Plants having enhanced yield-related traits and a method for making the same The present invention relates generally to the field of molecular biology and concerns a method for enhancing various yield-related traits by modulating expression in a plant of a nucleic acid encoding an Ornithine Decarboxylase (ODC) polypeptide. The present invention also concerns plants having modulated expression of a nucleic acid encoding an ODC polypeptide, which plants have enhanced yield-related traits relative to corresponding wild type plants or other control plants. The invention also provides constructs useful in the methods of the invention. In another embodiment, the present invention relates generally to the field of molecular biology and concerns a method for increasing various plant yield-related traits, by increasing expression in a plant of a nucleic acid sequence encoding a benzothiadiazole-induced homeodomain λ_(BIHD1) polypeptide. The present invention also concerns plants having increased expression of a nucleic acid sequence encoding a BIHD1 polypeptide, which plants have increased yield-related traits relative to control plants. The invention also provides constructs useful in the methods of the invention. In yet another embodiment, the present invention relates generally to the field of molecular biology and concerns a method for enhancing various yield-related traits by modulating expression in a plant of a nucleic acid encoding a MYB30. The present invention also concerns plants having modulated expression of a nucleic acid encoding a MYB30 polypeptide, which plants have enhanced yield-related traits relative to corresponding wild type plants or other control plants. The invention also provides constructs useful in the methods of the invention. In yet another embodiment, the present invention relates generally to the field of molecular biology and concerns a method for improving various plant growth characteristics by modulating expression in a plant of a nucleic acid encoding a THOM (tomato homeobox) protein. The present invention also concerns plants having modulated expression of a nucleic acid encoding a THOM polypeptide, which plants have improved growth characteristics relative to corresponding wild type plants or other control plants. The invention also provides constructs useful in the methods of the invention. In a further embodiment, the present invention relates generally to the field of molecular biology and concerns a method for increasing various plant yield-related traits, by increasing expression in a plant of a nucleic acid sequence encoding a benzothiadiazole-induced Jiomeodomain 2 (BIHD2) polypeptide. The present invention also concerns plants having increased expression of a nucleic acid sequence encoding a BIHD2 polypeptide, which plants have increased yield-related traits relative to control plants. The invention also provides constructs useful in the methods of the invention.

Ornithin Decarboxylase (ODC)
Polyamines are basic aliphatic hydrocarbon compounds with two or more amino groups. Polyamines are ubiquitous natural substances occurring in organism with more than 20 types described. Examples of polyamines are spermine, spermidine and putrescine. Biological roles attributed to polyamines in plants include cell protection during abiotic stress and promotion of nucleic acid or protein biosynthesis. Enzymes catalyzing essential steps in polyamine biosynthesis include Spermine Synthase, Spermidine Synthase (SPDS) and several basic amino acid decarboxylases of the beta/alpha barrel fold type such as Ornithine Decarboxylases (ODC), Arginine Decarboxylase (ADC), S-adenosylmethionine Decarboxylase (SAMDC), Diaminopimelate Decarboxylase (DAPCD) and Carboxynorspermidine Decarboxylase (CANSDC). Genes encoding such enzymes have been isolated from prokaryotic and eukaryotic organism including plants. Beta/alpha-barrel fold decarboxylases segregate with respect to their phylogeny into four distinct groups containing ADCs, DAPDCs, ODCs, and CANSDCs (Lee et al. 2007. The Journal of Biological Chemistry Vol. 282, 27115-27125). These enzymes form homodimers. Two identical active sites are formed at the dimer interface between the N-terminal domain from one subunit and the C-terminal domain from the other.
Ornithine Decarboxylase or L-ornithine carboxy-lyase catalyses the decarboxilation of L-Ornithine to produce putrescine and CO2. ODCs are found in prokaryotes and eukaryotic organisms. The nomenclature assigned to ODC by the International Union Of Biochemistry And Molecular Biology is EC 22.214.171.124.
There has been considerable research in understanding the expression of plant polyamine metabolism-relate genes in response to stresses, and the use of such genes to alter the polyamine concentration in a cell. For example expression of a mouse ODC in carrot or a human ODC in transgenic rice plants altered the polyamine pools in the transgenic plant (Bastola and Minocha 1995. Plant Physiol. 1995. 109(1): 63-71. Lepri et al; 2001 Mol Genet Genomics. 2001 October; 266(2):303-12.). Immunomodulation of ODC in tobacco plants reportedly resulted in altered polyamine levels and developmental abnormalities and drawf phenotypes in the transgenic plants (Nolke et al; 2005. plant Biotechnology J. 3(2): 237-47. Expression of a cDNA encoding a mouse ODC in tobacco increased putrescine levels (Descenzo and Minocha 1993) Plant Mol Biol. 22, 113-127. In this study most transformant plants had normal appearance although those accumulating high levels of putrescine displayed stunted growth, wrinkled leaves and flowers with reduced stamen.
Surprisingly, it has now been found that modulating expression of a nucleic acid encoding an Ornithine Decarboxylase polypeptide gives plants having enhanced yield-related traits relative to control plants.
According to one embodiment, there is provided a method for enhancing yield related traits of a plant relative to control plants, comprising modulating expression of a nucleic acid encoding an Ornithine Decarboxylase polypeptide in a plant. The enhanced yield related traits comprised increased early vigour, increased seed yield and increased biomass.
Benzothiadiazole-induced Homeodomain Protein 1 (BIHD1)
DNA-binding proteins are proteins that comprise any of many DNA-binding domains and thus have a specific or general affinity to DNA. DNA-binding proteins include for example transcription factors that modulate the process of transcription, nucleases that cleave DNA molecules, and histones that are involved in DNA packaging in the cell nucleus.
Transcription factors are usually defined as proteins that show sequence-specific DNA binding affinity and that are capable of activating and/or repressing transcription. The Arabidopsis thaliana genome codes for at least 1533 transcriptional regulators, accounting for ˜5.9% of its estimated total number of genes (Riechmann et al. (2000) Science 290: 2105-2109). The Database of Rice Transcription Factors (DRTF) is a collection of known and predicted transcription factors of Oryza sativa L. ssp. indica and Oryza sativa L. ssp. japonica, and currently contains 2,025 putative transcription factors (TF) gene models in indica and 2,384 in japonica, distributed in 63 families (Gao et al. (2006) Bioinformatics 2006, 22(10):1286-7).
One of these families is the superfamily of homeodomain (HD) transcription factors involved in many aspects of developmental processes. HD transcription factors are characterized by the presence of a homeodomain (HD), which is a 60-amino acid DNA-binding domain (BD). Arabidopsis thaliana and rice contain approximately 100 HD transcription factors, which can be further classified into subfamilies based on amino acid sequence identity (Richardt et al. (2007) Plant Phys 143(4): 1452-1466). Some of these subfamilies are characterized by the presence of additional conserved domains that facilitate DNA binding and/or protein-protein interactions.
One of these subfamilies is the BEL1 (BELL-1) subfamily (Reiser et al. (1995), Cell 83: 735-742), named after an Arabidopsis mutant bell1 with defective integument formation. BEL1 transcription factors are characterized, in addition to the homeodomain, by a conserved domain called the POX domain, found exclusively in plant proteins. Two motifs further characterize BEL1 polypeptides: the SKY box, and the VSLTGL box, named after the conserved amino acid residues they comprise.
A gene encoding a BEL1 homeodomain polypeptide was isolated from Oryza sativa, and its expression shown to be increased upon treatment with benzothiadiazole (BTH), a molecule capable of inducing disease resistance, but also upon inoculation with Magnaporthe grisea pathogen (Luo et al. (2005) Plant Biol 7: 459-468). It was named Oryza sativa benzothiadiazole induced homeodomain 1 (OsBIHD1). The gene was overexpressed in tobacco using the CaMV 35S promoter (Luo et al. (2005) J Ex Bot 56(420): 2673-2682). Transgenic tobacco plants showed enhanced disease tolerance, and in some instance, germinated apical buds, abnormal roots, reduced fertility or infertility.
Surprisingly, it has now been found that increasing expression of a nucleic acid sequence encoding a benzothiadiazole-induced homeodomain protein 1 (BIHD1) gives plants having increased yield-related traits relative to control plants.
According to one embodiment, there is provided a method for increasing yield-related traits in plants relative to control plants, comprising increasing expression of a nucleic acid sequence encoding a BIHD1 polypeptide as defined herein, in a plant. The increased yield-related traits comprise one or more of: increased early vigour, increased total seed yield per plant, increased number of filled seeds, increased total number of seeds, and increased harvest index.
MYB30 Protein
MYB domain proteins are transcription factors with a highly conserved DNA-binding domain. The MYB domain was originally described in the oncogene (v-myb) of avian myeloblastosis virus (Klempnauer et al. (1982) Cell 33, 453-63). Many vertebrates contain three genes related to v-Myb, c-Myb, A-Myb and B-Myb and other similar genes have been identified in insects, plants, fungi and slime moulds. The encoded proteins are crucial to the control of proliferation and differentiation in a number of cell types. MYB proteins contain one to four imperfect direct repeats of a conserved sequence of 50-53 amino acids which encodes a helix-turn-helix structure involved in DNA binding (Rosinski and Atchley (1998) J Mol Evol 46, 74-83). Three regularly spaced tryptophan residues, which form a tryptophan cluster in the three-dimensional helix-turn-helix structure, are characteristic of a MYB repeat. The three repeats in c-Myb are referred to as R1, R2 and R3; and repeats from other MYB proteins are categorised according to their similarity to R1, R2 or R3. MYB proteins can be classified into three subfamilies depending on the number of adjacent repeats in the MYB domain (one "MYB1R", two "R2R3-type MYB", three "MYB3R"). Since there is little sequence conservation outside of the MYB domain, MYB proteins have been clustered into subgroups based on conserved motifs identified outside of the MYB coding region (Stracke et al. 2001. Curr Opin Plant Biol. October; 4(5):447-56; Jiang et al. (2004) Genome Biology 5, R46). In contrast to animals, plants contain a MYB-protein subfamily that is characterised by the R2R3-type MYB domain.
Plant Myb genes are have been suggested to play important roles in regulation of secondary metabolism, cellular morphogenesis, pathogen resistance, and responses to growth regulators and stress. Additionally WO 2007099096 discloses a rice MYB4 protein useful for increasing seed yield in plants.
The MYB30 class of transcription factors constitutes a subgroup of Myb proteins sharing a common evolutionary origin and corresponding to the Group G09 reported by Jiang et al. 2004. Genes encoding some members of the MYB30 class of proteins have been implicated in physiological responses in guard cells and activation of the hypersensitive cell death response in Arabidopsis thaliana (Cominelli et al. Curr Biol. 2005 15(13):1196-200; Rivas and Roby FEBS Lett. 2006. 580(14):3498-504). The accumulation of extracellular VLCFA (very-long-chain fatty acids)-derived metabolites (leaf epidermal wax components) was affected in MYB30 knockout mutants and overexpressing lines in Arabidopsis thaliana (Vailleau et al. 2008. Plant Cell. March 7 [Epub ahead of print].).
Surprisingly, it has now been found that modulating expression of a nucleic acid encoding a MYB30 polypeptide gives plants having enhanced yield-related traits, in particular increased vegetative biomass and increased emergence vigour relative to control plants.
According to one embodiment, there is provided a method for enhanced yield-related traits of a plant relative to control plants, comprising modulating expression of a nucleic acid encoding a MYB30 polypeptide in a plant. The improved yield-related traits comprise increased biomass and increased emergence vigour.
Tomato Homeodomain (THOM)
Homeodomain leucine zipper (HDZip) proteins constitute a family of transcription factors characterized by the presence of a DNA-binding domain (HD) and an adjacent leucine zipper (Zip) motif. The homeodomain usually consists of 60 conserved amino acid residues that form a helix1-loop-helix2-turn-helix3 that binds DNA. This DNA binding site is usually pseudopalindromic. The leucine zipper, adjacent to the C-terminal end of the homeodomain, consists of several heptad repeats (at least four) in which usually a leucine (occasionally a valine or an isoleucine) appears every seventh amino acid. The leucine zipper is important for protein dimerisation. This dimerisation is a prerequisite for DNA binding (Sessa et al. (1993) EMBO J 12(9): 3507-3517), and may proceed between two identical HDZip proteins (homodimer) or between two different HDZip proteins (heterodimer).
Homeodomain genes are present in all eucaryotes, and constitute a gene family of at least 89 members in Arabidopsis thaliana. The leucine zipper is also found by itself in eukaryotes other than plants. However, the presence of both a homeodomain and a leucine zipper is plant-specific (found in at least 47 out of the 89 proteins in Arabidopsis), and has been encountered in moss in addition to vascular plants (Sakakibara et al. (2001) Mol Biol Evol 18(4): 491-502, which is incorporated herein by reference). The leucine zipper is then located at the C-terminal end of the homeodomain, these two features overlapping by three amino acids.
The Arabidopsis HDZip genes have been classified into four different classes, HDZip I to IV, based on sequence similarity criteria (Sessa et al. In: Plant Molecular Biology (NATO ASI Series, vol H81), pp 412-426, 1994). HD-Zip I and II genes are likely involved in signal transduction networks of light, dehydration-induced ABA, or auxin. These signal transduction networks are related to the general growth regulation of plants. The overexpression of sense or antisense HD-Zip I or II mRNA usually alters growth rate and development. Most members of the HD-Zip III subfamily play roles in cell differentiation in the stele. HD-Zip IV genes are related to the differentiation of the outermost cell layer (Sakakibara et al., 2001).
Several members of the closely related HD-Zip I and II families have been related to auxin signaling and transport. HDZip I and II genes also have been implicated in light signalling responses, including shade-avoidance, de-etiolation of dark-grown seedlings and blue light signaling. Furthermore, there is accumulating evidence that many HD-Zip I and II genes are related to regulation of developmental adaptation to environmental stress conditions such as drought, for an overview, see Agalou et al., Plant Molecular Biology 66, 87-103, 2008. By random binding site selection in vitro the favoured recognition site for the Arabidopsis HD-Zip family I protein Athb-1 was shown to be composed of two 5-bp half-sites that overlap at a central position, CAAT(A/T)ATTG (Sessa et al. EMBO J. 12, 3507-3517, 1993). The HD-Zip II protein Athb-2 interacts with a similar 9-bp sequence but shows a preference for a G/C base pair at the central position. This preference was shown to be determined by the presence of Glu and Thr residues at positions 46 and 56 of the 60-amino acid homeodomain, where HD-Zip I proteins characteristically contain, respectively, an Ala and a Trp residue (Sessa et al. J. Mol. Biol. 274, 303-309, 1997). THOM1 from tomato (Meisner and Theres, Planta 195, 541-547, 1995) is highly expressed in the vegetative shoot apical meristem, the floral meristem and axillary meristems. Young derivatives of these meristems show similar levels of THOM1 transcripts which decrease with increasing age of the respective tissue. HB-4, a member of the HD-Zip class II proteins and homologous to THOM, was shown to be induced in Arabidopsis by far-red-rich light treatment; whereas in sunflower, HB-4 is regulated by water availability and abscisic acid. It was postulated that sunflower HB-4 is involved in increasing desiccation tolerance (Manavella et al., Plant J. 48, 125-137, 2006).
Surprisingly, it has now been found that modulating expression of a nucleic acid encoding a THOM polypeptide gives plants having enhanced yield-related traits, in particular increased seed yield relative to control plants.
According one embodiment, there is provided a method for improving yield related traits of a plant relative to control plants, comprising modulating expression of a nucleic acid encoding a THOM polypeptide in a plant.
Benzothiadiazole-induced Homeodomain Protein 2 (BIHD2)
DNA-binding proteins are proteins that comprise any of many DNA-binding domains and thus have a specific or general affinity to DNA. DNA-binding proteins include for example transcription factors that modulate the process of transcription, nucleases that cleave DNA molecules, and histones that are involved in DNA packaging in the cell nucleus.
Transcription factors are usually defined as proteins that show sequence-specific DNA binding affinity and that are capable of activating and/or repressing transcription. The Arabidopsis thaliana genome codes for at least 1533 transcriptional regulators, accounting for ˜5.9% of its estimated total number of genes (Riechmann et al. (2000) Science 290: 2105-2109). The Database of Rice Transcription Factors (DRTF) is a collection of known and predicted transcription factors of Oryza sativa L. ssp. indica and Oryza sativa L. ssp. japonica, and currently contains 2,025 putative transcription factors (TF) gene models in indica and 2,384 in japonica, distributed in 63 families (Gao et al. (2006) Bioinformatics 2006, 22(10):1286-7).
One of these families is the superfamily of homeodomain (HD) transcription factors involved in many aspects of developmental processes. HD transcription factors are characterized by the presence of a homeodomain (HD), which is a 60-amino acid DNA-binding domain (BD). Arabidopsis thaliana and rice contain approximately 100 HD transcription factors, which can be further classified into subfamilies based on amino acid sequence identity (Richardt et al. (2007) Plant Phys 143(4): 1452-1466). Some of these subfamilies are characterized by the presence of additional conserved domains that facilitate DNA binding and/or protein-protein interactions.
One of these subfamilies is the BEL1 (BELL-1) subfamily (Reiser et al. (1995), Cell 83: 735-742), named after an Arabidopsis mutant bell1 with defective integument formation. BEL1 transcription factors are characterized, in addition to the homeodomain, by a conserved domain called the POX domain, found exclusively in plant proteins. Two motifs further characterize BEL1 polypeptides: the SKY box, and the VSLTGL box, named after the conserved amino acid residues they comprise.
A gene encoding a BEL1 homeodomain polypeptide was isolated from Oryza sativa, and its expression shown to be increased upon treatment with benzothiadiazole (BTH), a molecule capable of inducing disease resistance, but also upon inoculation with Magnaporthe grisea pathogen (Luo et al. (2005) Plant Biol 7: 459-468). It was named Oryza sativa benzothiadiazole induced homeodomain 1 (OsBIHD1). The gene was overexpressed in tobacco using the CaMV 35S promoter (Luo et al. (2005) J Ex Bot 56(420): 2673-2682). Transgenic tobacco plants showed enhanced disease tolerance, and in some instance, germinated apical buds, abnormal roots, reduced fertility or infertility.
Surprisingly, it has now been found that increasing expression of a nucleic acid sequence encoding a benzothiadiazole-induced homeodomain protein 2 (BIHD2) gives plants having increased yield-related traits relative to control plants.
According to one embodiment, there is provided a method for increasing yield-related traits in plants relative to control plants, comprising increasing expression of a nucleic acid sequence encoding a BIHD2 polypeptide as defined herein, in a plant. The increased yield-related traits comprise one or more of: increased early vigour, increased total seed yield per plant, increased number of filled seeds, increased total number of seeds, and increased harvest index.

Method for increasing plant yield by expressing a nucleic acid encoding an ornithine decarboxylase polypeptide and plants expressing the same


The invention describes anti-cancer therapies comprising using an LRP5 antagonist in combination with an anti-PD1 antibody, each as described herein.

Activation of the Wnt signaling pathway requires binding of extracellular Wnt ligands to the Frizzled receptor and to the co-receptor LRP5 (Accession number: UniProtKB-O75197/LRP5_HUMAN) or its closely related homologue LRP6 (Accession number: UniProtKB—O75581/LRP6_HUMAN). There are 19 Wnt proteins and 10 Frizzled receptors in mammalian cells. In the absence of Wnt ligand, cytoplasmic beta-catenin is phosphorylated by a protein complex consisting of the scaffolding proteins Axin and APC and the kinases GSK3beta and CK1a. Subsequent recognition by the ubiquitin ligase beta-TrcP leads to ubiquitin-mediated degradation of beta-catenin. In the presence of Wnt ligand, binding of Wnt to Frizzled and LRP5 leads to recruitment of the cytoplasmic effector protein Dvl and phosphorylation of the LRP5 cytoplasmic tail, which provides the docking site for Axin. Axin sequestration by LRP5 leads to the inactivation of the Axin-APC-GSK3beta complex and, therefore, intracellular beta-catenin stabilization and accumulation. Hence, cytoplasmic levels of beta-catenin rise, and beta-catenin migrates to the nucleus and complexes with members of the T-cell factor (TCF)/Lymphoid enhancer-binding factor (LEF) family of transcription factors. Basal transcription machinery and transcriptional co-activators are then recruited, including cAMP response element-binding protein (CREB)-binding protein (CBP) or its homolog p300, leading to expression of various target genes, including Axin2, cyclin D1, Naked1, Notum and c-Myc.
An additional level of ligand-dependent Wnt pathway regulation is mediated by the E3 ligase RNF43, and its closely related homologue ZNRF3, and by the secreted R-Spondin proteins (de Lau et al. "The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength". Genes Dev. 2014; 28(4):305-16). RNF43 mediates the ubiquitination of the Frizzled/LRP5 receptor complex at the cell surface, leading to its degradation and, thereby, inhibiting ligand-dependent Wnt pathway activity. The activity of RNF43 is counteracted by the R spondin family members (R-spondin 1 to 4 ligands). When R-Spondin ligand is present, it removes RNF43 from the cell surface, allowing Frizzled/LRP5 complex accumulation and enhancement of Wnt signaling in the presence of Wnt ligands.
Hyperactivation of Wnt signaling is involved in the pathogenesis of various, albeit not all, types of cancer in at least two different ways: in some cancer types frequent mutations in downstream signaling molecules contribute to constitutively activated Wnt pathway (e.g. APC mutations in colorectal cancer; beta-catenin activating mutation in hepatocellular carcinoma), while in other types of cancer, such as e.g. Triple Negative Breast Cancer (TNBC), Non Small Cell Lung Cancer (NSCLC), pancreatic adenocarcinoma and in a subset of Colo-Rectal Cancer (CRC) and endometrial cancers, Wnt signaling activation is driven by a ligand dependent mechanism (i.e. by an autocrine/paracrine Wnt activation), as detected by beta-catenin intracellular accumulation. In NSCLC, TNBC and pancreatic adenocarcinoma, ligand dependent Wnt activation is mediated by multiple mechanisms, including increased expression of the Wnt ligands and/or of LRP5 receptors, or silencing of LRP5 negative regulator DKK1 (TNBC: Khramtsov et al. "Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome". Am J Pathol. 2010; 176(6): 2911-20; NSCLC: Nakashima et al. "Wnt1 overexpression associated with tumor proliferation and a poor prognosis in non-small cell lung cancer patients". Oncol Rep. 2008; 19(1):203-9; Pancreatic cancer: Zhang et al. "Canonical wnt signaling is required for pancreatic carcinogenesis". Cancer Res. 2013; 73(15):4909-22). In particular, published data have shown that in healthy tissues (e.g. mammary and lung epithelium), beta-catenin is localized solely at the plasma membrane. In contrast, the majority of TNBC, NSCLC and pancreatic adenocarcinoma primary clinical samples showed beta-catenin intracellular accumulation (i.e. in the cytoplasm/nucleus; biomarker of Wnt signaling activation), due to aberrant Wnt signaling.
Because LRP5 functions as gatekeeper of ligand dependent Wnt signaling activation, it may be considered as target to achieve complete blockade of the pathway mediated by all 19 Wnt ligands and 10 Frizzled receptors.
An alternative method to the above described approach of directly targeting the cancer/cancer cells is cancer immunotherapy. Cancer immunotherapy is a branch of oncology in which the immune system is used to treat cancer, which is in stark contrast to existing common methods of treatment in which the tumour is directly excised or treated. This therapeutic concept is based on the identification of a number of proteins on the surface of T-cells which act to inhibit the immune function of these cells. Listed among these proteins is PD-1 (Programmed cell Death 1).
PD-1 is a cell surface receptor protein expressed on T-cells. PD-1 has two ligands, PD-L1 and PD-L2, which interact with the cell surface receptor. On ligand-binding, PD-1 induces an intracellular signal which negatively regulates T-cell response. Thus, typically, the protein functions as an "immune checkpoint" inhibitor, i.e. it acts to modulate the activity of cells in the immune system so as to regulate and limit autoimmune diseases. It has been recently understood that many cancers can protect themselves from the immune system by modifying "immune checkpoint" inhibitors and thus avoid detection.
Accordingly, it has also been shown in a range of different cancer settings that antagonistic PD-1 antibody molecules, such as e.g. nivolumab and pembrolizumab, can be used to stimulate the immune system and thereby treat cancer.
Despite the above described advances in the treatment of cancer, there is still a need for new therapeutic concepts for the treatment of cancer which show advantages over standard therapies. These advantages may include in vivo efficacy (e.g. improved clinical response, extend of the response, increase of the rate of response, duration of response, disease stabilization rate, duration of stabilization, time to disease progression, progression free survival (PFS) and/or overall survival (OS), later occurrence of resistance and the like), safe and well tolerated administration and reduced frequency and severity of adverse events. Specifically, there is a need for additional treatment options for patients with cancers like, e.g., lung cancer (e.g. NSCLC), melanoma, bladder and gastrointestinal cancers.
It is thus an object of the present invention to provide a novel treatment for cancer that is advantageous over treatments/methods of treatment currently used and/or known in the prior art.

LRP5 and PD-1 antagonist anticancer combination therapy


The needle assembly holder of the present invention has mounted about its receptacle end a rotatable safety sheath so that irrespective of how the tip of the cannula of the needle assembly is oriented with respect to the holder, the user can nonetheless obtain an unobstructed view of the tip of the cannula by rotating the safety sheath out of her line of sight. Friction drag is provided between the receptacle end of the needle assembly holder and the safety sheath so that the safety sheath would not freely rotate about the needle assembly holder absent a rotation force applied thereagainst.

In the '454 application, a double-ended needle assembly holder, used in conjunction with an evacuated blood collection tube, is disclosed to have a housing that is pivotable to a position in substantial alignment with the longitudinal axis of the needle such that, once the housing is pivoted to the alignment position, the needle is retained therein so as to preclude the sharp end of the needle from being exposed.
The '454 safety device works well but for the fact that the user of the device, for example a phlebotomist or a nurse, is oftentimes blocked by the housing from having a clear view of the tip of the needle (cannula) . To elaborate, ordinarily a phlebotomist, when obtaining fluid, as for example blood, from a patient, would position the cannula such that its bevel faces up. For this discussion, the bevel of a cannula is understood to be the sharp, butting end of the cannula. The reason that a phlebotomist wants to position the bevel of the cannula to face up is so that she can see the sharp point, rather than the round end, of the cannula so that the cannula can be more easily and accurately inserted into, for example the vein, of a patient. But since the needle assembly is threaded into the '454 safety device such that it may end up in any orientation, the safety housing attached to the '454 device would sometimes get in the way and prevent the phlebotomist from viewing the true angle of the cannula.

Needle assembly holder with rotatable safety sheath member and method of effecting proper alignment of a cannula using such needle assembly holder


A baseball board game including a plurality of tokens, each of which represent one of the players, a random number generator, a multiplicity of play money, and a game board having a baseball-like playing field and a multiplicity of playing spaces formed on the baseball-like playing field which cooperatively define a continuous closed path in the form of a baseball diamond along which the tokens are moveable in random increments. The multiplicity of spaces includes a starting corner space representing home plate and three additional corner spaces representing first base, second base and third base, respectively, a first group of spaces having monetary gains specified thereon associated with certain baseball-related events in a baseball player's life both on and off the field which have a positive pecuniary effect on a baseball player and a second group of space having monetary penalties specified thereon associated with certain baseball events on and off the field in a baseball player's life which have a negative pecuniary effect on a baseball player.

The present invention relates to a baseball board game. More particularly, it relates to a baseball board game which highlights the monetary, personal and business aspects of professional baseball players, both on and off the field, in a simulated traditional baseball game-like setting.
A variety of baseball board games have been proposed. For example, Seale, U.S. Pat. No. 2,769,639 discloses a game which attempts to simulate a traditional baseball game setting with pitchers and hitters of varying ability and where the outcome of the game is based on the game player's ability as a "manager" to make appropriate managerial moves, than on the elements of chance which are reduced to a minimum degree. Other board games have a sports game motif also have a more traditional rectangular path around a game board and deal, e.g., with the acquisition of teams and players (U.S. Pat. Nos. 4,010,957 and 4,486,022) or the ability of the game players to spell for educational purposes (U.S. Pat. No. 4,000,897). However, so far as is known, no presently available board game provides a simulated traditional baseball game-like setting while highlighting the total personal and business aspects of the game, both on and off the field, from a player's perspective in a simple and yet highly manner as herein proposed.


A rule based floorplanner for a macrocell array having a plurality of predetermined macrocells. The floorplanner uses a net list (23), a macrocell list (26), and a list of design constraints (31) and characteristics of the base array itself to derive an initial Burain score. A trial floorplan is attempted (33) and checked against a list of theoretical rules (39) and a list of empirical rules (38) to determine a measured Burain score (36) which accurately indicates the difficulty which can be expected when completing the design.

The present invention relates, in general, to automated design of integrated circuits, and more particularly to floorplanning for an integrated circuit which utilizes a macrocell array structure.
During the physical design process of a large, structured integrated circuit a floorplanning step, i.e. the automatic placing of logic, memory and other elements on the integrated circuit, has proven to be highly useful. Not only is the probability of successfully completing the physical layout increased by such a preliminary step, but the computer time and manual effort taken to complete this step is also reduced. One such floorplanner is found in U.S. Pat. No. 4,918,614, issued Apr. 17, 1990, to H. Modarres et al., which is incorporated herein by reference. The floorplanner described by Modarres et al examines the connectivity net list in an attempt to first place groups of cells in the most advantageous position, then to assign connections to routing channels so as to best assure successful completion of routing. The floorplanner estimates the probability of success based on the routing wires balanced by the actual space that is estimated to be required for routing these connections. However, this estimate does not take into account enough of the many variables that affect the success of this highly complex physical design process.
There is a need for a floorplanner which provides a highly reliable estimate of the probability for success during the balance of the physical design process. The floorplanner should incorporate a graphical interface to allow manual editing of the floor plan, a fast global router to allow accurate determination of the wire length contribution for each connection, a graphical display which will accurately indicate the areas of congestion to the designer, and which will allow manual editing of the floorplanning process. Since the entire process of floorplanning, cell placement, and interconnect routing are highly complex the floorplanner must incorporate both theoretical and empirical rules which take into account the complex components affecting success of the physical design process. The floor planner should derive an initial suitability score for the design based on the netlist information that accurately predicts the difficulty expected when completing the physical design. The floorplanner must then allow the floorplan to be manually altered for optimization. A more accurate suitability score should be readily derived to guide this optimization. Finally the floorplanner should output files that can interact directly with other physical design tools allowing very accurate prediction of integrated circuit timing without spending the computer time and expense required to actually design and test the integrated circuit.


In order to improve the quality of seam welding, an inverter seam resistance welding electric power supply apparatus reliably determines local weldability (conforming/defective) of seam welding by simply monitoring welding current. In a seam welding operation, when a current monitor time interval has elapsed, a CPU reads, from storage, measured current values I.sub.1 !, I.sub.2 !, etc., of each inverter cycle obtained during the current monitor time interval and computes an average current value I.sub.M1 ! thereof, according to an averaging method such as an arithmetic mean method. Then the CPU compares the average current value I.sub.M1 ! with a preselected monitoring value or range. If the average current value I.sub.M1 ! falls within the monitoring range, the CPU determines the occurrence of a conforming local welding whereas it determines the occurrence of a defective local welding if the average current value goes out of the monitoring range. For successive determinations of defective local welding for a preselected number of times, for instance, three, the CPU determines that a defective seam welding has occurred, and takes appropriate action immediately, for instance, by stopping the seam welding operation.

The present invention relates to an inverter resistance welding electric power supply apparatus for seam welding.
Seam welding is a process in which a pair of relatively thin metal plates are weld-jointed continuously or intermittently forming a seamlike welded line or lines. Seam welding may be applied to seaming metal housings of dry cells and semiconductor devices, fuel tank, etc.
FIG. 7 illustrates, as an example, seam welding of metal plates 100 and 102 along their margins. A pair of seam welding rolls 106 and 108 are moved relative to edges 100a and 102a of the metal plates 100 and 102 along a line 104 to be seamed (see dotted line in FIG. 7). In the meantime, electric current is continuously or intermittently supplied to the roller electrodes 106 and 108 to thereby seam weld the workpieces 100 and 102 along the line 104.
Seam welding may also be applied to sealing or encapsulating a tank 110, such as the one shown in FIG. 8. A pair of seam welding rolls 118 and 120 are moved relative to flanges or brims 112a and 114a of hat-like tank members 112 and 114 along a line 116 to be seamed (see dotted line in FIG. 8). In the meantime welding current is continuously or intermittently supplied to the welding electrodes 118 and 120 to thereby make the seam or joint 116.
Conventionally, the workpieces (100, 102), 110 are successively or constantly moved or translated by a feed gear whereas the seam welding rolls (106, 108, 118, 120) rotate around their axis.
During a seam welding operation, a resistance welding electric power supply apparatus supplies welding current to workpieces via welding electrodes, as mentioned above. The prior art inverter seam resistance welding electric power supply apparatus includes a feedback constant-current control feature which measures welding current on a cycle-by-cycle basis and controls it to be maintained at or near a desired level during a welding operation. The prior art apparatus, however, cannot successfully monitor or evaluate a quantity of welding current which is useful to determine the result of a weld or the quality of the seam welding. The reasons may be explained as follows:
The prior art apparatus employing a constant-current control measures welding current on an inverter switching cycle-by-cycle basis. The measured quantity or magnitude of welding current of a single switching cycle of the inverter contributes very little to weldability of seam welding. Thus, such a single cycle welding current value, as measured, does not carry useful information to reliably determine results of the welding. Going to an opposite extreme, one might propose an inverter seam welding resistance electric power supply apparatus which evaluates an average value of the entire welding current throughout a seam weld time. Such an entire current average value throughout the seam weld time, however, clearly disregards localities of seam welding, thus overlooking local defects of the seam weld since such a seam weld time is generally very long (for instance several minutes); much longer than a single spot weld time.

Inverter seam resistance welding electric power supply apparatus


An electrodynamic acoustic transducer has its diaphragm with a coil retained with respect to the magnetic system in discrete points along the periphery of the diaphragm, while the rest of the periphery of the diaphragm is not fixed. The diaphragm has tongues at its periphery which are thicker than the rest of the diaphragm, and which are retained between two ring-shaped engagement faces, which, in the preferred embodiment, are formed by a magnetic system which is arranged symmetrically on both sides of the diaphragm. The diaphragm has a flat coil with spiral wound windings, and the diaphragm with coil and termination is supplied integrally with a web of sheet or a film roll comprising a large number of diaphragms, making the diaphragm useful for mounting in the transducer by tape automated bonding.

The invention concerns an electrodynamic transducer, a diaphragm, a web of sheet having such a diaphragm and a magnet system for the transducer.
The concept electrodynamic acoustic transducer in particular comprises microphones which convert sound signals in the air into electrical signals, and sound generators which convert electrical signals into sound signals in the air. Traditionally, such transducers have a ring-shaped, wound coil of copper wire which is present in a ring-shaped air gap having a radially oriented magnetic field. Such coils are wound on automatic winding machines, and then the coils are to be mounted on a diaphragm, e.g., by gluing. After their manufacture on a winding machine, the coils and in particular their thin copper wires are vulnerable, and they must therefore be handled with great care in order not to be damaged and with great accuracy. The coils are to be mounted on the diaphragms with narrow tolerances, and also the diaphragm with the mounted coil is to be placed very precisely in the magnetic circuit.
It is increasingly required that microphones to be used in portable telephones shall have small physical dimensions, and it is simultaneously desired that such a small microphone is to have a sensitivity which is comparable to the sensitivity of a traditional, larger microphone. These requirements clash with each other, one reason being that a small diaphragm is less resilient than a corresponding larger diaphragm, and a small diaphragm therefore moves correspondingly less at the same sound pressure than a large diaphragm, which results in a smaller electrical output signal.


A method is described for establishing load limits for pipe connections to a turbine casing including the steps of: identifying a plurality of the pipe connections as key pipe load connections; developing transfer functions to model deformation of the casing based on loads applied to the key pipe connections; establishing individual load limits for each of the key pipe connections in the group by optimizing solutions to the transfer functions, and establishing a cumulative load limit for the group of key pipe load connections by optimizing solutions to the transfer functions.

The present invention relates to methods for avoiding excessive loads placed on turbine casings by pipes attached to the casing. In particular, the invention also relates to methods for optimizing the piping load limits for a turbine casing to minimize deformation of the casing due to the loads.
Deformation of a steam turbine casing can allow steam to leak around the seals at the tips of turbine buckets. This leakage reduces the amount of steam available to work on the downstream turbine buckets. Deformation of the casing can distort the seals which are intended to prevent the leakages of steam and gases.
Seals within a steam turbine generally include teeth static casing structure that interlace with the bucket covers. The gap between the teeth on the casing and the teeth on the buckets is narrow to prevent steam leakage over the covers of the blades. A steam turbine also has inter-stage seals between the stages of turbine buckets. The inter-stage seals prevent steam leakage through the turbine diaphragm packing that around the rotor shaft, and between each bucket stages. Deformation of the casing can distort the seals, and allow steam to escape through the seals and into the casing.
Excessive forces due to pipe connections on a turbine casing can occur during the assembly or operation of a turbine. Pipe loads tend to be high during turbine startup when the pipes and turbine heat up. The heating of the pipes and turbine casing during startup results in differential thermal expansions in the pipes and casing. The differential expansions between the pipes and casing apply loads on the casing that distort the casing shell. During turbine startup, distortions in the casing typically exaggerate the turbine bucket and seal clearances.
Excessive piping loads can also distort the turbine casing during turbine transient operations. Piping loads during transients, especially when cooling occurs in the pipes, tend to distort the turbine casing to reduce the clearances between the seals and buckets. If these clearances become too small, the stationary seals may "rub-out" as they scrap against the rotating buckets. Seals that rub-out do not provide effective sealing as they allow excessive steam leakage during steady state turbine operating conditions. Accordingly, excessive piping loads may damage and distort the seals between the casing and the buckets such that turbine performance is degraded.
Piping load limits are imposed on the turbine design to avoid excessive piping loads that unduly distort the casing. In the past, these limits have been based on empirical and historical information regarding prior piping loads on similar turbine casing. It was common for piping load limits to be developed using simple calculations of the loads on the casing. Conventional turbine casing design techniques were not particularly helpful in identifying those key pipe connections that distort the turbine casing (seals) or in establishing load limits for pipe connections. Accordingly, there is a long felt need for methods to establish pipe load limits on turbine casings that avoid excessive casing distortion.

Method to optimize pipe load limits on a turbine casing


Communication security is an ongoing problem. Over time, various protocols have been used and then replaced due to insufficient protection. For example, some client/server web communication used to rely on Secure Socket Layers (SSL) to protect communication, but was replaced with a more secure Transport Layer Security (TLS) protocol. TLS itself has undergone several revisions, and TLS 1.0 is now considered not secure. TLS and other protocols provide backwards compatibility, so while a higher security level is desired, communication may fallback to an undesirable level, e.g., TLS 1.0, if required by either communication endpoint. An intermediary to communication with an organization may capture data to facilitate analyzing it to determine what caused a fallback, and to decide if and how to remediate it. Remediation may vary depending on, for example, whether the cause was from within the organization, or external, such as from a client.

A large-scale cloud-based computer system may include multiple datacenters at various geographic locations to maintain millions of sets of application data for millions of organizations as well as provide millions of sets of application services such as those for customer relationship management, secured data access, online transaction processing, mobile apps, etc., to respective users and/or customers of these organizations. As datacenters grow, evolve and interconnect over time, and as computing resource needs for the organizations evolve over time, networks interconnecting devices continue to grow ever larger and more complex. In current network environments there may be many thousands of interconnected devices, such as client devices, servers, hubs, firewalls, switches, routers, etc.
An organization may have many different entities reachable over a network, such as private intranets, or public networks such as the Internet. The organization may contain many different hardware and software entities, such as data centers, servers, clients, mobile devices, Internet of Things (IoT) machines, etc. Accessing a network may be managed by firewalls that protect the network and its associated hardware/software entities. Firewalls may be positioned at network edges (or perimeters) to separate resources internal to the network from external entities/sources. Because malicious actors relentlessly attack networks, it is important to restrict access to organization entities and their associated resources, and to enforce security policies, such as use of strong cryptographic protocols. Communication with the organization may be monitored and firewalls used to restrict passage of data as needed.

Automated encryption degradation detection, reporting and remediation


A power recharger for use with a robot cleaner has a recharging terminal to which a battery terminal of the robot cleaner is docked and an anchor member on a rear side of the body of the recharging unit. The anchor member fills in the space defined between the wall of the room and the power recharger. The anchor member therefore securely supports the power recharger in the battery recharging process.

Generally, a robotic cleaner automatically runs around one or more rooms to perform cleaning operations. Because it runs inside of a building, an automatic robot cleaner must be electrically powered and the preferred source of electrical energy is a rechargeable battery mounted in the robotic cleaner by which the robotic cleaner can be operated cordlessly. While performing the automatic running and cleaning operation, the robot cleaner determines whether it needs its battery recharged, usually checking the level of the remaining power of the battery through, for example, the measurement of voltage from the battery, and if determining so, the robot cleaner returns to the station, for example, at the corner of the room where the power recharger 20 is positioned. Therefore, the battery in the robot cleaner can be recharged automatically.
As shown in FIG. 1, most rooms have a molding known as a "baseboard" 1 that is attached around the lower part of a room's walls. As the power recharger 20 of the robot cleaner 10 is usually stationed at the corner of the room, there usually occurs a gap 2 between the power recharger 20 and the walls 3. When a robotic cleaner 10 needs recharging and runs itself to the recharger 20, the robot cleaner's 10 contact with the charger terminals 22 can jostle the recharger unit 20 by the force transmitted by the robot cleaner 10 through the terminals 22, which are located above the top of the baseboard 1. As a result, docking of the rechargeable battery terminal 11 of the robot cleaner 10 and the power terminal 22 of the power recharger 20 becomes unstable.
Thus, there exists a need to squarely support a recharging station against a wall such that a wall baseboard or other structure that extends away from a room wall can be compensated for.

Power recharger for use with robot cleaner


A method and system for manipulating a three-dimensional object in a computer-aided design (CAD) environment utilizes a force feedback interface. A gravitational sphere is defined around each of the plurality of input parameters of a mathematical model defining a shape, location and orientation of the object. A force is applied to the force feedback interface based on the gravitational spheres and the position of the force feedback interface. An input signal is received from the force feedback interface based on the applied force indicating selection of one of the plurality of input parameters. The selected input parameter can then be edited according to an edit signal generated by the user via the force feedback interface. In addition, the edit signal can be limited according to predetermined constraints via the force feedback interface.

In a CAD environment, the operator uses a combination of keyboard, mouse, and/or tablet to manipulate objects, and a flat screen to display visual feedback. This interface is very effective for 2 Degree-of-Freedom (DoF) drawings such as sections and projections, but has some major limitations for three-dimensional object design and manipulation.
In three-dimensional Cartesian space, position and orientation are defined by three positional coordinates X, Y and Z, and three angular coordinates, pitch, yaw and roll, for a total of 6 DoF. Designing, modeling, and assembling CAD surfaces and solid objects in space using a 2 DoF interface is non-intuitive, time consuming, and requires extensive training. In fact, position is controlled by three variables, but a mouse or tablet allows access to only two variables at a time (i.e. horizontal and vertical position in the plane of the mouse or tablet). Thus, a designer can control only a subset of positional information at any one time. Further, rotation about a given axis requires only one variable for definition. However, there is no rotational input available with the conventional tools. Thus, the designer must translate from a positional mouse displacement to a rotational displacement in order to understand the effect of their input.
A 6 DoF joystick, such as a Spaceball.TM. manufactured by Spaceball Technologies, provides six degrees of freedom. However, the six degrees of freedom do not match position and orientation. Rather, they match the speed at which those parameters are changed. The difference, which may seem subtle, is difficult to cope with and requires extensive training to become proficient.
The same objects modeled with a two-dimensional interface can also be modeled directly in three-dimensions. A virtual reality (VR) environment is one such example. In this case, the object is presented to the designer in a manner which more accurately mimics the presentation of an actual object. The object is placed in the same three-dimensional space as the designer. Thus, the designer would need an interface tool which has 6 DoF allowing position and orientation to be manipulated directly. Such an interface does not exist today.

Method and system for manipulating a three-dimensional object utilizing a force feedback interface


A bone fastener is adapted to deliver biologically active substances to a bone site. An applicator is saturated with the substance and is disposed within an inner cavity of the fastener, near the bone site. Channels through the body of the fastener permit the substance to flow to the bone site. The substance can include therapeutic drugs, such as antibiotics, analgesics, bone morphogenic proteins, DNA, chemotherapy drugs and angiogenesis factors.

Orthopedic fasteners have been used to repair bone fractures in the body of a human or other animal. For example, intramedullary nails are used to repair fractures in long bones of the body, such as the human femur. Intramedullary nails have also been used as a tool for lengthening femur bones, whereby the femur is surgically fractured and incrementally separated and allowed to regrow over time. In addition, reconstruction screws are used in hip reconstruction surgery and fracture plates are used for spine fractures.
In either case, an infection may occur at the fracture site or a bone growth factor may be required at the fracture site to stimulate bone growth. In those cases, further surgery may be required to deliver a therapeutic drug to the fracture site.

Apparatus and method for administering a biologically active substance to a bone


A method and system for detecting 3D objects in images is disclosed. In particular, a method and system for Ileo-Cecal Valve detection in 3D computed tomography (CT) images using incremental parameter learning and ICV specific prior learning is disclosed. First, second, and third classifiers are sequentially trained to detect candidates for position, scale, and orientation parameters of a box that bounds an object in 3D image. In the training of each sequential classifier, new training samples are generated by scanning the object's configuration parameters in the current learning projected subspace (position, scale, orientation), based on detected candidates resulting from the previous training step. This allows simultaneous detection and registration of a 3D object with full 9 degrees of freedom. ICV specific prior learning can be used to detect candidate voxels for an orifice of the ICV and to detect initial ICV box candidates using a constrained orientation alignment at each candidate voxel.

The present invention relates 3D object detection in images, and more particularly, to automated Ileo-Cecal Valve (ICV) detection in colon CT data using incremental parameter learning.
Detecting and segmenting human anatomic structures in 3D medical image volumes (e.g., CT, MRI, etc.) is a challenging problem, which is typically more difficult than detecting anatomic structures in 2D images. Human anatomic structures are highly deformable by nature, leading to large intra-class variation in the shape, appearance, and pose (orientation) of such structures in 3D medical images. Furthermore, the pose of an anatomic structure is typically unknown in advance of detection. If the pose of an anatomic structure were known prior to detection, it would be possible to train a model for the same category of anatomic structure with a fixed pose specification and pre-align all testing data with the known pose information to evaluate their fitness against the learned model. However, in order to determine the pose configuration of an anatomic structure, the structure itself must be first detected, because pose estimation is only meaningful where the structure exists. Accordingly, a method for simultaneous detection and registration of 3D anatomic structures is need.
Many three dimensional (3D) detection and segmentation problems are confronted with searching in a high dimensional space. For example, a 3D similarity transformation is characterized by nine parameters: three position parameters, three orientation parameters, and three scale parameters. It is very expensive to search the entire space for detection of an object. The search for all these parameters becomes computationally prohibitive, even if coarse-to-fine strategies are involved.
The Ileo-Cecal Valve (ICV) is a small anatomic structure connecting the small and large intestines in the human body. The normal functionality of the ICV (opening and closing on demand) allows food to pass into the large intestine (i.e., colon) from the small intestine. The ICV being stuck in either the open or closed position can cause serious medical consequences. Furthermore, detecting the ICV in 3D computed tomography (CT) volumes is important for accurate colon segmentation and for distinguishing false positives from polyps in colon cancer diagnosis. The size of the ICV is sensitive to the weight of the patient and whether the ICV is healthy or diseased. Because the ICV is part of the colon, which is highly deformable, the position and orientation of the ICV can vary greatly. Due to large variations in the position, size, and orientation of the ICV, detecting the ICV in CT volumes can be very difficult. Accordingly, a method for automatically detecting the size, position, and orientation of the ICV is needed.

Method and system for detection and registration of 3D objects using incremental parameter learning


A semiconductor device is provided. The semiconductor device includes an element; a mounting board; and a single film made of a conductive material directly coupling the element with the mounting board.

1. Technical Field
The present invention relates to a semiconductor device, a method of manufacturing a semiconductor device, an electroluminescence device, and a method of manufacturing an electroluminescence device.
2. Related Art
In recent years, a method of manufacturing an electro-optical device has been developed (see Japanese Unexamined Patent Publication No. 2002-082633) as a way to join two different types of boards together to manufacture a joined board. According to this method, an electro-optical device is manufactured by joining an electro-optical board provided with a light-emitting element, such as an organic electroluminescence (EL) device, and a driving circuit board (semiconductor device) provided with a driving element that makes the light emitting element emit light.
In this method of manufacturing a joined board, an electro-optical board and a driving circuit board are separately provided and then the two boards are joined together to form an electro-optical device. Therefore, a process required for forming the driving circuit board after forming or printing a driving element, such as a thin-film transistor (TFT), can be reduced, and thereby significantly reduce the possibility of damaging the driving element during the manufacturing process. Also, since the electro-optical board and the driving circuit board are manufactured in separate steps, the yield can be increased. It is also possible to join an electro-optical board and a driving circuit board manufactured by different plants or manufacturers, which is highly advantageous in reducing manufacturing costs. Also, it is possible to manufacture a wide-screen electro-optical device with a comparatively low investment in a plant and equipment.
According to Publication No. 2002-082633, a TFT is printed and conductively coupled on a wiring board that is wired with an anisotropic conductive paste (ACP). This structure, however, may cause a defective contact between the wiring board and the TFT due to variations in the height of the bumps on the wiring board.
Also, since a narrow gap between the TFT pads may cause a short-circuit between neighboring pads with an ACP therebetween, the TFT size and the number of terminals are limited.
Furthermore, when conductive coupling the wiring board and the TFT, a load imposed on the TFT for coupling the wiring board and the TFT with the ACP is so large that a crack may develop in the TFT.
In order to address the above-mentioned problems, the present invention provides a semiconductor device, a method of manufacturing a semiconductor device, an EL device using a semiconductor device, and a method of manufacturing an EL device that can ensure a narrow pitch between the pads of semiconductor elements, e.g. the TFT, improve conductivity to the semiconductor elements, and prevent damage to the semiconductor elements.

Method of manufacturing an electroluminescence device


The invention is intended to always ensure a sufficient level of patient positioning accuracy regardless of the skills of individual operators. In a patient positioning device for positioning a patient couch 59 and irradiating an ion beam toward a tumor in the body of a patient 8 from a particle beam irradiation section 4, the patient positioning device comprises an X-ray emission device 26 for emitting an X-ray along a beam line m from the particle beam irradiation section 4, an X-ray image capturing device 29 for receiving the X-ray and processing an X-ray image, a display unit 39B for displaying a current image of the tumor in accordance with a processed image signal, a display unit 39A for displaying a reference X-ray image of the tumor which is prepared in advance, and a positioning data generator 37 for executing pattern matching between a comparison area A being a part of the reference X-ray image and including an isocenter and a comparison area B or a final comparison area B in the current image, thereby producing data used for positioning of the patient couch 59 during irradiation.

1. Field of the Invention
The present invention relates to a patient positioning device and a patient positioning method. More particularly, the present invention relates to a patient positioning device and a patient positioning method, which are suitably employed in a particle beam treatment system for irradiating a charged particle beam (ion beam), such as a proton and a carbon ion, to a tumor for treatment.
2. Description of the Related Art
There is known a treatment method of setting an isocenter (irradiation target center) at a tumor, e.g., a cancer, in the body of a patient and irradiating an ion beam, such as a proton, to the tumor. An apparatus for use with such a treatment method comprises a charged particle beam generator, a beam transport system, and a rotating gantry. An ion beam accelerated by the charged particle beam generator reaches the rotating gantry through a first beam transport system, and is irradiated to the tumor from an irradiation nozzle after having passed through a second beam transport system provided in the rotating gantry.
In the apparatus thus constructed, the patient must be caused to lie in a proper position relative to the irradiation nozzle so that the ion beam is irradiated to only the isocenter without damaging normal cells. A patient positioning device for use with irradiation of the particle beam is a device for positioning a patient couch to make the patient lie in the proper position (see, e.g., Patent Reference 1, JP,A 2000-510023 (pages 27–31 and FIGS. 1, 6, 7A and 7B)). Particularly, in the case of irradiating the ion beam, for example, a proton beam, activation energy for the proton beam is selected so as to stop protons at the isocenter and apply most of the proton energy to only cells in the tumor, which is positioned at the isocenter, by utilizing a characteristic that most of the proton energy is released upon the stop of protons (this phenomenon is called "Brag peak"). Therefore, the alignment of the ion beam with the isocenter is very important.
In a known patient positioning device, to ensure accurate positioning of the patient relative to the irradiation nozzle, the position of the isocenter is decided beforehand relative to monuments (or landmarks, i.e., anatomical base points; for example, portions of the patient's skeleton), which are set in the patient body. Usually, the position of the isocenter including a diseased tissue, e.g., a tumor, is marked on a DRR (digitally reconstructed radiograph). Then, display images looking from other directions are edited as required.
In a state where the patient lies on a patient couch prior to the irradiation of a proton beam, an X-ray source is disposed on a path of the proton beam, and an X-ray receiver is disposed on the side opposed to the X-ray source with respect to the patient along the path of the proton beam. The X-ray receiver produces an X-ray image of the tumor and its surroundings in the patient body. On this occasion, in order to align the isocenter on a beam line, through which the proton beam passes in the irradiation nozzle, with the tumor, the direction in and the distance by which the patient couch is moved relative to the irradiation nozzle must be determined by employing the offset distance on an X-ray image from each of the particular monuments to the center of the X-ray beam and the offset distance on the DRR from the same particular monument to the isocenter. Positioning control of the patient couch is performed based on the thus-determined direction and distance of movement of the patient couch.

Patient positioning device and patient positioning method


The invention is to develop a protecting group that does not solidify or insolubilize a compound in which a functional group has been protected, and facilitates separation and purification after a reaction. Disclosed is a trityl compound represented by General Formula (1):

In regard to the synthesis of peptides or the synthesis of various compounds, there are occasions in which a reaction needs to be performed after protecting a functional group such as a carboxy group, a hydroxy group, an amino group, an amide group, or a mercapto group. Regarding such a protecting group, a group that is capable of protection by a simple and convenient method and can be removed under mild conditions, is desirable. For example, as a protecting group for a carboxy group, a benzyl ester (Bn) and a tert-butyl ester are known. Furthermore, it has been recently reported that a benzyl alcohol compounds, a trityl compounds, and a fluorine compounds are useful as protecting groups (Patent Literatures 1, 2, and 3).

Abstract: wherein Y represents a hydroxy group or a halogen atom; at least one of R1 to R15 represents a group represented by Formula (2):—O—R16—X-A  (2)while the other groups each represent a hydrogen atom, a halogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms;                R16 represents a linear or branched alkylene group having 1 to 16 carbon atoms;        X represents O or CONR17 (here, R17 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms); and        A represents a group represented by, for example, Formula (3):

Abstract: wherein R18, R19, and R20, which may be identical or different, each represent a linear or branched alkyl group having 1 to 6 carbon atoms, or an aryl group which may have a substituent.


A filter for separating water from hydrocarbon fuel includes fibers rendered hydrophobic with a silane surface treatment preceded by contact with a cationic surfactant in an aromatic hydrocarbon solvent.

Coalescence of water droplets is a well known phenomenon and is the basis of coalescence filters, which are known and used for separating water from fuel at the upstream side of the engine. The operation of coalescent filters is based on the idea of creating an --OH group molecular structure on its surface. An --OH group, while acted on by a water molecule, reacts on the water drop surface, annexes it and diminishes its durability. Water drops continue to aggregate and accumulate around this nucleus of water until the water drop grows to a size large enough to detach it from the surface and fall down by gravity forces to the filter sump. In this mechanism, the filter surface is always partially clogged by a thin film of water on the outer surface of the filter due to a strong interaction with hydroxyl groups.
Absorption filters use hydrophilic surfaces that absorb water and are transversed by hydrocarbon fluids. Water absorption causes gradual saturation of the paper filter, that is limited to a specific water capacity, beyond which it is clogged and loses its capability to pass the necessary fuel flow to the engine i.e., causing engine starvation.


An electrodeionization apparatus is provided comprising an ion-concentrating compartment partially bounded by an anion permeable membrane and also partially bounded by a cation permeable membrane, and a first ion exchange material domain disposed within the ion-concentrating compartment, wherein the first ion exchange material domain is contiguous with at least a portion of an ion-concentrating compartment side surface of one of the anion permeable membrane and the cation permeable membrane, and is spaced apart from the other one of the one of the anion permeable membrane and the cation permeable membrane. In the case where the one of the anion permeable membrane and the cation permeable membrane, having the at least a portion of an ion-concentrating compartment side surface with which the first ion exchange material domain is contiguous, is an anion permeable membrane, the first ion exchange material domain is an anion exchange material predominant domain. In the case where the one of the anion permeable membrane and the cation permeable membrane, having the at least a portion of an ion-concentrating compartment side surface with which the first ion exchange material domain is contiguous, is a cation permeable membrane, the first ion exchange material domain is a cation exchange material predominant domain.

Performance of an electrodeionization apparatus depends on the rejection/blockage/encapsulation of impurity ions in the ion-concentrating compartments, that have migrated from the ion-depleting compartments through their respective ion permeable membranes. The ion-concentrating compartments in an electrodeionization apparatus may be filled with either: (a) water, or an aqueous solution, which receives the impurity ions, or (b) water, or an aqueous solution, in conjunction with some ion-conducting materials. When the ion-concentrating compartment spacers are filled with non-ionconductive mesh, the ions from the ion-depleting compartments directly enter the liquid phase of the ion-concentrating compartments at the membrane surface. Solution mixing, ion migration, and ion diffusion take place to provide a homogeneous liquid at a distance from the membrane surfaces. When the ion-concentrating compartments contain ion-conductive materials, the impurities that have migrated out of the ion-depleting compartments will remain in their respective ion-conductive phases until the impurities either: (a) perform ion-exchange with another ion from solution, or (b) are transferred to the liquid phase, by migration, along with a corresponding oppositely charged ion from the oppositely charged ion-exchange material.
For the normal salt ions, such as: Na+, K+, Li+, etc. and Cl−, Br−, NO3−, SO42−, etc., migrating into the ion-concentrating compartments, their concentration merely increases in the liquid flowing through the ion-concentrating compartments.
For acidic and basic ions, the transition of these ions into solution from the ion exchange material phase can cause an acid/base reaction to occur, forming a neutral compound. For example, the following reactions may occur:H+(aq)+OH−(aq)→H2O(l)H+(aq)+CH3COO−(aq)→CH3COOH(aq) (acetic acid formation)H+(aq)+HCO3−(aq)→H2CO3(aq)→CO2(aq)+H2O(l) (carbonic acid formation)NH4+(aq)+OH−(aq)→NH4OH(aq)→NH3(aq)+H2O(l) (ammonia formation)
In cases where the positive and negative ions entering the solution phase form a compound with low solubility, high local concentration levels can be developed, leading to the formation of a precipitate. For example, the following mechanisms may be operative:Ca2+(aq)+CO32−(aq)→CaCO3(s)andMg2+(aq)+2OH−(aq)→Mg(OH)2(s)
Controlling the location where these scaling reactions occur is vital to both the ability of an electrodeionization apparatus to produce high resistivity product water and to reduce scale formation in the ion-concentrating compartments. The effect of the configuration of the ion exchange material in the ion-concentrating compartment on the product water resistivity arises from the fact that neutral species formed in the ion-concentrating compartments from acid/base neutralization reactions are not rejected by one of the two ion-permeable membranes. The formed neutral species, such as CO2, CH3COOH and other weak acids, can diffuse through a low pH cation permeable membrane, but if they come into contact with a high pH anion permeable membrane, they are ionized and rejected. Similarly, weak bases such as NH3 are not rejected by the anion permeable membranes and are able to diffuse through the anion permeable membranes, but become ionized when in contact with a low pH cation permeable membrane. The rate at which this back diffusion (e.g. CO2 or CH3COOH through a cation permeable membrane, or NH3 through an anion permeable membrane) occurs is dependent on the local concentration of the species in the ion-concentrating compartment and its location with respect to the membrane surface, and also the intrinsic membrane properties.
In an electrodeionization apparatus containing inert mesh filled ion-concentrating compartment spacers, the concentrations of these neutral weak acid and weak base species do not build up at the membrane surfaces and their back diffusion into the ion-depleting compartments is minimal. However, this is not the case in an electrodeionization apparatus with ion-exchange material filled ion-concentrating compartments. With ion exchange material structures of pure anion, pure cation or mixed bed ion exchange resins, weak acid and base impurity species can travel within an ion exchange material phase all the way through the thickness of the ion-concentrating compartment to the surface of the opposing ion permeable membrane. At this interface, the ion can encounter either a hydronuim ion (cation permeable membrane surface) or a hydroxide ion (anion permeable membrane surface) and form a neutral molecule. Due to the low linear velocity at the membrane surface, a high concentration of these neutral species can form, creating a large driving force for the back diffusion of these species into the adjacent ion-depleting compartments. Once these species are transported into the ion-depleting compartments through this back diffusion, ionization occurs which reduces the product water resistivity.

Arrangement of ion exchange material within an electrodeionization apparatus


A method for operating a cooling fan of a vehicle including detecting at least one of a battery charge of a battery of the vehicle and a state of engagement of an air conditioning system of the vehicle and rotating the cooling fan in a direction to expel air from an engine compartment of the vehicle based on at least one of a detected battery charge of the battery or a detected state of engagement of the air conditioning system.

Aerodynamic drag on motor vehicles has an effect on the fuel economy of the vehicle and the carbon footprint of the vehicle. As consumer demand for improved fuel economy has increased, methods and structures for reducing aerodynamic drag on motor vehicles have been sought. Cooling drag is a significant factor in the overall aerodynamic drag on the vehicle. Cooling drag is a result of air entering a front facie of the vehicle and impinging against components within an engine compartment of the vehicle, imparting a force on the vehicle opposite to the direction of travel. The effects of cooling drag are more pronounced at higher vehicle speeds, such as during highway travel, and may significantly decrease fuel economy.
Accordingly, a need exists for alternative systems and methods for reducing cooling drag on a vehicle.

Vehicles incorporating cooling drag reduction systems and methods

Toyota Motor Engineering & Manufacturing North America, Inc.


A battery electrode substrate which is constituted of a porous metallic body structure having communicating pores at a porosity of at least 90% and an Fe/Ni multilayer structure wherein the skeletal portion of the porous metallic body is composed mainly of Fe and has an Ni covering layer on the surface thereof while pores communicating with the inside and outside of Fe skeletal portion exist in the Fe skeletal portion and the inside of the pores is covered with Ni. The electrode substrate is produced by applying an iron oxide powder of at most 20 .mu.m in an average particle size on a porous resin core body; heat treating the core to remove an organic resin component while simultaneously sintering Fe to obtain a porous Fe body; and then covering the Fe skeletal portion with Ni by electroplating. In this process, the iron oxide can be used in combination with carbon powder. Further, a nickel porous sintered body can also be produced using nickel oxide in place of iron oxide.

1. Field of the Invention
The present invention relates to a process for producing a porous metallic material to be used as an electrode substrate for use in an alkaline secondary battery principally such as a nickel-cadmium battery, a nickel-zinc battery or a nickel-hydrogen battery.
2. Description of the Prior Art
Storage batteries for use as various electric power sources include lead storage batteries and alkaline storage batteries. Among them, the alkaline storage batteries have been widely used in various portable apparatuses in the form of a miniature battery and in industrial applications in the form of a large-sized one, for example, because they can be expected to be high in reliability and can be miniaturized to be lightweight. In these alkaline storage batteries, materials for negative electrodes include zinc, iron, hydrogen, etc. in addition to cadmium. However, positive electrodes are nickel electrodes in almost all cases though an air electrode, a silver oxide electrode, etc. are partially adopted. Replacement of a sintered type for a pocket type has attained improvements in properties and enabled hermetic sealing thereof to widen the scope of uses thereof.
In a common powder-sintered type substrate, however, the strength thereof is greatly lowered when the porosity thereof is set to be at least 85%. Thus, there is a limit to filling it with an active material. Accordingly, there is a limit to increasing the capacity of a battery. In view of the above, a foamed substrate and a fibrous substrate have been adopted and put into practical use as substrates having a far higher porosity of at least 90% or the like in place of the sintered substrate. Processes for producing such a high-porosity porous metallic body substrate include a plating process as disclosed in Japanese Patent Laid-Open No. 174,484/1982, and a sintering process as disclosed in Japanese Patent Publication No. 17,554/1963 and the like. The plating process is a method wherein the skeletal surface of a foamed resin such as a urethane foam is coated with a carbon powder or the like to effect such a treatment thereof as to be rendered electrically conductive, and further subjected to Ni electrodeposition by electroplating, followed by burning out the foamed resin and the carbon to obtain a porous metallic material. On the other hand, according to the sintering process, the skeletal surface of a foamed resin such as a urethane foam is dipped in and coated with a slurry of a metal powder, followed by heating to sinter the metal powder.
As shown in the prior art, application of a porous metallic body to a battery plate substrate has made a great contribution to an increase in the capacity of a battery. In production of a porous metallic body according to the plating process as disclosed in Japanese Patent Laid-Open No. 174,484/1982, however, a porous resin core body must be coated with carbon to effect such a treatment thereof as to be rendered electrically conductive for electroplating. Carbon is necessary only in a step of production, but unnecessary in the porous metallic body because it is finally burnt out. Thus, coating the core body with carbon for such a treatment to make it electrically conductive not only entails an increase in the cost of a product, but also is believed to affect the quality of the product because of residual carbon. In this respect, an improvement has been desired. On the other hand, the production of a porous metallic body according to the sintering process as disclosed in Japanese Patent Publication No. 17,554/1963 does not fundamentally involve the above-mentioned problems, but can hardly secure desirable properties such as mechanical strength properties and electrical properties required of a battery plate substrate because dense sintering of a skeletal portion in the form of a porous body is difficult. On the other hand, Japanese Patent Publication No. 4,136/1994, directed to a process for producing a porous iron catalyst carrier, also discloses a method of obtaining a porous Fe body using an iron powder, an iron oxide powder, etc. According to this method, however, no properties required of a battery electrode substrate can be secured like in the foregoing cases, for example, because none other than a porous sintered body having a coarse skeletal portion can be obtained.

Battery electrode substrate and process for producing the same

Matsushita Electric Industrial Co., Ltd.


A batcher has a brake (E) connected to the packing roll (B) for slowing the packing roll as during an unwinding phase to vary the packing ratio between the packing roll (B) and the drive roll (A). A drive mechanism (D) utilizes a single drive clutch for imparting a free wheeling action to the packing roll during unwinding so as to facilitate operation of the brake in effecting the proper packing ratio.

This invention relates to surface winders and to an improved apparatus and method for facilitating a reverse winding operation.
Batchers and other surface winders have been provided with electronic controls such as illustrated in U. S. Pat. No. 4,588,931 to facilitate varying the packing ratio between the support rolls. The packing ratio between the respective drive rolls and packing rolls plays an important part in the building of even cloth on other web rolls whether in a forward or in a reverse direction as when unwinding. Such apparatus is expensive and prone to give problems in the hostile environment of a textile mill. The problem of reversing the direction of a surface winder such as a batcher as illustrated herein comes from the tendency of the cloth or other web to pucker or sag just ahead of the support rolls causing an undesirable build up of loose fabric. This is especially true when reversing the direction of winding in order to build a tight roll in a reverse direction. By readily and infinitely varying the packing ratio adjustments may be made to produce a smooth roll wherein sagging is avoided and a superior building operation is provided.


A method of bridging partial tightnesses of moveable members received in guides and driven by electric drive motors provides an automatic monitoring function. Within a tightness region, a releasing force is varied in one or several steps. An automatic bridging function is utilized, which corresponds to the rotary speed course, and an automatically operating control operates so that the releasing force is increased only in a limited region of the identified bridging location.

The present invention relates to a method of monitoring a partial tightness on movable members, such as for example window panes or movable roof. These components of motor vehicles are provided in increased numbers in the electrical drive which are operatable remotely. Tightness occurs when, for example, wind deflectors which are arranged before the movable roofs are subjected to increased air resistance while traveling with increased traveling speed. In these situations an actuation of removable roof occurs.
Manual bridging functions are provided for electrical drives utilized for actuation of window panes or movable roofs, so that the driven displaceable members at the location of a tightness can be moved by hand over the tightness location. A manual engagement of the operator during driving of a vehicle distracts it and can lead to critical traveling situations, in which the driver may not pay undivided attention to the traffic.
In other embodiments of the window panes or movable roofs, reference runs are provided in the movable systems. The reference runs load not insignificantly the electrical drive, since they have a calibration function. Reference runs moreover are time consuming, and during the reference runs not all operations occur, which later during operation of the window panes or movable roofs can occur.
Accordingly, it is an object of the present invention to provide a method of bridging of partial tightness of movable members, which avoids the disadvantages of the prior art.
In keeping with these objects and with others which will become apparent hereinafter, one feature of present invention resides, briefly stated, in a method of bridging partial tightness of a movable members, in accordance with which an automatic monitoring function is provided, and within a tightness region a releasing force is varied in one or several steps.
With the inventive solution, an automatic bridging function is utilized, which corresponds to the rotary speed course. An automatically operating control operates so that only in the small limited region of the bridging location which is identified as such, the releasing force is increased by a certain amount. When a one-time increase of the releasing force is not sufficient for a certain amount to overcome the tightness location, then it is increased by automatic bridging function in a stepped manner in several starting routines to a maximum value. When with a releasing force below the maximum releasing force, the overcoming of the tightness location is performed, then the releasing force required for overcoming the obstacle is stored in an adaptive storage unit. The maximum value of the releasing force can be preset on the automatic bridging function, so that depending on the application, predetermined maximum releasing forces are provided or can be allowed. Also the step widths at which the reducing force is raised within the starting routine in a stepped manner can be preselected variably for the automatic bridging function.
The stepped increase of the releasing force can be embedded for example in a first run to an obstacle with subsequent reversing of the drive. If the obstacle is located outside of the region in which the tightless location is localized, the drive is reversed. If the tightness location is inside the back window, the releasing force is increased only in the region in which the tightness location is provided. After several starts and runs on the obstacle, a stepped increase of the releasing force in the region of the back window is provided, until the maximum fixed releasing force is achieved.
When the obstacle representing the tightness location is finally overcome without reversing of the electrical drive, the rotary speed adaptation can be adjusted to the changed obstacle. The releasing force which directly overcomes the obstacle or the rotary speed adaptation can be stored in a storage which is associated with the automatic bridging function.
The novel features which are considered as characteristic for the present invention are set forth in particular in the appended claims. The invention itself, however, both as to its construction and its method of operation, together with additional objects and advantages thereof, will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings.

Method of bridging partial tightness on movable members


Devices, systems, and methods for supporting and/or stabilizing a patient can help to position a patient relative to a therapeutic laser beam, for example, inhibiting motion or deflection during a refractive procedure on the eyes, and the like. A stabilizing structural member can support a chair or other patient support near shoulders of the patient, and the member may remain stationary while the chair is driven in a horizontal plane by a linkage. Often, a nominal patient center of gravity is located between the support member and a portion of the patient support which is supported by the linkage to reduce cantilever effects. The member may be rigidly attached to a vertical motion stage which moves the chair at an angle, for example at an angle normal to the horizontal plane.

The present invention relates generally to devices, systems, and methods for supporting and positioning patients, particularly for performing refractive surgery on eyes and the like. Embodiments of the present invention provide an improved patient support structure (such as a chair, bed, or table) which can help to stabilize the patient and/or minimize motion adjacent the head of the patient. Other embodiments provide mechanisms for positioning the head and body of a patient and stabilizing the patient support, providing improved patient stability during surgery. The invention may be particularly useful for enhancing the speed, ease, safety, and efficacy of laser eye surgical procedures such as photorefractive keratectomy ("PRK"), laser in situ keratomileusis ("LASIK"), and the like.
Laser eye surgical procedures typically employ ultraviolet or infrared lasers to remove a microscopic layer of stromal tissue from the cornea to alter the cornea's refractive properties. Excimer laser systems generally use argon and fluorine gas to create a non-thermal laser light which can break molecular bonds in a process known as photoablation. Such systems result in the photodecomposition of the corneal tissue, but generally do not cause significant thermal damage to adjacent and underlying tissues of the eye. The photoablation removes the stromal tissue to change the shape or contour of the cornea and can be used to correct myopia (near-sightedness), hyperopia (far-sightedness), astigmatism, high-order aberrations, and the like.
Existing laser eye surgery systems have generally included an operator interface for use by the laser system operator in setting up, controlling, monitoring, and generally directing the laser treatment of the patient's eyes. Accurate photoablation of corneal tissues benefits from precise alignment between the eye and the therapeutic laser beam transmitted from the laser system. Many laser eye surgical alignment systems have a patient seat over bed so that the patient is treated while seated, while lying down, or while reclined in a supine position. To align the patient with the laser beam delivery optics, the system operator generally positions the seat or bed into alignment with the laser system. A particularly advantageous user interface and patient support system is described in U.S. patent application Ser. No. 10/226,867, entitled "Improved Interface for Laser Eye Surgery" as filed on Aug. 20, 2002, the full disclosure of which is incorporated herein by reference. Embodiments of that advantageous system make use of a contoured patient treatment chair to help position a patient into nominal alignment with the laser, allowing the system operator to make fine adjustments using the system interface. As the system can be moved quickly to the nominal alignment for treatment of the left or right eyes, this improved interface system provides significant advantages in ease of use, overall procedure speed, and alignment accuracy. Another patient support system is described in U.S. patent application Ser. No. 11/335,177, entitled "Compression Head Pillow and Neck Angle Adjustment Mechanism for Refractive Laser Surgery and the Like" as filed on Jan. 18, 2006, the full disclosure of which is incorporated herein by reference. Embodiments of that system may allow both the height of the patient's head and the angle of the patient's neck to be established independently, and/or may inhibit movement or deflection of the head of the patient from an aligned position.
While known patient support and user interface systems have allowed a large number of patients to benefit from the advantages of laser eye surgery, still further improvements would be desirable. For example, it would be advantageous to more accurately position the patient into alignment with laser system and inhibit movement of the patient from the aligned configuration. It would also be advantageous to accommodate the wide range of patient physiologies, ideally without decreasing the speed or increasing the complexity of the alignment procedure. Preferably, these benefits would be provided without decreasing the system operator's access to the patient. At least some of these potential advantages may be realized by the systems, devices, and methods described herein below.


A locking device for mounting a heat dissipating device to a CPU mounted on a printed circuit board, includes a back plate mounted below the circuit board and a retainer. The back plate includes a plurality of posts extending upwardly through the circuit board and engaging with screws thereat. The retainer includes a mounting section attached to the heat dissipating device and a plurality of spring locking sections extending radially from the mounting section. The locking sections are downwardly pressable to engage with the respective posts and screws whereby the retainer mounts the heat dissipating device to the electronic component.

As computer technology continues advancing, electronic components such as central processing units (CPUs) of computers are made to provide faster operational speed and greater functional capabilities, which results in the CPUs generating a significant amount of heat. It is desirable to dissipate the generated heat quickly, for example, by using a heat sink attached to the CPU in enclosures. Generally, a locking device is required for mounting the heat sink to the CPU.
In the earlier time, a heat sink is mounted to a CPU via bolts which extends through a mounting section of the heat sink to engage with a printed circuit board on which the CPU is mounted. However, using of bolts to remove or install the heat sink is complicated and time-consuming.
Nowadays, a heat sink is often securely placed on a CPU mounted on a socket via a plate-type clamp which comprises a pressing portion crossing through and resting on the heat sink and a pair of locking legs formed at opposite ends of the pressing portion to engage with catches of the socket. Unfortunately, the plate-type clamp which generally has a great width occupies space of the heat sink which is originally desired to form more heat-dissipating fins for the heat sink. The clamp thus obviously reduces the heat dissipating surface area of the heat sink when sacrificing these desired fins and therefore decreases the heat dissipating efficiency of the heat sink. Furthermore, the plate-type clamp has a great rigidity. Thus, a large force and a tool is required to install or remove such clamps. However, the tools for installation or removal of the clamp are easy to accidentally strike the board and cause any undesired damage of the board or anything thereon. Moreover, because the deformation of the clamp is uncontrollable the contact force between the heat sink and the CPU is not capable of being adjusted to an optimized value according to the profile and weight of the heat sink to ensure the heat sink firmly and intimately contacting the CPU without damaging the CPU.

Locking device for heat dissipating device

Fu Zhun Precision Industry (Shen Zhen) Co., Ltd.