bluuebunny/crossref_metadata_2025 huggingface dataset:
A Different Vision of Ancient Settlement Dynamics: Creation and Application of a Model of Evolution of Roman Settlement of the Plateau Lorrain (France)
Authors: Nüsslein Antonin
Published: February 2019

Research concerning settlement dynamics is mainly based on data from archaeological field survey. This method of investigation provides researchers with a lot of information that can help to identify trends and to model the evolution of settlement structure at different scales. Nonetheless, field survey data is sometimes incomplete and only shows a snapshot of the settlements. This static information lacks a certain number of parameters (evolution of architectural, economic, social features, etc.) which are essential to perceive the inherent evolution of the settlements and therefore to visualize their own evolution within the dynamics of settlement trajectory networks. On the other hand, data from archaeological excavations enable us to detect those phenomena. This paper aims to propose a methodological approach to try to resolve this lack of parameters: the creation of an evolutionary model of the settlements from the information collected during excavations. Applied to the sites discovered by field survey, and combined with other analytical tools, the model allows for a better understanding of the diversification phenomena and the processes of spatial development of the settlement pattern. This method, which offers solutions to enhance the static information provided by survey data, was designed for the study of Roman settlement of the Plateau Lorrain (France), but it can be applied to other periods and to other regions as well.
Can Human Flourishing Be Liberal?
Authors: Alexander Gregory S.
Published: February 2019

The renewed interest in virtue ethics raises again a persistent question, namely, the relationship between the virtue ethics theory and liberalism as a political philosophy. Virtue ethicists focus on the good—i.e., human flourishing—and debate what constitutes that good. This focus creates a problem for liberals who are rights-oriented, which is the dominant form of contemporary liberalism.

The recent and timely book by Menachem Mautner, Human Flourishing, Liberal Theory, and the Arts, reminds us, however, that liberalism comes in many stripes. There is no one liberalism. Rather, there are many liberalisms. I discuss three aspects of Mautner’s remarkable and important book: first, his conception of human flourishing and its relationship to liberalism; second, his argument that a liberal political order committed to human flourishing ought to promote the arts; and third, his argument that the liberalism of flourishing is better able than neutralist liberalism to compete with religion in providing what Mautner calls “Big Meaning.”
Law in Theory and History: New Essays on a Neglected Dialogue edited by Maksymilian Del Mar and Michael Lobban*
Authors: Swaminathan Shivprasad
Published: February 2019

This volume is an important contribution to a topic which has seen something of a resurgence lately and one from which both legal theorists and legal historians will greatly benefit. Some of the essays in this volume tackle questions on the ground floor, as it were, of interactions between legal theory and legal history. Others offer metatheoretical reflections on legal theory and legal history. Some combine the two. Given that the essays offer a rich variety of perspectives and do not unfold according to a master plan, it would be ill advised for a reviewer to impose an artificial order on them to be able to discuss the whole in one go. Instead, the discussion in this review will revolve primarily around some key themes revolving around the method and aims of legal theory.
The Problem of Dependency of Corrective Justice: Corrective Entitlements and Private Transactions
Authors: Eenmaa-Dimitrieva Helen
Published: February 2019

Several legal philosophers have argued that the principle of corrective justice provides the best explanation of various areas of the law—especially the law of torts. On the other hand, some philosophers of law and many economists of law have argued that the principle of corrective justice is not an independent principle of justice. I call this the problem of dependency. If the critics are right, the principle of corrective justice cannot be an explanation of a large area of our law as it claims to be.

I argue that the increasingly complex forms of the problem of dependency that the critics have proposed lose their force once we have a better understanding of the principle of corrective justice and its relationships with other principles. The principle of corrective justice does not serve a conception of distributive justice or efficiency and can provide an explanation of a large area of our law despite the criticism. It does so independently as a principle of justice that is reflected in our legal practice.
Nobody’s Perfect: Moral Responsibility in Negligence
Authors: Herstein Ori J.
Published: February 2019

Given the unwittingness of negligence, personal responsibility for negligent conduct is puzzling. After all, how is it that one is responsible for what one did not intend to do or was unaware that one was doing? How, therefore, is one’s agency involved with one’s negligence so as to ground one’s responsibility for it? Negligence is an unwitting failure in agency to meet a standard requiring conduct that falls within one’s competency. Accordingly, negligent conduct involves agency in that negligence is a manifestation of agency failure. Now, nobody’s perfect. Human agency is innately fallible, and a measure of agency failure is, therefore, unavoidable. The more one’s negligence manifests failure in one’s agency as an individual, the more one is responsible for it. In contrast, the more one’s negligence involves the shortcomings innate to all human agency the less responsible one becomes, because one’s agency as an individual is less and less involved in one’s failure. Determinative of the measure of individual and of human failings mixed into an instance of negligent phi-ing is the background quality of one’s agency at meeting one’s competency at phi-ing. That is, how able one is at delivering on what one is able to competently do. The more able, the less one’s occasional instances of negligence involve manifestations of failures of one’s agency as an individual—nobody’s perfect—and are more manifestations of one’s agency’s innate human fallibility, making one less and less responsible for one’s negligence.
Regulatory Risks Faced by the Transportation Sharing Economy: Workforces at Stake
Authors: CORRÊA Ana Maria
Published: February 2019

The rise of sharing economy platforms is ubiquitous throughout the world.1Their success is attributed to the fact that they directly connect supply and demand by enabling individuals to share goods and personal services, with minimal initial barriers to entry. In addition, they outsource their workforce – making it less expensive and easier to expand internationally. Similar to other global supply chains, workers are mediated by a third party and technology is fundamental to that.2
ON THE CROSSING NUMBER OF THE CARTESIAN PRODUCT OF A SUNLET GRAPH AND A STAR GRAPH
Authors: HAYTHORPE MICHAEL , NEWCOMBE ALEX
Published: February 2019

The exact crossing number is only known for a small number of families of graphs. Many of the families for which crossing numbers have been determined correspond to cartesian products of two graphs. Here, the cartesian product of the sunlet graph, denoted ${\mathcal{S}}_{n}$, and the star graph, denoted $K_{1,m}$, is considered for the first time. It is proved that the crossing number of ${\mathcal{S}}_{n}\Box K_{1,2}$ is $n$, and the crossing number of ${\mathcal{S}}_{n}\Box K_{1,3}$ is $3n$. An upper bound for the crossing number of ${\mathcal{S}}_{n}\Box K_{1,m}$ is also given.
Volatiles mediate host-selection in the corn hoppers Dalbulus maidis (Hemiptera: Cicadellidae) and Peregrinus maidis (Hemiptera: Delphacidae)
Authors: Coll Aráoz M.V. , Jacobi V.G. , Fernandez P.C. , Luft Albarracin E. , Virla E.G. , Hill J.G. , Catalán C.A.N.
Published: February 2019

Volatile organic compounds (VOCs) released by plants are generally involved in host recognition and host selection for many phytophagous insects. However, for leafhoppers and planthoppers, host recognition is mainly thought to involve a phototactic response, but it is not clear if a host plant could be selected based on the volatile cues it emits. In this study we evaluated olfactory responses in dual choice tests of two Hemiptera species, Dalbulus maidis (De Long) (Cicadellidae) and Peregrinus maidis (Ashmead) (Delphacidae), vectors of maize-stunting diseases, to three maize (Zea mays L.) germplasms, a temperate and a tropical hybrid and a landrace. VOCs emitted by the germplasms were collected and identified using gas chromatography-mass spectrometry. The temperate hybrid released significantly more VOCs than the tropical hybrid and the landrace, and its volatile profile was dominated by (±)-linalool. D. maidis preferred odours emitted from the temperate hybrid, whereas P. maidis preferred odours from the tropical hybrid and the landrace over the temperate one. In order to test if linalool plays a role in the behavioural responses, we assayed this compound in combination with the tropical hybrid, to provide other contextual olfactory cues. D. maidis was attracted to the tropical hybrid plus a 0.0001% linalool solution, indicating that this compound could be part of a blend of attractants. Whereas addition of linalool resulted in a slight, though not significant, reduction in host VOC attractiveness for P. maidis. Both hopper species responded to olfactory cues in the absence of supplementary visual cues.
Understanding susceptibility and targeting treatment in non-alcoholic fatty liver disease in children; moving the fulcrum
Authors: Fitzpatrick Emer
Published: February 2019

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of paediatric liver disease, affecting 10% of school-aged children and 44–70% of obese children and young people (CYP) in the western world. Encompassing a spectrum from simple steatosis to steatohepatitis and progressive fibrosis, the disease is rapidly becoming the most common indication for liver transplantation. The molecular pathogenesis of NAFLD remains only partially understood. Development and progression of NAFLD is influenced by genetic and nutritional factors, insulin resistance, oxidative stress, gut microbiome, bile acid metabolism and lipid/glucose handling and is closely associated with overweight and obesity. Lifestyle change is the only proven effective treatment for paediatric NAFLD, however this is difficult to achieve in many. Given that moderate or severe fibrosis is already present in 30–50% of children with NAFLD at the time of presentation, progression in CYP may be more rapid, though adequate outcome data do not yet exist in this cohort. CYP with NAFLD are an excellent population in which to study underlying mechanisms and interventions to correct disease progression as they are largely unaffected by other environmental influences such as alcohol and may represent the more severe end of the spectrum in terms of early onset. Undoubtedly genetic and epigenetic mechanisms determine a large proportion of susceptibility to the disease and potentially, identification of individuals at risk may allow for targeted therapy. This review with give a clinical perspective of paediatric NAFLD focused on identifying those at risk of progressive disease and what to consider in attempting to modify risk.
A study of possible extra-framework cation ordering in Pbca leucite structures with stoichiometry RbCsX2+Si5O12 (X = Mg, Ni, Cd)
Authors: Bell Anthony M. T. , Henderson C. Michael B.
Published: February 2019

Leucites are silicate framework structures with some of the silicon framework cations partially replaced by divalent or trivalent cations. A monovalent extraframework alkali metal cation is also incorporated to balance the charges. We have previously reported Pbca leucite structures with the stoichiometries Cs2X2+Si5O12 (X = Mg, Mn, Co, Ni, Cu, Zn, Cd) and Rb2X2+Si5O12 (X = Mg, Mn, Ni, Cd). These orthorhombic leucite structures have all the silicon and non-silicon framework cations completely ordered onto separate crystallographic sites. This structure has five distinct Si sites and 1 X site; there are also two distinct sites for the extra-framework Cs or Rb. We have recently synthesised leucite analogues with two different extra-framework cations, these have the stoichiometry RbCsX2+Si5O12 (X = Mg, Ni, Cd). The initial Rietveld refinements assumed 50% Cs and 50% Rb on each of the two extra-framework cation sites. The refined structures for X = Ni and Cd have (within error limits) complete extra-framework cation site disorder. However, for X = Mg there is partial ordering of the extra-framework cation sites, the site occupancies are:- Cs1 0.37(3), Rb1 0.63(3), Cs2 0.63(3), Rb2 0.37(3).
WONDERFUL JOURNEY
Authors: Pasztory Esther
Published: February 2019

When I was a child, my favorite book was Wonderful Journey by Selma Lagerlof in Hungarian translation. The story is about a boy who is turned into a Tom Thumb for bad behavior. He joins a flock of wild geese and travels with them on the back of a goose on a series of adventures through towns and forests, even under the sea to an “Atlantis.” He speaks the language of the animals and learns good behavior. As a reward, after a year, he is transformed back into a regular boy and goes home. He looks up wonderingly at the flock of geese going on another adventure but can no longer understand the language of animals. He is sad. At this point, I always cried. (I did not know that the story, written in 1907, took place in Sweden and was a geography lesson of Sweden, specifically. It is available now in English as the Wonderful Adventures of Nils. Selma Lagerlof received the Nobel Prize.)
COCHIS: Stable and coherent implicits
Authors: SCHRIJVERS TOM , OLIVEIRA BRUNO C.D.S. , WADLER PHILIP , MARNTIROSIAN KOAR
Published: February 2019

Implicit programming (IP) mechanisms infer values by type-directed resolution, making programs more compact and easier to read. Examples of IP mechanisms include Haskell’s type classes, Scala’s implicits, Agda’s instance arguments, Coq’s type classes and Rust’s traits. The design of IP mechanisms has led to heated debate: proponents of one school argue for the desirability of strong reasoning properties, while proponents of another school argue for the power and flexibility of local scoping or overlapping instances. The current state of affairs seems to indicate that the two goals are at odds with one another and cannot easily be reconciled. This paper presents COCHIS, the Calculus Of CoHerent ImplicitS, an improved variant of the implicit calculus that offers flexibility while preserving two key properties:coherenceandstability of type substitutions. COCHIS supports polymorphism, local scoping, overlapping instances, first-class instances and higher-order rules, while remaining type-safe, coherent and stable under type substitution. We introduce a logical formulation of how to resolve implicits, which is simple but ambiguous and incoherent, and a second formulation, which is less simple but unambiguous, coherent and stable. Every resolution of the second formulation is also a resolution of the first, but not conversely. Parts of the second formulation bear a close resemblance to a standard technique for proof search called focusing. Moreover, key for its coherence is a rigorous enforcement of determinism.
Taxing the bilingual mind: Effects of simultaneous interpreting experience on verbal and executive mechanisms
Authors: García Adolfo M. , Muñoz Edinson , Kogan Boris
Published: February 2019

This paper reviews the neurocognitive particularities of subjects with sustained experience in simultaneous interpreting, a highly demanding form of bilingual processing. The literature converges into three broad empirical patterns. First, significant neurocognitive differences, including behavioral enhancements in verbal and executive domains, are observable after only one or two years of training. Second, such effects, both in interpreting students and/or professional interpreters, seem robust for crucial linguistic (e.g., translation) and executive (e.g., working memory) aspects of the activity, but not for more marginally relevant ones (e.g., conflict resolution) – suggesting that they are non-generalizable beyond directly taxed functions. Third, though more tentatively, some of the observed verbal and executive effects seem to be mutually independent and uninfluenced by other bilingual-experience-related factors (e.g., L2 competence), which could highlight their distinctive relation with interpreting practice. In sum, this particular model of expertise sheds novel light on the adaptive capacity of cognitive systems in bilinguals.
Adults with familial hypercholesterolaemia have healthier dietary and lifestyle habits compared with their non-affected relatives: the SAFEHEART study
Authors: Arroyo-Olivares Raquel , Alonso Rodrigo , Quintana-Navarro Gracia , Fuentes-Jiménez Francisco , Mata Nelva , Muñiz-Grijalvo Ovidio , Díaz-Díaz José L , Zambón Daniel , Arrieta Francisco , García-Cruces Jesús , Garrido-Sanjuan Juan A , Banegas José R , Mata Pedro
Published: February 2019

Objective

Healthy lifestyle habits are the cornerstone in the management of familial hypercholesterolaemia (FH). Nevertheless, dietary studies on FH-affected populations are scarce. The present study analyses dietary habits, adherence to a Mediterranean diet pattern and physical activity in an adult population with FH and compares them with their non-affected relatives.

Design

Cross-sectional study.

Setting

Data came from SAFEHEART, a nationwide study in Spain.

Participants

Individuals (n 3714) aged ≥18 years with a genetic diagnosis of FH (n2736) and their non-affected relatives (n 978). Food consumption was evaluated using a validated FFQ.

Results

Total energy intake was lower in FH patients v. non-affected relatives (P<0·005). Percentage of energy from fats was also lower in the FH population (35 % in men, 36 % in women) v. those non-affected (38 % in both sexes, P<0·005), due to the lower consumption of saturated fats (12·1 % in FH patients, 13·2 % in non-affected, P<0·005). Consumption of sugars was lower in FH patients v. non-affected relatives (P<0·05). Consumption of vegetables, fish and skimmed milk was higher in the FH population (P<0·005). Patients with FH showed greater adherence to a Mediterranean diet pattern v. non-affected relatives (P<0·005). Active smoking was lower and moderate physical activity was higher in people with FH, especially women (P<0·005).

Conclusions

Adult patients with FH report healthier lifestyles than their non-affected family members. They eat a healthier diet, perform more physical activity and smoke less. However, this patient group’s consumption of saturated fats and sugars still exceeds guidelines.
Evaluating a heat-tolerant wheat germplasm in a heat stress environment
Authors: Lordkaew Sittichai , Yimyam Narit , Wongtamee Anupong , Jamjod Sansanee , Rerkasem Benjavan
Published: February 2019

Heat stress, a regular risk to wheat in the subtropics, is a growing threat in other wheat producing regions as the global temperature rises. This paper reports on three experiments evaluating 49 entries of the 13th High Temperature Wheat Yield Trial (13HTWYT) from the International Centre for Maize and Wheat Improvement (distributed in 2014), with Fang 60 as the local check, at two locations at Chiang Mai, Thailand, a designated representative of the wheat mega-environment 5, in which temperature for the coolest month averages >17.5 °C and the crop is subjected to high temperature for the entire growing season. The wheat was grown in the lowland (elevation 330 m) at Chiang Mai University in (i) sand culture to simulate the condition of non-limiting nutrient and water supply and (ii) in the field and (iii) as an on-farm trial in the highlands (elevation 800 m) at Mae Wang district of Chiang Mai province. Heat tolerance in the wheat germplasm, recently developed for adaptation to high temperature, was indicated by longer pre-heading duration, and the positive correlation between days to heading and grain yield all three experiments. The longer time before heading enabled development of larger spikes that produced more seeds from more and larger spikelets and more competent florets. However, with the number of spikes that was either lower than or similar to Fang 60, none of the recently developed 13HTWYT entries out-yielded the local check from the 1970s.
Region, Nation, and Social Science:An Interview with Joseph L. Love on 50 Years of Studying Brazil
Authors: Frank Zephyr , Goodman Glen , Woodard James
Published: February 2019

In late September 2016, the Lemann Institute for Brazilian Studies at University of Illinois at Urbana-Champaign (UIUC) hosted a symposium on regionalism in Brazilian history to celebrate the fiftieth anniversary of Professor Joseph L. Love's arrival at Illinois. Organized by the Institute's director, Professor Jerry Dávila, the symposium brought together historians from the United States and Brazil for a day-long discussion of an issue that continues to attract scholarly attention in both countries. Love himself contributed to the study of Brazilian regionalism with two landmark studies:Rio Grande do Sul and Brazilian Regionalism, 1882–1930(1971) andSão Paulo in the Brazilian Federation, 1889–1937(1980). The latter was produced alongside John Wirth'sMinas Gerais in the Brazilian Federation, 1889–1937(1977) and Robert Levine'sPernambuco in the Brazilian Federation, 1889–1937(1978) as part of a larger project conceived and carried out through a decade's worth of unprecedentedly close collaboration. At Illinois, Love inspired hundreds of undergraduates with his award-winning teaching and trained a bi-national cohort of graduate students who have gone on to careers of great distinction in Brazil and in the United States.
The Press and Brazilian Narratives ofUncle Tom's Cabin:Slavery and the Public Sphere in Rio de Janeiro, ca. 1855
Authors: Castilho Celso Thomas
Published: February 2019

In March 1855, a literary newspaper in Rio de Janeiro printed the first installment of Nísia Floresta's “Páginas de uma vida obscura,” a serialized short story inspired by Harriet Beecher Stowe'sUncle Tom's Cabin(1852). Seven more chapters followed, keeping “Páginas” in the public eye for months. TheJornal do Commercio, arguably the national paper of record, mentioned the story in its announcements. Floresta (pseudonym of Dionísia Gonçalves Pinto, 1810–1885) centered her storyline on the Congo-born Domingos, the “Brazilian Tom,” who exemplified the attributes of Christian virtuosity and resignation found in Stowe's internationally famous novel. Set in the nineteenth century, “Páginas” begins with the ten-year-old Domingos's enslavement on the African coast, and highlights the human devastation of the internal slave trade through his movements across Minas Gerais and on to Porto Alegre and Rio de Janeiro. It ends with Domingos's death, at age 54, grief-stricken over his son's recent passing. In part, Floresta's “Páginas” emerged from the Brazilian schoolteacher's longstanding critiques of patriarchy, nation, and education. Twenty years earlier, Floresta had drawn from Mary Wollstonecraft'sA Vindication of the Rights of Womanto writeDireito das mulheres e injustiça dos homens(1832), a book that went through three editions in its first decade. More directly though, Floresta had connected to the so-called “Tom mania” while living in Paris in 1852. The following year, back in Rio, she wrote a pamphlet on women's education—Opúsculo humanitário(1853)—that parsed key aspects ofUncle Tom's Cabin, among a larger discussion of women's achievements internationally. Two Rio newspapers excerpted the pamphlet, and, boldly, published the chapters focused on Uncle Tom. This attention in the press raised the profile of a book the public already knew to be controversial, as newspapers had earlier carried reports of port authorities seizing shipments ofUncle Tom's Cabinin Rio, Salvador, and Fortaleza. In writing “Páginas,” then, two years after theOpúsculo, Floresta not only carried forward her literary dialogue with Stowe, but also posed the work as a challenge to the status quo. “Páginas” was necessary, she explained, because “slavery is not an issue of concern in the press.” If overstated, given that the topic of slavery was quite prevalent in public discourse, Floresta's assertion nonetheless signals an opportunity for scholars to probe further into the relationship between slavery and the public sphere in the mid nineteenth century. More specifically, it suggests connections to be explored between the press and the early reception ofUncle Tom's Cabinin Brazil, and, more broadly, connections between the representations of slavery in the press, and the institution's enduring legitimacy.
More Evidence Humans Migrated to the Americas via Coastal Route
Authors: Cook Terri
Published: February 2019

A new chronology shows that ice-free areas existed along the British Columbia coast earlier than previously thought.
Disruption of the FasL/Fas axis protects against inflammation-derived tumorigenesis in chronic liver disease
Authors: Cubero Francisco Javier , Woitok Marius Maximilian , Zoubek Miguel E. , de Bruin Alain , Hatting Maximilian , Trautwein Christian
Published: February 2019

Fas Ligand (FasL) and Fas (APO-1/CD95) are members of the TNFR superfamily and may trigger apoptosis. Here, we aimed to elucidate the functional role of Fas signaling in an experimental model of chronic liver disease, the hepatocyte-specific NEMO knockout (NEMOΔhepa) mice. We generated NEMOΔhepa /Faslpr mice, while NEMOΔhepa, NEMOf/f as well as Faslpranimals were used as controls, and characterized their phenotype during liver disease progression. Liver damage was evaluated by serum transaminases, histological, immunofluorescence procedures, and biochemical and molecular biology techniques. Proteins were detected by western Blot, expression of mRNA by RT-PCR, and infiltration of inflammatory cells was determined by FACs analysis, respectively. Faslpr mutation in NEMOΔhepa mice resulted in overall decreased liver injury, enhanced hepatocyte survival, and reduced proliferation at 8 weeks of age compared with NEMOΔhepa mice. Moreover, NEMOΔhepa/Faslpr animals elicited significantly decreased parameters of liver fibrosis, such as Collagen IA1, MMP2, and TIMP1, and reduced proinflammatory macrophages and cytokine expression. At 52 weeks of age, NEMOΔhepa/Faslpr exhibited less malignant growth as evidenced by reduced HCC burden associated with a significantly decreased number of nodules and LW/BW ratio and decreased myeloid populations. Deletion of TNFR1 further reduced tumor load of 52-weeks-old NEMOΔhepa/Faslpr mice. The functionality of FasL/Fas might affect inflammation-driven tumorigenesis in an experimental model of chronic liver disease. These results help to develop alternative therapeutic approaches and extend the limitations of tumor therapy against HCC.
Defective proteostasis in celiac disease as a new therapeutic target
Authors: Maiuri Luigi , Villella Valeria R , Piacentini Mauro , Raia Valeria , Kroemer Guido
Published: February 2019

Cystic fibrosis (CF) is a disease caused by loss-of-function mutations affecting the CF transmembrane conductance regulator (CFTR), a chloride channel. Recent evidence indicates that CFTR is inhibited by a gluten/gliadin-derived peptide (P31-43), causing an acquired state of CFTR inhibition within the gut that contributes to the pathogenesis of celiac disease (CD). Of note, CFTR inhibition does not only cause intra- and extracellular ion imbalances but also affects proteostasis by activating transglutaminase-2 (TGM2) and by disabling autophagy. These three phenomena (CFTR inhibition, TGM2 activation, and autophagy impairment) engage in multiple self-amplifying circuitries, thus forming an “infernal trio”. The trio hinders enterocytes from returning to homeostasis and instead locks them in an irreversible pro-inflammatory state that ultimately facilitates T lymphocyte-mediated immune responses against another gluten/gliadin-derived peptide (P57–68), which,upon deamidation by activated TGM2, becomes fully antigenic. Hence, the pathogenic protein gliadin exemplifies a food constituent the exceptional immunogenicity of which arises from a combination of antigenicity (conferred by deaminated P57–68) and adjuvanticity (conferred by P31-43). CF can be treated by agents targeting the “infernal trio” including CFTR potentiators, TGM2 inhibitors, and autophagy enhancers. We speculate that such agents may also be used for CD therapy and indeed could constitute close-to-etiological treatments of this enteropathy.
CIC protein instability contributes to tumorigenesis in glioblastoma
Authors: Bunda Severa , Heir Pardeep , Metcalf Julie , Li Annie Si Cong , Agnihotri Sameer , Pusch Stefan , Yasin Mamatjan , Li Mira , Burrell Kelly , Mansouri Sheila , Singh Olivia , Wilson Mark , Alamsahebpour Amir , Nejad Romina , Choi Bethany , Kim David , von Deimling Andreas , Zadeh Gelareh , Aldape Kenneth
Published: February 2019

Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigenesis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor suppressive function in GBM through an alternative mechanism. We find that CIC protein levels are negligible in GBM due to continuous proteasome-mediated degradation, which is mediated by the E3 ligase PJA1 and show that this occurs through binding of CIC to its DNA target and phosphorylation on residue S173. PJA1 knockdown increased CIC stability and extended survival using in-vivo models of GBM. Deletion of the ERK binding site resulted in stabilization of CIC and increased therapeutic efficacy of ERK inhibition in GBM models. Our results provide a rationale to target CIC degradation in Ras/ERK-driven tumors, including GBM, to increase efficacy of ERK inhibitors.
Chaperone activation and client binding of a 2-cysteine peroxiredoxin
Authors: Teixeira Filipa , Tse Eric , Castro Helena , Makepeace Karl A. T. , Meinen Ben A. , Borchers Christoph H. , Poole Leslie B. , Bardwell James C. , Tomás Ana M. , Southworth Daniel R. , Jakob Ursula
Published: February 2019

Many 2-Cys-peroxiredoxins (2-Cys-Prxs) are dual-function proteins, either acting as peroxidases under non-stress conditions or as chaperones during stress. The mechanism by which 2-Cys-Prxs switch functions remains to be defined. Our work focuses on Leishmania infantum mitochondrial 2-Cys-Prx, whose reduced, decameric subpopulation adopts chaperone function during heat shock, an activity that facilitates the transition from insects to warm-blooded host environments. Here, we have solved the cryo-EM structure of mTXNPx in complex with a thermally unfolded client protein, and revealed that the flexible N-termini of mTXNPx form a well-resolved central belt that contacts and encapsulates the unstructured client protein in the center of the decamer ring. In vivo and in vitro cross-linking studies provide further support for these interactions, and demonstrate that mTXNPx decamers undergo temperature-dependent structural rearrangements specifically at the dimer-dimer interfaces. These structural changes appear crucial for exposing chaperone-client binding sites that are buried in the peroxidase-active protein.
Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy
Authors: Caswell-Jin Jennifer L. , McNamara Katherine , Reiter Johannes G. , Sun Ruping , Hu Zheng , Ma Zhicheng , Ding Jie , Suarez Carlos J. , Tilk Susanne , Raghavendra Akshara , Forte Victoria , Chin Suet-Feung , Bardwell Helen , Provenzano Elena , Caldas Carlos , Lang Julie , West Robert , Tripathy Debu , Press Michael F. , Curtis Christina
Published: February 2019

Genomic changes observed across treatment may result from either clonal evolution or geographically disparate sampling of heterogeneous tumors. Here we use computational modeling based on analysis of fifteen primary breast tumors and find that apparent clonal change between two tumor samples can frequently be explained by pre-treatment heterogeneity, such that at least two regions are necessary to detect treatment-induced clonal shifts. To assess for clonal replacement, we devise a summary statistic based on whole-exome sequencing of a pre-treatment biopsy and multi-region sampling of the post-treatment surgical specimen and apply this measure to five breast tumors treated with neoadjuvant HER2-targeted therapy. Two tumors underwent clonal replacement with treatment, and mathematical modeling indicates these two tumors had resistant subclones prior to treatment and rates of resistance-related genomic changes that were substantially larger than previous estimates. Our results provide a needed framework to incorporate primary tumor heterogeneity in investigating the evolution of resistance.
Electrochromic semiconductors as colorimetric SERS substrates with high reproducibility and renewability
Authors: Cong Shan , Wang Zhen , Gong Wenbin , Chen Zhigang , Lu Weibang , Lombardi John R. , Zhao Zhigang
Published: February 2019

Electrochromic technology has been actively researched for displays, adjustable mirrors, smart windows, and other cutting-edge applications. However, it has never been proposed to overcome the critical problems in the field of surface-enhanced Raman scattering (SERS). Herein, we demonstrate a generic electrochromic strategy for ensuring the reproducibility and renewability of SERS substrates, which are both scientifically and technically important due to the great need for quantitative analysis, standardized production and low cost in SERS. This color-changing strategy is based on a unique quantitative relationship between the SERS signal amplification and the coloration degree within a certain range, in which the SERS activity of the substrate can be effectively inferred by judging the degree of color change. Our results may provide a first step toward the rational design of electrochromic SERS substrates with a high sensitivity, reproducibility, and renewability.
Publisher Correction: Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders
Authors: Nist-Lund Carl A. , Pan Bifeng , Patterson Amy , Asai Yukako , Chen Tianwen , Zhou Wu , Zhu Hong , Romero Sandra , Resnik Jennifer , Polley Daniel B. , Géléoc Gwenaelle S. , Holt Jeffrey R.
Published: February 2019

The original version of this Article contained errors in Fig. 5. In panels i and j the three rightmost x-axis labels inadvertently read ‘Tmc1’ instead of ‘Tmc2’. These errors have been corrected in both the PDF and HTML versions of the Article.
A recombinant vesicular stomatitis-based Lassa fever vaccine elicits rapid and long-term protection from lethal Lassa virus infection in guinea pigs
Authors: Stein Derek R. , Warner Bryce M. , Soule Geoff , Tierney Kevin , Frost Kathy L. , Booth Stephanie , Safronetz David
Published: February 2019

The World Health Organization has identified Lassa virus (LASV) as one of the top five pathogens to cause a severe outbreak in the near future. This study assesses the ability of a leading vaccine candidate, recombinant Vesicular stomatitis virus expressing LASV glycoprotein (VSVΔG/LASVGPC), and its ability to induce rapid and long-term immunity to lethal guinea pig-adapted LASV (GPA-LASV). Outbred guinea pigs were vaccinated with a single dose of VSVΔG/LASVGPC followed by a lethal challenge of GPA-LASV at 7, 14, 25, 189, and 355 days post-vaccination. Statistically significant rapid and long-term protection was achieved at all time points with 100% protection at days 7 and 14 post-vaccination. While 83 and 87% protection were achieved at 25 days and 6 months post-vaccination, respectively. When guinea pigs were challenged one year after vaccination 71% protection was achieved. Notable infectious virus was isolated from the serum and tissues of some but not all animals. Total LASVGPC-specific IgG titers were also measured on a monthly basis leading up to LASV challenge however, it is unclear if antibody alone correlates with short and long term survival. These studies confirm that a single dose of VSVΔG/LASVGPC can induce rapid and long-term protection from LASV infection in an aggressive outbred model of infection, and supports further development in non-human primates.
Metapopulation Model from Pathogen’s Perspective: A Versatile Framework to Quantify Pathogen Transfer and Circulation between Environment and Hosts
Authors: Chen Shi , Lanzas Cristina , Lee Chihoon , Zenarosa Gabriel L. , Arif Ahmed A. , Dulin Michael
Published: February 2019

Metapopulation models have been primarily explored in infectious disease epidemiology to study host subpopulation movements and between-host contact structures. They also have the potential to investigate environmental pathogen transferring. In this study, we demonstrate that metapopulation models serve as an ideal modeling framework to characterize and quantify pathogen transfer between environment and hosts. It therefore unifies host, pathogen, and environment, collectively known as the epidemiological triad, a fundamental concept in epidemiology. We develop a customizable and generalized pathogen-transferring model where pathogens dwell in and transferring (via contact) between environment and hosts. We analyze three specific case studies: pure pathogen transferring without pathogen demography, source-sink dynamics, and pathogen control via external disinfection. We demonstrate how pathogens circulate in the system between environment and hosts, as well as evaluate different controlling efforts for healthcare-associated infections (HAIs). For pure pathogen transferring, system equilibria can be derived analytically to explicitly quantify long-term pathogen distribution in the system. For source-sink dynamics and pathogen control via disinfection, we demonstrate that complete eradication of pathogens can be achieved, but the rates of converging to system equilibria differ based on specific model parameterization. Direct host-host pathogen transferring and within-host dynamics can be future directions of this modeling framework by adding specific modules.
The biodiversity Composition of Microbiome in Ovarian Carcinoma Patients
Authors: Zhou Bo , Sun Chaoyang , Huang Jia , Xia Meng , Guo Ensong , Li Na , Lu Hao , Shan Wanying , Wu Yifan , Li Yuan , Xu Xiaoyan , Weng Danhui , Meng Li , Hu Junbo , Gao Qinglei , Ma Ding , Chen Gang
Published: February 2019

Ovarian carcinoma is caused by multiple factors, but its etiology associated with microbes and infection is unknown. Using 16S rRNA high-throughput sequencing methods, the diversity and composition of the microbiota from ovarian cancer tissues (25 samples) and normal distal fallopian tube tissues (25 samples) were analyzed. High-throughput sequencing showed that the diversity and richness indexes were significantly decreased in ovarian cancer tissues compared to tissues from normal distal fallopian tubes. The ratio of the two phyla for Proteobacteria/Firmicutes was notably increased in ovarian cancer, which revealed that microbial composition change might be associated with the process of ovarian cancer development. In addition, transcriptome-sequencing (RNA-seq) analyses suggested that the transcriptional profiles were statistically different between ovarian carcinoma and normal distal fallopian tubes. Moreover, a set of genes including 84 different inflammation-associated or immune-associated genes, which had been named as the human antibacterial-response genes were also modulated expression. Therefore, we hypothesize that the microbial composition change, as a novel risk factor, may be involving the initiation and progression of ovarian cancer via influencing and regulating the local immune microenvironment of fallopian tubes except for regular pathways.
Plasmodium falciparum histidine-rich protein (PfHRP2 and 3) diversity in Western and Coastal Kenya
Authors: Nderu David , Kimani Francis , Thiong’o Kelvin , Karanja Evaline , Akinyi Maureen , Too Edwin , Chege William , Nambati Eva , Meyer Christian G. , Velavan Thirumalaisamy P.
Published: February 2019

Plasmodium falciparum histidine-rich proteins 2 (PfHRP2) based RDTs are advocated in falciparum malaria-endemic regions, particularly when quality microscopy is not available. However, diversity and any deletion in the pfhrp2 and pfhrp3 genes can affect the performance of PfHRP2-based RDTs. A total of 400 samples collected from uncomplicated malaria cases from Kenya were investigated for the amino acid repeat profiles in exon 2 of pfhrp2 and pfhrp3 genes. In addition, PfHRP2 levels were measured in 96 individuals with uncomplicated malaria. We observed a unique distribution pattern of amino acid repeats both in the PfHRP2 and PfHRP3. 228 PfHRP2 and 124 PfHRP3 different amino acid sequences were identified. Of this, 214 (94%) PfHRP2 and 81 (65%) PfHRP3 amino acid sequences occurred only once. Thirty-nine new PfHRP2 and 20 new PfHRP3 amino acid repeat types were identified. PfHRP2 levels were not correlated with parasitemia or the number of PfHRP2 repeat types. This study shows the variability of PfHRP2, PfHRP3 and PfHRP2 concentration among uncomplicated malaria cases. These findings will be useful to understand the performance of PfHRP2-based RDTs in Kenya.
Gaze training supports self-organization of movement coordination in children with developmental coordination disorder
Authors: Słowiński Piotr , Baldemir Harun , Wood Greg , Alizadehkhaiyat Omid , Coyles Ginny , Vine Samuel , Williams Genevieve , Tsaneva-Atanasova Krasimira , Wilson Mark
Published: February 2019

Children with developmental coordination disorder (DCD) struggle with the acquisition of coordinated motor skills. This paper adopts a dynamical systems perspective to assess how individual coordination solutions might emerge following an intervention that trained accurate gaze control in a throw and catch task. Kinematic data were collected from six upper body sensors from twenty-one children with DCD, using a 3D motion analysis system, before and after a 4-week training intervention. Covariance matrices between kinematic measures were computed and distances between pairs of covariance matrices calculated using Riemannian geometry. Multidimensional scaling was then used to analyse differences between coordination patterns. The gaze trained group revealed significantly higher total coordination (sum of all the pairwise covariances) following training than a technique-trained control group. While the increase in total coordination also significantly predicted improvement in task performance, the distinct post-intervention coordination patterns for the gaze trained group were not consistent. Additionally, the gaze trained group revealed individual coordination patterns for successful catch attempts that were different from all the coordination patterns before training, whereas the control group did not. Taken together, the results of this interdisciplinary study illustrate how gaze training may encourage the emergence of coordination via self-organization in children with DCD.
Culturable endophytic fungal communities associated with plants in organic and conventional farming systems and their effects on plant growth
Authors: Xia Ye , Sahib Mohammad Radhi , Amna Amna , Opiyo Stephen Obol , Zhao Zhenzhen , Gao Yu Gary
Published: February 2019

As compared to organic farming system, conventional farming system relies on higher inputs of synthetic agrochemicals, which may reduce the abundance, diversity, and beneficial effects of plant endophytic fungal communities. This study compares the diversity and abundance of culturable endophytic fungal communities associated with four plant species –corn, tomato, pepper, and watermelon grown in separate organic and conventional fields. In all, 740 fungal isolates were identified, of which 550 were from the organic fields and 190 from the conventional ones. These fungal isolates were grouped into eight orders and 22 species, with the two most abundant species being Trichoderma sp. and Pichia guilliermondi. The fungal species diversity and abundance were both significantly higher in the organic than in the conventional fields. All the isolated endophytic fungi improved tomato plants’ shoot growth and biomass significantly, as compared with the water control. Six fungal isolates also exhibited activity that enhanced tomato fruit yields. These results suggest that these endophytic fungi might be a considerable boost to sustainable agricultural production, while also reducing the agricultural application of chemicals and thus benefiting the environment and human health.
Extreme sediment fluxes in a dryland flash flood
Authors: Hooke J. M.
Published: February 2019

A flash flood on 28th September, 2012, rose to a peak discharge of 2357 m3 s−1 from zero within one hour in the ephemeral Nogalte channel in SE Spain. Channel morphology and sediment sizes were measured at existing monitored sites before and after the flood and peak flow hydraulics calculated from surveyed floodmarks and cross-sections. Maximum peak sediment fluxes were calculated as ~600 kg s−1 m−1, exceeding maximum published, measured dryland channel values by 10 times and common perennial stream fluxes by 100 times. These high fluxes fit the established simple bedload flux - shear stress relations for dryland channels very well, but now extended over a much wider data range. The high sediment fluxes are corroborated by deposits at >1 m height in a channel-side tank, with 90 mm diameter sediment carried in suspension, by transport of large blocks and by massive net aggradation as extensive, structureless channel bars. Very high sediment supply and rapid hydrograph rise and recession produced the conditions for these exceptional sediment dynamics. The results demonstrate the extreme sediment loads that may occur in dryland flash floods and have major implications for catchment and channel management.
Local agro-pastoralists’ perspectives on forage species diversity, habitat distributions, abundance trends and ecological drivers for sustainable livestock production in West Africa
Authors: Naah John-Baptist S. N. , Braun Boris
Published: February 2019

Despite the importance of local ecological knowledge of forage plants, there has been little discussion on how local agro-pastoralists perceive forage species diversity, abundance trends, habitat distributions and ecological drivers influencing changing abundance trends over time in rural West Africa’s savannas. In estimating, assessing and investigating the ecological variables, we performed elaborate ethnobotanical surveys in seven villages in northern Ghana and nine villages in southern-central Burkina Faso. Data were analyzed using descriptive statistics, bivariate correlation analysis and cognitive salience index calculations to disentangle the dynamics of local responses to ecological variables considered in this study. Our results revealed that agro-pastoralists exhibited extensive knowledge on forage species diversity, habitat types, abundance trends and ecological drivers. According to agro-pastoralists interviewed, about 82 percent of all forage species known to them were commonly available in local landscapes, while a majority of our interviewees indicated that available forage resources have shown a gradually increasing trend over the past few years. Rainfall variability, tree cutting and drought were the topmost perceived threats causing changes in the trends of forage species abundance. Given our findings, local perceptions of agro-pastoralists could have substantial practical implications in favor of forage-related biodiversity conservation and sustainable livestock production.