Adaptive control of movement deceleration during saccades

As you read this text, your eyes make saccades that guide your fovea from one word to the next. Accuracy of these movements require the brain to monitor and learn from visual errors. A current model suggests that learning is supported by two different adaptive processes, one fast (high error sensitivity, low retention), and the other slow (low error sensitivity, high retention). Here, we searched for signatures of these hypothesized processes and found that following experience of a visual error, there was an adaptive change in the motor commands of the subsequent saccade. Surprisingly, this adaptation was not uniformly expressed throughout the movement. Rather, after experience of a single error, the adaptive response in the subsequent trial was limited to the deceleration period. After repeated exposure to the same error, the acceleration period commands also adapted, and exhibited resistance to forgetting during set-breaks. In contrast, the deceleration period commands adapted more rapidly, but suffered from poor retention during these same breaks. State-space models suggested that acceleration and deceleration periods were supported by a shared adaptive state which re-aimed the saccade, as well as two separate processes which resembled a two-state model: one that learned slowly and contributed primarily via acceleration period commands, and another that learned rapidly but contributed primarily via deceleration period commands.     

The structure of dopamine induced α-synuclein oligomers

Inclusions of aggregated α-synuclein (α-syn) in dopaminergic neurons are a characteristic histological marker of Parkinson’s disease (PD). In vitro, α-syn in the presence of dopamine (DA) at physiological pH forms SDS-resistant non-amyloidogenic oligomers. We used a combination of biophysical techniques, including sedimentation velocity analysis, small angle X-ray scattering (SAXS) and circular dichroism spectroscopy to study the characteristics of α-syn oligomers formed in the presence of DA. Our SAXS data show that the trimers formed by the action of DA on α-syn consist of overlapping worm-like monomers, with no end-to-end associations. This lack of structure contrasts with the well-established, extensive β-sheet structure of the amyloid fibril form of the protein and its pre-fibrillar oligomers. We propose on the basis of these and earlier data that oxidation of the four methionine residues at the C- and N-terminal ends of α-syn molecules prevents their end-to-end association and stabilises oligomers formed by cross linking with DA-quinone/DA-melanin, which are formed as a result of the redox process, thus inhibiting formation of the β-sheet structure found in other pre-fibrillar forms of α-syn.     

Seasonal variability of diurnal in-stream nitrate concentration oscillations under hydrologically stable conditions

Seasonal and diurnal variations of in-stream NO₃-N concentration oscillations were studied through high-frequency measurements of streamwater’s physical, chemical parameters (in-stream NO₃-N concentration, water temperature, dissolved oxygen, pH) and hydrometeorological variables (stream discharge, solar radiation) under hydrologically stable conditions. The study was carried out in 2006, within the 42 km² forested Pade? stream watershed in the southwestern part of Slovenia, which is characterized by distinctive hydrogeological settings (flysch) and climate conditions (transitional area between the Mediterranean and continental climate). Fine temporal data resolution (15-min interval) enabled identification of the factors responsible for seasonal variability in the diurnal pattern of the streamwater NO₃-N concentrations versus seasonal and diurnal behavior of meteorological and other water chemistry constituents. The observed seasonal variability of in-stream NO₃-N daily oscillations indicates the important role of primary production uptake, particularly during seasons when deciduous vegetation is dormant and light levels in the stream are high. Highest daily NO₃-N concentration amplitudes (0.3 mg/l-N) and daily changes in the NO₃-N flux (0.4–0.5 g/s-N) were observed in spring; the NO₃-N concentration oscillations in summer showed a considerably smaller effect of the in-stream uptake (maximum NO₃-N daily concentration amplitude 0.1 mg/l-N; daily change in the NO₃-N flux 0.02 g/s-N). Seasonal shifts in the timing of daily maximum (up to 6 h) and minimum NO₃-N concentrations (between 1 and 3 h) provided some additional indications of seasonal changes in the in-stream primary production uptake and its relation to the terrestrial component of the forested watershed.     

Physiologically-based pharmacokinetic modelling for the reduction of animal use in the discovery of novel pharmaceuticals

The challenges of physiologically-based pharmacokinetic (PBPK) modelling and approaches to replacing the use of animals, in order to determine drug pharmacokinetics, are discussed. Reference is made to the limitations of in vivo animal studies in drug discovery. In particular, the ways in which animal studies contribute to drug attrition during the post-preclinical phase of testing are considered.     

The Fowler Syndrome-Associated Protein FLVCR2 Is an Importer of Heme

Mutations in FLVCR2, a cell surface protein related by homology and membrane topology to the heme exporter/retroviral receptor FLVCR1, have recently been associated with Fowler syndrome, a vascular disorder of the brain. We previously identified FLVCR2 to function as a receptor for FY981 feline leukemia virus (FeLV). However, the cellular function of FLVCR2 remains unresolved. Here, we report the cellular function of FLVCR2 as an importer of heme, based on the following observations. First, FLVCR2 binds to hemin-conjugated agarose, and binding is competed by free hemin. Second, mammalian cells and Xenopus laevis oocytes expressing FLVCR2 display enhanced heme uptake. Third, heme import is reduced after the expression of FLVCR2-specific small interfering RNA (siRNA) or after the binding of the FY981 FeLV envelope protein to the FLVCR2 receptor. Finally, cells overexpressing FLVCR2 are more sensitive to heme toxicity, a finding most likely attributable to enhanced heme uptake. Tissue expression analysis indicates that FLVCR2 is expressed in a broad range of human tissues, including liver, placenta, brain, and kidney. The identification of a cellular function for FLVCR2 will have important implications in elucidating the pathogenic mechanisms of Fowler syndrome and of phenotypically associated disorders.Membrane transporters play essential roles in cellular homeostasis by importing substrates critical for cell growth and differentiation or by exporting substrates that cause toxicity. There are five major categories of membrane transporters consisting of over 550 transporter superfamilies (41). The major facilitator superfamily (MFS) is the largest and most diverse superfamily, consisting of over 10,000 members (31, 41). Transporters in this superfamily consist of 12 to 14 transmembrane (TM)-spanning segments and transport substrates as diverse as sugars, polyols, drugs, neurotransmitters, amino acids, organic/inorganic ions, and peptides (31). Recently, a disruption of MFS transporters that is associated with human diseases has been described, further confirming their role in the maintenance of normal cell homeostasis. The DIRC2 MFS transporter (substrate transported unknown) is disrupted in renal cell carcinoma cosegregating with a t(2;3)(q35;q21) chromosomal translocation (4). Mutations in the thiamine transporter THTR1 have been shown to be responsible for Rogers syndrome (14, 21), a thiamine-responsive megaloblastic anemia. We have recently reported that a disruption in the heme exporter FLVCR1 (MFSD7B) plays a role in Diamond Blackfan anemia (DBA) (40), a fatal infant anemia characterized by a block in erythroid progenitor cell development (3, 12, 13). The abrogation of FLVCR1 function in primary human hematopoietic stem cells (40) or in a human erythroid cell line (37) specifically disrupts erythropoiesis, mimicking the hematological features observed for patients with DBA. We have reported previously that FLVCR1 is disrupted not as a consequence of mutations in the FLVCR1 coding region but due to the aberrant splicing of specific FLVCR1 exons that reduces the expression and cell surface localization of the encoded FLVCR1 protein (40). Interestingly, the THTR1 and FLVCR1 proteins were shown previously to function as receptors for entry by feline leukemia retrovirus (FeLV) subgroup A (FeLV-A) (25) and FeLV-C (36, 46), respectively. These viruses disrupt the cellular function of these proteins in infected cats and can induce diseases that correlate with Rogers syndrome (17) and DBA (1, 28).Recently, mutations in the cell surface protein FLVCR2 (MFSD7C), an MFS transporter member, have been shown to be associated with Fowler syndrome (22, 26), a proliferative vascular disorder of the brain (16). A previous study (6) suggested that FLVCR2 functions as a calcium-chelate transporter based on its expression in murine and human tissues involved in calcium homeostasis. We have shown previously that FLVCR2 is highly related to the heme exporter/retroviral receptor FLVCR1 (7), and we have recently shown it to function as a receptor for the subgroup C FeLV variant FY981 (42). Based on its close sequence relationship to the heme exporter/retroviral receptor FLVCR1 and based on previous reports showing that retroviruses often adapt to use closely related cell surface proteins as receptors for infection (27, 30, 44), we investigated the heme transport function of FLVCR2. Here, we show the physiological function of FLVCR2 as an importer of heme.     

Laying the foundations for a new classification of Agaonidae (Hymenoptera: Chalcidoidea), a multilocus phylogenetic approach

A phylogeny of the Agaonidae (Chalcidoidea) in their restricted sense, pollinators of Ficus species (Moraceae), is estimated using 4182 nucleotides from six genes, obtained from 101 species representing 19 of the 20 recognized genera, and four outgroups. Data analysed by parsimony and Bayesian inference methods demonstrate that Agaonidae are monophyletic and that the previous classification is not supported. Agaonidae are partitioned into four groups: (i) Tetrapus, (ii) Ceratosolen + Kradibia, (iii) some Blastophaga + Wiebesia species, and (iv) all genera associated with monoecious figs and a few Blastophaga and Wiebesia. The latter group is subdivided into subgroups: (i) Pleistodontes, (ii) Blastophaga psenes and neocaledonian Dolichoris, (iii) some Blastophaga and Wiebesia species, and (iv) Platyscapa, all afrotropical genera and all genera associated with section Conosycea. Eleven genera were recovered as monophyletic, six were para‐ or polyphyletic, and two cannot be tested with our data set. Based on our phylogeny we propose a new classification for the Agaonidae. Two new subfamilies are proposed: Tetrapusiinae for the genus Tetrapus, and Kradibiinae for Ceratosolen + Kradibia. Liporrhopalum is synonymized with Kradibia and the subgenus Valisia of Blastophaga is elevated to generic rank. These changes resulted in 36 new combinations. Finally, we discuss the hypothesis of co‐speciation between the pollinators and their host species by comparing the two phylogenies. © The Willi Hennig Society 2009.