Three-dimensional structures of the flagellar dynein–microtubule complex by cryoelectron microscopy

The outer dynein arms (ODAs) of the flagellar axoneme generate forces needed for flagellar beating. Elucidation of the mechanisms underlying the chemomechanical energy conversion by the dynein arms and their orchestrated movement in cilia/flagella is of great importance, but the nucleotide-dependent three-dimensional (3D) movement of dynein has not yet been observed. In this study, we establish a new method for reconstructing the 3D structure of the in vitro reconstituted ODA–microtubule complex and visualize nucleotide-dependent conformational changes using cryoelectron microscopy and image analysis. As the complex went from the rigor state to the relaxed state, the head domain of the β heavy chain shifted by 3.7 nm toward the B tubule and inclined 44° inwards. These observations suggest that there is a mechanism that converts head movement into the axonemal sliding motion

A microtubule-dynein tethering complex regulates the axonemal inner dynein f (I1)

Motility of cilia/flagella is generated by a coordinated activity of thousands of dyneins. Inner dynein arms (IDAs) are particularly important for the formation of ciliary/flagellar waveforms, but the molecular mechanism of IDA regulation is poorly understood. Here, we show using cryo-electron tomography and biochemical analyses of Chlamydomonas flagella that a conserved protein FAP44 forms a complex that tethers IDA f (I1 dynein) head domains to the A-tubule of the axonemal outer doublet microtubule. In wild-type flagella, IDA f showed little nucleotide-dependent movement except for a tilt in the fbeta head perpendicular to the microtubule-sliding direction. In the absence of the tether complex, however, addition of ATP and vanadate caused a large conformational change in the IDA f head domains, suggesting that the movement of IDA f is mechanically restricted by the tether complex. Motility defects in flagella missing the tether demonstrates the importance of the IDA f-tether interaction in the regulation of ciliary/flagellar beating

Convergence of the Gaussian Expansion Method in Dimensionally Reduced Yang-Mills Integrals

We advocate a method to improve systematically the self-consistent harmonic approximation (or the Gaussian approximation), which has been employed extensively in condensed matter physics and statistical mechanics. We demonstrate the {\em convergence} of the method in a model obtained from dimensional reduction of SU($N$) Yang-Mills theory in $D$ dimensions. Explicit calculations have been carried out up to the 7th order in the large-N limit, and we do observe a clear convergence to Monte Carlo results. For $D \gtrsim 10$ the convergence is already achieved at the 3rd order, which suggests that the method is particularly useful for studying the IIB matrix model, a conjectured nonperturbative definition of type IIB superstring theory.Comment: LaTeX, 4 pages, 5 figures; title slightly changed, explanations added (16 pages, 14 figures), final version published in JHE

Patched1 Haploinsufficiency Increases Adult Bone Mass and Modulates Gli3 Repressor Activity

SummaryHedgehog (Hh)-Patched1 (Ptch1) signaling plays essential roles in various developmental processes, but little is known about its role in postnatal homeostasis. Here, we demonstrate regulation of postnatal bone homeostasis by Hh-Ptch1 signaling. Ptch1-deficient (Ptch1+/−) mice and patients with nevoid basal cell carcinoma syndrome showed high bone mass in adults. In culture, Ptch1+/− cells showed accelerated osteoblast differentiation, enhanced responsiveness to the runt-related transcription factor 2 (Runx2), and reduced generation of the repressor form of Gli3 (Gli3rep). Gli3rep inhibited DNA binding by Runx2 in vitro, suggesting a mechanism that could contribute to the bone phenotypes seen in the Ptch1 heterozygotes. Moreover, systemic administration of the Hh signaling inhibitor cyclopamine decreased bone mass in adult mice. These data provide evidence that Hh-Ptch1 signaling plays a crucial role in postnatal bone homeostasis and point to Hh-Ptch1 signaling as a potential molecular target for the treatment of osteoporosis

ジコ メンエキセイ スイエン ニ タイスル ステロイド チリョウ コウカ ハンテイ ニ Ga scintigraphy ガ ユウヨウ デアッタ 1レイ

Some cases of chronic idiopathic pancreatitis associated with autoimmune disease havebeen reported. The autoimmune pancreatitis revealed a diffusely irregular and narrowedpancreatic duct and responded well to steroid treatment. We report a case of autoimmunepancreatitis with a significant role of Gallium scintigraphy in response to steroid therapy.A sixty seven-year-old male, with upper abdominal pain, appetite loss and thirst, presenteddiffuse pancreatic swelling on abdominal ultrasonography, and diffuse irregular narrowingof the pancreatic duct and stenosis of the distal common bile duct. Gallium-67 scitigraphyrevealed high uptake in the whole pancreas. The patient underwent pancreatic biopsy torule out pancreatic cancer and malignant lymphoma. The definitive diagnosis was autoimmunepancreatitis. The patient recovered quickly with steroid therapy after the biopsy

スイ カセイ ノウホウ ニ タイスル フククウキョウカ ノホウ イ フンゴウジュツ : イヘキ トノ ユチャク オ ゼンテイ ト シナイ アンゼンナ ジュツシキ

A forty seven-year-old male who had been in clinical follow-up for a pancreatic pseudocystunderwent a laparoscopic cystogastrostomy through the lesser peritoneal sac in 1996. Thisprocedure is performed by creating a cystotomy and posterior gastrotomy through whichan Endo GIATM is applied. The mouth of cystogastrostomy is closed using continuous suturesby Endo STITCHTM. This approach does not rely on adhesions between the pseudocyst andposterior wall of the stomach, and offers clear advantages over previously described techniquesin the management of pancreatic pseudocyst

Detection of RBM15-MKL1 Fusion Was Useful for Diagnosis and Monitoring of Minimal Residual Disease in Infant Acute Megakaryoblastic Leukemia

Acute megakaryocytic leukemia (AMKL) with t(1;22)(p13;q13) is a distinct category of myeloid leukemia by WHO classification and mainly reported in infants and young children. Accurate diagnosis of this type of AMKL can be difficult, because a subset of patients have a bone marrow (BM) blast percentage of less than 20% due to BM fibrosis. Therefore, it is possible that past studies have underestimated this type of AMKL. We present here the case of a 4-month-old female AMKL patient who was diagnosed by presence of the RBM15-MKL1 (OTT-MAL) fusion transcript by RT-PCR. In addition, we monitored RBM15-MKL1 fusion at several time points as a marker of minimal residual disease (MRD), and found that it was continuously negative after the first induction chemotherapy even by nested RT-PCR. Detection of the RBM15-MKL1 fusion transcript thus seems to be useful for accurate diagnosis of AMKL with t(1;22)(p13;q13). We recommend that the RBM15-MKL1 fusion transcript be analyzed for all suspected AMKL in infants and young children. Furthermore, monitoring of MRD using this fusion transcript would be useful in treatment of AMKL with t(1;22)(p13;q13)

Systematic study of the SO(10) symmetry breaking vacua in the matrix model for type IIB superstrings

We study the properties of the space-time that emerges dynamically from the matrix model for type IIB superstrings in ten dimensions. We calculate the free energy and the extent of space-time using the Gaussian expansion method up to the third order. Unlike previous works, we study the SO(d) symmetric vacua with all possible values of d within the range $2 \le d \le 7$, and observe clear indication of plateaus in the parameter space of the Gaussian action, which is crucial for the results to be reliable. The obtained results indeed exhibit systematic dependence on d, which turns out to be surprisingly similar to what was observed recently in an analogous work on the six-dimensional version of the model. In particular, we find the following properties: i) the extent in the shrunken directions is given by a constant, which does not depend on d; ii) the ten-dimensional volume of the Euclidean space-time is given by a constant, which does not depend on d except for d = 2; iii) The free energy takes the minimum value at d = 3. Intuitive understanding of these results is given by using the low-energy effective theory and some Monte Carlo results.Comment: 33 pages, 10 figures; minor corrections, reference added. arXiv admin note: substantial text overlap with arXiv:1007.088

Testing the Gaussian expansion method in exactly solvable matrix models

The Gaussian expansion has been developed since early 80s as a powerful analytical method, which enables nonperturbative studies of various systems using `perturbative' calculations. Recently the method has been used to suggest that 4d space-time is generated dynamically in a matrix model formulation of superstring theory. Here we clarify the nature of the method by applying it to exactly solvable one-matrix models with various kinds of potential including the ones unbounded from below and of the double-well type. We also formulate a prescription to include a linear term in the Gaussian action in a way consistent with the loop expansion, and test it in some concrete examples. We discuss a case where we obtain two distinct plateaus in the parameter space of the Gaussian action, corresponding to different large-N solutions. This clarifies the situation encountered in the dynamical determination of the space-time dimensionality in the previous works.Comment: 30 pages, 15 figures, LaTeX; added references for section