Search PubMed⌕ Search

Biomedical subjects

J Jiang

Publications and source records attributed to J Jiang.

At least 55 records · Page 3Linked to original sources

Enhanced in vitro maturation of subcultivated fetal human hepatocytes in three dimensional culture using poly-L-lactic acid scaffolds in the presence of oncostatin M.

Fetal human liver cell fractions, which contain large numbers of hepatocyte progenitors, have high proliferation potential in vitro. To create an engineered liver tissue equivalent of a clinically significant size, however, repeated subcultivation and functional maturation are necessary in vitro. A commercially available human fetal liver cell fraction that was cultivated for some time in vitro has been reported to lose liver specific functions almost completely. We therefore investigated the effects of oncostatin M (OSM) and hepatocyte growth factor (HGF) in long-term three-dimensional (3D) culture using macroporous poly-L-lactic acid (PLLA) scaffolds on the restoration of such liver-specific functions of the fraction. 3D culture using PLLA scaffolds with OSM remarkably enhanced the albumin production and cytochrome P450 1A1/2 capacity with the culture time. HGF alone had no preferable effect on these functions even in 3D culture. Alpha-fetoprotein production was consistently suppressed in the 3D culture compared with that in monolayers. This suppression was not observed in the same types of culture of hepatocarcinoma Hep G2 cells. Despite these favorable observations on the 3D culture with OSM, the final attained functional levels at the 5th week were still over ten-times lower than those of Hep G2 cells when standardized with a cellular DNA amount. Although further improvement is needed for the complete functional restoration and maturation in vitro, these results demonstrate that a combination of 3D culture using PLLA scaffolds and OSM offers promising culture conditions for in vitro maturation of human hepatocyte progenitors.

Albumins↗

Identification of a 118-kb DNA fragment containing the locus of blast resistance gene Pi-2(t) in rice.

Rice blast disease, caused by the fungal pathogen Pyricularia grisea Sacc., is one of the most devastating crop diseases worldwide. Previous studies have shown that the dominant blast resistance gene Pi-2(t) confers resistance to a broad spectrum of pathogenic strains. Using a population of 292 recombinant inbred lines combined with bioinformatic analysis, we mapped Pi-2(t) between the SSR (simple-sequence repeat) marker SSR140 and the RFLP (restriction fragment length polymorphism) marker JSH12, 0.9 cM from both SSR140 and JSH12. A physical map consisting of six overlapping BAC (bacterial artificial chromosome) clones was anchored to the region containing the Pi-2(t) locus. By analyzing recombination events in this region, the Pi-2(t) locus was localized to a DNA fragment of 118 kb in length. The detailed genetic and physical maps of the Pi-2(t) locus will facilitate both molecular isolation of the gene and marker-assisted transfer of the gene in breeding programs.

Genes, Plant↗

Genome sequencing of a 239-kb region of rice chromosome 10L reveals a high frequency of gene duplication and a large chloroplast DNA insertion.

In this study we describe a 239-kb region on the long arm of rice chromosome 10 that contains a high density (71%) of locally duplicated genes, including 24 copies of a glutathione S-transferase gene. Intriguingly, embedded within this cluster is a large insertion (approximately 33 kb) of rice (Oryza sativa) chloroplast DNA that is derived from two separate regions of the chloroplast genome. We used DNA fiber-based fluorescence in situ hybridization (fiber-FISH) analyses of O. sativa spp. japonica nuclei to confirm that the insertion of organellar DNA was not a cloning artifact. The sequence of the chloroplast insertion is nearly identical (99.7% identity) to the corresponding regions in the published rice chloroplast genome sequence, suggesting that the transfer event occurred recently. PCR amplification and sequence analysis in two subspecies of rice, O. sativa spp. japonica and spp. indica, indicates that the transfer event predated the divergence of these two subspecies. The chloroplast insertion is flanked by a 2.1-kb perfect direct repeat that is unique to this location in the rice genome.

Base Sequence↗

Overexpression of kidney phosphatidylinositol 4-kinasebeta and phospholipase C(gamma1) proteins in two rodent models of polycystic kidney disease.

Our studies of renal phosphoinositide levels and metabolism in the pcy mouse with polycystic kidney disease (PKD) suggest that phosphatidylinositol kinase (PtdInsK) and phospholipase C (PLC) are elevated in this renal disorder. Therefore, the steady-state levels of select isoforms of these enzymes were examined in renal cytosolic and particulate (detergent-soluble) fractions in male and female normal and CD1-pcy/pcy (pcy) mice at 60, 120 and 180 days of age, and in male and female normal and diseased (Han:SPRD-cy) rats at 28 and 70 days of age. Disease-related increases in phosphatidylinositol 4-kinasebeta (PtdIns4Kbeta) and PLC(gamma1) levels were present in both models. PtdIns4Kbeta levels were higher by as much as 233% in pcy mice and by 95% in diseased Han:SPRD-cy rats compared to normals of the same age and gender. Steady-state levels of PLC(gamma1) were as much as 74% and 35% higher in pcy mice and diseased Han:SPRD-cy rats, respectively, compared to their controls. The consistency of these alterations in two accepted models of PKD indicates the importance of the phosphoinositide signalling pathway in the evolution of this disorder, and represents a potential site for therapeutic intervention.

1-Phosphatidylinositol 4-Kinase↗

Synthesis and characterization of uranyl compounds with iminodiacetate and oxydiacetate displaying variable denticity.

Eight uranyl compounds containing the dicarboxylate ligands iminodiacetate (IDA) or oxydiacetate (ODA) have been characterized in the solid state. The published polymeric structures for [UO(2)(C(4)H(6)NO(4))(2)] and [UO(2)(C(4)H(4)O(5))](n) have been confirmed, while Ba[UO(2)(C(4)H(5)NO(4))(2)] x 3H(2)O, [(CH(3))(2)NH(CH(2))(2)NH(CH(3))(2)][UO(2)(C(4)H(4)O(5))(2)] [orthorhombic space group Pnma, a = 10.996(5) A, b = 21.42(1) A, c = 8.700(3) A, Z = 4], and [C(2)H(5)NH(2)(CH(2))(2)NH(2)C(2)H(5)][UO(2)(C(4)H(4)O(5))(2)] [monoclinic space group P2(1)/n, a = 6.857(3) A, b = 9.209(5) A, c = 16.410(7) A, beta = 91.69(3), Z = 2] contain monomeric anions. The distance from the uranium atom to the central heteroatom (O or N) in the ligand varies. Crystallographic study shows that U-heteroatom (O/N) distances fall into two groups, one 2.6-2.7 A in length and one 3.1-3.2 A, the latter implying no bonding interaction. By contrast, EXAFS analysis of bulk samples suggests that either a long U-heteroatom (O/N) distance (2.9 A) or a range of distances may be present. Three possible structural types, two symmetric and one asymmetric, are identified on the basis of these results and on solid-state (13)C NMR spectroscopy. The two ligands in the complex can be 1,4,7-tridentate, giving five-membered rings, or 1,7-bidentate, to form an eight-membered ring. (C(4)H(12)N(2))[(UO(2))(2)(C(4)H(5)NO(4))(2)(OH)(2)] x 8H(2)O [monoclinic space group P2(1)/a, a = 7.955(9) A, b = 24.050(8) A, c = 8.223(6) A, beta = 112.24(6), Z = 2], (C(2)H(10)N(2))[(UO(2))(2)(C(4)H(5)NO(4))(2)(OH)(2)] x 4H(2)O, and (C(6)H(13)N(4))(2)[(UO(2))(2)(C(4)H(4)O(5))(2)(OH)(2)] x 2H(2)O [monoclinic space group C2/m, a = 19.024(9) A, b = 7.462(4) A, c = 2.467(6) A, beta = 107.75(4), Z = 4] have a dimeric structure with two capping tridentate ligands and two mu(2)-hydroxo bridges, giving edge-sharing pentagonal bipyramids.

Journal Article↗

A case-control study of childhood leukaemia and paternal occupational contact level in rural Sweden.

In a national case-control study in Sweden, we investigated whether in rural areas (where susceptible individuals are more prevalent than in urban areas) leukaemia risk was higher among the young children of fathers with many work contacts, as the infective hypothesis has predicted. A total of 1935 cases diagnosed in 1958-1998 together with 7736 age-matched (within 1 year) population controls (of whom 970 and 3880 respectively were aged 0-4) were linked to paternal occupational details as recorded in the census closest to the year of birth. Applying the two classifications of occupational contact level used in a study of rural Scotland, the odds ratios for children aged 0-4 years in the highest contact category (which includes teachers) in the most rural Swedish counties were 3.47 (95% CI 1.54, 7.85) and 1.59 (1.07, 2.38) respectively, relative to the medium and low (reference) category; no such excess was found in urban or intermediate counties. There was also a significant positive trend at ages 0-4 in the rural counties across the three levels of increasing occupational contact (P for trend 0.02 and 0.03, respectively), but again not in the urban or intermediate counties. No such effect or trend was found at ages 5-14 in any of the three county groupings. The findings confirm those of a recent study in rural Scotland, and also suggest that unusual population mixing (as occurred in Scotland as a result of the North Sea oil industry) is not a necessary requirement for the effect, since comparable mixing has not been a feature of rural Sweden.

Adolescent↗

Enhanced in vitro maturation of fetal mouse liver cells with oncostatin M, nicotinamide, and dimethyl sulfoxide.

Although cells isolated from fetal liver are one of the major sources for liver tissue engineering, it is still very difficult to induce them to fully differentiate in vitro into mature hepatocytes. We therefore investigated the effects of nicotinamide (NA), dimethyl sulfoxide (DMSO), and oncostatin M (OSM) on differentiation in terms of the expression of various liver-specific functions, because these factors have been reported to induce the emergence of possible hepatocyte progenitor cells (small hepatocytes) in adult rat hepatocyte culture or maturation of fetal mouse liver cells in culture. Fetal liver cells isolated from mouse embryos were cultured for 5 weeks in collagen-precoated plates. NA (10 mM) and DMSO (1%) remarkably enhanced the emergence of small hepatocytes, and OSM also synergistically enhanced the selective growth of small hepatocytes and inhibited the growth of blood cell populations. In the presence of these three factors, such small hepatocytes became dominant in culture, so that they covered almost 60-70% of confluence after week 2. In addition, some of them piled up over the small hepatocyte monolayer and displayed distinctively differentiated morphology, such as the emergence of binucleated cells, formation of tight gap junctions, and possible bile duct structures. Although OSM alone had very weak effects on hepatocyte functions, albumin secretion and cytochrome P450IA1/2 capacity were greatly enhanced when combined with NA or DMSO. This functional observation closely agreed with the emergence of small hepatocytes. In contrast, ammonium removal was strongly dependent on DMSO alone. DNA amount basis functions of fetal cells with three factors at week 5 were 1/7 for albumin secretion, 3 times higher for ammonium removal, and 1/10 for P450 capacity, compared with those of cultured adult mouse hepatocytes. These results show that inclusion of NA, DMSO, and OSM in the culture medium significantly enhances in vitro maturation of fetal liver cells when compared with conventional culture conditions.

Albumins↗

Identification of two novel human dynein light chain genes, DNLC2A and DNLC2B, and their expression changes in hepatocellular carcinoma tissues from 68 Chinese patients.

Two full-length cDNAs, DNLC2A and DNLC2B, were cloned and characterized. Their open reading frames respectively encode 96 amino acids which are most closely homologous to roadblock/LC7, one member of an ancient dynein light chain protein family, conserved in nematode, fruit fly, mouse and rat. The DNLC2A was expressed in 12 of 16 human tissues examined, with especially strong expression in heart, liver and brain, whereas there was weak expression in lung, prostate, testis, small intestine and colon. The expression of DNLC2B was generally high compared with that of DNLC2A except in liver. Northern blotting and/or semi-quantitative RT-PCR analysis examined the expression changes of DNLC2A and DNLC2B in 68 hepatocellular carcinoma tissue samples. It was revealed that DNLC2A was up-regulated (45 out of the 68 cases) while DNLC2B was down-regulated (44 out of 68 cases), compared with their adjacent tumor-free liver tissues. Interestingly, among the total 68 liver cancer samples tested, DNLC2A was up-regulated while DNLC2B was down-regulated in 28 cases; DNLC2A was up-regulated while no obvious change was observed for DNLC2B in 10 cases; no obvious change was observed for DNLC2A while DNLC2B was down-regulated in 14 cases. Although the underlying mechanism is not clear to date, the apparent up-regulation of DNLC2A and down-regulation of DNLC2B suggest that these genes might be involved in tumor progression. On the other hand, the different expression changes of the two homologous genes indicate that hepatocellular carcinomas are caused by different pathological mechanisms. In addition, DNLC2A was assigned to human chromosome 20q12-q13.11 near the marker D20S106 by radiation hybrid mapping.

Adult↗

[Clinical tolerance test of recombinant human thrombopoietin].

OBJECTIVE: To evaluate the safety of domestic recombinant human thrombopoietin (rhTPO) in human body and the its effects on hemogram and platelet function, and induction of anti-rhTPO antibody. METHODS: In the single dose tolerance test, twenty-seven healthy volunteers were randomly divided into 4 groups. rhTPO was injected subcutaneously at the doses of 0.25 microg/kg, 0.5 microg/kg, 1 microg/kg, and 2 microg/kg respectively. In the multiple dose tolerance test, 7 patients with non-Hodgkin lymphoma or acute leukemia after chemotherapy received rhTPO at the dose of 1.0 microg/kg for 7 - 14 days. The symptoms (if any), complete blood count, platelet aggregation test, serum chemistry, and anti-rhTPO antibody were followed serially. RESULTS: Out of the 27 healthy volunteers receiving single dose of rhTPO, one showed transient increase of body temperature to 37.4 degrees C six hours after the injection; one felt mild fatigue, anorexia, and somnolence the day after injection, and one showed transient elevation of alanine transminase (ALT) and asparate aminotransferase (AST) levels. Single dose administration of rhTPO at the doses of 0.5 microg/kg, 1.0 microg/kg, and 2.0 microg/kg was associated dose-dependently with 24% - 52% increase of platelet count, peaking at the day 14 and returning to the baseline Level by, day 21. No abnormality was observed in aggregation function when the platelet count peaked. Single dose administration of rhTPO showed no influence on red blood cells and white blood cells. In the multiple dose group, rhTPO at the dose of 1.0 microg x kg(-1) x d(-1) for 7 - 14 days was well tolerated by patients with hemotological malignancies. One patient developed transient slight elevation of serum ALT and AST. After the treatment with rhTPO, platelet counts increased to some extent in 4 patients. Low titer (1:5) of anti-rhTPO antibody was found transiently in one patient. CONCLUSION: A single bolus subcutanenous injection of 0.25 - 2.0 microg/kg rhTPO and daily subcutaneous injection of 1.0 microg/kg rhTPO for 7 - 14 days are well tolerated by human beings and without significant adverse effect. rhTPO increases peripheral platelet count and has no effect on aggregation function. Circulating anti-rhTPO antibody occurs after multiple administration of rhTPO. However, its clinical significance remains to be studied.

Acute Disease↗

Intravenous delivery of naked plasmid DNA for in vivo cytokine expression.

We previously demonstrated that electroporation-mediated cytokine gene delivery into muscle is an effective approach for long-term systemic delivery of cytokines. Here we show that hydrodynamics-based gene delivery into mice by intravenous administration of naked plasmid DNA is a more efficient procedure for expressing cytokines in vivo. A large volume of Ringer's solution containing an interleukin-10 (IL-10) expression plasmid pCAGGS-IL10 was rapidly injected into the tail vein of mice. Serum IL-10 levels increased in a dose-dependent manner with a saturation level (50.8 +/- 12.1 microg/ml) 10,000-fold higher than we obtained by the electroporation-mediated method. High levels of serum IL-10 were sustained for at least 2 weeks following a single injection. These results demonstrate that hydrodynamics-based gene delivery could induce sustained high-level expression of cytokines, which would be useful for further studies of cytokine function in vivo and the development of novel immunotherapeutic strategies for systemic cytokine gene therapy.

Animals↗

Synthesis, structure, spectroscopic properties, and electrochemistry of rare earth sandwich compounds with mixed 2,3-naphthalocyaninato and octaethylporphyrinato ligands.

A series of 14 heteroleptic rare earth sandwich complexes [M(III)-(nc)(oep)] (M=Y, La-Lu except Ce and Pm; nc=2,3-naphthalocyaninate; oep = octaethylporphyrinate) have been prepared by a one-pot procedure from corresponding [M(acac)3] . nH2O (acac = acetylacetonate), metal-free porphyrin H2(oep), and naphthalonitrile the presence of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in n-octanol. The molecular structures of four of these complexes (M = Sm, Gd, Y, Lu) are isostructural, exhibiting a slightly distorted square antiprismatic geometry with two domed ligands. The interplanar distance decreases from 2.823 to 2.646 A along the series as a result of lanthanide contraction. The whole series of complexes have also been characterized spectroscopically. All the electronic absorptions, except the two B-bands due to nc and the oep rings, are metal-dependent, indicating that there are substantial pi-pi interactions. The hole or the unpaired electron in these double-deckers is delocalized over both macrocyclic ligands, as evidenced by the co-appearance of the IR marker bands for the nc*- (1315-1325 cm(-1)) and oep*- (1510-1531 cm(-1)) T radical ions. Three one-electron oxidation couples and up to three one-electron reduction couples have been revealed by electrochemical methods. All the potentials are linearly dependent on the size of the metal center. The changes in absorption spectra during the first electro-oxidation and reduction of the La(III), Eu(III), and Y(III) double-deckers have also been studied spectroelectrochemically. The spectral data recorded for [M(III)(nc)(oep)]-(M = Y, La-Lu except Ce and Pm) reduced chemically with hydrazine hydrate are in accord with those obtained by spectroelectrochemical methods. The first heteroleptic naphthalocyaninate-containing triple-deckers [M(III)2(nc)-(oep)2] (M = Nd, Eu) have also been prepared by a raise-by-one-story method by using [M(III)(nc)(oep)] (M = Nd, Eu), [M(acac)3] . nH2O (M = Nd, Eu), and H2(oep) as starting materials. The compounds adopt a symmetrical triple-decker structure with two outer oep rings and one inner nc ring, which has been confirmed by 'H NMR spectroscopy and X-ray structural determination of the Nd complex. Both compounds give a near-IR absorption at 1021 nm (for M=Nd) or 1101 nm (for M = Eu), which has rarely been observed for neutral (or hole-free) triple-decker complexes and can be ascribed to the lowest-energy Q'(0, 0) transition. Similarly to the double-decker analogues. these triple-decker complexes undergo a series of one-electron transfer processes with a relatively small potential gap (1.1 -1.2 V) between the first oxidation and the first reduction.

Journal Article↗

Receptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis.

The p53 tumor suppressor protein is mutated in more than 50% of all human cancers, which makes the study of its functions and activities critical for the understanding and management of cancer. In response to cellular stresses, p53 is activated and can mediate cell cycle arrest and/or apoptosis via the upregulation of numerous target genes. Here, we have identified EphA2 as a target gene of the p53 family, that is, p53, p73, and p63. We also found that an increase of EphA2 transcript levels correlated with an increase of EphA2 protein expression, and induction of EphA2 in response to DNA damage corresponded with p53 activation. Furthermore, we identified a p53 response element located within the EphA2 promoter that is responsive to wild-type p53, p73, and p63, but not mutant p53. Interestingly, the ligand for EphA2, ephrin-A1, is also regulated by p53. EphA2 and ephrin-A1 are members of the Eph family of receptor tyrosine kinases and ligands, which are implicated in a number of developmental processes. To analyse the role of EphA2 in p53-mediated tumor suppression, we generated stable cell lines capable of expressing exogenous EphA2 in a tetracycline-repressible system. We found that EphA2 expression resulted in an increase in apoptosis. Thus, we hypothesize that the activated EphA2 may serve to impair anti-apoptotic signaling, perhaps by disrupting focal adhesions and thereby sensitize cells to pro-apoptotic stimuli.

Apoptosis↗

CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation.

Proper folding of proteins (either newly synthesized or damaged in response to a stressful event) occurs in a highly regulated fashion. Cytosolic chaperones such as Hsc/Hsp70 are assisted by cofactors that modulate the folding machinery in a positive or negative manner. CHIP (carboxyl terminus of Hsc70-interacting protein) is such a cofactor that interacts with Hsc70 and, in general, attenuates its most well characterized functions. In addition, CHIP accelerates ubiquitin-dependent degradation of chaperone substrates. Using an in vitro ubiquitylation assay with recombinant proteins, we demonstrate that CHIP possesses intrinsic E3 ubiquitin ligase activity and promotes ubiquitylation. This activity is dependent on the carboxyl-terminal U-box. CHIP interacts functionally and physically with the stress-responsive ubiquitin-conjugating enzyme family UBCH5. Surprisingly, a major target of the ubiquitin ligase activity of CHIP is Hsc70 itself. CHIP ubiquitylates Hsc70, primarily with short, noncanonical multiubiquitin chains but has no appreciable effect on steady-state levels or half-life of this protein. This effect may have heretofore unanticipated consequences with regard to the chaperoning activities of Hsc70 or its ability to deliver substrates to the proteasome. These studies demonstrate that CHIP is a bona fide ubiquitin ligase and indicate that U-box-containing proteins may comprise a new family of E3s.

Animals↗

p73 cooperates with DNA damage agents to induce apoptosis in MCF7 cells in a p53-dependent manner.

p73, a member of the p53 family, can induce apoptosis in cancer cells. Since p53-mediated apoptosis can be augmented by various cancer chemotherapeutic agents, it has been hypothesized that the status of the endogenous p53 gene in cancer cells is a key determinant in the outcome of cancer therapy. To determine whether p73 can sensitize cancer cells to apoptosis by DNA damage agents, several MCF7 adenocarcinoma cell lines that inducibly express p73 or p53 under a tetracycline-regulated promoter were generated. We found that at relevant physiological levels, p73, but not p53, is capable of sensitizing MCF7 cells to apoptosis induced by chemotherapeutic agents. In addition, we found that p73 can cooperate with the DNA damaging agent camptothecin to activate the initiator caspase 2. Furthermore, we found that p73 can cooperate with DNA damaging agents or p53 to induce some p53 target genes and activate their promoters. In contrast, in MCF7E6 cells that ectopically express the human papillomavirus E6 oncogene and are functionally p53-null, the ability of p73 to sensitize cells to apoptosis is abrogated. Taken together, these results suggest that a functional interaction between p53 and p73 in MCF7 cells leads to enhanced induction of apoptosis.

Adenocarcinoma↗

Cloning, expression patterns, and chromosome localization of three human and two mouse homologues of GABA(A) receptor-associated protein.

Type A receptors of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, contain alpha, beta, delta, gamma, and rho subunits. The gamma subunit has four subtypes: gamma1, gamma2, gamma3, andgamma4. GABA(A) receptor-associated protein (GABARAP) was previously demonstrated to act as a linker protein between microtubules and the gamma2 subunit of GABA(A) receptors. However, no other linker proteins have been identified as mediating the linkage of microtubules and the remaining subunits of GABA(A) receptors. In this study we identified three human paralogues (GABARAPL1, GABARAPL2, and GABARAPL3) and two mouse orthologues (Gabarapl1 and Gabarapl2) of human GABARAP, all of which encoded 117 amino acids, as does Gabarapl. The expression patterns of GABARAPL1, GABARAPL2, and GABARAP in 16 adult tissues showed that they were expressed ubiquitously. The expression levels of GABARAPL1 as a 2.3-kb transcript were very high in brain, heart, peripheral blood leukocytes, liver, kidney, placenta, and skeletal muscle, very low in thymus and small intestine, and moderate in other tissues tested. The unique 1.35-kb transcript of GABARAPL2 was expressed at high levels in heart, brain, testis, prostate, ovary, spleen, and skeletal muscle, at very low levels in lung, thymus, and small intestine, and moderately in other tissues tested. For GABARAP, a 1.3-kb transcript was abundantly expressed in all tested tissues with small variation. The expression patterns of Gabarapl1 and Gabarapl2 were similar to those of their counterparts in human. In addition, GABARAPL1 was localized to human chromosome 12p12.3 and GABARAPL2 to 16q22.3-q24.1 by RH mapping, while GABARAP and GABARAPL3 were found to be localized at chromosomes 17p13.2 and 15q25.1, respectively, by searching the related databases. Sequence comparison of the cDNAs and their corresponding genomic sequences shows that GABARAP, GABARAPL1, and GABARAPL2 are composed of four exons each, while GABARAPL3 is distributed only at one exon.

Adaptor Proteins, Signal Transducing↗