The Extensive (but Fragile) Authority of the WTO Appellate Body

The authority of an international court (IC) is not necessarily evolutionary and its development unidirectional. This article addresses the authority of the Appellate Body (AB) of the World Trade Organization (WTO) and shows how it rapidly and almost immediately became extensive, but has since exhibited signs of becoming more fragile. The article applies a typology of IC authority developed by Alter, Helfer and Madsen (2014) and explains the transformation from narrow authority (a dispute resolution venue under the GATT based on political negotiations) to extensive authority (a judicialized WTO dispute settlement system with a sophisticated case law) and presents empirical indicators of the rise of the AB’s authority. Such rapid development of extensive authority is arguably a unique case in international politics at the multilateral level. That authority nonetheless remains fragile, and shows signs that it could decline significantly for reasons we explain.

Hit proteins, mitochondria and cancer

The histidine triad (HIT) superfamily comprises proteins that share the histidine triad motif, His-ϕ-His-ϕ-His-ϕ-ϕ, where ϕ is a hydrophobic amino acid. HIT proteins are ubiquitous in prokaryotes and eukaryotes. HIT proteins bind nucleotides and exert dinucleotidyl hydrolase, nucleotidylyl transferase or phosphoramidate hydrolase enzymatic activity. In humans, 5 families of HIT proteins are recognized. The accumulated epidemiological and experimental evidence indicates that two branches of the superfamily, the HINT (Histidine Triad Nucleotide Binding) members and FHIT (Fragile Histidine Triad), have tumor suppressor properties but a conclusive physiological role can still not be assigned to these proteins. Aprataxin forms another discrete branch of the HIT superfamily, is implicated in DNA repair mechanisms and unlike the HINT and FHIT members, a defective protein can be conclusively linked to a disease, ataxia with oculomotor apraxia type 1. The scavenger mRNA decapping enzyme, DcpS, forms a fourth branch of the HIT superfamily. Finally, the GalT enzymes, which exert specific nucleoside monophosphate transferase activity, form a fifth branch that is not implicated in tumorigenesis. The molecular mechanisms by which the HINT and FHIT proteins participate in bioenergetics of cancer are just beginning to be unraveled. Their purported actions as tumor suppressors are highlighted in this review.

Mainstreaming a Decade's Experiences in Watershed Management to Meet the Challenges of Environmental Change in the Hindu Kush-Himalayas

Like other mountain areas in the world, the Hindu Kush-Himalayan (HKH) region is particularly vulnerable to climate change. Ongoing climate change processes are projected to have a high impact on the HKH region, and accelerated warming has been reported in the Himalayas. These climate change impacts will be superimposed on a variety of other environmental and social stresses, adding to the complexity of the issues. The sustainable use of natural resources is crucial to the long-term stability of the fragile mountain ecosystems in the HKH and to sustain the socio-ecological resilience that forms the basis of sustainable livelihoods in the region. In order to be prepared for these challenges, it is important to take stock of previous research. The ‘People and Resource Dynamics Project’ (PARDYP), implemented by International Centre for Integrated Mountain Development (ICIMOD), provides a variety of participatory options for sustainable land management in the HKH region. The PARDYD project was a research for development project that operated in five middle mountain watersheds across the HKH – two in Nepal and one each in China, India, and Pakistan. The project ran from 1996 to 2006 and focused on addressing the marginalisation of mountain farmers, the use and availability of water, issues relating to land and forest degradation and declining soil fertility, the speed of regeneration of degraded land, and the ability of the natural environment to support the growing needs of the region’s increasing population. A key learning from the project was that the opinion of land users is crucial to the acceptance (and, therefore, successful application) of new technologies and approaches. A major challenge at the end of every project is to promote knowledge sharing and encourage the cross-fertilization of ideas (e.g., in the case of PARDYP, with other middle mountain inhabitants and practitioners in the region) and to share lessons learned with a wider audience. This paper will highlight how the PARDYP findings, including ways of addressing soil fertility and water scarcity, have been mainstreamed in the HKH region through capacity building (international, regional, and national training courses), networking, and the provision of backstopping services. In addition, in view of the challenges in watershed management in the HKH connected to environmental change, the lessons learned from the PARDYP are now being used by ICMOD to define and package climate change proof technology options to address climate change adaptation.

Cerebellar disorders in childhood: cognitive problems

Over the last decade, increasing evidence of cognitive functions of the cerebellum during development and learning processes could be ascertained. Posterior fossa malformations such as cerebellar hypoplasia or Joubert syndrome are known to be related to developmental problems in a marked to moderate extent. More detailed analyses reveal special deficits in attention, processing speed, visuospatial functions, and language. A study about Dandy Walker syndrome states a relationship of abnormalities in vermis lobulation with developmental problems. Further lobulation or volume abnormalities of the cerebellum and/or vermis can be detected in disorders as fragile X syndrome, Downs's syndrome, William's syndrome, and autism. Neuropsychological studies reveal a relation of dyslexia and attention deficit disorder with cerebellar functions. These functional studies are supported by structural abnormalities in neuroimaging in these disorders. Acquired cerebellar or vermis atrophy was found in groups of children with developmental problems such as prenatal alcohol exposure or extreme prematurity. Also, focal lesions during childhood or adolescence such as cerebellar tumor or stroke are related with neuropsychological abnormalities, which are most pronounced in visuospatial, language, and memory functions. In addition, cerebellar atrophy was shown to be a bad prognostic factor considering cognitive outcome in children after brain trauma and leukemia. In ataxia teleangiectasia, a neurodegenerative disorder affecting primarily the cerebellar cortex, a reduced verbal intelligence quotient and problems of judgment of duration are a hint of the importance of the cerebellum in cognition. In conclusion, the cerebellum seems to play an important role in many higher cognitive functions, especially in learning. There is a suggestion that the earlier the incorrect influence, the more pronounced the problems.

Properties of an injectable low modulus PMMA bone cement for osteoporotic bone

The use of polymethylmethacrylate (PMMA) cement to reinforce fragile or broken vertebral bodies (vertebroplasty) leads to extensive bone stiffening. Fractures in the adjacent vertebrae may be the consequence of this procedure. PMMA with a reduced Young's modulus may be more suitable. The goal of this study was to produce and characterize stiffness adapted PMMA bone cements. Porous PMMA bone cements were produced by combining PMMA with various volume fractions of an aqueous sodium hyaluronate solution. Porosity, Young's modulus, yield strength, polymerization temperature, setting time, viscosity, injectability, and monomer release of those porous cements were investigated. Samples presented pores with diameters in the range of 25-260 microm and porosity up to 56%. Young's modulus and yield strength decreased from 930 to 50 MPa and from 39 to 1.3 MPa between 0 and 56% porosity, respectively. The polymerization temperature decreased from 68 degrees C (0%, regular cement) to 41 degrees C for cement having 30% aqueous fraction. Setting time decreased from 1020 s (0%, regular cement) to 720 s for the 30% composition. Viscosity of the 30% composition (145 Pa s) was higher than the ones received from regular cement and the 45% composition (100-125 Pa s). The monomer release was in the range of 4-10 mg/mL for all porosities; showing no higher release for the porous materials. The generation of pores using an aqueous gel seems to be a promising method to make the PMMA cement more compliant and lower its mechanical properties to values close to those of cancellous bone.

Eosinophilic esophagitis: analysis of food impaction and perforation in 251 adolescent and adult patients

BACKGROUND ; AIMS: Eosinophilic esophagitis is a rapidly emerging, chronic inflammatory disorder. Prolonged inflammation evokes structural alterations and a fragile esophageal wall prone to perforation/rupture and food impaction. This report assesses the risk of spontaneously arising and procedure-induced complications and proposes practical recommendations. METHODS: The Swiss Esophageal Esophagitis Database documented 251 confirmed cases. A chart review identified which patients had required endoscopic bolus removal and/or experienced transmural esophageal perforation/rupture. In addition, a MEDLINE search for "eosinophilic esophagitis" with "esophageal perforation" or "esophageal rupture" was undertaken. RESULTS: During an 18-year period, 87 patients (34.7%) experienced 134 food impactions requiring flexible (124, 92.5%) or rigid (10, 7.5%) endoscopic bolus removal. Transmural perforation occurred in 20% (2/10) of rigid procedures, and 1 esophageal rupture (Boerhaave's syndrome) was observed. CONCLUSIONS: Bolus removal by rigid endoscopy is a high-risk procedure and should be avoided in eosinophilic esophagitis patients who require a gentler approach. Whether food impaction and esophageal wall remodeling can be prevented with anti-inflammatory medication is still undetermined. All Boerhaave's syndrome cases should be evaluated for underlying eosinophilic esophagitis.

A Missense Mutation in the SERPINH1 Gene in Dachshunds with Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a hereditary disease occurring in humans and dogs. It is characterized by extremely fragile bones and teeth. Most human and some canine OI cases are caused by mutations in the COL1A1 and COL1A2 genes encoding the subunits of collagen I. Recently, mutations in the CRTAP and LEPRE1 genes were found to cause some rare forms of human OI. Many OI cases exist where the causative mutation has not yet been found. We investigated Dachshunds with an autosomal recessive form of OI. Genotyping only five affected dogs on the 50 k canine SNP chip allowed us to localize the causative mutation to a 5.82 Mb interval on chromosome 21 by homozygosity mapping. Haplotype analysis of five additional carriers narrowed the interval further down to 4.74 Mb. The SERPINH1 gene is located within this interval and encodes an essential chaperone involved in the correct folding of the collagen triple helix. Therefore, we considered SERPINH1 a positional and functional candidate gene and performed mutation analysis in affected and control Dachshunds. A missense mutation (c.977C>T, p.L326P) located in an evolutionary conserved domain was perfectly associated with the OI phenotype. We thus have identified a candidate causative mutation for OI in Dachshunds and identified a fifth OI gene.

Dynamics of supercooled water in highly compacted clays studied by neutron scattering

The freezing behavior of water confined in compacted charged and uncharged clays (montmorillonite in Na-and Ca-forms, illite in Na-and Ca-forms, kaolinite and pyrophyllite) was investigated by neutron scattering. Firstly, the amount of frozen (immobile) water was measured as a function of temperature at the IN16 backscattering spectrometer, Institute Laue-Langevin (ILL). Water in uncharged, partly hydrophobic (kaolinite) and fully hydrophobic (pyrophyllite) clays exhibited a similar freezing and melting behavior to that of bulk water. In contrast, water in charged clays which are hydrophilic could be significantly supercooled. To observe the water dynamics in these clays, further experiments were performed using quasielastic neutron scattering. At temperatures of 250, 260 and 270 K the diffusive motion of water could still be observed, but with a strong reduction in the water mobility as compared with the values obtained above 273 K. The diffusion coefficients followed a non-Arrhenius temperature dependence well described by the Vogel-Fulcher-Tammann and the fractional power relations. The fits revealed that Na-and Ca-montmorillonite and Ca-illite have similar Vogel-Fulcher-Tammann temperatures (T-VFT, often referred to as the glass transition temperature) of similar to 120 K and similar temperatures at which the water undergoes the 'strong-fragile' transition, T-s similar to 210 K. On the other hand, Na-illite had significantly larger values of T-VFT similar to 180 K and T-s similar to 240 K. Surprisingly, Ca-illite has a similar freezing behavior of water to that of montmorillonites, even though it has a rather different structure. We attribute this to the stronger hydration of Ca ions as compared with the Na ions occurring in the illite clays.

Carbon sequestration in community forests: trade-offs, multiple outcomes and institutional diversity in the Bolivian Amazon

Carbon sequestration in community forests presents a major challenge for the Reducing Emissions from Deforestation and Forest Degradation (REDD+) programme. This article uses a comparative analysis of the agricultural and forestry practices of indigenous peoples and settlers in the Bolivian Amazon to show how community-level institutions regulate the trade-offs between community livelihoods, forest species diversity, and carbon sequestration. The authors argue that REDD+ implementation in such areas runs the risk of: 1) reinforcing economic inequalities based on previous and potential land use impacts on ecosystems (baseline), depending on the socio-cultural groups targeted; 2) increasing pressure on land used for food production, possibly reducing food security and redirecting labour towards scarce off-farm income opportunities; 3) increasing dependence on external funding and carbon market fluctuations instead of local production strategies; and 4) further incentivising the privatization and commodification of land to avoid transaction costs associated with collective property rights. The article also advises against taking a strictly economic, market-based approach to carbon sequestration, arguing that such an approach could endanger fragile socio-ecological systems. REDD+ schemes should directly support existing efforts towards forest sustainability rather than simply compensating local land users for avoiding deforestation and forest degradation

Genetic Engineering of Induced Pluripotent Stem Cells and Reprogramming to Motor Neurons to Elucidate Selective Motor Neuron Death in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, fatal within 1 to 5 years after onset of symptoms. About 3 out of 100’000 persons are diagnosed with ALS and there is still no cure available [1, 2]. 95% of all cases occur sporadically and the aetiology remains largely unknown [XXXX]. However, up to now 16 genes were identified to play a role in the development of familial ALS. One of these genes is FUS that encodes for the protein fused in sarcoma/translocated in liposarcoma (FUS/TLS). Mutations in this gene are responsible for some cases of sporadic as well as of inherited ALS [3]. FUS belongs to the family of heterogeneous nuclear ribonucleoproteins and is predicted to be involved in several cellular functions like transcription regulation [4], RNA splicing [5, 6], mRNA transport in neurons [7] and microRNA processing [8]. Aberrant accumulation of mutated FUS has been found in the cytoplasm of motor neurons from ALS patients [9]. The mislocalization of FUS is based on a mutation in the nuclear localization signal of FUS [10]. However, it is still unclear if the cytoplasmic localization of FUS leads to a toxic gain of cytoplasmic function and/or a loss of nuclear function that might be crucial in the course of ALS. The goal of this project is to characterize the impact of ALS-associated FUS mutations on in vitro differentiated motor neurons. To this end, we edit the genome of induced pluripotent stem cells (iPSC) using transcription activator-like effector nucleases (TALENs) [11,12] to create three isogenic cell lines, each carrying an ALS-associated FUS mutation (G156E, R244C and P525L). These iPSC’s will then be differentiated to motor neurons according to a recently establishe protocol (Ref Wichterle) and serve to study alterations in the transcriptome, proteome and metabolome upon the expression of ALS-associated FUS. With this approach, we hope to unravel the molecular mechanism leading to FUS-associated ALS and to provide new insight into the emerging connection between misregulation of RNA metabolism and neurodegeneration, a connection that is currently implied in a variety of additional neurological diseases, including spinocerebellar ataxia 2 (SCA-2), spinal muscular atrophy (SMA), fragile X syndrome, and myotonic dystrophy.

Genetic Engineering of Induced Pluripotent Stem Cells and Reprogramming to Motor Neurons to Elucidate Selective Motor Neuron Death in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, fatal within 1 to 5 years after onset of symptoms. About 3 out of 100’000 persons are diagnosed with ALS and there is still no cure available [1, 2]. 95% of all cases occur sporadically and the aetiology remains largely unknown [3]. However, up to now 16 genes were identified to play a role in the development of familial ALS. One of these genes is FUS that encodes for the protein fused in sarcoma (FUS). Mutations in this gene are responsible for some cases of sporadic as well as of inherited ALS [4]. FUS belongs to the family of heterogeneous nuclear ribonucleoproteins and is predicted to be involved in several cellular functions like transcription regulation, RNA splicing, mRNA transport in neurons and microRNA processing [5] Aberrant accumulation of mutated FUS has been found in the cytoplasm of motor neurons from ALS patients [6]. The mislocalization of FUS is based on a mutation in the nuclear localization signal of FUS [7]. However, it is still unclear if the cytoplasmic localization of FUS leads to a toxic gain of cytoplasmic function and/or a loss of nuclear function that might be crucial in the course of ALS. The goal of this project is to characterize the impact of ALS-associated FUS mutations on in vitro differentiated motor neurons. To this end, we edit the genome of induced pluripotent stem cells (iPSC) using transcription activator-like effector nucleases (TALENs) [8,9] to create three isogenic cell lines, each carrying an ALS-associated FUS mutation (G156E, R244C and P525L). These iPSC’s will then be differentiated to motor neurons according to a recently established protocol [10] and serve to study alterations in the transcriptome, proteome and metabolome upon the expression of ALS-associated FUS. With this approach, we hope to unravel the molecular mechanism leading to FUS-associated ALS and to provide new insight into the emerging connection between misregulation of RNA metabolism and neurodegeneration, a connection that is currently implied in a variety of additional neurological diseases, including spinocerebellar ataxia 2 (SCA-2), spinal muscular atrophy (SMA), fragile X syndrome, and myotonic dystrophy. [1] Cleveland, D.W. et al. (2001) Nat Rev Neurosci 2(11): 806-819 [2] Sathasivam, S. (2010) Singapore Med J 51(5): 367-372 [3] Schymick, J.C. et al. (2007) Hum Mol Genet Vol 16: 233-242 [4] Pratt, A.J. et al. (2012). Degener Neurol Neuromuscul Dis 2012(2): 1-14 [5] Lagier-Tourenne, C. Hum Mol Genet, 2010. 19(R1): p. R46-64 [6] Mochizuki, Y. et al. (2012) J Neurol Sci 323(1-2): 85-92 [7] Dormann, D. et al. (2010) EMBO J 29(16): 2841-2857 [8] Hockemeyer, D. et al. (2011) Nat Biotech 29(8): 731-734 [9] Joung, J.K. and J.D. Sander (2013) Nat Rev Mol Cell Biol 14(1): 49-55 [10]Amoroso, M.W. et al. (2013) J Neurosci 33(2): 574-586.

Can eye movements bias memory recall?

A large body of research suggests that when we retrieve visual information from memory, we look back to the location where we encoded these objects. It has been proposed that the oculomotor trace we act out during encoding is stored in long-term memory, along other contents of the episodic representation. If memory recall triggers the eyes to revisit the location where the stimulus was encoded, is there also an effect in the reverse direction? Can eye movements trigger memory recall? In Experiment 1 participants encoded two faces at two different locations on the computer screen. Then, the average face (morph) of these two faces appeared in either of the two encoding locations and participants had to indicate whether it resembles more the first or second face. In Experiment 2 the morph appeared in a new location, but participants had to repeat one of the oculomotor traces that was used during encoding. Participants’ morph perception was influenced both by the location and the eye-movement it was presented with. Our results suggest that eye-movements can bias memory recall, but only in a short-lasting and rather fragile way.

Bounded Seas: Island Parsing Without Shipwrecks

Imprecise manipulation of source code (semi-parsing) is useful for tasks such as robust parsing, error recovery, lexical analysis, and rapid development of parsers for data extraction. An island grammar precisely defines only a subset of a language syntax (islands), while the rest of the syntax (water) is defined imprecisely. Usually, water is defined as the negation of islands. Albeit simple, such a definition of water is naive and impedes composition of islands. When developing an island grammar, sooner or later a programmer has to create water tailored to each individual island. Such an approach is fragile, however, because water can change with any change of a grammar. It is time-consuming, because water is defined manually by a programmer and not automatically. Finally, an island surrounded by water cannot be reused because water has to be defined for every grammar individually. In this paper we propose a new technique of island parsing - bounded seas. Bounded seas are composable, robust, reusable and easy to use because island-specific water is created automatically. We integrated bounded seas into a parser combinator framework as a demonstration of their composability and reusability.

Probing the effect of minor groove interactions on the catalytic efficiency of DNAzymes 8–17 and 10–23

DNAzymes (Dz) 8–17 and 10–23 are two widely studied and well-characterized RNA-cleaving DNA catalysts. In an effort to further improve the understanding of the fragile interactions and dynamics of the enzymatic mechanism, this study examines the catalytic efficiency of minimally modified DNAzymes. Five single mutants of Dz8–17 and Dz10–23 were prepared by replacing the adenine residues in the corresponding catalytic cores with 3-deazaadenine units. Kinetic assays were used to assess the effect on the catalytic activity and thereby identify the importance of hydrogen bonding that arises from the N3 atoms. The results suggest that modifications at A15 and A15.0 of Dz8–17 have a significant influence and show a reduction in catalytic activity. Modification at each location in Dz10–23 results in a decrease of the observed rate constants, with A12 appearing to be the most affected with a reduction of ∼80% of kobs and ∼25% of the maximal cleavage rate compared to the wild-type DNAzyme. On the other hand, modification of A12 in Dz8–17 showed an ∼130% increase in kobs, thus unraveling a new potential site for the introduction of chemical modifications. A pH-profile analysis showed that the chemical cleavage step is rate-determining, regardless of the presence and/or location of the mutation. These findings point towards the importance of the N3-nitrogens of certain adenine nucleotides located within the catalytic cores of the DNAzymes for efficient catalytic activity and further suggest that they might directly partake in maintaining the appropriate tertiary structure. Therefore, it appears that minor groove interactions constitute an important feature of DNAzymes as well as ribozymes.