A structural interpretation of measurement and some related epistemological issues

Measurement is widely applied because its results are assumed to be more reliable than opinions and guesses, but this reliability is sometimes justified in a stereotyped way. After a critical analysis of such stereotypes, a structural characterization of measurement is proposed, as partly empirical and partly theoretical process, by showing that it is in fact the structure of the process that guarantees the reliability of its results. On this basis the role and the structure of background knowledge in measurement and the justification of the conditions of object-relatedness (“objectivity”) and subject-independence (“intersubjectivity”) of measurement are specifically discussed.     

Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity

Mutations in SPINK5, encoding the serine protease inhibitor LEKTI, cause Netherton syndrome, a severe autosomal recessive genodermatosis. Spink5(-/-) mice faithfully replicate key features of Netherton syndrome, including altered desquamation, impaired keratinization, hair malformation and a skin barrier defect. LEKTI deficiency causes abnormal desmosome cleavage in the upper granular layer through degradation of desmoglein 1 due to stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme-like hyperactivity. This leads to defective stratum corneum adhesion and resultant loss of skin barrier function. Profilaggrin processing is increased and implicates LEKTI in the cornification process. This work identifies LEKTI as a key regulator of epidermal protease activity and degradation of desmoglein 1 as the primary pathogenic event in Netherton syndrome.     

Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor

Changes in membrane potential affect ion channels and transporters, which then alter intracellular chemical conditions. Other signalling pathways coupled to membrane potential have been suggested but their underlying mechanisms are unknown. Here we describe a novel protein from the ascidian Ciona intestinalis that has a transmembrane voltage-sensing domain homologous to the S1-S4 segments of voltage-gated channels and a cytoplasmic domain similar to phosphatase and tensin homologue. This protein, named C. intestinalis voltage-sensor-containing phosphatase (Ci-VSP), displays channel-like 'gating' currents and directly translates changes in membrane potential into the turnover of phosphoinositides. The activity of the phosphoinositide phosphatase in Ci-VSP is tuned within a physiological range of membrane potential. Immunocytochemical studies show that Ci-VSP is expressed in Ciona sperm tail membranes, indicating a possible role in sperm function or morphology. Our data demonstrate that voltage sensing can function beyond channel proteins and thus more ubiquitously than previously realized.     

Amyloid-like fibrils of ribonuclease A with three-dimensional domain-swapped and native-like structure

Amyloid or amyloid-like fibrils are elongated, insoluble protein aggregates, formed in vivo in association with neurodegenerative diseases or in vitro from soluble native proteins, respectively. The underlying structure of the fibrillar or 'cross-beta' state has presented long-standing, fundamental puzzles of protein structure. These include whether fibril-forming proteins have two structurally distinct stable states, native and fibrillar, and whether all or only part of the native protein refolds as it converts to the fibrillar state. Here we show that a designed amyloid-like fibril of the well-characterized enzyme RNase A contains native-like molecules capable of enzymatic activity. In addition, these functional molecular units are formed from a core RNase A domain and a swapped complementary domain. These findings are consistent with the zipper-spine model in which a cross-beta spine is decorated with three-dimensional domain-swapped functional units, retaining native-like structure.     

Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity

Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.     

Mid-infrared images of beta Pictoris and the possible role of planetesimal collisions in the central disk

When viewed in optical starlight scattered by dust, the nearly edge-on debris disk surrounding the A5V star beta Pictoris (distance 19.3 pc; ref. 1) extends farther than 1,450 au from the star. Its large-scale complexity has been well characterized, but the detailed structure of the disk's central approximately 200-au region has remained elusive. This region is of special interest, because planets may have formed there during the star's 10-20-million-year lifetime, perhaps resulting in both the observed tilt of 4.6 degrees relative to the large-scale main disk and the partial clearing of the innermost dust. A peculiarity of the central disk (also possibly related to the presence of planets) is the asymmetry in the brightness of the 'wings', in which the southwestern wing is brighter and more extended at 12 microm than the northeastern wing. Here we present thermal infrared images of the central disk that imply that the brightness asymmetry results from the presence of a bright clump composed of particles that may differ in size from dust elsewhere in the disk. We suggest that this clump results from the collisional grinding of resonantly trapped planetesimals or the cataclysmic break-up of a planetesimal.     

Aspartate 338 contributes to the cationic specificity and to driver-amino acid coupling in the insect cotransporter KAAT1

To investigate the peculiar ionic specificity of KAAT1, an Na⁺- and K⁺-coupled amino acid cotransporter from Lepidoptera, a detailed analysis of membrane topology predictions was performed, together with sequence comparison with strictly Na⁺-dependent mammalian cotransporters from the same family. The analysis identified aspartate 338, a residue present also in the other cotransporter accepting K⁺ (CAATCH1), but absent in most mammalian transporters that have, instead, an asparagine in the corresponding position. Mutation of D338 in KAAT1 led either to non-functional transporters (D338G, D338C), or to an altered ionic selectivity (D338E, D338N), observable in uptake experiments and in electrophysiological properties. In particular, in D338E, the transport activity, while persisting in the presence of Na⁺, appeared to be completely abolished in the presence of K⁺. D338E also showed uncoupling between transport-associated current and uptake. The opposite mutation in the -aminobutyric acid transporter rGAT-1 (N327D) resulted in complete loss of function. In conclusion, aspartate 338 in KAAT1 appears to be important in allowing K⁺, in addition to Na⁺, to drive the transport mechanism, although other residues in different parts of the protein may also play a role in the complete determination of ionic selectivity.Received 23 September 2003; received after revision 11 November 2003; accepted 25 November 2003     

Science and technology for water purification in the coming decades

One of the most pervasive problems afflicting people throughout the world is inadequate access to clean water and sanitation. Problems with water are expected to grow worse in the coming decades, with water scarcity occurring globally, even in regions currently considered water-rich. Addressing these problems calls out for a tremendous amount of research to be conducted to identify robust new methods of purifying water at lower cost and with less energy, while at the same time minimizing the use of chemicals and impact on the environment. Here we highlight some of the science and technology being developed to improve the disinfection and decontamination of water, as well as efforts to increase water supplies through the safe re-use of wastewater and efficient desalination of sea and brackish water.