Embodied Anomaly Resolution in Molecular Genetics: A Case Study of RNAi

Scientific anomalies are observations and facts that contradict current scientific theories and they are instrumental in scientific theory change. Philosophers of science have approached scientific theory change from different perspectives as Darden (Theory change in science: Strategies from Mendelian genetics, 1991) observes: Lakatos (In: Lakatos, Musgrave (eds) Criticism and the growth of knowledge, 1970) approaches it as a progressive “research programmes” consisting of incremental improvements (“monster barring” in Lakatos, Proofs and refutations: The logic of mathematical discovery, 1976), Kuhn (The structure of scientific revolutions, 1996) observes that changes in “paradigms” are instigated by a crisis from some anomaly, and Hanson (In: Feigl, Maxwell (eds) Current issues in the philosophy of science, 1961) proposes that discovery does not begin with hypothesis but with some “problematic phenomena requiring explanation”. Even though anomalies are important in all of these approaches to scientific theory change, there have been only few investigations into the specific role anomalies play in scientific theory change. Furthermore, much of these approaches focus on the theories themselves and not on how the scientists and their experiments bring about scientific change (Gooding, Experiment and the making of meaning: Human agency in scientific observation and experiment, 1990). To address these issues, this paper approaches scientific anomaly resolution from a meaning construction point of view. Conceptual integration theory (Fauconnier and Turner, Cogn Sci 22:133–187, 1996; The way we think: Conceptual blending and mind’s hidden complexities, 2002) from cognitive linguistics describes how one constructs meaning from various stimuli, such as text and diagrams, through conceptual integration or blending. The conceptual integration networks that describe the conceptual integration process characterize cognition that occurs unconsciously during meaning construction. These same networks are used to describe some of the cognition while resolving an anomaly in molecular genetics called RNA interference (RNAi) in a case study. The RNAi case study is a cognitive-historical reconstruction (Nersessian, In: Giere (ed) Cognitive models of science, 1992) that reconstructs how the RNAi anomaly was resolved. This reconstruction traces four relevant molecular genetics publications in describing the cognition necessary in accounting for how RNAi was resolved through strategies (Darden 1991), abductive reasoning (Peirce, In: Hartshorne, Weiss (eds) Collected papers, 1958), and experimental reasoning (Gooding 1990). The results of the case study show that experiments play a crucial role in formulating an explanation of the RNAi anomaly and the integration networks describe the experiments’ role. Furthermore, these results suggest that RNAi anomaly resolution is embodied. It is embodied in a sense that cognition described in the cognitive-historical reconstruction is experientially based.

Bacterial peptide deformylase inhibitor PMT analogs inhibit cancer cell growth by interacting with human peptide deformylase

Potent inhibitors of human peptide deformylase （HsPDF） were screened using known PMT analog inhibi- tors of bacterial peptide deformylase. Forty-three species of PMT analogs that are non-peptidyl bacterial PDF inhibitors like actinonin were selected using virtual screening GOLD. Ten species out of 43 that could bind to HsPDF were selected and their antitumor activities were tested. Among them, four species （PMT-172, PMT-173, PMT-199, and PMT-201） showed excellent growth inhibition of cancer cell in the MTT assay. HsPDF-PMT binding was confirmed through a 1H-CPMG-T2 filter NMR experiment leading to a significant change in peak intensity for PMT-172 and PMT-199. These results suggest that PMT analogs could possibly interact with HsPDF and be a novel anticancer drug candidate.     

The role of Drosophila Piezo in mechanical nociception

Transduction of mechanical stimuli by receptor cells is essential for senses such as hearing, touch and pain. Ion channels have a role in neuronal mechanotransduction in invertebrates; however, functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, no mechanoreceptor potential C (NOMPC), a member of transient receptor potential (TRP) ion channel family, acts as a mechanotransducer in Drosophila melanogaster and Caenorhabditis elegans; however, it has no orthologues in mammals. Degenerin/epithelial sodium channel (DEG/ENaC) family members are mechanotransducers in C. elegans and potentially in D. melanogaster; however, a direct role of its mammalian homologues in sensing mechanical force has not been shown. Recently, Piezo1 (also known as Fam38a) and Piezo2 (also known as Fam38b) were identified as components of mechanically activated channels in mammals. The Piezo family are evolutionarily conserved transmembrane proteins. It is unknown whether they function in mechanical sensing in vivo and, if they do, which mechanosensory modalities they mediate. Here we study the physiological role of the single Piezo member in D. melanogaster (Dmpiezo; also known as CG8486). Dmpiezo expression in human cells induces mechanically activated currents, similar to its mammalian counterparts. Behavioural responses to noxious mechanical stimuli were severely reduced in Dmpiezo knockout larvae, whereas responses to another noxious stimulus or touch were not affected. Knocking down Dmpiezo in sensory neurons that mediate nociception and express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of Dmpiezo in these same neurons rescued the phenotype of the constitutive Dmpiezo knockout larvae. Accordingly, electrophysiological recordings from ppk-positive neurons revealed a Dmpiezo-dependent, mechanically activated current. Finally, we found that Dmpiezo and ppk function in parallel pathways in ppk-positive cells, and that mechanical nociception is abolished in the absence of both channels. These data demonstrate the physiological relevance of the Piezo family in mechanotransduction in vivo, supporting a role of Piezo proteins in mechanosensory nociception.     

Restoration of vision after transplantation of photoreceptors

Cell transplantation is a potential strategy for treating blindness caused by the loss of photoreceptors. Although transplanted rod-precursor cells are able to migrate into the adult retina and differentiate to acquire the specialized morphological features of mature photoreceptor cells, the fundamental question remains whether transplantation of photoreceptor cells can actually improve vision. Here we provide evidence of functional rod-mediated vision after photoreceptor transplantation in adult Gnat1?/? mice, which lack rod function and are a model of congenital stationary night blindness. We show that transplanted rod precursors form classic triad synaptic connections with second-order bipolar and horizontal cells in the recipient retina. The newly integrated photoreceptor cells are light-responsive with dim-flash kinetics similar to adult wild-type photoreceptors. By using intrinsic imaging under scotopic conditions we demonstrate that visual signals generated by transplanted rods are projected to higher visual areas, including V1. Moreover, these cells are capable of driving optokinetic head tracking and visually guided behaviour in the Gnat1?/? mouse under scotopic conditions. Together, these results demonstrate the feasibility of photoreceptor transplantation as a therapeutic strategy for restoring vision after retinal degeneration.     

红松体细胞胚胎培养技术体系的建立

以5个红松家系未成熟合子胚为材料,首次建立了红松体细胞胚胎(somaticembryo,SE)培养体系,为红松人工种子培育苗及基因转化奠定了基础实验表明:在GLH培养基上黑暗培养约6周后,5个红松家系未成熟胚的SE诱导率分别为46.31%、28.2%、26.57%、17.81%、9.652% 红松遗传类型、合子胚发育程度对SE诱导率影响均达到极显著的水平;遗传类型和合子胚发育程度之间的交互作用达到极显著水平,但合子胚发育程度与培养基类型间、遗传类型与培养基类型之间的交互作用不显著     

AHP在高校办学规模决策分析中的应用

介绍AHP在高校办学规模决策分析中的应用,给出了一种标度AHP相对重要性的新方法,并通过实例验证了此方法优于原有的标度法。     

Robust digital receiver for EPC sensor network

A robust digital receiver based on a matched filter (MF) is proposed for the radio frequency identification (RFID) reader system to enhance the reliability of signal processing in the electronic product code (EPC) sensor network (ESN). The performance of the proposed receiver is investigated by examining the anti-collision algorithm in the EPC global Class1 Generation2 protocol. The validity and usefulness are demonstrated by both computer simulations and experiments. Based on the verification  results, comparing with the conventional zero crossing detector (ZCD) based receiver, the proposed receiver is very robust against strong amplitude distortions and considerable frequency deviations happening on the backscattered signal from a passive tag.     

Human papillomavirus 16 E5 up-regulates the expression of vascular endothelial growth factor through the activation of epidermal growth factor receptor, MEK/ ERK1,2 and PI3K/Akt

The E5 oncoprotein of human papillomavirus (HPV) 16 plays an important role in early cervical carcinogenesis. Vascular endothelial growth factor (VEGF) plays a central role in switching on the angiogenic phenotype during early cervical carcinogenesis. However, the relationship between E5 and VEGF has not previously been examined. To clarify the regulatory role of E5 in VEGF expression, we transferred the E5 gene into various cell types. E5 increased VEGF expression. The addition of epidermal growth factor receptor (EGFR) inhibitor significantly suppressed VEGF expression, demonstrating that E5 stimulates VEGF expression through the activation of EGFR. E5-mediated EGFR activation was accompanied by phosphorylation of Akt and ERK1/2, which are also involved in VEGF expression. Furthermore, the mRNA stability of VEGF was not affected by E5, but VEGF promoter activity could be modulated by inhibitors of the EGFR, MEK-ERK1/2 and PI3K/Akt pathways in E5-expressing cells. Collectively, these novel results suggest that HPV 16 E5 increases VEGF expression by activating EGFR, MEK/ERK1/2 and PI3K/Akt. Received 23 November 2005; received after revision 10 January 2006; accepted 9 February 2006     

Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10(-8)) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10(-31) and P = 1.3 × 10(-35) for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.     

eIF2A,an initiator tRNA carrier refractory to eIF2α kinases,functions synergistically with eIF5B

The initiator tRNA (Met-tRNA _i ^Met ) at the P site of the small ribosomal subunit plays an important role in the recognition of an mRNA start codon. In bacteria, the initiator tRNA carrier, IF2, facilitates the positioning of Met-tRNA _i ^Met on the small ribosomal subunit. Eukarya contain the Met-tRNA _i ^Met carrier, eIF2 (unrelated to IF2), whose carrier activity is inhibited under stress conditions by the phosphorylation of its α-subunit by stress-activated eIF2α kinases. The stress-resistant initiator tRNA carrier, eIF2A, was recently uncovered and shown to load Met-tRNA _i ^Met on the 40S ribosomal subunit associated with a stress-resistant mRNA under stress conditions. Here, we report that eIF2A interacts and functionally cooperates with eIF5B (a homolog of IF2), and we describe the functional domains of eIF2A that are required for its binding of Met-tRNA _i ^Met , eIF5B, and a stress-resistant mRNA. The results indicate that the eukaryotic eIF5B–eIF2A complex functionally mimics the bacterial IF2 containing ribosome-, GTP-, and initiator tRNA-binding domains in a single polypeptide.