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Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism., Nature Communications, 12 (1), ISSN:2041-1723

Maternal exposure to microbes and other environmental factors is known to induce adaptive changes in the progeny, but little is understood about how development of the progeny is changed. We show thatCaenorhabditis elegansundergoes additional embryonic cell divisions in response to maternal gut microbes such as one producing the biopolymer γ-poly-DL-glutamic acid. The divisions coincide with anatomical changes including left-right asymmetric cell alignment, doubling the association between intestinal cells and primordial germ cells, and improved fecundity. The developmental changes are regulated by soma-to-germline transmission of endogenous RNAi and the miR-35 microRNA family, which targets the LIN-23/CDC-25 pathway. Our findings challenge the widespread assumption thatC. eleganshas an invariant cell lineage that consists of 959 somatic cells and provide insights into how organisms optimize embryogenesis to adapt to environmental changes through epigenetic controls.

We present new results on up to $6^{th}$ order cumulants of net baryon-number fluctuations at small values of the baryon chemical potential, $\mu_B$, obtained in lattice QCD calculations with physical values of light and strange quark masses. Representation of the Taylor expansions of higher order cumulants in terms of the ratio of the two lowest order cumulants, $M_B/\sigma_B^2=\chi_1^B(T,\mu_B)/\chi_2^B(T,\mu_B)$, allows for a parameter free comparison with data on net proton-number cumulants obtained by the STAR Collaboration in the Beam Energy Scan at RHIC. We show that recent high statistics data on skewness and kurtosis ratios of net proton-number distributions, obtained at beam energy $\sqrt{s_{_{NN}}}=54.4$ GeV, agree well with lattice QCD results on cumulants of net baryon-number fluctuations close to the pseudo-critical temperature, $T_{pc}(\mu_B)$, for the chiral transition in QCD. We also present first results from a next-to-leading order expansion of $5^{th}$ and $6^{th}$ order cumulants on the line of pseudo-critical temperatures., Comment: 13 pages, 11 figures, minor corrections and updates of references

We calculated the QCD equation of state using Taylor expansions that include contributions from up to sixth order in the baryon strangeness and electric charge chemical potentials. Calculations have been performed with the Highly Improved Staggered Quark action in the temperature range T epsilon [135 MeV 330 MeV] using up to four different sets of lattice cutoffs corresponding to lattices of size N sigma 3x N tau with aspect ratio N sigma/N tau = 4 and N tau=6-16. The strange quark mass is tuned to its physical value and we use two strange to light quark mass ratios ms/ml = 20 and 27 which in the continuum limit correspond to a pion mass of about 160 and 140 MeV respectively. Sixth order results for Taylor expansion coefficients are used to estimate truncation errors of the fourth order expansion. We show that truncation errors are small for baryon chemical potentials less then twice the temperature (mu(B) 0.9.

We calculated the QCD equation of state using Taylor expansions that include contributions from up to sixth order in the baryon, strangeness and electric charge chemical potentials. Calculations have been performed with the Highly Improved Staggered Quark action in the temperature range $T\in [135~{\rm MeV}, 330~{\rm MeV}]$ using up to four different sets of lattice cut-offs corresponding to lattices of size $N_��^3\times N_��$ with aspect ratio $N_��/N_��=4$ and $N_��=6-16$. The strange quark mass is tuned to its physical value and we use two strange to light quark mass ratios $m_s/m_l=20$ and $27$, which in the continuum limit correspond to a pion mass of about $160$ MeV and $140$ MeV espectively. Sixth-order results for Taylor expansion coefficients are used to estimate truncation errors of the fourth-order expansion. We show that truncation errors are small for baryon chemical potentials less then twice the temperature ($��_B\le 2T$). The fourth-order equation of state thus is suitable for the modeling of dense matter created in heavy ion collisions with center-of-mass energies down to $\sqrt{s_{NN}}\sim 12$ GeV. We provide a parametrization of basic thermodynamic quantities that can be readily used in hydrodynamic simulation codes. The results on up to sixth order expansion coefficients of bulk thermodynamics are used for the calculation of lines of constant pressure, energy and entropy densities in the $T$-$��_B$ plane and are compared with the crossover line for the QCD chiral transition as well as with experimental results on freeze-out parameters in heavy ion collisions. These coefficients also provide estimates for the location of a possible critical point. We argue that results on sixth order expansion coefficients disfavor the existence of a critical point in the QCD phase diagram for $��_B/T\le 2$ and $T/T_c(��_B=0) > 0.9$., Updated to correspond to journal version. The ancillary files, which contain tables of the basic thermodynamic observables calculated for baryon chemical potentials \mu_B/T < 2.2 in the temperature range 135 MeV < T < 280 MeV and for the cases \mu_Q = \mu_S = 0 and n_S=0, n_Q/n_B=0.4, can be found in version v1

Ferromagnets are key materials for sensing and memory applications. In contrast, antiferromagnets that represent the more common form of magnetically ordered materials, have so far found less practical application beyond their use for establishing reference magnetic orientations via exchange bias. This might change in the future due to the recent progress in materials research and discoveries of antiferromagnetic spintronic phenomena suitable for device applications. Experimental demonstrations of the electrical switching and electrical detection of the N\'eel order open a route towards memory devices based on antiferromagnets. Apart from the radiation and magnetic-field hardness, memory cells fabricated in antiferromagnets are inherently multilevel which could be used for neuromorphic computing. Switching speeds attainable in antiferromagnets far exceed those of the ferromagnetic and semiconductor memory technologies. Here we review the recent progress in electronic spin-transport and spin-torque phenomena in antiferromagnets that are dominantly of the relativistic quantum mechanics origin. We discuss their utility in pure antiferromagnetic or hybrid ferromagnetic/antiferromagnetic memory devices, Comment: Part of a collection of reviews on antiferromagnetic spintronics

The dynamic process of adipose differentiation involves stepwise expressions of transcription factors and proteins specific to the mature fat cell phenotype. In this study, it was revealed that expression levels of IntS6 and IntS11, subunits of the Integrator complex, were increased in 3T3-L1 cells in the period when the cells reached confluence and differentiated into adipocytes, while being reduced to basal levels after the completion of differentiation. Suppression of IntS6 or IntS11 expression using siRNAs in 3T3-L1 preadipocytes markedly inhibited differentiation into mature adipocytes, based on morphological findings as well as mRNA analysis of adipocyte-specific genes such as Glut4, perilipin and Fabp4. Although Pparγ2 protein expression was suppressed in IntS6 or IntS11-siRNA treated cells, adenoviral forced expression of Pparγ2 failed to restore the capacity for differentiation into mature adipocytes. Taken together, these findings demonstrate that increased expression of Integrator complex subunits is an indispensable event in adipose differentiation. Although further study is necessary to elucidate the underlying mechanism, the processing of U1, U2 small nuclear RNAs may be involved in cell differentiation steps.

Nonalcoholic steatohepatitis (NASH) is a disorder characterized by simultaneous fat accumulation and chronic inflammation in the liver. In this study, Pin1 expression was revealed to be markedly increased in the livers of mice with methionine choline-deficient (MCD) diet-induced NASH, a rodent model of NASH. In addition, Pin1 KO mice were highly resistant to MCD-induced NASH, based on a series of data showing simultaneous fat accumulation, chronic inflammation, and fibrosis in the liver. In terms of Pin1-induced fat accumulation, it was revealed that the expression levels of peroxisome proliferator-activated receptor α and its target genes were higher in the livers of Pin1 KO mice than in controls. Thus, resistance of Pin1 KO mice to hepatic steatosis is partially attributable to the lack of Pin1-induced down-regulation of peroxisome proliferator-activated receptor α, although multiple other mechanisms are apparently involved. Another mechanism involves the enhancing effect of hematopoietic Pin1 on the expressions of inflammatory cytokines such as tumor necrosis factor and monocyte chemoattractant protein 1 through NF-κB activation, eventually leading to hepatic fibrosis. Finally, to distinguish the roles of hematopoietic or nonhematopoietic Pin1 in NASH development, mice lacking Pin1 in either nonhematopoietic or hematopoietic cells were produced by bone marrow transplantation between wild-type and Pin1 KO mice. The mice having nonhematopoietic Pin1 exhibited fat accumulation without liver fibrosis on the MCD diet. Thus, hepatic Pin1 appears to be directly involved in the fat accumulation in hepatocytes, whereas Pin1 in hematopoietic cells contributes to inflammation and fibrosis. In summary, this is the first study to demonstrate that Pin1 plays critical roles in NASH development. This report also raises the possibility that hepatic Pin1 inhibition to the appropriate level might provide a novel therapeutic strategy for NASH.

Macrophages are integrated into adipose tissues and interact with adipocytes in obese subjects, thereby exacerbating adipose insulin resistance. This study aimed to elucidate the molecular mechanism underlying the insulin-sensitizing effect of the angiotensin II receptor blocker (ARB) valsartan, as demonstrated in clinical studies. Insulin signaling, i.e., insulin receptor substrate-1 and Akt phosphorylations, in 3T3-L1 adipocytes was impaired markedly by treatment with tumor necrosis factor-α (TNFα) or in the culture medium of lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages, and valsartan had no effects on these impairments. However, in contrast, when cocultured with RAW 264.7 cells using a transwell system, the LPS-induced insulin signaling impairment in 3T3-L1 adipocytes showed almost complete normalization with coaddition of valsartan. Furthermore, valsartan strongly suppressed LPS-induced productions of cytokines such as interleukin (IL)-1β, IL-6, and TNFα with nuclear factor-κB activation and c-Jun NH2-terminal kinase phosphorylation in RAW 264.7 and primary murine macrophages. Very interestingly, this effect of valsartan was also observed in THP-1 cells treated with angiotensin II type 1 (AT1) siRNA or a peroxisome proliferator-activated receptor-γ (PPARγ) antagonist as well as macrophages from AT1a receptor-knockout mice. We conclude that valsartan suppresses the inflammatory response of macrophages, albeit not via PPARγ or the AT1a receptor. This suppression appears to secondarily improve adipose insulin resistance.

In evolution, body plan complexity increases due to an increase in the number of individualized cell types. Yet, there is very little understanding of the mechanisms that produce this form of organismal complexity. One model for the origin of novel cell types is the sister cell-type model. According to this model, each cell type arises together with a sister cell type through specialization from an ancestral cell type. A key prediction of the sister cell-type model is that gene expression profiles of cell types exhibit tree structure. Here we present a statistical model for detecting tree structure in transcriptomic data and apply it to transcriptomes from ENCODE and FANTOM5. We show that transcriptomes of normal cells harbour substantial amounts of hierarchical structure. In contrast, cancer cell lines have less tree structure, suggesting that the emergence of cancer cells follows different principles from that of evolutionary cell-type origination.

The two purposes of the present study were 1) to determine the oxygen consumption in working skeletal muscle from the oxygenation measured by near-infrared continuous-wave spectroscopy (NIRcws) with the arterial occlusion method during the resting condition, INT(VT), and INT(MAX) and 2) to examine whether the decline rate of oxygenation is related to maximal oxygen uptake. Eight healthy males (aged 19.8 +/- 0.4 yr, height 166.9 +/- 17.4 cm, weight 62.1 +/- 2.5 kg, and maximal oxygen uptake [VO2max] 55.9 +/- 1.9 ml/kg x min(-1)) took part in this study. The oxygenation was measured by NIRcws during the Wingate anaerobic test (WAnT) and two intermittent pedalling exercises of VT (INT(VT)) and maximal (INT(MAX)) work intensity. The decline rates of oxygenation obtained during the resting condition, INT(VT), and INT(MAX) with arterial occlusion were 0.43 +/- 0.05%/sec, 4.94 +/- 0.31%/sec, and 8.16 +/- 0.38%/sec, respectively, and that during the WAnT without arterial occlusion was 8.73 +/- 0.49%/sec. The decline rate of oxygenation during the WAnTwas significantly (p < 0.0001) related to maximal oxygen uptake (VO2max). These findings indicate that O2 is utilized from the early phase, even during a supramaximal pedalling exercise, and that the oxidative metabolic capacity may be a factor contributing to supramaximal exercises. Therefore the arterial occlusion method with NIRcws is suitable for the evaluation of the muscle O2 consumption during exercise noninvasively.

The analytic continuation needed for the extraction of transport coefficients necessitates in principle a continuous function of the Euclidean time variable. We report on progress towards achieving the continuum limit for 2-point correlator measurements in thermal SU(3) gauge theory, with specific attention paid to scale setting. In particular, we improve upon the determination of the critical lattice coupling and the critical temperature of pure SU(3) gauge theory, estimating r0*Tc ~ 0.7470(7) after a continuum extrapolation. As an application the determination of the heavy quark momentum diffusion coefficient from a correlator of colour-electric fields attached to a Polyakov loop is discussed., Comment: 7 pages. To appear in the Proceedings of the 31st International Symposium on Lattice Field Theory, July 29 - August 3, 2013, Mainz, Germany

We study thermodynamic properties of 2+1 flavor QCD with improved Wilson quarks coupled with the RG improved Iwasaki glue, using the fixed scale approach. We present the results for the equation of state, renormalized Polyakov loop, and chiral condensate., Comment: 7 pages, 7 figures, proceedings of the 30th International Symposium on Lattice Field Theory, June 24-29, 2012, Cairns, Australia

We extend our previous study of the QCD phase structure in the heavy quark region to non-zero chemical potentials. To identify the critical point where the first order deconfining transition terminates, we study an effective potential defined by the probability distribution function of the plaquette and the Polyakov loop. The reweighting technique is shown to be powerful in evaluating the effective potential in a wide range of the plaquette and Polyakov loop expectation values. We adopt the cumulant expansion to overcome the sign problem in the calculation of complex phase of the quark determinant. We find that the method provides us with an intuitive and powerful way to study the phase structure. We estimate the location of the critical point at finite chemical potential in the heavy quark region., Comment: 7 pages, 7 figures; XXIX International Symposium on Lattice Field Theory - Lattice 2011

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is a unique enzyme that associates with the pSer/Thr-Pro motif and catalyzes cis-trans isomerization. We identified Pin1 in the immunoprecipitates of overexpressed IRS-1 with myc and FLAG tags in mouse livers and confirmed the association between IRS-1 and Pin1 by not only overexpression experiments but also endogenously in the mouse liver. The analysis using deletion- and point-mutated Pin1 and IRS-1 constructs revealed the WW domain located in the N terminus of Pin1 and Ser-434 in the SAIN (Shc and IRS-1 NPXY binding) domain of IRS-1 to be involved in their association. Subsequently, we investigated the role of Pin1 in IRS-1 mediation of insulin signaling. The overexpression of Pin1 in HepG2 cells markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events: phosphatidylinositol 3-kinase binding with IRS-1 and Akt phosphorylation. In contrast, the treatment of HepG2 cells with Pin1 siRNA or the Pin1 inhibitor Juglone suppressed these events. In good agreement with these in vitro data, Pin1 knock-out mice exhibited impaired insulin signaling with glucose intolerance, whereas adenoviral gene transfer of Pin1 into the ob/ob mouse liver mostly normalized insulin signaling and restored glucose tolerance. In addition, it was also demonstrated that Pin1 plays a critical role in adipose differentiation, making Pin1 knock-out mice resistant to diet-induced obesity. Importantly, Pin1 expression was shown to be up-regulated in accordance with nutrient conditions such as food intake or a high-fat diet. Taken together, these observations indicate that Pin1 binds to IRS-1 and thereby markedly enhances insulin action, essential for adipogenesis.

Glucose transporter 1 (GLUT1) is widely distributed throughout various tissues and contributes to insulin-independent basal glucose uptake. Using a split-ubiquitin membrane yeast two-hybrid system, we newly identified 4F2 heavy chain (4F2hc) as a membrane protein interacting with GLUT1. Though 4F2hc reportedly forms heterodimeric complexes between amino acid transporters, such as LAT1 and LAT2, and regulates amino acid uptake, we investigated the effects of 4F2hc on GLUT1 expression and the associated glucose uptake. First, FLAG-tagged 4F2hc and hemagglutinin-tagged GLUT1 were overexpressed in human embryonic kidney 293 cells and their association was confirmed by coimmunoprecipitation. The green fluorescent protein-tagged 4F2hc and DsRed-tagged GLUT1 showed significant, but incomplete, colocalization at the plasma membrane. In addition, an endogenous association between GLUT1 and 4F2hc was demonstrated using mouse brain tissue and HeLa cells. Interestingly, overexpression of 4F2hc increased the amount of GLUT1 protein in HeLa and HepG2 cells with increased glucose uptake. In contrast, small interfering RNA (siRNA)-mediated 4F2hc gene suppression markedly reduced GLUT1 protein in both cell types, with reduced glucose uptake. While GLUT1 mRNA levels were not affected by overexpression or gene silencing of 4F2hc, GLUT1 degradation after the addition of cycloheximide was significantly suppressed by 4F2hc overexpression and increased by 4F2hc siRNA treatment. Taken together, these observations indicate that 4F2hc is likely to be involved in GLUT1 stabilization and to contribute to the regulation of not only amino acid but also glucose metabolism.

We study the quark mass dependence of the finite temperature QCD phase transition in the heavy quark region using an effective potential defined through the probability distribution function of the average plaquette. Performing a simulation of SU(3) pure gauge theory, we first confirm that the distribution function has two peaks indicating that the phase transition is of first order in the heavy quark limit, while the first order transition turns into a crossover as the quark mass decreases from infinity, where the mass dependence of the distribution function is evaluated by the reweighting method combined with the hopping parameter expansion. We determine the endpoint of the first order transition region for N_f=1, 2, 3 and 2+1 cases. The quark mass dependence of the latent heat is also evaluated in the first order transition region., Comment: 13 pages, 17 figures, 3 tables

We study scaling behavior of a chiral order parameter performing a simulation of two-flavor QCD with improved Wilson quarks. It has been shown that the scaling behavior of the chiral order parameter defined by a Ward-Takahashi identity agrees with the scaling function of the three-dimensional O(4) spin model at zero chemical potential. We extend the scaling study to finite density QCD. Calculating derivatives of the chiral order parameter with respect to the chemical potential in two-flavor QCD, the scaling property of chiral phase transition is discussed in the low density region. We moreover calculate the curvature of the phase boundary of the chirl phase transition in the temperature and chemical potential plane assuming the O(4) scaling relation., Comment: 7 pages, 6 figures, poster presented at the XXVIII International Symposium on Lattice Field Theory, June 14-19 2010, Villasimius, Italy

We propose a new approach to finite density QCD based on a histogram method with phase quenched simulations at finite chemical potential. Integrating numerically the derivatives of the logarithm of the quark determinant with respect to the chemical potential, we calculate the reweighting factor and the complex phase of the quark determinant. The complex phase is handled with a cumulant expansion to avoid the sign problem. We examine the applicability of this method., Comment: 7 pages, 11 figures

We present the status of our study on the equation of state in 2+1 flavor QCD with non-perturbatively improved Wilson quarks coupled with the RG improved glue. We apply the T-integration method to non-perturbatively calculate the equation of state by the fixed-scale approach., Comment: 7 pages, 7 figures, talk presented at the XXVIII International Symposium on Lattice Field Theory, June 14-19 2010, Villasimius, Italy

Intraperitoneal injection of indomethacin (5, 10 and 20 mg/kg) caused acute gastric mucosal lesions in the conscious restrained rat and also hypersecretion of gastric acid. Cimetidine, an H2-receptor antagonist, was found to prevent gastric mucosal bleeding and acid secretion induced by indomethacin. Elcatonin at higher doses than 2.5 U/kg (0.5 microgram/kg) was effective for protecting the gastric mucosa against indomethacin irritation, and it inhibited acid output in response to this ulcerogen. The acid inhibitory effect of elcatonin might be implicated in its cytoprotective action.

We propose a new method to use gamma-ray bursts (GRBs) as an alternative probe of the dark energy. By calibrating luminosity-variability and luminosity-lag time relations at low redshift where distance-redshift relations have been already determined from type Ia supernova (SNIa), GRBs at high redshift can be used as a distance indicator. We investigate the potential impact of future GRB data on determining the current matter density $\Omega_{m}$ and the dark energy equation of state $w$ which is assumed to be constant. We show that a combined analysis of a data set expected from the {\it Swift} and the current SNIa data results in excellent determination of both $\Omega_{m}$ and $w$., Comment: 4 pages, 6 figures, corrected some typos

The Hall-plateau width and the activation energy were measured in the bilayer quantum Hall state at filling factor ��=2, 1 and 2/3, by changing the total electron density and the density ratio in the two quantum wells. Their behavior are remarkably different from one to another. The ��=1 state is found stable over all measured range of the density difference, while the ��=2/3$ state is stable only around the balanced point. The ��=2 state, on the other hand, shows a phase transition between these two types of the states as the electron density is changed., 5 pages including figures, RevTeX

We have measured the Hall-plateau width and the activation energy of the bilayer quantum Hall (BLQH) states at the Landau-level filling factor $��=1$ and 2 by tilting the sample and simultaneously changing the electron density in each quantum well. The phase transition between the commensurate and incommensurate states are confirmed at $��=1$ and discovered at $��=2$. In particular, three different $��=2$ BLQH states are identified; the compound state, the coherent commensurate state, and the coherent incommensurate state., 4 pages including 5 figures

The t(14;19)(q32;q13) is a recurring translocation found in leukemic cells of some patients with chronic lymphocytic leukemia (CLL). The BCL3 gene was identified on chromosome 19 adjacent to the breakpoint of the translocation, and has been proposed to be a candidate proto-oncogene which may play a role in leukemogenesis. The current study of a Japanese patient with CLL revealed that the (14;19) is reciprocal at the molecular level; the BCL3 gene was juxtaposed to the 5' side of the S alpha 1 switch region of the immunoglobulin heavy chain gene (IGH) on the der(14) chromosome, and the IGH gene 5' to the S alpha 1 region was joined to chromosome 19 sequences on the der(19) reciprocal partner chromosome. The breakpoint on chromosome 19 was 16 kb upstream of the first exon of the BCL3 gene and 7 bp of chromosome 19 sequences were deleted at the point of the junction. The t(14;19) translocations so far molecularly analyzed consistently occurred within one of the two S alpha switch regions; however, sequence analysis of the chromosome 19 regions involved in the translocation failed to demonstrate an obvious sequence similarity with the switch region. The chromosomal breaks on chromosome 19 from two CLL patients having the t(14;19) were within Alu repeated sequences.

In 15 normal mothers the stress effects of labor on zinc and copper distributions in erythrocytes and plasma were investigated. Lower levels of total zinc and of zinc derived from both carbonic anhydrase isoenzymes (CA-I and CA-II), especially from CA-I, in erythrocytes were obtained immediately after delivery. On the other hand, there was a significant increase in total plasma zinc concentration only on admission to hospital in labor, although albumin-bound zinc concentration remained elevated throughout the entire labor. These results suggest that there are unexplained disparities between the changes in zinc levels in maternal erythrocytes and plasma during labor.

The generation of autoantibodies and deposition of immune complexes (ICs) in tissue play a primary role in autoimmune diseases. However, the IC-triggered response consists of complex mechanisms that make it difficult to identify the pathogenesis and develop specific therapy. We clarified here a sequential mechanism for the induction of hypersensitivity angiitis by analyzing the responsible Fc receptor (FcR), effector cells, and mediators in an animal model using FcR-deficient mice. In this model, rheumatoid factor-mediated skin vasculitis was induced in wild-type mice, whereas FcRgamma-deficient mice did not develop the vasculitis. Adoptive transfer of various FcR(+) cells into FcRgamma-deficient mice showed that mast cells but not macrophages derived from wild-type mice triggered skin vasculitis. Mast cells derived from either FcgammaRIII-deficient or tumor necrosis factor (TNF)-deficient mice did not possess the inducibility of skin vasculitis. These results indicate that triggering of vascular inflammation was induced by mast cells through IC binding on FcgammaRIII. TNF produced by such activated mast cells was mainly responsible for the pathogenesis of autoantibody-mediated vasculitis. These findings illustrate the clinical significance of mast cells, Fcgamma receptors, and TNF in IC-induced vasculitis syndrome.

T lymphocytes can be activated clonotypically through TCR/CD3 complex or polyclonally via the CD2 molecule. Whether CD2-mediated activation is dependent on TCR/CD3 expression or signaling is controversial. We have re-explored this issue by using a series of CD2-transfected, TCR/CD3 surface membrane-negative human and mouse T cells. Our results clearly show that such T cells can be triggered for IL-2 secretion and increases in intracellular Ca2+ through the CD2 molecule in the absence of surface expression of TCR/CD3 complexes. These responses are only observed when cells express high levels of CD2 and there is a critical threshold of CD2 expression necessary for such activation in the absence of CD3. Concomitant expression of TCR/CD3 complex markedly lowers the level of CD2 required for activation via the latter pathway. These results provide a clear resolution of the controversy concerning the requirement for surface CD3 expression in T cell activation through CD2 and further suggest a possible role for CD2 in activation of TCR/CD3-negative cells.