.
Published: August 2014

Although specific antibody induced by pathogens or vaccines is a key component of protection against infectious threats, some viruses, such as dengue, induce antibody that enhances the development of infection. In contrast, antibody-dependent enhancement of bacterial infection is largely unrecognized. Here, we demonstrate that in a significant portion of patients with bronchiectasis and Pseudomonas aeruginosa lung infection, antibody can protect the bacterium from complement-mediated killing. Strains that resist antibody-induced, complement-mediated killing produce lipopolysaccharide containing O-antigen. The inhibition of antibody-mediated killing is caused by excess production of O-antigen–specific IgG2 antibodies. Depletion of IgG2 to O-antigen restores the ability of sera to kill strains with long-chain O-antigen. Patients with impaired serum-mediated killing of P. aeruginosa by IgG2 have poorer respiratory function than infected patients who do not produce inhibitory antibody. We suggest that excessive binding of IgG2 to O-antigen shields the bacterium from other antibodies that can induce complement-mediated killing of bacteria. As there is significant sharing of O-antigen structure between different Gram-negative bacteria, this IgG2-mediated impairment of killing may operate in other Gram-negative infections. These findings have marked implications for our understanding of protection generated by natural infection and for the design of vaccines, which should avoid inducing such blocking antibodies.
Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection
Authors: Penaloza-MacMaster Pablo , Kamphorst Alice O. , Wieland Andreas , Araki Koichi , Iyer Smita S. , West Erin E. , O’Mara Leigh , Yang Shu , Konieczny Bogumila T. , Sharpe Arlene H. , Freeman Gordon J. , Rudensky Alexander Y. , Ahmed Rafi
Published: August 2014

Regulatory T (T reg) cells are critical for preventing autoimmunity mediated by self-reactive T cells, but their role in modulating immune responses during chronic viral infection is not well defined. To address this question and to investigate a role for T reg cells in exhaustion of virus-specific CD8 T cells, we depleted T reg cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). T reg cell ablation resulted in 10–100-fold expansion of functional LCMV-specific CD8 T cells. Rescue of exhausted CD8 T cells was dependent on cognate antigen, B7 costimulation, and conventional CD4 T cells. Despite the striking recovery of LCMV-specific CD8 T cell responses, T reg cell depletion failed to diminish viral load. Interestingly, T reg cell ablation triggered up-regulation of the molecule programmed cell death ligand-1 (PD-L1), which upon binding PD-1 on T cells delivers inhibitory signals. Increased PD-L1 expression was observed especially on LCMV-infected cells, and combining T reg cell depletion with PD-L1 blockade resulted in a significant reduction in viral titers, which was more pronounced than that upon PD-L1 blockade alone. These results suggest that T reg cells effectively maintain CD8 T cell exhaustion, but blockade of the PD-1 inhibitory pathway is critical for elimination of infected cells.
Hydration of protein–RNA recognition sites
Authors: Barik Amita , Bahadur Ranjit Prasad
Published: August 2014

We investigate the role of water molecules in 89 protein–RNA complexes taken from the Protein Data Bank. Those with tRNA and single-stranded RNA are less hydrated than with duplex or ribosomal proteins. Protein–RNA interfaces are hydrated less than protein–DNA interfaces, but more than protein–protein interfaces. Majority of the waters at protein–RNA interfaces makes multiple H-bonds; however, a fraction do not make any. Those making H-bonds have preferences for the polar groups of RNA than its partner protein. The spatial distribution of waters makes interfaces with ribosomal proteins and single-stranded RNA relatively ‘dry’ than interfaces with tRNA and duplex RNA. In contrast to protein–DNA interfaces, mainly due to the presence of the 2′OH, the ribose in protein–RNA interfaces is hydrated more than the phosphate or the bases. The minor groove in protein–RNA interfaces is hydrated more than the major groove, while in protein–DNA interfaces it is reverse. The strands make the highest number of water-mediated H-bonds per unit interface area followed by the helices and the non-regular structures. The preserved waters at protein–RNA interfaces make higher number of H-bonds than the other waters. Preserved waters contribute toward the affinity in protein–RNA recognition and should be carefully treated while engineering protein–RNA interfaces.
Quantitative models for accelerated protein dissociation from nucleosomal DNA
Authors: Chen Cai , Bundschuh Ralf
Published: August 2014

Binding of transcription factors to their binding sites in promoter regions is the fundamental event in transcriptional gene regulation. When a transcription factor binding site is located within a nucleosome, the DNA has to partially unwrap from the nucleosome to allow transcription factor binding. This reduces the rate of transcription factor binding and is a known mechanism for regulation of gene expression via chromatin structure. Recently a second mechanism has been reported where transcription factor off-rates are dramatically increased when binding to target sites within the nucleosome. There are two possible explanations for such an increase in off-rate short of an active role of the nucleosome in pushing the transcription factor off the DNA: (i) for dimeric transcription factors the nucleosome can change the equilibrium between monomeric and dimeric binding or (ii) the nucleosome can change the equilibrium between specific and non-specific binding to the DNA. We explicitly model both scenarios and find that dimeric binding can explain a large increase in off-rate while the non-specific binding model cannot be reconciled with the large, experimentally observed increase. Our results suggest a general mechanism how nucleosomes increase transcription factor dissociation to promote exchange of transcription factors and regulate gene expression.
Molecular basis for the differential interaction of plant mitochondrial VDAC proteins with tRNAs
Authors: Salinas Thalia , El Farouk-Ameqrane Samira , Ubrig Elodie , Sauter Claude , Duchêne Anne-Marie , Maréchal-Drouard Laurence
Published: August 2014

In plants, the voltage-dependent anion-selective channel (VDAC) is a major component of a pathway involved in transfer RNA (tRNA) translocation through the mitochondrial outer membrane. However, the way in which VDAC proteins interact with tRNAs is still unknown. Potato mitochondria contain two major mitochondrial VDAC proteins, VDAC34 and VDAC36. These two proteins, composed of a N-terminal α-helix and of 19 β-strands forming a β-barrel structure, share 75% sequence identity. Here, using both northwestern and gel shift experiments, we report that these two proteins interact differentially with nucleic acids. VDAC34 binds more efficiently with tRNAs or other nucleic acids than VDAC36. To further identify specific features and critical amino acids required for tRNA binding, 21 VDAC34 mutants were constructed and analyzed by northwestern. This allowed us to show that the β-barrel structure of VDAC34 and the first 50 amino acids that contain the α-helix are essential for RNA binding. Altogether the work shows that during evolution, plant mitochondrial VDAC proteins have diverged so as to interact differentially with nucleic acids, and this may reflect their involvement in various specialized biological functions.
Drivers and Trajectories of Resistance to New First-Line Drug Regimens for Tuberculosis
Authors: Shrestha Sourya , Knight Gwenan M. , Fofana Mariam , Cohen Ted , White Richard G. , Cobelens Frank , Dowdy David W.
Published: August 2014

Background.  New first-line drug regimens for treatment of tuberculosis (TB) are in clinical trials: emergence of resistance is a key concern. Because population-level data on resistance cannot be collected in advance, epidemiological models are important tools for understanding the drivers and dynamics of resistance before novel drug regimens are launched.

Methods.  We developed a transmission model of TB after launch of a new drug regimen, defining drug-resistant TB (DR-TB) as resistance to the new regimen. The model is characterized by (1) the probability of acquiring resistance during treatment, (2) the transmission fitness of DR-TB relative to drug-susceptible TB (DS-TB), and (3) the probability of treatment success for DR-TB versus DS-TB. We evaluate the effect of each factor on future DR-TB prevalence, defined as the proportion of incident TB that is drug-resistant.

Results.  Probability of acquired resistance was the strongest predictor of the DR-TB proportion in the first 5 years after the launch of a new drug regimen. Over a longer term, however, the DR-TB proportion was driven by the resistant population's transmission fitness and treatment success rates. Regardless of uncertainty in acquisition probability and transmission fitness, high levels (>10%) of drug resistance were unlikely to emerge within 50 years if, among all cases of TB that were detected, 85% of those with DR-TB could be appropriately diagnosed as such and then successfully treated.

Conclusions.  Short-term surveillance cannot predict long-term drug resistance trends after launch of novel first-line TB regimens. Ensuring high treatment success of drug-resistant TB through early diagnosis and appropriate second-line therapy can mitigate many epidemiological uncertainties and may substantially slow the emergence of drug-resistant TB.
Efficacy of Recombinant Human Interleukin 7 in a Patient With Severe Lymphopenia-Related Progressive Multifocal Leukoencephalopathy
Authors: Gasnault Jacques , de Goër de Herve Marie-Ghislaine , Michot Jean-Marie , Hendel-Chavez Houria , Seta Vannina , Mazet Anne-Aurélie , Croughs Thérèse , Stankoff Bruno , Bourhis Jean-Henri , Lambotte Olivier , Delfraissy Jean-François , Taoufik Yassine
Published: August 2014

In this study, we report the case of a patient with profound lymphopenia after allogenic bone marrow transplantation who developed severe progressive multifocal leukoencephalopathy. Single-agent recombinant human interleukin-7 therapy was associated with restoration of anti-John Cunningham polyomavirus (JCV) T-cell responses, JCV clearance from cerebrospinal fluid, and a dramatic clinical improvement.
The Distinctiveness of Soviet Culture
Authors: Brooks Jeffrey , Zhuk Sergei I.
Published: August 2014

The quintessentially Soviet element of cultural development in the USSR between 1932 and 1991 was Socialist Realism. The period prior to the 1930s was its preface and that from the mid-1950s a long post-script. By the mid-1980s, Soviet publics had moved irreversibly beyond Socialist Realism in all the arts, and no viable new contender could assume the particularist mantle. The best official offerings to compete with new Western movements after 1945 were too little and too late. In the absence of a viable particularist contender and with institutions of isolationism eroding, Soviet culture inexorably drew closer to its counterparts abroad. By 1991 it had been gone so long that its formal passing was hardly noticed.
Substance Use in Specific Settings
Authors: Ames Genevieve , Moore Roland S.
Published: August 2014

National surveys in the United States and elsewhere reveal a wide range in rates of heavy drinking across occupations, with the highest in construction and lowest in educational industries. Young adults in the military have higher heavy drinking rates than their civilian counterparts, with the highest among Army and Marine personnel. Civilian and military heavy and binge drinking and drinking on the job have been linked to specific kinds of work-related problems of high consequences to employer, employees, and the military. In 1998, the estimated employment-related costs of alcohol abuse in the United States were $135 billion; the projected costs 15 years hence are much higher. Guided by theoretical advances, links between specific environmental factors and undesirable drinking behavior have been identified and explained in the context of work culture. Results of these research endeavors have provided guidelines for research and intervention focused on prevention of alcohol-related problems in the civilian and military workplace.
African-American Political Participation
Authors: Philpot Tasha S. , Walton Hanes
Published: August 2014

This chapter describes the evolution of African-American political participation. Beginning with early findings in Black political participation, it discusses the major paradigm shifts in this research and their catalysts. The chapter concludes by providing a roadmap for future research in the field.