SUBCLINICAL HYPOTHYROIDISM—Recognition and Treatment

Often patients in whom there is little to suggest myxedema or cretinism have subclinical hypothyroidism. Once the condition is suspected, it can be diagnosed by determination of protein-bound iodine and, if the PBI is low, by response to therapy with thyroid hormone.Patients in the following categories should have protein-bound iodine determination: Those having (1) a history of previous treatment for hypothyroidism; (2) suboptimal development in children; (3) ovarian dysfunction, infertility, habitual abortion or unusual menopausal disorders; (4) symptoms of malaise and debility, such as undue fatigue, somnolence, mental asthenia and anxiety; (5) unexplained anemia; (6) colloid goiter, adenomatous goiter and cancer of the thyroid gland.If hypothyroidism is diagnosed, administration of thyroid hormone in increasing amounts, as determined by serial serum PBI tests, should be carried out indefinitely. Instruction of the patient is essential.     

Recognition versus identity — the role of biometrics

The distinction between the recognition of an individual using an automated biometric system and the fundamental notion of their identity is subtle and therefore provokes much debate relating to privacy and other societal issues. This article seeks to clarify some of these issues relating to biometric recognition and identity by providing a framework, and by distinguishing between the technology and societal issues.     

How Does Individual Recognition Evolve? Comparing Responses to Identity Information in Polistes Species with and Without Individual Recognition

A wide range of complex social behaviors are facilitated by the recognition of individual conspecifics. Individual recognition requires sufficient phenotypic variation to provide identity information as well as receivers that process and respond to identity information. Understanding how a complex trait such as individual recognition evolves requires that we consider how each component has evolved. Previous comparative studies have examined phenotypic variability in senders and receiver learning abilities, although little work has compared receiver responses to identity information among related species with and without individual recognition. Here, we compare responses to identity information in two Polistes paper wasps: P. fuscatus, which visually recognizes individuals, and P. metricus, which does not normally show evidence of individual recognition. Although the species differ in individual recognition, the results of this study show that receiver responses to experimentally manipulated identity information are surprisingly similar in both species. Receivers direct less aggression toward identifiable individuals than unidentifiable individuals. Therefore, the responses necessary for individual recognition may pre‐date its evolution in the P. fuscatus lineage. Additionally, our data demonstrate the apparent binary differences in a complex behavior between the two species, such as individual recognition, likely involve incremental differences along a number of axes.     

Why is Real-World Visual Object Recognition Hard?

Progress in understanding the brain mechanisms underlying vision requires the construction of computational models that not only emulate the brain's anatomy and physiology, but ultimately match its performance on visual tasks. In recent years, “natural” images have become popular in the study of vision and have been used to show apparently impressive progress in building such models. Here, we challenge the use of uncontrolled “natural” images in guiding that progress. In particular, we show that a simple V1-like model—a neuroscientist's “null” model, which should perform poorly at real-world visual object recognition tasks—outperforms state-of-the-art object recognition systems (biologically inspired and otherwise) on a standard, ostensibly natural image recognition test. As a counterpoint, we designed a “simpler” recognition test to better span the real-world variation in object pose, position, and scale, and we show that this test correctly exposes the inadequacy of the V1-like model. Taken together, these results demonstrate that tests based on uncontrolled natural images can be seriously misleading, potentially guiding progress in the wrong direction. Instead, we reexamine what it means for images to be natural and argue for a renewed focus on the core problem of object recognition—real-world image variation.     

Does Sleep Really Influence Face Recognition Memory?

Mounting evidence implicates sleep in the consolidation of various kinds of memories. We investigated the effect of sleep on memory for face identity, a declarative form of memory that is indispensable for nearly all social interaction. In the acquisition phase, observers viewed faces that they were required to remember over a variable retention period (0–36 hours). In the test phase, observers viewed intermixed old and new faces and judged seeing each before. Participants were classified according to acquisition and test times into seven groups. Memory strength (d′) and response bias (c) were evaluated. Substantial time spent awake (12 hours or more) during the retention period impaired face recognition memory evaluated at test, whereas sleep per se during the retention period did little to enhance the memory. Wakefulness during retention also led to a tightening of the decision criterion. Our findings suggest that sleep passively and transiently shelters face recognition memory from waking interference (exposure) but does not actively aid in its long-term consolidation.     

Recognition of nuclear targeting signals by Karyopherin-β proteins

The Karyopherin-β family of nuclear transport factors mediates the majority of nucleocytoplasmic transport. Although each of the 19 Karyopherin-βs transports unique sets of cargos, only three classes of nuclear localization and export signals, or NLSs and NESs, have been characterized. The short basic classical-NLS was first discovered in the 1980s and their karyopherin-bound structures were first reported more than 10 years ago. More recently, structural and biophysical studies of Karyopherin-β2-cargo complexes led to definition of the complex and diverse PY-NLS. Structural knowledge of the leucine-rich NES is finally available more than 10 years after the discovery of its recognition by the exportin CRM1. We review recent findings relating to how these three classes of nuclear targeting signals are recognized by their Karyopherin-β nuclear transport factors.     

Recognition of HIV-TAR RNA using neomycin–benzimidazole conjugates

Synthesis of a novel class of compounds and their biophysical studies with TAR-RNA are presented. The synthesis of these compounds was achieved by conjugating neomycin, an aminoglycoside, with benzimidazoles modeled from a B-DNA minor groove binder, Hoechst 33258. The neomycin–benzimidazole conjugates have varying linkers that connect the benzimidazole and neomycin units. The linkers of varying length (5–23 atoms) in these conjugates contain one to three triazole units. The UV thermal denaturation experiments showed that the conjugates resulted in greater stabilization of the TAR-RNA than either neomycin or benzimidazole used in the synthesis of conjugates. These results were corroborated by the FID displacement and tat-TAR inhibition assays. The binding of ligands to the TAR-RNA is affected by the length and composition of the linker. Our results show that increasing the number of triazole groups and the linker length in these compounds have diminishing effect on the binding to TAR-RNA. Compounds that have shorter linker length and fewer triazole units in the linker displayed increased affinity towards the TAR RNA.     

Recognition of Non-α-amino Substrates by Pyrrolysyl-tRNA Synthetase

Pyrrolysyl-tRNA synthetase (PylRS), an aminoacyl-tRNA synthetase (aaRS) recently found in some methanogenic archaea and bacteria, recognizes an unusually large lysine derivative, l-pyrrolysine, as the substrate, and attaches it to the cognate tRNA (tRNA^Pyl). The PylRS-tRNA^Pyl pair interacts with none of the endogenous aaRS-tRNA pairs in Escherichia coli, and thus can be used as a novel aaRS-tRNA pair for genetic code expansion. The crystal structures of the Methanosarcina mazei PylRS revealed that it has a unique, large pocket for amino acid binding, and the wild type M. mazei PylRS recognizes the natural lysine derivative as well as many lysine analogs, including N^?-(tert-butoxycarbonyl)-l-lysine (Boc-lysine), with diverse side chain sizes and structures. Moreover, the PylRS only loosely recognizes the α-amino group of the substrate, whereas most aaRSs, including the structurally and genetically related phenylalanyl-tRNA synthetase (PheRS), strictly recognize the main chain groups of the substrate. We report here that wild type PylRS can recognize substrates with a variety of main-chain α-groups: α-hydroxyacid, non-α-amino-carboxylic acid, N_α-methyl-amino acid, and d-amino acid, each with the same side chain as that of Boc-lysine. In contrast, PheRS recognizes none of these amino acid analogs. By expressing the wild type PylRS and its cognate tRNA^Pyl in E. coli in the presence of the α-hydroxyacid analog of Boc-lysine (Boc-LysOH), the amber codon (UAG) was recoded successfully as Boc-LysOH, and thus an ester bond was site-specifically incorporated into a protein molecule. This PylRS-tRNA^Pyl pair is expected to expand the backbone diversity of protein molecules produced by both in vivo and in vitro ribosomal translation.     

How Does the Brain Solve Visual Object Recognition?

Mounting evidence suggests that 'core object recognition,' the ability to rapidly recognize objects despite substantial appearance variation, is solved in the brain via a cascade of reflexive, largely feedforward computations that culminate in a powerful neuronal representation in the inferior temporal cortex. However, the algorithm that produces this solution remains poorly understood. Here we review evidence ranging from?individual neurons and neuronal populations to behavior and computational models. We propose that understanding this algorithm will require using neuronal and psychophysical data to sift through many computational models, each based on building blocks of small, canonical subnetworks with a common functional goal.     

MTH1 Substrate Recognition—An Example of Specific Promiscuity

MTH1 (NUDT1) is an oncologic target involved in the prevention of DNA damage. We investigate the way MTH1 recognises its substrates and present substrate-bound structures of MTH1 for 8-oxo-dGTP and 8-oxo-rATP as examples of novel strong and weak binding substrate motifs. Investigation of a small set of purine-like fragments using 2D NMR resulted in identification of a fragment with weak potency. The protein-ligand X-Ray structure of this fragment provides insight into the role of water molecules in substrate selectivity. Wider fragment screening by NMR resulted in three new protein structures exhibiting alternative binding configurations to the key Asp-Asp recognition element of the protein. These inhibitor binding modes demonstrate that MTH1 employs an intricate yet promiscuous mechanism of substrate anchoring through its Asp-Asp pharmacophore. The structures suggest that water-mediated interactions convey selectivity towards oxidized substrates over their non-oxidised counterparts, in particular by stabilization of a water molecule in a hydrophobic environment through hydrogen bonding. These findings may be useful in the design of inhibitors of MTH1.     

Nuclear import by karyopherin-βs: Recognition and inhibition

Proteins in the karyopherin-β family mediate the majority of macromolecular transport between the nucleus and the cytoplasm. Eleven of the 19 known human karyopherin-βs and 10 of the 14 S. cerevisiae karyopherin-βs mediate nuclear import through recognition of nuclear localization signals or NLSs in their cargos. This receptor-mediated process is essential to cellular viability as proteins are translated in the cytoplasm but many have functional roles in the nucleus. Many known karyopherin-β-cargo interactions were discovered through studies of the individual cargos rather than the karyopherins, and this information is thus widely scattered in the literature. We consolidate information about cargos that are directly recognized by import-karyopherin-βs and review common characteristics or lack thereof among cargos of different import pathways. Knowledge of karyopherin-β-cargo interactions is also critical for the development of nuclear import inhibitors and the understanding of their mechanisms of inhibition. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import.     

Recognition of RNA duplex by a neomycin–Hoechst 33258 conjugate

DNA minor groove binding drugs such as Hoechst 33258 have been shown to bind to a number of RNA structures. Similarly, RNA binding ligands such as neomycin have been shown by us to bind to a number of A-form DNA structures. A neomycin–Hoechst 33258 conjugate was recently shown to bind B-DNA, where Hoechst exhibits high affinity for the minor groove of A/T tract DNA and neomycin docks into the major groove. Further studies now indicate that the Hoechst moiety of the conjugate can be driven to bind RNA duplex as a consequence of neomycin binding in the RNA major groove. This is the first example of Hoechst 33258 binding to RNA duplex not containing bulges or loop motifs.     

Mate Recognition: Should Fly Stay or Should Fly Go?

Recent studies have shown that male fruit flies use close-range olfactory cues to assess the status of potential mating partners. The presence of a volatile, male-derived pheromone can suppress the default male behavioral state of courting females.     

Recognition of β-hairpin motifs in proteins by using the composite vector

A composite vector method for predicting β-hairpin motifs in proteins is proposed by combining the score of matrix, increment of diversity, the value of distance and auto-correlation information to express the information of sequence. The prediction is based on analysis of data from 3,088 non-homologous protein chains including 6,035 β-hairpin motifs and 2,738 non-β-hairpin motifs. The overall accuracy of prediction and Matthew’s correlation coefficient are 83.1% and 0.59, respectively. In addition, by using the same methods, the accuracy of 80.7% and Matthew’s correlation coefficient of 0.61 are obtained for other dataset with 2,878 non-homologous protein chains, which contains 4,884 β-hairpin motifs and 4,310 non-β-hairpin motifs. Better results are also obtained in the prediction of the β-hairpin motifs of proteins by analysis of the CASP6 dataset.     

Molecular Basis for the Recognition of Long-chain Substrates by Plant α-Glucosidases

Sugar beet α-glucosidase (SBG), a member of glycoside hydrolase family 31, shows exceptional long-chain specificity, exhibiting higher k_cat/K_m values for longer malto-oligosaccharides. However, its amino acid sequence is similar to those of other short chain-specific α-glucosidases. To gain structural insights into the long-chain substrate recognition of SBG, a crystal structure complex with the pseudotetrasaccharide acarbose was determined at 1.7 Å resolution. The active site pocket of SBG is formed by a (β/α)₈ barrel domain and a long loop (N-loop) bulging from the N-terminal domain similar to other related enzymes. Two residues (Phe-236 and Asn-237) in the N-loop are important for the long-chain specificity. Kinetic analysis of an Asn-237 mutant enzyme and a previous study of a Phe-236 mutant enzyme demonstrated that these residues create subsites +2 and +3. The structure also indicates that Phe-236 and Asn-237 guide the reducing end of long substrates to subdomain b2, which is an additional element inserted into the (β/α)₈ barrel domain. Subdomain b2 of SBG includes Ser-497, which was identified as the residue at subsite +4 by site-directed mutagenesis.